EP2925129A1 - Composés pro-neurogènes - Google Patents

Composés pro-neurogènes

Info

Publication number
EP2925129A1
EP2925129A1 EP12883358.9A EP12883358A EP2925129A1 EP 2925129 A1 EP2925129 A1 EP 2925129A1 EP 12883358 A EP12883358 A EP 12883358A EP 2925129 A1 EP2925129 A1 EP 2925129A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
independently selected
carbazol
dibromo
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12883358.9A
Other languages
German (de)
English (en)
Other versions
EP2925129A4 (fr
Inventor
Steven L. Mcknight
Andrew A. Pieper
Joseph M. Ready
Jef K. De Brabander
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Texas System
Original Assignee
University of Texas System
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Texas System filed Critical University of Texas System
Priority claimed from US13/594,223 external-priority patent/US9962368B2/en
Publication of EP2925129A1 publication Critical patent/EP2925129A1/fr
Publication of EP2925129A4 publication Critical patent/EP2925129A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/24—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
    • A61P25/28—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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • 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
    • 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
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention relates generally to the discovery of pro-neurogenic compounds capable of promoting neurogenesis and/or reducing neuronal cell death.
  • neuronal stem cells there are two maj or reservoirs of neuronal stem cells, one located in the subgranular zone (SGZ) of the hippocampal dentate gyrus and another in the subventricular zone (SVZ) (Gross, Natl. Rev. 2000, 1, 67-72).
  • SGZ subgranular zone
  • SVZ subventricular zone
  • Neural stem cells in the SVZ facilitate formation of new neurons that migrate rostrally to populate the olfactory bulb, while neural stem cells in the SGZ produce neurons that integrate locally in the granular layer of the dentate gyrus, a region of the hippocampus that exhibits lifelong structural and functional plasticity.
  • the process of new neuron formation in the adult mouse brain can be influenced by environmental, chemical and genetic variables. As demonstrated by Gage and colleagues, neurogenesis in the adult mouse brain is enhanced when animals are exposed to an enriched environment (Kempermann et al., Nature 1997, 386, 493-495) or able to exercise voluntarily (van Praag et al., Nat. Neuro-sci. 1999, 2, 266-270). More recently, anti-depressant drugs have been shown to enhance levels of adult neurogenesis in animals, including humans (Schmidt et al., Behav Pharmacol. 2007 Sep;18(5-6):391-418; Boldrini et al.,
  • NPAS3 neuronal PAS domain protein 3
  • CNS central nervous system
  • Animals missing both copies of the NPAS3 gene suffer a profound loss of adult hippocampal neurogenesis coupled with significant behavioral deficits (Pieper et al., Proc. Natl. Acad. Sci. USA 2005, 102, 14052-14057). Knowing that impaired post-natal neurogenesis elicits unfavorable phenotypic deficits, it is predicted that pro-neurogenic chemical compounds should exhibit favorable therapeutic benefits.
  • This invention relates generally to compounds that promote the generation or the survival of existing neurons in the mammalian brain. For the purpose of simplicity these compounds are referred to as being pro- neurogenic. In certain embodiments, the compounds promote the generation or survival of neurons in the post-natal mammalian brain. In certain embodiments, the compounds promote the survival, growth, development and/or function of neurons, particularly CNS, brain, cerebral, and hippocampal neurons.
  • the compounds stimulate post-natal hippocampal neurogenesis, which while not wishing to be bound by theory, is believed to represent a therapeutic target for a variety of neuropsychiatric and neurodegenerative diseases, including (but not limited to) schizophrenia,major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, abuse of neuro-active drugs (such as alcohol, opiates, methamphetamine, phencyclidine, and cocaine), retinal degeneration, spinal cord injury, and peripheral nerve injury.
  • neuro-active drugs such as alcohol, opiates, methamphetamine, phencyclidine, and cocaine
  • the compounds stimulate post-natal hypothalamic neurogenesis, which can provide therapeutic benefits in weight management, such as physiological weight loss associated with various conditions, including but not limited to, normal aging, chemotherapy, radiation therapy, stress, drug abuse, anorexia, as well as other diseases discussed herein.
  • the presently disclosed embodiments also feature compositions (e.g., pharmaceutical compositions) that include such compounds as well as methods of making, identifying, and using such compounds.
  • methods for promoting post-natal mammalian neurogenesis and/or reducing neuronal cell death in a subject in need thereof comprising administering an effe or a pharmaceutically acceptable salt thereof:
  • each of R 1 , R 2 , R 3 , and R 4 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, Ci-C 6 alkoxy, Ci-C 6 thioalkoxy, Ci-C 6 haloalkoxy, Ci-C 6 thiohaloalkoxy, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, -N 3 , cyano, -NH 2 , -NH(C r C 6 alkyl), -N(C r C 6 alkyl) 2 , -NHC(0)(C r C 6 alkyl), and nitro;
  • R and R' are defined according to (1), (2), (3), (4), or (5) below:
  • each of R 5 , R 6 , R 7 , and R 8 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, C 1 -C6 alkoxy, C 1 -C6 thioalkoxy, C 1 -C6 haloalkoxy, C 1 -C6 thiohaloalkoxy, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 2 -C6 alkynyl, cyclopropyl, -N 3 , cyano,
  • each of R and R' is, independently, hydrogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl;
  • R and R' together with C 2 and C3, respectively, form a fused heterocyclic ring containing from 5-6 ring atoms, wherein from 1 -2 of the ring atoms is independently selected from N, NH, N(Ci-C6 alkyl), NC(0)(Ci-C6 alkyl), O, and S; and wherein said heterocyclic ring is optionally substituted with from 1-3 independently selected R a ; OR
  • R and R' together with C 2 and C3, respectively, form a fused heteroaryl ring containing from 5-6 ring atoms, wherein from 1 -2 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl ring is optionally substituted with from 1 -3 independently selected R b ;
  • L 1 is:
  • A is:
  • heterocycloalkylene containing from 3-5 ring atoms, wherein from 1-2 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heterocycloalkylene is (a) substituted with 1 oxo; and (b) is optionally further substituted with from 1 -4 independently selected R a ;
  • Z is:
  • n is 0, 1, or 2 or (v) heterocycloalkenyl containing from 5-6 ring atoms, wherein from 1 -3 of the ring atoms is independently selected from N, NH, N(d-C 6 alkyl), NC(0)(Ci-C 6 alkyl), O, and S; and wherein said heterocycloalkenyl is optionally substituted with from 1 -4 independently selected R a ;
  • heteroaryl containing from 5-14 ring atoms, wherein from 1 -6 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1 -4 independently selected R b ; or
  • the aryl portion is optionally substituted with from 1-4 independently selected R b , and
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • the aryl portion from is optionally substituted with from 1 -4 independently selected R b , and
  • (2) from 1 -2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C r C 6 alkyl), NC(0)(C r C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1 -3 independently selected R a ;
  • (1) from 1 -2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • (1) from 1 -2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • R 9 is hydrogen; or Q-C3 alkyl that is optionally substituted with hydroxyl or C 1 -C3 alkoxy; each of R and R is independently selected from the substituents delineated collectively in (a) through (1) below:
  • heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;
  • Ci-Ce alkyl or Ci-Ce haloalkyl each of which is optionally substituted with from 1-3 R d ;
  • the aryl portion is optionally substituted with from 1-4 independently selected R b , and
  • the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;
  • the aryl portion from is optionally substituted with from 1-4 independently selected R b , and
  • (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C C 6 alkyl), NC(0)(C C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C C 6 alkyl), NC(0)(C C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • R 12 is:
  • heteroaryl containing from 5-14 ring atoms, wherein from 1 -6 of the ring atoms is independently selected firom N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1 -4 R b ; or
  • Ci-Ce alkyl or Ci-Ce haloalkyl each of which is optionally substituted with from 1 -3 R d ;
  • the aryl portion is optionally substituted with from 1-4 independently selected R b , and
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • the aryl portion from is optionally substituted with from 1 -4 independently selected R b , and
  • (1) from 1 -2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • heteroarylcycloalkyl containing from 8-14 ring atoms wherein: (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • R 13 is:
  • heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;
  • the aryl portion is optionally substituted with from 1-4 independently selected R b , and
  • the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;
  • the aryl portion from is optionally substituted with from 1-4 independently selected R b , and
  • heterocyclyl portion is independently selected from N, NH, N(Ci-C 6 alkyl), NC(0)(C C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C r C 6 alkyl), NC(0)(C r C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • heteroaryl portion is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and (2) the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • R b at each occurrence is independently selected from the substituents delineated in (aa) through (dd) below:
  • Ci-Ce alkoxy (aa) Ci-Ce alkoxy; Ci-Ce haloalkoxy; Ci-Ce thioalkoxy; Ci-Ce thiohaloalkoxy; -0-(CH 2 )i_ 3 - [0(CH 2 ) 1 . 3 ] i_3-H; -Ci-Cg alkyl, C r C 6 haloalkyl,
  • (cc) C 3 -C 6 cycloalkyl or heterocyclyl containing from 5-6 ring atoms, wherein from 1 -2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(Ci-C 6 alkyl), NC(0)(Ci-C 6 alkyl), O, and S; and wherein each of said phenyl and heterocyclyl is optionally substituted with from 1 -3 independently selected R a ; and
  • R d at each occurrence is, independently selected from hydroxyl, Ci-C 6 alkoxy, Ci-C 6 thioalkoxy, C r
  • R e at each occurrence is, independently selected from hydroxyl, Ci-C 6 alkoxy; Ci-C 6 thioalkoxy; C r
  • one or more of (A), (B), or (C) apply.
  • each of L 1 and L 2 must be C1-C3 alkylene, which is optionally substituted with from 1-2
  • Z must be other than heteroaryl containing from 5-14 (e.g., 5-6 or 6) ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 independently selected R b ; e.g., other than substituted pyridyl, e.g., other than pyridyl substituted with C r C 3 alkyl (e.g., CH 3 ), e.g., other than 2 or 6-methylpyridyl.
  • R b e.g., other than substituted pyridyl, e.g., other than pyridyl substituted with C r C 3 alkyl (e.g., CH 3 ), e.g., other than 2 or 6-methylpyridyl.
  • each of R 10 and R 11 cannot be optionally substituted naphthyl (e.g., each of R 10 and R 11 cannot be unsubstituted naphthyl).
  • each of R 10 and R 11 is other than optionally substituted naphthyl (e.g., unsubstituted naphthyl) when R and R' are defined according to definitions (1), (2), and (4); and
  • A is CR AI R A2 ⁇ g ⁇ CHOR 9 , e.g., CHOH), and each of L 1 and L 2 is C r C 3 alkylene (e.g., each of L 1 and L 2 is CH 2 ).
  • R 12 and/or R 13 cannot be substituted phenyl.
  • R 12 and/or R 13 cannot be substituted phenyl when R and R' are defined according to definition (1); and A is CR A1 R A2 (e.g., CHOR 9 , e.g., CHOH), and each of L 1 and L 2 is C r C 3 alkylene (e.g., each of L 1 and L 2 is CH 2 ).
  • (A), (B), or (C) applies. In other embodiments, (A) and (B); or (A) and (C); or
  • methods for promoting post-natal mammalian neurogenesis in a subject in need thereof include administering to the subject an effective amount of a compound having alt thereof.
  • each of R 1 , R 2 , R 3 , and R 4 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, Ci-C 6 alkoxy, Ci-Ce thioalkoxy, Ci-Ce haloalkoxy, Ci-Ce thiohaloalkoxy, Ci-Ce alkyl, Ci-Ce haloalkyl, cyano, -NH 2 , -NH(Ci-C 6 alkyl), -N(C C 6 alkyl) 2 , -NHC(0)(C r C 6 alkyl), and nitro;
  • R and R' are defined according to (1), (2), (3), (4), or (5) below:
  • each of R 5 , R 6 , R 7 , and R 8 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, Ci-Ce alkoxy, Ci-Ce thioalkoxy, Ci-Ce haloalkoxy, Ci-Ce halothioalkoxy, Ci-Ce alkyl, Ci-Ce haloalkyl, cyano, -NH 2 , -NH(C C 6 alkyl), N(C r C 6 alkyl) 2 , -NHC(0)(C C 6 alkyl), and nitro; OR
  • each of R and R' is, independently, hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl
  • R and R' together with C 2 and C3, respectively, form a fused heterocyclic ring containing from 5-6 ring atoms, wherein from 1 -2 of the ring atoms is independently selected from N, NH, N(Ci-C6 alkyl), NC(0)(Ci-C6 alkyl), O, and S; and wherein said heterocyclic ring is optionally substituted with from 1 -3 independently selected R a ; OR
  • R and R' together with C 2 and C 3 , respectively, form a fused heteroaryl ring containing from 5-6 ring atoms, wherein from 1 -2 of the ring atoms is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl ring is optionally substituted with from 1 -3 independently selected R b ;
  • L 1 is:
  • A is: (i) CR R , wherein each of R and R is independently selected from hydrogen, halo, Q- C 3 alkyl, or OR 9 ; or
  • heterocycloalkylene containing from 3-5 ring atoms, wherein from 1-2 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heterocycloalkylene is (a) substituted with 1 oxo; and (b) is optionally further substituted with from 1 -4 independently selected R a ;
  • A is not CH 2 .
  • one of R A1 and R ⁇ can be hydrogen, halo, C1-C3 alkyl, or OR 9 ; and the other of R A1 and R ⁇ can be halo, C1-C3 alkyl, or OR 9 .
  • heterocycloalkenyl containing from 5-6 ring atoms, wherein from 1 -3 of the ring atoms is independently selected from N, NH, N(C r C 6 alkyl), NC(0)(C r C 6 alkyl), O, and S; and wherein said heterocycloalkenyl is optionally substituted with from 1 -4 independently selected R a ;
  • heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 independently selected R b ; or
  • the aryl portion is optionally substituted with from 1-4 independently selected R b , and
  • the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;
  • the aryl portion from is optionally substituted with from 1-4 independently selected R b
  • (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(Ci-C 6 alkyl), NC(0)(C C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • heterocyclyl portion is independently selected from N, NH, N(Ci-C 6 alkyl), NC(0)(C C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • R 9 is hydrogen; or Q-C3 alkyl that is optionally substituted with hydroxyl or C 1 -C3 alkoxy;
  • each of R 10 and R 11 is independently selected from the substituents delineated collectively in (a) through (1) below:
  • heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;
  • Ci-Ce alkyl or Ci-Ce haloalkyl each of which is optionally substituted with from 1-3 R d ;
  • the aryl portion is optionally substituted with from 1-4 independently selected R b , and
  • the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;
  • arylheterocyclyl containing from 8-14 ring atoms, wherein: (1) the aryl portion from is optionally substituted with from 1-4 independently selected R b , and
  • (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C C 6 alkyl), NC(0)(C C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C r C 6 alkyl), NC(0)(C r C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • R 12 is:
  • heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ; or
  • Ci-Ce alkyl or Ci-Ce haloalkyl each of which is optionally substituted with from 1 -3 R d ;
  • the aryl portion is optionally substituted with from 1-4 independently selected R b , and
  • the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;
  • the aryl portion from is optionally substituted with from 1 -4 independently selected R b , and
  • (1) from 1 -2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • (2) from 1 -2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C r C 6 alkyl), NC(0)(C r C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1 -3 independently selected R a ;
  • (1) from 1 -2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • R 13 is:
  • heteroaryl containing from 5-14 ring atoms, wherein from 1 -6 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1 -4 R b ;
  • the aryl portion is optionally substituted with from 1-4 independently selected R b , and
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • the aryl portion from is optionally substituted with from 1 -4 independently selected R b
  • (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(Ci-C 6 alkyl), NC(0)(C C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • heterocyclyl portion is independently selected from N, NH, N(Ci-C 6 alkyl), NC(0)(C C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • R b at each occurrence is independently selected from the substituents delineated in (aa) through (dd) below:
  • Ci-Ce alkoxy (aa) Ci-Ce alkoxy; Ci-Ce haloalkoxy; Ci-Ce thioalkoxy; Ci-Ce thiohaloalkoxy; Ci-Ce alkyl, Ci-C 6 haloalkyl, -NH(C C 6 alkyl), N(C r C 6 alkyl) 2 , -NHC(0)(C C 6 alkyl), wherein the alkyl portion of each is optionally substituted with from 1-3 independently selected R e ;
  • R c at each occurrence is, independently selected from halo, i- e alkoxy, i- e thioalkoxy, i- e haloalkoxy, C C 6 thiohaloalkoxy, C C 6 alkyl, C C 6 haloalkyl, -NH 2 , -NH(C C 6 alkyl), N(C r C 6 alkyl) 2 , - NHC(0)(Ci-C 6 alkyl), and cyano;
  • R d at each occurrence is, independently selected from hydroxyl, i- e alkoxy, i- e thioalkoxy, Cp C 6 haloalkoxy, C C 6 thiohaloalkoxy, C C 6 alkyl, C C 6 haloalkyl, -NH 2 , -NH(C C 6 alkyl), N(C C 6 alkyl) 2 , - NHC(0)(C r C 6 alkyl), and cyano; and
  • R e at each occurrence is, independently selected from hydroxyl, Ci-C 6 alkoxy; Ci-C 6 thioalkoxy; C r C 6 haloalkoxy; C r C 6 thiohaloalkoxy; -NH 2 ; -NH(C r C 6 alkyl); N(C r C 6 alkyl) 2 ; -NHC(0)(C r C 6 alkyl); cyano; -C(0)H; -C(0)(C r C 6 alkyl); -C(0)(C r C 6 haloalkyl); C(0)OH; -C(0)0(C r C 6 alkyl); -C(0)NH 2 ; - C(0)NH(C r C 6 alkyl); C(0)N(C r C 6 alkyl) 2 ; -S0 2 (C r C 6 alkyl); -S0 2 NH 2 ; -S0 2 NH(C r C 6 alkyl); -S0
  • Cy is a saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring system
  • one or more of (A), (B), or (C) apply.
  • each of L 1 and L 2 must be C 1 -C3 alkylene, which is optionally substituted with from 1 -2 independently selected R c when A is CH 2 ; or
  • Z must be other than heteroaryl containing from 5-14 (e.g., 5-6 or 6)ring atoms, wherein from 1 -6 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1 -4 independently selected R b ; e.g., other than substituted pyridyl, e.g., other than pyridyl substituted with C 1 -C3 alkyl (e.g., CH 3 ), e.g., other than 2 or 6-methylpyridyl.
  • each of R 10 and R 11 cannot be optionally substituted naphthyl (e.g., each of R 10 and R 11 cannot be unsubstituted naphthyl).
  • each of R 10 and R 11 is other than optionally substituted naphthyl (e.g., unsubstituted naphthyl) when R and R' are defined according to definitions (1), (2), and (4); and
  • A is CR AI R A2 ⁇ g ⁇ CHOR 9 , e.g., CHOH), and each of L 1 and L 2 is C r C 3 alkylene (e.g., each of L 1 and L 2 is CH 2 ).
  • R and/or R cannot be substituted phenyl.
  • R and/or R cannot be substituted phenyl when R and R' are defined according to definition (1); and A is CR A1 R A2 (e.g., CHOR 9 , e.g., CHOH), and each of L 1 and L 2 is C r C 3 alkylene (e.g., each of L 1 and L 2 is CH 2 ).
  • A is CR A1 R A2 (e.g., CHOR 9 , e.g., CHOH), and each of L 1 and L 2 is C r C 3 alkylene (e.g., each of L 1 and L 2 is CH 2 ).
  • (A), (B), or (C) applies.
  • (A) and (B); or (A) and (C); or (B) and (C) applies.
  • (A), (B), and (C) apply.
  • methods for promoting post-natal mammalian neurogenesis in a subject in need thereof include administering to the subject an effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof, in which R and R' together with C 2 and C3, respectively, form a fused phenyl ring having formula (II):
  • R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , A, and Z can be as defined anywhere herein.
  • (A), (B), or (C) applies. In other embodiments, (A) and (B); or (A) and (C); or (B) and (C) applies. In still other embodiments, (A), (B), or (C) apply.
  • methods for promoting post-natal mammalian neurogenesis in a subject in need thereof include administering to the subject an effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof, in which:
  • each of L 1 and L 2 is CH 2 ;
  • A is CR A1 R A2 , wherein one of R A1 and R ⁇ is OR 9 , and the other is hydrogen.;
  • Z is -NR 10 R U ;
  • each of R 10 and R 11 is independently selected from (a) hydrogen;
  • Ci-Ce alkyl or Ci-Ce haloalkyl each of which is optionally substituted with from 1-3 R d ;
  • (A), (B), or (C) applies. In other embodiments, (A) and (B); or (A) and (C); or (B) and (C) applies. In still other embodiments, (A), (B), and (C) apply.
  • compositions e.g., a pharmaceutical composition
  • a pharmaceutical composition which includes a compound of formula (I) (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein and a pharmaceutically acceptable carrier.
  • the compositions can include an effective amount of the compound or salt.
  • the compositions can further include one or more additional therapeutic agents.
  • antidepressant medications including selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, and other antidepressant medications including but not limited to venlafaxine, nefazadone, bupropion, mirtazapine, lithium and trazodone
  • acetylcholinesterase inhibitors including but not limited to Aricept, Reminyl, and Exelon.
  • dosage forms are featured, which includes from about 0.05 milligrams to about 2,000 milligrams (e.g., from about 0.1 milligrams to about 1,000 milligrams, from about 0.1 milligrams to about 500 milligrams, from about 0.1 milligrams to about 250 milligrams, from about 0.1 milligrams to about 100 milligrams, from about 0.1 milligrams to about 50 milligrams, or from about 0.1 milligrams to about 25 milligrams) of a compound of formula (I) (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein.
  • the dosage forms can further include a pharmaceutically acceptable carrier and/or an additional therapeutic agent.
  • the compounds of formula (I) themselves (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein are featured.
  • any of the formula (I) compounds specifically described herein are featured.
  • each of R 1 , R 2 , R 3 , and R 4 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, Ci-Ce alkoxy, Ci-Ce thioalkoxy, Ci-Ce haloalkoxy, Ci-Ce thiohaloalkoxy, Ci-Ce alkyl, Ci-Ce haloalkyl, C 2 -C6 alkynyl, cyclopropyl, -N 3 , cyano,
  • R and R' are defined according to (1) or (2) below:
  • each of R 5 , R 6 , R 7 , and R 8 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, Ci-Ce alkoxy, Ci-Ce thioalkoxy, Ci-Ce haloalkoxy, Ci-Ce thiohaloalkoxy, Ci-Ce alkyl, Ci-Ce haloalkyl, C 2 -C6 alkynyl, cyclopropyl, -N 3 , cyano,
  • C 3 respectively, form a fused heteroaryl ring containing 6 ring atoms, wherein from 1 -2 independently selected ring atoms is N; and wherein said heteroaryl ring is optionally substituted with from 1-2
  • each of L 1 and L 2 is, independently, Q-C 3 alkylene, which is optionally substituted with from 1-2 independently selected R c ;
  • A is:
  • R 9 is hydrogen or C 1 -C 3 alkyl that is optionally substituted with hydroxyl or C 1 -C 3 alkoxy; or
  • heterocycloalkylene containing from 3-5 ring atoms, wherein from 1-2 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heterocycloalkylene is (a) substituted with 1 oxo; and (b) is optionally further substituted with from 1 -4 independently selected R a ;
  • Z is:
  • heterocycloalkenyl containing from 5-6 ring atoms, wherein from 1 -3 of the ring atoms is independently selected from N, NH, N(d-C 6 alkyl), NC(0)(Ci-C 6 alkyl), O, and S; and wherein said heterocycloalkenyl is optionally substituted with from 1 -4 independently selected R a ;
  • heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 independently selected R b ; or
  • the aryl portion is optionally substituted with from 1-4 independently selected R b , and
  • the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;
  • the aryl portion from is optionally substituted with from 1-4 independently selected R b , and
  • (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C C 6 alkyl), NC(0)(C C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C r C 6 alkyl), NC(0)(C r C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • heteroarylcycloalkyl containing from 8-14 ring atoms, wherein: (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • each of R 10 and R 11 is independently selected from the substituents delineated collectively in (a) through (1) below:
  • heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;
  • the aryl portion is optionally substituted with from 1-4 independently selected R b , and
  • the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;
  • the aryl portion from is optionally substituted with from 1-4 independently selected R b , and
  • heterocyclyl portion is independently selected from N, NH, N(Ci-C 6 alkyl), NC(0)(C C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C r C 6 alkyl), NC(0)(C r C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • heteroarylcycloalkyl containing from 8-14 ring atoms wherein: (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • R 10 and R 11 must be selected from (b), (c), (g), (h), (i), j), and (k);
  • R 12 is:
  • heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ; or
  • the aryl portion is optionally substituted with from 1-4 independently selected R b , and
  • the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;
  • the aryl portion from is optionally substituted with from 1-4 independently selected R b , and
  • (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C C 6 alkyl), NC(0)(C C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(Ci-C 6 alkyl), NC(0)(C C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • R 13 is:
  • heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;
  • the aryl portion is optionally substituted with from 1-4 independently selected R b , and
  • the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;
  • the aryl portion from is optionally substituted with from 1-4 independently selected R b , and
  • heterocyclyl portion is independently selected from N, NH, N(Ci-C 6 alkyl), NC(0)(C C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • heterocyclyl portion is independently selected from N, NH, N(C r C 6 alkyl), NC(0)(C r C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ; or
  • (1) from 1 -2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • R b at each occurrence is independently selected from the substituents delineated in (aa) through (dd) below:
  • (cc) C3-C6 cycloalkyl or heterocyclyl containing from 5-6 ring atoms, wherein from 1 -2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(Ci-C6 alkyl), NC(0)(Ci-C6 alkyl), O, and S; and wherein each of said phenyl and heterocyclyl is optionally substituted with from 1 -3 independently selected R a ; and
  • R d at each occurrence is, independently selected from hydroxyl, Ci-C 6 alkoxy, Ci-C 6 thioalkoxy, C r C 6 haloalkoxy, C C 6 thiohaloalkoxy, C C 6 alkyl, C C 6 haloalkyl, -NH 2 , -NH(C C 6 alkyl), N(C C 6 alkyl) 2 , - NHC(0)(Ci-C 6 alkyl), and cyano; and
  • R e at each occurrence is, independently selected from hydroxyl, C 1 -C6 alkoxy; C 1 -C6 thioalkoxy; Cp C 6 haloalkoxy; C C 6 thiohaloalkoxy; -NH 2 ; -NH(C C 6 alkyl); N(C C 6 alkyl) 2 ; -NHC(0)(C C 6 alkyl); cyano; -C(0)H; -C(0)(Ci-C 6 alkyl); -C(0)(C r C 6 haloalkyl); C(0)OH; -C(0)0(C r C 6 alkyl); -C(0)NH 2 ; - C(0)NH(Ci-C 6 alkyl); C(0)N(C r C 6 alkyl) 2 ; -S0 2 (C r C 6 alkyl); -S0 2 NH 2 ; -S0 2 NH(C r C 6 alkyl); -S0 2 N(C
  • R 3 and R 6 cannot both be hydrogen when A is CH 2 , and R and R' are defined according to definition (1);
  • R 3 cannot be hydrogen when A is CH 2 , and R and R' are defined according to definition (2);
  • R 3 and R 6 cannot both be chloro when A is CH 2 , R and R' are defined according to definition (1), Z is -OR 12 , and R 12 is unsubstituted phenyl;
  • R 3 and R 6 cannot both be bromo when A is CH 2
  • R and R' are defined according to definition (1)
  • Z is -OR 12
  • R 12 is phenyl that is substituted with pyridyl or alkyl that is substituted with from 1 -3 R e ;
  • R 3 and R 6 cannot both be hydrogen when A is CH(CH 3 ), R and R' are defined according to definition (1), Z is NR 10 R U , R 10 is CH 3 , and R 11 is unsubstituted phenyl;
  • compositions are featured that include the above-described compounds (or salts thereof as described herein) and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier In embodiments, 1, 2, 3, 4, 5, or 6 of the above described provisions can apply.
  • each of R 1 , R 2 , R 3 , and R 4 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, Ci-Ce alkoxy, Ci-Ce thioalkoxy, Ci-Ce haloalkoxy, Ci-Ce thiohaloalkoxy, Ci-Ce alkyl, Ci-Ce haloalkyl, C 2 -C6 alkynyl, cyclopropyl, -N 3 , cyano,
  • R and R' are defined according to (1) or (2) below:
  • each of R 5 , R 6 , R 7 , and R 8 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, Ci-Ce alkoxy, Ci-Ce thioalkoxy, Ci-Ce haloalkoxy, Ci-Ce thiohaloalkoxy, Ci-Ce alkyl, Ci-Ce haloalkyl, C 2 -C6 alkynyl, cyclopropyl, -N 3 , cyano,
  • each of L 1 and L 2 is, independently, Q-C 3 alkylene, which is optionally substituted with from 1-2 independently selected R c ;
  • A is:
  • R 9 is Q-C 3 alkyl that is optionally substituted with hydroxyl or C 1 -C 3 alkoxy;
  • heterocycloalkylene containing from 3-5 ring atoms, wherein from 1-2 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heterocycloalkylene is (a) substituted with 1 oxo; and (b) is optionally further substituted with from 1 -4 independently selected R a ;
  • Z is:
  • heterocycloalkenyl containing from 5-6 ring atoms, wherein from 1 -3 of the ring atoms is independently selected from N, NH, N(d-C 6 alkyl), NC(0)(Ci-C 6 alkyl), O, and S; and wherein said heterocycloalkenyl is optionally substituted with from 1 -4 independently selected R a ;
  • heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 independently selected R b ; or
  • the aryl portion is optionally substituted with from 1-4 independently selected R b , and
  • the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;
  • the aryl portion from is optionally substituted with from 1-4 independently selected R b , and
  • (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C C 6 alkyl), NC(0)(C C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C r C 6 alkyl), NC(0)(C r C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • heteroarylcycloalkyl containing from 8-14 ring atoms, wherein: (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;
  • the aryl portion is optionally substituted with from 1-4 independently selected R b , and
  • the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;
  • the aryl portion from is optionally substituted with from 1-4 independently selected R b , and
  • heterocyclyl portion is independently selected from N, NH, N(Ci-C 6 alkyl), NC(0)(C C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C r C 6 alkyl), NC(0)(C r C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • heteroarylcycloalkyl containing from 8-14 ring atoms wherein: (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • R 10 and R 11 must be selected from (b), (c), (g), (h), (i), j), and (k);
  • R 12 is:
  • heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ; or
  • the aryl portion is optionally substituted with from 1-4 independently selected R b , and
  • the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;
  • the aryl portion from is optionally substituted with from 1-4 independently selected R b , and
  • (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C C 6 alkyl), NC(0)(C C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(Ci-C 6 alkyl), NC(0)(C C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • R 13 is:
  • heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;
  • the aryl portion is optionally substituted with from 1-4 independently selected R b , and
  • the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;
  • the aryl portion from is optionally substituted with from 1-4 independently selected R b , and
  • heterocyclyl portion is independently selected from N, NH, N(Ci-C 6 alkyl), NC(0)(C C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;
  • (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • heterocyclyl portion is independently selected from N, NH, N(C r C 6 alkyl), NC(0)(C r C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ; or
  • (1) from 1 -2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • R b at each occurrence is independently selected from the substituents delineated in (aa) through (dd) below:
  • (cc) C3-C6 cycloalkyl or heterocyclyl containing from 5-6 ring atoms, wherein from 1 -2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(Ci-C6 alkyl), NC(0)(Ci-C6 alkyl), O, and S; and wherein each of said phenyl and heterocyclyl is optionally substituted with from 1 -3 independently selected R a ; and
  • R d at each occurrence is, independently selected from hydroxyl, Ci-C 6 alkoxy, Ci-C 6 thioalkoxy, C r C 6 haloalkoxy, C C 6 thiohaloalkoxy, C C 6 alkyl, C C 6 haloalkyl, -NH 2 , -NH(C C 6 alkyl), N(C C 6 alkyl) 2 , - NHC(0)(Ci-C 6 alkyl), and cyano; and
  • R e at each occurrence is, independently selected from hydroxyl, C 1 -C6 alkoxy; C 1 -C6 thioalkoxy; Cp C 6 haloalkoxy; C C 6 thiohaloalkoxy; -NH 2 ; -NH(C C 6 alkyl); N(C C 6 alkyl) 2 ; -NHC(0)(C C 6 alkyl); cyano; -C(0)H; -C(0)(Ci-C 6 alkyl); -C(0)(C r C 6 haloalkyl); C(0)OH; -C(0)0(C r C 6 alkyl); -C(0)NH 2 ; - C(0)NH(Ci-C 6 alkyl); C(0)N(C r C 6 alkyl) 2 ; -S0 2 (C r C 6 alkyl); -S0 2 NH 2 ; -S0 2 NH(C r C 6 alkyl); -S0 2 N(C
  • R 3 and R 6 cannot both be hydrogen when A is CH 2 , and R and R' are defined according to definition (1);
  • R 3 cannot be hydrogen when A is CH 2 , and R and R' are defined according to definition (2);
  • R 3 and R 6 cannot both be chloro when A is CH 2 , R and R' are defined according to definition (1), Z is -OR 12 , and R 12 is unsubstituted phenyl;
  • R 3 and R 6 cannot both be bromo when A is CH 2
  • R and R' are defined according to definition (1)
  • Z is -OR 12
  • R 12 is phenyl that is substituted with pyridyl or alkyl that is substituted with from 1 -3 R e ;
  • R 3 and R 6 cannot both be hydrogen when A is CH(CH 3 ), R and R' are defined according to definition (1), Z is NR 10 R U , R 10 is CH 3 , and R 11 is unsubstituted phenyl.
  • compositions are featured that include the above-described compounds (or salts thereof as described herein) and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier In embodiments, 1, 2, 3, 4, or 5 of the above described provisions can apply.
  • each of R 1 , R 2 , R 3 , and R 4 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, Ci-Ce alkoxy, Ci-Ce thioalkoxy, Ci-Ce haloalkoxy, Ci-Ce thiohaloalkoxy, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkynyl, cyclopropyl, -N 3 , cyano,
  • R and R' are defined according to (1) or (2) below:
  • each of R 5 , R 6 , R 7 , and R 8 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, Ci-Ce alkoxy, Ci-Ce thioalkoxy, Ci-Ce haloalkoxy, Ci-Ce thiohaloalkoxy, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkynyl, cyclopropyl, -N 3 , cyano,
  • C 3 respectively, form a fused heteroaryl ring containing 6 ring atoms, wherein from 1 -2 independently selected ring atoms is N; and wherein said heteroaryl ring is optionally substituted with from 1-2
  • each of L 1 and L 2 is, independently, Q-C 3 alkylene, which is optionally substituted with from 1 -2 independently selected R c ;
  • A is CR A1 R A2 , wherein one of R A1 and R ⁇ is -OH, and the other of R A1 and R ⁇ is hydrogen or C r C 3 alkyl;
  • Z is -OR 12 or -S(0) n R 13 , wherein n is 0, 1 , or 2;
  • each of R 12 and R 13 is:
  • heteroaryl containing from 5-14 ring atoms, wherein from 1 -6 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1 -4 R b ;
  • Ci-Ce alkyl or Ci-Ce haloalkyl e.g., Ci-Ce alkyl, each of which is substituted with from 1 -3 R d ; or
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • the aryl portion from is optionally substituted with from 1 -4 independently selected R b , and
  • (1) from 1 -2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • (2) from 1 -2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C r C 6 alkyl), NC(0)(C r C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1 -3 independently selected R a ;
  • (1) from 1 -2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1 -3 independently selected R b ; and
  • the cycloalkyl portion is optionally substituted with from 1 -4 independently selected R a ;
  • R b at each occurrence is independently selected from the substituents delineated in (aa) through (dd) below:
  • (cc) C3-C6 cycloalkyl or heterocyclyl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected fromN, NH, N(Ci-C6 alkyl), NC(0)(Ci-C6 alkyl), O, and S; and wherein each of said phenyl and heterocyclyl is optionally substituted with from
  • R c at each occurrence is, independently selected from halo, Ci-C 6 alkoxy, Ci-C 6 thioalkoxy, Ci-C 6 haloalkoxy, C r C 6 thiohaloalkoxy, C r C 6 alkyl, C r C 6 haloalkyl, -NH 2 , -NH(C r C 6 alkyl), N(C r C 6 alkyl) 2 , - NHC(0)(C r C 6 alkyl), and cyano;
  • R d at each occurrence is, independently selected from hydroxyl, Ci-C 6 alkoxy, Ci-C 6 thioalkoxy, C r C 6 haloalkoxy, C C 6 thiohaloalkoxy, C C 6 alkyl, C C 6 haloalkyl, -NH 2 , -NH(C C 6 alkyl), N(C C 6 alkyl) 2 , - NHC(0)(Ci-C 6 alkyl), and cyano; and
  • R e at each occurrence is, independently selected from hydroxyl, C 1 -C6 alkoxy; C 1 -C6 thioalkoxy; Cp C 6 haloalkoxy; C C 6 thiohaloalkoxy; -NH 2 ; -NH(C C 6 alkyl); N(C C 6 alkyl) 2 ; -NHC(0)(C C 6 alkyl); cyano; -C(0)H; -C(0)(Ci-C 6 alkyl); -C(0)(C r C 6 haloalkyl); C(0)OH; -C(0)0(C r C 6 alkyl); -C(0)NH 2 ; - C(0)NH(Ci-C 6 alkyl); C(0)N(C r C 6 alkyl) 2 ; -S0 2 (C r C 6 alkyl); -S0 2 NH 2 ; -S0 2 NH(C r C 6 alkyl); -S0 2 N(C
  • 1, 2, 3, or 4 of the following can apply:
  • Z is -OR 12 , and R 12 is phenyl substituted with chloro, formyl, or -NHC(0)CH 3 ;
  • Z is -OR 12 , and R 12 is phenyl substituted with -NHC(0)CH 3 ; and provided that R 3 and R 6 cannot both be bromo when R and R' are defined according to definition (1), Z is -SR , and R is phenyl substituted with
  • compositions are featured that include the above-described compounds (or salts thereof as described herein) and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier In embodiments, 1, 2, 3, 4, or 5 of the above described provisions can apply.
  • each of R 1 , R 2 , R 3 , and R 4 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, Ci-C 6 alkoxy, Ci-C 6 thioalkoxy, Ci-C 6 haloalkoxy, Ci-C 6 thiohaloalkoxy, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, -N 3 , cyano,
  • R and R' together with C 2 and C3, respectively, form a fused heterocyclic ring containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms is independently selected from N, NH, N(Ci-C6 alkyl),
  • each of L 1 and L 2 is, independently, C 1 -C3 alkylene, which is optionally substituted with from 1-2 independently selected R c ;
  • A is:
  • R A1 R A2 (i) CR A1 R A2 , wherein one of R A1 and R A2 is independently selected from hydrogen, halo, C 1 -C3 alkyl, and OR 9 ; and the other of R A1 and R A2 is independently selected from halo, C 1 -C3 alkyl, and OR 9 ; wherein R 9 is hydrogen or C 1 -C3 alkyl that is optionally substituted with hydroxyl or C 1 -C3 alkoxy; or
  • C6-C 10 aryl that is optionally substituted with from 1 -4 independently selected R b ; or (vii) heteroaryl containing from 5-14 ring atoms, wherein from 1 -6 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1 -4 independently selected R b ; or
  • each of R 10 and R 11 is independently selected from the substituents delineated collectively in (a) through (g) below:
  • heteroaryl containing from 5-14 ring atoms, wherein from 1 -6 of the ring atoms is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1 -4 R b ;
  • R 10 and R 11 must be selected from (b) and (c);
  • R 12 is:
  • heteroaryl containing from 5-14 ring atoms, wherein from 1 -6 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1 -4 R b ;
  • R 13 is:
  • heteroaryl containing from 5-14 ring atoms, wherein from 1 -6 of the ring atoms is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1 -4 R b ;
  • R b at each occurrence is independently selected from the substituents delineated in (aa) through (dd) below:
  • (cc) C 3 -C 6 cycloalkyl or heterocyclyl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected fromN, NH, N(Ci-C 6 alkyl), NC(0)(Ci-C 6 alkyl), O, and S; and wherein each of said phenyl and heterocyclyl is optionally substituted with from
  • R c at each occurrence is, independently selected from halo, Ci-Ce alkoxy, Ci-Ce thioalkoxy, Ci-Ce haloalkoxy, C C 6 thiohaloalkoxy, C C 6 alkyl, C C 6 haloalkyl, -NH 2 , -NH(C C 6 alkyl), N(C r C 6 alkyl) 2 , - NHC(0)(Ci-C 6 alkyl), and cyano;
  • R d at each occurrence is, independently selected from hydroxyl, Ci-Ce alkoxy, Ci-Ce thioalkoxy, Cp C 6 haloalkoxy, C C 6 thiohaloalkoxy, C C 6 alkyl, C C 6 haloalkyl, -NH 2 , -NH(C C 6 alkyl), N(C C 6 alkyl) 2 , - NHC(0)(Ci-C 6 alkyl), and cyano; and
  • R e at each occurrence is, independently selected from hydroxyl, Ci-Ce alkoxy; Ci-Ce thioalkoxy; Cp C 6 haloalkoxy; C C 6 thiohaloalkoxy; -NH 2 ; -NH(C C 6 alkyl); N(C C 6 alkyl) 2 ; -NHC(0)(C C 6 alkyl); cyano; -C(0)H; -C(0)(Ci-C 6 alkyl); -C(0)(C r C 6 haloalkyl); C(0)OH; -C(0)0(C r C 6 alkyl); -C(0)NH 2 ; - C(0)NH(C r C 6 alkyl); C(0)N(C r C 6 alkyl) 2 ; -S0 2 (C r C 6 alkyl); -S0 2 NH 2 ; -S0 2 NH(C r C 6 alkyl); -S0 2 N(C r C 6 al
  • provision (A) described herein can apply.
  • each of R 1 , R 2 , R 3 , and R 4 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, Ci-Ce alkoxy, Ci-Ce thioalkoxy, Ci-Ce haloalkoxy, Ci-Ce thiohaloalkoxy, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkynyl, cyclopropyl, -N 3 , cyano,
  • each of R and R' is, independently, hydrogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl;
  • each of L 1 and L 2 is, independently, Q-C3 alkylene, which is optionally substituted with from 1-2 independently selected R c ;
  • A is:
  • R A1 R A2 (i) CR A1 R A2 , wherein one of R A1 and R A2 is independently selected from hydrogen, fluoro, chloro, C1-C3 alkyl, and OR 9 ; and the other of R A1 and R ⁇ is independently selected from fluoro, chloro, C1-C3 alkyl, and OR 9 ; wherein R 9 is hydrogen or Q-C3 alkyl that is optionally substituted with hydroxyl or C1-C3 alkoxy; or
  • heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 independently selected R b ; or
  • each of R 10 and R 11 is independently selected from the substituents delineated collectively in (a) through (g) below:
  • heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;
  • Ci-Ce alkyl or Ci-Ce haloalkyl each of which is optionally substituted with from 1-3 R d ;
  • R 10 and R 11 must be selected from (b) and (c);
  • each of R 12 and R 13 is::
  • heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;
  • R b at each occurrence is independently selected from the substituents delineated in (aa) through (dd) below:
  • R d at each occurrence is, independently selected from hydroxyl, i- e alkoxy, i- e thioalkoxy, Cp C 6 haloalkoxy, C r C 6 thiohaloalkoxy, C r C 6 alkyl, C r C 6 haloalkyl, -NH 2 , -NH(C r C 6 alkyl), N(C r C 6 alkyl) 2 , - NHC(0)(C r C 6 alkyl), and cyano; and
  • R e at each occurrence is, independently selected from hydroxyl, Ci-C 6 alkoxy; Ci-C 6 thioalkoxy; C r C 6 haloalkoxy; C r C 6 thiohaloalkoxy; -NH 2 ; -NH(C r C 6 alkyl); N(C r C 6 alkyl) 2 ; -NHC(0)(C r C 6 alkyl); cyano; -C(0)H; -C(0)(C r C 6 alkyl); -C(0)(C r C 6 haloalkyl); C(0)OH; -C(0)0(C r C 6 alkyl); -C(0)NH 2 ; - C(0)NH(C r C 6 alkyl); C(0)N(C r C 6 alkyl) 2 ; -S0 2 (C r C 6 alkyl); -S0 2 NH 2 ; -S0 2 NH(C r C 6 alkyl); -S0
  • A is CR ⁇ R ⁇ , in which each of R A1 and R ⁇ is, independently, hydrogen, halo, or C 1 -C3 alkyl; or A is CR A1 R A2 , in which one of R A1 and R ⁇ is halo (e.g., fluoro), and the other of R A1 and R ⁇ is, independently, hydrogen, halo, or C 1 -C3 alkyl (e.g., hydrogen); or
  • R A is CR A1 R A2 , in which one of R A1 and R ⁇ is halo (e.g., fluoro), and the other of R A1 and R ⁇ is hydrogen; and
  • R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , and Z can be as defined anywhere herein; or a salt (e.g., pharmaceutically acceptable salt) thereof.
  • (B) and/or (C) applies.
  • R A1 and R ⁇ can be OR 9 .
  • the other of R A1 and R ⁇ can be as defined anywhere herein; e.g., the other of R A1 and R ⁇ can be hydrogen or C 1 -C3 alkyl.
  • one of R A1 and R ⁇ can be OR 9 , and the other of R A1 and R ⁇ is hydro gen or C1 -C3 alkyl.
  • R can be hydrogen or C1 -C3 alkyl; and R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , and Z can be as defined anywhere herein; or a salt (e.g., pharmaceutically acceptable salt) thereof.
  • one or more of the following apply, e.g., when A is CHOH and Z is NR 10 R U :
  • each of R 3 and R 6 is CH 3 ; and/or each of R 3 and R 6 is bromo; and/or each of R 3 and R 6 is chloro; and/or one of R 3 and R 6 is CH 3 (e.g., R 6 ), and the other is bromo (e.g., R 3 );
  • R 10 and R 11 are heteroaryl as defined anywhere herein;
  • L 1 and/or L 2 is C 2 -C 3 alkylene (optionally substituted);
  • compounds of formula (III) are featured in which Z is other than NR 10 R U ; and R 1 , R 2 , R 3 , R 4 , Z, and A can be as defined anywhere herein; or a salt (e.g., pharmaceutically acceptable salt) thereof.
  • (B) and/or (C) applies.
  • compounds of formula (III) are featured in which Z is -OR 12 and/or -S(0) n R 13 ; and R 1 , R 2 , R 3 , R 4 , and A can be as defined anywhere herein; or a salt (e.g., pharmaceutically acceptable salt) thereof.
  • (B) and/or (C) applies.
  • heterocycloalkylene containing from 3-5 ring atoms, wherein from 1-2 of the ring atoms is independently selected fromN, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heterocycloalkylene is (a) substituted with 1 oxo; and (b) is optionally further substituted with from 1-4 independently selected R a ; and R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , and Z can be as defined anywhere herein; or a salt (e.g., pharmaceutically acceptable salt) thereof.
  • Ri - R 5 are each independently selected from hydrogen, halo, hydroxyl, sulfhydryl, Ci-C 6 alkoxy, C r Ce thioalkoxy, C 1 -C6 haloalkoxy, C 1 -C6 thiohaloalkoxy, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 2 -C6 alkynyl, cyclopropyl, -N 3 , cyano, -NH 2 , -NH(C C 6 alkyl), -N(C C 6 alkyl) 2 , -NHC(0)(C C 6 alkyl), and nitro;
  • X is C6-C 10 aryl that is optionally substituted with 1 -4 R b ; or heteroaryl containing 5-14 ring atoms, wherein from 1 -6 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S, and wherein said heteroaryl is optionally substituted with 1-4 R b ;
  • each of L 1 and L 2 is, independently, C 1 -C3 alkylene, which is optionally substituted with from 1 -2 independently selected R c ;
  • R A is CR A1 R A2 , wherein one of R A1 and R ⁇ is independently selected from hydrogen, fluoro, chloro, C 1 -C3 alkyl, and OR 9 ; and the other of R A1 and R ⁇ is independently selected from fluoro, chloro, C 1 -C3 alkyl, and OR 9 ; wherein R 9 is hydrogen or C 1 -C3 alkyl that is optionally substituted with hydroxyl or C 1 -C3 alkoxy;
  • Z is -NR 10 R U or -OR 12 ;
  • each of R 10 and R 11 is independently selected from the substituents delineated collectively in (a) through (g) below:
  • heteroaryl containing from 5-14 ring atoms, wherein from 1 -6 of the ring atoms is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1 -4 R b ;
  • R 10 and R 11 must be selected from (b) and (c);
  • R 12 is: :
  • heteroaryl containing from 5-14 ring atoms, wherein from 1 -6 of the ring atoms is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1 -4 R b ;
  • (cc) C 3 -C 6 cycloalkyl or heterocyclyl containing from 5-6 ring atoms, wherein from 1 -2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(Ci-C 6 alkyl), NC(0)(Ci-C 6 alkyl), O, and S; and wherein each of said phenyl and heterocyclyl is optionally substituted with from 1 -3 independently selected R a ; and
  • R d at each occurrence is, independently selected from hydroxyl, Ci-Ce alkoxy, Ci-Ce thioalkoxy, Cp
  • R e at each occurrence is, independently selected from hydroxyl, Ci-Ce alkoxy; Ci-Ce thioalkoxy; Cp
  • L 3 (C r C 6 alkylene)-biotin, where in L 3 is a -0-, -NH-, -NCH 3 -, -C(O)-, -C(0)NH-, -
  • compound of formula (VI) can have a R 3 that is selected from halo, hydroxyl, sulfhydryl, Ci-C 6 alkoxy, Ci-C 6 thioalkoxy, Ci-C 6 haloalkoxy, Ci-C 6 thiohaloalkoxy, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, -N 3 , cyano, -NH 2 , -NH(C r C 6 alkyl), -N(C r C 6 alkyl) 2 , -NHC(0)(C r C 6 alkyl), and nitro.
  • R3 is halo such as bromo.
  • each of Ri, R 2 , R4 and R 5 is hydrogen.
  • compound of formula (VI) can have X that is C6-C10 aryl substituted with one or more halo such as bromo.
  • X can be 4-bromophenyl.
  • X can also be heteroaryl containing 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C3 alkyl), O, and S, and wherein said heteroaryl is optionally substituted with 1 -4 R b .
  • X can be pyridine optionally substituted with 1-4 R b .
  • compound of formula (VI) can have A that is CR A1 R A2 , wherein each of R A1 and R ⁇ is, independently, hydrogen, C1-C3 alkyl, or OR 9 .
  • R A1 and R ⁇ is OR 9 ; and the other of R A1 and R ⁇ is hydrogen or C1-C3 alkyl.
  • one of R A1 and R ⁇ can be OH; and the other of R A1 and R ⁇ can be hydrogen.
  • A is CR A1 R A2 and wherein the carbon attached to R A1 and R ⁇ is substituted with four different substituents.
  • the carbon attached to to R A1 and R ⁇ can be (R) or (S) configured.
  • the (R) configured formula (VI) compound can be substantially free of a formula (VI) compound that is S configured at the carbon atom attached to to R A1 and R ⁇ .
  • the (S) configured formula (VI) compound can be substantially free of a formula (VI) compound that is (R) configured at the carbon atom attached to to R A1 and R ⁇ .
  • the compound of formula (VI), in some embodiments, can be (+) or (-) (dextrorotatory).
  • the (+) (dextrorotatory) compound can be substantially free of a formula (I) compound that is (levororotatory). In some embodiments, the (-) (levororotatory) compound can be substantially free of a formula (I) compound that is (+) (dextrorotatory).
  • the presently disclosed embodiments relate generally to stimulating neurogenesis (e.g., post-natal neurogenesis, e.g., post-natal hippocampal and/or hypothalamic neurogenesis) and protecting neurons from death with a compound of formula (I) (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein.
  • neurogenesis e.g., post-natal neurogenesis, e.g., post-natal hippocampal and/or hypothalamic neurogenesis
  • a salt e.g., a pharmaceutically acceptable salt
  • methods of promoting the generation of neurons are featured.
  • methods of promoting the survival, growth, development and/or function of neurons, particularly CNS, brain, cerebral, hippocampal and hypothalamic neurons are featured.
  • methods of stimulating post-natal hippocampal and/or hypothalamic neurogenesis are featured.
  • such methods can include in vitro methods, e.g., contacting a sample (e.g., a cell or tissue) with a compound of formula (I) (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein.
  • the methods can include administering a compound of formula (I) (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein to a subject (e.g., a mammal, such as a human).
  • the presently disclosed embodiments include and feature methods of screening for (thereby identifying) compounds that stimulate neurogenesis (e.g., post-natal neurogenesis, e.g., post-natal hippocampal and/or hypothalamic neurogenesis) or protect newborn neurons from cell death.
  • neurogenesis e.g., post-natal neurogenesis, e.g., post-natal hippocampal and/or hypothalamic neurogenesis
  • protect newborn neurons from cell death e.g., such as those described in the Examples section.
  • methods for treating e.g., controlling, relieving, ameliorating, alleviating, or slowing the progression of
  • methods for preventing e.g., delaying the onset of or reducing the risk of developing
  • the methods include administering to the subject an effective amount of a compound of formula (I) (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein to the subject.
  • a compound of formula (I) (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein in the preparation of, or for use as, a medicament for the treatment (e.g., controlling, relieving, ameliorating, alleviating, or slowing the progression of) or prevention (e.g., delaying the onset of or reducing the risk of developing) of one or more diseases, disorders, or conditions caused by, or associated with, insufficient (e.g., aberrant) neurogenesis or unwanted neuronal cell death is featured.
  • a salt e.g., a pharmaceutically acceptable salt
  • the one or more diseases, disorders, or conditions can include neuropathies, nerve trauma, and neurodegenerative diseases.
  • the one or more diseases, disorders, or conditions can be diseases, disorders, or conditions caused by, or associated with insufficient neurogenesis (e.g., aberrant hippocampal and/or hypothalamic neurogenesis) as is believed to occur in neuropsychiatric diseases, or aberrant neuronal cell death as is believed to occur in neurodegenerative diseases.
  • insufficient neurogenesis e.g., aberrant hippocampal and/or hypothalamic neurogenesis
  • Examples of the one or more diseases, disorders, or conditions include, but are not limited to, schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis,
  • Huntington's disease, stroke, radiation therapy, chronic stress, and abuse of neuro-active drugs such as alcohol, opiates, methamphetamine, phencyclidine, and cocaine
  • retinal degeneration spinal cord injury, peripheral nerve injury, physiological weight loss associated with various conditions, and cognitive decline associated with normal aging, radiation therapy, and chemotherapy.
  • the subject can be a subject in need thereof (e.g., a subject identified as being in need of such treatment, such as a subject having, or at risk of having, one or more of the diseases or conditions described herein). Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).
  • the subject can be a mammal. In certain embodiments, the subject can be a human.
  • methods of making the compounds described herein include taking any one of the intermediate compounds described herein and reacting it with one or more chemical reagents in one or more steps to produce a compound of formula (I) (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein.
  • compounds in which A is CHOH, and each of L 1 and L 2 is C 1 -C3 alkylene can be converted to compounds in which A is C(O), and each of L 1 and L 2 is C 1 -C3 alkylene (e.g., each of L 1 and L 2 is CH 2 ) that is substituted with Ci-C 6 thioalkoxy (e.g., -SCH 3 ).
  • the methods include contacting the starting material with an oxidizing agent sulfur trioxide pyridine complex (see, e.g., Example 7a and 7b).
  • methods of making the pharmaceutical compositions described herein are featured.
  • the methods include taking any one or more of the compounds of formula (I) (and/or compounds of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein, and mixing said compound(s) with one or more pharmaceutically acceptable carriers.
  • kits for the treatment e.g., controlling, relieving, ameliorating, alleviating, or slowing the progression of
  • prevention e.g., delaying the onset of or reducing the risk of developing
  • the kits include (i) a compound of formula (I) (and/or compounds of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein; and (ii) instructions that include a direction to administer said compound to a subject (e.g., a patient).
  • Embodiments can include, for example, any one or more of the following features.
  • R 3 is selected from halo, hydroxyl, sulfhydryl, Ci-Ce alkoxy, Ci-Ce thioalkoxy, Ci-Ce haloalkoxy, Cp C 6 thiohaloalkoxy, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, -N 3 , cyano, -NH 2 , -NH(Ci-C 6 alkyl), -N(C r C 6 alkyl) 2 , -NHC(0)(C r C 6 alkyl), and nitro.
  • R 3 is halo (e.g., bromo).
  • each of R 1 , R 2 , and R 4 is hydrogen.
  • R 6 is selected from halo, hydroxyl, sulfhydryl, Ci-C 6 alkoxy, Ci-C 6 thioalkoxy, Ci-C 6 haloalkoxy, C r C 6 thiohaloalkoxy, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, -N 3 , cyano, -NH 2 , -NH(Ci-C 6 alkyl), -N(C r C 6 alkyl) 2 , -NHC(0)(C r C 6 alkyl), and nitro.
  • R 6 is halo (e.g., bromo) or C r C 6 alkyl (e.g., CH 3 ). In embodiments, R 6 is halo (e.g., bromo). In embodiments, each of R 5 , R 7 , and R 8 is hydrogen.
  • each of R 3 and R 6 is an independently selected substituent that is other than hydrogen. In certain embodiments, each of R 3 and R 6 is independently selected from halo, hydroxyl, sulfhydryl, Ci-Ce alkoxy, Ci-Ce thioalkoxy, Ci-Ce haloalkoxy, Ci-Ce thiohaloalkoxy, Ci-Ce alkyl, Ci-Ce haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, -N 3 , cyano, -NH 2 , -NH(C C 6 alkyl), -N(C C 6 alkyl) 2 , -NHC(0)(C C 6 alkyl), and nitro.
  • R 3 can be halo (e.g., bromo); and R 6 can be halo (e.g., bromo) or Ci-Ce alkyl (e.g., CH 3 ); e.g., halo (e.g., bromo).
  • each of R 1 , R 2 , and R 4 is hydrogen; and each of R 5 , R 7 , and R 8 is hydrogen.
  • R and R' together with C 2 and C 3 , respectively, form a fused heteroaryl ring containing from 5-6 ring atoms, wherein from 1 -2 of the ring atoms is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl ring is optionally substituted with from 1 -3
  • R and R' together with C 2 and C 3 , respectively, form a fused heteroaryl ring containing - 6 ring atoms, wherein from 1 -2 independently selected ring atoms is N; and wherein said heteroaryl ring is optionally substituted with from 1 -2 independently selected R b .
  • R and R' together with C 2 and C 3 , respectively, form a fused heterocyclic ring containing from 5-6 ring atoms, wherein from 1 -2 of the ring atoms is independently selected from N, NH, N(Ci-C 6 alkyl), NC(0)(Ci-C 6 alkyl), O, and S; and wherein said heterocyclic ring is optionally substituted with from 1 -3 independently selected R a .
  • R and R' together with C 2 and C 3 , respectively, form a fused heterocyclic ring containing 6 ring atoms, wherein from 1 -2 of the ring atoms is independently selected from N, NH, N(Ci-C6 alkyl), and NC(0)(Ci-C6 alkyl); and wherein said heterocyclic ring is optionally substituted with from 1-3 independently selected R a .
  • R and R' is, independently, hydrogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl (e.g., Ci-C 6 alkyl, or Ci-Ce haloalkyl; e.g., C 1 -C6 alkyl).
  • Each of L 1 and L 2 is, independently, C 1 -C3 straight chain alkylene, which is optionally substituted with from 1 -2 independently selected R c .
  • each of L 1 and L 2 is CH 2 .
  • R A is CR A1 R A2 , in which each of R A1 and R ⁇ is, independently, hydrogen, halo, C r C 3 alkyl, or OR 9 .
  • A is other than CH 2 .
  • one of R A1 and R ⁇ can be independently selected from hydrogen, halo, C 1 -C3 alkyl, and OR 9 ; and the other of R A1 and R ⁇ can be independently selected from halo, C 1 -C3 alkyl, and OR 9 .
  • one of R A1 and R ⁇ is halo, C 1 -C3 alkyl, or OR 9 (e.g., halo or OR 9 ); and the other is hydrogen or Cl - C3 alkyl.
  • one of R A1 and R ⁇ is halo, and the other of R A1 and R ⁇ is hydrogen or halo.
  • one of R A1 and R ⁇ is fluoro, and the other of R A1 and R ⁇ is hydrogen or fluoro.
  • one of R A1 and R ⁇ is OR 9 ; and the other of R A1 and R ⁇ is C 1 -C3 alkyl.
  • one of R A1 and R ⁇ is OH; and the other of R A1 and R A2 is CH3.
  • the carbon attached to R A1 and R A2 is substituted with four different substituents (for purposes of clarification, these four substituents include R A1 and R ⁇ ) and is therefore a stereogenic center.
  • the carbon attached to R A1 and R ⁇ is (R) configured, meaning that the carbon attached to R A1 and R ⁇ has the (R) configuration (Cahn Ingold Prelog sequence rules notation).
  • Such compounds are sometimes referred to herein as an "(R) -configured compound” (this term also includes compounds that further contain one or more stereogenic centers in addition to the (R)-CR A1 R A2 stereogenic center).
  • the carbon attached to R A1 and R ⁇ is (S) configured, meaning that the carbon attached to R A1 and R ⁇ has the (S) configuration (Cahn Ingold Prelog sequence rules notation).
  • Such compounds are sometimes referred to herein as an "(S)-configured compound” (this term also includes compounds that further contain one or more stereogenic centers in addition to the (S)-CR A1 R A2 stereogenic center).
  • the (R) configured compound (or salt, e.g., a pharmaceutically acceptable salt, thereof) is substantially free of (e.g., contains less than about 5% of, less than about 2% of, less than about 1%, less than about 0.5% of) a formula (I) compound (or salt thereof as described herein) that is (S) configured at the carbon attached to R A1 and R ⁇ (i.e., a formula (I) compound in which the carbon attached to R A1 and R A2 has the (S) configuration).
  • the (R) configured compound can be an (R)-enantiomer that is substantially free of its opposing (S) enantiomer.
  • an (R) configured compound can be substantially free of a diastereomer in which the carbon attached to R A1 and R ⁇ has the (S) configuration.
  • the (R) configured compound can be additionally in substantially pure form (e.g., contains less than about 5% of, less than about 2% of, less than about 1%, less than about 0.5% of other substances, including, for example, one or more of other formula (I) compounds, non- formula (I) compounds, or biological media).
  • the (S) configured compound (or salt, e.g., a pharmaceutically acceptable salt, thereof) is substantially free of (e.g., contains less than about 5% of, less than about 2% of, less than about 1%, less than about 0.5% of) a formula (I) compound (or salt thereof as described herein) that is (R) configured at the carbon attached to R A1 and R ⁇ (i.e., a formula (I) compound in which the carbon attached to R A1 and R A2 has the (R) configuration).
  • the (S) configured compound can be an (S)-enantiomer that is substantially free of its opposing (R) enantiomer.
  • the (S) configured compound can be substantially free of a diastereomer in which the carbon attached to R A1 and R ⁇ has the (R) configuration.
  • the (S) configured compound can be additionally in substantially pure form (e.g., contains less than about 5% of, less than about 2% of, less than about 1%, less than about 0.5% of other substances, including, for example, one or more of other formula (I) compounds, non- formula (I) compounds, or biological media).
  • a formula (I) compound is (+) (dextrorotatory) when in the presence of plane polarized light.
  • a formula (I) compound is (-) (levororotatory) when in the presence of plane polarized light.
  • the (+) (dextrorotatory) compound is substantially free of (e.g., contains less than about 5% of, less than about 2% of, less than about 1%, less than about 0.5%) a formula (I) compound (or salt thereof as described herein) that is (-) (levororotatory).
  • the (+) (dextrorotatory) compound can be additionally in substantially pure form (e.g., contains less than about 5% of, less than about 2% of, less than about 1%, less than about 0.5% of other substances, including, for example, one or more of other formula (I) compounds, non-formula (I) compounds, or biological media).
  • the (-) (levororotatory) compound is substantially free of (e.g., contains less than about 5% of, less than about 2% of, less than about 1%, less than about 0.5%) a formula (I) compound (or salt thereof as described herein) that is (+) (dextrorotatory).
  • the (-) (levororotatory) compound can be additionally in substantially pure form (e.g., contains less than about 5% of, less than about 2% of, less than about 1%, less than about 0.5% of other substances, including, for example, one or more of other formula (I) compounds, non-formula (I) compounds, or biological media).
  • R A is CR A1 R A2 , wherein each of R A1 and R ⁇ is, independently, hydrogen, halo, C r C 3 alkyl, or OR 9 .
  • one of R A1 and R ⁇ is independently selected from hydrogen, halo, Q-C3 alkyl, and OR 9 ; and the other of R A1 and R ⁇ is independently selected from halo, C 1 -C3 alkyl, and OR 9 .
  • one of R and R is halo, and the other of R and R is hydrogen, halo, or C1-C3 alkyl.
  • one of R A1 and R ⁇ is halo, and the other of R A1 and R ⁇ is hydrogen.
  • one of R A1 and R ⁇ is fluoro, and the other of R A1 and R ⁇ is hydrogen.
  • each of R A1 and R ⁇ is, independently, halo; e.g., each of R A1 and R ⁇ is fluoro.
  • one of R A1 and R ⁇ is -OH, and the other of R A1 and R ⁇ is hydrogen.
  • A is CR A1 R A2 , wherein one of R A1 and R ⁇ is independently selected from hydrogen, halo, C1-C3 alkyl, and OR 9 ; and the other of R A1 and R ⁇ is independently selected from halo, C1-C3 alkyl, and OR 9 ; wherein R 9 is hydrogen or C1-C3 alkyl that is optionally substituted with hydroxyl or C1-C3 alkoxy.
  • one of R A1 and R ⁇ is OR 9 , and the other is hydrogen, wherein R 9 is hydrogen.
  • one of R A1 and R ⁇ is halo, and the other of R A1 and R ⁇ is hydrogen or halo.
  • one of R A1 and R ⁇ is fluoro, and the other of R A1 and R ⁇ is hydrogen or fluoro.
  • one of R A1 and R ⁇ is OR 9 ; and the other of R A1 and R ⁇ is C1-C3 alkyl.
  • one of R A1 and R ⁇ is OH; and the other of R A1 and R ⁇ is CH3.
  • Z is: (i) -NR 10 R U ; or (ii) -C(O)NR 10 R u ; or (iii) -OR 12 ; or (iv) -S(0) n R 13 , wherein n is 0, 1, or 2.
  • R 10 and R 11 is: (b) C 6 -Ci 0 aryl that is optionally substituted with from 1-4 R b ; or (c) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1 -4 R b ; and the other of R 10 and R 11 is hydrogen or Ci-C 6 alkyl.
  • Z is -OR 12 or -S(0) n R 13 .
  • Z is -OR 12 .
  • R 12 is C6-C10 aryl that is optionally substituted with from 1-4 R b .
  • R 12 is Ci-Ce alkyl or Ci-Ce haloalkyl (e.g., Ci-Ce alkyl), each of which is substituted with from 1-3 R d .
  • R 12 is other than Ci-Ce alkyl or Ci-Ce haloalkyl (e.g., Ci-Ce alkyl), each of which is unsubstituted or substituted with from 1 -3 R d .
  • R 3 can be selected from halo, hydroxyl, sulfhydryl, Ci-Ce alkoxy, Ci-Ce thioalkoxy, Ci-Ce haloalkoxy, Ci-C 6 thiohaloalkoxy, C C 6 alkyl, C C 6 haloalkyl, cyano, -NH 2 , -NH(C C 6 alkyl), N(C C 6 alkyl) 2 , - NHC(0)(Ci-C6 alkyl), and nitro.
  • R 3 can be halo (e.g., bromo).
  • each of R 1 , R 2 , and R 4 can be hydrogen.
  • L 1 can be C1-C3 straight chain alkylene, which is optionally substituted with from 1-2 independently selected R c .
  • L 1 can be CH 2 .
  • L 2 can be Q-C3 straight chain alkylene, which is optionally substituted with from 1-2 independently selected R c .
  • L 2 can be CH 2 .
  • Each of L 1 and L 2 can be, independently, C1-C3 straight chain alkylene, which is optionally substituted with from 1-2 independently selected R c .
  • each of L 1 and L 2 can be CH 2 .
  • A can be CR R , in which each of R and R is, independently, hydrogen, halo, Q-C3 alkyl, or
  • A can be CR A1 R A2 , in which each of R A1 and R ⁇ is, independently, hydrogen, halo, or C 1 -C3 alkyl.
  • A can be CR A1 R A2 , in which one of R A1 and R ⁇ is halo (e.g., fluoro), and the other of R A1 and R A2 is, independently, hydrogen, halo, or C 1 -C3 alkyl (e.g., hydrogen).
  • R A can be CR A1 R A2 , in which one of R A1 and R ⁇ is halo (e.g., fluoro), and the other of R A1 and R A2 is hydrogen.
  • halo e.g., fluoro
  • R A1 and R ⁇ can be halo or OR 9 , and the other is hydrogen.
  • R A1 and R ⁇ can be OR 9 .
  • the other of R A1 and R ⁇ can be as defined anywhere herein; e.g., the other of R A1 and R ⁇ can be hydrogen or C 1 -C3 alkyl.
  • one of R A1 and R ⁇ can be OR 9 .
  • the other of R A1 and R ⁇ can be as defined anywhere herein; e.g., the other of R A1 and R ⁇ can be hydrogen or C 1 -C3 alkyl.
  • R A1 and R ⁇ can be hydrogen or C 1 -C3 alkyl.
  • R 9 can be hydrogen.
  • R A1 and R ⁇ can be halo.
  • the other of R A1 and R ⁇ can be as defined anywhere herein; e.g., the other of R A1 and R ⁇ can be hydrogen, C 1 -C3 alkyl, or halo.
  • one of R A1 and R ⁇ can be halo (e.g., fluoro), and the other of R A1 and R ⁇ is hydrogen.
  • the carbon attached to R A1 and R ⁇ can have the R configuration.
  • the carbon attached to R A1 and R ⁇ can have the S configuration.
  • Each of L 1 and L 2 is, independently, Q-C3 alkylene, which is optionally substituted with from 1-2 independently selected R c .
  • each of L 1 and L 2 can be CH 2 .
  • Z can be -NR 10 R U .
  • R 10 and R 11 can be C6-C 10 aryl that is optionally substituted with from 1-4 R b .
  • R 10 and R 11 can be C6-C 10 aryl that is optionally substituted with from 1-4 R b , and the other is hydrogen or Ci-Ce alkyl.
  • R 10 and R 11 can be C6-C 10 aryl that is optionally substituted with from 1-4 R b , and the other is hydrogen.
  • one of R 10 and R 11 can be unsubstituted phenyl, and the other is hydrogen.
  • one of R 10 and R 11 can be phenyl that is substituted with 1 R b , and the other is hydrogen.
  • R b can be Ci-Ce alkoxy (e.g., OCH 3 ).
  • one of R 10 and R 11 can be 3-methoxyphenyl, and the other is hydrogen.
  • Z can be -OR 12 .
  • R 12 can be Ci-Ce alkyl or Ci-Ce haloalkyl, each of which is optionally substituted with from 1-3 R c .
  • R 12 can be C 6 -Ci 0 aryl that is optionally substituted with from 1 -4 R b .
  • R 12 can be unsubstituted phenyl.
  • Z can be -S(0) n R 13 , in which n can be 0, 1, or 2.
  • R can be C 6 -Ci 0 aryl that is optionally substituted with from 1-4 R b .
  • R 13 can be unsubstituted phenyl.
  • Z can be heterocycloalkenyl containing from 5-6 ring atoms, wherein from 1 -3 of the ring atoms is independently selected firom N, NH, N(C r C 6 alkyl), NC(0)(C r C 6 alkyl), O, and S; and wherein said heterocycloalkenyl is optionally substituted with from 1 -4 independently selected R a .
  • R 6 can be selected from halo, hydroxyl, sulfhydryl, Ci-Ce alkoxy, Ci-Ce thioalkoxy, Ci-Ce haloalkoxy, Ci-C 6 thiohaloalkoxy, C C 6 alkyl, C C 6 haloalkyl, cyano, -NH 2 , -NH(C C 6 alkyl), N(C C 6 alkyl) 2 , - NHC(0)(Ci-C6 alkyl), and nitro.
  • R 6 can be halo (e.g., bromo).
  • each of R 5 , R 7 , and R 8 can be hydrogen.
  • any one or more of the R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , A, and Z embodiments described herein can be combined with any one or more of the R 5 , R 6 , R 7 , and R 8 embodiments described herein.
  • Each of L 1 and L 2 can be CH 2 .
  • A can be CR A1 R A2 , wherein one of R A1 and R ⁇ is OR 9 , and the other is hydrogen.
  • Z is -NR 10 R U ; and each of R 10 and R 11 can be independently selected from: (a) hydrogen; (b) C 6 - Cio aryl that is optionally substituted with from 1 -4 R b ; (d) Ci-C 6 alkyl or Ci-C 6 haloalkyl, each of which is optionally substituted with from 1 -3 R d ; and (f) C 2 -C 6 alkenyl or C 2 -C 6 alkynyl.
  • R 3 and R 6 can be halo (e.g., bromo); and each of R 1 , R 2 , R 4 , R 5 , R 7 , and R 8 can be hydrogen.
  • R 9 can be hydrogen.
  • One of R 10 and R 11 can be C 6 -Ci 0 aryl that is optionally substituted with from 1 -4 R b , and the other is hydrogen.
  • One of R 10 and R 11 can be unsubstituted phenyl, and the other is hydrogen.
  • One of R 10 and R 11 can be phenyl that is substituted with 1 R b , and the other is hydrogen.
  • R b can be Ci-C 6 alkoxy (e.g., OCH 3 ).
  • One of R 10 and R 11 can be 3-methoxyphenyl, and the other is hydrogen.
  • Each of L 1 and L 2 is CH 2 .
  • A is CR A1 R A2 , wherein one of R A1 and R ⁇ is OR 9 , and the other is hydrogen.
  • Z is -NR 10 R U ; and each of R 10 and R 11 is independently selected from: (a) hydrogen; (b) C6-C 10 aryl that is optionally substituted with from 1 -4 R b ; (d) C 1 -C6 alkyl or C 1 -C6 haloalkyl, each of which is optionally substituted with from 1 -3 R d ; and (f) C 2 -C6 alkenyl or C 2 -C6 alkynyl.
  • Embodiment can include one or more of the following features.
  • R 3 and R 6 is halo (e.g., bromo); and each of R 1 , R 2 , R 4 , R 5 , R 7 , and R 8 is hydrogen.
  • R 9 can be hydrogen.
  • One of R 10 and R 11 can be C6-C 10 aryl that is optionally substituted with from 1 -4 R b , and the other is hydrogen.
  • One of R 10 and R 11 can be unsubstituted phenyl, and the other is hydrogen.
  • One of R 10 and R 11 can be phenyl that is substituted with 1 R b , and the other is hydrogen.
  • R b can be C 1 -C6 alkoxy (e.g., OCH 3 ).
  • One of R 10 and R 11 can be 3-methoxyphenyl, and the other is hydrogen.
  • R and R' can be, independently, hydrogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R and R' can be, independently, C 1 -C6 alkyl (e.g., each of R and R' can be CH 3 ).
  • Each of R and R' can be hydrogen.
  • the compound of the present invention can include any one or more compounds selected from: R-l-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol;
  • a salt e.g., a pharmaceutically acceptable salt thereof (or any one or a subset thereof, e.g., as delineated in the claims).
  • the compound having formula (I) can be l-(3,6-dibromo-9H-carbazol-9-yl)- 3-(phenylamino)propan-2-ol; or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the compound having formula (I) can be R-l -(3,6-Dibromo-9H-carbazol-9- yl)-3-(3-methoxyphenylamino)-propan-2-ol; or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • R-l -(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol or a salt (e.g., a pharmaceutically acceptable salt) thereof can be substantially free of (e.g., contains less than about 5% of, less than about 2% of, less than about 1%, less than about 0.5% of) S-l-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3- methoxyphenylamino)-propan-2-ol or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the compound having formula (I) can be S-l-(3,6-Dibromo-9H-carbazol-9- yl)-3-(3-methoxyphenylamino)-propan-2-ol; or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • S-l -(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol or a salt (e.g., a pharmaceutically acceptable salt) thereof can be substantially free of (e.g., contains less than about 5% of, less than about 2% of, less than about 1%, less than about 0.5% of) R-l-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3- methoxyphenylamino)-propan-2-ol or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the compound having formula (I) can be the (+) (dextrorotatory) enantiomer of l-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol as described herein or a salt (e.g., a pharmaceutically acceptable salt) thereof. See, e.g., Example la and lb.
  • the (+) (dextrorotatory) enantiomer of l-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol as described herein or a salt (e.g., a pharmaceutically acceptable salt) thereof can be substantially free of (e.g., contains less than about 5% of, less than about 2% of, less than about 1%, less than about 0.5% of) the (-) (levorotatory) enantiomer of l-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol as described herein or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the compound having formula (I) can be the (-) (levorotatory) enantiomer of l-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol as described herein or a salt (e.g., a pharmaceutically acceptable salt) thereof. See, e.g., Example la and lb.
  • the (-) (levorotatory) enantiomer of l-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol as described herein or a salt (e.g., a pharmaceutically acceptable salt) thereof. See, e.g., Example la and lb.
  • the (-) (levorotatory) enantiomer of l-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-me
  • (levorotatory) enantiomer of l-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol as described herein or a salt (e.g., a pharmaceutically acceptable salt) thereof can be substantially free of (e.g., contains less than about 5% of, less than about 2% of, less than about 1%, less than about 0.5% of) the (+) (dextrorotatory) enantiomer of l-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol as described herein or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the compound can be (+) ( ⁇ iexiroroifliory)-N-(3-(3,6-dibromo-9H-carbazol-9- yl)-2-fluoropropyl)-3-methoxyaniline as described herein or a salt (e.g., a pharmaceutically acceptable salt) thereof. See, e.g., Example 144a and 144b.
  • pharmaceutically acceptable salt thereof can be substantially free of (e.g., contains less than about 5% of, less than about 2% of, less than about 1%, less than about 0.5% of) the (-) (dextrorotatory) enantiomer of N-(3- (3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxyaniline as described herein or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • the compound can be (-) ( ⁇ 5?exiroroiaiory)-N-(3-(3,6-dibromo-9H-carbazol-9- yl)-2-fluoropropyl)-3-methoxyaniline as described herein or a salt (e.g., a pharmaceutically acceptable salt) thereof. See, e.g., Example 144a and 144b.
  • pharmaceutically acceptable salt thereof can be substantially free of (e.g., contains less than about 5% of, less than about 2% of, less than about 1%, less than about 0.5% of) the (+) (dextrorotatory) enantiomer of N-(3- (3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxyaniline as described herein or a salt (e.g., a pharmaceutically acceptable salt) thereof.
  • Compounds of formula (I), (II), (III), and (IV) are featured, including title compounds of Examples la, lb, 3a, 3b, 3d, 6a, 10, 13, 21, 22, 88b, 90, 92, 96, 97a, 97b, 102, 116, 117, 118, 119, 120, 121, 122, 132, 143, and 144a; or a pharmaceutically acceptable salt thereof.
  • compounds of formula (I), (II), (III), and (IV) can be used in a method for the treatment of a disease, disorder, or condition caused by unwanted neuronal cell death or associated with insufficient neurogenesis in a subject in need thereof.
  • the method can include administering to the subject an effective amount of a compound having formula (I), (II), (III), or (VI), or a pharmaceutically acceptable salt thereof, as defined herein.
  • the methods can further include detecting a resultant neurotrophism (e.g., neurogenesis; and/or determining that the patient has aberrant neurotrophism, particularly aberrant neurogenesis, particularly aberrant hippocampal and/or hypothalamic neurogenesis, or a disease or disorder associated therewith, particularly by detecting and/or diagnosing the same.
  • a resultant neurotrophism e.g., neurogenesis
  • determining that the patient has aberrant neurotrophism, particularly aberrant neurogenesis, particularly aberrant hippocampal and/or hypothalamic neurogenesis, or a disease or disorder associated therewith particularly by detecting and/or diagnosing the same.
  • the methods can further include detecting a resultant neurotrophism.
  • the methods can further include detecting determining that the subject has aberrant neurogenesis or death of neurons or a disease or disorder associated therewith, by detecting the same in said subject.
  • the methods can further include detecting a resultant hippocampal and/or hypothalamic neurogenesis.
  • the disease, disorder, or condition can be a neuropsychiatric and neurodegenerative disease, including (but not limited to) schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome,
  • a neuropsychiatric and neurodegenerative disease including (but not limited to) schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome,
  • spinocerebellar ataxia amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, and abuse of neuro-active drugs (such as alcohol, opiates, methamphetamine, phencyclidine, and cocaine), retinal degeneration, spinal cord injury, peripheral nerve injury, physiological weight loss associated with various conditions, and cognitive decline associated with normal aging, and chemotherapy.
  • neuro-active drugs such as alcohol, opiates, methamphetamine, phencyclidine, and cocaine
  • the compounds having formula (I) or a salt (e.g., a pharmaceutically acceptable salt) thereof provide at least about 27 (xlO 06 ) BrdU+ cells / mm 3 dentate gyrus when evaluated in the assay described in conjunction with Table 1 (i.e., evaluated for pro-neurogenic efficacy / neuroprotection in our standard in vivo assay at 10 ⁇ concentration in four 12 week old adult male C57/B16 mice..
  • the compounds having formula (I) or a salt (e.g., a pharmaceutically acceptable salt) thereof provide at least about 19 (xlO 06 ) BrdU+ cells / mm 3 dentate gyrus when evaluated in the assay described in conjunction with Table 1.
  • the compounds having formula (I) or a salt (e.g., a pharmaceutically acceptable salt) thereof provide from about 18 to about 30 (e.g., 18-27, 19-26, 20-25, 27-30, 27-29) (xlO 06 ) BrdU+ cells / mm 3 dentate gyrus when evaluated in the assay described in conjunction with Table 1.
  • the compounds having formula (I) or a salt (e.g., a pharmaceutically acceptable salt) thereof provide from about 18 to about 26 (e.g., 19-26, 20-25) (xlO 06 ) BrdU+ cells / mm 3 dentate gyrus when evaluated in the assay described in conjunction with Table 1.
  • the compounds having formula (I) or a salt (e.g., a pharmaceutically acceptable salt) thereof provide from about 27 to about 30 (e.g., 27-29) (xlO 06 ) BrdU+ cells / mm 3 dentate gyrus when evaluated in the assay described in conjunction with Table 1.
  • a composition e.g., a pharmaceutical composition
  • any compound, composition, or method described herein can also include any one or more of the other features delineated in the detailed description and/or in the claims.
  • mammal includes organisms, which include mice, rats, cows, sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans.
  • an effective amount refers to an amount of a compound that confers a therapeutic effect (e.g., treats, e.g., controls, relieves, ameliorates, alleviates, or slows the progression of; or prevents, e.g., delays the onset of or reduces the risk of developing, a disease, disorder, or condition or symptoms thereof) on the treated subject.
  • the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • An effective amount of the compound described above may range from about 0.01 mg/kg to about 1000 mg/kg, (e.g., from about 0.1 mg/kg to about 100 mg/kg, from about 1 mg/kg to about 100 mg/kg). Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.
  • halo or halogen refers to any radical of fluorine, chlorine, bromine or iodine.
  • substituent (radical) prefix names are derived from the parent hydride by either (i) replacing the "ane” in the parent hydride with the suffixes "yl,” “diyl,” “triyl,” “tetrayl,” etc.; or (ii) replacing the "e” in the parent hydride with the suffixes "yl,” “diyl,” “triyl,” “tetrayl,” etc. (here the atom(s) with the free valence, when specified, is (are) given numbers as low as is consistent with any established numbering of the parent hydride).
  • Accepted contracted names e.g., adamantyl, naphthyl, anthryl, phenanthryl, furyl, pyridyl, isoquinolyl, quinolyl, and piperidyl, and trivial names, e.g., vinyl, allyl, phenyl, and thienyl are also used herein throughout.
  • Conventional numbering/lettering systems are also adhered to for substituent numbering and the nomenclature of fused, bicyclic, tricyclic, polycyclic rings.
  • radicals, substituents, and ranges are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
  • alkyl, alkoxy, alkenyl, and the like denote both straight and branched groups.
  • alkyl refers to a saturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms.
  • Ci-C6 alkyl indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it. Any atom can be optionally substituted, e.g., by one or more subsituents.
  • alkyl groups include without limitation methyl, ethyl, n-propyl, z ' opropyl, and teri-butyl.
  • straight chain C n . m alkylene refers to a non-branched divalent alkyl linking group having n to m carbon atoms. Any atom can be optionally substituted, e.g., by one or more subsituents. Examples include methylene (i.e., -CH 2 -).
  • haloalkyl refers to an alkyl group, in which at least one hydrogen atom is replaced by halo. In some embodiments, more than one hydrogen atom (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ) are replaced by halo. In these embodiments, the hydrogen atoms can each be replaced by the same halogen (e.g., fluoro) or the hydrogen atoms can be replaced by a combination of different halogens (e.g., fluoro and chloro).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Addiction (AREA)
  • Psychology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Indole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

De manière générale, cette technologie concerne des composés et des procédés pour stimuler la neurogenèse (par ex., neurogenèse post-natale, comprenant la neurogenèse hippocampique et hypothalamique post-natale) et/ou pour protéger la cellule neuronale de la mort cellulaire. Divers composés sont décrits. Des tests d'activité in vivo suggèrent que ces composés peuvent avoir des bénéfices thérapeutiques dans les maladies neuropsychiatriques et/ou neurodégénératives telles que la schizophrénie, la dépression majeure, le trouble bipolaire, le vieillissement normal, l'épilepsie, la lésion cérébrale d'origine traumatique, le stress post-traumatique, la maladie de Parkinson, la maladie d'Alzheimer, le syndrome de Down, l'ataxie spinocérébelleuse, la sclérose latérale amyotrophique, la maladie de Huntington, l'AVC, la radiothérapie, le stress chronique, l'abus de médicaments neuroactifs, la dégénérescence rétinienne, la lésion médullaire, la lésion d'un nerf périphérique, la perte de poids physiologique associée à diverses affections, ainsi que le déclin cognitif associé au vieillissement normal, la chimiothérapie, et autre.
EP12883358.9A 2012-08-24 2012-08-24 Composés pro-neurogènes Withdrawn EP2925129A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13/594,223 US9962368B2 (en) 2009-01-09 2012-08-24 Pro-neurogenic compounds
PCT/US2012/052283 WO2014031125A1 (fr) 2012-08-24 2012-08-24 Composés pro-neurogènes

Publications (2)

Publication Number Publication Date
EP2925129A1 true EP2925129A1 (fr) 2015-10-07
EP2925129A4 EP2925129A4 (fr) 2016-06-08

Family

ID=50150277

Family Applications (1)

Application Number Title Priority Date Filing Date
EP12883358.9A Withdrawn EP2925129A4 (fr) 2012-08-24 2012-08-24 Composés pro-neurogènes

Country Status (8)

Country Link
EP (1) EP2925129A4 (fr)
JP (1) JP6231566B2 (fr)
CN (2) CN108329253A (fr)
AU (2) AU2012388221B2 (fr)
BR (1) BR112015003919A2 (fr)
CA (1) CA2882923A1 (fr)
IL (1) IL237341A0 (fr)
WO (1) WO2014031125A1 (fr)

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2007139634A (ru) 2007-10-25 2009-04-27 Сергей Олегович Бачурин (RU) Новые тиазол-, триазол- или оксадиазол-содержащие тетрациклические соединения
RU2544856C2 (ru) 2008-01-25 2015-03-20 Сергей Олегович Бачурин НОВЫЕ ПРОИЗВОДНЫЕ 2,3,4,5-ТЕТРАГИДРО-1-ПИРИДО[4,3-b]ИНДОЛА И СПОСОБЫ ИХ ПРИМЕНЕНИЯ
US8546381B2 (en) 2008-03-24 2013-10-01 Medivation Technologies, Inc. Bridged heterocyclic compounds and methods of use
WO2009120717A2 (fr) 2008-03-24 2009-10-01 Medivation Technologies, Inc. Pyrido[3,4-b]indoles et leurs procédés d'utilisation
AU2009308708B2 (en) 2008-10-31 2015-11-19 Medivation Technologies, Inc. Azepino [4, 5-b] indoles and methods of use
US9962368B2 (en) 2009-01-09 2018-05-08 Board Of Regents Of The University Of Texas System Pro-neurogenic compounds
US9162980B2 (en) 2009-01-09 2015-10-20 Board Of Regents Of The University Of Texas System Anti-depression compounds
EP2385829B1 (fr) 2009-01-09 2018-08-01 Board of Regents of the University of Texas System Composés pro-neurogéniques
US8362277B2 (en) 2009-01-09 2013-01-29 Board Of Regents Of The University Of Texas System Pro-neurogenic compounds
CN102480955B (zh) 2009-04-29 2015-08-05 梅迪维新技术公司 吡啶并[4,3-b]吲哚类和使用方法
WO2011038163A1 (fr) 2009-09-23 2011-03-31 Medivation Technologies, Inc. Pyrido[3,4-b]indoles et leurs méthodes d'utilisation
WO2011038164A1 (fr) 2009-09-23 2011-03-31 Medivation Technologies, Inc. Composés hétérocycliques pontés et leurs méthodes d'utilisation
BR112012006640A2 (pt) 2009-09-23 2019-09-24 Medivation Technologies Inc composto, composição farmacêutica, método de tratamento de um distúrbio cognitivo, distúrbiopsocótico, distúrbio mediado por neurotransmissor ou um distúrbio neuronal e kit
WO2011103485A1 (fr) 2010-02-18 2011-08-25 Medivation Technologies, Inc. Dérivés de pyrido[4,3-b]indole et de pyrido[3,4-b]indole tétracycliques condensés et leurs procédés d'utilisation
WO2011103433A1 (fr) 2010-02-18 2011-08-25 Medivation Technologies, Inc. Pyrido[4,3-b]indole et dérivés de pyrido[3,4-b]indole et procédés d'utilisation
WO2011103460A1 (fr) 2010-02-18 2011-08-25 Medivation Technologies, Inc. Dérivés de pyrido[4,3-b]indole et pyrido[3,4-b]indole tétracyclique condensés et procédés d'utilisation
WO2011103430A1 (fr) 2010-02-19 2011-08-25 Medivation Technologies, Inc. Dérivés de pyrido[4,3-b]indole et de pyrido[3,4-b]indole et procédés d'utilisation
AU2011274787B2 (en) 2010-07-07 2016-06-16 Board Of Regents Of The University Of Texas System Pro-neurogenic compounds
JP2014505737A (ja) 2011-02-18 2014-03-06 メディベイション テクノロジーズ， インコーポレイテッド 糖尿病を処置する化合物および方法
WO2012112962A1 (fr) 2011-02-18 2012-08-23 Medivation Technologies, Inc. Composés et procédés de traitement du diabète
US9035056B2 (en) 2011-02-18 2015-05-19 Medivation Technologies, Inc. Pyrido[4,3-b]indole and pyrido[3,4-b]indole derivatives and methods of use
US9434747B2 (en) 2011-02-18 2016-09-06 Medivation Technologies, Inc. Methods of treating diabetes
AU2013259294B2 (en) * 2012-05-11 2017-04-06 Synchronicity Pharma, Inc. Carbazole-containing sulfonamides as cryptochrome modulators
US9701676B2 (en) 2012-08-24 2017-07-11 Board Of Regents Of The University Of Texas System Pro-neurogenic compounds
EP3068388A4 (fr) * 2013-11-11 2017-04-12 Board of Regents of the University of Texas System Composés neuroprotecteurs et leur utilisation
WO2015070237A1 (fr) 2013-11-11 2015-05-14 Board Of Regents Of The University Of Texas System Produits chimiques neuroprotecteurs et leurs procédés d'identification et d'utilisation
TWI690521B (zh) 2014-04-07 2020-04-11 美商同步製藥公司 作為隱花色素調節劑之含有咔唑之醯胺類、胺基甲酸酯類及脲類
JP7327039B2 (ja) * 2019-09-25 2023-08-16 富士通株式会社 活動量管理プログラム、活動量管理システム、及び活動量管理方法

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1094063A1 (fr) * 1999-10-18 2001-04-25 Applied Research Systems ARS Holding N.V. 9-(Pipérazinylalkyl)carbazoles comme modulateurs de Bax
AU2002228316A1 (en) * 2001-01-29 2002-08-12 Insight Strategy And Marketing Ltd Carbazole derivatives and their uses as heparanase inhibitors
US20070203236A1 (en) * 2006-01-11 2007-08-30 Smith Jeffrey W Novel antagonists of the human fatty acid synthase thioesterase
WO2009082268A2 (fr) * 2007-12-21 2009-07-02 Alla Chem, Llc Ligands dalpha-adrénorécepteurs, de récepteurs de dopamine, de l'histamine, d'imidazoline et de sérotonine ainsi que leurs procédés d'utilisation
RU2544856C2 (ru) * 2008-01-25 2015-03-20 Сергей Олегович Бачурин НОВЫЕ ПРОИЗВОДНЫЕ 2,3,4,5-ТЕТРАГИДРО-1-ПИРИДО[4,3-b]ИНДОЛА И СПОСОБЫ ИХ ПРИМЕНЕНИЯ
US8907097B2 (en) * 2008-10-31 2014-12-09 Medivation Technologies, Inc. Pyrido[4,3-b]indoles containing rigid moieties
EP2385829B1 (fr) * 2009-01-09 2018-08-01 Board of Regents of the University of Texas System Composés pro-neurogéniques
US8362277B2 (en) 2009-01-09 2013-01-29 Board Of Regents Of The University Of Texas System Pro-neurogenic compounds
WO2011054851A1 (fr) 2009-11-05 2011-05-12 Glaxosmithkline Llc Nouveau procédé
AU2011274787B2 (en) * 2010-07-07 2016-06-16 Board Of Regents Of The University Of Texas System Pro-neurogenic compounds

Also Published As

Publication number Publication date
AU2012388221B2 (en) 2017-08-31
CN108329253A (zh) 2018-07-27
IL237341A0 (en) 2015-04-30
JP2015529663A (ja) 2015-10-08
EP2925129A4 (fr) 2016-06-08
CN104754941B (zh) 2018-02-27
WO2014031125A1 (fr) 2014-02-27
BR112015003919A2 (pt) 2017-07-04
CA2882923A1 (fr) 2014-02-27
CN104754941A (zh) 2015-07-01
AU2017268635A1 (en) 2017-12-21
AU2012388221A1 (en) 2015-04-09
JP6231566B2 (ja) 2017-11-15

Similar Documents

Publication Publication Date Title
US20180318255A1 (en) Pro-Neurogenic Compounds
AU2012388221B2 (en) Pro-neurogenic compounds
US9884820B2 (en) Pro-neurogenic compounds
US10183011B2 (en) Anti-depression compounds
US9446042B2 (en) Pro-neurogenic compounds
CA2748813A1 (fr) Composes pro-neurogeniques

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20150310

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAX Request for extension of the european patent (deleted)
RA4 Supplementary search report drawn up and despatched (corrected)

Effective date: 20160506

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 31/405 20060101ALI20160429BHEP

Ipc: A01N 43/38 20060101AFI20160429BHEP

Ipc: C07D 209/82 20060101ALI20160429BHEP

17Q First examination report despatched

Effective date: 20170801

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20191114