US009095572B2

(12) United States Patent (10) Patent No.: US 9,095,572 B2 McKnight et al. (45) Date of Patent: * Aug. 4, 2015

(54) PRO-NEUROGENIC COMPOUNDS C07D 413/06 (2013.01); C07D 471/04 (2013.01); C07D 495/04 (2013.01); C07F (75) Inventors: Steven L. Might Dallas, TX (US); 5/022 (2013.01) AndrewJoseph M. A. Pieper,G. Carrollton, Plano, TX S.(US); is: (58) Field of Classification Search Jef K. De Brabander, Flower Mound, CPC ...... C07D 209/82: A61K 31/403 TX (US) USPC ...... 548/444; 514/411 See application file for complete search history. (73) Assignee: Board of Regents of The University of Texas System, Austin, TX (US) (56) References Cited (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S. PATENT DOCUMENTS U.S.C. 154(b) by 0 days. 3,409,628 A 1 1/1968 Berger et al. This patent is Subject to a terminal dis- 3,518.250 A 6, 1970 Schumaker laimer 5,306,609 A 4/1994 Mihayashi et al. C 6,187,785 B1 2/2001 Zefirov et al. 6,468,996 B1 10/2002 Jeppesen et al. (21) Appl. No.: 13/177,981 6,514,968 B1 2/2003 TenBrink 6,770,656 B2 8/2004 Halazy et al. (22) Filed: Jul. 7, 2011 6,835,513 B2 12/2004 Jubranet al. 6,849,640 B2 2/2005 Ennis et al. (65) Prior Publication Data 6,864,025 B2 3/2005 Law et al. US 2012/0022096 A1 Jan. 26, 2012 (Continued) FOREIGN PATENT DOCUMENTS Related U.S. Application Data CN 1.01139347 A 3, 2008 (63) Continuation-in-part of application No. 12/832,056, CN 101429198 A 5, 2009 filed on Jul. 7, 2010, now Pat. No. 8.362,277, which is o a continuation-in-part of application No. 12/685,652, (Continued) filed on Jan. 11, 2010. OTHER PUBLICATIONS (60) Provisional application No. 61/143,755, filed on Jan. 9, 2009. Pieper et al. (Cell, 142 (Jul. 9, 2010), p. 39-51).* (51) Int. Cl. (Continued) C07D 209/82 (2006.01) A6 IK3I/403 (2006.01) A6 IK3I/404 (2006.01) Primary Examiner — Robert Havlin A6 IK3I/4045 (2006.01) (74) Attorney, Agent, or Firm — Grenberg Traurig, LLP: A6 IK3I/437 (2006.01) David J. Dykeman; Fang Xie A6 IK3I/4439 (2006.01) A6 IK3I/506 (2006.01) C07D 209/08 (2006.01) (57) ABSTRACT CO7D 209/86209/88 30:2006.O1 8: This technology relates generally to compounds and methods CO7D 40/06 (2006.015 for stimulating neurogenesis (e.g., post-natal neurogenesis, CO7D 40/12 (2006.01) including post-natal hippocampal and hypothalamic neuro CO7D 403/06 (2006.01) genesis) and/or protecting neuronal cell from cell death. Vari CO7D 403/2 (2006.01) ous compounds are disclosed herein. In vivo activity tests CO7D 405/2 (2006.01) Suggest that these compounds may have therapeutic benefits CO7D 413/06 (2006.01) in neuropsychiatric and/or neurodegenerative diseases Such CO7D 47L/04 (2006.01) as Schizophrenia, major depression, bipolar disorder, normal CO7D 495/04 (2006.01) aging, epilepsy, traumatic brain injury, post-traumatic stress C07F 5/02 (2006.01) disorder, Parkinson's disease, Alzheimer's disease, Down (52) U.S. Cl. syndrome, spinocerebellar ataxia, amyotrophic lateral scle CPC ...... A6 IK3I/404 (2013.01); A61 K3I/403 rosis, Huntington's disease, stroke, radiation therapy, chronic (2013.01); A61K 31/4045 (2013.01); A61 K stress, abuse of a neuro-active drug, retinal degeneration, 31/437 (2013.01); A61 K3I/4439 (2013.01): spinal cord injury, peripheral nerve injury, physiological A61 K3I/506 (2013.01); C07D 209/08 weight loss associated with various conditions, as well as (2013.01); C07D 209/82 (2013.01); C07D cognitive decline associated with normal aging, chemo 209/86 (2013.01); C07D 209/88 (2013.01); therapy, and the like. C07D401/06 (2013.01); C07D401/12 (2013.01); C07D 403/06 (2013.01); C07D 403/12 (2013.01); C07D405/12 (2013.01); 43 Claims, 47 Drawing Sheets US 9,095,572 B2 Page 2

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US 9,095,572 B2 1. 2 PRO-NEUROGENC COMPOUNDS to enhance levels of adult neurogenesis in animals, including humans (Schmidt et al., Behav Pharmacol. 2007 September; CROSS REFERENCE TO RELATED 18(5-6):391-418; Boldrini et al., Neuropsychopharmacology APPLICATIONS 2009, 34,2376-2389). Among many genes reported to impact adult neurogenesis is the gene encoding neuronal PAS This application is a continuation-in-part application of domain protein 3 (NPAS3), a central nervous system (CNS)- U.S. application Ser. No. 12/832,056, filed on Jul. 7, 2010, specific transcription factor that has been associated with which is a continuation-in-part of U.S. application Ser. No. Schizophrenia and bipolar disorder (Kamnasaran et al., J. 12/685,652, filed on Jan. 11, 2010, which claims the benefit of Med. Genet. 2003, 40, 325-332: Pickard et al., Am. J. Med. and priority to U.S. Provisional Application No. 61/143,755, 10 Genet. B. Neuropsychiatr. Genet. 2005, 136B, 26-32: Pickard filed on Jan. 9, 2009; each of these prior applications is et al., Ann. Med. 2006, 38, 439-448; Pickard et al., Mol. incorporated herein by reference in its entirety. Psychiatry. 2009, 14, 874-884; Lavedan et al., Pharmacoge nomics 2008, 9: 289-301). Animals missing both copies of STATEMENT REGARDING FEDERALLY 15 the NPAS3 gene suffer a profound loss of adult hippocampal SPONSORED RESEARCH neurogenesis coupled with significant behavioral deficits (Pieper et al., Proc. Natl. Acad. Sci. USA 2005, 102, 14052 This invention was made with government Support under 14057). Knowing that impaired post-natal neurogenesis elic Grant Numbers 5DP1OD00027605, 5R37MH05938809, and its unfavorable phenotypic deficits, it is predicted that pro 1RO1MH087986, which were awarded by the National Insti neurogenic chemical compounds should exhibit favorable tute of Health; the Government has certain rights in the inven therapeutic benefits. tion.

TECHNICAL FIELD SUMMARY

25 This presently disclosed embodiments relate generally to This presently disclosed embodiments relate generally to the discovery of pro-neurogenic compounds capable of pro compounds that promote the generation or the Survival of moting neurogenesis and/or reducing neuronal cell death. existing neurons in the mammalian brain. For the purpose of BACKGROUND simplicity these compounds are referred to as being pro 30 neurogenic. In certain embodiments, the compounds promote It is now accepted that the adult vertebrate brain fosters the the generation or Survival of neurons in the post-natal mam birth and functional incorporation of newly formed neurons malian brain. In certain embodiments, the compounds pro (Goldman and Nottebohm, Proc Natl Acad Sci USA 1983, mote the Survival, growth, development and/or function of 80: 2390-2394; Paton and Nottebohm, Science 1984, 225, neurons, particularly CNS, brain, cerebral, and hippocampal 35 neurons. In certain embodiments, the compounds stimulate 1046-1048; Burd and Nottebohm, JComp Neurol 1985, 240: post-natal hippocampal neurogenesis, which while not wish 143-152). However, it was long thought that no new neurons ing to be bound by theory, is believed to representatherapeu could be added to the adult mammalian brain. This dogma tic target for a variety of neuropsychiatric and neurodegen was challenged in the 1960s when autoradiographic evi erative diseases, including (but not limited to) schizophrenia, dence of new neuron formation in the hippocampal dentate 40 major depression, bipolar disorder, normal aging, epilepsy, gyrus, olfactory bulb, and cerebral cortex of the adult rat was traumatic brain injury, post-traumatic stress disorder, Parkin presented (Altman, J. Science 1962, 135, 1127-1128; Alt son's disease, Alzheimer's disease, Down syndrome, spinoc man, J.J CompNeurol 1966, 128:431-474; Altman, Anat Rec erebellar ataxia, amyotrophic lateral sclerosis, Huntington's 1963, 145:573-591; Altman and Das, J. Comp. Neurol. 1965, 45 disease, stroke, radiation therapy, chronic stress, abuse of 124, 319-335; Altman and Das, J. Comp Neurol 1966, 126: neuro-active drugs (such as alcohol, opiates, methamphet 337-390). It is now accepted that within all mammalian spe amine, phencyclidine, and cocaine), retinal degeneration, spi cies, including humans (Eriksson et al., Nat. Med. 1998, nal cord injury, and peripheral nerve injury. In certain 4(11), 1313-1317), there are two major reservoirs of neuronal embodiments, the compounds stimulate post-natal hypotha stem cells, one located in the subgranular Zone (SGZ) of the 50 lamic neurogenesis, which can provide therapeutic benefits in hippocampal dentate gyms and another in the Subventricular weight management, such as physiological weight loss asso Zone (SVZ) (Gross, Natl. Rev. 2000, 1, 67-72). Neural stem ciated with various conditions, including but not limited to, cells in the SVZ facilitate formation of new neurons that normal aging, chemotherapy, radiation therapy, stress, drug migrate rostrally to populate the olfactory bulb, while neural abuse, anorexia, as well as other diseases discussed herein. stem cells in the SGZ produce neurons that integrate locally in 55 The presently disclosed embodiments also feature compo the granular layer of the dentate gyms, a region of the hip sitions (e.g., pharmaceutical compositions) that include Such pocampus that exhibits lifelong structural and functional compounds as well as methods of making, identifying, and plasticity. using Such compounds. Other features and advantages are The process of new neuron formation in the adult mouse 60 described in, or will be apparent from, the present specifica brain can be influenced by environmental, chemical and tion and accompanying drawings. genetic variables. As demonstrated by Gage and colleagues, Accordingly, in one aspect, methods for promoting post neurogenesis in the adult mouse brain is enhanced when natal mammalian neurogenesis and/or reducing neuronal cell animals are exposed to an enriched environment (Kemper death in a subject in need thereof are described, the method mann et al., Nature 1997, 386, 493-495) or able to exercise 65 comprising administering an effective amount of a compound voluntarily (van Praag et al., Nat. Neuro-sci. 1999, 2, 266 having formula (I) or a pharmaceutically acceptable salt 270). More recently, anti-depressant drugs have been shown thereof: US 9,095,572 B2 3 4 (ii) a bond that directly connects A in formula (I) to Z in (I) formula (I); R4 R A is: M (i) CR'R'', wherein each of R'' and R' is independently R3 C3 selected from hydrogen, halo, C-C alkyl, or OR; or X-R (ii) C=O; or R2 N (iii) C-C cycloalkylene that is (a) substituted with 1 oxo; V L-A and (b) optionally further substituted with from 1-4 R V independently selected R'; or L-Z2 10 (iv) heterocycloalkylene containing from 3-5 ring atoms, wherein from 1-2 of the ring atoms is independently wherein: selected from N, NH, N(C-C alkyl), O, and S; and each of R. R. R., and R is independently selected from wherein said heterocycloalkylene is (a) substituted with hydrogen, halo, hydroxyl, Sulfhydryl, C-C alkoxy, C-C, 15 1 oxo; and (b) is optionally further substituted with from thioalkoxy, C-C haloalkoxy, C-C thiohaloalkoxy, C-C, 1-4 independently selected R': alkyl, C-C haloalkyl, C-C alkynyl, cyclopropyl. —N. Z is: cyano. —NH2, —NH(C-C alkyl). —N(C-C alkyl). (i) NR'R''; or —NHC(O)(C-C alkyl), and nitro: (ii) C(O)NR'R''; or R and R' are defined according to (1), (2), (3), (4), or (5) (iii) OR'; or below: (iv) —S(O).R', wherein n is 0, 1, or 2 or (1) Rand R' together with C and C, respectively, form a (v) heterocycloalkenyl containing from 5-6 ring atoms, fused phenyl ring having formula (II): wherein from 1-3 of the ring atoms is independently selected from N, NH, N(C-C alkyl), NC(O)(C-C, 25 alkyl), O, and S; and wherein said heterocycloalkenyl is (II) optionally substituted with from 1-4 independently selected R': (vi) C-C aryl that is optionally substituted with from 1-4 independently selected R'; or 30 (vii) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C-C alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 inde pendently selected R'; or 35 (viii) Cs-Carylcycloalkyl, wherein: (1) the aryl portion is optionally substituted with from wherein each of R. R. R', and R is independently 1-4 independently selected R', and selected from hydrogen, halo, hydroxyl, Sulfhydryl, C-C, (2) the cycloalkyl portion is optionally substituted with alkoxy, C-C thioalkoxy, C-C haloalkoxy, C-C thioha from 1-4 independently selected R': loalkoxy, C-C alkyl, C-Chaloalkyl, C-C alkynyl, cyclo 40 O propyl. —N., cyano. —NH, -NH(C-C alkyl). —N(C- (ix) arylheterocyclyl containing from 8-14 ring atoms, C alkyl). - NHC(O)(C-C alkyl), and nitro; OR wherein: (2) each of R and R' is, independently, hydrogen, C-C, (1) the aryl portion from is optionally substituted with alkyl, or C-Chaloalkyl; OR from 1-4 independently selected R', and (3)R and R' together with C and C, respectively, form a 45 (2) from 1-2 of the ring atoms of the heterocyclyl portion fused heterocyclic ring containing from 5-6 ring atoms, is independently selected from N, NH, N(C-C, wherein from 1-2 of the ring atoms is independently selected alkyl), NC(O)(C-C alkyl), O, and S; and wherein from N, NH, N(C-C alkyl), NC(O)(C-C alkyl), O, and S; said heterocyclyl portion is optionally substituted and wherein said heterocyclic ring is optionally Substituted with from 1-3 independently selected R': with from 1-3 independently selected R'; OR 50 O (4) R and R' together with C and C, respectively, form a (X) heteroarylheterocyclyl containing from 8-14 ring fused C-C cycloalkyl ring that is optionally Substituted with atoms, wherein: from 1-4 independently selected R'; OR (1) from 1-2 of the ring atoms of the heteroaryl portion is (5) R and R' together with C, and C, respectively, form a independently selected from N, NH, N(C-C alkyl), fused heteroaryl ring containing from 5-6 ring atoms, wherein 55 O, and S; and wherein said heteroaryl portion is from 1-2 of the ring atoms is independently selected from N. optionally substituted with from 1-3 independently NH, N(C-C alkyl), O, and S; and wherein said heteroaryl selected R'; and ring is optionally substituted with from 1-3 independently (2) from 1-2 of the ring atoms of the heterocyclyl portion selected R: is independently selected from N, NH, N(C-C, L' is: 60 alkyl), NC(O)(C-C alkyl), O, and S; and wherein (i) C-C straight chain alkylene, which is optionally sub said heterocyclyl portion is optionally substituted stituted with from 1-2 independently selected R; or with from 1-3 independently selected R': (ii) a bond that directly connects N in the 5-membered ring O of formula (I) to A in formula (I); (xi) heteroarylcycloalkyl containing from 8-14 ring atoms, L is: 65 wherein: (i) C-C straight chain alkylene, which is optionally Sub (1) from 1-2 of the ring atoms of the heteroaryl portion is stituted with from 1-2 independently selected R; or independently selected from N, NH, N(C-C alkyl). US 9,095,572 B2 5 6 O, and S; and wherein said heteroaryl portion is R’ is: optionally substituted with from 1-3 independently (i) Co-C aryl that is optionally substituted with from 1-4 selected R'; and R; or (2) the cycloalkyl portion is optionally substituted with (ii) heteroaryl containing from 5-14 ring atoms, wherein from 1-4 independently selected R': 5 from 1-6 of the ring atoms is independently selected R is hydrogen; or C-C alkyl that is optionally substituted from N. NH, N(C-C alkyl), O, and S; and wherein said with hydroxyl or C-C alkoxy: heteroaryl is optionally substituted with from 1-4 R”; or (iii) C-C alkyl or C-C haloalkyl, each of which is each of R'' and R'' is independently selected from the optionally substituted with from 1-3 R' or substituents delineated collectively in (a) through (k) below: 10 (iv) Cs-Carylcycloalkyl, wherein: (a) hydrogen; (1) the aryl portion is optionally substituted with from (b) Co-C aryl that is optionally substituted with from 1-4 1-4 independently selected R', and R; (2) the cycloalkyl portion is optionally substituted with (c) heteroaryl containing from 5-14 ring atoms, wherein from 1-4 independently selected R': from 1-6 of the ring atoms is independently selected 15 O from N. NH, N(C-C alkyl), O, and S; and wherein said (V) arylheterocyclyl containing from 8-14 ring atoms, heteroaryl is optionally substituted with from 1-4 R: wherein: (1) the aryl portion from is optionally substituted with (d) C-C alkyl or C-Chaloalkyl, each of which is option from 1-4 independently selected R', and ally substituted with from 1-3 R': (2) from 1-2 of the ring atoms of the heterocyclyl portion (e) —C(O)(C-C alkyl). —C(O)(C-C haloalkyl), or is independently selected from N, NH, N(C-C, —C(O)C(C-C alkyl); alkyl), NC(O)(C-C alkyl), O, and S; and wherein (f) C-C alkenyl or C-C alkynyl: said heterocyclyl portion is optionally substituted (g) Cs-Carylcycloalkyl, wherein: with from 1-3 independently selected R': (1) the aryl portion is optionally substituted with from 25 O 1-4 independently selected R', and (vi) heteroarylheterocyclyl containing from 8-14 ring (2) the cycloalkyl portion is optionally substituted with atoms, wherein: (1) from 1-2 of the ring atoms of the heteroaryl portion is from 1-4 independently selected R': independently selected from N, NH, N(C-C alkyl). (h) arylheterocyclyl containing from 8-14 ring atoms, 30 O, and S; and wherein said heteroaryl portion is wherein: optionally substituted with from 1-3 independently (1) the aryl portion from is optionally substituted with selected R'; and from 1-4 independently selected R', and (2) from 1-2 of the ring atoms of the heterocyclyl portion (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C-C, is independently selected from N, NH, N(C-C, 35 alkyl), NC(O)(C-C alkyl), O, and S; and wherein alkyl). NC(O)(C-C alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted said heterocyclyl portion is optionally substituted with from 1-3 independently selected R': with from 1-3 independently selected R': O (i) heteroarylheterocyclyl containing from 8-14 ring (vii) heteroarylcycloalkyl containing from 8-14 ring atoms, wherein: 40 atoms, wherein: (1) from 1-2 of the ring atoms of the heteroaryl portion is (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(C-C alkyl). independently selected from N, NH, N(C-C alkyl), O, and S; and wherein said heteroaryl portion is O, and S; and wherein said heteroaryl portion is optionally substituted with from 1-3 independently optionally substituted with from 1-3 independently 45 selected R'; and selected R'; and (2) the cycloalkyl portion is optionally substituted with (2) from 1-2 of the ring atoms of the heterocyclyl portion from 1-4 independently selected R': is independently selected from N, NH, N(C-C, R is: alkyl). NC(O)(C-C alkyl), O, and S; and wherein (i) Co-C aryl that is optionally substituted with from 1-4 said heterocyclyl portion is optionally substituted 50 R; or with from 1-3 independently selected R': (ii) heteroaryl containing from 5-14 ring atoms, wherein () heteroarylcycloalkyl containing from 8-14 ring atoms, from 1-6 of the ring atoms is independently selected wherein: from N. NH, N(C-C alkyl), O, and S; and wherein said (1) from 1-2 of the ring atoms of the heteroaryl portion is heteroaryl is optionally substituted with from 1-4 R: independently selected from N, NH, N(C-C alkyl), 55 (iii) Cs-Carylcycloalkyl, wherein: O, and S; and wherein said heteroaryl portion is (1) the aryl portion is optionally substituted with from optionally substituted with from 1-3 independently 1-4 independently selected R', and selected R'; and (2) the cycloalkyl portion is optionally substituted with (2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R': 60 O from 1-4 independently selected R': (iv) arylheterocyclyl containing from 8-14 ring atoms, (k) C-C cycloalkyl or C-C cycloalkenyl, each of which wherein: is optionally substituted with from 1-4 independently (1) the aryl portion from is optionally substituted with selected R'; and from 1-4 independently selected R', and (1) C7-Caralkyl, wherein the aryl portion is optionally the 65 (2) from 1-2 of the ring atoms of the heterocyclyl portion aryl portion from is optionally substituted with from 1-4 is independently selected from N, NH, N(C-C, independently selected R', alkyl), NC(O)(C-C alkyl), O, and S; and wherein US 9,095,572 B2 7 8 said heterocyclyl portion is optionally substituted (O) (C-C alkyl), C-C alkoxy; C-C haloalkoxy; with from 1-3 independently selected R': C-C thioalkoxy; C-C thiohaloalkoxy; C-C alkyl, O and C-C haloalkyl: (v) heteroarylheterocyclyl containing from 8-14 ring R at each occurrence is, independently selected from halo, atoms, wherein: C-C alkoxy, C-C thioalkoxy, C-C haloalkoxy, C-C, (1) from 1-2 of the ring atoms of the heteroaryl portion is thiohaloalkoxy, C-C alkyl, C-Chaloalkyl, - NH, NH independently selected from N, NH, N(C-C alkyl), (C-C alkyl), N(C-C alkyl). —NHC(O)(C-C alkyl), and O, and S; and wherein said heteroaryl portion is cyano; optionally substituted with from 1-3 independently 10 R" at each occurrence is, independently selected from selected R'; and hydroxyl, C-C alkoxy, C-C thioalkoxy, C-Chaloalkoxy, (2) from 1-2 of the ring atoms of the heterocyclyl portion C-C thiohaloalkoxy, C-C alkyl, C-Chaloalkyl, -NH2, is independently selected from N, NH, N(C-C, —NH(C-C alkyl), N(C-C alkyl). —NHC(O)(C-C, alkyl), NC(O)(C-C alkyl), O, and S; and wherein 15 alkyl), and cyano; and said heterocyclyl portion is optionally substituted R at each occurrence is, independently selected from with from 1-3 independently selected R': hydroxyl, C-C alkoxy; C-C thioalkoxy; C-C, O haloalkoxy; C-C thiohaloalkoxy; —NH; —NH(C-C, (vi) heteroarylcycloalkyl containing from 8-14 ring atoms, alkyl); N(C-C alkyl); NHC(O)(C-C alkyl); cyano; wherein: —C(O)H; —C(O)(C-C alkyl); —C(O)(C-C haloalkyl); C(O)OH: –C(O)O(C-C alkyl); –C(O)NH; –C(O)NH (1) from 1-2 of the ring atoms of the heteroaryl portion is (C-C alkyl); C(O)N(C-C alkyl); SO(C-C alkyl); independently selected from N, NH, N(C-C alkyl). —SONH; SONHCC-C alkyl);—SON(C-C alkyl); O, and S; and wherein said heteroaryl portion is and L-(C-C alkylene)-Cy, where in L is a —O , optionally substituted with from 1-3 independently 25 —NH —NCH , —C(O)—, selected R'; and - C(O)NH-, - C(O)NCH, -NHC(O) or NCHC (2) the cycloalkyl portion is optionally substituted with (O)—, and Cy is a saturated, partially unsaturated or aromatic from 1-4 independently selected R': carbocyclic or heterocyclic ring system; R" at each occurrence is, independently selected from halo, 30 or a pharmaceutically acceptable salt thereof. hydroxyl, C-C alkoxy, C-C thioalkoxy, C-Chaloalkoxy, In some embodiments, one or more of (A), (B), or (C) C-C thiohaloalkoxy, oxo, thioxo. —NH, -N(C-C alkyl). apply. C-C alkyl, C-C haloalkyl, -NH2, —NH(C-C alkyl). (A) Provided that when R and R' are defined according to N(C-C alkyl). definition (3), then: —NHC(O)(C-C alkyl), and cyano; 35 (i) each of L' and L. must be C-C alkylene, which is R” at each occurrence is independently selected from the optionally substituted with from 1-2 independently selected substituents delineated in (aa) through (dd) below: R when A is CH; or (aa) C-C alkoxy; C-C haloalkoxy; C-C thioalkoxy; (ii) Z must be other than heteroaryl containing from 5-14 C-C, thiohaloalkoxy; —O—(CH), O 40 (e.g., 5-6 or 6) ring atoms, wherein from 1-6 of the ring atoms (CH2). H. —C-C alkyl, C-C haloalkyl, is independently selected from N, NH, N(C-C alkyl), O, and —NH(C-C alkyl), N(C-C alkyl). —NHC(O)(C- S; and wherein said heteroaryl is optionally substituted with Calkyl), wherein the alkyl portion of each is optionally from 1-4 independently selected R”; e.g., other than substi substituted with from 1-3 independently selected R: tuted pyridyl, e.g., other than pyridyl Substituted with C-C, (bb) halo: hydroxyl; cyano; nitro; NH; azido: sulfhy 45 alkyl (e.g., CH), e.g., other than 2 or 6-methylpyridyl. dryl; C-C alkenyl: C-C alkynyl; —C(O)H; —C(O) (B) Each of R" and R' cannot be optionally substituted (C-C alkyl); —C(O)(C-C haloalkyl); C(O)OH: naphthyl (e.g., each of R'' and R' cannot be unsubstituted —C(O)C(C-C alkyl); C(O)NH; C(O)NH(C- naphthyl). In embodiments, each of R'' and R'' is other than C alkyl); C(O)N(C-C alkyl). —SO(C-C alkyl); optionally Substituted naphthyl (e.g., unsubstituted naphthyl) 50 when R and R' are defined according to definitions (1), (2), —SONH; —SONHCC-C alkyl); —SON(C-C, and (4); and A is CR'R' (e.g., CHOR, e.g., CHOH), and alkyl). each of L' and L is C-C alkylene (e.g., each of L' and L is (cc) C-C cycloalkyl or heterocyclyl containing from 5-6 CH). ring atoms, wherein from 1-2 of the ring atoms of the (C) R' and/or R' cannot be substituted phenyl. In heterocyclyl is independently selected from N. NH, 55 embodiments, R'' and/or R' cannot be substituted phenyl N(C-C alkyl), NC(O)(C-C alkyl), O, and S; and when R and R' are defined according to definition (1); and A wherein each of said phenyl and heterocyclyl is option is CR'R' (e.g., CHOR, e.g., CHOH), and each of L' and ally substituted with from 1-3 independently selected L is C-C alkylene (e.g., each of L' and L is CH). R"; and 60 In some embodiments, (A), (B), or (C) applies. In other (dd) phenyl or heteroaryl containing from 5-6 ring atoms, embodiments, (A) and (B); or (A) and (C); or (B) and (C) wherein from 1-2 of the ring atoms of the heteroaryl is applies. In still other embodiments, (A), (B), and (C) apply. independently selected from N. NH, N(C-C alkyl), O, In another aspect, methods for promoting post-natal mam and S.; wherein each of said phenyl and heteroaryl is malian neurogenesis in a subject in need thereofare featured. optionally substituted with from 1-3 substituents inde 65 The method includes administering to the subject an effective pendently selected from halo: hydroxyl; cyano; nitro: amount of a compound having formula (I) or a pharmaceuti —NH; —NH(C-C alkyl), N(C-C alkyl). —NHC cally acceptable salt thereof. US 9,095,572 B2 9 10 (ii) a bond that directly connects A in formula (I) to Z in (I) formula (I); R4 R A is: M (i) CR'R'', wherein each of R'' and R' is independently R3 C3 5 selected from hydrogen, halo, C-C alkyl, or OR; or X-R (ii) C=O; or R2 N (iii) C-C cycloalkylene that is (a) substituted with 1 oxo; V L-A and (b) optionally further substituted with from 1-4 R V independently selected R'; or L-Z2 10 (iv) heterocycloalkylene containing from 3-5 ring atoms, wherein from 1-2 of the ring atoms is independently wherein: selected from N, NH, N(C-C alkyl), O, and S; and each of R. R. R., and R is independently selected from wherein said heterocycloalkylene is (a) substituted with hydrogen, halo, hydroxyl, Sulfhydryl, C-C alkoxy, C-C, 15 1 oxo; and (b) is optionally further substituted with from thioalkoxy, C-C haloalkoxy, C-C thiohaloalkoxy, C-C, 1-4 independently selected R': alkyl, C-C haloalkyl, cyano. —NH, -NH(C-C alkyl). Z is: —N(C-C alkyl). —NHC(O)(C-C alkyl), and nitro: (i) NR'R''; or R and R' are defined according to (1), (2), (3), (4), or (5) (ii) C(O)NR'R''; or below: (iii) OR'; or (iv) —S(O).R', wherein n is 0, 1, or 2 or (1) Rand R' together with C and C, respectively, form a (v) heterocycloalkenyl containing from 5-6 ring atoms, fused phenyl ring having formula (II): wherein from 1-3 of the ring atoms is independently selected from N, NH, N(C-C alkyl), NC(O)(C-C, 25 alkyl), O, and S; and wherein said heterocycloalkenyl is (II) optionally substituted with from 1-4 independently selected R': (vi) C-C aryl that is optionally substituted with from 1-4 independently selected R'; or 30 (vii) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C-C alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 inde pendently selected R'; or 35 (viii) Cs-Carylcycloalkyl, wherein: (1) the aryl portion is optionally substituted with from wherein each of R. R. R', and R is independently 1-4 independently selected R', and selected from hydrogen, halo, hydroxyl, Sulfhydryl, C-C, (2) the cycloalkyl portion is optionally substituted with alkoxy, C-C thioalkoxy, C-Chaloalkoxy, C-Chalothio from 1-4 independently selected R': alkoxy, C-C alkyl, C-C haloalkyl, cyano. —NH, -NH 40 O (C-C alkyl), N(C-C alkyl). —NHC(O)(C-C alkyl), and (ix) arylheterocyclyl containing from 8-14 ring atoms, nitro; OR wherein: (2) each of R and R' is, independently, hydrogen, C-C, (1) the aryl portion from is optionally substituted with alkyl, or C-Chaloalkyl; OR from 1-4 independently selected R', and (3)R and R' together with C and C, respectively, form a 45 (2) from 1-2 of the ring atoms of the heterocyclyl portion fused heterocyclic ring containing from 5-6 ring atoms, is independently selected from N, NH, N(C-C, wherein from 1-2 of the ring atoms is independently selected alkyl), NC(O)(C-C alkyl), O, and S; and wherein from N, NH, N(C-C alkyl), NC(O)(C-C alkyl), O, and S; said heterocyclyl portion is optionally substituted and wherein said heterocyclic ring is optionally Substituted with from 1-3 independently selected R': with from 1-3 independently selected R'; OR 50 O (4) R and R' together with C and C, respectively, form a (X) heteroarylheterocyclyl containing from 8-14 ring fused C-C cycloalkyl ring that is optionally Substituted with atoms, wherein: from 1-4 independently selected R'; OR (1) from 1-2 of the ring atoms of the heteroaryl portion is (5) R and R' together with C, and C, respectively, form a independently selected from N, NH, N(C-C alkyl), fused heteroaryl ring containing from 5-6 ring atoms, wherein 55 O, and S; and wherein said heteroaryl portion is from 1-2 of the ring atoms is independently selected from N. optionally substituted with from 1-3 independently NH, N(C-C alkyl), O, and S; and wherein said heteroaryl selected R'; and ring is optionally substituted with from 1-3 independently (2) from 1-2 of the ring atoms of the heterocyclyl portion selected R: is independently selected from N, NH, N(C-C, L' is: 60 alkyl), NC(O)(C-C alkyl), O, and S; and wherein (i) C-C straight chain alkylene, which is optionally sub said heterocyclyl portion is optionally substituted stituted with from 1-2 independently selected R; or with from 1-3 independently selected R': (ii) a bond that directly connects N in the 5-membered ring O of formula (I) to A in formula (I); (xi) heteroarylcycloalkyl containing from 8-14 ring atoms, L is: 65 wherein: (i) C-C straight chain alkylene, which is optionally Sub (1) from 1-2 of the ring atoms of the heteroaryl portion is stituted with from 1-2 independently selected R; or independently selected from N, NH, N(C-C alkyl). US 9,095,572 B2 11 12 O, and S; and wherein said heteroaryl portion is R’ is: optionally substituted with from 1-3 independently (i) Co-C aryl that is optionally substituted with from 1-4 selected R'; and R; or (2) the cycloalkyl portion is optionally substituted with (ii) heteroaryl containing from 5-14 ring atoms, wherein from 1-4 independently selected R': 5 from 1-6 of the ring atoms is independently selected R is hydrogen; or C-C alkyl that is optionally substituted from N. NH, N(C-C alkyl), O, and S; and wherein said with hydroxyl or C-C alkoxy: heteroaryl is optionally substituted with from 1-4 R”; or (iii) C-C alkyl or C-C haloalkyl, each of which is each of R'' and R'' is independently selected from the optionally substituted with from 1-3 R' or substituents delineated collectively in (a) through (k) below: 10 (iv) Cs-Carylcycloalkyl, wherein: (a) hydrogen; (1) the aryl portion is optionally substituted with from (b) Co-C aryl that is optionally substituted with from 1-4 1-4 independently selected R', and R; (2) the cycloalkyl portion is optionally substituted with (c) heteroaryl containing from 5-14 ring atoms, wherein from 1-4 independently selected R': from 1-6 of the ring atoms is independently selected 15 O from N. NH, N(C-C alkyl), O, and S; and wherein said (V) arylheterocyclyl containing from 8-14 ring atoms, heteroaryl is optionally substituted with from 1-4 R: wherein: (1) the aryl portion from is optionally substituted with (d) C-C alkyl or C-Chaloalkyl, each of which is option from 1-4 independently selected R', and ally substituted with from 1-3 R': (2) from 1-2 of the ring atoms of the heterocyclyl portion (e) —C(O)(C-C alkyl). —C(O)(C-C haloalkyl), or is independently selected from N, NH, N(C-C, —C(O)C(C-C alkyl); alkyl), NC(O)(C-C alkyl), O, and S; and wherein (f) C-C alkenyl or C-C alkynyl: said heterocyclyl portion is optionally substituted (g) Cs-Carylcycloalkyl, wherein: with from 1-3 independently selected R': (1) the aryl portion is optionally substituted with from 25 O 1-4 independently selected R', and (vi) heteroarylheterocyclyl containing from 8-14 ring (2) the cycloalkyl portion is optionally substituted with atoms, wherein: (1) from 1-2 of the ring atoms of the heteroaryl portion is from 1-4 independently selected R': independently selected from N, NH, N(C-C alkyl). (h) arylheterocyclyl containing from 8-14 ring atoms, 30 O, and S; and wherein said heteroaryl portion is wherein: optionally substituted with from 1-3 independently (1) the aryl portion from is optionally substituted with selected R'; and from 1-4 independently selected R', and (2) from 1-2 of the ring atoms of the heterocyclyl portion (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C-C, is independently selected from N, NH, N(C-C, 35 alkyl), NC(O)(C-C alkyl), O, and S; and wherein alkyl). NC(O)(C-C alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted said heterocyclyl portion is optionally substituted with from 1-3 independently selected R': with from 1-3 independently selected R': O (i) heteroarylheterocyclyl containing from 8-14 ring (vii) heteroarylcycloalkyl containing from 8-14 ring atoms, wherein: 40 atoms, wherein: (1) from 1-2 of the ring atoms of the heteroaryl portion is (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(C-C alkyl). independently selected from N, NH, N(C-C alkyl), O, and S; and wherein said heteroaryl portion is O, and S; and wherein said heteroaryl portion is optionally substituted with from 1-3 independently optionally substituted with from 1-3 independently 45 selected R'; and selected R'; and (2) the cycloalkyl portion is optionally substituted with (2) from 1-2 of the ring atoms of the heterocyclyl portion from 1-4 independently selected R': is independently selected from N, NH, N(C-C, R is: alkyl). NC(O)(C-C alkyl), O, and S; and wherein (i) Co-C aryl that is optionally substituted with from 1-4 said heterocyclyl portion is optionally substituted 50 R; or with from 1-3 independently selected R': (ii) heteroaryl containing from 5-14 ring atoms, wherein () heteroarylcycloalkyl containing from 8-14 ring atoms, from 1-6 of the ring atoms is independently selected wherein: from N. NH, N(C-C alkyl), O, and S; and wherein said (1) from 1-2 of the ring atoms of the heteroaryl portion is heteroaryl is optionally substituted with from 1-4 R: independently selected from N, NH, N(C-C alkyl), 55 (iii) Cs-Carylcycloalkyl, wherein: O, and S; and wherein said heteroaryl portion is (1) the aryl portion is optionally substituted with from optionally substituted with from 1-3 independently 1-4 independently selected R', and selected R'; and (2) the cycloalkyl portion is optionally substituted with (2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R': 60 O from 1-4 independently selected R': (iv) arylheterocyclyl containing from 8-14 ring atoms, (k) C-C cycloalkyl or C-C cycloalkenyl, each of which wherein: is optionally substituted with from 1-4 independently (1) the aryl portion from is optionally substituted with selected R'; and from 1-4 independently selected R', and (1) C7-Caralkyl, wherein the aryl portion is optionally the 65 (2) from 1-2 of the ring atoms of the heterocyclyl portion aryl portion from is optionally substituted with from 1-4 is independently selected from N, NH, N(C-C, independently selected R', alkyl), NC(O)(C-C alkyl), O, and S; and wherein US 9,095,572 B2 13 14 said heterocyclyl portion is optionally substituted R at each occurrence is, independently selected from halo, with from 1-3 independently selected R': C-C alkoxy, C-C thioalkoxy, C-C haloalkoxy, C-C, O thiohaloalkoxy, C-C alkyl, C-Chaloalkyl, - NH, -NH (v) heteroarylheterocyclyl containing from 8-14 ring (C-C alkyl), N(C-C alkyl). —NHC(O)(C-C alkyl), and atoms, wherein: cyano; (1) from 1-2 of the ring atoms of the heteroaryl portion is R" at each occurrence is, independently selected from independently selected from N, NH, N(C-C alkyl), hydroxyl, C-C alkoxy, C-C thioalkoxy, C-Chaloalkoxy, O, and S; and wherein said heteroaryl portion is C-C thiohaloalkoxy, C-C alkyl, C-Chaloalkyl, -NH2, optionally substituted with from 1-3 independently 10 —NH(C-C alkyl), N(C-C alkyl). - NHC(O)(C-C, selected R'; and alkyl), and cyano; and (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C-C, R at each occurrence is, independently selected from alkyl). NC(O)(C-C alkyl), O, and S; and wherein hydroxyl, C-C alkoxy; C-C thioalkoxy; C-C, said heterocyclyl portion is optionally substituted 15 haloalkoxy; C-C thiohaloalkoxy; —NH; —NH(C-C, with from 1-3 independently selected R': alkyl); N(C-C alkyl); NHC(O)(C-C alkyl); cyano; O —C(O)H; —C(O)(C-C alkyl); —C(O)(C-C haloalkyl); (vi) heteroarylcycloalkyl containing from 8-14 ring atoms, C(O)OH: –C(O)O(C-C alkyl); –C(O)NH; C(O)NH wherein: (C-C alkyl); C(O)N(C-C alkyl); SO(C-C alkyl); (1) from 1-2 of the ring atoms of the heteroaryl portion is —SONH;—SONH(C-C alkyl);—SON(C-C alkyl); independently selected from N, NH, N(C-C alkyl). and L-(C-C alkylene)-Cy, where in L is a —O , O, and S; and wherein said heteroaryl portion is —NH —NCH , —C(O)—, optionally substituted with from 1-3 independently - C(O)NH-, - C(O)NCH, -NHC(O) or NCHC selected R'; and 25 (O)—, and Cy is a saturated, partially unsaturated or aromatic (2) the cycloalkyl portion is optionally substituted with carbocyclic or heterocyclic ring system; from 1-4 independently selected R': or a salt (e.g., pharmaceutically acceptable salt) thereof. Rateach occurrence is, independently selected from halo, In some embodiments, one or more of (A), (B), or (C) hydroxyl, C-C alkoxy, C-C thioalkoxy, C-Chaloalkoxy, 30 apply. C-C thiohaloalkoxy, oxo, thioxo, =NH, =NCC-C alkyl). (A) Provided that when R and R' are defined according to C-C alkyl, C-C haloalkyl, -NH, -NH(C-C alkyl). definition (3), then: N(C-C alkyl). —NHC(O)(C-C alkyl), and cyano; (i) each of L' and L’ must be C-C alkylene, which is R” at each occurrence is independently selected from the optionally substituted with from 1-2 independently selected substituents delineated in (aa) through (dd) below: 35 R when A is CH; or (aa) C-C alkoxy: C-C haloalkoxy; C-C thioalkoxy; (ii) Z must be other than heteroaryl containing from 5-14 C-C thiohaloalkoxy; C-C alkyl, C-C haloalkyl, (e.g., 5-6 or 6) ring atoms, wherein from 1-6 of the ring atoms —NH(C-C alkyl), N(C-C alkyl). —NHC(O)(C- is independently selected from N, NH, N(C-C alkyl), O, and Calkyl), wherein the alkyl portion of each is optionally 40 S; and wherein said heteroaryl is optionally substituted with substituted with from 1-3 independently selected R: from 1-4 independently selected R'; e.g., other than substi (bb) halo: hydroxyl; cyano; nitro; NH; azido: sulfhy tuted pyridyl, e.g., other than pyridyl Substituted with C-C, dryl; C-C alkenyl: C-C alkynyl; —C(O)H; —C(O) alkyl (e.g., CH), e.g., other than 2 or 6-methylpyridyl. (C-C alkyl); —C(O)(C-C haloalkyl); C(O)CH: (B) Each of R" and R' cannot be optionally substituted - C(O)O(C-C alkyl); –C(O)NH; C(O)NH(C-C, 45 naphthyl (e.g., each of R'' and R' cannot be unsubstituted alkyl); C(O)N(C-C alkyl); —SO(C-C alkyl); naphthyl). In embodiments, each of R'' and R'' is other than —SONH; —SONHCC-C alkyl); —SON(C-C, optionally Substituted naphthyl (e.g., unsubstituted naphthyl) alkyl). when R and R' are defined according to definitions (1), (2), (cc) C-C cycloalkyl or heterocyclyl containing from 5-6 and (4); and A is CR'R' (e.g., CHOR, e.g., CHOH), and ring atoms, wherein from 1-2 of the ring atoms of the 50 each of L' and L is C-C alkylene (e.g., each of L' and L is heterocyclyl is independently selected from N. NH, CH). N(C-C alkyl), NC(O)(C-C alkyl), O, and S; and (C) R' and/or R' cannot be substituted phenyl. In wherein each of said phenyl and heterocyclyl is option embodiments, R'' and/or R' cannot be substituted phenyl when R and R' are defined according to definition (1); and A ally substituted with from 1-3 independently selected 55 is CR'R' (e.g., CHOR, e.g., CHOH), and each of L' and R"; and L is C-C alkylene (e.g., each of L' and L is CH). (dd) phenyl or heteroaryl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heteroaryl is In embodiments, (A), (B), or (C) applies. In other embodi independently selected from N. NH, N(C-C alkyl), O, ments, (A) and (B); or (A) and (C); or (B) and (C) applies. In 60 still other embodiments, (A), (B), and (C) apply. and S.; wherein each of said phenyl and heteroaryl is In another aspect, methods for promoting post-natal mam optionally substituted with from 1-3 substituents inde malian neurogenesis in a subject in need thereofare featured. pendently selected from halo: hydroxyl; cyano; nitro: The methods include administering to the subject an effective —NH; —NH(C-C alkyl), N(C-C alkyl). —NHC amount of a compound having formula (I) or a pharmaceuti (O)(C-C alkyl), C-C alkoxy: C-C haloalkoxy: 65 cally acceptable salt thereof, in which RandR' together with C-C thioalkoxy; C-C thiohaloalkoxy; C-C alkyl, C and C, respectively, form a fused phenyl ring having and C-C haloalkyl, formula (II): US 9,095,572 B2 15 16 nefazadone, bupropion, mirtazapine, lithium and traZodone) (II) and acetylcholinesterase inhibitors (including but not limited R6 to Aricept, Reminyl, and Exelon). In another aspect, dosage forms are featured, which R N R7 includes from about 0.05 milligrams to about 2,000 milli grams (e.g., from about 0.1 milligrams to about 1,000 milli R8. grams, 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 10 milligrams to about 50 milligrams, or from about 0.1 milli grams to about 25 milligrams) of a compound of formula (I) (and/or a compound of any of the other formulae described For purposes of clarification, it is understood that com herein) or a salt (e.g., a pharmaceutically acceptable salt) pounds in which R and R together with C and C, respec thereof as defined anywhere herein. The dosage forms can tively, form a fused phenyl ring having formula (II) corre 15 further include a pharmaceutically acceptable carrier and/or spond to compounds having the following general formula: an additional therapeutic agent. In one aspect, the compounds of formula (I) themselves (and/or a compound of any of the other formulae described (III) herein) or a salt (e.g., a pharmaceutically acceptable salt) thereofas defined anywhere herein are featured. In another aspect, any of the formula (I) compounds specifically described herein are featured. In one aspect, compounds having formula (I) are featured.

25 (I) R4

3 R C3 R 30 Yo-R in which R', R. R. R. L., L, A, and Z can be as defined 2 N^ anywhere herein. R V In embodiments, (A), (B), or (C) applies. In other embodi L-A ments, (A) and (B); or (A) and (C); or (B) and (C) applies. In R M still other embodiments, (A), (B), or (C) apply. 35 In another aspect, methods for promoting post-natal mam malian neurogenesis in a subject in need thereofare featured. wherein: The method includes administering to the subject an effective each of R. R. R. and R is independently selected from amount of a compound having formula (I) or a pharmaceuti hydrogen, halo, hydroxyl, Sulfhydryl, C-C alkoxy, C-C, cally acceptable salt thereof, in which: 40 thioalkoxy, C-C haloalkoxy, C-C thiohaloalkoxy, C-C, each of L' and L is CH: alkyl, C-C haloalkyl, C-C alkynyl, cyclopropyl. —N. A is CR'R'', wherein one of R and R is OR, and the cyano, other is hydrogen; —NH, -NH(C-C alkyl). —N(C-C alkyl). —NHC(O) Z is NR'R''; and (C-C alkyl), and nitro: each of R'' and R' is independently selected from 45 R and R' are defined according to (1) or (2) below: (a) hydrogen; (1) RandR together with C and C, respectively, form a (b) C-C aryl that is optionally substituted with from 1-4 fused phenyl ring having formula (II): R; (d) C-C alkyl or C-Chaloalkyl, each of which is option ally substituted with from 1-3 R': 50 (II) (f) C-C alkenyl or C-C alkynyl. In embodiments, (A), (B), or (C) applies. In other embodi ments, (A) and (B); or (A) and (C); or (B) and (C) applies. In still other embodiments, (A), (B), and (C) apply. In one aspect, compositions (e.g., a pharmaceutical com 55 position) are featured, 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) thereofas defined anywhere herein and a pharmaceutically acceptable carrier. In some embodiments, the compositions 60 can include an effective amount of the compound or salt. In wherein each of R. R. R', and R is independently Some embodiments, the compositions can further include one selected from hydrogen, halo, hydroxyl, Sulfhydryl, C-C, or more additional therapeutic agents. These may include, but alkoxy, C-C thioalkoxy, C-C haloalkoxy, C-C thioha are not limited to, antidepressant medications (including loalkoxy, C-C alkyl, C, Chaloalkyl, C-C alkynyl, cyclo selective serotonin reuptake inhibitors, tricyclic antidepres 65 propyl. —N, cyano, sants, monoamine oxidase inhibitors, and other antidepres —NH, -NH(C-C alkyl). —N(C-C alkyl). —NHC(O) sant medications including but not limited to Venlafaxine, (C-C alkyl), and nitro; OR US 9,095,572 B2 17 18 (2) R and R' together with C and C, respectively, form a alkyl), NC(O)(C-C alkyl), O, and S; and wherein fused Rand R together with C and C, respectively, form a said heterocyclyl portion is optionally substituted fused heteroaryl ring containing 6 ring atoms, wherein from with from 1-3 independently selected R': 1-2 independently selected ring atoms is N., and wherein said O heteroaryl ring is optionally substituted with from 1-2 inde 5 pendently selected R': (xi) heteroarylcycloalkyl containing from 8-14 ring atoms, each of L' and L is, independently, C-C alkylene, which wherein: is optionally substituted with from 1-2 independently (1) from 1-2 of the ring atoms of the heteroaryl portion is selected R: independently selected from N, NH, N(C-C alkyl). A is: 10 O, and S; and wherein said heteroaryl portion is (i) CR'R'', wherein each of R'' and R' is independently optionally substituted with from 1-3 independently selected from hydrogen, halo, C-C alkyl, and OR, selected R'; and wherein R is hydrogen or C-C alkyl that is optionally (2) the cycloalkyl portion is optionally substituted with substituted with hydroxyl or C-C alkoxy; or from 1-4 independently selected R': (ii) C=O; or 15 each of R'' and R'' is independently selected from the (iii) C-C cycloalkylene that is (a) substituted with 1 oxo; substituents delineated collectively in (a) through (k) below: and (b) optionally further substituted with from 1-4 (a) hydrogen; independently selected R'; or (iv) heterocycloalkylene containing from 3-5 ring atoms, (b) S-C aryl that is optionally substituted with from 1-4 wherein from 1-2 of the ring atoms is independently R; selected from N, NH, N(C-C alkyl), O, and S; and (c) heteroaryl containing from 5-14 ring atoms, wherein wherein said heterocycloalkylene is (a) substituted with from 1-6 of the ring atoms is independently selected 1 oxo; and (b) is optionally further substituted with from from N. NH, N(C-C alkyl), O, and S; and wherein said 1-4 independently selected R': heteroaryl is optionally substituted with from 1-4 R: Z is: 25 (d) C-C alkyl or C-Chaloalkyl, each of which is option (i) NR'R''; or ally substituted with from 1-3 R' (ii) C(O)NR'R''; or (e) —C(O)(C-C alkyl), —C(O)(C-C haloalkyl), or (iii) OR'; or —C(O)C(C-C alkyl); (iv)—S(O),R', wherein n is 0, 1, or 2 or (f) C-C alkenyl or C-C alkynyl: (v) heterocycloalkenyl containing from 5-6 ring atoms, 30 (g) Cs-Carylcycloalkyl, wherein: wherein from 1-3 of the ring atoms is independently selected from N, NH, N(C-C alkyl), NC(O)(C-C, (1) the aryl portion is optionally substituted with from alkyl), O, and S; and wherein said heterocycloalkenyl is 1-4 independently selected R', and optionally substituted with from 1-4 independently (2) the cycloalkyl portion is optionally substituted with selected R': 35 from 1-4 independently selected R': (vi) C-C aryl that is optionally substituted with from 1-4 (h) arylheterocyclyl containing from 8-14 ring atoms, independently selected R'; or wherein: (vii) heteroaryl containing from 5-14 ring atoms, wherein (1) the aryl portion from is optionally substituted with from 1-6 of the ring atoms is independently selected from 1-4 independently selected R', and from N, NH, N(C-C alkyl), O, and S; and wherein said 40 (2) from 1-2 of the ring atoms of the heterocyclyl portion heteroaryl is optionally substituted with from 1-4 inde is independently selected from N, NH, N(C-C, pendently selected R'; or alkyl), NC(O)(C-C alkyl), O, and S; and wherein (viii) Cs-Carylcycloalkyl, wherein: said heterocyclyl portion is optionally substituted (1) the aryl portion is optionally substituted with from with from 1-3 independently selected R': 1-4 independently selected R', and 45 (2) the cycloalkyl portion is optionally substituted with (i) heteroarylheterocyclyl containing from 8-14 ring from 1-4 independently selected R': atoms, wherein: O (1) from 1-2 of the ring atoms of the heteroaryl portion is (ix) arylheterocyclyl containing from 8-14 ring atoms, independently selected from N, NH, N(C-C alkyl), wherein: 50 O, and S; and wherein said heteroaryl portion is (1) the aryl portion from is optionally substituted with optionally substituted with from 1-3 independently from 1-4 independently selected R', and selected R'; and (2) from 1-2 of the ring atoms of the heterocyclyl portion (2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C-C, is independently selected from N, NH, N(C-C, alkyl). NC(O)(C-C alkyl), O, and S; and wherein 55 alkyl), NC(O)(C-C alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted said heterocyclyl portion is optionally substituted with from 1-3 independently selected R': with from 1-3 independently selected R': O (j) heteroarylcycloalkyl containing from 8-14 ring atoms, (X) heteroarylheterocyclyl containing from 8-14 ring wherein: atoms, wherein: 60 (1) from 1-2 of the ring atoms of the heteroaryl portion is (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(C-C alkyl). independently selected from N, NH, N(C-C alkyl), O, and S; and wherein said heteroaryl portion is O, and S; and wherein said heteroaryl portion is optionally substituted with from 1-3 independently optionally substituted with from 1-3 independently selected R'; and 65 selected R'; and (2) from 1-2 of the ring atoms of the heterocyclyl portion (2) the cycloalkyl portion is optionally substituted with is independently selected from N, NH, N(C-C, from 1-4 independently selected R': US 9,095,572 B2 19 20 (k) C-C cycloalkyl or C-C cycloalkenyl, each of which (2) the cycloalkyl portion is optionally substituted with is optionally substituted with from 1-4 independently from 1-4 independently selected R': selected R'; and O (1) C7-Caralkyl, wherein the aryl portion is optionally the (iv) arylheterocyclyl containing from 8-14 ring atoms, aryl portion from is optionally substituted with from 1-4 wherein: independently selected R', (1) the aryl portion from is optionally substituted with provided that one of R'' and R' must be selected from (b). from 1-4 independently selected R', and (c), (g), (h), (i), (), and (k); (2) from 1-2 of the ring atoms of the heterocyclyl portion R’ is: is independently selected from N, NH, N(C-C, 10 alkyl), NC(O)(C-C alkyl), O, and S; and wherein (i) C-C aryl that is optionally substituted with from 1-4 said heterocyclyl portion is optionally substituted R; or with from 1-3 independently selected R': (ii) heteroaryl containing from 5-14 ring atoms, wherein O from 1-6 of the ring atoms is independently selected (v) heteroarylheterocyclyl containing from 8-14 ring from N, NH, N(C-C alkyl), O, and S; and wherein said 15 atoms, wherein: heteroaryl is optionally substituted with from 1-4 R”; or (1) from 1-2 of the ring atoms of the heteroaryl portion is (iii) C-C alkyl or C-C haloalkyl, each of which is sub independently selected from N, NH, N(C-C alkyl). stituted with from 1-3 R': O, and S; and wherein said heteroaryl portion is (iv) Cs-Carylcycloalkyl, wherein: optionally substituted with from 1-3 independently (1) the aryl portion is optionally substituted with from selected R'; and 1-4 independently selected R', and (2) from 1-2 of the ring atoms of the heterocyclyl portion (2) the cycloalkyl portion is optionally substituted with is independently selected from N, NH, N(C-C, from 1-4 independently selected R': alkyl), NC(O)(C-C alkyl), O, and S; and wherein O said heterocyclyl portion is optionally substituted (V) arylheterocyclyl containing from 8-14 ring atoms, 25 with from 1-3 independently selected R': wherein: O (1) the aryl portion from is optionally substituted with (vi) heteroarylcycloalkyl containing from 8-14 ring atoms, from 1-4 independently selected R', and wherein: (2) from 1-2 of the ring atoms of the heterocyclyl portion (1) from 1-2 of the ring atoms of the heteroaryl portion is 30 independently selected from N, NH, N(C-C alkyl), is independently selected from N, NH, N(C-C, O, and S; and wherein said heteroaryl portion is alkyl), NC(O)(C-C alkyl), O, and S; and wherein optionally substituted with from 1-3 independently said heterocyclyl portion is optionally substituted selected R'; and with from 1-3 independently selected R': (2) the cycloalkyl portion is optionally substituted with O 35 from 1-4 independently selected R': (vi) heteroarylheterocyclyl containing from 8-14 ring Rateach occurrence is, independently selected from halo, atoms, wherein: hydroxyl, C-C alkoxy, C-C thioalkoxy, C-Chaloalkoxy, (1) from 1-2 of the ring atoms of the heteroaryl portion is C-C thiohaloalkoxy, oxo, thioxo, =NH, =NCC-C alkyl). independently selected from N, NH, N(C-C alkyl), C-C alkyl, C-C haloalkyl, -NH2, —NH(C-C alkyl). O, and S; and wherein said heteroaryl portion is 40 N(C-C alkyl). optionally substituted with from 1-3 independently —NHC(O)(C-C alkyl), and cyano; selected R'; and R” at each occurrence is independently selected from the (2) from 1-2 of the ring atoms of the heterocyclyl portion substituents delineated in (aa) through (dd) below: is independently selected from N, NH, N(C-C, (aa) C-C alkoxy; C-C haloalkoxy; C-C thioalkoxy; alkyl). NC(O)(C-C alkyl), O, and S; and wherein 45 C-C thiohaloalkoxy; —O-(CH2)-(CH2) - said heterocyclyl portion is optionally substituted H; —C-C alkyl, C-Chaloalkyl, with from 1-3 independently selected R': —NH(C-C alkyl), N(C-C alkyl). —NHC(O)(C- O Calkyl), wherein the alkyl portion of each is optionally (vii) heteroarylcycloalkyl containing from 8-14 ring substituted with from 1-3 independently selected R: atoms, wherein: 50 (bb) halo: hydroxyl; cyano; nitro; —NH; azido: sulfhy (1) from 1-2 of the ring atoms of the heteroaryl portion is dryl; C-C alkenyl: C-C alkynyl: —C(O)H; —C(O) independently selected from N, NH, N(C-C alkyl). (C-C alkyl); —C(O)(C-C haloalkyl); C(O)OH: O, and S; and wherein said heteroaryl portion is —C(O)O(C-C alkyl); C(O)NH; C(O)NH(C-C, optionally substituted with from 1-3 independently alkyl); C(O)N(C-C alkyl); SO(C-C alkyl); selected R'; and 55 —SONH; —SONHC-C alkyl); —SON(C-C, (2) the cycloalkyl portion is optionally substituted with alkyl). from 1-4 independently selected R': (cc) C-C cycloalkyl or heterocyclyl containing from 5-6 R is: ring atoms, wherein from 1-2 of the ring atoms of the (i) Co-C aryl that is optionally substituted with from 1-4 heterocyclyl is independently selected from N. NH, R; or 60 N(C-C alkyl), NC(O)(C-C alkyl), O, and S; and (ii) heteroaryl containing from 5-14 ring atoms, wherein wherein each of said phenyl and heterocyclyl is option from 1-6 of the ring atoms is independently selected ally substituted with from 1-3 independently selected from N, NH, N(C-C alkyl), O, and S; and wherein said R"; and heteroaryl is optionally substituted with from 1-4 R: (dd) phenyl or heteroaryl containing from 5-6 ring atoms, (iii) Cs-Carylcycloalkyl, wherein: 65 wherein from 1-2 of the ring atoms of the heteroaryl is (1) the aryl portion is optionally substituted with from independently selected from N. NH, N(C-C alkyl), O, 1-4 independently selected R', and and S.; wherein each of said phenyl and heteroaryl is US 9,095,572 B2 21 22 optionally substituted with from 1-3 substituents inde In one aspect, compounds having formula (I) are featured. pendently selected from halo: hydroxyl; cyano; nitro: —NH; —NH(C-C alkyl), N(C-C alkyl). —NHC (O) (C-C alkyl), C-C alkoxy; C-C haloalkoxy; (I) C-C thioalkoxy; C-C thiohaloalkoxy; C-C alkyl, R4 3 and C-C haloalkyl, R C3, R at each occurrence is, independently selected from halo, Y-RM C-C alkoxy, C-C thioalkoxy, C-C haloalkoxy, C-C, 2 N^ thiohaloalkoxy, C-C alkyl, C-Chaloalkyl, - NH, NH 10 R V L-A (C-C alkyl), N(C-C alkyl). —NHC(O)(C-C alkyl), and R V cyano; R at each occurrence is, independently selected from hydroxyl, C-C alkoxy, C-C thioalkoxy, C-Chaloalkoxy, 15 wherein: C-C thiohaloalkoxy, C-C alkyl, C-Chaloalkyl, -NH2, each of R. R. R. and R is independently selected from —NH(C-C alkyl), N(C-C alkyl). —NHC(O)(C-C, hydrogen, halo, hydroxyl, Sulfhydryl, C-C alkoxy, C-C, alkyl), and cyano; and thioalkoxy, C-C haloalkoxy, C-C thiohaloalkoxy, C-C, alkyl, C-C haloalkyl, C-C alkynyl, cyclopropyl. —N. R at each occurrence is, independently selected from cyano, hydroxyl, C-C alkoxy; C-C thioalkoxy; C-C, —NH, -NH(C-C alkyl), N(C-C alkyl). - NHC(O) haloalkoxy; C-C thiohaloalkoxy; —NH; —NH(C-C, (C-C alkyl), and nitro: alkyl); N(C-C alkyl); NHC(O)(C-C alkyl); cyano; R and R' are defined according to (1) or (2) below: —C(O)H; —C(O)(C-C alkyl); —C(O)(C-C haloalkyl); (1) RandR' together with C, and C, respectively, form a C(O)CH; C(O)O(C-C alkyl); –C(O)NH; –C(O)NH 25 fused phenyl ring having formula (II): (C-C alkyl); C(O)N(C-C alkyl); —SO(C-C alkyl); —SONH; SONHCC-C alkyl);—SON(C-C alkyl); (II) and L-(C-C alkylene)-biotin, where in L is a —O , 30

or a pharmaceutically acceptable salt thereof.

In embodiments, 1, 2, 3, 4, 5, or 6 of the following can 35 apply provided that RandR cannot both behydrogen when A is CH, and R and R' are defined according to definition wherein each of R. R. R', and R is independently (1): 40 selected from hydrogen, halo, hydroxyl, sulfhydryl, C-C, alkoxy, C-C thioalkoxy, C-C haloalkoxy, C-C thioha provided that R cannot behydrogen when A is CH, andR loalkoxy, C-C alkyl, C-Chaloalkyl, C-C alkynyl, cyclo and R' are defined according to definition (2): propyl. —N, cyano, provided that R and R cannot both be chloro when A is —NH —NH(C-C alkyl). —N(C-C alkyl). —NHC 45 (O)(C-C alkyl), and nitro; OR CHR and R' are defined according to definition (1), Z (2) RandR together with C and C, respectively, form a is —OR'', and R' is unsubstituted phenyl: fused Rand R together with C and C, respectively, form a provided that R and R' cannot both be bromo when A is fused heteroaryl ring containing 6 ring atoms, wherein from CHR and R' are defined according to definition (1), Z 1-2 independently selected ring atoms is N., and wherein said 50 heteroaryl ring is optionally substituted with from 1-2 inde is —OR'', and R' is phenyl that is substituted with pendently selected R': pyridyl or alkyl that is substituted with from 1-3 R: each of L' and L is, independently, C-C alkylene, which provided that RandR cannot both behydrogen when A is is optionally substituted with from 1-2 independently CH(CH), R and R' are defined according to definition selected R: (1), Z is NR'R'', R' is CH, and R'' is unsubstituted 55 A is: phenyl: (i) CR'R'', wherein each of R'' and R' is independently selected from hydrogen, halo, C-C alkyl, and OR, provided that when A is CR'R'', and one of R'' and R' wherein R is C-C alkyl that is optionally substituted is OH (i.e., R is H), then the other of R' and R' is with hydroxyl or C-C alkoxy; or C-C alkyl. 60 (ii) C=O; or (iii) C-C cycloalkylene that is (a) substituted with 1 oxo; and (b) optionally further substituted with from 1-4 In another aspect, pharmaceutical compositions are fea independently selected R'; or tured that include the above-described compounds (or salts (iv) heterocycloalkylene containing from 3-5 ring atoms, thereofas described herein) and a pharmaceutically accept 65 wherein from 1-2 of the ring atoms is independently able carrier. In embodiments, 1, 2, 3, 4, 5, or 6 of the above selected from N, NH, N(C-C alkyl), O, and S; and described provisions can apply. wherein said heterocycloalkylene is (a) substituted with US 9,095,572 B2 23 24 1 oxo; and (b) is optionally further substituted with from (d) C-C alkyl or C-Chaloalkyl, each of which is option 1-4 independently selected R': ally substituted with from 1-3 R' Z is: (e) —C(O)(C-C alkyl), —C(O)(C-C haloalkyl), or (i) NR'R''; or —C(O)C(C-C alkyl); (ii) C(O)NR'R''; or (f) C-C alkenyl or C-C alkynyl: (iii) OR'; or (g) C-C arylcycloalkyl, wherein: (iv) - S(O).R', wherein n is 0, 1, or 2 or (1) the aryl portion is optionally substituted with from (v) heterocycloalkenyl containing from 5-6 ring atoms, 1-4 independently selected R', and wherein from 1-3 of the ring atoms is independently (2) the cycloalkyl portion is optionally substituted with selected from N, NH, N(C-C alkyl), NC(O)(C-C, 10 from 1-4 independently selected R': alkyl), O, and S; and wherein said heterocycloalkenyl is (h) arylheterocyclyl containing from 8-14 ring atoms, optionally substituted with from 1-4 independently wherein: selected R': (1) the aryl portion from is optionally substituted with (vi) C-C aryl that is optionally substituted with from 1-4 from 1-4 independently selected R', and independently selected R'; or 15 (2) from 1-2 of the ring atoms of the heterocyclyl portion (vii) heteroaryl containing from 5-14 ring atoms, wherein is independently selected from N, NH, N(C-C, from 1-6 of the ring atoms is independently selected alkyl), NC(O)(C-C alkyl), O, and S; and wherein from N. NH, N(C-C alkyl), O, and S; and wherein said said heterocyclyl portion is optionally substituted heteroaryl is optionally substituted with from 1-4 inde with from 1-3 independently selected R': pendently selected R'; or (i) heteroarylheterocyclyl containing from 8-14 ring (viii) Cs-Carylcycloalkyl, wherein: atoms, wherein: (1) the aryl portion is optionally substituted with from (1) from 1-2 of the ring atoms of the heteroaryl portion is 1-4 independently selected R', and independently selected from N, NH, N(C-C alkyl), (2) the cycloalkyl portion is optionally substituted with O, and S; and wherein said heteroaryl portion is from 1-4 independently selected R': 25 optionally substituted with from 1-3 independently O selected R'; and (ix) arylheterocyclyl containing from 8-14 ring atoms, (2) from 1-2 of the ring atoms of the heterocyclyl portion wherein: is independently selected from N, NH, N(C-C, (1) the aryl portion from is optionally substituted with alkyl), NC(O)(C-C alkyl), O, and S; and wherein from 1-4 independently selected R', and 30 said heterocyclyl portion is optionally substituted (2) from 1-2 of the ring atoms of the heterocyclyl portion with from 1-3 independently selected R': is independently selected from N, NH, N(C-C, () heteroarylcycloalkyl containing from 8-14 ring atoms, alkyl), NC(O)(C-C alkyl), O, and S; and wherein wherein: said heterocyclyl portion is optionally substituted (1) from 1-2 of the ring atoms of the heteroaryl portion is with from 1-3 independently selected R': 35 independently selected from N, NH, N(C-C alkyl), O O, and S; and wherein said heteroaryl portion is (X) heteroarylheterocyclyl containing from 8-14 ring optionally substituted with from 1-3 independently atoms, wherein: selected R'; and (1) from 1-2 of the ring atoms of the heteroaryl portion is (2) the cycloalkyl portion is optionally substituted with independently selected from N, NH, N(C-C alkyl), 40 from 1-4 independently selected R': O, and S; and wherein said heteroaryl portion is (k) C-C cycloalkyl or C-Cs cycloalkenyl, each of which optionally substituted with from 1-3 independently is optionally substituted with from 1-4 independently selected R'; and selected R'; and (2) from 1-2 of the ring atoms of the heterocyclyl portion (1) C7-Caralkyl, wherein the aryl portion is optionally the is independently selected from N, NH, N(C-C, 45 aryl portion from is optionally substituted with from 1-4 alkyl). NC(O)(C-C alkyl), O, and S; and wherein independently selected R', said heterocyclyl portion is optionally substituted provided that one of R'' and R' must be selected from (b). with from 1-3 independently selected R': (c), (g), (h), (i), (), and (k); O R2 is: (xi) heteroarylcycloalkyl containing from 8-14 ring atoms, 50 (i) Co-C aryl that is optionally substituted with from 1-4 wherein: R; or (1) from 1-2 of the ring atoms of the heteroaryl portion is (ii) heteroaryl containing from 5-14 ring atoms, wherein independently selected from N, NH, N(C-C alkyl). from 1-6 of the ring atoms is independently selected O, and S; and wherein said heteroaryl portion is from N, NH, N(C-C alkyl), O, and S; and wherein said optionally substituted with from 1-3 independently 55 heteroaryl is optionally substituted with from 1-4 R”; or selected R'; and (iii) C-C alkyl or C-C haloalkyl, each of which is sub (2) the cycloalkyl portion is optionally substituted with stituted with from 1-3 R': from 1-4 independently selected R': (iv) Cs-Carylcycloalkyl, wherein: each of R'' and R'' is independently selected from the (1) the aryl portion is optionally substituted with from substituents delineated collectively in (a) through (k) below: 60 1-4 independently selected R', and (a) hydrogen; (2) the cycloalkyl portion is optionally substituted with (b) S-C aryl that is optionally substituted with from 1-4 from 1-4 independently selected R': RP; O (c) heteroaryl containing from 5-14 ring atoms, wherein (V) arylheterocyclyl containing from 8-14 ring atoms, from 1-6 of the ring atoms is independently selected 65 wherein: from N. NH, N(C-C alkyl), O, and S; and wherein said (1) the aryl portion from is optionally substituted with heteroaryl is optionally substituted with from 1-4 R: from 1-4 independently selected R', and US 9,095,572 B2 25 26 (2) from 1-2 of the ring atoms of the heterocyclyl portion O is independently selected from N, NH, N(C-C, (vi) heteroarylcycloalkyl containing from 8-14 ring atoms, alkyl). NC(O)(C-C alkyl), O, and S; and wherein wherein: said heterocyclyl portion is optionally substituted (1) from 1-2 of the ring atoms of the heteroaryl portion is with from 1-3 independently selected R': independently selected from N, NH, N(C-C alkyl). O, and S; and wherein said heteroaryl portion is O optionally substituted with from 1-3 independently (vi) heteroarylheterocyclyl containing from 8-14 ring selected R'; and atoms, wherein: (2) the cycloalkyl portion is optionally substituted with (1) from 1-2 of the ring atoms of the heteroaryl portion is from 1-4 independently selected R': independently selected from N, NH, N(C-C alkyl). 10 Rateach occurrence is, independently selected from halo, O, and S; and wherein said heteroaryl portion is hydroxyl, C-C alkoxy, C-C thioalkoxy, C-Chaloalkoxy, optionally substituted with from 1-3 independently C-C thiohaloalkoxy, oxo, thioxo, =NH, =NCC-C alkyl). selected R'; and C-C alkyl, C-C haloalkyl, -NH2, —NH(C-C alkyl). (2) from 1-2 of the ring atoms of the heterocyclyl portion N(C-C alkyl). 15 —NHC(O)(C-C alkyl), and cyano; is independently selected from N, NH, N(C-C, R” at each occurrence is independently selected from the alkyl), NC(O)(C-C alkyl), O, and S; and wherein substituents delineated in (aa) through (dd) below: said heterocyclyl portion is optionally substituted (aa) C-C alkoxy; C-C haloalkoxy; C-C thioalkoxy; with from 1-3 independently selected R': C-C, thiohaloalkoxy; —O—(CH)--O O (CH2). H. —C-C alkyl, C-Chaloalkyl, (vii) heteroarylcycloalkyl containing from 8-14 ring —NH(C-C alkyl), N(C-C alkyl). —NHC(O)(C- atoms, wherein: Calkyl), wherein the alkyl portion of each is optionally (1) from 1-2 of the ring atoms of the heteroaryl portion is substituted with from 1-3 independently selected R: independently selected from N, NH, N(C-C alkyl). (bb) halo: hydroxyl; cyano; nitro; —NH; azido: sulfhy O, and S; and wherein said heteroaryl portion is 25 dryl; C-C alkenyl: C-C alkynyl; —C(O)H; —C(O) optionally substituted with from 1-3 independently (C-C alkyl); —C(O)(C-C haloalkyl); C(O)OH: —C(O)C(C-C alkyl); C(O)NH; –C(O)NH(C- selected R'; and C alkyl); C(O)N(C-C alkyl); SO(C-C alkyl); (2) the cycloalkyl portion is optionally substituted with —SONH; —SONHC-C alkyl); —SON(C-C, from 1-4 independently selected R': alkyl). R is: 30 (cc) C-C cycloalkyl or heterocyclyl containing from 5-6 (i) Co-Co aryl that is optionally substituted with from 1-4 ring atoms, wherein from 1-2 of the ring atoms of the R; or heterocyclyl is independently selected from N. NH, N(C-C alkyl), NC(O)(C-C alkyl), O, and S; and (ii) heteroaryl containing from 5-14 ring atoms, wherein wherein each of said phenyl and heterocyclyl is option from 1-6 of the ring atoms is independently selected 35 ally substituted with from 1-3 independently selected from N. NH, N(C-C alkyl), O, and S; and wherein said R"; and heteroaryl is optionally substituted with from 1-4 R: (dd) phenyl or heteroaryl containing from 5-6 ring atoms, (iii) Cs-Carylcycloalkyl, wherein: wherein from 1-2 of the ring atoms of the heteroaryl is (1) the aryl portion is optionally substituted with from independently selected from N. NH, N(C-C alkyl), O, 1-4 independently selected R', and 40 and S.; wherein each of said phenyl and heteroaryl is optionally substituted with from 1-3 substituents inde (2) the cycloalkyl portion is optionally substituted with pendently selected from halo: hydroxyl; cyano; nitro: from 1-4 independently selected R': —NH; —NH(C-C alkyl), N(C-C alkyl). —NHC O (O) (C-C alkyl), C-C alkoxy; C-C haloalkoxy; (iv) arylheterocyclyl containing from 8-14 ring atoms, 45 C-C thioalkoxy; C-C thiohaloalkoxy; C-C alkyl, wherein: and C-C haloalkyl, R at each occurrence is, independently selected from halo, (1) the aryl portion from is optionally substituted with C-C alkoxy, C-C thioalkoxy, C-C haloalkoxy, C-C, from 1-4 independently selected R', and thiohaloalkoxy, C-C alkyl, C-Chaloalkyl, - NH, NH (2) from 1-2 of the ring atoms of the heterocyclyl portion (C-C alkyl), N(C-C alkyl). —NHC(O)(C-C alkyl), and is independently selected from N, NH, N(C-C, 50 cyano; alkyl). NC(O)(C-C alkyl), O, and S; and wherein R" at each occurrence is, independently selected from said heterocyclyl portion is optionally substituted hydroxyl, C-C alkoxy, C-C thioalkoxy, C-Chaloalkoxy, with from 1-3 independently selected R': C-C thiohaloalkoxy, C-C alkyl, C-Chaloalkyl, -NH2, O —NH(C-C alkyl), N(C-C alkyl). —NHC(O)(C-C, 55 alkyl), and cyano; and (v) heteroarylheterocyclyl containing from 8-14 ring R at each occurrence is, independently selected from atoms, wherein: hydroxyl, C-C alkoxy; C-C thioalkoxy; C-C, (1) from 1-2 of the ring atoms of the heteroaryl portion is haloalkoxy; C-C thiohaloalkoxy; —NH; —NH(C-C, independently selected from N, NH, N(C-C alkyl). alkyl); N(C-C alkyl); —NHC(O)(C-C alkyl): cyano; O, and S; and wherein said heteroaryl portion is 60 —C(O)H; —C(O)(C-C alkyl); —C(O)(C-C haloalkyl); optionally substituted with from 1-3 independently C(O)OH: –C(O)O(C-C alkyl); –C(O)NH; –C(O)NH selected R'; and (C-C alkyl); C(O)N(C-C alkyl); SO(C-C alkyl); (2) from 1-2 of the ring atoms of the heterocyclyl portion —SONH;—SONH(C-C alkyl);—SON(C-C alkyl); is independently selected from N, NH, N(C-C, and L-(C-C alkylene)-biotin, where in L is a —O , alkyl). NC(O)(C-C alkyl), O, and S; and wherein 65 NH-, - NCH C(O) , —C(O)NH-, - C(O) said heterocyclyl portion is optionally substituted NCH , – NHC(O)—, or - NCHC(O)–: with from 1-3 independently selected R': or a pharmaceutically acceptable salt thereof. US 9,095,572 B2 27 28 In embodiments, 1, 2, 3, 4, or 5 of the following can apply —NH, -NH(C-C alkyl). —N(C-C alkyl). —NHC(O) provided that RandR cannot both behydrogen when A is (C-C alkyl), and nitro; OR CH, and R and R' are defined according to definition (2) RandR together with C and C, respectively, form a (1): fused R and R' together with C and C, respectively, form a provided that R cannot behydrogen when A is CH, andR fused heteroaryl ring containing 6 ring atoms, wherein from and R' are defined according to definition (2): 1-2 independently selected ring atoms is N., and wherein said provided that R and R cannot both be chloro when A is heteroaryl ring is optionally substituted with from 1-2 inde CHR and Rare defined according to definition (1), Z pendently selected R': is —OR', and R' is unsubstituted phenyl: each of L' and L is, independently, C-C alkylene, which provided that R and R' cannot both be bromo when A is 10 is optionally substituted with from 1-2 independently CHR and Rare defined according to definition (1), Z selected R: is —OR', and R' is phenyl that is substituted with A is CR'R'', wherein one of R' and R' is -OH, and pyridyl or alkyl that is substituted with from 1-3 R; and the other of R'' and R' is hydrogen or C-C alkyl: provided that RandR cannot both behydrogen when A is 15 Z is —OR' or -S(O).R', wherein n is 0, 1, or 2: CH(CH), R and R' are defined according to definition each of R'' and R' is: (1), Z is NR'R'', R' is CH, and R'' is unsubstituted (i) C-C aryl that is optionally substituted with from 1-4 phenyl. R; or In another aspect, pharmaceutical compositions are fea (ii) heteroaryl containing from 5-14 ring atoms, wherein tured that include the above-described compounds (or salts from 1-6 of the ring atoms is independently selected thereofas described herein) and a pharmaceutically accept from N, NH, N(C-C alkyl), O, and S; and wherein said able carrier. In embodiments, 1, 2, 3, 4, or 5 of the above heteroaryl is optionally substituted with from 1-4 R: described provisions can apply. (iii) C-C alkyl or C-C haloalkyl (e.g., C-C alkyl). In another aspect, compounds having formula (I) are fea each of which is substituted with from 1-3 R'; or tured 25 (iv) Cs-Carylcycloalkyl, wherein: (1) the aryl portion is optionally substituted with from 1-4 independently selected R', and (I) (2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R': , 30 O R3 C3 (V) arylheterocyclyl containing from 8-14 ring atoms, X-R wherein: R2 N (1) the aryl portion from is optionally substituted with V from 1-4 independently selected R', and L-A 35 (2) from 1-2 of the ring atoms of the heterocyclyl portion R M is independently selected from N, NH, N(C-C, alkyl), NC(O)(C-C alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted wherein: with from 1-3 independently selected R': each of R. R. R., and R is independently selected from 40 O hydrogen, halo, hydroxyl, Sulfhydryl, C-C alkoxy, C-C, (vi) heteroarylheterocyclyl containing from 8-14 ring thioalkoxy, C-C haloalkoxy, C-C thiohaloalkoxy, C-C, atoms, wherein: alkyl, C-C haloalkyl, C-C alkynyl, cyclopropyl. —N. (1) from 1-2 of the ring atoms of the heteroaryl portion is cyano, independently selected from N, NH, N(C-C alkyl). —NH, -NH(C-C alkyl), N(C-C alkyl). - NHC(O) 45 O, and S; and wherein said heteroaryl portion is (C-C alkyl), and nitro: optionally substituted with from 1-3 independently R and R' are defined according to (1) or (2) below: selected R'; and (1) Rand R' together with C and C, respectively, form a (2) from 1-2 of the ring atoms of the heterocyclyl portion fused phenyl ring having formula (II): is independently selected from N, NH, N(C-C, 50 alkyl), NC(O)(C-C alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted (II) with from 1-3 independently selected R': O (vii) heteroarylcycloalkyl containing from 8-14 ring 55 atoms, wherein: (1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(C-C alkyl). O, and S; and wherein said heteroaryl portion is optionally substituted with from 1-3 independently 60 selected R'; and (2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R': wherein each of R. R. R', and R is independently Rateach occurrence is, independently selected from halo, selected from hydrogen, halo, hydroxyl, Sulfhydryl, C-C, hydroxyl, C-C alkoxy, C-C thioalkoxy, C-Chaloalkoxy, alkoxy, C-C thioalkoxy, C-C haloalkoxy, C-C thioha 65 C-C thiohaloalkoxy, oxo, thioxo, =NH, =NCC-C alkyl). loalkoxy, C-C alkyl, C-Chaloalkyl, C-C alkynyl, cyclo C-C alkyl, C-C haloalkyl, -NH2, —NH(C-C alkyl). propyl. —N, cyano, N(C-C alkyl). US 9,095,572 B2 29 30 —NHC(O)(C-C alkyl), and cyano; provided that RandR cannot both be bromo when Rand R” at each occurrence is independently selected from the R" are defined according to definition (1), Z is - SR". substituents delineated in (aa) through (dd) below: and R' is phenyl substituted with —OH. (aa) C-C alkoxy; C-C haloalkoxy; C-C thioalkoxy; In another aspect, pharmaceutical compositions are fea C-C thiohaloalkoxy; —O—(CH), O(CH). 5 tured that include the above-described compounds (or salts 3—H; —C-C alkyl, C-C haloalkyl, thereofas described herein) and a pharmaceutically accept —NH(C-C alkyl). —N(C-C alkyl), NHC(O)(C- able carrier. In embodiments, 1, 2, 3, 4, or 5 of the above Calkyl), wherein the alkyl portion of each is optionally described provisions can apply. substituted with from 1-3 independently selected R: In another aspect, compounds having formula (I) are fea (bb) halo: hydroxyl; cyano; nitro; NH; azido: sulfhy 10 tured: dryl; C-C alkenyl: C-C alkynyl; —C(O)H; —C(O) (C-C alkyl); —C(O)(C-C haloalkyl); C(O)OH: - C(O)O(C-C alkyl); C(O)NH; C(O)NH(C- (I) C alkyl); C(O)N(C-C alkyl); SO(C-C alkyl); 15 —SONH; —SONHCC-C alkyl); —SON(C-C, alkyl). (cc) C-C 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(C-C alkyl), NC(O)(C-C alkyl), O, and S; and wherein each of said phenyl and heterocyclyl is option ally substituted with from 1-3 independently selected R"; and wherein: (dd) phenyl or heteroaryl containing from 5-6 ring atoms, 25 wherein from 1-2 of the ring atoms of the heteroaryl is each of R', R, R, and R is independently selected from independently selected from N. NH, N(C-C alkyl), O, hydrogen, halo, hydroxyl, sulfhydryl, C-C alkoxy, C-C, and S.; wherein each of said phenyl and heteroaryl is thioalkoxy, C-C haloalkoxy, C-C thiohaloalkoxy, C-C, optionally substituted with from 1-3 substituents inde alkyl, C-C haloalkyl, C-C alkynyl, cyclopropyl. —N. pendently selected from halo: hydroxyl; cyano; nitro: 30 cyano, —NH; NH(C-C alkyl), N(C-C alkyl), NHC —NH, -NH(C-C alkyl). —N(C-C alkyl). —NHC(O) (O)(C-C alkyl), C-C alkoxy: C-C haloalkoxy: (C-C alkyl), and nitro: C-C thioalkoxy; C-C thiohaloalkoxy; C-C alkyl, RandR together with C and C, respectively, form a fused and C-C haloalkyl, heterocyclic ring containing from 5-6 ring atoms, wherein R at each occurrence is, independently selected from halo, 35 from 1-2 of the ring atoms is independently selected from N. C-C alkoxy, C-C thioalkoxy, C-C haloalkoxy, C-C, NH, N(C-C alkyl), NC(O)(C-C alkyl), O, and S; and thiohaloalkoxy, C-C alkyl, C-Chaloalkyl, - NH, NH wherein said heterocyclic ring is optionally substituted with from 1-3 independently selected R': (C-C alkyl), N(C-C alkyl). —NHC(O)(C-C alkyl), and each of L' and L is, independently, C-C alkylene, which cyano; 40 R at each occurrence is, independently selected from is optionally substituted with from 1-2 independently hydroxyl, C-C alkoxy, C-C thioalkoxy, C-Chaloalkoxy, selected R: C-C thiohaloalkoxy, C-C alkyl, C-Chaloalkyl, -NH2, A is: —NH(C-C alkyl), N(C-C alkyl). —NHC(O)(C-C, (i) CR'R'', wherein one of R' and R' is independently alkyl), and cyano; and 45 selected from hydrogen, halo, C-C alkyl, and OR; and R at each occurrence is, independently selected from the other of R'' and R' is independently selected from hydroxyl, C-C alkoxy; C-C thioalkoxy; C-C, halo, C-C alkyl, and OR; wherein R is hydrogen or haloalkoxy; C-C thiohaloalkoxy; —NH; —NH(C-C, C-C alkyl that is optionally substituted with hydroxyl alkyl); N(C-C alkyl); NHC(O)(C-C alkyl); cyano; or C-C alkoxy; or —C(O)H; —C(O)(C-C alkyl); —C(O)(C-C haloalkyl); 50 (ii) C=O: C(O)OH: C(O)O(C-C alkyl); –C(O)NH; C(O)NH Z is: (C-C alkyl); C(O)N(C-C alkyl); —SO(C-C alkyl); (i) NR'R''; or —SONH; SONHCC-C alkyl);—SON(C-C alkyl); (ii) C(O)NR'R''; or and L-(C-C alkylene)-biotin, where in L is a —O , (iii) OR'; or NH-, - NCH , —C(O) , C(O)NH-, -C(O) 55 (iv) - S(O),R', wherein n is 0, 1, or 2 or NCH-, -NHC(O)—, or - NCHC(O)–: (vi) C-C aryl that is optionally substituted with from 1-4 or a pharmaceutically acceptable salt thereof. independently selected R'; or In embodiments, 1, 2, 3, or 4 of the following can apply: (vii) heteroaryl containing from 5-14 ring atoms, wherein provided that Rand R cannot both be hydrogen when R from 1-6 of the ring atoms is independently selected and R' are defined according to definition (1): 60 from N. NH, N(C-C alkyl), O, and S; and wherein said provided that RandR cannot both be chloro when Rand heteroaryl is optionally substituted with from 1-4 inde Rare defined according to definition (1), Z is —OR', pendently selected R'; or and R'' is phenyl substituted with chloro, formyl, or each of R'' and R' is independently selected from the NHC(O)CH: substituents delineated collectively in (a) through (k) below: provided that RandR cannot both be bromo when Rand 65 (a) hydrogen; R" are defined according to definition (1), Z is —OR'', (b) Co-C aryl that is optionally substituted with from 1-4 and R' is phenyl substituted with NHC(O)CH; and R; US 9,095,572 B2 31 32 (c) heteroaryl containing from 5-14 ring atoms, wherein R at each occurrence is, independently selected from halo, from 1-6 of the ring atoms is independently selected C-C alkoxy, C-C thioalkoxy, C-C haloalkoxy, C-C, from N. NH, N(C-C alkyl), O, and S; and wherein said thiohaloalkoxy, C-C alkyl, C-Chaloalkyl, - NH, NH heteroaryl is optionally substituted with from 1-4 R: (C-C alkyl), N(C-C alkyl). —NHC(O)(C-C alkyl), and (d) C-C alkyl or C-Chaloalkyl, each of which is option cyano; ally substituted with from 1-3 R': R" at each occurrence is, independently selected from (e) —C(O)(C-C alkyl). —C(O)(C-C haloalkyl), or hydroxyl, C-C alkoxy, C-C thioalkoxy, C-Chaloalkoxy, —C(O)C(C-C alkyl); C-C thiohaloalkoxy, C-C alkyl, C-Chaloalkyl, -NH2, (f) C-C alkenyl or C-C alkynyl: —NH(C-C alkyl), N(C-C alkyl). —NHC(O)(C-C, and 10 (1) C7-Caralkyl, wherein the aryl portion is optionally the alkyl), and cyano; and aryl portion from is optionally substituted with from 1-4 R at each occurrence is, independently selected from independently selected R', hydroxyl, C-C alkoxy; C-C thioalkoxy; C-C, provided that one of R'' and R' must be selected from (b) haloalkoxy; C-C thiohaloalkoxy; —NH; —NH(C-C, and (c); 15 alkyl); N(C-C alkyl); NHC(O)(C-C alkyl); cyano; R2 is: —C(O)H; —C(O)(C-C alkyl); —C(O)(C-C haloalkyl); (i) Co-C aryl that is optionally substituted with from 1-4 C(O)OH: –C(O)O(C-C alkyl); –C(O)NH; C(O)NH R; or (C-C alkyl); C(O)N(C-C alkyl); SO(C-C alkyl); (ii) heteroaryl containing from 5-14 ring atoms, wherein —SONH; SONHCC-C alkyl);—SON(C-C alkyl); from 1-6 of the ring atoms is independently selected and L-(C-C alkylene)-biotin, where in L is a —O , from N, NH, N(C-C alkyl), O, and S; and wherein said NH-, - NCH C(O) , —C(O)NH-, - C(O) heteroaryl is optionally substituted with from 1-4 R: NCH , – NHC(O)—, or - NCHC(O)–: R is: or a pharmaceutically acceptable salt thereof. (i) Co-C aryl that is optionally substituted with from 1-4 In embodiments, provision (A) described hereincan apply. R; or 25 In another aspect, compounds having formula (I) are fea (ii) heteroaryl containing from 5-14 ring atoms, wherein tured: from 1-6 of the ring atoms is independently selected from N, NH, N(C-C alkyl), O, and S; and wherein said (I) heteroaryl is optionally substituted with from 1-4 R: R4 Rateach occurrence is, independently selected from halo, 30 3 hydroxyl, C-C alkoxy, C-C thioalkoxy, C-Chaloalkoxy, R C3, C-C thiohaloalkoxy, oxo, thioxo, =NH. =NCC-C alkyl). M C-C alkyl, C-C haloalkyl, -NH2, —NH(C-C alkyl). X-R N(C-C alkyl). 2 N R V —NHC(O)(C-C alkyl), and cyano; 35 L1-A R” at each occurrence is independently selected from the R V substituents delineated in (aa) through (dd) below: L2n (aa) C-C alkoxy; C-C haloalkoxy; C-C thioalkoxy; C-C thiohaloalkoxy; —O—(CH), O(CH2). 3—H; —C-C alkyl, C-C haloalkyl, 40 wherein: —NH(C-C alkyl). —N(C-C alkyl), NHC(O)(C- each of R', R, R, and R is independently selected from Calkyl), wherein the alkyl portion of each is optionally hydrogen, halo, hydroxyl, sulfhydryl, C-C alkoxy, C-C, substituted with from 1-3 independently selected R: thioalkoxy, C-C haloalkoxy, C-C thiohaloalkoxy, C-C, (bb) halo: hydroxyl; cyano; nitro; NH; azido: sulfhy alkyl, C-C haloalkyl, C-C alkynyl, cyclopropyl. —N. dryl; C-C alkenyl: C-C alkynyl; —C(O)H; —C(O) 45 cyano, (C-C alkyl); —C(O)(C-C haloalkyl); C(O)OH: —NH —NH(C-C alkyl). —N(C-C alkyl). —NHC —C(O)C(C-C alkyl); C(O)NH; C(O)NH(C- (O)(C-C alkyl), and nitro: C alkyl); C(O)N(C-C alkyl). —SO(C-C alkyl); each of RandR is, independently, hydrogen, C-C alkyl, —SONH; —SONHCC-C alkyl); —SON(C-C, or C-C haloalkyl: alkyl). 50 each of L' and L is, independently, C-C alkylene, which (cc) C-C cycloalkyl or heterocyclyl containing from 5-6 is optionally substituted with from 1-2 independently ring atoms, wherein from 1-2 of the ring atoms of the selected R: heterocyclyl is independently selected from N. NH, A is: N(C-C alkyl), NC(O)(C-C alkyl), O, and S; and (i) CR'R'', wherein one of R'' and R' is independently wherein each of said phenyl and heterocyclyl is option 55 Selected from hydrogen, fluoro, chloro, C-C alkyl, and ally substituted with from 1-3 independently selected OR: and the other of R'' and R' is independently R"; and selected from fluoro, chloro, C-C alkyl, and OR; (dd) phenyl or heteroaryl containing from 5-6 ring atoms, wherein R is hydrogen or C-C alkyl that is optionally wherein from 1-2 of the ring atoms of the heteroaryl is substituted with hydroxyl or C-C alkoxy; or independently selected from N. NH, N(C-C alkyl), O, 60 (ii) C=O: and S.; wherein each of said phenyl and heteroaryl is Z is: optionally substituted with from 1-3 substituents inde (i) NR'R''; or pendently selected from halo: hydroxyl; cyano; nitro: (ii) C(O)NR'R''; or —NH; —NH(C-C alkyl), N(C-C alkyl). —NHC (iii) OR'; or (O) (C-C alkyl), C-C alkoxy; C-C haloalkoxy; 65 (iv) - S(O),R', wherein n is 0, 1, or 2 or C-C thioalkoxy; C-C thiohaloalkoxy; C-C alkyl, (vi) C-C aryl that is optionally substituted with from 1-4 and C-C haloalkyl, independently selected R'; or US 9,095,572 B2 33 34 (vii) heteroaryl containing from 5-14 ring atoms, wherein (O) (C-C alkyl), C-C alkoxy; C-C haloalkoxy; from 1-6 of the ring atoms is independently selected C-C thioalkoxy; C-C thiohaloalkoxy; C-C alkyl, from N. NH, N(C-C alkyl), O, and S; and wherein said and C-C haloalkyl, heteroaryl is optionally substituted with from 1-4 inde R at each occurrence is, independently selected from halo, pendently selected R'; or 5 C-C alkoxy, C-C thioalkoxy, C-C haloalkoxy, C-C, each of R'' and R'' is independently selected from the thiohaloalkoxy, C-C alkyl, C-Chaloalkyl, - NH, NH substituents delineated collectively in (a) through (k) below: (C-C alkyl), N(C-C alkyl). —NHC(O)(C-C alkyl), and (a) hydrogen; cyano; (b) S-C aryl that is optionally substituted with from 1-4 R" at each occurrence is, independently selected from R; 10 (c) heteroaryl containing from 5-14 ring atoms, wherein hydroxyl, C-C alkoxy, C-C thioalkoxy, C-Chaloalkoxy, from 1-6 of the ring atoms is independently selected C-C thiohaloalkoxy, C-C alkyl, C-Chaloalkyl, -NH2, from N. NH, N(C-C alkyl), O, and S; and wherein said —NH(C-C alkyl), N(C-C alkyl). —NHC(O)(C-C, heteroaryl is optionally substituted with from 1-4 R: alkyl), and cyano; and (d) C-C alkyl or C-Chaloalkyl, each of which is option 15 R at each occurrence is, independently selected from ally substituted with from 1-3 R': hydroxyl, C-C alkoxy; C-C thioalkoxy; C-C, (e) —C(O)(C-C alkyl). —C(O)(C-C haloalkyl), or haloalkoxy; C-C thiohaloalkoxy; —NH; —NH(C-C, —C(O)C(C-C alkyl); alkyl); N(C-C alkyl); NHC(O)(C-C alkyl); cyano; (f) C-C alkenyl or C-C alkynyl: —C(O)H; —C(O)(C-C alkyl); —C(O)(C-C haloalkyl); and C(O)OH: –C(O)O(C-C alkyl); –C(O)NH; C(O)NH (1) C7-Caralkyl, wherein the aryl portion is optionally the (C-C alkyl); C(O)N(C-C alkyl); SO(C-C alkyl); aryl portion from is optionally substituted with from 1-4 —SONH; SONHCC-C alkyl);—SON(C-C alkyl); independently selected R', and L-(C-C alkylene)-biotin, where in L is a —O , provided that one of R'' and R' must be selected from (b) NH-, - NCH C(O) , —C(O)NH-, - C(O) and (c); 25 NCH , – NHC(O)—, or - NCHC(O)–: each of R'' and R' is: or a pharmaceutically acceptable salt thereof. (i) Co-C aryl that is optionally substituted with from 1-4 In one aspect, compounds of formula (III) are featured in R; or which: (ii) heteroaryl containing from 5-14 ring atoms, wherein A is CR'R'', in which each of R'' and R' is, indepen from 1-6 of the ring atoms is independently selected 30 dently, hydrogen, halo, or C-C alkyl, or from N. NH, N(C-C alkyl), O, and S; and wherein said A is CR'R'', in which one of R'' and R' is halo (e.g., heteroaryl is optionally substituted with from 1-4 R: fluoro), and the other of R' and R' is, independently, hydro Rateach occurrence is, independently selected from halo, gen, halo, or C-C alkyl (e.g., hydrogen); or hydroxyl, C-C alkoxy, C-C thioalkoxy, C-Chaloalkoxy, A is CR'R'', in which one of R'' and R' is halo (e.g., C-C thiohaloalkoxy, oxo, thioxo, NH, =N(C-C alkyl). 35 fluoro), and the other of R' and R' is hydrogen; and C-C alkyl, C-C haloalkyl, -NH2, —NH(C-C alkyl). R", R. R. R. L. L., and Z can be as defined anywhere N(C-C alkyl). herein; or a salt (e.g., pharmaceutically acceptable salt) —NHC(O)(C-C alkyl), and cyano; thereof. R” at each occurrence is independently selected from the In embodiments, (B) and/or (C) applies. substituents delineated in (aa) through (dd) below: 40 In one aspect, compounds of formula (III) are featured in (aa) C-C alkoxy; C-C haloalkoxy; C-C thioalkoxy; which: C-C, thiohaloalkoxy; —O—(CH), O one of R'' and R' can be OR. In embodiments, the other (CH2). H. —C-C alkyl, C-C haloalkyl, of R'' and R' can be as defined anywhere herein; e.g., the —NH(C-C alkyl). —N(C-C alkyl), NHC(O)(C- other of R' and R' can be hydrogen or C-C alkyl. For Calkyl), wherein the alkyl portion of each is optionally 45 example, one of R'' and R' can be OR, and the other of R' substituted with from 1-3 independently selected R: and R' is hydrogen or C-C alkyl. In embodiments, R can (bb) halo: hydroxyl; cyano; nitro; NH; azido: sulfhy be hydrogen or C-C alkyl; and dryl; C-C alkenyl: C-C alkynyl; —C(O)H; —C(O) R", R. R. R. L. L., and Z can be as defined anywhere (C-C alkyl); —C(O)(C-C haloalkyl); C(O)OH: herein; or a salt (e.g., pharmaceutically acceptable salt) - C(O)O(C-C alkyl); C(O)NH; C(O)NH(C- 50 thereof. C alkyl); C(O)N(C-C alkyl). —SO(C-C alkyl); In embodiments, one or more of the following apply, e.g., —SONH; —SONHCC-C alkyl); —SON(C-C, when A is CHOH and Z is NR'R'': alkyl). each of R and R is CH; and/or each of R and R is (cc) C-C cycloalkyl or heterocyclyl containing from 5-6 bromo; and/or each of RandR is chloro; and/or one of ring atoms, wherein from 1-2 of the ring atoms of the 55 RandR is CH (e.g., R), and the other is bromo (e.g., heterocyclyl is independently selected from N. NH, R3); N(C-C alkyl), NC(O)(C-C alkyl), O, and S; and each of R'' and R'' is other than hydrogen; wherein each of said phenyl and heterocyclyl is option each of R'' and R' is hydrogen; ally substituted with from 1-3 independently selected one of R'' and R'' is heteroaryl as defined anywhere R"; and 60 herein; (dd) phenyl or heteroaryl containing from 5-6 ring atoms, L' and/or L is C-C alkylene (optionally substituted); wherein from 1-2 of the ring atoms of the heteroaryl is (B) and/or (C) applies. independently selected from N, NH, N(C-C alkyl), O, In one aspect, compounds of formula (III) are featured in and S.; wherein each of said phenyl and heteroaryl is which Z is other than NR'R''; and R,R,R,R,L,L, Z, optionally substituted with from 1-3 substituents inde 65 and A can be as defined anywhere herein; or a salt (e.g., pendently selected from halo: hydroxyl; cyano; nitro: pharmaceutically acceptable salt) thereof. In embodiments, —NH; —NH(C-C alkyl), N(C-C alkyl). —NHC (B) and/or (C) applies. US 9,095,572 B2 35 36 In one aspect, compounds of formula (III) are featured in (1) C7-Caralkyl, wherein the aryl portion is optionally the which Zis-OR'' and/or S(O),R'; and R',R,R,R,L, aryl portion from is optionally substituted with from 1-4 L°, and A can be as defined anywhere herein; or a salt (e.g., independently selected R', pharmaceutically acceptable salt) thereof. In embodiments, provided that one of R'' and R' must be selected from (b) (B) and/or (C) applies. 5 and (c); In one aspect, compounds of formula (III) are featured in R’ is: which A is (ii) C=O; and/or (iv) heterocycloalkylene con (i) Co-C aryl that is optionally substituted with from 1-4 taining from 3-5 ring atoms, wherein from 1-2 of the ring R; or atoms is independently selected from N, NH, N(C-C alkyl). (ii) heteroaryl containing from 5-14 ring atoms, wherein O, and S; and wherein said heterocycloalkylene is (a) substi 10 from 1-6 of the ring atoms is independently selected tuted with 1 oxo; and (b) is optionally further substituted with from N. NH, N(C-C alkyl), O, and S; and wherein said from 1-4 independently selected R'; and R', R. R. R. L', heteroaryl is optionally substituted with from 1-4 R: L°, and Z can be as defined anywhere herein; or a salt (e.g., Rateach occurrence is, independently selected from halo, pharmaceutically acceptable salt) thereof. hydroxyl, C-C alkoxy, C-C thioalkoxy, C-Chaloalkoxy, In yet another aspect, compounds of formula (VI) are fea 15 C-C thiohaloalkoxy, oxo, thioxo, =NH, =NCC-C alkyl). tured: C-C alkyl, C-C haloalkyl, -NH2, —NH(C-C alkyl). —N(C-C alkyl). —NHC(O)(C-C alkyl), and cyano; R”) at each occurrence is independently selected from the (VI) substituents delineated in (aa) through (dd) below: R4 (aa) C-C alkoxy; C-C haloalkoxy; C-C thioalkoxy; C-C thiohaloalkoxy; —O(CH), O(CH) R3 Rs 3H, C-C alkyl, C-C haloalkyl, -NH(C-C alkyl). —N(C-C alkyl). - NHC(O)(C-C alkyl), wherein X the alkyl portion of each is optionally substituted with R5 25 from 1-3 independently selected R: (bb) halo: hydroxyl; cyano; nitro; —NH; azido: sulfhy R L1 dryl; C-C alkenyl: C-C alkynyl: —C(O)H; —C(O) (C-C alkyl); —C(O)(C-C haloalkyl); —C(O)OH: - C(O)O(C-C alkyl); C(O)NH; –C(O)NH(C- 30 C alkyl); C(O)N(C-C alkyl); SO(C-C alkyl); —SONH; —SONHC-C alkyl); —SON(C-C, wherein: alkyl); R-Rs are each independently selected from hydrogen, (cc) C-C cycloalkyl or heterocyclyl containing from 5-6 halo, hydroxyl, Sulfhydryl, C-C alkoxy, C-C thioalkoxy, ring atoms, wherein from 1-2 of the ring atoms of the C-C haloalkoxy, C-C thiohaloalkoxy, C-C alkyl, C-C, 35 heterocyclyl is independently selected from N. NH, haloalkyl, C-C alkynyl, cyclopropyl. —N, cyano, -NH2, N(C-C alkyl), NC(O)(C-C alkyl), O, and S; and —NH(C-C alkyl). —N(C-C alkyl). —NHC(O)(C-C, wherein each of said phenyl and heterocyclyl is option alkyl), and nitro: ally substituted with from 1-3 independently selected X is Co-Co aryl that is optionally substituted with 1-4 R: R"; and or heteroaryl containing 5-14 ring atoms, wherein from 1-6 of 40 (dd) phenyl or heteroaryl containing from 5-6 ring atoms, the ring atoms is independently selected from N. NH, N(C- wherein from 1-2 of the ring atoms of the heteroaryl is C. alkyl), O, and S, and wherein said heteroaryl is optionally independently selected from N, NH, N(C-C alkyl), O, substituted with 1-4 R: and S.; wherein each of said phenyl and heteroaryl is each of Land L is, independently, C-C alkylene, which optionally substituted with from 1-3 substituents inde is optionally substituted with from 1-2 independently 45 pendently selected from halo: hydroxyl; cyano; nitro: selected R: —NH; —NH(C-C alkyl), —N(C-C alkyl). A is CR'R'', wherein one of R'' and R' is indepen —NHC(O)(C-C alkyl), C-C alkoxy; C-C, dently selected from hydrogen, fluoro, chloro, C-C alkyl, haloalkoxy; C-C thioalkoxy; C-C thiohaloalkoxy; and OR: and the other of R'' and R' is independently C-C alkyl, and C-C haloalkyl; selected from fluoro, chloro, C-C alkyl, and OR; wherein 50 R at each occurrence is, independently selected from halo, R is hydrogen or C-C alkyl that is optionally substituted C-C alkoxy, C-C thioalkoxy, C-C haloalkoxy, C-C, with hydroxyl or C-C alkoxy: thiohaloalkoxy, C-C alkyl, C-Chaloalkyl, - NH, NH Z is NR'R'' or OR; (C-C alkyl), —N(C-C alkyl). —NHC(O)(C-C alkyl). each of R'' and R'' is independently selected from the and cyano; substituents delineated collectively in (a) through (k) below: 55 R" at each occurrence is, independently selected from (a) hydrogen; hydroxyl, C-C alkoxy, C-C thioalkoxy, C-Chaloalkoxy, (b) Co-C aryl that is optionally substituted with from 1-4 C-C thiohaloalkoxy, C-C alkyl, C-Chaloalkyl, -NH2, R; —NH(C-C alkyl), —N(C-C alkyl). —NHC(O)(C-C, (c) heteroaryl containing from 5-14 ring atoms, wherein alkyl), and cyano; and from 1-6 of the ring atoms is independently selected 60 R at each occurrence is, independently selected from from N, NH, N(C-C alkyl), O, and S; and wherein said hydroxyl, C-C alkoxy; C-C thioalkoxy; C-C, heteroaryl is optionally substituted with from 1-4 R: haloalkoxy; C-C thiohaloalkoxy; —NH; —NH(C-C, (d) C-C alkyl or C-Chaloalkyl, each of which is option alkyl); N(C-C alkyl); NHC(O)(C-C alkyl); cyano; ally substituted with from 1-3 R': —C(O)H; —C(O)(C-C alkyl); —C(O)(C-C haloalkyl); (e) —C(O)(C-C alkyl). —C(O)(C-C haloalkyl), or 65 - C(O)OH: C(O)O(C-C alkyl); –C(O)NH; C(O) —C(O)C(C-C alkyl); NH(C-C alkyl); —C(O)N(C-C alkyl); —SO(C-C, (f) C-C alkenyl or C-C alkynyl; and alkyl); —SONH; —SONHCC-C alkyl); —SON(C-C, US 9,095,572 B2 37 38 alkyl); and L-(C-C alkylene)-biotin, where in L is a other formulae described herein) or a salt (e.g., a pharmaceu O , NH , NCH , —C(O)—, —C(O)NH , tically acceptable salt) thereofas defined anywhere herein to —C(O)NCH, -NHC(O) , or - NCHC(O)–: a Subject (e.g., a mammal. Such as a human). or a pharmaceutically acceptable salt thereof. Accordingly, in yet another aspect, the presently disclosed In certain embodiments, compound of formula (VI) can 5 embodiments include and feature methods of screening for have a R that is selected from halo, hydroxyl, sulfhydryl, (thereby identifying) compounds that stimulate neurogenesis C-C alkoxy, C-C thioalkoxy, C-C haloalkoxy, C-C, (e.g., post-natal neurogenesis, e.g., post-natal hippocampal thiohaloalkoxy, C-C alkyl, C-Chaloalkyl, C-C alkynyl, and/or hypothalamic neurogenesis) or protect newborn neu cyclopropyl. —N, cyano. —NH, -NH(C-C alkyl). rons from cell death. E.g., such as those described in the —N(C-C alkyl). —NHC(O)(C-C alkyl), and nitro. In 10 Examples section. Some embodiments, R is halo Such as bromo. In certain In one aspect, methods for treating (e.g., controlling, embodiments, each of R. R. R. and Rs is hydrogen. relieving, ameliorating, alleviating, or slowing the progres In certain embodiments, compound of formula (VI) can sion of) or methods for preventing (e.g., delaying the onset of have X that is C-C aryl substituted with one or more halo or reducing the risk of developing) one or more diseases, Such as bromo. For example, X can be 4-bromophenyl. X can 15 disorders, or conditions caused by, or associated with insuf also be heteroaryl containing 5-14 ring atoms, wherein from ficient (e.g., aberrant) neurogenesis or unwanted neuronal 1-6 of the ring atoms is independently selected from N, NH, cell death in a subject in need thereofare featured. The meth N(C-C alkyl). O, and S, and wherein said heteroaryl is ods include administering to the Subject an effective amount optionally substituted with 1-4 R. For example, X can be of a compound of formula (I) (and/or a compound of any of pyridine optionally substituted with 1-4 R. the otherformulae described herein) or a salt (e.g., a pharma In certain embodiments, compound of formula (VI) can ceutically acceptable salt) thereofas defined anywhere herein have A that is CR'R'', wherein each of R'' and R' is, to the subject. independently, hydrogen, C-C alkyl, or OR. In some In another aspect, the use of a compound of formula (I) embodiments, one of R'' and R' is OR: and the other of R' (and/or a compound of any of the other formulae described and R' is hydrogen or C-C alkyl. For example, one of R' 25 herein) or a salt (e.g., a pharmaceutically acceptable salt) and R' can be OH; and the other of R'' and R' can be thereofas defined anywhere herein in the preparation of, or hydrogen. for use as, a medicament for the treatment (e.g., controlling, In some embodiments, A is CR'R'' and wherein the relieving, ameliorating, alleviating, or slowing the progres carbon attached to R' and R' is substituted with four dif sion of) or prevention (e.g., delaying the onset of or reducing ferent substituents. The carbonattached to R' and R' can be 30 the risk of developing) of one or more diseases, disorders, or (R) or (S) configured. In an embodiment, the (R) configured conditions caused by, or associated with, insufficient (e.g., formula (VI) compound can be substantially free of a formula aberrant) neurogenesis or unwanted neuronal cell death is (VI) compound that is S configured at the carbon atom featured. attached to R' and R". In some embodiments, the (S) con In embodiments, the one or more diseases, disorders, or figured formula (VI) compound can be substantially free of a 35 conditions can include neuropathies, nerve trauma, and neu formula (VI) compound that is (R) configured at the carbon rodegenerative diseases. In embodiments, the one or more atom attached to R' and R'. diseases, disorders, or conditions can be diseases, disorders, The compound of formula (VI), in Some embodiments, can or conditions caused by, or associated with insufficient neu be (+) or (-) (dextrorotatory). In some embodiments, the (+) rogenesis (e.g., aberrant hippocampal and/or hypothalamic (dextrorotatory) compound can be substantially free of a for 40 neurogenesis) as is believed to occur in neuropsychiatric dis mula (I) compound that is (levororotatory). In some embodi eases, or aberrant neuronal cell death as is believed to occur in ments, the (-) (levororotatory) compound can be substan neurodegenerative diseases. Examples of the one or more tially free of a formula (I) compound that is (+) diseases, disorders, or conditions include, but are not limited (dextrorotatory). to, Schizophrenia, major depression, bipolar disorder, normal Any of the aforementioned compounds can be used in any 45 aging, epilepsy, traumatic brain injury, post-traumatic stress of the methods or compositions described anywhere herein. disorder, Parkinson's disease, Alzheimer's disease, Down The presently disclosed embodiments relate generally to syndrome, spinocerebellar ataxia, amyotrophic lateral scle Stimulating neurogenesis (e.g., post-natal neurogenesis, e.g., rosis, Huntington's disease, stroke, radiation therapy, chronic post-natal hippocampal and/or hypothalamic neurogenesis) stress, and abuse of neuro-active drugs (such as alcohol, opi and protecting neurons from death with a compound of for 50 ates, methamphetamine, phencyclidine, and cocaine), retinal mula (I) (and/or a compound of any of the other formulae degeneration, spinal cord injury, peripheral nerve injury, described herein) or a salt (e.g., a pharmaceutically accept physiological weight loss associated with various conditions, able salt) thereofas defined anywhere herein. and cognitive decline associated with normal aging, radiation For example, methods of promoting the generation of neu therapy, and chemotherapy. rons are featured. As another example, methods of promoting 55 In some embodiments, the Subject can be a Subject in need the Survival, growth, development and/or function of neu thereof (e.g., a Subject identified as being in need of Such rons, particularly CNS, brain, cerebral, hippocampal and treatment, such as a Subject having, or at risk of having, one or hypothalamic neurons are featured. As a further example, more of the diseases or conditions described herein). Identi methods of stimulating post-natal hippocampal and/or hypo fying a Subject in need of Such treatment can be in the judg thalamic neurogenesis are featured. 60 ment of a Subject or a health care professional and can be In some embodiments, such methods can include in vitro Subjective (e.g. opinion) or objective (e.g. measurable by a methods, e.g., contacting a sample (e.g., a cell or tissue) with test or diagnostic method). In some embodiments, the Subject a compound of formula (I) (and/or a compound of any of the can be a mammal. In certain embodiments, the Subject can be other formulae described herein) or a salt (e.g., a pharmaceu a human. tically acceptable salt) thereofas defined anywhere herein. In 65 In another aspect, methods of making the compounds other embodiments, the methods can include administering a described herein are featured. In embodiments, the methods compound of formula (I) (and/or a compound of any of the include taking any one of the intermediate compounds US 9,095,572 B2 39 40 described herein and reacting it with one or more chemical embodiments, each of R and R is independently selected reagents in one or more steps to produce a compound of from halo, hydroxyl, sulfhydryl, C-C alkoxy, C-C thio formula (I) (and/or a compound of any of the other formulae alkoxy, C-C haloalkoxy, C-C thiohaloalkoxy, C-C, described herein) or a salt (e.g., a pharmaceutically accept alkyl, C-C haloalkyl, C-C alkynyl, cyclopropyl. —N. able salt) thereofas defined anywhere herein. cyano. —NH, -NH(C-C alkyl). —N(C-C alkyl). In some embodiments, compounds in which A is CHOH, NHC(O)(C-C alkyl), and nitro. For example, R can be and each of L' and L is C-C alkylene (e.g., each of L' and halo (e.g., bromo); and R' can be halo (e.g., bromo) or C-C, L is CH-) can be converted to compounds in which A is alkyl (e.g., CH); e.g., halo (e.g., bromo). In embodiments, C(O), and each of L' and L is C-C alkylene (e.g., each of L' each of R', R, and R is hydrogen; and each of R. R7, andR and L is CH,) that is substituted with C-C thioalkoxy (e.g., 10 is hydrogen. —SCH). The methods include contacting the starting mate rial with an oxidizing agent Sulfur trioxide pyridine complex In embodiments, RandR together with C and C, respec (see, e.g., Example 7a and 7b). tively, form a fused heteroaryl ring containing from 5-6 ring In one aspect, methods of making the pharmaceutical com atoms, wherein from 1-2 of the ring atoms is independently positions described herein are featured. In embodiments, the 15 selected from N, NH, N(C-C alkyl), O, and S; and wherein methods include taking any one or more of the compounds of said heteroaryl ring is optionally substituted with from 1-3 formula (I) (and/or compounds of any of the other formulae independently selected R. described herein) or a salt (e.g., a pharmaceutically accept For example, R and R together with C and C, respec able salt) thereofas defined anywhere herein, and mixing said tively, form a fused heteroaryl ring containing -6 ring atoms, compound(s) with one or more pharmaceutically acceptable wherein from 1-2 independently selected ring atoms is N; and carriers. wherein said heteroaryl ring is optionally substituted with In one aspect, kits for the treatment (e.g., controlling, from 1-2 independently selected R. relieving, ameliorating, alleviating, or slowing the progres In embodiments, RandR together with C and C, respec sion of) or prevention (e.g., delaying the onset of or reducing tively, form a fused heterocyclic ring containing from 5-6 ring the risk of developing) of one or more diseases, disorders, or 25 atoms, wherein from 1-2 of the ring atoms is independently conditions caused by, or associated with insufficient (e.g., selected from N, NH, N(C-C alkyl), NC(O)(C-C alkyl). aberrant) neurogenesis or unwanted neuronal cell death are O, and S; and wherein said heterocyclic ring is optionally featured. The kits include (i) a compound of formula (I) substituted with from 1-3 independently selected R. (and/or compounds of any of the other formulae described For example, R and R together with C and C, respec herein) or a salt (e.g., a pharmaceutically acceptable salt) 30 tively, form a fused heterocyclic ring containing 6 ring atoms, thereofas defined anywhere herein; and (ii) instructions that wherein from 1-2 of the ring atoms is independently selected include a direction to administer said compound to a subject from N, NH, N(C-C alkyl), and NC(O)(C-C alkyl); and (e.g., a patient). wherein said heterocyclic ring is optionally substituted with Embodiments can include, for example, any one or more of from 1-3 independently selected R. the following features. 35 In embodiments, R and R' is, independently, hydrogen, R is selected from halo, hydroxyl, sulfhydryl, C-C, C-C alkyl, or C-C haloalkyl (e.g., C-C alkyl, or C-C, alkoxy, C-C thioalkoxy, C-C haloalkoxy, C-C thioha haloalkyl, e.g., C-C alkyl). loalkoxy, C-C alkyl, C-Chaloalkyl, C-C alkynyl, cyclo Each of L' and L is, independently, C-C straight chain propyl. —N., cyano. —NH, -NH(C-C alkyl). —N(C- alkylene, which is optionally substituted with from 1-2 inde C NHC(O)(C-C alkyl), and nitro. In embodiments, R is 40 pendently selected R. For example, each of L' and L is CH. halo (e.g., bromo). In embodiments, each of R', R, and R is A is CR'R'', in which each of R'' and R' is, indepen hydrogen. dently, hydrogen, halo, C-C alkyl, or OR. RandR' together with C and C, respectively, form a fused In some embodiments, A is other than CH2. phenyl ring having formula (II): In embodiments, one of R' and R' can be independently 45 selected from hydrogen, halo, C-C alkyl, and OR: and the other of R'' and R' can be independently selected fromhalo, (II) C-C alkyl, and OR. For example, one of R'' and R' is halo, C-C alkyl, or OR (e.g., halo or OR); and the other is hydrogen or C1-C3 alkyl. 50 In embodiments, one of R' and R' is halo, and the other of R'' and R' is hydrogen or halo. For example, one of R' and R' is fluoro, and the other of R'' and R' is hydrogen or fluoro. In either embodiments, one of R'' and R' is OR: and the other of R' and R' is C-C alkyl. For example, one of 55 R'' and R' is OH; and the other of R'' and R' is CH3. In embodiments, the carbon attached to R' and R' is substituted with four different substituents (for purposes of R is selected from halo, hydroxyl, sulfhydryl, C-C, clarification, these four substituents include R' and R')and alkoxy, C-C thioalkoxy, C-C haloalkoxy, C-C thioha is therefore a stereogenic center. loalkoxy, C-C alkyl, C-Chaloalkyl, C-C alkynyl, cyclo 60 In certain embodiments, the carbon attached to R' and propyl. —N, cyano. —NH, -NH(C-C alkyl). —N(C- R' is (R) configured, meaning that the carbon attached to C alkyl). —NHC(O)(C-C alkyl), and nitro. In R'' and R' has the (R) configuration (Cahn Ingold Prelog embodiments, R is halo (e.g., bromo) or C-C alkyl (e.g., sequence rules notation). Such compounds are sometimes CH). In embodiments, R is halo (e.g., bromo). In embodi referred to herein as an “(R)-configured compound' (this ments, each of R. R. and R is hydrogen. 65 term also includes compounds that further contain one or In embodiments, each of R and R is an independently more stereogenic centers in addition to the (R) CR'R'' selected Substituent that is other than hydrogen. In certain Stereogenic center). US 9,095,572 B2 41 42 In other embodiments, the carbon attached to R' and R' that is (+) (dextrorotatory). In certain embodiments, the (-) is (S) configured, meaning that the carbon attached to R' and (levororotatory) compound can be additionally in Substan R" has the (S) configuration (Cahn Ingold Prelog sequence tially pure form (e.g., contains less than about 5% of less than rules notation). Such compounds are sometimes referred to about 2% of less than about 1%, less than about 0.5% of other herein as an "(S)-configured compound' (this term also Substances, including, for example, one or more of other includes compounds that further contain one or more stereo formula (I) compounds, non-formula (I) compounds, or bio genic centers in addition to the (5) —CR'R' stereogenic logical media). center). A is: (i) CR'R'', wherein each of R' and R' is inde In embodiments, the (R) configured compound (or salt, pendently selected from hydrogen, halo, C-C alkyl, and e.g., a pharmaceutically acceptable salt, thereof) is Substan 10 OR, wherein R is C-C alkyl that is optionally substituted tially free of (e.g., contains less than about 5% of less than with hydroxyl or C-C alkoxy; or (ii) C=O. about 2% of less than about 1%, less than about 0.5% of) a A is CR'R'', wherein each of R'' and R' is, indepen formula (I) compound (or salt thereof as described herein) dently, hydrogen, halo, C-C alkyl, or OR. that is (S) configured at the carbon attached to R' and R' In embodiments, one of R' and R' is independently (i.e., a formula (I) compound in which the carbon attached to 15 selected from hydrogen, halo, C-C alkyl, and OR; and the R'' and R' has the (S) configuration). For example, the (R) other of R'' and R' is independently selected from halo, configured compound can be an (R)-enantiomer that is Sub C-C alkyl, and OR. stantially free of its opposing (S) enantiomer. As another In certain embodiments, one of R' and R' is halo, and the example, an (R) configured compound can be substantially other of R'' and R' is hydrogen, halo, or C-C alkyl. In free of a diastereomerin which the carbonattached to R' and embodiments, one of R'' and R' is halo, and the other of R' R“has the (S) configuration. In certain embodiments, the (R) and R' is hydrogen. For example, one of R' and R' is configured compound can be additionally in Substantially fluoro, and the other of R' and R' is hydrogen. pure form (e.g., contains less than about 5% of less than In other embodiments, each of R'' and R' is, indepen about 2% of less than about 1%, less than about 0.5% of other dently, halo; e.g., each of R'' and R' is fluoro. Substances, including, for example, one or more of other 25 In embodiments, one of R'' and R' is -OH, and the other formula (I) compounds, non-formula (I) compounds, or bio of R'' and R' is hydrogen. logical media). In embodiments, A is CR'R'', wherein one of R'' and In embodiments, the (S) configured compound (or salt, R' is independently selected from hydrogen, halo, C-C, e.g., a pharmaceutically acceptable salt, thereof) is Substan alkyl, and OR: and the other of R'' and R' is independently tially free of (e.g., contains less than about 5% of less than 30 selected from halo, C-C alkyl, and OR; wherein R is about 2% of, less than, about 1%, less than about 0.5% of) a hydrogen or C-C alkyl that is optionally substituted with formula (I) compound (or salt thereof as described herein) hydroxyl or C-C alkoxy. that is (R) configured at the carbon attached to R' and R' In certain embodiments, one of R'' and R' is OR, and the (i.e., a formula (I) compound in which the carbon attached to other is hydrogen, wherein R is hydrogen. R'' and R' has the (R) configuration). For example, the (S) 35 In embodiments, one of R'' and R' is halo, and the other configured compound can be an (S)-enantiomer that is Sub of R'' and R' is hydrogen or halo. For example, one of R' stantially free of its opposing (R) enantiomer. As another and R' is fluoro, and the other of R'' and R' is hydrogen or example, the (S) configured compound can be substantially fluoro. free of a diastereomerin which the carbonattached to R' and In other embodiments, one of R'' and R' is OR: and the R“has the (R) configuration. In certain embodiments, the (S) 40 other of R'' and R' is C-C alkyl. For example, one of R' configured compound can be additionally in Substantially and R' is OH; and the other of R'' and R' is CH3. pure form (e.g., contains less than about 5% of less than Z is: (i) NR'R''; or (ii) C(O)NR'R'': or (iii) about 2% of less than about 1%, less than about 0.5% of other —OR'; or (iv)—S(O),R', wherein n is 0, 1, or 2. Substances, including, for example, one or more of other Zis NR'R''. In embodiments, one of R'' and R'' is: (b) formula (I) compounds, non-formula (I) compounds, or bio 45 Co-Co aryl that is optionally substituted with from 1-4 R”; or logical media). (c) heteroaryl containing from 5-14 ring atoms, wherein from In certain embodiments, a formula (I) compound is (+) 1-6 of the ring atoms is independently selected from N, NH, (dextrorotatory) when in the presence of plane polarized N(C-C alkyl). O, and S; and wherein said heteroaryl is light. optionally substituted with from 1-4 R”; and the other of R' In certain embodiments, a formula (I) compound is (-) 50 and R' is hydrogen or C-C alkyl. (levororotatory) when in the presence of plane polarized Z is OR' or S(O).R. light. In embodiments, Zis—OR''. In certain embodiments, R' In embodiments, the (+) (dextrorotatory) compound is Sub is Co-Co aryl that is optionally substituted with from 1-4 R. stantially free of (e.g., contains less than about 5% of less In embodiments, R' is C-C alkyl or C-C haloalkyl than about 2% of less than about 1%, less than about 0.5%) a 55 (e.g., C-C alkyl), each of which is substituted with from 1-3 formula (I) compound (or salt thereof as described herein) R". In other embodiments, R' is other than C-C alkyl or that is (-) (levororotatory). In certain embodiments, the (+) C-C haloalkyl (e.g., C-C alkyl), each of which is unsub (dextrorotatory) compound can be additionally in Substan stituted or substituted with from 1-3 R'. tially pure form (e.g., contains less than about 5% of less than Rican be selected from halo, hydroxyl, sulfhydryl, C-C, about 2% of less than about 1%, less than about 0.5% of other 60 alkoxy, C-C thioalkoxy, C-C haloalkoxy, C-C thioha Substances, including, for example, one or more of other loalkoxy, C-C alkyl, C-Chaloalkyl, cyano. —NH, -NH formula (I) compounds, non-formula (I) compounds, or bio (C-C alkyl), N(C-C alkyl). —NHC(O)(C-C alkyl), and logical media). nitro. E.g., R can be halo (e.g., bromo). In embodiments, In embodiments, the (-) (levororotatory) compound is Sub each of R', R, and R' can be hydrogen. stantially free of (e.g., contains less than about 5% of less 65 L' can be C-C straight chain alkylene, which is option than about 2% of less than about 1%, less than about 0.5%) a ally substituted with from 1-2 independently selected R. formula (I) compound (or salt thereof as described herein) E.g., L' can be CH2. US 9,095,572 B2 43 44 L can be C-C straight chain alkylene, which is option ally substituted with from 1-2 independently selected R. E.g., L can be CH. R6 (II) Each of L' and Li can be, independently, C-C straight R R7 chain alkylene, which is optionally substituted with from 1-2 independently selected R. E.g., each of L' and Li can be rs CH. C A can be CR'R'', in which each of R'' and R' is, independently, hydrogen, halo, C-C alkyl, or OR. >'s A can be CR'R'', in which each of R' and R' is, 10 independently, hydrogen, halo, or C-C alkyl. A can be CR'R'', in which one of R' and R' is halo (e.g., fluoro), and the other of R' and R' is, independently, R” can be selected from halo, hydroxyl, sulfhydryl, C-C, hydrogen, halo, or C-C alkyl (e.g., hydrogen). alkoxy, C-C thioalkoxy, C-C haloalkoxy, C-C thioha A can be CR'R'', in which one of R' and R' is halo 15 loalkoxy, C-C alkyl, C-Chaloalkyl, cyano. —NH, -NH (e.g., fluoro), and the other of R' and R' is hydrogen. (C-C alkyl), N(C-C alkyl). —NHC(O)(C-C alkyl), and One of R'' and R' can be halo or OR, and the other is nitro. E.g., R can be halo (e.g., bromo). In embodiments, hydrogen. each of R. R', and R can be hydrogen. Any one or more of One of R'' and R' can be OR. In embodiments, the other the R', R. R. R. L., L, A, and Z embodiments described of R'' and R' can be as defined anywhere herein; e.g., the herein can be combined with any one or more of the R. R. other of R' and R' can be hydrogen or C-C alkyl. For R", and Rembodiments described herein. example, one of R'' and R' can be OR, and the other of R' Each of L' and Li can be CH: A can be CR'R'', wherein and R' is hydrogen. In embodiments, R can be hydrogen. one of R'' and R' is OR, and the other is hydrogen; Z is One of R' and R' can behalo. In embodiments, the other 25 - NR'R''; and each of R'' and R' can be independently of R'' and R' can be as defined anywhere herein; e.g., the selected from: (a) hydrogen; (b) Co-Co aryl that is optionally other of R'' and R' can be hydrogen, C-C alkyl, or halo. substituted with from 1-4 R”; (d) C-C alkyl or C-C, For example, one of R' and R' can be halo (e.g., fluoro), haloalkyl, each of which is optionally substituted with from and the other of R'' and R' is hydrogen. 1-3 R', and (t) C-C alkenyl or C-C alkynyl. The carbon attached to R' and R' can have the R con 30 Each of RandR can behalo (e.g., bromo); and each of R', figuration. R. R. R. R. and Rican be hydrogen. R can be hydrogen. The carbon attached to R' and R' can have the S con One of R'' and R' can be Co-Co aryl that is optionally figuration. substituted with from 1-4 R', and the other is hydrogen. One Each of L' and Lis, independently, C-C alkylene, which of R'' and R' can be unsubstituted phenyl, and the other is is optionally substituted with from 1-2 independently 35 hydrogen. One of R'' and R' can bephenyl that is substituted selected R. E.g., each of L' and L’ can be CH. with 1 R, and the other is hydrogen. R” can be C-C alkoxy Z can be NR'R''. (e.g., OCH). One of R'' and R' can be 3-methoxyphenyl, One of R'' and R' can be C-C aryl that is optionally and the other is hydrogen. substituted with from 1-4 R. 40 Each of L' and L is CH: A is CR'R'', wherein one of One of R'' and R' can be Co-Co aryl that is optionally R'' and R' is OR, and the other is hydrogen; Z is substituted with from 1-4 R', and the other is hydrogen or - NR'R''; and each of R'' and is independently selected C-C alkyl. from: (a) hydrogen; (b) C-C aryl that is optionally substi One of R'' and R' can be Co-Co aryl that is optionally tuted with from 1-4 R”; (d) C-C alkyl or C-C haloalkyl, substituted with from 1-4 R', and the other is hydrogen. For 45 each of which is optionally substituted with from 1-3 R', and example, one of R'' and R' can be unsubstituted phenyl, and (f) C-C alkenyl or C-C alkynyl. Embodiment can include the other is hydrogen. As another example, one of R'' and R' one or more of the following features. can be phenyl that is substituted with 1 R, and the other is Each of RandR is halo (e.g., bromo); and each of R', R, hydrogen. In embodiments, R' can be C-C alkoxy (e.g., R. R. R', and R is hydrogen. R can be hydrogen. One of OCH). For example, one of R'' and R' can be 3-methox 50 R" and R' can be Co-Co aryl that is optionally substituted yphenyl, and the other is hydrogen. with from 1-4 R', and the other is hydrogen. One of R'' and Zcan be -OR''. In embodiments, R' can be C-C alkyl or R' can be unsubstituted phenyl, and the other is hydrogen. C-Chaloalkyl, each of which is optionally substituted with One of R'' and R' can bephenyl that is substituted with 1 R, from 1-3 R. In other embodiments, R' can be C-C aryl and the other is hydrogen. R' can be C-C alkoxy (e.g., that is optionally substituted with from 1-4 R. For example, 55 OCH). One of R'' and R' can be 3-methoxyphenyl, and the R' can be unsubstituted phenyl. other is hydrogen. Z can be S(O),R', in which n can be 0, 1, or 2. In other In embodiments, (A), (B), or (C) applies. In other embodi embodiments, R' can be Co-Co aryl that is optionally sub ments, (A) and (B); or (A) and (C); or (B) and (C) applies. In stituted with from 1-4 R. For example, R' can be unsubsti still other embodiments, (A), (B), or (C) apply. tuted phenyl. 60 Each of R and R' can be, independently, hydrogen, C-C, Z can be heterocycloalkenyl containing from 5-6 ring alkyl, or C-C haloalkyl. Each of R and R' can be, indepen atoms, wherein from 1-3 of the ring atoms is independently dently, C-C alkyl (e.g., each of R and R' can be CH). Each selected from N, NH, N(C-C alkyl), NC(O)(C-C alkyl). of R and R' can be hydrogen. O, and S; and wherein said heterocycloalkenyl is optionally The compound having formula (I) can include any one or substituted with from 1-4 independently selected R'. 65 more of or be selected from: RandR' together with C and C, respectively, form a fused R-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxypheny phenyl ring having formula (II): lamino)-propan-2-ol;

US 9,095,572 B2 49 50 1-(8-bromo-2-cyclopropyl-3,4-dihydro-1H-pyrido4.3-bin tically acceptable salt) thereof can be substantially free of dol-5(2H)-yl)-3-phenoxypropan-2-ol; (e.g., contains less than about 5% of less than about 2% of 8-bromo-5-(2-hydroxy-3-phenoxypropyl)-3,4-dihydro-1H less than about 1%, less than about 0.5% of) the (-) (levoro pyrido4.3-bindole-2(5H)-carbonitrile; tatory) enantiomer of 1-(3,6-Dibromo-9H-carbazol-9-yl)-3- 8-bromo-5-(2-fluoro-3-phenoxypropyl)-2,3,4,5-tetrahydro 5 (3-methoxyphenylamino)-propan-2-ol as described herein or 1H-pyrido4,3-bindole; a salt (e.g., a pharmaceutically acceptable salt) thereof. 1-(cyclohexylamino)-3-(3,6-dibromo-9H-carbazol-9-yl) In certain embodiments, the compound having formula (I) propan-2-ol; can be the (-) (levorotatory) enantiomer of 1-(3,6-Dibromo (9-(2-hydroxy-3-(phenylthio)propyl)-9H-carbazole-3,6-di 9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol carbonitrile; 10 as described herein or a salt (e.g., a pharmaceutically accept 9-(2-hydroxy-3-phenoxypropyl)-9H-carbazole-3,6-dicarbo able salt) thereof. See, e.g., Example 1a and 1b. In embodi nitrile; ments, the (-) (levorotatory) enantiomer of 1-(3,6-Dibromo R N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)- 9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol 3-methoxyaniline as described herein or a salt (e.g., a pharmaceutically accept S N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)- 15 able salt) thereof can be substantially free of (e.g., contains 3-methoxyaniline less than about 5% of less than about 2% of, less than about N-(2-(3,6-dibromo-9H-carbazol-9-yl)ethyl)aniline; 1%, less than about 0.5% of) the (+) (dextrorotatory) enanti 2-(6-Amino-3-imino-3H-xanthen-9-yl)-4-(6-(5-(3-(3-(3,6- omer of 1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methox dibromo-91'-carbazol-9-yl)-2-hydroxypropylamino)phe yphenylamino)-propan-2-olas described herein or a salt (e.g., noxy)pentylamino)-6-oxohexylcarbamoyl)benzoic acid a pharmaceutically acceptable salt) thereof. AND 2-(6-amino-3-imino-3H-xanthen-9-yl)-5-(6-(5-(3- In certain embodiments, the compound can be (+) (dex (3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropy trorotatory)-N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoro lamino)phenoxy)pentylamino)-6-oxohexylcarbamoyl) propyl)-3-methoxyaniline as described herein or a salt (e.g., a benzoic acid; pharmaceutically acceptable salt) thereof. See, e.g., Example 1-(8-bromo-2-methyl-3,4-dihydro-1H-pyrido4.3-bindol-5 25 144a and 144b. In embodiments, the (+) (levorotatory) enan (2H)-yl)-3-phenoxypropan-2-ol; tiomer of N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoro 6-(4-bromophenyl)(2-hydroxy-3-phenoxypropyl)amino) propyl)-3-methoxyaniline as described herein or a salt (e.g., a nicotinonitrile; pharmaceutically acceptable salt) thereof can be substantially 1-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)py free of (e.g., contains less than about 5% of less than about ridin-2(1H)-one: 30 2% of less than about 1%, less than about 0.5% of) the (-) or a salt (e.g., a pharmaceutically acceptable salt) thereof (dextrorotatory) enantiomer of N-(3-(3,6-dibromo-9H-car (or any one or a subset thereof, e.g., as delineated in the bazol-9-yl)-2-fluoropropyl)-3-methoxyaniline as described claims). herein or a salt (e.g., a pharmaceutically acceptable salt) In certain embodiments, the compound having formula (I) thereof. can be 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylamino) 35 In certain embodiments, the compound can be (-) (dex propan-2-ol; or a salt (e.g., a pharmaceutically acceptable trorotatory)-N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoro salt) thereof. propyl)-3-methoxyaniline as described herein or a salt (e.g., a In certain embodiments, the compound having formula (I) pharmaceutically acceptable salt) thereof. See, e.g., Example can be R-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methox 144a and 144b. In embodiments, the (-) (levorotatory) enan yphenylamino)-propan-2-ol; or a salt (e.g., a pharmaceuti 40 tiomer of N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoro cally acceptable salt) thereof. In embodiments, R-1-(3,6-Di propyl)-3-methoxyaniline as described herein or a salt (e.g., a bromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)- pharmaceutically acceptable salt) thereof can be substantially propan-2-olora salt (e.g., a pharmaceutically acceptable salt) free of (e.g., contains less than about 5% of less than about thereof can be substantially free of (e.g., contains less than 2% of less than about 1%, less than about 0.5% of) the (+) about 5% of, less than about 2% of less than about 1%, less 45 (dextrorotatory) enantiomer of N-(3-(3,6-dibromo-9H-car than about 0.5% of) S-1-(3,6-Dibromo-9H-carbazol-9-yl)-3- bazol-9-yl)-2-fluoropropyl)-3-methoxyaniline as described (3-methoxyphenylamino)-propan-2-ol or a salt (e.g., a phar herein or a salt (e.g., a pharmaceutically acceptable salt) maceutically acceptable salt) thereof. thereof. In certain embodiments, the compound having formula (I) Compounds of formula (I), (II), (III), and (IV) are featured, can be S-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methox 50 including title compounds of Examples 1a, 1b, 3a, 3b, 3d, 6a, yphenylamino)-propan-2-ol; or a salt (e.g., a pharmaceuti 10, 13, 21, 22, 88b, 90,92, 96, 97a,97b, 102,116, 117, 118, cally acceptable salt) thereof. In embodiments, S-1-(3,6-Di 119, 120, 121, 122, 132,143, and 144a: or a pharmaceutically bromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)- acceptable salt thereof. propan-2-olora salt (e.g., a pharmaceutically acceptable salt) In various embodiments, compounds of formula (I), (II), thereof can be substantially free of (e.g., contains less than 55 (III), and (IV) can be used in a method for the treatment of a about 5% of, less than about 2% of less than about 1%, less disease, disorder, or condition caused by unwanted neuronal than about 0.5% of) R-1-(3,6-Dibromo-9H-carbazol-9-yl)-3- cell death or associated with insufficient neurogenesis in a (3-methoxyphenylamino)-propan-2-ol or a salt (e.g., a phar subject in need thereof. The method can include administer maceutically acceptable salt) thereof. ing to the Subject an effective amount of a compound having In certain embodiments, the compound having formula (I) 60 formula (I), (II), (III), or (VI), or a pharmaceutically accept can be the (+) (dextrorotatory) enantiomer of 1-(3,6-Di able salt thereof, as defined herein. bromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-pro The methods can further include detecting a resultant neu pan-2-ol as described herein or a salt (e.g., a pharmaceutically rotrophism (e.g., neurogenesis; and/or determining that the acceptable salt) thereof. See, e.g., Example la and 1b. In patient has aberrant neurotrophism, particularly aberrant neu embodiments, the (+) (dextrorotatory) enantiomer of 1-(3,6- 65 rogenesis, particularly aberranthippocampal and/or hypotha Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)- lamic neurogenesis, or a disease or disorder associated there propan-2-ol as described herein or a salt (e.g., a pharmaceu with, particularly by detecting and/or diagnosing the same. US 9,095,572 B2 51 52 The methods can further include detecting a resultant neu objective (i.e., measurable by some test or marker) or Subjec rotrophism. tive (i.e., Subject gives an indication of or feels an effect). An The methods can further include detecting determining effective amount of the compound described above may that the Subject has aberrant neurogenesis or death of neurons range from about 0.01 mg/kg to about 1000 mg/kg, (e.g., from or a disease or disorder associated therewith, by detecting the 5 about 0.1 mg/kg to about 100 mg/kg, from about 1 mg/kg to same in said subject. about 100 mg/kg). Effective doses will also vary depending The methods can further include detecting a resultant hip on route of administration, as well as the possibility of co pocampal and/or hypothalamic neurogenesis. usage with other agents. The disease, disorder, or condition can be a neuropsychi The term “halo' or “halogen refers to any radical of fluo atric and neurodegenerative disease, including (but not lim 10 ited to) Schizophrenia, major depression, bipolar disorder, rine, chlorine, bromine or iodine. normal aging, epilepsy, traumatic brain injury, post-traumatic In general, and unless otherwise indicated, Substituent stress disorder, Parkinson's disease, Alzheimer's disease, (radical) prefix names are derived from the parent hydride by Down syndrome, spinocerebellar ataxia, amyotrophic lateral either (i) replacing the “ane' in the parent hydride with the Sclerosis, Huntington's disease, stroke, radiation therapy, 15 suffixes “yl,”“diyl.”“triyl.”“tetrayl,” etc.; or (ii) replacing the chronic stress, and abuse of neuro-active drugs (such as alco “e' in the parent hydride with the suffixes “yl,” “diyl.”“triyl.” hol, opiates, methamphetamine, phencyclidine, and cocaine), “tetrayl, etc. (here the atom(s) with the free valence, when retinal degeneration, spinal cord injury, peripheral nerve specified, is (are) given numbers as low as is consistent with injury, physiological weight loss associated with various con any established numbering of the parent hydride). Accepted ditions, and cognitive decline associated with normal aging, contracted names, e.g., adamantyl, naphthyl, anthryl, and chemotherapy. phenanthryl, furyl, pyridyl, isoquinolyl, quinolyl, and pip In some embodiments, the compounds having formula (I) eridyl, and trivial names, e.g., vinyl, allyl, phenyl, and thienyl or a salt (e.g., a pharmaceutically acceptable salt) thereof are also used herein throughout. Conventional numbering/ provide at least about 27 (x10') BrdU+ cells/mm dentate lettering systems are also adhered to for Substituent number gyrus when evaluated in the assay described in conjunction 25 ing and the nomenclature of fused, bicyclic, tricyclic, poly with Table 1 (i.e., evaluated for pro-neurogenic efficacy/neu cyclic rings. roprotection in our standard in vivo assay at 10 LM concen The following definitions are used, unless otherwise tration in four 12 week old adult male C57B16 mice. described. Specific and general values listed below for radi In some embodiments, the compounds having formula (I) cals, Substituents, and ranges, are for illustration only; they do or a salt (e.g., a pharmaceutically acceptable salt) thereof 30 not exclude other defined values or other values within provide at least about 19 (x10') BrdU+ cells/mm dentate defined ranges for the radicals and Substituents. Unless oth gyrus when evaluated in the assay described in conjunction erwise indicated, alkyl, alkoxy, alkenyl, and the like denote with Table 1. both straight and branched groups. In some embodiments, the compounds having formula (I) The term “alkyl refers to a saturated hydrocarbon chain or a salt (e.g., a pharmaceutically acceptable salt) thereof 35 that may be a straight chain or branched chain, containing the provide from about 18 to about 30 (e.g., 18-27, 19-26, 20-25, indicated number of carbon atoms. For example, C-C alkyl 27-30, 27-29) (x10') BrdU+ cells/mm dentate gyrus when indicates that the group may have from 1 to 6 (inclusive) evaluated in the assay described in conjunction with Table 1. carbon atoms in it. Any atom can be optionally Substituted, In some embodiments, the compounds having formula (I) e.g., by one or more Substituents. Examples of alkyl groups or a salt (e.g., a pharmaceutically acceptable salt) thereof 40 include without limitation methyl, ethyl, n-propyl, isopropyl. provide from about 18 to about 26 (e.g., 19-26, 20-25) (x10 and tert-butyl. o6) BrdU+ cells/mm dentate gyrus when evaluated in the As used herein, the term “straight chain C, alkylene.” assay described in conjunction with Table 1. employed alone or in combination with other terms, refers to In some embodiments, the compounds having formula (I) a non-branched divalent alkyl linking group having n to m or a salt (e.g., a pharmaceutically acceptable salt) thereof 45 carbon atoms. Any atom can be optionally Substituted, e.g., provide from about 27 to about 30 (e.g., 27-29) (x10') by one or more substituents. Examples include methylene BrdU+ cells/mm dentate gyrus when evaluated in the assay (i.e., —CH2—). described in conjunction with Table 1. The term “haloalkyl refers to an alkyl group, in which at In embodiments, a composition (e.g., a pharmaceutical least one hydrogenatom is replaced by halo. In some embodi composition) can include an amount effective to achieve the 50 ments, more than one hydrogen atom (e.g., 2, 3, 4, 5, 6, 7, 8, levels described above. 9, 10, 11, 12, 13, or 14) are replaced by halo. In these embodi In embodiments, any compound, composition, or method ments, the hydrogenatoms can each be replaced by the same described herein can also include any one or more of the other halogen (e.g., fluoro) or the hydrogen atoms can be replaced features delineated in the detailed description and/or in the by a combination of different halogens (e.g., fluoro and claims. 55 chloro). “Haloalkyl also includes alkyl moieties in which all hydrogens have been replaced by halo (sometimes referred to DEFINITIONS herein as perhaloalkyl, e.g., perfluoroalkyl. Such as trifluo romethyl). Any atom can be optionally substituted, e.g., by The term “mammal’ includes organisms, which include one or more substituents. mice, rats, cows, sheep, pigs, rabbits, goats, horses, monkeys, 60 As referred to herein, the term “alkoxy' refers to a group of dogs, cats, and humans. formula —O(alkyl). Alkoxy can be, for example, methoxy An effective amount” refers to an amount of a compound (—OCH), ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, that confers a therapeutic effect (e.g., treats, e.g., controls, sec-butoxy, pentoxy, 2-pentoxy, 3-pentoxy, or hexyloxy. relieves, ameliorates, alleviates, or slows the progression of Likewise, the term “thioalkoxy' refers to a group of formula or prevents, e.g., delays the onset of or reduces the risk of 65 —S(alkyl). Finally, the terms “haloalkoxy' and “thioalkoxy” developing, a disease, disorder, or condition or symptoms refer to —O(haloalkyl) and—S(haloalkyl), respectively. The thereof) on the treated subject. The therapeutic effect may be term "sulfhydryl refers to —SH. As used herein, the term US 9,095,572 B2 53 54 “hydroxyl employed alone or in combination with other The term “cycloalkenyl refers to partially unsaturated terms, refers to a group of formula—OH. monocyclic, bicyclic, tricyclic, or other polycyclic hydrocar The term “aralkyl refers to an alkyl moiety in which an bon groups. A ring carbon (e.g., Saturated or unsaturated) is alkyl hydrogen atom is replaced by an aryl group. One of the the point of attachment of the cycloalkenyl substituent. Any carbons of the alkyl moiety serves as the point of attachment atom can be optionally Substituted e.g., by one or more Sub of the aralkyl group to another moiety. Any ring or chain atom stituents. Cycloalkenyl moieties can include, e.g., cyclohex can be optionally Substituted e.g., by one or more substitu enyl, cyclohexadienyl, or norbornenyl. ents. Non-limiting examples of “aralkyl include benzyl, As used herein, the term “cycloalkylene' refers to a diva 2-phenylethyl, and 3-phenylpropyl groups. lent monocyclic cycloalkyl group having the indicated num 10 ber of ring atoms. The term “alkenyl refers to a straight or branched hydro As used herein, the term "heterocycloalkylene' refers to a carbon chain containing the indicated number of carbon divalent monocyclic heterocyclyl group having the indicated atoms and having one or more carbon-carbon double bonds. number of ring atoms. Any atom can be optionally Substituted, e.g., by one or more The term “aryl” refers to an aromatic monocyclic, bicyclic Substituents. Alkenyl groups can include, e.g., vinyl, allyl, 15 (2 fused rings), or tricyclic (3 fused rings), or polycyclic (>3 1-butenyl, and 2-hexenyl. One of the double bond carbons can fused rings) hydrocarbon ring system. One or more ring optionally be the point of attachment of the alkenyl substitu atoms can be optionally substituted, e.g., by one or more ent. Substituents. Aryl moieties include, e.g., phenyland naphthyl. The term “alkynyl refers to a straight or branched hydro The term "heteroaryl” refers to an aromatic monocyclic, carbon chain containing the indicated number of carbon bicyclic (2 fused rings), tricyclic (3 fused rings), or polycyclic atoms and having one or more carbon-carbon triple bonds. (>3 fused rings) hydrocarbon groups having one or more Alkynyl groups can be optionally Substituted, e.g., by one or heteroatom ring atoms independently selected from O, N (it is more Substituents. Alkynyl groups can include, e.g., ethynyl, understood that one or two additional groups may be present propargyl, and 3-hexynyl. One of the triple bond carbons can to complete the nitrogen Valence and/or form a salt), or S. One optionally be the point of attachment of the alkynyl substitu 25 or more ring atoms can be optionally substituted, e.g., by one ent. or more Substituents. The term "heterocyclyl refers to a fully saturated mono Examples of heteroaryl groups include, but are not limited cyclic, bicyclic, tricyclic or other polycyclic ring system hav to, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, acridinyl, ing one or more constituent heteroatom ring atoms indepen benzob thienyl, benzothiazolyl, B-carbolinyl, carbazolyl, dently selected from O, N (it is understood that one or two 30 coumarinyl, chromenyl, cinnolinyl, dibenzob.dfuranyl. additional groups may be present to complete the nitrogen furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolyl, valence and/or form a salt), or S. The heteroatom or ring isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isox carbon can be the point of attachment of the heterocyclyl azolyl, naphthyridinyl, oxazolyl, perimidinyl, phenanthridi Substituent to another moiety. Any atom can be optionally nyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothi Substituted, e.g., by one or more Substituents. Heterocyclyl 35 azinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, groups can include, e.g., tetrahydrofuryl, tetrahydropyranyl. pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl pyridazi piperidyl (piperidino), piperazinyl, morpholinyl (mor nyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, pholino), pyrrolinyl, and pyrrolidinyl. By way of example, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, the phrase "heterocyclic ring containing from 5-6 ring atoms, triazolyl, and Xanthenyl. wherein from 1-2 of the ring atoms is independently selected 40 The terms “arylcycloalkyl and “arylheterocyclyl refer to from N, NH, N(C-C alkyl), NC(O)(C-C alkyl), O, and S; bicyclic, tricyclic, or other polycyclic ring systems that and wherein said heterocyclic ring is optionally Substituted include an aryl ring fused to a cycloalkyl and heterocyclyl, with from 1-3 independently selected R' would include (but respectively. Similarly, the terms "heteroarylheterocyclyl. not be limited to) tetrahydrofuryl, tetrahydropyranyl, pip and "heteroarylcycloalkyl refer to bicyclic, tricyclic, or eridyl (piperidino), piperazinyl, morpholinyl (morpholino), 45 other polycyclic ring systems that include a heteroaryl ring pyrrolinyl, and pyrrolidinyl. fused to a heterocyclyl and cycloalkyl, respectively. Any atom The term "heterocycloalkenyl refers to partially unsatur can be substituted, e.g., by one or more substituents. For ated monocyclic, bicyclic, tricyclic, or other polycyclic example, arylcycloalkyl can include indanyl: arylheterocy hydrocarbon groups having one or more (e.g., 1-4) heteroa clyl can include 2,3-dihydrobenzofuryl, 1,2,3,4-tetrahy tom ring atoms independently selected from O, N (it is under 50 droisoquinolyl, and 2.2-dimethylchromanyl. stood that one or two additional groups may be present to The descriptors “C=O or “C(O)” refers to a carbonatom complete the nitrogen Valence and/or form a salt), or S. A ring that is doubly bonded to an oxygen atom. carbon (e.g., Saturated or unsaturated) or heteroatom can be The term “oxo” refers to double bonded oxygen when a the point of attachment of the heterocycloalkenyl substituent. Substituent on carbon. When oxo is a Substituent on nitrogen Any atom can be optionally Substituted, e.g., by one or more 55 or Sulfur, it is understood that the resultant groups has the Substituents. Heterocycloalkenyl groups can include, e.g., structures N->O and S(O) and SO, respectively. dihydropyridyl, tetrahydropyridyl, dihydropyranyl. 4,5-dihy As used herein, the term "cyano employed alone or in drooxazolyl. 4,5-dihydro-1H-imidazolyl, 1,2,5,6-tetrahydro combination with other terms, refers to a group of formula pyrimidinyl, and 5,6-dihydro-2H-1,3oxazinyl. —CN, wherein the carbon and nitrogen atoms are bound The term “cycloalkyl refers to a fully saturated monocy 60 together by a triple bond. clic, bicyclic, tricyclic, or other polycyclic hydrocarbon In general, when a definition for a particular variable groups. Any atom can be optionally Substituted, e.g., by one includes both hydrogen and non-hydrogen (halo, alkyl, aryl, or more substituents. A ring carbon serves as the point of etc.) possibilities, the term “substituent(s) other than hydro attachment of a cycloalkyl group to another moiety. gen” refers collectively to the non-hydrogen possibilities for Cycloalkyl moieties can include, e.g., cyclopropyl, cyclobu 65 that particular variable. tyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and The term “substituent” refers to a group “substituted on, norbornyl (bicycle 2.2.1]heptyl). e.g., an alkyl, haloalkyl, cycloalkyl, heterocyclyl, heterocy US 9,095,572 B2 55 56 cloalkenyl, cycloalkenyl, aryl, or heteroaryl group at any which 40% of newborn cells in the SGZ normally die, would atom of that group. In one aspect, the Substituent(s) on agroup allow detection of compounds that enhance either prolifera are independently any one single, or any combination of two tion or survival of newborn cells in the dentate gyrus. or more of the permissible atoms or groups of atoms delin FIG. 2: Surgical placement of cannula and pumps did not eated for that Substituent. In another aspect, a Substituent may 5 affect hippocampal neurogenesis or Survival of newborn neu itself be substituted with any one of the above substituents. rons on the contralateral side of the brain. Mice infused with Further, as used herein, the phrase “optionally substituted vehicle (artificial cerebrospinal fluid) over seven days by means unsubstituted (e.g., Substituted with a H) or Substi means of Surgically implanted Alzet osmotic minipumps (Ve tuted. As used herein, the term "substituted” means that a hicle Infusion, n=5) displayed no difference in hippocampal hydrogenatom is removed and replaced by a Substituent. It is 10 neural precursor cell proliferation, as assessed by BrdU incor understood that Substitution at a given atom is limited by poration normalized for dentate gyrus Volume, from mice Valency. treated identically except not having undergone Surgery (No Descriptors such as "C-Clo aryl that is optionally Substi Surgery, n=4). When Alzet osmotic minipumps were loaded tuted with from 1-4 independently selected R” (and the like) with fibroblast growth factor 2 (FGF-2: 10 mg/mL) (n=5), is intended to include both an unsubstituted Co-Co aryl group 15 however, hippocampal neural precursor cell proliferation and a Co-Co aryl group that is Substituted with from 1-4 roughly doubled with respect to both of the other two groups independently selected R. The use of a substituent (radical) (*, p<0.001, Student's t test). prefix names such as alkyl without the modifier “optionally FIG. 3: Ectopic incorporation of BrdU served to eliminate substituted” or “substituted' is understood to mean that the molecules from further consideration. Immunohistochemical particular substituent is unsubstituted. However, the use of staining of BrdU in the hippocampal field should normally be “haloalkyl without the modifier “optionally substituted” or restricted to the SGZ of the dentate gyrus, as shown on the “Substituted” is still understood to mean an alkyl group, in left. The in vivo neurogenic screen employed was designed to which at least one hydrogen atom is replaced by halo. detect small molecules that selectively stimulated BrdU In some embodiments, R” can be as defined in anyone, two, incorporation into replicating cells of the SGZ. Infrequently, three, or all of (aa) through (dd). For example, R' can be as 25 Some compounds exhibited non-specific BrdU incorporation defined in (aa) and (bb) or combinations thereof. in ectopic regions. Such as CA3, CA1, cortex, and striatum, as The phrase “Cy is a saturated, partially unsaturated or shown on the right. Any molecules that demonstrated ectopic aromatic carbocyclic or heterocyclic ring system” in the defi incorporation of BrdU were eliminated from the study. nition of R is understood to include each of the rings systems FIG. 4: Screening of 100 pools of 10 compounds identified defined above (e.g., Cy can be coumarinyl or the ring com 30 10 pools with pro-neurogenic efficacy. The total number of ponent of biotin optionally substituted as defined anywhere BrdU-labeled cells in the dentate gyrus subgranular Zone herein). (SGZ) approximately doubled following seven day infusion The details of one or more embodiments are set forth in the with fibroblast growth factor 2 (FGF-2: 10 mg/mL) (n=5) description below. Other features and advantages of the pres relative to mice infused with vehicle (artificial cerebrospinal ently disclosed embodiments will be apparent from the 35 fluid (aCSF) (n=5). Each pool often compounds was tested description and from the claims. for pro-neurogenic efficacy over a 7 day period in two inde pendent mice at 10 uM concentration for each individual BRIEF DESCRIPTION OF THE DRAWINGS compound. Pools 7, 14, 18, 19, 41, 53, 54, 61, 69 and 70 displayed comparable stimulation of neural precursor cell FIG. 1: Pulse-chase analysis of BrdU-labeling identified 40 proliferation as FGF-2 infusion. The majority of pools dis magnitude and timing of cell death following birth of new played no effect on hippocampal neural precursor cell prolif neurons in the dentate gyrus. 12 week old wild type male eration. C57/B6 mice were individually housed without access to FIG. 5: Re-evaluation of positive pools verified statistical running wheels and injected on day 0 with BrdU (50 mg/kg, significance of enhanced BrdU-incorporation. Subsequent to i.p.). Neural precursor cell proliferation in the dentate gyrus 45 their initial identification, pools 7, 14, 18, 19, 41, 53, 54, 61. (DG) subgranular Zone (SGZ) and granular layer (GL) was 69, and 70 were re-evaluated in 2 additional mice each. Subsequently monitored through immunohistochemistry for Results shown are average with SEM of all 4 mice evaluated BrdU on days 1, 5, 10, 15, 20, and 25 days post-injection. for each compound. All pools significantly (, P-0.001, Stu Four mice were evaluated at each time point, and 25-30 dent's t test) stimulated neural precursor cell proliferation in adjacent coronal sections through the hippocampus (pro 50 the hippocampal dentate gyrus SGZ relative to vehicle con gressing posteriorly from the point where the Suprapyramidal trol. and infrapyramidal blades are joined at the crest region and FIG. 6: Pro-neurogenic pools were broken down to identify the dentate gyrus is oriented horizontally beneath the corpus individual pro-neurogenic compounds. (A) In vivo evaluation callosum) from each mouse were examined. On days 1 and 5. of the ten individual compounds that composed pool #7 almost 100% of BrdU-positive cells within the DG were 55 revealed that compound #3 stimulated either the proliferation localized in the SGZ. The total number of cells decreased or survival of neural precursor cells in the SGZ, whereas the approximately 40% between days 1 and 5, in accordance with remaining individual components of pool #7 did not. In this the appearance of apoptotic cell bodies in the SGZ. By day 10, document this molecule is interchangeably referred to as some BrdU positive cells had migrated into the GL, with no “P7C3 or “Example 45 Compound. Each compound was significant change in total number of BrdU-positive cells in 60 infused at two different concentrations (100 uM (A and B) the DG. By day 15, BrdU-positive cells in the SGZ declined and 10 uM (C and D)) in two mice each. Example 45 Com as the number of BrdU-positive cells in the GL stayed con pound showed either pro-neurogenic or neuroprotective stant, Suggesting that some of the cells migrating out of the activity at both concentrations. Below the graphs are typical SGZ and into the GL between days 10 and 15 underwent results of BrdU incorporation in the SGZ, which is notably apoptosis. This trend continued through days 20-25. These 65 greater in animals infused with either Pool #7 or Example 45 results indicated that daily injection of BrdU over a one week Compound. (B) Molecular formulas and weights of indi period of continuous molecule infusion, a time period during vidual pro-neurogenic compounds identified through the in US 9,095,572 B2 57 58 Vivo Screen. (C) Re-Supplied compounds were evaluated in animals/group), administered a single pulse of BrdU via IP three mice per compound at 10 uM concentration to verify injection (150 mg/kg), and then sacrificed 1 hour, 1 day, 5 that the pro-neurogenic or neuroprotective effect on neural days or 30 days later for immunohistochemical detection of stem cells was not an artifact of storage conditions in the BrdU incorporation into cells localized in the subgranular UTSWMC chemical compound library. Re-supplied com layer of the dentate gyrus. No significant differences were pounds were verified to be 99% pure by mass spectrometry observed between groups at the 1 hour or 1 day time points, and shown to retain either pro-proliferative or neuroprotec though at one day there was a trend towards increased BrdU+ tive properties in vivo in neural stem cells. All compounds cells in the Example 45 Compound-treated group. At the 5 significantly (*, P<0.001, Student's t test) stimulated neural day time point, by which time 40% of newborn neurons precursor cell proliferation in the hippocampal dentate gyrus 10 normally die, animals that received Example 45 Compound SGZ relative to vehicle control. showed a statistically significant (*, P<0.001, Student's t test) FIG. 7: Neurogenic efficacy of orally administered 25% increase in BrdU+ cells compared to the vehicle-only Example 45 Compound was dose-related. The graph on the control group. This difference between groups progressed top shows that the concentration of Example 45 Compound in with time such that mice that received a daily oral dose of brain tissue of mice that were administered compound by 15 Example 45 Compound for 30 days, starting 24 hours after daily oral gavage for 7 consecutive days correlated with the the pulse administration of BrdU, exhibited a 5-fold increase dose of Example 45 Compound administered. The graph on in the abundance of BrdU+ cells in the dentate gyrus relative the bottom shows that pro-neurogenic or neuroprotective effi to vehicle-only controls. In this longer-term trial, BrdU+ cells cacy of Example 45 Compound was roughly double that of were observed both in the SGZ and the granular layer of the vehicle control at doses ranging from 5 to 40 mg/kg. At dentate gyrus. decreasing dosage of Example 45 Compound the amount of FIG. 11: Quantification of short term (1 hour pulse) BrdU neurogenesis decreased accordingly, until it reached levels no incorporation and cleaved-caspase 3 (CCSP3) formation in greater than vehicle control at compound doses below 1.0 the dentate gyrus showed that NPAS3-deficient mice have the mg/kg. Results shown are the average obtained from analysis same rate of proliferation of newborn cells in the dentate as of 5 adult wild type male mice at each dose. 25 wild type littermates (BrdU), but roughly twice the level of FIG. 8: Analysis of molecules related structurally to programmed cell death (CCSP3) (*, P<0.01, Student’s ttest). Example 45 Compound (P7C3) revealed a region of the com Three 6 week old male mice (NPAS3-deficient or wild type pound that could be chemically modified without loss of in littermates) in each group were evaluated. vivo activity. An in vivo SAR study was conducted using 37 FIG. 12: Granule cell neurons in the dentate gyrus of chemical analogs of Example 45 Compound, each evaluated 30 NPAS3-deficient mice displayed morphological deficits in in 4 or 5 adult C57/B6 male mice. Some analogs revealed dendritic branching and spine density. (A) Golgi-Cox stain activity comparable to the parent compound, whereas others ing of the dentate gyrus illustrates that dendritic arborization showed significantly diminished activity, or evidence of pro of dentate gyrus granule cell neurons in npas3 mice is neurogenic effect intermediate between vehicle and FGF substantially less developed than in wild type littermates. controls. This exercise enabled identification of regions of the 35 Results shown are representative of 15 sections from five parent compound that might be amenable to chemical modi 12-14 week old adult male mice of each genotype. (B) In fication without loss of activity. As an example, Example 62 addition to obviously reduced dendritic length and branching, Compound retained robust activity with the aniline ring of granular neurons in the dentate gyms of npas3 mice also Example 45 Compound substituted by an anisidine. This exhibited significantly reduced spine density relative to wild derivative compound was exploited to yield a fluorescent 40 type littermates (*, P<0.00001, Student's t test). These geno derivative by attaching a coumarin moiety to the N-phenyl type-specific differences were not exhibited by neurons in the r1ng. CA1 region of the hippocampus. FIG. 9: Activity of Example 62 Compound is enantiomer FIG. 13: In hippocampal slice preparation from npas3. specific. (A) (+) and (-) enantiomers of Example 62 Com mice, synaptic transmission was increased both in the outer pound were prepared. (B) Evaluation of Example 62 Com 45 molecular layer of the dentate gyrus (A) and the CA1 region pound enantiomers showed that in vivo pro-neurogenic or of the hippocampus (B) relative to hippocampal slices from neuroprotective efficacy was fully retained by the (+) enanti wild type mice. Extended treatment with Example 45 Com omer in a dose-dependent manner, while the (-) enantiomer pound normalized synaptic responses in the dentate gyms but showed diminished activity. Each enantiomer was evaluated not the CA 1 region of npas3 mice. Extended treatment at each dose in between 3 and 5 three month old adult wild 50 with Example 45 Compound did not affect wild-type type male C57/B6 mice. responses. Data are presented as the meantSEM. Each group FIG.10: Example 45 Compound enhances the survival of consisted of 1 or 2 slice preparation from each of 5 mice. newborn neurons in the dentate gyrus. (A) Immunohis FIG. 14: Example 45 Compound has pro-neurogenic or tochemical staining for doublecortin (DCX), an antigen spe neuroprotective efficacy in the dentate gyrus of NPAS3-defi cifically and transiently expressed in proliferating hippocam 55 cient animals. Six 12 week old npas3 mice were orally pal neural precursor cells when they become irreversibly administered vehicle or Example 45 Compound (20 mg/kg/d) committed to neuronal differentiation, was substantially for 12 days, and also injected daily with BrdU (50 mg/kg). At increased in newborn neurons in mice that were administered the end of day 12, mice were sacrificed and tissue was stained Example 45 Compound (20 mg/kg) daily for 30 days by oral for BrdU and doublecortin (DCX). BrdU staining showed gavage, relative to that seen in mice that received vehicle only. 60 that Example 45 Compound increased the magnitude of neu These results are representative of 10 sections each from 5 rogenesis in npas3 mice by roughly 4-fold, as graphically mice in each group, and demonstrate that Example 45 Com represented above (*, P<0.001, Student's t test). DCX stain pound specifically promoted hippocampal neurogenesis. (B) ing shows that Example 45 Compound also promoted more Example 45 Compound enhances hippocampal neurogenesis extensive process formation in differentiating neurons of the by promoting survival of newborn neurons. Three month old 65 adult dentate gyrus in npas3 mice. wild type C57/B6 male mice were exposed to orally-deliv FIG. 15: Golgi-Cox staining of neurons in the dentate gyms ered Example 45 Compound or vehicle for 30 days (n=5 shows that extended daily treatment of npas3 mice with US 9,095,572 B2 59 60 Example 45 Compound (20 mg/kg/d) enhanced dendritic Example 45 Compound-treated rats displayed significantly arborization. Hi-power micrographs are shown on top, and a enhanced hippocampal neurogenesis, as assessed by BrdU lower power micrograph illustrating the entire dentate gyrus incorporation, relative to vehicle treated rats. Many more of is shown below. the BrdU-labeled cells were noted to have migrated into the FIG. 16: Measured thickness of hippocampal subfields in 5 granular layer in Example 45 Compound-treated rats in com npas3 and wild type littermate mice that were treated with parison to vehicle treated animals, consistent with their func Example 45 Compound (20 mg/kg/d) or vehicle every day tional incorporation into the dentate gyms as properly wired from embryonic day 14 until 3 months of age demonstrated neurons. The scale bar represents 50 mM. (C) Relative to that Example 45 Compound selectively increased the thick vehicle-treated animals. Example 45 Compound-treated rats ness of the dentate gyrus granular cell layer to a level 10 displayed significantly lower number of cleaved caspase approaching wild type thickness (*, P<0.01, Student's t test), 3-positive cells in the dentate gyms, indicating that P7C3 was without affecting thickness of the pyramidal cell layers of capable of inhibitingapoptosis in the aged rat brain. The scale CA1 or CA3 regions. bar represents 50 mM. (D) Relative to vehicle-treated ani FIG. 17: Immunohistochemical detection of cleaved mals. Example 45 Compound-treated rats were observed to caspase 3 (CCSP3), a marker of apoptosis, showed elevated 15 maintain stable body weight as a function of terminal aging. levels of programmed cell death in the dentate gyrus of In all graphs data are expressed as meantSEM. NPAS3-deficient animals. Apoptosis in NPAS3-deficientani FIG.22: Example 45 Compound Preserves Mitochondrial mals was inhibited by treatment with Example 45 Compound Membrane Potential in Parallel to Proneurogenic Activity (20 mg/kg/d, p.o., for 12 days), whereas analogous treatment U2OS cells were loaded with tetramethylrhodamine methyl with vehicle alone had no effect. Images shown are represen ester (TMRM) dye and then exposed to the calcium iono tative of 10-12 sections evaluated per animal, with 3-5 eight phore A23 187 either in the presence or absence of test com week-old male NPAS3-deficient mice per group. pounds. Example 45 Compound (A) preserved mitochondrial FIG. 18: Example 45 Compound acts mechanistically in membrane potential following exposure to the calcium iono the mitochondria. (A) Example 45 Compound preserved phore A23 187 in a dose-dependent manner. The protective mitochondrial membrane potential following exposure to the 25 effect of P7C3 was enantiomeric specific. The (R)-enanti calcium ionophore A23 187 in a dose dependent manner as omer of another compound (B) blocked dye release at levels judged by fluorescent imaging of TMRM dye, a cell-per as low as 1 nM, whereas the (S)-enantiomer (C) failed to meant, cationic red-orange fluorescent dye that is readily block dye release even at the highest drug dose tested (100 sequestered by intact mitochondria. (B) The protective effect nM). A proneurogenic compound, P7C3A20 (D) exhibited of Example 62 Compound was enantiomeric specific, with 30 dye release protection at all doses tested, yet compounds the (+) enantiomer retaining activity more so than the (-) having less proneurogenic activity (E and F) were less effec enantiomer. tive in preserving mitochondrial membrane potential at any FIG. 19: Example 45 Compound as compared to a known test dose. Each compound was evaluated in triplicate with drug. (A) Both Example 45 Compound and the Dimebon similar results. anti-histamine enhanced hippocampal neurogenesis (B), and 35 FIG. 23: Example 45 Compound Preserves Mitochondrial protected mitochondria from dissolution following toxic Membrane Potential in Cultured Primary Cortical Neurons. exposure to the calcium ionophore A23 187 (C). In the in vivo Cortical neurons cultures from rats on embryonic day 14 were assay of neurogenesis the Example 45 Compound exhibited a loaded with tetramethylrhodamine methyl ester(TMRM) dye higher ceiling of efficacy than the Dimebon anti-histamine. In after 6 days of maturation. The top panels (no calcium iono all three assays, the Example 45 Compound performed with 40 phore) show that the dye alone did not affect the health of greater relative potency than the Dimebon anti-histamine. neurons. The remaining panels are from cells that were FIG. 20: Effect of Example 45 Compound in aged rats. (A) exposed to the calcium ionophore A23 187 at time Zero. With Example 45 Compound (20 mg/kg/d, i.p.) and BrdU (50 vehicle-alone, cortical neuron mitochondrial membrane mg/kg, i.p.) were administered daily for 7 days to 12-18 potential was rapidly lost after exposure to the ionophore. month old Fisher 344 rats (n=4 in each group). P7C3 pro 45 Escalating doses of Example 45 Compound (A) preserved moted neural precursor cell proliferation by roughly 5 fold mitochondrial membrane potential following exposure to the compared to vehicle. (p<0.001, Students ttest). DCX stain calcium ionophore A23 187 in a dose dependent manner, with ing demonstrates that P7C3 specifically promoted neuronal full protection achieved at 1 mM. The less active compound differentiation and dendritic branching. These micrographs (B) was less effective in preserving mitochondrial membrane were taken at the same magnification. Scale bar 50 mm. Data 50 potential at any dose tested. Results shown are representative are expressed as mean+/-SEM. (B) Latency to find the hidden of 10 fields analyzed in each of 2 experimental runs for all platform in the Morris water maze task, as well as (C) swim conditions. speed and locomotor activity (D) in aged rats treated with FIG. 24. Example 45 Compound (P7C3) Provides Thera P7C3 or vehicle both before and after 2 months of treatment peutic Benefit in Animal Model of Amyotrophic Lateral Scle did not differ between groups. Data are expressed as mean+/- 55 rosis (ALS). Female G93A SOD1 mice (n=30 in each group, SEM. (E) Quantification of food intake (upper panel) and with all mice sibling matched across treatment groups) were fasting blood glucose levels in aged rats did not differ with treated with either vehicle or P7C3 (10 mg/kg i.p. twice daily) respect to whether rats received P7C3 or vehicle. Data are starting at 40 days of age. P7C3-treated mice showed a sig expressed as mean+/-SEM. nificant delay in disease progression, as evidenced by the later FIG. 21: Example 45 Compound Enhances Hippocampal 60 age by which they dropped to 10% below their maximum Neurogenesis, Ameliorates Cognitive Decline, and Prevents weight (A). P7C3-treated mice also attain a neurological Weight Loss in Terminally Aged Rats (A) Prior to treatment, severity score of 2 at a later age than vehicle treated mice (B), both groups (n 23 for each group) showed similar frequency again indicating that P7C3-treatment slows disease progres of crossings through the goal platform. After 2 months of sion. This score is determined as follows: 0 =full extension treatment, however, Example 45 Compound-treated rats dis 65 ofhind legs away from lateral midline when the test mouse is played a statistically significant increase of crossings through Suspended by its tail, and can hold this for 2 seconds, Sus the goal platform area relative to vehicle treated rats. (B) pended 2-3 times; 1 =collapse or partial collapse of leg US 9,095,572 B2 61 62 extension towards lateral midline (weakness) or trembling of Compounds hind legs during tail Suspension, 2-toes curl under at least In one aspect, the presently disclosed embodiments feature twice during walking of 12 inches, or any part of foot drags compounds having general formula (I): along cage bottom/table, 3’ rigid paralysis or minimal joint movement, foot not being used for forward motion; and 5 4-mouse cannot right itself within 30 seconds from either (I) side. With further disease progression, vehicle-treated mice R4 show the expected decline in retention time on the accelerat 3 R C3, ing rotarod, with retention time averaged across 4 trials (C. M open bars). P7C3-treated mice, however, show a consistent 10 Yo-R trend towards improved performance on this task after onset 2 N^ of disease (C, filled bars), with statistically significant R V L1-A improvement on days 131, 138 and 145 (*, p<0.001, Stu R M 2 dent's t Test). All graphical data shown above is mean+/- LS SEM, with statistical analysis conducted using the Students 15 tTest). As another means of disease progression, walking gait was evaluated. FIG.24D shows footprint data from two sis Here and throughout this specification, R', R. R. R. R. ters (VEH and P7C3) on day 92 (before disease onset) and R', L', L, A, and Z can be as defined anywhere herein. day 118 (after disease onset). Front paws are dipped in red It is appreciated that certain features of the presently dis ink, and back paws are dipped in black ink. The VEH-treated mouse shows the expected decline in gait after disease onset closed embodiments, which are, for clarity, described in the on day 188, while her P7C3-treated sister showed preserva context of separate embodiments, can also be provided in tion of normal gait on day 118. All analysis was conducted combination in a single embodiment. Conversely, various blind to treatment group. features of the presently disclosed embodiments which are, FIG. 25. Example 6a Compound (P7C3A20) Provides 25 for brevity, described in the context of a single embodiment, Therapeutic Benefit in Animal Model of Parkinson's Disease. can also be provided separately or in any Suitable Sub-com Mice were treated with MPTP (30 mg/kg i.p.) or Vehicle only bination. for 5 days and then immunohistochemically analyzed for Thus, for ease of exposition, it is also understood that tyrosine hydroxylase staining (TH) 21 days later (A). Treat where in this specification, a variable (e.g., R') is defined by ment with MPTP and Vehicle (n-6) reduced the number of 30 “as defined anywhere herein” (or the like), the definitions for TH+ neurons in the Substantia nigra (B) by approximately that particular variable include the first occurring and broad 50% (*, p=0.0002, Student's t test) relative to mice that est generic definition as well as any sub-generic and specific received Vehicle only (n=8). MPTP-mediated cell deathin the definitions delineated anywhere in this specification. substantia nigra was significantly attenuated (*, p=0.005) in Variables R', R. R. R. mice that additionally received P7C3A20 (10 mg/kg i.p. 35 In some embodiments, one or two of R. R. R. and R' twice daily) (n=5). TH+ neurons in the substantia nigra of (e.g., one of, e.g., R) is selected from halo, hydroxyl, Sulf every mouse were counted blind to treatment group by two hydryl, C-C alkoxy, C-C thioalkoxy, C-C haloalkoxy, investigators using Image J Software, and results were aver C-C thiohaloalkoxy, C-C alkyl, C-C haloalkyl, cyano, aged. —NH, NH(C-C alkyl), N(C-C alkyl). —NHC(O) FIG. 26. Example 45 Compound (P7C3) Provides Thera 40 (C-C alkyl), and nitro; and the others are hydrogen. peutic Benefit in Animal Model of Huntington's Disease. 40 In certain embodiments, one or two of R', R. R. and R' female R6/2 mice were included in each of VEH (vehicle) and (e.g., one of e.g., R) is selected from halo, C-C alkoxy, P7C3 (10 mg/kg P7C3 i.p. twice daily) groups, and treatment C-C haloalkoxy, C-C alkyl, C-C haloalkyl, cyano, and was begun at 6 weeks of age. (A) Treatment with P7C3 nitro; and the others are hydrogen. statistically significantly extends survival of R6/2 mice 45 In certain embodiments, one or two of R. R. R. and R' (p<0.001, Gehan-Breslow-Wilcoxon test). (B) At 14 weeks (e.g., one of, e.g., R) is selected from halo, C-C alkyl, and of age, P7C3-treated R6/2 mice also show statistically C-C haloalkyl; and the others are hydrogen. improved objective measures of general condition (lower In certain embodiments, one or two of R', R. R. and R' score corresponds to better general better condition, (e.g., one of e.g., R) is selected from halo and C-C alkyl; *p-0.0001, Student's t Test). All measurements were con 50 and the others are hydrogen. ducted blind to genotype and treatment group. In certain embodiments, one or two R', R. R. and R' FIG. 27. Example 45 Compound (P7C3) Augments Hypo (e.g., one of e.g., R) is halo (e.g., bromo or chloro) and thalamic Neurogenesis. Administration of P7C3 for a one C-C alkyl, and the others are hydrogen. month period of time augments proliferation of hypothalamic In certain embodiments, one or two of R. R. R. and R' neural precursor cells (shown in red) in the arcuate nucleus 55 (e.g., one of, e.g., R) is bromo; and the others are hydrogen. (ARC), dorsomedial hypothalamus (DMH) and ventralme In some embodiments, R is selected from halo, hydroxyl, dial hypothalamus (VMH). Micrographs shown are represen Sulfhydryl, C-C alkoxy, C-C thioalkoxy, C-C, tative of staining from every third section throughout the haloalkoxy, C-C thiohaloalkoxy, C-C alkyl, C-C, hypothalamus in 4-6 mice for each treatment group. haloalkyl, cyano, NH, NH(C-C alkyl), N(C-C, 60 alkyl), -NHC(O)(C-C alkyl), and nitro; and each of R', DETAILED DESCRIPTION R, and R' can be as defined anywhere herein. In certain embodiments, R is selected from halo, The presently disclosed embodiments relate generally to hydroxyl, sulfhydryl, C-C alkoxy, C-C thioalkoxy, C-C, Stimulating neurogenesis (e.g., post-natal neurogenesis, e.g., haloalkoxy, C-C thiohaloalkoxy, C-C alkyl, C-C, post-natal hippocampal and/or hypothalamic neurogenesis) 65 haloalkyl, cyano, NH, NH(C-C alkyl), N(C-C, and/or promoting the Survival of existing neurons by reducing alkyl). NHC(O)(C-C alkyl), and nitro; and each of R', neuronal cell death. R, and R is hydrogen. US 9,095,572 B2 63 64 In some embodiments, R is selected from halo, C-C, In certain embodiments, L is a bond that directly connects alkoxy, C-C haloalkoxy, C-C alkyl, C-C haloalkyl, A in formula (I) to Z in formula (I): cyano, and nitro; and each of R', R, and R' can be as defined Non-Limiting Combinations of Variables L' and L’ anywhere herein. In some embodiments, each of L' and L is, independently, In certain embodiments, R is selected from halo, C-C, 5 C-C alkylene, which is optionally substituted with from 1-2 alkoxy, C-C haloalkoxy, C-C alkyl, C-C haloalkyl, independently selected R. cyano, and nitro; and each of R', R, and R is hydrogen. In certain embodiments, each of L' and L is CH. In some embodiments, R is selected from halo, C-C, In certain embodiments, one of L' and L is CH (e.g., L'), alkyl, and C-Chaloalkyl; and each of R', R, and R' can be and the other (e.g., L') is methylene that is substituted with 1 10 or 2 (e.g. 1) independently selected R, in which R can be as as defined anywhere herein. defined anywhere herein. In certain embodiments, R is selected from halo, C-C, In certain embodiments, each of L' and L is methylene alkyl, and C-C haloalkyl; and each of R', R, and R is that is substituted with 1 or 2 (e.g. 1) independently selected hydrogen. R. in which R can be as defined anywhere herein. In some embodiments, R is selected from halo and C-C, 15 In some embodiments, L' is C1-C5 (e.g., C-C) straight alkyl; and each of R', R, and R' can be as defined anywhere chain alkylene, which is optionally substituted with from 1-2 herein. independently selected R, and L is a bond that directly In certain embodiments, R is selected from halo and connects A informula (I) to Zinformula (I). In embodiments, C-C alkyl; and each of R', R, and R is hydrogen. L' can be, for example, methylene (i.e., —CH2—) or meth In some embodiments, R is halo (e.g., bromo or chloro); ylene that is substituted with 1 or 2 (e.g., 1) independently and each of R', R, and R' can be as defined anywhere herein. selected R (e.g., C-C alkyl, e.g., C-C alkyl, e.g., CH). In certain embodiments, R is halo (e.g., bromo or chloro); Variable A and each of R', R, and R is hydrogen. I In some embodiments, A is: In some embodiments, R is bromo; and each of R', R, and (i) CR'R'', wherein each of R'' and R' is independently R" can be as defined anywhere herein. 25 selected from hydrogen, halo, C-C alkyl, or OR; or In certain embodiments, R is bromo; and each of R. R. (ii) C=O; or and R is hydrogen. (iv) heterocycloalkylene containing from 3-5 ring atoms, In some embodiments, each of R', R. R. and R is inde wherein from 1-2 of the ring atoms is independently pendently selected from hydrogen, halo, and C-C alkyl. selected from N, NH, N(C-C alkyl), O, and S; and 30 wherein said heterocycloalkylene is (a) substituted with In certain embodiments, each of R. R. R. and R is 1 oxo; and (b) is optionally further substituted with from independently selected from hydrogen and halo(e.g., bromo 1-4 independently selected R". or chloro). In some embodiments, A is CR'R'', in which each of R' In some embodiments, each of R', R. R. and R is hydro and R' is, independently, hydrogen, halo, C-C alkyl, or gen. 35 OR (e.g., hydrogen, halo, or OR). In some embodiments, when any one or more of R. R. R. In certain embodiments. A can be CR'R'', in which each and R' can be a substituent other than hydrogen, said sub of R' and R' is, independently, hydrogen, halo, or C-C, stituent, or each of said Substituents, is other than C-C alkyl alkyl. (e.g., other than C-C alkyl, e.g., other than CH). In certain embodiments. A can be CR'R'', in which one Variable L' 40 of R'' and R' is halo (e.g., fluoro), and the other of R'' and In some embodiments, L' is C1-C5 (e.g., C-C) straight R" is, independently, hydrogen, halo, or C-C alkyl (e.g., chain alkylene, which is optionally substituted with from 1-2 hydrogen). independently selected R. In certain embodiments, one of R' and R' is hydrogen. In In certain embodiments, L' is methylene (i.e., —CH2—). embodiments, one of R'' and R' is halo or OR, and the In other embodiments, L' is methylene that is substituted with 45 other is hydrogen. 1 or 2 (e.g., 1) independently selected R. In embodiments, R In certain embodiments, one of R' and R' can be OR. In is C-C alkyl (e.g., C-C alkyl, e.g., CH). embodiments, the other of R'' and R' can be as defined In certain embodiments, L' is ethylene (i.e., anywhere herein; e.g., the other of R' and R' can be hydro —CHCH ). In other embodiments, L' is ethylene that is gen or C-C alkyl. For example, one of R' and R' can be substituted with 1 or 2 (e.g. 1) independently selected R. In 50 OR, and the other of R' and R' is hydrogen. In embodi embodiments, R is C-C alkyl (e.g., C-C alkyl, e.g., CH). ments, R can be hydrogen or R can be C-C alkyl (e.g., Variable L’ CH). In some embodiments, L is C1-C5 (e.g., C-C) straight In certain embodiments, one of R' and R' can behalo. In chain alkylene, which is optionally substituted with from 1-2 embodiments, the other of R'' and R' can be as defined independently selected R. 55 anywhere herein; e.g., the other of R' and R' can be hydro In certain embodiments, L is methylene (i.e., —CH2—). gen, C-C alkyl, or halo. For example, one of R' and R' In other embodiments, L' is methylene that is substituted with can be halo (e.g., fluoro), and the other of R' and R' is 1 or 2 (e.g., 1) independently selected R. In embodiments, R hydrogen. is C-C alkyl (e.g., C-C alkyl, e.g., CH). In embodiments, In embodiments, one of R'' and R' is halo or OR, and the R is C-C alkoxy, C-C thioalkoxy, C-C haloalkoxy, or 60 other is hydrogen. For example, one of R' and R' can be C-C thiohaloalkoxy. For example, R can be C-C (e.g., OR, and the other is hydrogen. In embodiments, R can be C-C) thioalkoxy, such as —SCH. hydrogen. R can be C-C alkyl (e.g., CH). In certain embodiments, L is ethylene (i.e., As another example, one of R'' and R' can be halo (e.g., —CH2CH, ). In other embodiments, L is ethylene that is fluoro), and the other is hydrogen. substituted with 1 or 2 (e.g. 1) independently selected R. For 65 In other embodiments, each of R' and R' is a substituent example, the ethylene carbon more proximal to Z in formula other than hydrogen. (I) can be substituted as described in the preceding paragraph. For example, each of R' and R' can behalo (e.g., fluoro). US 9,095,572 B2 65 66 As another example, one of R' and R' can be OR (e.g., Each of L' and L is methylene that is substituted with 1 or in which R is hydrogen), and the other is C-C alkyl (e.g., 2 (e.g., 1) independently selected R, in which R can be as CH). defined anywhere herein. For example: As a further example, each of R' and R' can be C-C, each of R' and R' can be a substituent other than hydro alkyl (e.g., CH). gen (e.g., one of which is CH), and In still other embodiments, each of R' and R' is hydro each of L' and L is methylene that is substituted with gen. C-C alkyl, such as CH). Embodiments can further include any one or more of the In some embodiments: following features. A is heterocycloalkylene containing from 3-5 (e.g., 5) ring When the carbon attached to R' and R' is substituted 10 atoms, in which from 1-2 of the ring atoms is independently with four different substituents, the carbon attached to R' selected from N. NH, N(C-C alkyl), O, and S; and wherein and R' can have the R configuration. said heterocycloalkylene is (a) substituted with 1 oxo; and (b) When the carbon attached to R' and R' is substituted is optionally further substituted with from 1-4 independently with four different substituents, the carbon attached to R' selected R'; and and R' can have the S configuration. 15 L' is C1-C5 (e.g., C-C) straight chain alkylene, which is II. In some embodiments, A is C—O. optionally substituted with from 1-2 independently selected III. In some embodiments, A is heterocycloalkylene con R, and taining from 3-5 ring atoms, in which from 1-2 of the ring L is a bond that directly connects A in formula (I) to Z in atoms is independently selected from N, NH, N(C-C alkyl). formula (I). O, and S; and wherein said heterocycloalkylene is (a) substi Variable Z tuted with 1 oxo (e.g., 1 OXO on a ring carbon); and (b) is I In some embodiments, Z is: optionally further substituted with from 1-4 independently (i) NR'R''; or Selected R. (ii) C(O)NR'R''; or In certain embodiments, A is heterocycloalkylene contain (iii) OR'; or ing 5 ring atoms, in which from 1-2 of the ring atoms is 25 (iv) - S(O),R', wherein n is 0, 1, or 2; or independently selected from N. NH, N(C-C alkyl), O, and (v) heterocycloalkenyl containing from 5-6 ring atoms, S; and wherein said heterocycloalkylene is (a) substituted wherein from 1-3 of the ring atoms is independently with 1 oxo; and (b) is optionally further substituted with from selected from N, NH, N(C-C alkyl), NHC(O)(C-C, 1-4 independently selected R. For example, A can be: alkyl), O, and S; and wherein said heterocycloalkenyl is 30 optionally substituted with from 1-4 independently selected R': (vi) C-C aryl that is optionally substituted with from 1-4 independently selected R”; or (vii) heteroaryl containing from 5-14 ring atoms, wherein N 35 from 1-6 of the ring atoms is independently selected from N. NH, N(C-C alkyl), O, and S; and wherein said sk heteroaryl is optionally substituted with from 1-4 inde O pendently selected R. In certain embodiments, Z is as defined in (i), (iii), (iv), (v), Non-Limiting Combinations of Variables L. L., and A 40 (vi), or (vii) in the preceding paragraph. In some embodiments: In certain embodiments, Z is as defined in (i), (iii), (iv), (v), A is (i) CR'R'', wherein each of R'' and R' is indepen or (vii) in the preceding paragraph. dently selected from hydrogen, halo, C-C alkyl, or OR; or In certain embodiments, Z is as defined in (i), (iii), (v), or (ii) C=O; and (vii) in the preceding paragraph. each of L' and L is, independently, C-C alkylene, which 45 In certain embodiments, Z is as defined in (i), (iii), or (iv) in is optionally substituted with from 1-2 independently the preceding paragraph. Selected R. In certain embodiments, Z is: In some embodiments: (i) NR'R''; or A is CR'R'', wherein each of R'' and R' is indepen (iii) OR'; or dently selected from hydrogen, halo, C-C alkyl, or OR; and 50 (v) heterocycloalkenyl containing from 5-6 ring atoms, each of Land L is, independently, C-C alkylene, which wherein from 1-3 of the ring atoms is independently is optionally substituted with from 1-2 independently selected from N, NH, N(C-C alkyl), NC(O)(C-C, Selected R. alkyl), O, and S; and wherein said heterocycloalkenyl is Embodiments can include one or more of the following optionally substituted with from 1-4 independently features 55 Selected R. Each of R'' and R' can be as defined anywhere herein. In certain embodiments, Z is: (i) —NR'R''; or (iii) Each of L' and L is CH. OR*. One of L' and L is CH (e.g., L'), and the other (e.g., L) In certain embodiments, Z is: (i) - NR'R''; or (iv) is methylene that is Substituted with 1 or 2 (e.g. 1) indepen —S(O),R', wherein n is 0, 1, or 2. dently selected in which R can be as defined anywhere 60 In certain embodiments, Zis: (iii) —OR'; or (iv)—S(O), herein. For example: R", wherein n is 0, 1, or 2. L' can be CH; and In certain embodiments, Z does not include heterocyclyl One of R'' and R' is hydrogen; and (e.g., a nitrogenous heterocyclyl, e.g., piperazinyl or piperidi L can be methylene that is substituted with 1 or 2 (e.g., 1) nyl) as part of its structure (e.g., as a fused ring or attached to independently selected R (e.g., C-C (e.g., C-C) 65 another ring by a bond). alkyl, such as CH, or C-C (e.g., C-C) thioalkoxy, In certain embodiments, Z is other than heterocycloalkenyl Such as —SCH); containing from 5-6 ring atoms, wherein from 1-3 of the ring US 9,095,572 B2 67 68 atoms is independently selected from N, NH, N(C-C alkyl). (1) C7-Caralkyl, wherein the aryl portion is optionally the NC(O)(C-C alkyl), O, and S; and wherein said heterocy aryl portion from is optionally substituted with from 1-4 cloalkenyl is optionally substituted with from 1-4 indepen independently selected R', dently selected R'. and the other of R'' and R' can be as defined anywhere In certain embodiments, Z is other than heteroaryl contain herein. ing from 5-14 ring atoms, wherein from 1-6 of the ring atoms In some embodiments, R'' and R' cannot be C-Cs is independently selected from N. NH, N(C-C alkyl). O, and cycloalkyl or C-C cycloalkenyl, each of which is optionally S; and wherein said heteroaryl is optionally substituted with substituted with from 1-4 independently selected R'. from 1-4 independently selected R' (e.g., other than pyridyl). In some embodiments, one of R'' and R' is independently 10 selected from the substituents delineated collectively in (b). II. In some embodiments, Z is NR'R''. (c), (g) through (j), and (1) above; and the other of R'' and R' A. In some embodiments, one of R'' and R'' is hydrogen, can be as defined anywhere herein. and the other of R" and R'' is a substituent other than hydro In some embodiments, one of R'' and R' is independently gen. selected from the substituents delineated collectively in (b). In some embodiments, one of R'' and R'' is hydrogen or a 15 (c), and (g) through (i); and the other of R'' and R' can be as substituent other than hydrogen, and the other of R'' and R' defined anywhere herein. is a Substituent other than hydrogen. In some embodiments, one of R'' and R' is independently In some embodiments, each of R'' and R'' is a substituent selected from: other than hydrogen. (b) C-C aryl that is optionally substituted with from 1-4 In some embodiments, each of R'' and R' is hydrogen. R; B. In some embodiments, one of R'' and R'' is indepen (c) heteroaryl containing from 5-14 ring atoms, wherein dently selected from the substituents delineated collectively from 1-6 of the ring atoms is independently selected from N. in (b), (c), (g) through (k), and (1) below: NH, N(C-C alkyl), O, and S; and wherein said heteroaryl is (b) Co-C aryl that is optionally substituted with from 1-4 optionally substituted with from 1-4 R: R; 25 and the other of R'' and R' can be as defined anywhere (c) heteroaryl containing from 5-14 ring atoms, wherein herein. from 1-6 of the ring atoms is independently selected In some embodiments, one of R" and R' is Co-Co aryl from N, NH, N(C-C alkyl), O, and S; and wherein said (e.g., C.) that is optionally substituted with from 1-4 (e.g., heteroaryl is optionally substituted with from 1-4 R: 1-3, 1-2, or 1) R'; and the other R'' and R' can be as defined (g) Cs-Carylcycloalkyl, wherein: 30 anywhere herein. (1) the aryl portion is optionally substituted with from In certain embodiments, Rat each occurrence is indepen 1-4 independently selected R', and dently selected from halo; or C-C alkoxy; C-C, (2) the cycloalkyl portion is optionally substituted with haloalkoxy: C-C thioalkoxy: C-C thiohaloalkoxy: C-C, from 1-4 independently selected R': alkyl, C-Chaloalkyl, -NH(C-C alkyl), N(C-C alkyl). (h) arylheterocyclyl containing from 8-14 ring atoms, 35 and NHC(O)(C-C alkyl), each of which is optionally wherein: substituted with from 1-3 independently selected R. (1) the aryl portion from is optionally substituted with In certain embodiments, Rat each occurrence is indepen from 1-4 independently selected R', and dently selected from C-C alkoxy; C-Chaloalkoxy; C-C, (2) from 1-2 of the ring atoms of the heterocyclyl portion thioalkoxy; and C-C thiohaloalkoxy, each of which is is independently selected from N, NH, N(C-C, 40 optionally substituted with from 1-3 independently selected alkyl). NC(O)(C-C alkyl), O, and S; and wherein R. In embodiments, R” can further include halo. said heterocyclyl portion is optionally substituted In certain embodiments, Rat each occurrence is indepen with from 1-3 independently selected R': dently selected from C-C alkoxy and C-C haloalkoxy, (i) heteroarylheterocyclyl containing from 8-14 ring each of which is optionally substituted with from 1-3 inde atoms, wherein: 45 pendently selected R. In embodiments, R” can further (1) from 1-2 of the ring atoms of the heteroaryl portion is include halo. independently selected from N, NH, N(C-C alkyl), In certain embodiments, Rat each occurrence is indepen O, and S; and wherein said heteroaryl portion is dently selected from C-C alkoxy, each of which is option optionally substituted with from 1-3 independently ally substituted with from 1-3 independently selected R. In selected R'; and 50 embodiments, R is C-C alkoxy (e.g., OCH). In embodi (2) from 1-2 of the ring atoms of the heterocyclyl portion ments, R” can further include halo. is independently selected from N, NH, N(C-C, In certain embodiments, one of R'' and R'' is unsubsti alkyl). NC(O)(C-C alkyl), O, and S; and wherein tuted phenyl, and the other of R'' and R' can be as defined said heterocyclyl portion is optionally substituted anywhere herein. with from 1-3 independently selected R': 55 In certain embodiments, one of R'' and R' is phenyl that () heteroarylcycloalkyl containing from 8-14 ring atoms, is substituted with 1 R, and the other of R'' and R' can be as wherein: defined anywhere herein. R' can be as defined anywhere (1) from 1-2 of the ring atoms of the heteroaryl portion is herein (e.g., R can be C-C alkoxy, e.g., OCHs). For independently selected from N, NH, N(C-C alkyl). example, one of R'' and R' can be 3-methoxyphenyl. In O, and S; and wherein said heteroaryl portion is 60 embodiments, R” can further include halo. optionally substituted with from 1-3 independently C. In some embodiments, when one of R'' and R'' is selected R'; and independently selected from the substituents delineated col (2) the cycloalkyl portion is optionally substituted with lectively in (b), (c), (g) through (k), and (1) above, the other of from 1-4 independently selected R': R'' and R' can be: (k) C-C cycloalkyl or C-C cycloalkenyl, each of which 65 (a) hydrogen; or is optionally substituted with from 1-4 independently (d) C-C alkyl or C-Chaloalkyl (e.g., C-C alkyl), each selected R'; and of which is optionally substituted with from 1-3 R'; or US 9,095,572 B2 69 70 (e) —C(O)(C-C alkyl). —C(O)(C-C haloalkyl), or In certain embodiments, R is C-C alkyl (e.g., C-C, —C(O)C(C-C alkyl); or alkyl, e.g., CH), which is optionally substituted with from (f) C-C alkenyl or C-C alkynyl. 1-3 (e.g., 1 or 2, e.g., 1) R. In embodiments, each occurrence In certain embodiments, the other of R'' and R'' is: of R can be independently selected from NH, NH(C- (a) hydrogen; or 5 C alkyl), N(C-C alkyl), and NHC(O)(C-C alkyl). (d) C-C alkyl or C-Chaloalkyl (e.g., C-C alkyl), each In some embodiments, R' is Co-Co aryl that is optionally of which is optionally substituted with from 1-3 R'; or substituted with from 1-4 (e.g., 1-3, 1-2, or 1) R'. (e) —C(O)(C-C alkyl). —C(O)(C-C haloalkyl), or —C(O)C(C-C alkyl). In certain embodiments, Rat each occurrence is indepen In certain embodiments, the other of R'' and R'' is: 10 dently selected from halo; or C-C alkoxy; C-C, (a) hydrogen; or haloalkoxy; C-C thioalkoxy; C-C thiohaloalkoxy; C-C, (d) C-C alkyl or C-Chaloalkyl (e.g., C-C alkyl), each alkyl, C-Chaloalkyl, -NH(C-C alkyl), N(C-C alkyl). of which is optionally substituted with from 1-3 R' or and —NHC(O)(C-C alkyl), each of which is optionally (e)—C(O)(C-C alkyl), or—C(O)(C-C haloalkyl). substituted with from 1-3 independently selected R. In certain embodiments, the other of R'' and R' can be: 15 In certain embodiments, Rat each occurrence is indepen (a) hydrogen; or dently selected from C-C alkoxy; C-Chaloalkoxy; C-C, (d) C-C alkyl (e.g., C-C alkyl, e.g., CH), which is thioalkoxy; and C-C thiohaloalkoxy, each of which is optionally substituted with from 1-3 R'; or optionally substituted with from 1-3 independently selected (e)—C(O)(C-C alkyl), e.g., C-C alkyl, e.g., CHs. R. In certain embodiments, the other of R'' and R' can be: 20 In certain embodiments, Rat each occurrence is indepen (a) hydrogen; or dently selected from C-C alkoxy and C-C haloalkoxy, (d) C-C alkyl (e.g., C-C alkyl, e.g., CH), which is each of which is optionally substituted with from 1-3 inde optionally substituted with from 1-3 R'. pendently selected R. In certain embodiments, the other of R'' and R' can be In certain embodiments, Rat each occurrence is indepen hydrogen. 25 dently selected from C-C alkoxy, each of which is option In certain embodiments, the other of R'' and R' can be (d) ally substituted with from 1-3 independently selected R. In or (e) or any subset thereof. embodiments, R is C1-C alkoxy (e.g., OCHs). E In some embodiments, one of R'' and R'' is Co-Co In embodiments, R” can further include halo. (e.g., C.) aryl that is optionally substituted with from 1-4R, In certain embodiments, R' is unsubstituted phenyl. and the other is hydrogen or C-C alkyl (e.g., C-C alkyl, 30 In certain embodiments, R' is phenyl that is substituted e.g., CHs). with 1 R. R' can be as defined anywhere herein (e.g., R” can In some embodiments, one of R'' and R' is Co-Co (e.g., be C-C alkoxy, e.g., OCH). For example, R' can be C.) aryl that is optionally substituted with from 1-4 R', and 3-methoxyphenyl. the other is hydrogen. IV. In some embodiments, Z is S(O),R', in which in In certain embodiments, one of R'' and R'' is unsubsti- 35 can be 0, 1, or 2. tuted phenyl, and the other is hydrogen. In some embodiments, R' is Co-Co aryl that is optionally In certain embodiments, one of R'' and R' is phenyl that substituted with from 1-4 (e.g., 1-3, 1-2, or 1) R'. is substituted with 1 R, and the other is hydrogen. In embodi In certain embodiments, Rat each occurrence is indepen ments, R is C1-C alkoxy (e.g., C-C alkoxy, e.g., OCHs). dently selected from halo; or C-C alkoxy; C-C, For example, one of R'' and R'' is 3-methoxyphenyl, and the 40 haloalkoxy: C-C thioalkoxy: C-C thiohaloalkoxy: C-C, other is hydrogen. alkyl, C-Chaloalkyl, -NH(C-C alkyl), N(C-C alkyl). IFI In some embodiments, each of R'' and R' cannot be and NHC(O)(C-C alkyl), each of which is optionally optionally substituted naphthyl (e.g., each of R'' and R' substituted with from 1-3 independently selected R. cannot be unsubstituted naphthyl). In embodiments, each of In certain embodiments, Rat each occurrence is indepen R'' and R'' is other than optionally substituted naphthyl (e.g., 45 dently selected from C-C alkoxy; C-Chaloalkoxy; C-C, unsubstituted naphthyl) when RandR' are defined according thioalkoxy; and C-C thiohaloalkoxy, each of which is to definitions (1), (2), and (4); and A is CR'R' (e.g., optionally substituted with from 1-3 independently selected CHOR, e.g., CHOH), and each of L' and L is C-C alky R. lene (e.g., each of L' and L is CH). In certain embodiments, Rat each occurrence is indepen IG. In some embodiments, one of R'' and R' is hydrogen, 50 dently selected from C-C alkoxy and C-C haloalkoxy, and the other is heteroaryl containing from 5-14 ring atoms, each of which is optionally substituted with from 1-3 inde wherein from 1-6 of the ring atoms is independently selected pendently selected R. from N. NH, N(C-C alkyl). O, and S; and wherein said In certain embodiments, Rat each occurrence is indepen heteroaryl is optionally substituted with from 1-4 R. dently selected from C-C alkoxy, each of which is option In certain embodiments, one of R'' and R'' is hydrogen, 55 ally substituted with from 1-3 independently selected R. In and the other is heteroaryl containing from 5-6 ring atoms, embodiments, R is C-C alkoxy (e.g., OCH). wherein from 1-2 of the ring atoms is independently selected In embodiments, R” can further include halo. from N. NH, N(C-C alkyl). O, and S; and wherein said In certain embodiments, R' is unsubstituted phenyl. heteroaryl is optionally substituted with from 1-2 R. In certain embodiments, R' is phenyl that is substituted III. In some embodiments, Z is —OR'. 60 with 1 R. R' can be as defined anywhere herein (e.g., R” can In some embodiments, R' is C-C alkyl or C-C, be C-C alkoxy, e.g., OCH). For example, R' can be haloalkyl, each of which is optionally substituted with from 3-methoxyphenyl. 1-3 R. In embodiments, R'' and/or R' cannot be substituted phe In some embodiments, R' is C-C alkyl, which is option nyl. In embodiments, R'' and/or R' cannot be substituted ally substituted with from 1-3 R. 65 phenyl when RandR' are defined according to definition (1): In certain embodiments, R' is C-C alkyl (e.g., C-C, and A is CR'R' (e.g., CHOR, e.g., CHOH), and each of L' alkyl, e.g., CH). and L is C-C alkylene (e.g., each of L' and L is CH). US 9,095,572 B2 71 IV. In some embodiments, Z is heterocycloalkenyl con

taining from 5-6 ring atoms, wherein from 1-3 of the ring (III) atoms is independently selected from N, NH, N(C-C alkyl). NC(O)(C-C alkyl), O, and S; and wherein said heterocy cloalkenyl is optionally substituted with from 1-4 indepen dently selected R'. In certain embodiments, Z is heterocycloalkenyl contain ing 6 ring atoms, wherein from 1-3 of the ring atoms is independently selected from N, NH, N(C-C alkyl), NC(O) (C-C alkyl). O, and S; and wherein said heterocycloalkenyl 10 is optionally substituted with from 1-4 independently Selected R. In certain embodiments, from 1-3 of the ring atoms is independently selected from N. NH, N(C-C alkyl), and in which R', R. R. R. L', L, A and Z can be as defined NC(O)(C-C alkyl). 15 anywhere herein. In certain embodiments, Rat each occurrence is, indepen In some embodiments, one or two of R. R. R. and R' dently selected from oxo, thioxo, =NH, and —N(C-C, (e.g., one of, e.g., R) is selected from halo, hydroxyl, Sulf alkyl), e.g., =NH. hydryl, C-C alkoxy, C-C thioalkoxy, C-C haloalkoxy, For example, Z can be: C-C thiohaloalkoxy, C-C alkyl, C-C haloalkyl, cyano, —NH, NH(C-C alkyl), N(C-C alkyl). —NHC(O) (C-C alkyl), and nitro; and the others are hydrogen. In certain embodiments, one or two of R. R. R. and R' (e.g., one of e.g., R) is selected from halo, C-C alkoxy, 25 C-C haloalkoxy, C-C alkyl, C-C haloalkyl, cyano, and nitro; and the others are hydrogen. In certain embodiments, one or two of R. R. R', and R' (e.g., one of, e.g., R) is selected from halo, C-C alkyl, and C-C haloalkyl; and the others are hydrogen. 30 In certain embodiments, one or two of R. R. R. and R' In some embodiments, Z is heteroaryl containing from (e.g., one of e.g., R) is selected from halo and C-C alkyl; 5-14 ring atoms, wherein from 1-6 of the ring atoms is inde and the others are hydrogen. pendently selected from N, NH, N(C-C alkyl). O, and S; and In certain embodiments, one or two of R. R. R. and R' wherein said heteroaryl is optionally substituted with from (e.g., one of e.g., R) is halo (e.g., bromo or chloro) and 1-4 R. 35 C-C alkyl; and the others are hydrogen. In certain embodiments, Z is heteroaryl containing from In certain embodiments, one or two of R. R. R', and R' 5-10 ring atoms, wherein from 1-4 of the ring atoms is inde (e.g., one of, e.g., R) is bromo; and the others are hydrogen. pendently selected from N, NH, and N(C-C alkyl); and In some embodiments; R is selected from halo, hydroxyl, wherein said heteroaryl is optionally substituted with from Sulfhydryl, C-C alkoxy, C-C thioalkoxy, C-C, 1-2 R. 40 haloalkoxy, C-C thiohaloalkoxy, C-C alkyl, C-C, Variables R and R' haloalkyl, cyano, NH, NH(C-C alkyl), N(C-C, alkyl). NHC(O)(C-C alkyl), and nitro; and each of R, In some embodiments, R and R' together with C and C. R", and R can be as defined anywhere herein. respectively, form a fused phenyl ring having formula (II): In certain embodiments, R is selected from halo, 45 hydroxyl, Sulfhydryl, C-C alkoxy, C-C thioalkoxy, C-C, haloalkoxy, C-C thiohaloalkoxy, C-C alkyl, C-C, (II) haloalkyl, cyano, NH, -NH(C-C alkyl), N(C-C, R6 alkyl), -NHC(O)(C-C alkyl), and nitro; and each of R, R R7 R", and R is hydrogen. 50 In some embodiments, R is selected from halo, C-C, rs alkoxy, C-C haloalkoxy, C-C alkyl, C-C haloalkyl, C3 2 cyano, and nitro; and each of R. R. and R' can be as defined anywhere herein. x's In certain embodiments, R is selected from halo, C-C, 55 alkoxy, C-C haloalkoxy, C-C alkyl, C-C haloalkyl, cyano, and nitro; and each of R. R. and R is hydrogen. In some embodiments, R is selected from halo, C-C, in which each of R. R. R. and R is independently alkyl, and C-Chaloalkyl; and each of R. R. and R can be selected from hydrogen, halo, hydroxyl, Sulfhydryl, C-C, as defined anywhere herein. alkoxy, C-C thioalkoxy, C-Chaloalkoxy, C-Chalothio 60 In certain embodiments, R is selected from halo, C-C, alkoxy, C-C alkyl, C-C haloalkyl, cyano. —NH2, —NH alkyl, and C-C haloalkyl; and each of R. R. and R is (C-C alkyl), N(C-C alkyl). —NHC(O)(C-C alkyl), and hydrogen. nitro. In some embodiments, R is selected from halo and C-C, For purposes of clarification, it is understood that com alkyl; and each of R. R. and R can be as defined anywhere pounds in which R and R' together with C and C, respec 65 herein. tively, form a fused phenyl ring having formula (II) corre In certain embodiments, R is selected from halo and spond to compounds having the following general formula: C-C alkyl; and each of R. R', and R is hydrogen. US 9,095,572 B2 73 74 In some embodiments, R is halo (e.g., bromo or chloro); fluoro). As another example, one of R'' and R' can be OR and each of R. R', and R can be as defined anywhere herein. (e.g., in which R is hydrogen), and the other is C-C alkyl In certain embodiments, R is halo (e.g., bromo or chloro); (e.g., CH). and each of R. R. and R is hydrogen. Each of R' and R' is hydrogen. In some embodiments, R is bromo; and each of R. R. and A is CR'R'', wherein each of R'' and R' is indepen Rican be as defined anywhere herein. dently selected from hydrogen, halo, C-C alkyl, or OR; and In certain embodiments, R is bromo; and each of R. R. each of L' and L is, independently, C-C alkylene, which is and R is hydrogen. optionally substituted with from 1-2 independently selected In some embodiments, each of R. R. R', and R is inde R. pendently selected from hydrogen, halo, and C-C alkyl. 10 {D} In certain embodiments, each of R. R. R. and R is Z is NR'R'', in which R'' and R' can be as defined independently selected from hydrogen and halo(e.g., bromo anywhere herein. or chloro). One of R'' and R'' is Co-Co aryl that is optionally substi In some embodiments, each of R. R. R. and R is hydro 15 tuted with from 1-4 R. In embodiments, the other of R'' and gen. R'' is hydrogen or C-C alkyl (e.g., CH4). In embodiments, In some embodiments, when any one or more of R. R. R. the other of R'' and R' is hydrogen. and R can be a substituent other than hydrogen, said sub In certain embodiments, one of R'' and R'' is unsubsti stituent, or each of said Substituents, is other than C-C alkyl tuted phenyl, and the other is hydrogen. (e.g., C-C alkyl, e.g., CH). In certain embodiments, one of R'' and R' is phenyl that Embodiments can include any one or more of the features is substituted with 1 R, and the other is hydrogen. In embodi described anywhere herein, including (but not limited to) ments, R is C1-C alkoxy (e.g., C-C alkoxy, e.g., OCHs). those described below. For example, one of R'' and R'' is 3-methoxyphenyl, and the {A} other is hydrogen. Each of R', R. R. and R' can be as defined anywhere 25 Zis–OR' or S(O),R', in which R'' and R' can be as herein. defined anywhere herein. R is selected from halo, hydroxyl, sulfhydryl, C-C, Embodiments can include features from any one, two, alkoxy, C-C thioalkoxy, C-C haloalkoxy, C-C thioha three, or four of{A}, {B}, {C}, and {D}; or any combinations loalkoxy, C-C alkyl, C-Chaloalkyl, cyano, -NH2, —NH thereof. (C-C alkyl), N(C-C alkyl). —NHC(O)(C-C alkyl), and 30 nitro; and each of R', R, and R' can be as defined anywhere In some embodiments: herein (e.g., each of R', R, and R is hydrogen). R is a substituent other than hydrogen (e.g., halo and R is selected from halo and C-C alkyl; and each of R', C-C alkyl; e.g., halo, e.g., bromo); and each of R', R, and R, and R' can be as defined anywhere herein (e.g., each of R" can be as defined anywhere herein (e.g., each of R', R, R. R. and R is hydrogen). 35 and R is hydrogen); and R is halo (e.g., bromo or chloro); and each of R', R, and R is a substituent other than hydrogen (e.g., halo and R" can be as defined anywhere herein (e.g., each of R', R, C-C alkyl; e.g., halo, e.g., bromo); and each of R. R. and and R is hydrogen). Rican be as defined anywhere herein (e.g., each of R. R. R is bromo; and each of R', R, and R' can be as defined and R is hydrogen). anywhere herein (e.g., each of R. R. and R is hydrogen). 40 In some embodiments: Each of R. R. R. and R is independently selected from R is a substituent other than hydrogen (e.g., halo and hydrogen and halo(e.g., bromo or chloro). C-C alkyl; e.g., halo, e.g., bromo); and each of R', R, and Each of R', R. R. and R is hydrogen. R" can be as defined anywhere herein (e.g., each of R', R, {B} and R is hydrogen); and Each of L' and L is, independently, C-C alkylene, which 45 R is a substituent other than hydrogen (e.g., halo and is optionally substituted with from 1-2 independently C-C alkyl; e.g., halo, e.g., bromo); and each of R. R. and Selected R. R can be as defined anywhere herein (e.g., each of R. R. Each of L' and L is CH. and R is hydrogen); and One of L' and L is CH (e.g., L'), and the other (e.g., L) A is CR'R'', wherein each of R'' and R' is indepen is methylene that is Substituted with 1 or 2 (e.g. 1) indepen 50 dently selected from hydrogen, halo, C-C alkyl, or OR; and dently selected R, in which R can be as defined anywhere each of L' and L is, independently, C-C alkylene, which is herein. optionally substituted with from 1-2 independently selected Each of L' and L is methylene that is substituted with 1 or R. 2 (e.g., 1) independently selected R, in which R can be as Embodiments can include any one or more features defined anywhere herein. 55 described herein (e.g., as described under {B} and {C} L' is C-C (e.g., C-C) straight chain alkylene, which is above). optionally substituted with from 1-2 independently selected In some embodiments: R, and L is a bond that directly connects A in formula (I) to R is a substituent other than hydrogen (e.g., halo and Z in formula (I). C-C alkyl; e.g., halo, e.g., bromo); and each of R', R, and {C} 60 R" can be as defined anywhere herein (e.g., each of R', R, One of R'' and R' is OR, and the other is hydrogen. In and R is hydrogen); and embodiments, R can be hydrogen. R can be C-C alkyl R is a substituent other than hydrogen (e.g., halo and (e.g., CH). C-C alkyl; e.g., halo, e.g., bromo); and each of R. R. and One of R'' and R' can behalo (e.g., fluoro), and the other Rican be as defined anywhere herein (e.g., each of R. R. is hydrogen. 65 and R is hydrogen); and Each of R'' and R' can be a substituent other than hydro A is CR'R'', wherein each of R'' and R' is indepen gen. For example, each of R' and R' can be halo (e.g., dently selected from hydrogen, halo, C-C alkyl, or OR; and US 9,095,572 B2 75 76 each of L' and L is, independently, C-C alkylene, which is ments can include features from any one, two, three, or four of optionally substituted with from 1-2 independently selected {A}, {B}, (C), and {D}; or any combinations thereof. R; and In some embodiments, Zis-OR'' and/or—S(O),R'; and Z is NR'R'', in which R'' and R' can be as defined R", R. R. R. L. L., and A can be as defined anywhere anywhere herein. herein; or a salt (e.g., pharmaceutically acceptable salt) Embodiments can include any one or more features thereof. In embodiments, (B) and/or (C) applies. Embodi described herein (e.g., as described under {B}, {C}, and {D} ments can include features from any one, two, three, or four of above). {A}, {B}, {C}, and {D}; or any combinations thereof. In some embodiments: In some embodiments, A is (ii) C=O; and/or (iv) hetero each of L' and L is CH: 10 cycloalkylene containing from 3-5 ring atoms, wherein from A is CR'R'', wherein one of R and R is OR, and the 1-2 of the ring atoms is independently selected from N, NH, other is hydrogen; N(C-C alkyl), O, and S; and wherein said heterocycloalky Z is NR'R''; and lene is (a) substituted with 1 oxo; and (b) is optionally further each of R'' and R' is independently selected from substituted with from 1-4 independently selected R'; and R', (a) hydrogen; 15 R. R. R. L', L, and Z can be as defined anywhere herein; (b) Co-Co aryl that is optionally substituted with from 1-4 or a salt (e.g., pharmaceutically acceptable salt) thereof. R; Embodiments can include features from any one, two, three, (d) C-C alkyl or C-Chaloalkyl, each of which is option or four of {A}, {B}, {C}, and {D}; or any combinations ally substituted with from 1-3 R': thereof. (f) C-C alkenyl or C-C alkynyl. In some embodiments, each of R and R' is, independently, Embodiments can include any one or more features hydrogen, C-C alkyl, or C-C haloalkyl. described herein (e.g., as described under {A}, {C}, and {D} In embodiments, Rand R' can each be the same or differ above). ent. In some embodiments: 25 In certain embodiments, each of RandR is, independently, A is CR'R'', in which each of R'' and R' is, indepen C-C alkyl, e.g., each of R and R' is CH. dently, hydrogen, halo, or C-C alkyl, or In other embodiments, each of R and R' is hydrogen. A is CR'R'', in which one of R'' and R' is halo (e.g., Embodiments can include any one or more of the features fluoro), and the other of R' and R' is, independently, hydro described anywhere herein, including (but not limited to) gen, halo, or C-C alkyl (e.g., hydrogen); or 30 A is CR'R'', in which one of R'' and R' is halo (e.g., those described in conjunction with Formula (III). fluoro), and the other of R' and R' is hydrogen; and III. In some embodiments, RandR together with C and R. R. R. R. L., L, and Z can be as defined anywhere C, respectively, form a fused heterocyclic ring containing herein; or a salt (e.g., pharmaceutically acceptable salt) from 5-6 ring atoms, wherein from 1-2 of the ring atoms is thereof. 35 independently selected from N, NH, N(C-C alkyl), NC(O) Embodiments can include features from any one, two, (C-C alkyl). O, and S; and wherein said heterocyclic ring is three, or four of{A}, {B}, {C}, and {D}; or any combinations optionally substituted with from 1-3 independently selected thereof. R". For purposes of clarification and illustration, a non-lim In some embodiments: iting example of these compounds is provided below (for one of R'' and R' can be OR. In embodiments, the other 40 mula (IV)): of R'' and R' can be as defined anywhere herein; e.g., the other of R'' and R' can be hydrogen or C-C alkyl. For example, one of R'' and R' can be OR, and the other of R' (IV) and R' is hydrogen. In embodiments, R can be hydrogen; and 45 R. R. R. R. L. L., and Z can be as defined anywhere herein; or a salt (e.g., pharmaceutically acceptable salt) thereof. In embodiments, one or more of the following apply, e.g., when A is CHOH and Z is NR'R'': 50 each of R and R is CH; and/or each of R and R is bromo; and/or each of RandR is chloro; and/or one of RandR is CH (e.g., R), and the other is bromo (e.g., R3); each of R" and R' is other than hydrogen; 55 in which R', R. R. R. L., L, A, and Z can be as defined each of R'' and R'' is hydrogen; anywhere herein. Here, R and R' together with C and C. one of R'' and R' is heteroaryl as defined anywhere respectively, form a fused heterocyclic ring containing 5-6 herein; ring atoms. L' and/or L is C-C alkylene (optionally substituted); Embodiments can include any one or more of the features (B) and/or (C) applies. 60 described anywhere herein, including (but not limited to) Embodiments can include features from any one, two, those described in conjunction with Formula (III). In certain three, or four of {A}, {C}, and {D}; or any combinations embodiments, R' can be hydrogen or C-C alkyl (e.g., thereof. CH). In some embodiments, Z is other than NR'R''; and R', In some embodiments, it is provided: R. R. R. L', Li, Z, and A can be as defined anywhere 65 (i) each of L' and L’ must be C-C alkylene, which is herein; or a salt (e.g., pharmaceutically acceptable salt) optionally substituted with from 1-2 independently selected thereof. In embodiments, (B) and/or (C) applies. Embodi R when A is CH; or US 9,095,572 B2 77 78 (ii) Z must be other than heteroaryl containing from 5-14 Optical isomers can be obtained in pure form by standard (e.g., 5-6 or 6) ring atoms, wherein from 1-6 of the ring atoms procedures known to those skilled in the art, and include, but is independently selected from N. NH, N(C-C alkyl). O, and are not limited to, diastereomeric salt formation, kinetic reso S; and wherein said heteroaryl is optionally substituted with lution, and asymmetric synthesis. See, for example, Jacques, from 1-4 independently selected R”; e.g., other than substi 5 et al., Enantiomers, Racemates and Resolutions (Wiley Inter tuted pyridyl, e.g., other than pyridyl Substituted with C-C, science, New York, 1981); Wilen, S. H., et al., Tetrahedron alkyl (e.g., CH), e.g., other than 2 or 6-methylpyridyl. 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Com IV. In some embodiments, RandR' together with C and pounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of C, respectively, form a fused C-C cycloalkyl ring that is Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, optionally substituted with from 1-4 independently selected 10 R". For purposes of clarification and illustration, a non-lim Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972), iting example of such compounds is provided below (formula each of which is incorporated herein by reference in their (V)): entireties. It is also understood that the presently disclosed embodiments encompass all possible regioisomers, and mix 15 tures thereof, which can be obtained in pure form by standard

(V) separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin layer chromatography, and high-performance liquid chroma tography. The compounds of the presently disclosed embodiments include the compounds themselves, as well as their salts and their prodrugs, if applicable. A salt, for example, can be formed between an anion and a positively charged substituent (e.g., amino) on a compound described herein. Suitable 25 anions include chloride, bromide, iodide, Sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and in which R', R. R. R. L., L, A, and Z can be as defined acetate. Likewise, a salt can also be formed between a cation anywhere herein. Here, R and R' together with C, and C. and a negatively charged Substituent (e.g., carboxylate) on a respectively, form a fused C cycloalkyl ring. Embodiments compound described herein. Suitable cations include sodium can include any one or more of the features described any 30 ion, potassium ion, magnesium ion, calcium ion, and an where herein, including (but not limited to) those described in ammonium cation such as tetramethylammonium ion. conjunction with Formula (III). Examples of prodrugs include Calkyl esters of carboxylic IV. In some embodiments, R and R together with C, and acid groups, which, upon administration to a subject, are C, respectively, form a fused heteroaryl ring containing from capable of providing active compounds. 5-6 ring atoms, wherein from 1-2 of the ring atoms is inde 35 pendently selected from N, NH, N(C-C alkyl). O, and S; and Pharmaceutically acceptable salts of the compounds of the wherein said heteroaryl ring is optionally substituted with presently disclosed embodiments include those derived from from 1-3 independently selected R”. See, e.g., the title com pharmaceutically acceptable inorganic and organic acids and pound of Example 13. Embodiments can include any one or bases. As used herein, the term “pharmaceutically acceptable more of the features described anywhere herein, including 40 salt” refers to a salt formed by the addition of a pharmaceu (but not limited to) those described in conjunction with For tically acceptable acid or base to a compound disclosed mula (III). herein. As used herein, the phrase “pharmaceutically accept Any genus, Subgenus, or specific compound described able” refers to a substance that is acceptable for use in phar herein can include one or more of the stereochemistry fea maceutical applications from a toxicological perspective and tures described herein (e.g., as delineated in the Summary). 45 does not adversely interact with the active ingredient. Compound Forms and Salts Examples of Suitable acid salts include acetate, adipate, The compounds of the presently disclosed embodiments alginate, aspartate, benzoate, benzenesulfonate, bisulfate, may contain one or more asymmetric centers and thus occur butyrate, citrate, camphorate, camphorsulfonate, diglucon as racemates and racemic mixtures, enantiomerically ate, dodecylsulfate, ethanesulfonate, formate, fumarate, glu enriched mixtures, single enantiomers, individual diastere 50 coheptanoate, glycolate, hemisulfate, heptanoate, hexanoate, omers and diastereomeric mixtures. All Such isomeric forms hydrochloride, hydrobromide, hydroiodide, 2-hydroxy of these compounds are expressly included in the presently ethanesulfonate, lactate, maleate, malonate, methane disclosed embodiments. The compounds of the presently dis Sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pal closed embodiments may also contain linkages (e.g., carbon moate, pectinate, persulfate, 3-phenylpropionate, phosphate, carbon bonds, carbon-nitrogen bonds Such as amide bonds) 55 picrate, pivalate, propionate, salicylate, Succinate, Sulfate, wherein bond rotation is restricted about that particular link tartrate, thiocyanate, tosylate and undecanoate. Other acids, age, e.g. restriction resulting from the presence of a ring or Such as Oxalic, while not in themselves pharmaceutically double bond. Accordingly, all cis/trans and E/Z isomers and acceptable, may be employed in the preparation of salts use rotational isomers are expressly included in the presently ful as intermediates in obtaining the compounds of the pres disclosed embodiments. The compounds of the presently dis 60 ently disclosed embodiments and their pharmaceutically closed embodiments may also be represented in multiple acceptable acid addition salts. Salts derived from appropriate tautomeric forms, in Such instances, the presently disclosed bases include alkali metal (e.g., Sodium); alkaline earth metal embodiments expressly includes all tautomeric forms of the (e.g., magnesium), ammonium and N-(alkyl) salts. The compounds described herein, even though only a single tau presently disclosed embodiments also envision the quater tomeric form may be represented. All such isomeric forms of 65 nization of any basic nitrogen-containing groups of the com Such compounds are expressly included in the presently dis pounds disclosed herein. Water or oil-soluble or dispersible closed embodiments. products may be obtained by Such quaternization. Salt forms US 9,095,572 B2 79 80 of the compounds of any of the formulae herein can be amino preferred process conditions (i.e., reaction temperatures, acid salts of carboxyl groups (e.g. L-arginine, -lysine, -histi times, mole ratios of reactants, solvents, pressures, etc.) are dine salts). given, other process conditions can also be used unless oth Lists of suitable salts are found in Remington’s Pharma erwise stated. Optimum reaction conditions may vary with ceutical Sciences, 17th ed., Mack Publishing Company, Eas 5 the particular reactants or solvent used, but Such conditions ton, Pa., 1985, p. 1418; Journal of Pharmaceutical Science, can be determined by one skilled in the art by routine optimi 66, 2 (1977); and “Pharmaceutical Salts: Properties, Selec Zation procedures. Those skilled in the art of organic synthe tion, and Use A Handbook; Wermuth, C. G. and Stahl, P. H. sis will recognize that the nature and order of the synthetic (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 ISBN steps presented may be varied for the purpose of optimizing 3-906390-26-8 each of which is incorporated herein by ref 10 the formation of the compounds described herein. erence in their entireties. Synthetic chemistry transformations (including protecting The neutral forms of the compounds may be regenerated by group methodologies) useful in synthesizing the compounds contacting the salt with a base or acid and isolating the parent described herein are known in the art and include, for compound in the conventional manner. The parent form of the example, those Such as described in R. C. Larock, Compre compound differs from the various Saltforms in certain physi 15 hensive Organic Transformations, 2d. ed., Wiley-VCH Pub cal properties, such as Solubility in polar solvents, but other lishers (1999); P. G. M. Wuts and T. W. Greene, Protective wise the salts are equivalent to the parent form of the com Groups in Organic Synthesis, 4th Ed., John Wiley and Sons pound for the purposes of the presently disclosed (2007); L. Fieser and M. Fieser, Fieser and Fieser's Reagents embodiments. for Organic Synthesis, John Wiley and Sons (1994); and L. In addition to salt forms, the presently disclosed embodi 20 Paquette, ed., Encyclopedia of Reagents for Organic Synthe ments provide compounds which are in a prodrug form. Pro sis, John Wiley and Sons (1995), and subsequent editions drugs of the compounds described herein are those com thereof. pounds that undergo chemical changes under physiological The processes described herein can be monitored accord conditions to provide the compounds of the presently dis ing to any Suitable method known in the art. For example, closed embodiments. Additionally, prodrugs can be con 25 product formation can be monitored by spectroscopic means, verted to the compounds of the presently disclosed embodi Such as nuclear magnetic resonance spectroscopy (e.g., "Hor ments by chemical or biochemical methods in an ex vivo 'C), infrared spectroscopy (FT-IR), spectrophotometry (e.g., environment. For example, prodrugs can be slowly converted UV-visible), or mass spectrometry (MS), or by chromatogra to the compounds of the presently disclosed embodiments phy Such as high performance liquid chromatography when placed in a transdermal patch reservoir with a suitable 30 (HPLC) or thin layer chromatography (TLC). enzyme or chemical reagent. Prodrugs are often useful Preparation of Compounds can Involve the Protection and because, in some situations, they may be easier to administer Deprotection of Various Chemical groups. The need for pro than the parent drug. They may, for instance, be more bio tection and deprotection, and the selection of appropriate available by oral administration than the parent drug. The protecting groups can be readily determined by one skilled in prodrug may also have improved solubility in pharmacologi 35 the art. The chemistry of protecting groups can be found, for cal compositions over the parent drug. A wide variety of example, in Greene, et al., Protective Groups in Organic prodrug derivatives are known in the art, such as those that Synthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated rely on hydrolytic cleavage or oxidative activation of the herein by reference in its entirety. prodrug. An example, without limitation, of a prodrug would The reactions of the processes described herein can be be a compound of the presently disclosed embodiments 40 carried out in suitable solvents which can be readily selected which is administered as an ester (the “prodrug), but then is by one of skill in the art of organic synthesis. Suitable solvents metabolically hydrolyzed to the carboxylic acid, the active can be substantially nonreactive with the starting materials entity. Additional examples include peptidyl derivatives of a (reactants), the intermediates, or products at the temperatures compound of the presently disclosed embodiments. at which the reactions are carried out, i.e., temperatures which The presently disclosed embodiments also include various 45 can range from the solvents freezing temperature to the hydrate and Solvate forms of the compounds. Solvents boiling temperature. A given reaction can be carried The compounds of the presently disclosed embodiments out in one solvent or a mixture of more than one solvents. may also contain unnatural proportions of atomic isotopes at Depending on the particular reaction step, Suitable solvents one or more of the atoms that constitute such compounds. For for a particular reaction step can be selected. example, the compounds may be radiolabeled with radioac 50 Resolution of racemic mixtures of compounds can be car tive isotopes, such as for example tritium (H), iodine-125 ried out by any of numerous methods known in the art. An ('I) or carbon-14 (''C). All isotopic variations of the com example method includes preparation of the Mosher's ester pounds of the presently disclosed embodiments, whether or amide derivative of the corresponding alcohol or amine, radioactive or not, are intended to be encompassed within the respectively. The absolute configuration of the ester oramide Scope of the presently disclosed embodiments. 55 is then determined by proton and/or 'F NMR spectroscopy. Synthesis An example method includes fractional recrystallization The compounds of the presently disclosed embodiments using a "chiral resolving acid' which is an optically active, can be conveniently prepared in accordance with the proce salt-forming organic acid. Suitable resolving agents for frac dures outlined in the Examples section, from commercially tional recrystallization methods are, for example, optically available starting materials, compounds known in the litera 60 active acids. Such as the D and L forms of tartaric acid, ture, or readily prepared intermediates, by employing stan diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, dard synthetic methods and procedures known to those malic acid, lactic acidor the various optically active camphor skilled in the art. Standard synthetic methods and procedures Sulfonic acids. Resolution of racemic mixtures can also be for the preparation of organic molecules and functional group carried out by elution on a column packed with an optically transformations and manipulations can be readily obtained 65 active resolving agent (e.g., dinitrobenzoylphenylglycine). from the relevant scientific literature or from standard text Suitable elution solvent compositions can be determined by books in the field. It will be appreciated that where typical or one skilled in the art. US 9,095,572 B2 81 82 The compounds of the presently disclosed embodiments mula 7 may be achieved in the presence of an aldehyde and a can be prepared, for example, using the reaction pathways reducing agent Such as Sodium cyano borohydride (NaC and techniques as described below. NBH) to provide the tertiary 1,2-aminoalcohol of formula 8. A series of carbazole 1,2-aminoalcohol compounds of for mula 3 may be prepared by the method outlined in Scheme 1. The 9-oxiranylmethyl-9H-carbazole of formula 2 may be Scheme 2 prepared from an appropriately substituted carbazole of for R4 Rs mula 1 and epichlorohydrin in the presence of a strong base R3 R6 Such as Sodium hydride. 10 HNR10 Scheme 1 R O C R - Y - N R4 Rs R3 R6 R R8 15

O R2 R7 -e- 2 N R4 Rs R R8 R3 R6 1 R4 Rs R3 R6 R2 O C R7 amine protecting HNRoR11 He 25 N group (P) R R R Rs N NHR10 R Rs OH 30 4 O R4 Rs 2 R3 R6 9-oxiranylmethyl-9H-carbazole 35 R3 R O C R7 --RX N R Rs R10 N 1.

40 OH P 5 R4 Rs OH R3 R6 45

R O C R7 -e-acid The oxiranyl ring of formula 2 may be opened in the N presence of a primary or secondary amine to produce the R Rs 1,2-amino alcohol of formula 3. Such reactive primary or 50 R10 secondary amines can be, but are not limited to, phenethy N Y lamine, 3-phenylallyl amine, and N-Substituted piperazines OR P and the like. Alternatively, a variety of carbazole 1,2-aminoalcohol 6 compounds of formula 8 may be prepared by the method 55 R4 Rs outlined in Scheme 2. The epoxide of 9-oxiranylmethyl-9H R3 R6 carbazole of formula 2 may be opened with a primary amine, H.NR", to produce the secondary aminoalcohol of formula 4 and then protected with an amine protecting group (P) such as R O SC R7 tert-butoxycarbonyl (Boc) to afford the protected aminoalo 60 N RCHO chol of formula 5. Next, the hydroxyl group of formula 5 may R Rs (reductive amination) be alkylated with a strong base such as Sodium hydride and an N -R10 alkylating agent (RX) Such as an alkylhalide, tosylate, triflate H or mesylate to produce the ether of formula 6. Removal of the OR amine protecting group in the presence of a suitable acid can 65 provide the desired OR ether compounds of formula 7. Finally, reductive alkylation of the secondary amine of for US 9,095,572 B2 84 -continued A series of substituted indole compounds of formula 11 R4 Rs and 12 may be prepared by the method outlined below in R3 R6 Scheme 3. Compounds of formula 1 1 may be prepared by the alkylation of an indole of formula 9 with an epoxide A, for 5 example with epichlorohydrin or epibromohydrin, in the R O SC R presence of a strong base such as potassium hydroxide (KOH) N or n-butyllithium (n-Bulli) to produce the oxiranyl indole of R R8 formula 10. Next, opening of the epoxide of compounds of NRR formula 10 with a primary amine, substituted alcohol or thiol 10 rall 10 in the presence of a strong base or a mild Lewis acid such as OR lithium bromide (LiBr) or bismuth chloride (BiCl) can pro vide the alcohol of formula 1 1. Additionally, compounds of formula 12 may be prepared by opening an epoxide B at the less hindered position with the indole nitrogen of formula 9.

Scheme 3 O

Rs R6 XS-( R 5 R6 eer O NH X = Cl, Br e HYRs R4 A R4 N Y = O, N, S

R R R R 3 R 2 R2 9 11 10

O R7 N-3 B

Rs R6 OH

R4 er N --/ R7

R3 R R 12 US 9,095,572 B2 85 86 In addition, a variety of epoxide derivatives may be pre such as diethylaminosulfur trifluoride (DAST). Nitrogen-het pared by following the methods outlined in Scheme 4. The eroarylated compounds of formula 17 may be prepared in the secondary alcohol of compounds of formula 1 1 may be oxi presence of a catalytic amount of copper iodide and a het dized using an oxidizing agent or under Swern-like oxidation eroaryl iodide starting from compounds of formula 1 1 (where conditions to provide the ketone of formula 13 which can Y—N). Finally, sulfoxides and sulfones of formula 18 may be further undergo reductive amination to provide the amine of prepared under oxidative conditions, for example in the pres compound 14. Alternatively, the secondary alcohol may be ence of m-chloroperoxybenzoic acid (m-CPBA), starting converted into an ester using a carboxylic acid anhydride from sulfides of formula 1 1 (where Y—S).

Scheme 4

14

13 1) oxidation of OH 2) reductive amination capping with (RCOO oxidation with RoNH or alkyl halide

n N-- R8

11

m-CPBA fluorination YR3 = SRs 1. CIC(O)OCH 2. (Heteroary)-I, CuI 3. NaOH

Rs R6 s OH R4 N S(O).Rs

R 3 n = 1 or 2 R R2 R8 18 Y(heteroary)

17

(where Z—R"C(O)) or an ether (where Z-alklyl) using stan Pharmaceutical Compositions dard alkylation conditions to produce compounds of formula 65 The term “pharmaceutically acceptable carrier refers to a 15. Fluorine compounds of formula 16 may be prepared by carrier or adjuvant that may be administered to a Subject (e.g., reaction of the alcohol of formula 1 1 with a fluorinating agent a patient), together with a compound of the presently dis US 9,095,572 B2 87 88 closed embodiments, and which does not destroy the phar The following are examples (Formulations 1-4) of capsule macological activity thereof and is nontoxic when adminis formulations. tered in doses sufficient to deliver atherapeutic amount of the compound. Capsule Formulations Pharmaceutically acceptable carriers, adjuvants and 5 vehicles that may be used in the compositions of the presently disclosed embodiments include, but are not limited to, ion exchangers, alumina, aluminum Stearate, lecithin, self-emul Capsule Formulations sifying drug delivery systems (SEDDS) such as d-C.-toco Formula- Formula- Formula- Formula pherol polyethyleneglycol 1000 succinate, surfactants used in 10 tion 1: tion 2; tion 3: tion 4; pharmaceutical dosage forms such as Tweens or other similar Capsule Formulation mg/capsule mg/capsule mg/capsule mg capsule polymeric delivery matrices, serum proteins. Such as human Carbazole (solid 100 400 400 200 serum albumin, buffer Substances such as phosphates, gly Solution) Silicon Dioxide O.625 2.5 3.75 1875 cine, Sorbic acid, potassium Sorbate, partial glyceride mix 15 Magnesium Stearate O.12S O.S O.12S O.625 tures of Saturated vegetable fatty acids, water, salts, or elec NF2 trolytes, such as protamine Sulfate, disodium hydrogen Croscarmellose 11.000 44.0 40.O 2O.O Sodium NF phosphate, potassium hydrogen phosphate, Sodium chloride, Pluronic F68 NF 6.250 2S.O SO.O 2SO Zinc salts, colloidal silica, magnesium trisilicate, polyvinyl Silicon Dioxide NF O.625 2.5 3.75 1875 pyrrolidone, cellulose-based Substances, polyethylene gly Magnesium Stearate O.12S O.S 1.25 O.625 col, Sodium carboxymethylcellulose, polyacrylates, waxes, NF polyethylene-polyoxypropylene-block polymers, polyethyl Total 118.7SO 47S.OO 47S.OO 47S.OO ene glycol and wool fat. Cyclodextrins such as C.-, 3-, and Capsule Size No. 4 No. O No. O No. 2 Y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypro 25 Preparation of Solid Solution pyl-3-cyclodextrins, or other solubilized derivatives may also Crystalline carbazole (80 g/batch) and the povidone (NF be advantageously used to enhance delivery of compounds of K29/32 at 160 g/batch) are dissolved in methylene chloride the formulae described herein. (5000 mL). The solution is dried using a suitable solvent The compositions for administration can take the form of 30 spray dryer and the residue reduced to fine particles by grind bulk liquid Solutions or Suspensions, or bulk powders. More ing. The powder is then passed through a 30 mesh screen and commonly, however, the compositions are presented in unit confirmed to be amorphous by X-ray analysis. dosage forms to facilitate accurate dosing. The term “unit The Solid solution, silicon dioxide and magnesium Stearate dosage forms’ refers to physically discrete units suitable as are mixed in a suitable mixer for 10 minutes. The mixture is unitary dosages for human Subjects and other mammals, each 35 compacted using a suitable roller compactor and milled using unit containing a predetermined quantity of active material a suitable mill fitted with 30 mesh screen. Croscarmellose calculated to produce the desired therapeutic effect, in asso sodium, Pluronic F68 and silicon dioxide are added to the ciation with a suitable pharmaceutical excipient. Typical unit milled mixture and mixed further for 10 minutes. A premix is dosage forms include prefilled, premeasured ampules or made with magnesium Stearate and equal portions of the Syringes of the liquid compositions or pills, tablets, capsules, 40 mixture. The premix is added to the remainder of the mixture, losenges or the like in the case of solid compositions. In Such mixed for 5 minutes and the mixture encapsulated in hard compositions, the compound is usually a minor component shell gelatin capsule shells. (from about 0.1 to about 50% by weight or preferably from Use about 1 to about 40% by weight) with the remainder being In one aspect, methods for treating (e.g., controlling, various vehicles or carriers and processing aids helpful for 45 relieving, ameliorating, alleviating, or slowing the progres forming the desired dosing form. The amount administered depends on the compound for sion of) or methods for preventing (e.g., delaying the onset of mulation, route of administration, etc. and is generally or reducing the risk of developing) one or more diseases, empirically determined in routine trials, and variations will disorders, or conditions caused by, or associated with, aber necessarily occur depending on the target, the host, and the 50 rant (e.g., insufficient) neurogenesis or accelerated neuron route of administration, etc. Generally, the quantity of active cell death in a subject in need thereofare featured. The meth compound in a unit dose of preparation may be varied or ods include administering to the Subject an effective amount adjusted from about 1, 3, 10 or 30 to about 30, 100, 300 or of a compound of formula (I) (and/or a compound of any of 1000 mg, according to the particular application. In a particu the otherformulae described herein) or a salt (e.g., a pharma lar embodiment, unit dosage forms are packaged in a multi 55 ceutically acceptable salt) thereofas defined anywhere herein packadapted for sequential use. Such as blisterpack, compris to the subject. ing sheets of at least 6, 9 or 12 unit dosage forms. The actual In another aspect, the use of a compound of formula (I) dosage employed may be varied depending upon the require (and/or a compound of any of the other formulae described ments of the patient and the severity of the condition being herein) or a salt (e.g., a pharmaceutically acceptable salt) treated. Determination of the proper dosage for a particular 60 thereofas defined anywhere herein in the preparation of, or situation is within the skill of the art. Generally, treatment is for use as, a medicament for the treatment (e.g., controlling, initiated with Smaller dosages which are less than the opti relieving, ameliorating, alleviating, or slowing the progres mum dose of the compound. Thereafter, the dosage is sion of) or prevention (e.g., delaying the onset of or reducing increased by Small amounts until the optimum effect under the risk of developing) of one or more diseases, disorders, or the circumstances is reached. For convenience, the total daily 65 conditions caused by, or associated with, aberrant (e.g., insuf dosage may be divided and administered in portions during ficient) neurogenesis or exacerbated neuronal cell death is the day if desired. featured. US 9,095,572 B2 89 90 In embodiments, the one or more diseases, disorders, or of the presently disclosed embodiments will be administered conditions can include neuropathies, nerve trauma, and neu from about 1 to about 6 times per day or alternatively, as a rodegenerative diseases. In embodiments, the one or more continuous infusion. Such administration can be used as a diseases, disorders, or conditions can be diseases, disorders, chronic or acute therapy. or conditions caused by, or associated with aberrant (e.g., 5 Lower or higher-doses than those recited above may be insufficient) neurogenesis (e.g., aberrant hippocampal neuro required. Specific dosage and treatment regimens for any genesis as is believed to occur in neuropsychiatric diseases) particular patient will depend upon a variety of factors, or accelerated death of existing neurons. Examples of the one including the activity of the specific compound employed, the or more neuropsychiatric and neurodegenerative diseases age, body weight, general health status, sex, diet, time of include, but are not limited to, Schizophrenia, major depres 10 administration, rate of excretion, drug combination, the Sion, bipolar disorder, normal aging, epilepsy, traumatic brain severity and course of the disease, condition or symptoms, the injury, post-traumatic stress disorder, Parkinson's disease, patient’s disposition to the disease, condition or symptoms, Alzheimer's disease, Down syndrome, spinocerebellar and the judgment of the treating physician. ataxia, amyotrophic lateral Sclerosis, Huntington's disease, Upon improvement of a patient's condition, a maintenance stroke, radiation therapy, chronic stress, and abuse of neuro 15 dose of a compound, composition or combination of the active drugs (such as alcohol, opiates, methamphetamine, presently disclosed embodiments may be administered, if phencyclidine, and cocaine), retinal degeneration, spinal cord necessary. Subsequently, the dosage or frequency of admin injury, peripheral nerve injury, physiological weight loss istration, or both, may be reduced, as a function of the Symp associated with various conditions, and cognitive decline toms, to a level at which the improved condition is retained associated with normal aging, radiation therapy, and chemo when the symptoms have been alleviated to the desired level. therapy. The resultant promotion of neurogenesis or Survival Patients may, however, require intermittent treatment on a of existing neurons (i.e. a resultant promotion of Survival, long-term basis upon any recurrence of disease symptoms. growth, development, function and/or generation of neurons) In some embodiments, the compounds described herein may be detected directly, indirectly or inferentially from an can be coadministered with one or more other therapeutic improvement in, oran amelioration of one or more symptoms 25 agents. In certain embodiments, the additional agents may be of the disease or disorder caused by or associated with aber administered separately, as part of a multiple dose regimen, rant neurogenesis or Survival of existing neurons. Suitable from the compounds of the presently disclosed embodiments assays which directly or indirectly detect neural survival, (e.g., sequentially, e.g., on different overlapping schedules growth, development, function and/or generation are known with the administration of one or more compounds of formula in the art, including axon regeneration in rat models (e.g. Park 30 (I) (including any Subgenera or specific compounds thereof)). et al., Science. 2008 Nov. 7:322:963-6), nerve regeneration in In other embodiments, these agents may be part of a single a rabbit facial nerve injury models (e.g. Zhang et al., J Transl dosage form, mixed together with the compounds of the pres Med. 2008 Nov. 5; 6(1):67); sciatic nerve regeneration in rat ently disclosed embodiments in a single composition. In still models (e.g. Sun et al., Cell Mol Neurobiol. 2008 Nov. 6): another embodiment, these agents can be given as a separate protection against motor neuron degeneration in mice (e.g. 35 dose that is administered at about the same time that one or Poesen et al., J. Neurosci. 2008 Oct. 15:28(42):10451-9); rat more compounds of formula (I) (including any Subgenera or model of Alzheimer's disease, (e.g. Xuan et al., Neurosci specific compounds thereof) are administered (e.g., simulta Lett. 2008 Aug. 8: 440(3):331-5); animal models of depres neously with the administration of one or more compounds of sion (e.g. Schmidt et al., Behav Pharmacol. 2007 September; formula (I) (including any Subgenera or specific compounds 18(5-6):391-418; Krishnan et al., Nature 2008, 455, 894 40 thereof)). When the compositions of the presently disclosed 902); and/or those exemplified herein. embodiments include a combination of a compound of the Administration formulae described herein and one or more additional thera The compounds and compositions described herein can, peutic or prophylactic agents, both the compound and the for example, be administered orally, parenterally (e.g., Sub additional agent can be present at dosage levels of between cutaneously, intracutaneously, intravenously, intramuscu 45 about 1 to 100%, and more preferably between about 5 to 95% larly, intraarticularly, intraarterially, intrasynovially, of the dosage normally administered in a monotherapy regi intrasternally, intrathecally, intralesionally and by intracra C. nial injection or infusion techniques), by inhalation spray, The compositions of the presently disclosed embodiments topically, rectally, nasally, buccally, vaginally, via an may contain any conventional non-toxic pharmaceutically implanted reservoir, by injection, Subdermally, intraperito 50 acceptable carriers, adjuvants or vehicles. In some cases, the neally, transmucosally, or in an ophthalmic preparation, with pH of the formulation may be adjusted with pharmaceutically a dosage ranging from about 0.01 mg/kg to about 1000 acceptable acids, bases or buffers to enhance the stability of mg/kg, (e.g., from about 0.01 to about 100 mg/kg, from about the formulated compound or its delivery form. 0.1 to about 100 mg/kg, from about 1 to about 100 mg/kg, The compositions may be in the form of a sterile injectable from about 1 to about 10 mg/kg) every 4 to 120 hours, or 55 preparation, for example, as a sterile injectable aqueous or according to the requirements of the particular drug. The oleaginous Suspension. This Suspension may be formulated interrelationship of dosages for animals and humans (based according to techniques known in the art using Suitable dis on milligrams per meter squared of body Surface) is described persing or wetting agents (such as, for example, Tween 80) by Freireich et al., Cancer Chemother. Rep. 50, 219 (1966). and Suspending agents. The sterile injectable preparation may Body Surface area may be approximately determined from 60 also be a sterile injectable solution or Suspension in a non height and weight of the patient. See, e.g., Scientific Tables, toxic parenterally acceptable diluent or solvent, for example, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970). In certain as a solution in 1,3-butanediol. Among the acceptable embodiments, the compositions are administered by oral vehicles and solvents that may be employed are mannitol, administration or administration by injection. The methods water, Ringer's Solution and isotonic sodium chloride solu herein contemplate administration of an effective amount of 65 tion. In addition, Sterile, fixed oils are conventionally compound or compound composition to achieve the desired employed as a solvent or Suspending medium. For this pur or stated effect. Typically, the pharmaceutical compositions pose, any bland fixed oil may be employed including Syn US 9,095,572 B2 91 92 thetic mono- or diglycerides. Fatty acids, such as oleic acid in Remington's Pharmaceutical Sciences, 21st Edition and its glyceride derivatives are useful in the preparation of (2005) published by Mack Publishing Company, which is injectables, as are natural pharmaceutically-acceptable oils, incorporated herein by reference in its entirety. Such as olive oil or castor oil, especially in their polyoxyethy Topically-transdermal patches are also included in the lated versions. These oil solutions or Suspensions may also presently disclosed embodiments. Also within the presently contain a long-chain alcohol diluent or dispersant, or car boxymethyl cellulose or similar dispersing agents which are disclosed embodiments is a patch to deliver active chemo commonly used in the formulation of pharmaceutically therapeutic combinations herein. A patch includes a material acceptable dosage forms such as emulsions and or Suspen layer (e.g., polymeric, cloth, gauze, bandage) and the com sions. Other commonly used Surfactants such as Tweens or 10 pound of the formulae hereinas delineated herein. One side of Spans and/or other similar emulsifying agents or bioavailabil the material layer can have a protective layer adhered to it to ity enhancers which are commonly used in the manufacture of resist passage of the compounds or compositions. The patch pharmaceutically acceptable solid, liquid, or other dosage can additionally include an adhesive to hold the patch in place forms may also be used for the purposes of formulation. on a Subject. An adhesive is a composition, including those of The compositions of the presently disclosed embodiments 15 may be orally administered in any orally acceptable dosage either natural or synthetic origin, that when contacted with the form including, but not limited to, capsules, tablets, emul skin of a Subject, temporarily adheres to the skin. It can be sions and aqueous Suspensions, dispersions and solutions. In water resistant. The adhesive can be placed on the patch to the case of tablets for oral use, carriers which are commonly hold it in contact with the skin of the subject for an extended used include lactose and corn starch. Lubricating agents, such period of time. The adhesive can be made of a tackiness, or as magnesium Stearate, are also typically added. For oral adhesive strength, such that it holds the device in place sub administration in a capsule form, useful diluents include lac tose and dried corn starch. When aqueous Suspensions and/or ject to incidental contact, however, upon an affirmative act emulsions are administered orally, the active ingredient may (e.g., ripping, peeling, or other intentional removal) the adhe be suspended or dissolved in an oily phase is combined with 25 sive gives way to the external pressure placed on the device or emulsifying and/or Suspending agents. If desired, certain the adhesive itself, and allows for breaking of the adhesion Sweetening and/or flavoring and/or coloring agents may be contact. The adhesive can be pressure sensitive, that is, it can added. allow for positioning of the adhesive (and the device to be The compositions of the presently disclosed embodiments adhered to the skin) against the skin by the application of may also be administered in the form of Suppositories for 30 rectal administration. These compositions can be prepared by pressure (e.g., pushing, rubbing.) on the adhesive or device. mixing a compound of the presently disclosed embodiments The compositions of the presently disclosed embodiments with a suitable non-irritating excipient which is solid at room may be administered by nasal aerosol or inhalation. Such temperature but liquid at the rectal temperature and therefore compositions are prepared according to techniques well will melt in the rectum to release the active components. Such 35 known in the art of pharmaceutical formulation and may be materials include, but are not limited to, cocoa butter, bees prepared as Solutions in saline, employing benzyl alcohol or wax and polyethylene glycols. Topical administration of the compositions of the presently other Suitable preservatives, absorption promoters to enhance disclosed embodiments is useful when the desired treatment bioavailability, fluorocarbons, and/or other solubilizing or involves areas or organs readily accessible by topical appli 40 dispersing agents known in the art. cation. For application topically to the skin, the composition A composition having the compound of the formulae should be formulated with a suitable ointment containing the herein and an additional agent (e.g., a therapeutic agent) can active components suspended or dissolved in a carrier. Car be administered using any of the routes of administration riers for topical administration of the compounds of the pres described herein. In some embodiments, a composition hav ently disclosed embodiments include, but are not limited to, 45 mineral oil, liquid petroleum, white petroleum, propylene ing the compound of the formulae herein and an additional glycol, polyoxyethylene polyoxypropylene compound, agent (e.g., a therapeutic agent) can be administered using an emulsifying wax and water. Alternatively, the composition implantable device. Implantable devices and related technol can be formulated with a Suitable lotion or cream containing ogy are known in the art and are useful as delivery systems the active compound Suspended or dissolved in a carrier with 50 where a continuous, or timed-release delivery of compounds Suitable emulsifying agents. Suitable carriers include, but are or compositions delineated herein is desired. Additionally, not limited to, mineral oil, Sorbitan monostearate, polysor the implantable device delivery system is useful for targeting bate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, specific points of compound or composition delivery (e.g., benzyl alcohol and water. The compositions of the presently localized sites, organs). Negrinet al., Biomaterials, 22(6):563 disclosed embodiments may also be topically applied to the 55 (2001). Timed-release technology involving alternate deliv lower intestinal tract by rectal Suppository formulation or in a Suitable enema formulation. ery methods can also be used in the presently disclosed In some embodiments, topical administration of the com embodiments. For example, timed-release formulations pounds and compositions described herein may be presented based on polymer technologies, Sustained-release techniques in the form of an aerosol, a semi-solid pharmaceutical com 60 and encapsulation techniques (e.g., polymeric, liposomal) position, a powder, or a solution. By the term “a semi-solid can also be used for delivery of the compounds and compo composition' is meant an ointment, cream, salve, jelly, or sitions delineated herein. other pharmaceutical composition of Substantially similar The presently disclosed embodiments will be further consistency Suitable for application to the skin. Examples of described in the following examples. It should be understood semi-solid compositions are given in Chapter 17 of The 65 that these examples are for illustrative purposes only and are Theory and Practice of Industrial Pharmacy, Lachman, Lie not to be construed as limiting the presently disclosed berman and Kanig, published by Lea and Febiger (1970) and embodiments in any manner. US 9,095,572 B2 93 94 EXAMPLES mmol) was added to a solution of 3,6-dibromocarbazole (0.500 g, 1.54 mmol) in DMF (1.5 mL) at ambient tempera Example la and 1b ture and stirred for 30 min until dissolved. Epibromohydrin (0.32 mL, 3.8 mmol) was added via syringe and the reaction P7C3-S16 and P7C3-S17: S- and R-1-(3,6-Dibromo was stirred at room temperature overnight. Upon completion, 9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-pro the solution was partitioned between EtOAc and H2O. The pan-2-ol aqueous layer was washed 3x with EtOAc, and the combined organics were washed with Saturated aqueous NaCl, dried over NaSO filtered, and concentrated in vacuo. The crude 10 residue was recrystallized from EtOAc/Hexane to afford the la desired product (389 mg, 66%). Br H NMR (CDC1,500 MHz) 88.10 (d. 2H, J=2.0 Hz), 7.54

(dd, 2H, J=2.0, 8.5 Hz), 7.31 (d. 2H, J=8.5 Hz), 4.62 (dd. 1H, J=2.5, 16.0 Hz), 4.25 (dd. 1H, J=5.5, 16.0 Hz), 3.29 (m, 1H), 15 2.79 (dd. 1H, J=4.0, 4.5 Hz), 2.46 (dd. 1H, J–2.5, 5.0 Hz). ESI m/z 381.0 (M+H", CHBr NO requires 379.9) Representative Procedure 2 Step 2. Synthesis of 1-(3,6-dibromo-9H-carbazol-9- yl)-3-(3-methoxyphenylamino)propan-2-ol

25 OMe and Br 1b Br

30 "N-N-O N OH N OH 35 (S) NH NH

40 OMe OMe

Following a literature procedure (Asso, V. Ghilardi, E.; Representative Procedure 1 45 Bertini, S.; Digiacomo, M.; Granchi, C.; Minutolo, F.; Rap poselli, S.; Bortolato, A.; Moro, S. Macchia, M. ChemMed Step 1. Synthesis of 3,6-Dibromo-9-(oxiran-2-ylm Chem, 2008, 3, 1530-1534) m-Anisidine (1.0 mL, 8.95 ethyl)-9H-carbazole (Epoxide 2-A) mmol) was added to a suspension of epoxide 2-A (3.02g, 7.92 mmol) in cyclohexane (73 mL). BiCls (0.657g, 2.08 mmol) 50 was added and the mixture was heated to reflux overnight. Upon completion, the reaction was partitioned between Br EtOAc and H2O. The aqueous layer was washed 3x with EtOAc, and the combined organics were washed with satu rated aqueous NaCl, dried over NaSO filtered, and concen Br 55 trated in vacuo. The crude residue was purified by chroma tography (SiO2, 0-50% EtOAc/Hexane) to afford the desired alcohol as an opaque yellow solid (998 mg, 25%). 'HNMR (CDC1,400 MHz) & 8.12 (d. 2H, J=1.6 Hz), 7.52 (dd, 2H, J=2.0, 8.8 Hz), 7.32 (d. 2H, J=8.8 Hz), 7.07 (dd. 1H, 60 J=8.0 Hz), 6.31 (dd. 1H, J–2.4, 8.0 Hz), 6.21 (dd. 1H, J=2.0, 8.0 Hz), 6.12 (dd. 1H, J=2.0, 2.4Hz), 4.34-4.39 (m,3H), 4.00 (brs, 1H), 3.71 (s, 3H), 3.30 (dd. 1H, J=3.6, 13.2 Hz), 3.16 (dd. 1H, J=6.4, 13.2 Hz), 2.16 (brs, 1H). Following a literature procedure (Asso, V., Ghilardi, E.; 'C NMR (CDC1, 100 MHz) & 1610, 149.2, 139.9 (2C), Bertini, S.; Digiacomo, M.; Granchi, C.; Minutolo, F.; Rap 65 130.4 (2C), 129.5 (2C), 123.8 (2C), 123.5 (2C), 112.8, 111.0 poselli, S.; Bortolato, A.; Moro, S. Macchia, M. ChemMed (2C), 106.7, 103.8, 99.8, 69.5, 55.3, 48.0, 47.4 Chem, 2008, 3, 1530-1534) powdered KOH (0.103 g, 1.85 ESI m/z 502.9 (IM+H", C.H. BrNO, requires 503.0)