JP2015529663A - Neurogenesis-promoting compound - Google Patents

Abstract

The present technology relates generally to compounds and methods that stimulate neurogenesis (eg, postnatal neurogenesis, including postnatal hippocampus and hypothalamic neurogenesis) and / or protect neurons from cell death. Various compounds are disclosed herein. In vivo activity studies show that these compounds are schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, posttraumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down's syndrome, spinocerebellar ataxia, muscle Amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, abuse of neurostimulants, retinal degeneration, spinal cord injury, peripheral nerve injury, physiological weight loss related to various conditions, and normal aging Suggests that it may have therapeutic effects on neuropsychiatric and / or neurodegenerative diseases such as cognitive decline associated with chemotherapy and the like.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is based on US Provisional Application No. 12 / 832,056 (2010 U.S. Application No. 13 / 594,223 (August 2012), which is a continuation-in-part of U.S. Application No. 13 / 177,981 (filed on Jul. 7, 2011) Each of which is hereby incorporated by reference in its entirety.

DESCRIPTION OF FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT This invention was made with government support under grant numbers 5DP10DOD00027605, 5R37MH05938809 and 1RO1MH087986 by the National Institutes of Health, and the government has certain rights in the invention.

TECHNICAL FIELD The present invention relates generally to the discovery of compounds that promote neurogenesis that have the ability to promote neurogenesis and / or reduce neuronal cell death.

Background Currently, it is accepted that the adult vertebrate brain promotes neuronal neurogenesis and functional uptake of newly formed neurons (Goldman and Nottebohm, Proc Natl Acad Sci USA 1983, 80: 2390- 2394; Paton and Nottebohm, Science 1984, 225, 1046-1048; Burd and Nottebohm, J Comp Neurol 1985, 240: 143-152). However, it has long been thought that new neurons cannot be added to the adult mammalian brain. This hypothesis was questioned in the 1960s when autoradiographic evidence of new neuronal formation in the adult rat hippocampal dentate gyrus, olfactory bulb, and cerebral cortex was presented (Altman, J. Science 1962, 135, 1127-1128; Altman, J. J Comp Neurol 1966, 128: 431-474; Altman, Anat Rec 1963, 145: 573-591; Altman and Das, J. Comp. Neurol. 1965, 124, 319-335; Altman and Das, J Comp Neurol 1966, 126: 337-390). Currently, all mammalian species including humans (Eriksson et al., Nat. Med. 1998, 4 (11), 1313-1317) have two major neuronal stem cell reservoirs, one of which is hippocampal dentate It is accepted that it is located in the subgranular subcellular zone (SGZ) and the other is in the subventricular zone (SVZ) (Gross, Natl. Rev. 2000, 1, 67-72). SVZ neural stem cells migrate rostrally to promote the formation of new neurons that form the olfactory bulb, whereas SGZ neural stem cells are granules of the dentate gyrus, a region of the hippocampus that exhibits structural and functional plasticity that lasts for life Generate neurons that integrate locally in layers.

  The process of formation of new neurons in the adult mouse brain can be affected by environmental, chemical and genetic variations. As demonstrated by Gage and colleagues, neurogenesis in the adult mouse brain exposes animals to a rich environment (Kempermann et al., Nature 1997, 386, 493-495) or is free to exercise (van Praag et al. al., Nat. Neuro-sci. 1999, 2, 266-270). More recently, antidepressants have been shown to increase the level of adult neurogenesis in animals, including humans (Schmidt et al., Behav Pharmacol. 2007 Sep; 18 (5-6): 391-418; Boldrini et al ., Neuropsychopharmacology 2009, 34, 2376-2389). Among the many genes that have been reported to affect adult neurogenesis, the neuronal PAS domain protein 3 (CNS) -specific transcription factor associated with schizophrenia and bipolar disorder ( There is a gene encoding NPAS3) (Kamnasaran et al., J. Med. Genet. 2003, 40, 325-332; Pickard et al., Am. J. Med. Genet. B. Neuropsychiatr. Genet. 2005, 136B , 26-32; Pickard et al., Ann. Med. 2006, 38, 439-448; Pickard et al., Mol. Psychiatry 2009, 14, 874-884; Lavedan et al., Pharmacogenomics 2008, 9: 289- 301). Animals lacking both copies of the NPAS3 gene have extensive loss of adult hippocampal neurogenesis combined with significant behavioral defects (Pieper et al., Proc. Natl. Acad. Sci. USA 2005, 102, 14052- 14057). The finding that impaired postnatal neurogenesis induces an unfavorable phenotypic defect predicts that proneurogenic compounds will show favorable therapeutic benefits.

SUMMARY The present invention relates generally to compounds that promote the generation of or the survival of existing neurons in the mammalian brain. For the purpose of simplicity, these compounds are called proneurogenic. In certain embodiments, the compounds promote neuronal cell generation or survival in the postnatal mammalian brain. In certain embodiments, the compounds promote the survival, proliferation, development and / or function of neurons, particularly CNS, brain, cerebrum and hippocampal neurons. In certain embodiments, the compound stimulates postnatal hippocampal neurogenesis, which is not desired to be bound by theory, but is schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury Post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, neurostimulant drugs (e.g. alcohol, opiates, It is believed to provide therapeutic targets for a variety of neuropsychiatric and neurodegenerative diseases including (but not limited to) abuse of methamphetamine, phencyclidine and cocaine), retinal degeneration, spinal cord injury and peripheral nerve injury. In certain embodiments, the compounds stimulate postnatal hypothalamic neurogenesis, including but not limited to normal aging, chemotherapy, radiation therapy, stress, drug abuse, eating disorders, and other diseases disclosed herein. It may provide a therapeutic benefit for weight management such as but not limited to physiological weight loss.

  Embodiments disclosed herein also relate to compositions comprising such compounds (eg, pharmaceutical compositions) as well as methods for making, identifying, and using such compounds. Other features and advantages are described in, or are apparent from, the specification and the accompanying drawings.

Accordingly, in one aspect, a method for promoting postnatal mammalian neurogenesis and / or suppressing neuronal cell death in a subject in need of treatment is described, wherein the method comprises a compound of formula (I)
Administering an effective amount of a compound having the formula: or a pharmaceutically acceptable salt thereof
Each of R ¹ , R ² , R ³ and R ⁴ is independently hydrogen, halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C _{6 thiohaloalkoxy,} C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 2 -C ₆ alkynyl, cyclopropyl, -N _3, a _{cyano, -NH 2, -NH (C 1} -C 6 alkyl ), —N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro;

R and R ′ are the following (1), (2), (3), (4) or (5)
(1) R and R ′ are combined with C ₂ and C ₃ respectively to form the formula (II)
Form a phenyl ring
Where R ⁵ , R ⁶ , R ⁷ and R ⁸ are each hydrogen, halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C _{6 thiohaloalkoxy,} C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 2 -C ₆ alkynyl, cyclopropyl, -N _3, a _cyano, -NH 2, -NH _(C 1 -C ₆ Alkyl), —N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro)); or
(2) each of R and R ′ is independently hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; or
(3) R and R ′ together with C ₂ and C ₃ respectively form a condensed heterocyclic ring containing 5 to 6 ring atoms (where 1 to 2 ring atoms are N, NH N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S; and the heterocyclic ring is optionally selected from 1 to 3 independently Optionally selected R ^a ); or
(4) R and R ′ together with C ₂ and C ₃ respectively form a fused C ₅ -C ₆ cycloalkyl ring, optionally containing 1 to 4 independently selected R ^a May be substituted with; or
(5) R and R ′ together with C ₂ and C ₃ respectively form a fused heteroaryl ring containing 5 to 6 ring atoms, wherein 1 to 2 of the ring atoms are N, NH, N (C ₁ -C ₃ alkyl), independently selected from O and S; and the heteroaryl ring is optionally defined as optionally substituted by 1 to 3 independently selected R ^b Is;

L ¹ is
(i) a C ₁ -C ₃ linear alkylene optionally substituted by 1 to 2 independently selected R ^c ; or
(ii) a bond directly linking N of the 5-membered ring of formula (I) to A of formula (I);
L ² is
(i) a C ₁ -C ₃ linear alkylene optionally substituted by 1 to 2 independently selected R ^c ; or
(ii) a bond directly linking A of formula (I) to Z of formula (I);
A is
(i) CR ^A1 R ^A2 wherein each of R ^A1 and R ^A2 is independently selected from hydrogen, halo, C ₁ -C ₃ alkyl or OR ⁹ ; or
(ii) C = O; or
(iii) (a) 1 oxo is substituted with, and (b) optionally 1-4 independent -C may be further substituted with R ^a C ₃ to be selected by ₅ cycloalkylene; Or
(iv) a heterocycloalkylene containing 3 to 5 ring atoms, wherein 1 to 2 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; The heterocycloalkylene is (a) substituted with 1 oxo and (b) optionally further substituted with 1 to 4 independently selected R ^a )
Is;

Z is
(i) -NR ¹⁰ R ^11; or
^{(ii) -C (O) NR} 10 R 11; or
(iii) ^{-OR 12;} or
(iv) -S (O) _n R ¹³ where n is 0, 1 or 2; or
(v) a heterocycloalkenyl including 5-6 ring atoms (wherein 1-3 is N, NH ring atoms, N _(C 1 -C _{6 alkyl), NC (O) (C} 1 -C ₆ alkyl), independently selected from O and S; and the heterocycloalkenyl may be optionally substituted with 1 to 4 independently selected R ^a );
(vi) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 independently selected R ^b ; or
(vii) a heteroaryl containing 5 to 14 ring atoms, wherein 1 to 6 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; Heteroaryl may be optionally substituted with 1-4 independently selected R ^b ); or
(viii) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a );
Or
(ix) arylheterocyclyls containing 8-14 ring atoms, where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a );
Or
(x) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a );
Or
(xi) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;

R ⁹ is or if either is hydrogen by a hydroxyl or _C 1 -C ₃ alkoxy substituted optionally may _C 1 -C ₃ alkyl;
Each of R ¹⁰ and R ¹¹ is the following (a) to (l)
(a) hydrogen;
(b) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ;
(c) 5 to 14 heteroaryl containing a ring atom (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl is optionally substituted with 1 to 4 R ^b );
(d) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl, each of which is optionally substituted with 1 to 3 R ^d ;
_{(e) -C (O) (} C 1 -C 6 _{alkyl), - C (O) (} C 1 -C 6 haloalkyl) or _{-C (O) O (C 1} -C 6 alkyl);
(f) C ₂ -C ₆ alkenyl or _C 2 -C ₆ alkynyl;
(g) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a );
(h) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a );
(i) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a );
(j) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a );
(k) C ₃ -C ₈ cycloalkyl or C ₃ -C ₈ cycloalkenyl optionally substituted with 1 to 4 independently selected R ^a ; and
(l) C ₇ -C ₁₂ aralkyl (wherein the aryl moiety may be optionally substituted with 1 to 4 R ^b , independently selected)
Independently selected from the substituents collectively described in

R ¹² is
(i) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or
(ii) heteroaryl including 5-14 ring atoms (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl may optionally be substituted with 1 to 4 R ^b ); or
(iii) optionally substituted with 1 to 3 R ^d C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; or
(iv) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a ); or
(v) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vi) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vii) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;

R ¹³ is
(i) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or
(ii) a heteroaryl containing 5 to 14 ring atoms, wherein 1 to 6 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; Heteroaryl is optionally substituted with 1 to 4 R ^b );
(iii) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a ); or
(iv) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(v) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vi) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;

Each R ^a is halo, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, oxo, thioxo, = NH, = N _(C 1 -C _{6 alkyl),} C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl, -NH 2, -NH (C 1} -C 6 alkyl), N _(C 1 -C _{6 alkyl)} 2, _{-NHC (O) (C 1 -C} 6 alkyl) and from cyano independently selected;

R ^b represents the following (aa) to (dd)
(aa) C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ thiohaloalkoxy; -O- (CH ₂ ) _1-3- [O (CH _{2) 1-3] 1-3 -H; -C} 1 -C 6 _alkyl, C 1 -C ₆ haloalkyl, -NH _(C 1 -C _{6 alkyl), - N (C 1 -C} 6 _alkyl) 2, —NHC (O) (C ₁ -C ₆ alkyl), wherein each of the alkyl moieties is optionally substituted with 1 to 3 independently selected R ^e ;
(bb) halo; hydroxy; cyano; nitro; -NH _2; azido; _sulfhydryl; C 2 -C _{6 alkenyl;} C 2 -C ₆ alkynyl; -C (O) H; -C (O) (C 1 -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); C (O) OH; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C ( O) NH _(C 1 -C ₆ alkyl); C (O) N ( C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH ( C ₁ -C ₆ alkyl); - SO ₂ N _(C 1 -C _{6 alkyl)} 2;
(cc) C ₃ -C ₆ cycloalkyl or heterocyclyl containing 5-6 ring atoms, wherein 1 to 2 ring atoms of the heterocyclyl are N, NH, N (C ₁ -C ₆ alkyl), NC (O ) (C ₁ -C ₆ alkyl), independently selected from O and S; and each of the cycloalkyl and heterocyclyl is optionally substituted with 1 to 3 independently selected R ^a );and
(dd) phenyl or heteroaryl containing 5-6 ring atoms, wherein 1-2 of the heteroaryl ring atoms are independently N, NH, N (C ₁ -C ₃ alkyl), O and S Wherein each of the phenyl and heteroaryl is optionally halo; hydroxyl; cyano; nitro; —NH ₂ ; —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , _{-NHC (O) (C 1 -C} 6 _alkyl), C 1 -C _{6 alkoxy;} C 1 -C _{6 haloalkoxy;} C 1 -C _{6 thioalkoxy;} C 1 -C _{6 thiohaloalkoxy;} C 1 -C Optionally substituted with 1 to 3 substituents independently selected from ₆ alkyl and C ₁ -C ₆ haloalkyl)
Independently selected from the substituents described in;

R ^c is halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently selected from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Is;

R ^d represents hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently selected from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Is;
Each R ^e is hydroxyl, C ₁ -C ₆ alkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thiohaloalkoxy; -NH ₂ ; -NH (C _1- C ₆ alkyl); N (C ₁ -C ₆ alkyl) ₂ ; —NHC (O) (C ₁ -C ₆ alkyl); cyano; —C (O) H; —C (O) (C ₁ -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); C (O) OH; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C (O ) NH _(C 1 -C ₆ alkyl); C (O) N ( C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH (C ₁ -C ₆ alkyl); - SO ₂ N _(C 1 -C _{6 alkyl) 2;} and ^{L 3} - _(C 1 -C ₆ alkylene) independently selected from -Cy, wherein, ^{L 3} is - _{-, - NH -, - NCH} 3 -, - C (O) -, - C (O) NH -, - C (O) NCH 3 -, - NHC (O) - or -NCH ₃ C (O) - And Cy is a saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring. ].

In some embodiments, one or more of (A), (B) or (C) is applied.
(A) If R and R ′ are defined according to definition (3),
(i) When A is CH ₂ , each of L ¹ and L ² must be C ₁ -C ₃ alkylene, optionally with 1 to 2 independently selected R ^c May be substituted; or
(ii) Z is 5-14 (e.g., 5-6 or 6) must be other than heteroaryl containing ring atoms, wherein 1-6 ring atoms are _{N, NH, N (C 1} - C ₃ alkyl), independently selected from O and S; and the heteroaryl may be optionally substituted with 1-4 independently selected R ^b ; for example, other than substituted pyridyl, such as Other than pyridyl substituted with C ₁ -C ₃ alkyl (eg, CH ₃ ), eg, other than 2- or 6-methylpyridyl.

(B) Each of R ¹⁰ and R ¹¹ must not be an optionally substituted naphthyl (eg, each of R ¹⁰ and R ¹¹ must not be an unsubstituted naphthyl). In certain embodiments, when R and R ′ are defined according to the definitions of definitions (1), (2) and (4), they are other than optionally substituted naphthyl (eg, unsubstituted naphthyl); CR ^A1 R ^A2 (eg, CHOR ⁹ , eg, CHOH), wherein each of L ¹ and L ² is C ₁ -C ₃ alkylene (eg, each of L ¹ and L ² is CH ₂ ).

(C) R ¹² and / or R ¹³ must not be substituted phenyl. In certain embodiments, when R and R ′ are defined according to the definition of definition (1), R ¹² and / or R ¹³ must not be substituted phenyl; CR ^A1 R ^A2 (eg, CHOR ⁹ , eg, , CHOH) and each of L ¹ and L ² is C ₁ -C ₃ alkylene (eg, each of L ¹ and L ² is CH ₂ ).

  In some embodiments, (A), (B) or (C) applies. In other embodiments, (A) and (B); or (A) and (C); or (B) and (C) apply. In still other embodiments, (A), (B) and (C) are applied.

In another aspect, the invention features a method of promoting postnatal mammalian neurogenesis in a subject in need of treatment. The method is directed to a formula (I)
Administering an effective amount of a compound having the formula: or a pharmaceutically acceptable salt thereof
Each of R ¹ , R ² , R ³ and R ⁴ is hydrogen, halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C _{6. thiohaloalkoxy,} C 1 -C _{6 alkyl,} C 1 -C ₆ haloalkyl, _{cyano, -NH 2, -NH (C 1} -C 6 _{alkyl), - N (C 1 -C} 6 _alkyl) 2, -NHC ( Independently selected from O) (C ₁ -C ₆ alkyl) and nitro;
R and R ′ are the following (1), (2), (3), (4) or (5)
(1) R and R ′ are combined with C ₂ and C ₃ respectively to form the formula (II)
Form a phenyl ring
Where R ⁵ , R ⁶ , R ⁷ and R ⁸ are each hydrogen, halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ halo _{thioalkoxyalkyl,} C 1 -C _{6 alkyl,} C 1 -C ₆ haloalkyl, _cyano, -NH 2, -NH _(C 1 -C ₆ alkyl), N _(C 1 -C _{6 alkyl)} 2, _{-NHC (O) (C 1 -C} 6 alkyl) and from a nitro independently selected); or
(2) each of R and R ′ is independently hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; or
(3) R and R ′ together with C ₂ and C ₃ respectively form a condensed heterocyclic ring containing 5 to 6 ring atoms (where 1 to 2 ring atoms are N, NH N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S; and the heterocyclic ring is optionally selected from 1 to 3 independently Optionally selected R ^a ); or
(4) Fused C ₅ -C ₆ cycloalkyl ring, wherein R and R ′ are each united with C ₂ and C ₃ and optionally substituted with 1 to 4 independently selected R ^a Form; or
(5) R and R ′ together with C ₂ and C ₃ respectively form a fused heteroaryl ring containing 5 to 6 ring atoms (where 1-2 ring atoms are N, NH, N (C ₁ -C ₃ alkyl), independently selected from O and S; and the heteroaryl ring may be optionally substituted by 1 to 3 independently selected R ^b )
Are defined according to:

L ¹ is
(i) a C ₁ -C ₃ linear alkylene optionally substituted by 1 to 2 independently selected R ^c ; or
(ii) a bond directly linking N of the 5-membered ring of formula (I) to A of formula (I);
L ² is
(i) a C ₁ -C ₃ linear alkylene optionally substituted by 1 to 2 independently selected R ^c ; or
(ii) a bond directly linking A of formula (I) to Z of formula (I);
A is
(i) CR ^A1 R ^A2 wherein each of R ^A1 and R ^A2 is independently selected from hydrogen, halo, C ₁ -C ₃ alkyl or OR ⁹ ; or
(ii) C = O; or
(iii) C ₃ -C ₅ cycloalkylene (which is substituted with (a) 1 oxo; and
(b) optionally further substituted with 1 to 4 independently selected R ^a ); or
(iv) a heterocycloalkylene containing 3 to 5 ring atoms, wherein 1 to 2 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; The heterocycloalkylene is (a) substituted with 1 oxo; and (b) optionally further substituted with 1 to 4 independently selected R ^a )
Is;
In some embodiments, A is not CH ₂ and in some embodiments when A is CR ^A1 R ^A2 , one of R ^A1 and R ^A2 can be hydrogen, halo, C ₁ -C ₃ alkyl, or OR ^9. The other of R ^A1 and R ^A2 may be halo, C ₁ -C ₃ alkyl or OR ⁹ ;

Z is
(i) -NR ¹⁰ R ^11; or
^{(ii) -C (O) NR} 10 R 11; or
(iii) ^{-OR 12;} or
(iv) -S (O) _n R ¹³ where n is 0, 1 or 2; or
(v) heterocycloalkenyl containing 5 to 6 ring atoms, wherein 1 to 3 ring atoms are N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl ), O and S; and the heterocycloalkenyl may be optionally substituted with 1 to 4 independently selected R ^a );
(vi) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 independently selected R ^b ; or
(vii) a heteroaryl containing 5 to 14 ring atoms, wherein 1 to 6 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; Heteroaryl may be optionally substituted with 1-4 independently selected R ^b ); or
(viii) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a ); or
(ix) arylheterocyclyls containing 8-14 ring atoms, where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(x) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(xi) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;

R ⁹ is or if either is hydrogen by a hydroxyl or _C 1 -C ₃ alkoxy substituted optionally may _C 1 -C ₃ alkyl;
Each of R ¹⁰ and R ¹¹ is the following (a) to (l)
(a) hydrogen;
(b) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ;
(c) 5 to 14 heteroaryl containing a ring atom (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl is optionally substituted with 1 to 4 R ^b );
(d) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl optionally substituted with 1 to 3 R ^d ;
_{(e) -C (O) (} C 1 -C 6 _{alkyl), - C (O) (} C 1 -C 6 haloalkyl) or _{-C (O) O (C 1} -C 6 alkyl);
(f) C ₂ -C ₆ alkenyl or _C 2 -C ₆ alkynyl;
(g) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a );
(h) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a );
(i) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a );
(j) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a );
(k) C ₃ -C ₈ cycloalkyl or C ₃ -C ₈ cycloalkenyl optionally substituted with 1 to 4 independently selected R ^a ; and
(l) C ₇ -C ₁₂ aralkyl (wherein the aryl moiety may be optionally substituted with 1 to 4 R ^b , independently selected)
Independently selected from the substituents collectively described in

R ¹² is
(i) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or
(ii) heteroaryl including 5-14 ring atoms (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl may optionally be substituted with 1 to 4 R ^b ); or
(iii) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl optionally substituted with 1 to 3 R ^d ; or
(iv) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a ); or
(v) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vi) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vii) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;

R ¹³ is
(i) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or
(ii) a heteroaryl containing 5 to 14 ring atoms, wherein 1 to 6 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; Heteroaryl is optionally substituted with 1 to 4 R ^b );
(iii) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a ); or
(iv) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(v) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vi) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;

Each R ^a is halo, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, oxo, thioxo, = NH, = N _(C 1 -C _{6 alkyl),} C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl, -NH 2, -NH (C 1} -C 6 alkyl), N _(C 1 -C _{6 alkyl)} 2, _{-NHC (O) (C 1 -C} 6 alkyl) and from cyano independently selected;

R ^b represents the following (aa) to (dd)
(aa) C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ thiohaloalkoxy; C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl,- NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , -NHC (O) (C ₁ -C ₆ alkyl) (wherein each of the alkyl moieties is optionally 1 to 3 Or independently selected R ^e );
(bb) halo; hydroxy; cyano; nitro; -NH _2; azido; _sulfhydryl; C 2 -C _{6 alkenyl;} C 2 -C ₆ alkynyl; -C (O) H; -C (O) (C 1 -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); C (O) OH; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C ( O) NH _(C 1 -C ₆ alkyl); C (O) N ( C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH ( C ₁ -C ₆ alkyl); - SO ₂ N _(C 1 -C _{6 alkyl)} 2;
(cc) C ₃ -C ₆ cycloalkyl or heterocyclyl containing 5-6 ring atoms, wherein 1 to 2 ring atoms of the heterocyclyl are N, NH, N (C ₁ -C ₆ alkyl), NC (O ) (C ₁ -C ₆ alkyl), independently selected from O and S; and each of the phenyl and heterocyclyl is optionally substituted with 1 to 3 independently selected R ^a ) ;and
(dd) phenyl or heteroaryl containing 5-6 ring atoms, wherein 1-2 of the heteroaryl ring atoms are independently N, NH, N (C ₁ -C ₃ alkyl), O and S Wherein each of the phenyl and heteroaryl is optionally halo; hydroxyl; cyano; nitro; —NH ₂ ; —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , _{-NHC (O) (C 1 -C} 6 _alkyl), C 1 -C _{6 alkoxy;} C 1 -C _{6 haloalkoxy;} C 1 -C _{6 thioalkoxy;} C 1 -C _{6 thiohaloalkoxy;} C 1 -C Optionally substituted with 1 to 3 substituents independently selected from ₆ alkyl and C ₁ -C ₆ haloalkyl)
Independently selected from the substituents described in;

R ^c is halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently selected from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Is;

R ^d represents hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently selected from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Is;
Each R ^e is hydroxyl, C ₁ -C ₆ alkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thiohaloalkoxy; -NH ₂ ; -NH (C _1- C ₆ alkyl); N (C ₁ -C ₆ alkyl) ₂ ; —NHC (O) (C ₁ -C ₆ alkyl); cyano; —C (O) H; —C (O) (C ₁ -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); C (O) OH; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C (O ) NH _(C 1 -C ₆ alkyl); C (O) N ( C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH (C _1- C ₆ alkyl); -SO ₂ N (C ₁ -C ₆ alkyl) ₂ independently selected; L ^3- (C ₁ -C ₆ alkylene) -Cy, wherein L ³ is -O- , _{NH -, - NCH 3 -,} - C (O) -, - C (O) NH -, - C (O) NCH 3 -, - NHC (O) - or -NCH ₃ C (O) - and is, Cy is a saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring. ]
Or a salt thereof (eg, a pharmaceutically acceptable salt).

In some embodiments, one or more of (A), (B) or (C) is applied.
(A) If R and R ′ are defined according to definition (3),
(i) When A is CH ₂ , each of L ¹ and L ² must be C ₁ -C ₃ alkylene, optionally with 1 to 2 independently selected R ^c May be substituted; or
(ii) Z is 5-14 (e.g., 5-6 or 6) must be other than heteroaryl containing ring atoms, wherein 1-6 ring atoms are _{N, NH, N (C 1} - C ₃ alkyl), independently selected from O and S; and the heteroaryl may be optionally substituted with 1-4 independently selected R ^b ; for example, other than substituted pyridyl, such as Other than pyridyl substituted with C ₁ -C ₃ alkyl (eg, CH ₃ ), eg, other than 2- or 6-methylpyridyl.

(B) Each of R ¹⁰ and R ¹¹ must not be an optionally substituted naphthyl (eg, each of R ¹⁰ and R ¹¹ must not be an unsubstituted naphthyl). In certain embodiments, when R and R ′ are defined according to the definitions of definitions (1), (2) and (4), they are other than optionally substituted naphthyl (eg, unsubstituted naphthyl); CR ^A1 R ^A2 (eg, CHOR ⁹ , eg, CHOH), wherein each of L ¹ and L ² is C ₁ -C ₃ alkylene (eg, each of L ¹ and L ² is CH ₂ ).

(C) R ¹² and / or R ¹³ must not be substituted phenyl. In certain embodiments, when R and R ′ are defined according to the definition of definition (1), R ¹² and / or R ¹³ must not be substituted phenyl; CR ^A1 R ^A2 (eg, CHOR ⁹ , eg, , CHOH) and each of L ¹ and L ² is C ₁ -C ₃ alkylene (eg, each of L ¹ and L ² is CH ₂ ).

  In some embodiments, (A), (B) or (C) applies. In other embodiments, (A) and (B); or (A) and (C); or (B) and (C) apply. In still other embodiments, (A), (B) and (C) are applied.

In another aspect, the invention features a method of promoting postnatal mammalian neurogenesis in a subject in need of treatment. The method comprises administering to a subject an effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein R and R ′ are combined with C ₂ and C ₃ respectively. , Formula (II)
Form a phenyl ring.

For clarity, compounds in which R and R ′ together with C ₂ and C ₃ , respectively, form a fused phenyl ring having the formula (II) have the following general formula:
[Wherein R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² , A and Z may be as defined herein. ]
To be interpreted as corresponding to a compound having

  In some embodiments, (A), (B) or (C) applies. In other embodiments, (A) and (B); or (A) and (C); or (B) and (C) apply. In still other embodiments, (A), (B) or (C) is applied.

In another aspect, the invention features a method of promoting postnatal mammalian neurogenesis in a subject in need of treatment. The method comprises administering to a subject an effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein
Each of L ¹ and L ² is CH ₂ ;
A is CR ^A1 R ^A2 , wherein one of R ^A1 and R ^A2 is OR ⁹ and the other is hydrogen;
Z is —NR ¹⁰ R ¹¹ ;
Each of R ¹⁰ and R ¹¹ is independently
(a) hydrogen;
(b) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ;
(d) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl optionally substituted with 1 to 3 R ^d ;
(f) a C ₂ -C ₆ alkenyl or _C 2 -C ₆ alkynyl.

  In some embodiments, (A), (B) or (C) applies. In other embodiments, (A) and (B); or (A) and (C); or (B) and (C) apply. In still other embodiments, (A), (B) and (C) are applied.

  In one aspect, features a composition (e.g., a pharmaceutical composition), which is a compound of formula (I) as defined herein (and / or any compound of any other formula described herein) or The salt (eg, a pharmaceutically acceptable salt) and a pharmaceutically acceptable carrier. In certain embodiments, the composition can include an effective amount of the compound or salt. In certain embodiments, the composition may further comprise one or more additional therapeutic agents. These include antidepressants (selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors and other antidepressants including but not limited to venlafexine, nefazadone, bupropion, mirtazapine, lithium and trazodone And cholinesterase inhibitors (including but not limited to Aricept, Reminyl and Exelon).

  In another aspect, it features a dosage form, which is about 0.05 milligrams to about 2,000 milligrams (eg, about 0.1 milligrams to about 1,000 milligrams, about 0.1 milligrams to about 500 milligrams, From about 0.1 milligram to about 250 milligrams, from about 0.1 milligrams to about 100 milligrams, from about 0.1 milligrams to about 50 milligrams or from about 0.1 milligrams to about 25 milligrams) as defined herein ( I) (and / or compounds of any other formulas described herein) or salts thereof (eg, pharmaceutically acceptable salts). The dosage form may further comprise a pharmaceutically acceptable carrier and / or additional therapeutic agent.

  In one aspect, a compound of formula (I) as defined herein (and / or any compound of any other formula described herein) or a salt thereof (eg, a pharmaceutically acceptable salt) ). In another aspect, it is characterized by any of the compounds of formula (I) specifically described herein.

In one aspect, the formula (I)
Or a pharmaceutically acceptable salt thereof, wherein
Each of R ¹ , R ² , R ³ and R ⁴ is hydrogen, halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C _6. Thiohaloalkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkynyl, cyclopropyl, —N ₃ , cyano, —NH ₂ , —NH (C ₁ -C ₆ alkyl), — Independently selected from N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro;

R and R ′ are the following (1) or (2)
(1) R and R ′ are combined with C ₂ and C ₃ respectively to form the formula (II)
Form a phenyl ring
Where R ⁵ , R ⁶ , R ⁷ and R ⁸ are each hydrogen, halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C _{6 thiohaloalkoxy,} C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 2 -C ₆ alkynyl, cyclopropyl, -N _3, a _cyano, -NH 2, -NH _(C 1 -C ₆ Alkyl), —N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro)); or
(2) R and R ′ together with C ₂ and C ₃ respectively form a fused heteroaryl ring containing 6 ring atoms (wherein 1-2 of the independently selected ring atoms are N And the heteroaryl ring may optionally be substituted with 1 to 2 independently selected R ^b )
As defined in accordance with

Each of L ¹ and L ² is independently C ₁ -C ₃ alkylene, which may optionally be substituted with 1 to 2 independently selected R ^c ;
A is
(i) CR ^A1 R ^A2 wherein each of R ^A1 and R ^A2 is independently selected from hydrogen, halo, C ₁ -C ₃ alkyl and OR ⁹ , wherein R ⁹ is hydrogen or optionally a hydroxy or _C 1 -C ₃ are optionally may _C 1 -C ₃ alkyl substituted with alkoxy); or
(ii) C = O; or
(iii) C ₃ -C ₅ cycloalkylene (which is (a) substituted with one oxo; and (b) optionally further substituted with 1 to 4 independently selected R ^a). Or); or
(iv) a heterocycloalkylene containing 3 to 5 ring atoms, wherein 1 to 2 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; The heterocycloalkylene is (a) substituted with 1 oxo; and (b) optionally further substituted with 1 to 4 independently selected R ^a )
Is;

Z is
(i) -NR ¹⁰ R ^11; or
^{(ii) -C (O) NR} 10 R 11; or
(iii) ^{-OR 12;} or
(iv) -S (O) _n R ¹³ where n is 0, 1 or 2; or
(v) heterocycloalkenyl containing 5 to 6 ring atoms, wherein 1 to 3 ring atoms are N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl ), O and S; and the heterocycloalkenyl may be optionally substituted with 1 to 4 independently selected R ^a );
(vi) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 independently selected R ^b ; or
(vii) a heteroaryl containing 5 to 14 ring atoms, wherein 1 to 6 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; Heteroaryl may be optionally substituted with 1-4 independently selected R ^b ); or
(viii) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a ); or
(ix) arylheterocyclyls containing 8-14 ring atoms, where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(x) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(xi) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;

Each of R ¹⁰ and R ¹¹ is the following (a) to (l)
(a) hydrogen;
(b) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ;
(c) 5 to 14 heteroaryl containing a ring atom (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl is optionally substituted with 1 to 4 R ^b );
(d) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl optionally substituted with 1 to 3 R ^d ;
_{(e) -C (O) (} C 1 -C 6 _{alkyl), - C (O) (} C 1 -C 6 haloalkyl) or _{-C (O) O (C 1} -C 6 alkyl);
(f) C ₂ -C ₆ alkenyl or _C 2 -C ₆ alkynyl;
(g) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a );
(h) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a );
(i) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a );
(j) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a );
(k) C ₃ -C ₈ cycloalkyl or C ₃ -C ₈ cycloalkenyl optionally substituted with 1 to 4 independently selected R ^a ; and
(l) C ₇ -C ₁₂ aralkyl (wherein the aryl moiety may be optionally substituted with 1 to 4 R ^b , independently selected)
Independently selected from the substituents collectively described in
Provided that one of R ¹⁰ and R ¹¹ must be selected from (b), (c), (g), (h), (i), (j) and (k);

R ¹² is
(i) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or
(ii) heteroaryl including 5-14 ring atoms (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl may optionally be substituted with 1 to 4 R ^b ); or
(iii) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl substituted with 1 to 3 R ^d ;
(iv) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a ); or
(v) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vi) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vii) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;

R ¹³ is
(i) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or
(ii) heteroaryl including 5-14 ring atoms (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and The heteroaryl is optionally substituted with 1 to 4 R ^b );
(iii) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a ); or
(iv) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(v) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vi) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;

Each R ^a is halo, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, oxo, thioxo, = NH, = N _(C 1 -C _{6 alkyl),} C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl, -NH 2, -NH (C 1} -C 6 alkyl), N _(C 1 -C _{6 alkyl)} 2, _{-NHC (O) (C 1 -C} 6 alkyl) and from cyano independently selected;

R ^b represents the following (aa) to (dd)
(aa) C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ thiohaloalkoxy; -O- (CH ₂ ) _1-3- [O (CH _{2) 1-3] 1-3 -H; -C} 1 -C 6 _alkyl, C 1 -C ₆ haloalkyl, -NH _(C 1 -C _{6 alkyl), - N (C 1 -C} 6 _alkyl) 2, —NHC (O) (C ₁ -C ₆ alkyl), wherein each of the alkyl moieties is optionally substituted with 1 to 3 independently selected R ^e ;
(bb) halo; hydroxy; cyano; nitro; -NH _2; azido; _sulfhydryl; C 2 -C _{6 alkenyl;} C 2 -C ₆ alkynyl; -C (O) H; -C (O) (C 1 -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); C (O) OH; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C ( O) NH _(C 1 -C ₆ alkyl); C (O) N ( C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH ( C ₁ -C ₆ alkyl); - SO ₂ N _(C 1 -C _{6 alkyl)} 2;
(cc) C ₃ -C ₆ cycloalkyl or heterocyclyl containing 5-6 ring atoms, wherein 1 to 2 ring atoms of the heterocyclyl are N, NH, N (C ₁ -C ₆ alkyl), NC (O ) (C ₁ -C ₆ alkyl), independently selected from O and S; and each of the phenyl and heterocyclyl is optionally substituted with 1 to 3 independently selected R ^a ) ;and
(dd) phenyl or heteroaryl containing 5-6 ring atoms, wherein 1-2 of the heteroaryl ring atoms are independently N, NH, N (C ₁ -C ₃ alkyl), O and S Wherein each of the phenyl and heteroaryl is optionally halo; hydroxyl; cyano; nitro; —NH ₂ ; —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , _{-NHC (O) (C 1 -C} 6 _alkyl), C 1 -C _{6 alkoxy;} C 1 -C _{6 haloalkoxy;} C 1 -C _{6 thioalkoxy;} C 1 -C _{6 thiohaloalkoxy;} C 1 -C Optionally substituted with 1 to 3 substituents independently selected from ₆ alkyl and C ₁ -C ₆ haloalkyl)
Independently selected from the substituents described in;

R ^c is halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently selected from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Is;

R ^d represents hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently selected from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Is;
R ^e are each _hydroxyl, C 1 -C _{6 alkoxy;} C 1 -C _{6 thioalkoxy;} C 1 -C _{6 haloalkoxy;} C 1 -C _{6 thiohaloalkoxy; -NH 2; -NH (C 1} - C ₆ alkyl); N (C ₁ -C ₆ alkyl) ₂ ; —NHC (O) (C ₁ -C ₆ alkyl); cyano; —C (O) H; —C (O) (C ₁ -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); C (O) OH; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C (O ) NH _(C 1 -C ₆ alkyl); C (O) N ( C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH (C ₁ -C ₆ alkyl); - SO ₂ N _(C 1 -C _{6 alkyl) 2;} and ^{L 3} - _(C 1 -C ₆ alkylene) - biotin, wherein, ^{L 3} is -O -, - NH-, _{NCH 3 -, - C (O} ) -, - C (O) NH -, - C (O) NCH 3 -, - NHC (O) - or -NCH ₃ C (O) - are independently selected from . ].

In some embodiments, the following one, two, three, four, five or six can be applied.
When A is CH ₂ and R and R ′ are defined according to definition (1), both R ³ and R ⁶ must not be hydrogen;
When A is CH ₂ and R and R ′ are defined according to definition (2), R ³ must not be hydrogen;
· A is CH _2, R and R 'are defined in accordance with the definition (1), Z is ^{-OR 12,} when ^{R 12} is unsubstituted phenyl, both ^{R 3} and ^{R 6} are a chloro must not;
A is CH ₂ , R and R ′ are defined according to definition (1), Z is —OR ¹² , R ¹² is phenyl substituted with pyridyl or alkyl substituted with 1 to 3 Re , Both R ³ and R ⁶ must not be bromo;
When A is CH (CH ₃ ), R and R ′ are defined according to definition (1), Z is NR ¹⁰ R ¹¹ , R ¹⁰ is CH ₃ and R ¹¹ is unsubstituted phenyl , R ³ and R ⁶ must not be hydrogen;
If A is CR ^A1 R ^A2 and one of R ^A1 and R ^A2 is OH (ie, R ⁹ is H), the other of R ^A1 and R ^A2 is C ₁ -C ₃ alkyl.

  In another aspect, a pharmaceutical composition comprising the above compound (or a salt thereof described herein) and a pharmaceutically acceptable carrier is featured. In certain embodiments, one, two, three, four, five or six of the above conditions can be applied.

In one aspect, the formula (I)
Or a pharmaceutically acceptable salt thereof, wherein
Each of R ¹ , R ² , R ³ and R ⁴ is hydrogen, halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C _6. Thiohaloalkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkynyl, cyclopropyl, —N ₃ , cyano, —NH ₂ , —NH (C ₁ -C ₆ alkyl), — Independently selected from N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro;

R and R ′ are the following (1) or (2)
(1) R and R ′ are combined with C ₂ and C ₃ respectively to form the formula (II)
In which R ⁵ , R ⁶ , R ⁷ and R ⁸ are each hydrogen, halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thio. Alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkynyl, cyclopropyl, -N ₃ , cyano,- _{NH 2, -NH (C 1 -C} 6 _{alkyl), - N (C 1 -C} 6 _alkyl) 2, are independently selected from _{-NHC (O) (C 1 -C} 6 alkyl) and nitro); Or
(2) R and R ′ together with C ₂ and C ₃ respectively form a fused heteroaryl ring containing 6 ring atoms (wherein 1-2 of the independently selected ring atoms are N And the heteroaryl ring may optionally be substituted with 1 to 2 independently selected R ^b )
As defined in accordance with
Each of L ¹ and L ² is independently C ₁ -C ₃ alkylene, which may optionally be substituted with 1 to 2 independently selected R ^c ;

A is
(i) CR ^A1 R ^A2 where each of R ^A1 and R ^A2 is independently selected from hydrogen, halo, C ₁ -C ₃ alkyl and OR ⁹ , wherein R ⁹ is optionally hydroxyl or C Or C ₁ -C ₃ alkyl optionally substituted with ₁ -C ₃ alkoxy); or
(ii) C = O; or
(iii) C ₃ -C ₅ cycloalkylene (which is (a) substituted with one oxo; and (b) optionally further substituted with 1 to 4 independently selected R ^a). Or); or
(iv) a heterocycloalkylene containing 3 to 5 ring atoms, wherein 1 to 2 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; The heterocycloalkylene is (a) substituted with 1 oxo; and (b) optionally further substituted with 1 to 4 independently selected R ^a )
Is;

Z is
(i) -NR ¹⁰ R ^11; or
^{(ii) -C (O) NR} 10 R 11; or
(iii) ^{-OR 12;} or
(iv) -S (O) _n R ¹³ where n is 0, 1 or 2; or
(v) heterocycloalkenyl containing 5 to 6 ring atoms, wherein 1 to 3 ring atoms are N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl ), O and S; and the heterocycloalkenyl may be optionally substituted with 1 to 4 independently selected R ^a );
(vi) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 independently selected R ^b ; or
(vii) a heteroaryl containing 5 to 14 ring atoms, wherein 1 to 6 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; Heteroaryl may be optionally substituted with 1-4 independently selected R ^b ); or
(viii) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a ); or
(ix) arylheterocyclyls containing 8-14 ring atoms, where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(x) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(xi) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;

Each of R ¹⁰ and R ¹¹ is the following (a) to (l)
(a) hydrogen;
(b) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ;
(c) 5 to 14 heteroaryl containing a ring atom (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl is optionally substituted with 1 to 4 R ^b );
(d) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl optionally substituted with 1 to 3 R ^d ;
_{(e) -C (O) (} C 1 -C 6 _{alkyl), - C (O) (} C 1 -C 6 haloalkyl) or _{-C (O) O (C 1} -C 6 alkyl);
(f) C ₂ -C ₆ alkenyl or _C 2 -C ₆ alkynyl;
(g) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a );
(h) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a );
(i) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a );
(j) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a );
(k) C ₃ -C ₈ cycloalkyl or C ₃ -C ₈ cycloalkenyl optionally substituted with 1 to 4 independently selected R ^a ; and
(l) C ₇ -C ₁₂ aralkyl, wherein the aryl moiety may be optionally substituted with 1-4 independently selected R ^b ,
Independently selected from the substituents collectively described in
Provided that one of R ¹⁰ and R ¹¹ must be selected from (b), (c), (g), (h), (i), (j) and (k);

R ¹² is
(i) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or
(ii) heteroaryl including 5-14 ring atoms (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl may optionally be substituted with 1 to 4 R ^b ); or
(iii) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl substituted with 1 to 3 R ^d ;
(iv) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a ); or
(v) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vi) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vii) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;
R ¹³ is
(i) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or
(ii) a heteroaryl containing 5 to 14 ring atoms, wherein 1 to 6 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; Heteroaryl is optionally substituted with 1 to 4 R ^b );
(iii) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a ); or
(iv) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(v) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vi) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;

Each R ^a is halo, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, oxo, thioxo, = NH, = N _(C 1 -C _{6 alkyl),} C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl, -NH 2, -NH (C 1} -C 6 alkyl), N _(C 1 -C _{6 alkyl)} 2, _{-NHC (O) (C 1 -C} 6 alkyl) and from cyano independently selected;

R ^b represents the following (aa) to (dd)
(aa) C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ thiohaloalkoxy; -O- (CH ₂ ) _1-3- [O (CH _{2) 1-3] 1-3 -H; -C} 1 -C 6 _alkyl, C 1 -C ₆ haloalkyl, -NH _(C 1 -C _{6 alkyl), - N (C 1 -C} 6 _alkyl) 2, —NHC (O) (C ₁ -C ₆ alkyl), wherein each of the alkyl moieties is optionally substituted with 1 to 3 independently selected R ^e ;
(bb) halo; hydroxy; cyano; nitro; -NH _2; azido; _sulfhydryl; C 2 -C _{6 alkenyl;} C 2 -C ₆ alkynyl; -C (O) H; -C (O) (C 1 -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); C (O) OH; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C ( O) NH _(C 1 -C ₆ alkyl); C (O) N ( C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH ( C ₁ -C ₆ alkyl); - SO ₂ N _(C 1 -C _{6 alkyl)} 2;
(cc) C ₃ -C ₆ cycloalkyl or heterocyclyl containing 5-6 ring atoms, wherein 1 to 2 ring atoms of the heterocyclyl are N, NH, N (C ₁ -C ₆ alkyl), NC (O ) (C ₁ -C ₆ alkyl), independently selected from O and S; and each of the phenyl and heterocyclyl is optionally substituted with 1 to 3 independently selected R ^a ) ;and
(dd) phenyl or heteroaryl containing 5-6 ring atoms, wherein 1-2 of the heteroaryl ring atoms are independently N, NH, N (C ₁ -C ₃ alkyl), O and S Wherein each of the phenyl and heteroaryl is optionally halo; hydroxyl; cyano; nitro; —NH ₂ ; —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , _{-NHC (O) (C 1 -C} 6 _alkyl), C 1 -C _{6 alkoxy;} C 1 -C _{6 haloalkoxy;} C 1 -C _{6 thioalkoxy;} C 1 -C _{6 thiohaloalkoxy;} C 1 -C Optionally substituted with 1 to 3 substituents independently selected from ₆ alkyl and C ₁ -C ₆ haloalkyl)
Independently selected from the substituents described in;

R ^c is halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently selected from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Is;
R ^d represents hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently selected from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Is;
R ^e are each _hydroxyl, C 1 -C _{6 alkoxy;} C 1 -C _{6 thioalkoxy;} C 1 -C _{6 haloalkoxy;} C 1 -C _{6 thiohaloalkoxy; -NH 2; -NH (C 1} - C ₆ alkyl); N (C ₁ -C ₆ alkyl) ₂ ; —NHC (O) (C ₁ -C ₆ alkyl); cyano; —C (O) H; —C (O) (C ₁ -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); C (O) OH; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C (O ) NH _(C 1 -C ₆ alkyl); C (O) N ( C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH (C ₁ -C ₆ alkyl); - SO ₂ N _(C 1 -C _{6 alkyl) 2;} and ^{L 3} - _(C 1 -C ₆ alkylene) - biotin, wherein, ^{L 3} is -O -, - NH-, _{NCH 3 -, - C (O} ) -, - C (O) NH -, - C (O) NCH 3 -, - NHC (O) - or -NCH ₃ C (O) - are independently selected from . ].

In some embodiments, the following one, two, three, four or five can be applied.
When A is CH ₂ and R and R ′ are defined according to definition (1), both R ³ and R ⁶ must not be hydrogen;
When A is CH ₂ and R and R ′ are defined according to definition (2), R ³ must not be hydrogen;
· A is CH _2, R and R 'are defined in accordance with the definition (1), Z is ^{-OR 12,} when ^{R 12} is unsubstituted phenyl, both ^{R 3} and ^{R 6} are a chloro must not;
A is CH ₂ , R and R ′ are defined according to definition (1), Z is —OR ¹² , R ¹² is phenyl substituted with pyridyl or alkyl substituted with 1 to 3 Re When R ³ and R ⁶ must not both be bromo; and • A is CH (CH ₃ ), R and R ′ are defined according to definition (1), and Z is NR ¹⁰ R ¹¹ And when R ¹⁰ is CH ₃ and R ¹¹ is unsubstituted phenyl, both R ³ and R ⁶ must not be hydrogen.

  In another aspect, a pharmaceutical composition comprising the above compound (or a salt thereof described herein) and a pharmaceutically acceptable carrier is featured. In embodiments, one, two, three, four or five of the above conditions can be applied.

In another aspect, the formula (I)
Or a pharmaceutically acceptable salt thereof, wherein
Each of R ¹ , R ² , R ³ and R ⁴ is hydrogen, halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C _6. Thiohaloalkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkynyl, cyclopropyl, —N ₃ , cyano, —NH ₂ , —NH (C ₁ -C ₆ alkyl), — Independently selected from N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro;
R and R ′ are the following (1) or (2)
(1) R and R ′ are combined with C ₂ and C ₃ respectively to form the formula (II)
Form a phenyl ring
Where R ⁵ , R ⁶ , R ⁷ and R ⁸ are each hydrogen, halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C _{6 thiohaloalkoxy,} C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 2 -C ₆ alkynyl, cyclopropyl, -N _3, a _cyano, -NH 2, -NH _(C 1 -C ₆ Alkyl), —N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro)); or
(2) R and R ′ together with C ₂ and C ₃ respectively form a fused heteroaryl ring containing 6 ring atoms (wherein 1-2 of the independently selected ring atoms are N And the heteroaryl ring is as defined according to optionally substituted with 1 to 2 independently selected R ^b ;
Each of L ¹ and L ² is independently C ₁ -C ₃ alkylene, which may optionally be substituted with 1 to 2 independently selected R ^c ;

A is CR ^A1 R ^A2 , wherein one of R ^A1 and R ^A2 is —OHR ^A1 and the other of R ^A2 is hydrogen or C ₁ -C ₃ alkyl;
Z is —OR ¹² or —S (O) _n R ¹³ , where n is 0, 1 or 2;
Each of R ¹² and R ¹³ is
(i) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or
(ii) a heteroaryl containing 5 to 14 ring atoms, wherein 1 to 6 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; Heteroaryl is optionally substituted with 1 to 4 R ^b );
(iii) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl (eg, C ₁ -C ₆ alkyl) substituted with 1 to 3 R ^d ; or
(iv) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a ); or
(v) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vi) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vii) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;

Each R ^a is halo, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, oxo, thioxo, = NH, = N _(C 1 -C _{6 alkyl),} C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl, -NH 2, -NH (C 1} -C 6 alkyl), N _(C 1 -C _{6 alkyl)} 2, _{-NHC (O) (C 1 -C} 6 alkyl) and from cyano independently selected;
R ^b represents the following (aa) to (dd)
(aa) C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ thiohaloalkoxy; -O- (CH ₂ ) _1-3- [O (CH _{2) 1-3] 1-3 -H; -C} 1 -C 6 _alkyl, C 1 -C ₆ haloalkyl, -NH _(C 1 -C _{6 alkyl), - N (C 1 -C} 6 _alkyl) 2, —NHC (O) (C ₁ -C ₆ alkyl), wherein each of the alkyl moieties is optionally substituted with 1 to 3 independently selected R ^e ;
(bb) halo; hydroxy; cyano; nitro; -NH _2; azido; _sulfhydryl; C 2 -C _{6 alkenyl;} C 2 -C ₆ alkynyl; -C (O) H; -C (O) (C 1 -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); C (O) OH; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C ( O) NH _(C 1 -C ₆ alkyl); C (O) N ( C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH ( C ₁ -C ₆ alkyl); - SO ₂ N _(C 1 -C _{6 alkyl)} 2;
(cc) C ₃ -C ₆ cycloalkyl or heterocyclyl containing 5-6 ring atoms, wherein 1 to 2 ring atoms of the heterocyclyl are N, NH, N (C ₁ -C ₆ alkyl), NC (O ) (C ₁ -C ₆ alkyl), independently selected from O and S; and each of the phenyl and heterocyclyl is optionally substituted with 1 to 3 independently selected R ^a ) ;and
(dd) phenyl or heteroaryl containing 5-6 ring atoms, wherein 1-2 of the heteroaryl ring atoms are independently N, NH, N (C ₁ -C ₃ alkyl), O and S Wherein each of the phenyl and heteroaryl is optionally halo; hydroxyl; cyano; nitro; —NH ₂ ; —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , _{-NHC (O) (C 1 -C} 6 _alkyl), C 1 -C _{6 alkoxy;} C 1 -C _{6 haloalkoxy;} C 1 -C _{6 thioalkoxy;} C 1 -C _{6 thiohaloalkoxy;} C 1 -C Optionally substituted with 1 to 3 substituents independently selected from ₆ alkyl and C ₁ -C ₆ haloalkyl)
Independently selected from the substituents described in;

R ^c is halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently selected from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Is;
R ^d represents hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently selected from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Is;

R ^e are each _hydroxyl, C 1 -C _{6 alkoxy;} C 1 -C _{6 thioalkoxy;} C 1 -C _{6 haloalkoxy;} C 1 -C _{6 thiohaloalkoxy; -NH 2; -NH (C 1} - C ₆ alkyl); N (C ₁ -C ₆ alkyl) ₂ ; —NHC (O) (C ₁ -C ₆ alkyl); cyano; —C (O) H; —C (O) (C ₁ -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); C (O) OH; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C (O ) NH _(C 1 -C ₆ alkyl); C (O) N ( C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH (C ₁ -C ₆ alkyl); - SO ₂ N _(C 1 -C _{6 alkyl) 2;} and ^{L 3} - _(C 1 -C ₆ alkylene) - biotin, wherein, ^{L 3} is -O -, - NH-, _{NCH 3 -, - C (O} ) -, - C (O) NH -, - C (O) NCH 3 -, - NHC (O) - or -NCH ₃ C (O) - are independently selected from . ].

In some embodiments, the following one, two, three or four can be applied.
When R and R ′ are defined according to definition (1), both R ³ and R ⁶ must not be hydrogen;
· R and R 'are defined in accordance with the definition (1), Z is ^{-OR 12,} when ^{R 12} is phenyl chloro, substituted with formyl or ^{_{-NHC (O) CH 3, R}} 3 and R Both ⁶ must not be chloro;
When R and R ′ are defined according to definition (1), Z is —OR ¹² and R ¹² is phenyl substituted with phenyl, then both R ³ and R ⁶ must not be bromo; And when R and R ′ are defined according to definition (1), Z is —SR ¹³ and R ¹³ is phenyl substituted with —OH, then both R ³ and R ⁶ must be bromo Don't be.

  In another aspect, in an embodiment featuring a pharmaceutical composition comprising the above compound (or salt thereof described herein) and a pharmaceutically acceptable carrier, one, two, three, four of the above conditions Or 5 can be applied.

In another aspect, the formula (I)
Or a pharmaceutically acceptable salt thereof, wherein
Each of R ¹ , R ² , R ³ and R ⁴ is hydrogen, halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C _6. Thiohaloalkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkynyl, cyclopropyl, —N ₃ , cyano, —NH ₂ , —NH (C ₁ -C ₆ alkyl), — Independently selected from N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro;
R and R ′ together with C ₂ and C ₃ respectively form a fused heterocyclic ring containing 5 to 6 ring atoms, wherein 1 to 2 of the ring atoms are N, NH, N ( C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S; and the heterocyclic ring is optionally selected from 1 to 3 independently selected R ^a may be substituted;
Each of L ¹ and L ² is independently C ₁ -C ₃ alkylene, which may optionally be substituted with 1 to 2 independently selected R ^c ;
A is
(i) CR ^A1 R ^A2 wherein one of R ^A1 and R ^A2 is independently selected from hydrogen, halo, C ₁ -C ₃ alkyl and OR ⁹ ; the other of R ^A1 and R ^A2 is independently _halo, selected from C 1 -C ₃ alkyl and oR ^9; where, ^{R 9} is a hydroxy or _C 1 -C ₃ which may have _C 1 -C ₃ alkyl substituted by alkoxy or optionally is hydrogen ); Or
(ii) C = O
Is;

Z is
(i) -NR ¹⁰ R ^11; or
^{(ii) -C (O) NR} 10 R 11; or
(iii) ^{-OR 12;} or
(iv) -S (O) _n R ¹³ where n is 0, 1 or 2; or
(vi) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 independently selected R ^b ; or
(vii) a heteroaryl containing 5 to 14 ring atoms, wherein 1 to 6 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; (Heteroaryl may be optionally substituted with 1-4 independently selected R ^b )
Or

Each of R ¹⁰ and R ¹¹ has the following (a) to (g)
(a) hydrogen;
(b) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ;
(c) 5 to 14 heteroaryl containing a ring atom (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl is optionally substituted with 1 to 4 R ^b );
(d) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl optionally substituted with 1 to 3 R ^d ;
_{(e) -C (O) (} C 1 -C 6 _{alkyl), - C (O) (} C 1 -C 6 haloalkyl) or _{-C (O) O (C 1} -C 6 alkyl);
(f) C ₂ -C ₆ alkenyl or _C 2 -C ₆ alkynyl; and
(g) C ₇ -C ₁₂ aralkyl, wherein the aryl moiety may be optionally substituted with 1-4 independently selected R ^{b s}
Independently selected from the substituents collectively described in
Provided that one of R ¹⁰ and R ¹¹ must be selected from (b) and (c);

R ¹² is
(i) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or
(ii) heteroaryl including 5-14 ring atoms (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl may optionally be substituted with 1 to 4 R ^b )
Is;
R ¹³ is
(i) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or
(ii) heteroaryl including 5-14 ring atoms (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl may optionally be substituted with 1 to 4 R ^b )
Is;
Each R ^a is halo, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, oxo, thioxo, = NH, = N _(C 1 -C _{6 alkyl),} C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl, -NH 2, -NH (C 1} -C 6 alkyl), N _(C 1 -C _{6 alkyl)} 2, _{-NHC (O) (C 1 -C} 6 alkyl) and from cyano independently selected;
R ^b represents the following (aa) to (dd)
(aa) C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ thiohaloalkoxy; -O- (CH ₂ ) _1-3- [O (CH _{2) 1-3] 1-3 -H; -C} 1 -C 6 _alkyl, C 1 -C ₆ haloalkyl, -NH _(C 1 -C _{6 alkyl), - N (C 1 -C} 6 _alkyl) 2, —NHC (O) (C ₁ -C ₆ alkyl), wherein each of the alkyl moieties is optionally substituted with 1 to 3 independently selected R ^e ;
(bb) halo; hydroxy; cyano; nitro; -NH _2; azido; _sulfhydryl; C 2 -C _{6 alkenyl;} C 2 -C ₆ alkynyl; -C (O) H; -C (O) (C 1 -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); C (O) OH; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C ( O) NH _(C 1 -C ₆ alkyl); C (O) N ( C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH ( C ₁ -C ₆ alkyl); - SO ₂ N _(C 1 -C _{6 alkyl)} 2;
(cc) C ₃ -C ₆ cycloalkyl or heterocyclyl containing 5-6 ring atoms, wherein 1 to 2 ring atoms of the heterocyclyl are N, NH, N (C ₁ -C ₆ alkyl), NC (O ) (C ₁ -C ₆ alkyl), independently selected from O and S; and each of the phenyl and heterocyclyl is optionally substituted with 1 to 3 independently selected R ^a ) ;and
(dd) phenyl or heteroaryl containing 5-6 ring atoms, wherein 1-2 of the heteroaryl ring atoms are independently N, NH, N (C ₁ -C ₃ alkyl), O and S Wherein each of the phenyl and heteroaryl is optionally halo; hydroxyl; cyano; nitro; —NH ₂ ; —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , _{-NHC (O) (C 1 -C} 6 _alkyl), C 1 -C _{6 alkoxy;} C 1 -C _{6 haloalkoxy;} C 1 -C _{6 thioalkoxy;} C 1 -C _{6 thiohaloalkoxy;} C 1 -C Optionally substituted with 1 to 3 substituents independently selected from ₆ alkyl and C ₁ -C ₆ haloalkyl)
Independently selected from the substituents described in;

R ^c is halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently selected from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Is;
R ^d represents hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently selected from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano And R ^e are each hydroxyl, C ₁ -C ₆ alkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thiohaloalkoxy; -NH ₂ ; C ₁ -C ₆ alkyl); N _(C 1 -C _{6 alkyl)} 2; -NHC (O) _(C 1 -C ₆ alkyl); cyano; -C (O) H; -C (O) (C 1 -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); C (O) H; -C (O) O ( C 1 -C 6 _{alkyl); - C (O) NH} 2; -C (O) NH (C 1 -C 6 alkyl); C (O) N ( C 1 -C _{6 alkyl)} 2; -SO _{2 (C} 1 -C _{6 alkyl); - SO 2 NH 2;} -SO 2 NH (C 1 -C 6 _{alkyl); - SO 2 N (C} 1 -C 6 _alkyl) 2; And L ^3- (C ₁ -C ₆ alkylene) -biotin, wherein L ³ is —O—, —NH—, —NCH ₃ —, —C (O) —, —C (O) NH—, — Independently selected from C (O) NCH ₃ —, —NHC (O) — or —NCH ₃ C (O) —. ].

  In certain embodiments, the conditions (A) described herein can be applied.

In another aspect, the formula (I)
Or a pharmaceutically acceptable salt thereof, wherein
Each of R ¹ , R ² , R ³ and R ⁴ is hydrogen, halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C _6. Thiohaloalkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkynyl, cyclopropyl, —N ₃ , cyano, —NH ₂ , —NH (C ₁ -C ₆ alkyl), — Independently selected from N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro;
Each of R and R ′ is independently hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;
Each of L ¹ and L ² is independently C ₁ -C ₃ alkylene, which may optionally be substituted with 1 to 2 independently selected R ^c ;

A is
(i) CR ^A1 R ^A2 (wherein one of R ^A1 and R ^A2 is independently selected from hydrogen, fluoro, chloro, C ₁ -C ₃ alkyl and OR ⁹ ; the other of R ^A1 and R ^A2 is fluoro , _chloro, C 1 -C ₃ alkyl and independently selected from oR ^9; where, ^{R 9} may _C 1 -C, optionally substituted by hydroxy or _C 1 -C ₃ alkoxy or optionally is hydrogen ₃ alkyl); or
(ii) C = O
Is;

Z is
(i) -NR ¹⁰ R ^11; or
^{(ii) -C (O) NR} 10 R 11; or
(iii) ^{-OR 12;} or
(iv) -S (O) _n R ¹³ where n is 0, 1 or 2; or
(vi) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 independently selected R ^b ; or
(vii) a heteroaryl containing 5 to 14 ring atoms, wherein 1 to 6 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; (Heteroaryl may be optionally substituted with 1-4 independently selected R ^b )
Or

Each of R ¹⁰ and R ¹¹ has the following (a) to (g)
(a) hydrogen;
(b) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ;
(c) 5 to 14 heteroaryl containing a ring atom (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl is optionally substituted with 1 to 4 R ^b );
(d) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl optionally substituted with 1 to 3 R ^d ;
_{(e) -C (O) (} C 1 -C 6 _{alkyl), - C (O) (} C 1 -C 6 haloalkyl) or _{-C (O) O (C 1} -C 6 alkyl);
(f) C ₂ -C ₆ alkenyl or _C 2 -C ₆ alkynyl; and
(g) C ₇ -C ₁₂ aralkyl, wherein the aryl moiety may be optionally substituted with 1-4 independently selected R ^{b s}
Independently selected from the substituents collectively described in
Provided that one of R ¹⁰ and R ¹¹ must be selected from (b) and (c);

Each of R ¹² and R ¹³ is
(i) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or
(ii) heteroaryl including 5-14 ring atoms (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl may optionally be substituted with 1 to 4 R ^b )
Is;
Each R ^a is halo, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, oxo, thioxo, = NH, = N _(C 1 -C _{6 alkyl),} C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl, -NH 2, -NH (C 1} -C 6 alkyl), N _(C 1 -C _{6 alkyl)} 2, _{-NHC (O) (C 1 -C} 6 alkyl) and from cyano independently selected;

R ^b represents the following (aa) to (dd)
(aa) C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ thiohaloalkoxy; -O- (CH ₂ ) _1-3- [O (CH _{2) 1-3] 1-3 -H; -C} 1 -C 6 _alkyl, C 1 -C ₆ haloalkyl, -NH _(C 1 -C _{6 alkyl), - N (C 1 -C} 6 _alkyl) 2, —NHC (O) (C ₁ -C ₆ alkyl), wherein each of the alkyl moieties is optionally substituted with 1 to 3 independently selected R ^e ;
(bb) halo; hydroxy; cyano; nitro; -NH _2; azido; _sulfhydryl; C 2 -C _{6 alkenyl;} C 2 -C ₆ alkynyl; -C (O) H; -C (O) (C 1 -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); C (O) OH; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C ( O) NH _(C 1 -C ₆ alkyl); C (O) N ( C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH ( C ₁ -C ₆ alkyl); - SO ₂ N _(C 1 -C _{6 alkyl)} 2;
(cc) C ₃ -C ₆ cycloalkyl or heterocyclyl containing 5-6 ring atoms, wherein 1 to 2 ring atoms of the heterocyclyl are N, NH, N (C ₁ -C ₆ alkyl), NC (O ) (C ₁ -C ₆ alkyl), independently selected from O and S; and each of the phenyl and heterocyclyl is optionally substituted with 1 to 3 independently selected R ^a ) ;and
(dd) phenyl or heteroaryl containing 5-6 ring atoms, wherein 1-2 of the heteroaryl ring atoms are independently N, NH, N (C ₁ -C ₃ alkyl), O and S Wherein each of the phenyl and heteroaryl is optionally halo; hydroxyl; cyano; nitro; —NH ₂ ; —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , _{-NHC (O) (C 1 -C} 6 _alkyl), C 1 -C _{6 alkoxy;} C 1 -C _{6 haloalkoxy;} C 1 -C _{6 thioalkoxy;} C 1 -C _{6 thiohaloalkoxy;} C 1 -C Optionally substituted with 1 to 3 substituents independently selected from ₆ alkyl and C ₁ -C ₆ haloalkyl)
Independently selected from the substituents described in;

R ^c is halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently selected from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Is;
R ^d represents hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently selected from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Is;
R ^e are each _hydroxyl, C 1 -C _{6 alkoxy;} C 1 -C _{6 thioalkoxy;} C 1 -C _{6 haloalkoxy;} C 1 -C _{6 thiohaloalkoxy; -NH 2; -NH (C 1} - C ₆ alkyl); N (C ₁ -C ₆ alkyl) ₂ ; —NHC (O) (C ₁ -C ₆ alkyl); cyano; —C (O) H; —C (O) (C ₁ -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); C (O) OH; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C (O ) NH _(C 1 -C ₆ alkyl); C (O) N ( C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH (C ₁ -C ₆ alkyl); - SO ₂ N _(C 1 -C _{6 alkyl) 2;} and ^{L 3} - _(C 1 -C ₆ alkylene) - biotin, wherein, ^{L 3} is -O -, - NH-, _{NCH 3 -, - C (O} ) -, - C (O) NH -, - C (O) NCH 3 -, - NHC (O) - or -NCH ₃ C (O) - are independently selected from . ].

In one aspect, characterized by a compound of formula (III) or a salt thereof (e.g., a pharmaceutically acceptable salt), wherein:
A is CR ^A1 R ^A2 where each of R ^A1 and R ^A2 is independently hydrogen, halo or C ₁ -C ₃ alkyl; or A is CR ^A1 R ^A2 where R ^{One of A1} and R ^A2 is halo (eg, fluoro) and the other of R ^A1 and R ^A2 is independently hydrogen, halo, or C ₁ -C ₃ alkyl (eg, hydrogen); or A is CR ^A1 R ^A2 , wherein one of R ^A1 and R ^A2 is halo (eg, fluoro) and the other of R ^A1 and R ^A2 is hydrogen;
R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² and Z may be as defined herein.

  In certain embodiments, (B) and / or (C) is applied.

In one aspect, characterized by a compound of formula (III) or a salt thereof (e.g., a pharmaceutically acceptable salt), wherein:
One of R ^A1 and R ^A2 can be OR ⁹ , and in certain embodiments, the other of R ^A1 and R ^A2 can be as defined herein; for example, the other of R ^A1 and R ^A2 is May be hydrogen or C ₁ -C ₃ alkyl, for example, one of R ^A1 and R ^A2 may be OR ⁹ R ^A1 and R ^A2 may be hydrogen or C ₁ -C ₃ alkyl, and in certain embodiments , R ⁹ may be hydrogen or C ₁ -C ₃ alkyl;
R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² and Z may be as defined herein.

In certain embodiments, for example, when A is CHOH and Z is NR ¹⁰ R ¹¹ , one or more of the following applies:
Each of R ³ and R ⁶ is CH ₃ ; and / or each of R ³ and R ⁶ is bromo; and / or each of R ³ and R ⁶ is chloro; and / or R ³ and One of R ⁶ is CH ₃ (eg, R ⁶ ) and the other is bromo (eg, R ³ );
Each of R ¹⁰ and R ¹¹ is other than hydrogen;
Each of R ¹⁰ and R ¹¹ is hydrogen;
One of R ¹⁰ and R ¹¹ is heteroaryl as defined herein;
L ¹ and / or L ² is C ₂ -C ₃ alkylene (optionally substituted);
• (B) and / or (C) applies.

In one aspect, it is characterized by a compound of formula (III) or a salt thereof (eg a pharmaceutically acceptable salt), wherein Z is other than NR ¹⁰ R ¹¹ ; R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² , Z and A may be as defined herein. In certain embodiments, (B) and / or (C) is applied.

In one aspect, it is characterized by a compound of formula (III) or a salt thereof (eg a pharmaceutically acceptable salt), wherein Z is —OR ¹² and / or —S (O) _n R ¹³ R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² and A may be as defined herein. In certain embodiments, (B) and / or (C) is applied.

In one aspect, it is characterized by a compound of formula (III) or a salt thereof (eg a pharmaceutically acceptable salt), wherein A is (ii) C = O; and / or (iv) 3-5 A heterocycloalkylene containing a ring atom, wherein one to two of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; and the heterocycloalkylene May be (a) substituted with 1 oxo; and (b) optionally further substituted with 1 to 4 independently selected R ^a ; R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² and Z may be as defined herein.

In yet another aspect, the formula (VI)
Or a pharmaceutically acceptable salt thereof, wherein
R _{1 to} R ₅ are each hydrogen, halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C _1- C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkynyl, cyclopropyl, -N ₃ , cyano, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ Alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro independently selected;
X is C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or heteroaryl containing 5 to 14 ring atoms, wherein 1 to 6 of the ring atoms are N, Independently selected from NH, N (C ₁ -C ₃ alkyl), O and S and the heteroaryl may be optionally substituted with 1 to 4 R ^b ;
Each of L ¹ and L ² is independently C ₁ -C ₃ alkylene, which may optionally be substituted with 1 to 2 independently selected R ^c ;
A is CR ^A1 R ^A2 , wherein one of R ^A1 and R ^A2 is independently selected from hydrogen, fluoro, chloro, C ₁ -C ₃ alkyl and OR ⁹ ; the other of R ^A1 and R ^A2 is fluoro, _chloro, C 1 -C ₃ alkyl and independently selected from oR ^9; where, ^{R 9} may _{C 1} to be substituted by hydroxy or _C 1 -C ₃ alkoxy or optionally is hydrogen - C ₃ alkyl;
Z is —NR ¹⁰ R ¹¹ or —OR ¹² ;
Each of R ¹⁰ and R ¹¹ has the following (a) to (g)
(a) hydrogen;
(b) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ;
(c) 5 to 14 heteroaryl containing a ring atom (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl is optionally substituted with 1 to 4 R ^b );
(d) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl optionally substituted with 1 to 3 R ^d ;
_{(e) -C (O) (} C 1 -C 6 _{alkyl), - C (O) (} C 1 -C 6 haloalkyl) or _{-C (O) O (C 1} -C 6 alkyl);
(f) C ₂ -C ₆ alkenyl or _C 2 -C ₆ alkynyl; and
(g) C ₇ -C ₁₂ aralkyl, wherein the aryl moiety may be optionally substituted with 1-4 independently selected R ^{b s}
Independently selected from the substituents collectively described in
Provided that one of R ¹⁰ and R ¹¹ must be selected from (b) and (c);
R ¹² is
(i) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or
(ii) heteroaryl including 5-14 ring atoms (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl may optionally be substituted with 1 to 4 R ^b )
Is;
Each R ^a is halo, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, oxo, thioxo, = NH, = N (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) ₂ It is independently selected from _{-NHC (O) (C 1 -C} 6 alkyl), and cyano;
R ^b represents the following (aa) to (dd)
(aa) C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ thiohaloalkoxy; -O (CH ₂ ) _1-3 [O (CH ₂ ) _1-3 ] _1-3 H; C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, —NH (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) ₂ , —NHC (O ) (C ₁ -C ₆ alkyl) (wherein each alkyl moiety may be substituted with R ^e is selected 1-3 independently optionally);
(bb) halo; hydroxy; cyano; nitro; -NH _2; azido; _sulfhydryl; C 2 -C _{6 alkenyl;} C 2 -C ₆ alkynyl; -C (O) H; -C (O) (C 1 -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); - C (O) OH ; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C _{(O) NH (C 1 -C} 6 alkyl); C (O) N ( C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH _(C 1 -C ₆ alkyl); - SO ₂ N _(C 1 -C _{6 alkyl)} 2;
(cc) C ₃ -C ₆ cycloalkyl or heterocyclyl containing 5-6 ring atoms, wherein 1 to 2 ring atoms of the heterocyclyl are N, NH, N (C ₁ -C ₆ alkyl), NC (O ) (C ₁ -C ₆ alkyl), independently selected from O and S; and each of the phenyl and heterocyclyl is optionally substituted with 1 to 3 independently selected R ^a ) ;and
(dd) phenyl or heteroaryl containing 5-6 ring atoms, wherein 1-2 of the heteroaryl ring atoms are independently N, NH, N (C ₁ -C ₃ alkyl), O and S Wherein each of the phenyl and heteroaryl is optionally halo; hydroxyl; cyano; nitro; —NH ₂ ; —NH (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) _{2 , -NHC (O) (C 1} -C 6 _alkyl), C 1 -C _{6 alkoxy;} C 1 -C _{6 haloalkoxy;} C 1 -C _{6 thioalkoxy;} C 1 -C ₆ thiohaloalkoxy; _{C 1} - Optionally substituted with 1 to 3 substituents independently selected from C ₆ alkyl and C ₁ -C ₆ haloalkyl)
Independently selected from the substituents described in;
R ^c is halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Selected;
R ^d represents hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Selected;
Each R ^e is hydroxyl, C ₁ -C ₆ alkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thiohaloalkoxy; -NH ₂ ; -NH (C _1- C _{6 alkyl); - N (C 1 -C} 6 _{alkyl) 2; -NHC (O) (} C 1 -C 6 alkyl); cyano; -C (O) H; -C (O) (C 1 -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); - C (O) OH ; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C _{(O) NH (C 1 -C} 6 alkyl); - C (O) N (C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH _(C 1 -C _{6 alkyl); - SO 2 N (C} 1 -C 6 _{alkyl) 2;} and ^{L 3} - _(C 1 -C ₆ alkylene) - are independently selected from biotin, where L ³ is -O -, - NH -, - NCH 3 -, - C (O) -, - C (O) NH -, - C (O) NCH 3 -, - NHC (O) - or -NCH ₃ C (O)-].

In some embodiments, the compound of formula (VI) is a halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 2 -C ₆ alkynyl, cyclopropyl, -N _3, a _cyano, -NH 2, -NH _(C 1 -C ₆ alkyl), - N _{(C 1} It may have R ³ selected from —C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro. In some embodiments, R ³ is halo, such as bromo. In some embodiments, each of R ₁ , R ₂ , R ₄ and R ₅ is hydrogen.

In certain embodiments, a compound of formula (VI) may have X being a C ₆ -C ₁₀ aryl substituted with one or more halo, such as bromo. For example, X can be 4-bromophenyl. X may be heteroaryl containing 5-14 ring atoms, wherein 1-6 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S And the heteroaryl may be optionally substituted with 1 to 4 R ^b . For example, X can be pyridine optionally substituted with 1 to 4 R ^b .

In some embodiments, the compound of Formula (VI) is CR ^A1 R ^A2 , wherein R ^A1 and R ^A2 are each independently hydrogen, C ₁ -C ₃ alkyl, or OR ⁹ Can do. In some embodiments, one of R ^A1 and R ^A2 is OR ⁹ ; the other of R ^A1 and R ^A2 can be hydrogen or C ₁ -C ₃ alkyl. For example, one of R ^A1 and R ^A2 can be OH; the other of R ^A1 and R ^A2 can be hydrogen.

In some embodiments, A is CR ^A1 R ^A2 and the carbon attached to R ^A1 and R ^A2 is substituted with 4 different substituents. The carbon attached to R ^A1 and R ^A2 can be in the (R) or (S) configuration. In one embodiment, the compound of formula (VI) in the (R) configuration can be substantially free of a compound of formula (VI) in which the carbon atom bonded to R ^A1 and R ^A2 is in the S configuration. It is. In some embodiments, the compound of formula (VI) in (S) configuration is substantially free of a compound of formula (VI) in the (R) configuration at the carbon atom bonded to R ^A1 and R ^A2. Is possible.

The compound of formula (VI) may be (+) or (−) (dextrorotatory) in certain embodiments.
In certain embodiments, a (+) (dextrorotatory) compound can be substantially free of a compound of formula (I) that is (Levorotatory). In some embodiments, the (−) (left-handed) compound can be substantially free of compounds of formula (I) that are (+) (right-handed).

  Any of the above compounds can be used in any method or composition described herein.

  Embodiments disclosed herein generally include a compound of formula (I) as defined herein (and / or a compound of any other formula described herein) or a salt thereof (e.g., pharmaceutically acceptable) It relates to the stimulation of neurogenesis (eg postnatal neurogenesis, eg postnatal hippocampus and / or hypothalamic neurogenesis) and the protection of neurons from death.

  For example, it features a method for promoting the generation of nerve cells. Other examples feature methods of promoting the survival, proliferation, development and / or function of neurons, particularly neurons in the CNS, brain, brain, hippocampus and hypothalamus. Yet another example features a method of stimulating postnatal hippocampus and / or hypothalamic neurogenesis.

  In certain embodiments, such methods are in vitro methods, such as a sample (eg, cell or tissue) and a compound of formula (I) as defined herein (and / or any of the other formulas described herein). Or a salt thereof (eg, a pharmaceutically acceptable salt). In other embodiments, the method comprises a compound of formula (I) as defined herein (and / or a compound of any other formula described herein) or a salt thereof (e.g., pharmaceutically acceptable). Administration to a subject (eg, a mammal such as a human).

  Thus, in yet another aspect, embodiments disclosed herein stimulate neurogenesis (eg, postnatal neurogenesis, eg, postnatal hippocampus and / or hypothalamic neurogenesis) or kill newborn neurons. It includes and features a method of screening (identifying thereby) for compounds that protect against it. For example, as described in the Examples section.

  In one aspect, one or more diseases, disorders or conditions are caused by or associated with insufficient (eg, abnormal) neurogenesis or unwanted neuronal cell death in a subject in need of treatment ( For example, it features a method of controlling, mitigating, improving, reducing, or delaying progression) or preventing (eg, delaying its onset or reducing the risk of occurrence). The method comprises subject to a compound of formula (I) as defined herein (and / or any compound of any other formula described herein) or a salt thereof (eg, a pharmaceutically acceptable salt). ) In an effective amount.

  In other aspects, treatment (eg, control, alleviation) of one or more diseases, disorders or conditions caused by or associated with insufficient (eg, abnormal) neurogenesis or unwanted neuronal cell death. A compound of formula (I) as defined herein (and / or in the manufacture of a medicament for improving, reducing or delaying progression) or prevention (e.g. delaying its onset or reducing the risk of occurrence) Or a compound of any of the other formulas described herein) or a salt thereof (eg, a pharmaceutically acceptable salt), or a compound thereof for use as a medicament.

  In certain embodiments, the one or more diseases, disorders or conditions may include neuropathy, neurotrauma and neurodegenerative diseases. In certain embodiments, the one or more diseases, disorders or conditions are considered to occur with inadequate neurogenesis (eg, abnormal hippocampus and / or hypothalamic neurogenesis) or neurodegenerative diseases, such as are thought to occur with neuropsychiatric disorders It can be a disease, disorder or condition caused by or associated with abnormal neuronal cell death. Examples of one or more diseases, disorders or conditions are schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, posttraumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellar ataxia , Amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress and neurostimulant drugs (e.g. alcohol, opiates, methamphetamine, phencyclidine and cocaine), retinal degeneration, spinal cord injury, This includes, but is not limited to, peripheral nerve injury, physiological weight loss associated with various conditions and cognitive decline associated with normal aging, radiation therapy and chemotherapy.

  In certain embodiments, the subject has been identified as in need of such treatment, such as a subject in need of treatment (eg, a subject having or at risk of having one or more of the diseases or conditions described above). Subject). Identification of a subject in need of such treatment may be at the discretion of the subject or medical professional and may be subjective (eg, findings) or objective (eg, measurable by testing or diagnostic methods). In certain embodiments, the subject can be a mammal. In certain embodiments, the subject can be a human.

  In another aspect, it features a method of making the compounds described herein. In certain embodiments, the method takes any one of the intermediate compounds described herein and reacts it with one or more chemical reactants in one or more steps to produce a compound of formula (I) as defined herein. Or a salt (eg, a pharmaceutically acceptable salt) thereof (or a compound of any other formula described herein).

In certain embodiments, a compound wherein A is CHOH and each of L ¹ and L ² is C ₁ -C ₃ alkylene (eg, each of L ¹ and L ² is CH ₂ ), wherein A is C (O) And each of L ¹ and L ² is C ₁ -C ₃ alkylene (eg, each of L ¹ and L ² is CH ₂ ) substituted with C ₁ -C ₆ thioalkoxy (eg, -SCH ₃ ) Can be converted to a compound. The method involves contacting the starting material with an oxidizing agent, sulfur trioxide pyridine complex (see, eg, Examples 7a and 7b).

  In one aspect, it features a method of making the pharmaceutical composition described herein. In certain embodiments, the method comprises a compound of formula (I) as defined herein (and / or any compound of any other formula described herein) or a salt thereof (e.g., pharmaceutically acceptable). Taking any one or more of the salt) and mixing the compound with one or more pharmaceutically acceptable carriers.

In one aspect, treatment (eg, control, alleviate) one or more diseases, disorders or conditions caused by or associated with insufficient (eg, abnormal) neurogenesis or unwanted neuronal cell death. Kits are described for improving, reducing, or delaying progression) or prevention (eg, delaying its onset or reducing the risk of occurrence). The kit comprises (i) a compound of formula (I) as defined herein (and / or any compound of any other formula described herein) or a salt thereof (eg, a pharmaceutically acceptable salt). And (ii) instructions (eg, patient) comprising instructions for administering the compound to the subject.

  Certain aspects may include any one or more of the following characteristics, for example.

R ³ is halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C ₁ -C _{6 haloalkyl,} C 2 -C ₆ alkynyl, cyclopropyl, -N _3, a _{cyano, -NH 2, -NH (C 1} -C 6 _{alkyl), - N (C 1 -C} 6 _alkyl) 2, -NHC Selected from (O) (C ₁ -C ₆ alkyl) and nitro. In some embodiments, R ³ is halo (eg, bromo). In certain embodiments, each of R ¹ , R ² and R ⁴ is hydrogen.

R and R ′ are combined with C ₂ and C ₃ respectively to form the formula (II)
Form a phenyl ring.

R ⁶ is halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C ₁ -C _{6 haloalkyl,} C 2 -C ₆ alkynyl, cyclopropyl, -N _3, a _{cyano, -NH 2, -NH (C 1} -C 6 _{alkyl), - N (C 1 -C} 6 _alkyl) 2, -NHC Selected from (O) (C ₁ -C ₆ alkyl) and nitro. In some embodiments, R ⁶ is halo (eg, bromo) or C ₁ -C ₆ alkyl (eg, CH ₃ ). In some embodiments, R ⁶ is halo (eg, bromo). In some embodiments, each of R ⁵ , R ⁷ and R ⁸ is hydrogen.

In certain embodiments, each of R ³ and R ⁶ is an independently selected substituent that is other than hydrogen. In certain embodiments, each of R ³ and R ⁶ is independently halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thio. _haloalkoxy, C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 2 -C ₆ alkynyl, cyclopropyl, -N _3, a _{cyano, -NH 2, -NH (C 1} -C 6 alkyl), - N Selected from (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro. For example, R ³ may be halo (eg, bromo); R ⁶ may be halo (eg, bromo) or C ₁ -C ₆ alkyl (eg, CH ₃ ); for example, halo (eg, bromo ). In some embodiments, each of R ¹ , R ² and R ⁴ is hydrogen; each of R ⁵ , R ⁷ and R ⁸ is hydrogen.

In certain embodiments, R and R ′ are each taken together with C ₂ and C ₃ to form a fused heteroaryl ring containing 5-6 ring atoms, wherein 1-2 of the ring atoms are N, NH , N (C ₁ -C ₃ alkyl), O and S; and the heteroaryl ring may be optionally substituted by 1 to 3 independently selected R ^b .

For example, a R and R 'are each C ₂ and C ₃ integrally to form a fused heteroaryl ring containing 6 ring atoms, wherein 1-2 of the selected independently ring atom is N And the heteroaryl ring may be optionally substituted with 1 to 2 independently selected R ^b .

In certain embodiments, R and R ′ are each taken together with C ₂ and C ₃ to form a fused heterocyclic ring containing 5-6 ring atoms, wherein 1-2 of the ring atoms are N, Independently selected from NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S; and the heterocyclic ring optionally has 1 to 3 independent And may be substituted with R ^a selected.

For example, R and R ′ together with C ₂ and C ₃ respectively form a fused heterocyclic ring containing 6 ring atoms, wherein 1 to 2 of the ring atoms are N, NH, N ( C ₁ -C ₆ alkyl) and NC (O) (C ₁ -C ₆ alkyl); and the heterocyclic ring is optionally selected from 1 to 3 independently selected R ^a May be substituted.

In some embodiments, R and R ′ are independently hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl (eg, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; eg, C _1- a C ₆ alkyl).

Each of L ¹ and L ² is independently a C ₁ -C ₃ linear alkylene, which is optionally substituted with 1 to 2 independently selected R ^c . For example, each of L ¹ and L ² is CH ₂ .

A is CR ^A1 R ^A2 where each of R ^A1 and R ^A2 is independently hydrogen, halo, C ₁ -C ₃ alkyl or OR ⁹ .

In some embodiments, A is other than CH _2.

In certain embodiments, one of R ^A1 and R ^A2 may be independently selected from hydrogen, halo, C ₁ -C ₃ alkyl and OR ⁹ ; the other of R ^A1 and R ^A2 is halo, C ₁ -C ₃ alkyl And OR ⁹ may be selected independently. For example, one of R ^A1 and R ^A2 is halo, C ₁ -C ₃ alkyl or OR ⁹ (eg, halo or OR ⁹ ); the other is hydrogen or C ₁ -C ₃ alkyl.

In some embodiments, one of R ^A1 and R ^A2 is halo and the other of R ^A1 and R ^A2 is hydrogen or halo. For example, one of R ^A1 and R ^A2 is fluoro and the other of R ^A1 and R ^A2 is hydrogen or fluoro. In either embodiment, one of R ^A1 and R ^A2 is OR ⁹ ; the other of R ^A1 and R ^A2 is C ₁ -C ₃ alkyl. For example, one of R ^A1 and R ^A2 is OH; the other of R ^A1 and R ^A2 is CH ₃ .

In some embodiments, the carbon attached to R ^A1 and R ^A2 is substituted with four different substituents (for clarity, these four substituents include R ^A1 and R ^A2 ), and therefore The asymmetric center.

In some embodiments, carbon bonded to R ^A1 and R ^A2 have the (R) configuration, the carbon bonded to R ^A1 and R ^A2 is (R) means having an arrangement (Cahn-Ingold-Prelog ranking Law display method). Such compounds may be referred to herein as “compounds of the (R) configuration” (this term also includes one or more asymmetric centers in addition to the (R) -CR ^A1 R ^A2 asymmetric center. In addition, including compounds).

In another embodiment, the carbon bonded to R ^A1 and R ^A2 have the (S) configuration, the carbon bonded to R ^A1 and R ^A2 is (S) means having an arrangement (Cahn-Ingold-Prelog Order law display method). Such compounds, herein sometimes referred to as “(S) configurational compounds” (this term also includes one or more asymmetric centers in addition to the (S) -CR ^A1 R ^A2 asymmetric center). Including compounds).

In certain embodiments, a compound of (R) configuration (or a salt thereof, eg, a pharmaceutically acceptable salt) has a carbon attached to R ^A1 and R ^A2 in the (S) configuration (ie, R ^A1 and R ^The carbon attached to ^A2 is substantially free of compounds of formula (I) having (S) configuration (eg, less than about 5%, less than about 2%, less than about 1%, less than about 0.5%). ). For example, a compound in the (R) configuration can be a (R) enantiomer substantially free of its opposite (S) enantiomer. As another example, a compound in the (R) configuration can be substantially free of diastereomers in which the carbon attached to R ^A1 and R ^A2 has the (S) configuration. In some embodiments, the (R) configuration compound may be further in a substantially pure form (e.g., including other compounds of formula (I), compounds not of formula (I), or biological media). Other materials less than about 5%, less than about 2%, less than about 1%, less than about 0.5%).

In some embodiments, a compound of (S) configuration (or a salt thereof, eg, a pharmaceutically acceptable salt) has a carbon bonded to R ^A1 and R ^A2 in the (R) configuration (ie, R ^A1 and R ^The carbon attached to ^A2 is substantially free of compounds of formula (I) having (R) configuration (eg, less than about 5%, less than about 2%, less than about 1%, less than about 0.5%). ). For example, a compound in the (S) configuration can be a (S) enantiomer substantially free of its opposite (R) enantiomer. As another example, a compound in the (S) configuration can be substantially free of diastereomers in which the carbon attached to R ^A1 and R ^A2 has the (R) configuration. In some embodiments, the (S) configuration compound may be further in a substantially pure form (eg, including other compounds of formula (I), non-formula (I) or biological media, for example). Other materials less than about 5%, less than about 2%, less than about 1%, less than about 0.5%).

In some embodiments, the compound of formula (I) is (+) (dextrorotatory) in the presence of plane polarized light.
In some embodiments, the compound of formula (I) is (−) (left-handed) in the presence of plane-polarized light.

  In some embodiments, a (+) (dextrorotatory) compound is substantially free of a compound of formula (I) (or a salt thereof described herein) that is (−) (left-handed) (eg, about 5 %, Less than about 2%, less than about 1%, less than about 0.5%). In some embodiments, the (+) (dextrorotatory) compound can be in a substantially more pure form (eg, other compounds of formula (I), non-formula (I) compounds or biological media, for example) Containing less than about 5%, less than about 2%, less than about 1%, less than about 0.5%).

  In some embodiments, the (−) (Levorotatory) compound is substantially free of a compound of Formula (I) (or a salt thereof described herein) that is (+) (dextrorotatory) (eg, about 5 %, Less than about 2%, less than about 1%, less than about 0.5%). In certain embodiments, the (-) (Left) compound can be further in a substantially pure form (e.g., other compounds of Formula (I), compounds not of Formula (I), or biological media). Containing less than about 5%, less than about 2%, less than about 1%, less than about 0.5%).

A is (i) CR ^A1 R ^A2 wherein each of R ^A1 and R ^A2 is independently selected from hydrogen, halo, C ₁ -C ₃ alkyl and OR ⁹ , wherein R ⁹ is Is C ₁ -C ₃ alkyl optionally substituted by hydroxyl or C ₁ -C ₃ alkoxy; or (ii) C═O.

A is CR ^A1 R ^A2 where each of R ^A1 and R ^A2 is independently hydrogen, halo, C ₁ -C ₃ alkyl or OR ⁹ .

In some embodiments, one of R ^A1 and R ^A2 is independently selected from hydrogen, halo, C ₁ -C ₃ alkyl, and OR ⁹ ; the other of R ^A1 and R ^A2 is independently halo, C ₁ -C ₃ It is selected from alkyl and oR ^9.

In some embodiments, one of R ^A1 and R ^A2 is halo and the other of R ^A1 and R ^A2 is hydrogen, halo, or C ₁ -C ₃ alkyl. In certain embodiments, one of R ^A1 and R ^A2 is halo and the other of R ^A1 and R ^A2 is hydrogen. For example, one of R ^A1 and R ^A2 is fluoro and the other of R ^A1 and R ^A2 is hydrogen.

In other embodiments, each of R ^A1 and R ^A2 is independently halo; for example, each of R ^A1 and R ^A2 is fluoro.

In some embodiments, one of R ^A1 and R ^A2 is —OHR ^A1 and the other of R ^A2 is hydrogen.

In some embodiments, A is CR ^A1 R ^A2 , wherein one of R ^A1 and R ^A2 is independently selected from hydrogen, halo, C ₁ -C ₃ alkyl, and OR ⁹ ; R ^A1 and R ^A2 the other is independently _halo, selected from C 1 -C ₃ alkyl and oR ^9; where, ^{R 9} is optionally substituted by hydroxy or _C 1 -C ₃ alkoxy or optionally is hydrogen _{C 1} - C ₃ alkyl.

In certain embodiments, one of R ^A1 and R ^A2 is OR ⁹ and the other is hydrogen, wherein R ⁹ is hydrogen.

In some embodiments, one of R ^A1 and R ^A2 is halo and the other of R ^A1 and R ^A2 is hydrogen or halo. For example, one of R ^A1 and R ^A2 is fluoro and the other of R ^A1 and R ^A2 is hydrogen or fluoro.

In other embodiments, one of R ^A1 and R ^A2 is OR ⁹ ; the other of R ^A1 and R ^A2 is C ₁ -C ₃ alkyl. For example, one of R ^A1 and R ^A2 is OH; the other of R ^A1 and R ^A2 is CH ₃ .

Z is (i) —NR ¹⁰ R ¹¹ ; or (ii) —C (O) NR ¹⁰ R ¹¹ ; or (iii) —OR ¹² ; or (iv) —S (O) _n R ¹³ , where , N is 0, 1 or 2.

Z is —NR ¹⁰ R ¹¹ . In certain embodiments, one of R ¹⁰ and R ¹¹ is (b) a C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or (c) a heteroaryl containing 5 to 14 ring atoms Wherein 1 to 6 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; and the heteroaryl optionally has 1 to 4 ^Optionally substituted with R ^b ; the other of R ¹⁰ and R ¹¹ is hydrogen or C ₁ -C ₆ alkyl.

Z is —OR ¹² or —S (O) _n R ¹³ .

In some embodiments, Z is —OR ¹² . In certain embodiments, R ¹² is C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b .

In certain embodiments, R ¹² is C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl (eg, C ₁ -C ₆ alkyl), each of which is substituted with 1 to 3 R ^d . In other embodiments, R ¹² is C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl (eg, C ₁ -C ₆ alkyl) that is unsubstituted or substituted with 1 to 3 R ^d. It is other than.

R ³ is halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C ₁ Selected from —C ₆ haloalkyl, cyano, —NH ₂ , —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro it can. For example, R ³ can be halo (eg, bromo). In certain embodiments, each of R ¹ , R ² and R ⁴ can be hydrogen.

L ¹ may be C ₁ -C ₃ straight chain alkylene, optionally substituted with 1 to 2 independently selected R ^c . For example, L ¹ can be CH ₂ .

L ² may be C ₁ -C ₃ straight chain alkylene, optionally substituted with 1 to 2 independently selected R ^c . For example, L ² can be CH ₂ .

Each of L ¹ and L ² may independently be a C ₁ -C ₃ linear alkylene, which is optionally substituted with 1 to 2 independently selected R ^c . For example, each of L ¹ and L ² can be CH ₂ .

A may be CR ^A1 R ^A2 where each of R ^A1 and R ^A2 is independently hydrogen, halo, C ₁ -C ₃ alkyl or OR ⁹ .

A may be CR ^A1 R ^A2 where each of R ^A1 and R ^A2 is independently hydrogen, halo or C ₁ -C ₃ alkyl.

A may be CR ^A1 R ^A2 where one of R ^A1 and R ^A2 is halo (eg, fluoro) and the other of R ^A1 and R ^A2 is independently hydrogen, halo or C ₁ -C ₃ alkyl (eg, hydrogen).

A may be CR ^A1 R ^A2 , where one of R ^A1 and R ^A2 is halo (eg, fluoro) and the other of R ^A1 and R ^A2 is hydrogen.

One of R ^A1 and R ^A2 may be halo or OR ⁹ and the other may be hydrogen.

One of R ^A1 and R ^A2 can be OR ⁹ . In certain embodiments, the other of R ^A1 and R ^A2 can be as defined herein; for example, the other of R ^A1 and R ^A2 can be hydrogen or C ₁ -C ₃ alkyl. For example, one of R ^A1 and R ^A2 can be OR ⁹ and the other of R ^A1 and R ^A2 can be hydrogen. In certain embodiments, R ⁹ can be hydrogen.

One of R ^A1 and R ^A2 can be halo. In certain embodiments, the other of R ^A1 and R ^A2 can be as defined herein; for example, the other of R ^A1 and R ^A2 can be hydrogen, C ₁ -C ₃ alkyl, or halo. For example, one of R ^A1 and R ^A2 can be halo (eg, fluoro) and the other of R ^A1 and R ^A2 can be hydrogen.

The carbon attached to R ^A1 and R ^A2 can have the R configuration.
The carbon attached to R ^A1 and R ^A2 can have the S configuration.

Each of L ¹ and L ² is independently C ₁ -C ₃ alkylene, which is optionally substituted with ₁ to 2 independently selected R ^c . For example, each of L ¹ and L ² can be CH ₂ .

Z may be ^-NR 10 ^{R 11.}

One of R ¹⁰ and R ¹¹ may be C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b .

One of R ¹⁰ and R ¹¹ can be C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b , and the other can be hydrogen or C ₁ -C ₆ alkyl.

One of R ¹⁰ and R ¹¹ is C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b , and the other can be hydrogen. For example, one of R ¹⁰ and R ¹¹ can be unsubstituted phenyl and the other can be hydrogen. As another example, one of R ¹⁰ and R ¹¹ can be phenyl substituted with 1 R ^b and the other can be hydrogen. In certain embodiments, R ^b can be C ₁ -C ₆ alkoxy (eg, OCH ₃ ). For example, one of R ¹⁰ and R ¹¹ can be 3-methoxyphenyl and the other can be hydrogen.

Z may be a ^{-OR 12.} In certain embodiments, R ¹² can be C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl, each of which is optionally substituted with 1 to 3 R ^c . In other embodiments, R ¹² can be C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b . For example, R ¹² can be unsubstituted phenyl.

Z may be —S (O) _n R ¹³ , where n may be 0, 1 or 2. In other embodiments, R ¹³ can be C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b . For example, R ¹³ can be unsubstituted phenyl.

Z may be a heterocycloalkenyl including 5-6 ring atoms, wherein 1-3 ring atoms are _{N, NH, N (C 1} -C 6 _{alkyl), NC (O) (C} 1 - C ₆ alkyl), independently selected from O and S; and the heterocycloalkenyl is optionally substituted with 1 to 4 independently selected R ^a .

R and R ′ are combined with C ₂ and C ₃ respectively to form the formula (II)
Form a phenyl ring.

R ⁶ is halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C ₁ Selected from —C ₆ haloalkyl, cyano, —NH ₂ , —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro it can. For example, R ⁶ can be halo (eg, bromo). In certain embodiments, each of R ⁵ , R ⁷ and R ⁸ can be hydrogen. Any one or more of the embodiments of R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² , A and Z described herein can be any of R ⁵ , R ⁶ , R ⁷ and R ⁸ described herein; It may be combined with any one or more of the embodiments.

Each of L ¹ and L ² may be CH ₂ ; A may be CR ^A1 R ^A2 , wherein one of R ^A1 and R ^A2 is OR ⁹ and the other is hydrogen; -NR ¹⁰ R ¹¹ ; each of R ¹⁰ and R ¹¹ is (a) hydrogen; (b) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; (d) C _1- C ₆ alkyl or C ₁ -C ₆ haloalkyl, each of which is optionally substituted by 1 to 3 R ^d ; and (f) C ₂ -C ₆ alkenyl or C ₂ -C ₆ Independently selected from alkynyl.

Each of R ³ and R ⁶ can be halo (eg, bromo); each of R ¹ , R ² , R ⁴ , R ⁵ , R ⁷ and R ⁸ can be hydrogen. R ⁹ can be hydrogen. One of R ¹⁰ and R ¹¹ is C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b , and the other can be hydrogen. One of R ¹⁰ and R ¹¹ can be unsubstituted phenyl and the other can be hydrogen. One of R ¹⁰ and R ¹¹ can be phenyl substituted with 1 R ^b and the other can be hydrogen. R ^b can be C ₁ -C ₆ alkoxy (eg, OCH ₃ ). One of R ¹⁰ and R ¹¹ can be 3-methoxyphenyl and the other can be hydrogen.

Each of L ¹ and L ² is CH ₂ ; A is CR ^A1 R ^A2 , wherein one of R ^A1 and R ^A2 is OR ⁹ and the other is hydrogen; Z is —NR ¹⁰ R be ^11; each of ^{R 10} and ^{R 11} are independently (a) hydrogen; (b) optionally 1 to 4 may _C 6 _{-C 10} aryl optionally substituted with ^{R b;} (d) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl, each of which is optionally substituted with 1 to 3 R ^d ; and (f) C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl. Selected from. Aspects can include one or more of the following characteristics.

Each of R ³ and R ⁶ is halo (eg, bromo); each of R ¹ , R ² , R ⁴ , R ⁵ , R ⁷ and R ⁸ is hydrogen. R ⁹ can be hydrogen. One of R ¹⁰ and R ¹¹ is C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b , and the other can be hydrogen. One of R ¹⁰ and R ¹¹ can be unsubstituted phenyl and the other can be hydrogen. One of R ¹⁰ and R ¹¹ can be phenyl substituted with 1 R ^b and the other can be hydrogen. R ^b can be C ₁ -C ₆ alkoxy (eg, OCH ₃ ). One of R ¹⁰ and R ¹¹ can be 3-methoxyphenyl and the other can be hydrogen.

  In some embodiments, (A), (B) or (C) applies. In other embodiments, (A) and (B); or (A) and (C); or (B) and (C) apply. In still other embodiments, (A), (B) or (C) is applied.

Each of R and R ′ may independently be hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. Each of R and R ′ can independently be C ₁ -C ₆ alkyl (eg, each of R and R ′ can be CH ₃ ). Each of R and R ′ can be hydrogen.

The compounds of the present invention may include any one or more compounds selected from:
R-1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol;
S-1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (2-iminopyridin-1 (2H) -yl) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylthio) propan-2-ol;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -N- (3-methoxyphenyl) acetamide;
5-((3,6-dibromo-9H-carbazol-9-yl) methyl) -3- (3-methoxyphenyl) -oxazolidine-2-one;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-one;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-methoxypropyl) -3-methoxyaniline;
1- (3,6-dimethyl-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol;
1- (3-bromo-6-methyl-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol;
1- (3,6-dichloro-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol;
1- (5-bromo-2,3-dimethyl-1H-indol-1-yl) -3- (phenylamino) propan-2-ol;
1- (3,6-dibromo-9H-pyrido [3,4-b] indol-9-yl) -3- (phenylamino) propan-2-ol;
1- (3-azidophenylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
1,3-bis (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
1- (9H-carbazol-9-yl) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxy-N- (3-methoxyphenyl) -propanamide;
Ethyl 5- (2-hydroxy-3- (3-methoxyphenylamino) propyl) -8-methyl-3,4-dihydro-1H-pyrido [4,3-b] indole-2 (5H) -carboxylate;
4- (3,6-dibromo-9H-carbazol-9-yl) -1- (phenylamino) butan-2-ol;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) propyl) aniline;
1- (3,6-dibromo-9H-carbazol-9-yl) -4- (phenylamino) butan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (pyridin-2-ylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3-((3-methoxyphenyl) (methyl) -amino) propan-2-ol;
3- (3,6-dibromo-9H-carbazol-9-yl) -1- (3-methoxyphenylamino) -1- (methylthio) propan-2-one;
3-Amino-1- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) pyridinium;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (pyrimidin-2-ylamino) propan-2-ol;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxy-N-methylaniline;
1- (3,6-dibromo-9H-carbazol-9-yl) -3-methoxypropan-2-ol;

1- (3,6-dibromo-9H-carbazol-9-yl) -4-phenylbutan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (1H-indol-1-yl) propan-2-ol;
3- (1- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -1H-1,2,3-triazol-4-yl) propan-1-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-ethoxyphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3,5-dimethyl-1H-pyrazol-1-yl) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylsulfinyl) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylsulfonyl) propan-2-ol;
1- (3-bromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol;
N- (5- (3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylamino) phenoxy) pentyl) -2- (7- (dimethylamino) -2- Oxo-2H-chromen-4-yl) acetamide;
1- (3,6-dibromo-9H-carbazol-9-yl) -3-phenoxypropan-2-ol;
N- (2- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropoxy) ethyl) -acetamide;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (pyridin-3-ylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (pyridin-4-ylamino) propan-2-ol;
1- (2,8-dimethyl-3,4-dihydro-1H-pyrido [4,3-b] indol-5 (2H) -yl) -3- (phenylamino) propan-2-ol;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2,2-difluoropropyl) -3-methoxyaniline;
1- (3,6-dibromo-9H-carbazol-9-yl) -3-phenoxypropan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (o-tolylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (m-tolylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (2-methoxyphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (naphthalen-1-ylamino) propan-2-ol;
1- (4-bromophenylamino) -3- (3,6-dichloro-9H-carbazol-9-yl) propan-2-ol;
1- (4-bromophenylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (4-ethoxyphenylamino) propan-2-ol;
1- (4-chlorophenylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenethylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (2-hydroxyethylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (2,4-dimethoxyphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (2,3-dimethylphenylamino) propan-2-ol;

1- (2-chlorophenylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
1- (tert-butylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (isopropylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (4-methoxyphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (m-tolylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3,5-dimethylphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3,4-dimethylphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3,4-dimethylphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (2,5-dimethylphenylamino) propan-2-ol;
1- (4-bromophenylamino) -3- (2,3-dimethyl-1H-indol-1-yl) propan-2-ol;
1- (2,3-dimethyl-1H-indol-1-yl) -3- (4-methoxyphenylamino) propan-2-ol;
1- (2,3-dimethyl-1H-indol-1-yl) -3- (4-ethoxyphenylamino) propan-2-ol;
1- (2,3-dimethyl-1H-indol-1-yl) -3- (p-tolylamino) propan-2-ol;
1- (2,3-dimethyl-1H-indol-1-yl) -3- (phenylamino) propan-2-ol oxalate;
1- (1H-indol-1-yl) -3- (4-methoxyphenylamino) propan-2-ol hydrochloride;
1- (1H-indol-1-yl) -3- (phenylamino) propan-2-ol oxalate;
1- (3,4-dihydro-1H-carbazol-9 (2H) -yl) -3- (m-tolylamino) propan-2-ol;
1- (9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
1- (3,6-dichloro-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
1- (9H-carbazol-9-yl) -3- (p-tolylamino) propan-2-ol;
1- (3,6-dichloro-9H-carbazol-9-yl) -3- (p-tolylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (p-tolylamino) propan-2-ol;
N- (4- (3- (9H-carbazol-9-yl) -2-hydroxypropoxy) phenyl) acetamide;
1- (9H-carbazol-9-yl) -3-phenoxypropan-2-ol;
1- (9H-carbazol-9-yl) -3- (4-methoxyphenylamino) propan-2-ol;
1- (benzylamino) -3- (9H-carbazol-9-yl) propan-2-ol;
Methyl 4- (3- (9H-carbazol-9-yl) -2-hydroxypropoxy) benzoate;
1- (9H-carbazol-9-yl) -3- (4-methoxyphenoxy) propan-2-ol;

1-amino-3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
(S) -1- (3,6-dibromo-9H-carbazol-9-yl) -3-phenoxypropan-2-ol;
(R) -1- (3,6-dibromo-9H-carbazol-9-yl) -3-phenoxypropan-2-ol;
3,6-dibromo-9- (2-fluoro-3-phenoxypropyl) -9H-carbazole;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -2-methylpropan-2-ol;
1- (2,8-dimethyl-3,4-dihydro-1H-pyrido [4,3-b] indol-5 (2H) -yl) -3- (3-methoxyphenylamino) propan-2-ol;
1- (4-azidophenylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
1- (3-azido-6-bromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (4-methoxyphenoxy) propan-2-ol;
1- (3,6-dichloro-9H-carbazol-9-yl) -3- (phenylsulfonyl) propan-2-ol;
3,6-dibromo-9- (2-fluoro-3- (phenylsulfonyl) propyl) -9H-carbazole;
S) -1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (phenylsulfonyl) propan-2-ol;
(R) -1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylsulfonyl) propan-2-ol;
1- (3,6-dicyclopropyl-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
1- (3,6-diiodo-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
1- (3,6-diethynyl-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol;
9- (2-hydroxy-3- (3-methoxyphenylamino) propyl) -9H-carbazole-3,6-dicarbonitrile;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) aniline;
3,6-dibromo-9- (2,2-difluoro-3-phenoxypropyl) -9H-carbazole;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -4-methoxyaniline;
N- (2-bromo-3- (3,6-dibromo-9H-carbazol-9-yl) propyl) -N- (4-methoxyphenyl) -4-nitrobenzenesulfonamide;
Ethyl 2- (4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropylamino) phenoxy) acetate; and N- (3- (3,6-dibromo-9H- Carbazol-9-yl) -2-fluoropropyl) -4- (2- (2-methoxyethoxy) ethoxy) aniline;
N- (2- (2- (4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropylamino) phenoxy) acetamido) ethyl) -5- (2-oxohexa Hydro-1H-thieno [3,4-d] imidazol-4-yl) pentanamide;
2- (4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropylamino) phenoxy) -N, N-dimethylacetamide;
2- (4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropylamino) phenoxy) -N- (2-hydroxyethyl) acetamide;
1- (bis (4-bromophenyl) amino) -3- (phenylamino) propan-2-ol;
(E) -3,6-dibromo-9- (3-phenoxyallyl) -9H-carbazole;
(E) -3,6-dibromo-9- (3-phenoxyprop-1-en-1-yl) -9H-carbazole;
1- (3,6-bis (trifluoromethyl) -9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;

1- (2,8-dibromo-10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl) -3- (3-methoxyphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylthio) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (4-methoxyphenylthio) propan-2-ol;
3,6-dibromo-9- (2-fluoro-3- (3-methoxyphenylthio) propyl) -9H-carbazole;
3,6-dibromo-9- (2-fluoro-3- (4-methoxyphenylthio) propyl) -9H-carbazole;
3,6-dibromo-9- (2-fluoro-3- (3-methoxyphenylsulfonyl) propyl) -9H-carbazole;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylsulfonyl) propan-2-ol;
3,6-dibromo-9- (2-fluoro-3- (4-methoxyphenylsulfonyl) propyl) -9H-carbazole;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (4-methoxyphenylsulfonyl) propan-2-ol;
3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylthio) phenol;
4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylthio) phenol;
3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylsulfonyl) phenol;
4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylsulfonyl) phenol;
1- (3-aminophenylthio) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
1- (4-aminophenylthio) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3-phenoxypropan-2-amine;
N-benzyl-2- (3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylthio) -phenoxy) acetamide;
N-benzyl-2- (4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylthio) -phenoxy) acetamide;
3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropylsulfonyl) phenol; N-benzyl-2- (3- (3- (3,6-dibromo-9H- Carbazol-9-yl) -2-hydroxypropylsulfonyl) -phenoxy) acetamide;
4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropylsulfonyl) phenol;
5- (5- (3- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-hydroxypropylamino) phenoxy) pentylcarbamoyl) -2- (6-hydroxy-3-oxo- 3H-xanthen-9-yl) benzoic acid;
1- (8-bromo-3,4-dihydro-1H-pyrido [4,3-b] indol-5 (2H) -yl) -3-phenoxypropan-2-ol;
1- (8-bromo-2-cyclopropyl-3,4-dihydro-1H-pyrido [4,3-b] indol-5 (2H) -yl) -3-phenoxypropan-2-ol;
8-bromo-5- (2-hydroxy-3-phenoxypropyl) -3,4-dihydro-1H-pyrido [4,3-b] indole-2 (5H) -carbonitrile;
8-bromo-5- (2-fluoro-3-phenoxypropyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole;
1- (cyclohexylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
(9- (2-hydroxy-3- (phenylthio) propyl) -9H-carbazole-3,6-dicarbonitrile;
9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3,6-dicarbonitrile;
RN- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline SN ((3- (3,6-dibromo-9H-carbazole) -9-yl) -2-fluoropropyl) -3-methoxyaniline N- (2- (3,6-dibromo-9H-carbazol-9-yl) ethyl) aniline;

2- (6-Amino-3-imino-3H-xanthen-9-yl) -4- (6- (5- (3- (3- (3,6-dibromo-9H-carbazol-9-yl)- 2-hydroxypropylamino) phenoxy) pentylamino) -6-oxohexylcarbamoyl) benzoic acid and 2- (6-amino-3-imino-3H-xanthen-9-yl) -5- (6- (5- (5- 3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylamino) phenoxy) pentylamino) -6-oxohexylcarbamoyl) benzoic acid;
1- (8-bromo-2-methyl-3,4-dihydro-1H-pyrido [4,3-b] indol-5 (2H) -yl) -3-phenoxypropan-2-ol;
6-((4-Bromophenyl) (2-hydroxy-3-phenoxypropyl) amino) nicotinonitrile;
1- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) pyridin-2 (1H) -one;
9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3-carbonitrile;
tert-butyl (5- (4-((3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) sulfonyl) phenoxy) pentyl) carbamate;
6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3-carbonitrile;
6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3-carboxamide;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (pyridin-2-yloxy) propan-2-ol;
Methyl 6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3-carboxylate;
6-Bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3-carboxylic acid;
6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [2,3-b] indole-3-carbonitrile;
9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [2,3-b] indole-3-carbonitrile;
tert-butyl 3- (2- (2- (2- (3-((3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) amino) phenoxy) ethoxy) ethoxy) Ethoxy) propanoate;
1- (3,6-dibromo-1,4-dimethoxy-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
1- (3,6-dibromo-1,8-dimethyl-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
2- (3,6-dibromo-9H-carbazol-9-yl) acetic acid;
1- (6-Bromo-3-methoxy-1-methyl-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
1- (4,6-dibromo-3-methoxy-1-methyl-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
1- (3,6-dibromo-4-methoxy-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylic acid;
6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylic acid;
Ethyl 6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylate;
9- (2-Fluoro-3-phenoxypropyl) -9H-carbazole-3,6-dicarbonitrile;
9- (2-hydroxy-2-methyl-3-phenoxypropyl) -9H-carbazole-3,6-dicarbonitrile;
1- (cyclohexyloxy) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
(E) -N- (3- (3,6-Dibromo-9H-carbazol-9-yl) prop-1-en-1-yl) -1,1,1-trifluoro-N- (3-methoxy Phenyl) methanesulfonamide;
1- (3,6-dibromo-9H-pyrido [2,3-b] indol-9-yl) -3-phenoxypropan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3-((6-methoxypyridin-2-yl) amino) propan-2-ol;

1- (8-bromo-5H-pyrido [4,3-b] indol-5-yl) -3-phenoxypropan-2-ol;
6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxamide;
8-bromo-5- (2-hydroxy-3-phenoxypropyl) -5H-pyrido [4,3-b] indole 2-oxide;
8-bromo-5- (2-hydroxy-3-phenoxypropyl) -5H-pyrido [3,2-b] indole 1-oxide;
(6-Bromo-9H-pyrido [3,4-b] indol-3-yl) methanol;
Ethyl 6-bromo-9H-pyrido [3,4-b] indole-3-carboxylate;
tert-butyl (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) carbamate;
2- (3,6-dibromo-9H-carbazol-9-yl) -N-methylacetamide;
3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropan-1-amine hydrochloride;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) acetamide;
2- (3,6-dibromo-9H-carbazol-9-yl) propanamide;
6-bromo-9H-pyrido [3,4-b] indole-3-carbonitrile;
6-bromo-3-methyl-9H-pyrido [3,4-b] indole;
Methyl (2- (3,6-dibromo-9H-carbazol-9-yl) acetyl) carbamate;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -1,1,1-trifluoro-N- (3-methoxyphenyl) methanesulfonamide;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -6-methoxypyridin-2-amine;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -1,1,1-trifluoro-N- (3-methoxyphenyl) methanesulfonamide; (3,6-dibromo-9H-carbazol-9-yl) -3-((4-methoxybenzyl) (3-methoxyphenyl) amino) propan-2-ol;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -2,2,2-trifluoroacetamide;
tert-butyl (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) carbamate;
5- (2-hydroxy-3-phenoxypropyl) -5H-pyrimido [5,4-b] indole-2-carboxylic acid;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) acetamide;
Ethyl (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) carbamate;
6-bromo-9- (3- (4-bromophenoxy) -2-hydroxypropyl) -9H-carbazole-3-carbonitrile;
Methyl 9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylate;
N- (3- (3-Bromo-6-methyl-9H-carbazol-9-yl) -2-fluoropropyl) -6-methoxypyridin-2-amine;
Or a salt thereof (eg, a pharmaceutically acceptable salt) (or any one or more subsets thereof, eg, as described in the claims).

  In some embodiments, the compound having Formula (I) is 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol; or a salt thereof (eg, a pharmaceutical Acceptable salt).

  In some embodiments, the compound having Formula (I) is R-1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol; It can be a salt (eg, a pharmaceutically acceptable salt). In some embodiments, R-1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol or a salt thereof (eg, pharmaceutically acceptable) Salt) is S-1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol or a salt thereof (for example, pharmaceutically acceptable Salt) (eg, less than about 5%, less than about 2%, less than about 1%, less than about 0.5%).

  In some embodiments, the compound having Formula (I) is S-1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol; It can be a salt (eg, a pharmaceutically acceptable salt). In some embodiments, S-1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol or a salt thereof (eg, pharmaceutically acceptable) R-1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol or a salt thereof (for example, pharmaceutically acceptable) Salt) (eg, less than about 5%, less than about 2%, less than about 1%, less than about 0.5%).

  In some embodiments, the compound having Formula (I) is a 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol as described herein. It can be a (+) (dextrorotatory) enantiomer or a salt thereof (eg, a pharmaceutically acceptable salt). See, for example, Examples 1a and 1b. In certain embodiments, the (+) (dextrorotatory) of 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol described herein. The enantiomer or salt thereof (eg, a pharmaceutically acceptable salt) is 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propane as described herein. It can be substantially free of the (−) (left-handed) enantiomer of 2-ol or a salt thereof (eg, a pharmaceutically acceptable salt) (eg, less than about 5%, less than about 2%, Less than about 1%, less than about 0.5%).

  In some embodiments, the compound having Formula (I) is a 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol as described herein. It can be a (−) (left-handed) enantiomer or a salt thereof (eg, a pharmaceutically acceptable salt). See, for example, Examples 1a and 1b. In some embodiments, the (−) (left-handed) enantiomer of 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol described herein. Or a salt thereof (eg, a pharmaceutically acceptable salt) is 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propane- It can be substantially free of the (+) (dextrorotatory) enantiomer of 2-ol or a salt thereof (eg, a pharmaceutically acceptable salt) (eg, less than about 5%, less than about 2%, Less than about 1%, less than about 0.5%).

  In certain embodiments, the compound has (+) (dextrorotatory) -N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3- described herein. It can be methoxyaniline or a salt thereof (eg, a pharmaceutically acceptable salt). See, for example, Examples 144a and 144b. In certain embodiments, the (+) (left-handed) enantiomer of N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline described herein, or a Salts (eg, pharmaceutically acceptable salts) of N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline described herein It may be substantially free of (−) (dextrorotatory) enantiomers or salts thereof (eg, pharmaceutically acceptable salts) (eg, less than about 5%, less than about 2%, less than about 1%). , Including less than about 0.5%).

  In some embodiments, the compound is a (-) (dextrorotatory) -N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxy as described herein. It can be aniline or a salt thereof (eg, a pharmaceutically acceptable salt). See, for example, Examples 144a and 144b. In certain embodiments, the (−) (left-handed) enantiomer of N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline described herein, or a Salts (eg, pharmaceutically acceptable salts) of N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline described herein It may be substantially free of (+) (dextrorotatory) enantiomers or salts thereof (eg, pharmaceutically acceptable salts) (eg, less than about 5%, less than about 2%, less than about 1%). , Including less than about 0.5%).

  Compounds of formula (I), (II), (III) and (IV) or pharmaceutically acceptable salts thereof are described in Examples 1a, 1b, 3a, 3b, 3d, 6a, 10, 13, 21, 22 88b, 90, 92, 96, 97a, 97b, 102, 116, 117, 118, 119, 120, 121, 122, 132, 143 and 144a.

  In various embodiments, the compounds of formulas (I), (II), (III) and (IV) are a disease, disorder or caused by unwanted neuronal cell death or insufficient neurogenesis in a subject in need of treatment. Can be used as a method of treating a condition. The method can include administering to a subject an effective amount of a compound having formula (I), (II), (III) or (VI) as defined herein, or a pharmaceutically acceptable salt thereof.

  The method further comprises detecting the obtained neurotrophism (e.g. neurogenesis) and / or particularly detecting and / or diagnosing it in patients who are associated with abnormal neurotropism, in particular abnormal neurogenesis, in particular Including the determination of having an abnormal hippocampus and / or hypothalamic neurogenesis or disease or disorder.

The method further includes detecting the resulting neuroactive effect.
The method further comprises determining that the subject has abnormal neurogenesis or neuronal death or a disease or disorder associated therewith by detecting it in the subject.
The method further includes detecting the resulting hippocampus and / or hypothalamic neurogenesis.

  Disease, disorder or condition is schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellar ataxia, muscle atrophic side Sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress and neurostimulant drugs (e.g. alcohol, opium, methamphetamine, phencyclidine and cocaine), retinal degeneration, spinal cord injury, peripheral nerve injury, various Psychiatric and neurodegenerative diseases including (but not limited to) physiological weight loss associated with these conditions and cognitive decline associated with normal aging and chemotherapy.

In certain embodiments, a compound having Formula (I) or a salt thereof (eg, a pharmaceutically acceptable salt) is at least about 27 (× 10 ⁻⁰⁶ ) BrdU ⁺ cells, as assessed in the assay described in conjunction with Table 1. / Mm ³ dentate gyrus is provided (ie evaluated in proneurogenesis / neuroprotection in our standard in vivo assay at 10 μM concentration in 4 12-week-old adult male C57 / B16 mice).

In certain embodiments, a compound having Formula (I) or a salt thereof (eg, a pharmaceutically acceptable salt) is at least about 19 (× 10 ⁻⁰⁶ ) BrdU ⁺ cells as evaluated in the assay described in conjunction with Table 1. / Mm Provides ³ dentate gyrus.

In some embodiments, a compound having Formula (I) or a salt thereof (eg, a pharmaceutically acceptable salt) is about 18 to about 30 (eg, 18-27, as evaluated in the assays described in conjunction with Table 1). 19～26,20～25,27～30,27～29) (providing × ^{10 -06)} BrdU ⁺ cells / mm ³ dentate gyrus.

In certain embodiments, a compound having Formula (I) or a salt thereof (eg, a pharmaceutically acceptable salt) is evaluated from about 18 to about 26 (eg, 19-26, 20-25) (× 10 ⁻⁰⁶ ) BrdU ⁺ cells / mm ³ dentate gyrus is provided.

In certain embodiments, a compound having Formula (I) or a salt thereof (eg, a pharmaceutically acceptable salt) is about 27 to about 30 (eg, 27-29) as evaluated in the assays described in conjunction with Table 1. (× 10 ⁻⁰⁶ ) BrdU ⁺ cells / mm ³ dentate gyrus is provided.

  In certain embodiments, a composition (eg, a pharmaceutical composition) can include an effective amount to achieve the above level.

  In certain embodiments, any compound, composition or method described herein may also include any one or more of the detailed descriptions and / or other characteristics recited in the claims.

The term “mammal” includes organisms including mice, rats, cows, sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats and humans.

  An “effective amount” is a therapeutic effect (eg, treatment, eg, control, alleviation, amelioration, reduction or delay in progression of treatment); or prevention, eg, delay in onset or risk of onset of a disease, disorder or condition or its symptoms ). The therapeutic effect can be objective (ie, measurable by some test or marker) or subjective (ie, subject shows or feels an effect). Effective amounts of the compounds can range from about 0.01 mg / kg to about 1000 mg / kg (eg, from about 0.1 mg / kg to about 100 mg / kg, from about 1 mg / kg to about 100 mg / kg). Effective amounts will also vary depending on route of administration as well as the possibility of co-use with other agents.

  The term “halo” or “halogen” refers to any group of fluorine, chlorine, bromine or iodine.

  In general, and unless otherwise indicated, the substituent (group) prefix is (i) replacing the “ane” of the parent hydride with the suffix “yl”, “diyl”, “triyl”, “tetrayl”, etc .; or (ii) Deriving from the hydrophile by replacing “e” of the hydride with the suffix “yl”, “diyl”, “triyl”, “tetrayl”, etc. When specifying, the lowest possible number that matches any of the numbering given by the parent hydride). Conventional short names such as adamantyl, naphthyl, anthryl, phenanthryl, furyl, pyridyl, isoquinolyl, quinolyl and piperidyl and conventional names such as vinyl, allyl, phenyl and thienyl are also used throughout this specification. Conventional numbering / marking systems are also followed for numbering and nomenclature of fused bicyclic, tricyclic, and polycyclic ring substituents.

  Unless otherwise noted, the following definitions are used: For groups, substituents and ranges, the specific and general values listed below are for illustration only and are not intended to exclude other defined values or other values within the defined range of groups and substituents. Absent. Unless otherwise specified, alkyl, alkoxy, alkenyl, etc. refer to both straight and branched chain groups.

The term “alkyl” refers to a saturated hydrocarbon chain containing the indicated number of carbon atoms, which may be straight or branched. For example, C ₁ -C ₆ alkyl represents a group that may have 1 to 6 (inclusive) carbon atoms in it. Any atom may be optionally substituted, for example with one or more substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl and tert-butyl.

The term “linear C _nm alkylene” used here, whether used alone or in combination with other terms, is a non-branched group connecting groups having _{n to m} carbon atoms. Refers to alkyl. Any atom may be optionally substituted, for example with one or more substituents. Examples include methylene (ie, —CH ₂ —).

  The term “haloalkyl” refers to an alkyl group in which at least one hydrogen atom is replaced by halo. In some embodiments, more than one (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ) A hydrogen atom replaces a halo. In these embodiments, multiple hydrogen atoms may be substituted with the same halogen (eg, fluoro) or multiple hydrogen atoms may be substituted with different halogen combinations (eg, fluoro and chloro). “Haloalkyl” also includes alkyl moieties in which all hydrogens are replaced by halos (herein, perhaloalkyls, such as perfluoroalkyls, such as trifluoromethyl) may be referred to. Any atom may be optionally substituted, for example with one or more substituents.

The term “alkoxy” as used herein refers to a group of formula —O (alkyl). Alkoxy can be, for example, methoxy (—OCH ₃ ), ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 2-pentoxy, 3-pentoxy or hexyloxy. Similarly, the term “thioalkoxy” refers to a group of formula —S (alkyl). Furthermore, the terms “haloalkoxy” and “thioalkoxy” refer to —O (haloalkyl) and —S (haloalkyl), respectively. The term “sulfhydryl” refers to —SH. As used herein, the term “hydroxyl”, whether used alone or in combination with other terms, refers to a group of formula OH.

  The term “aralkyl” refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. One of the carbons of the alkyl moiety serves as the point of attachment between the aralkyl group and the other moiety. Any ring or chain atom may be optionally substituted, for example with one or more substituents. Non-limiting examples of “aralkyl” include benzyl, 2-phenylethyl and 3-phenylpropyl groups.

  The term “alkenyl” refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon double bonds. Any atom may be optionally substituted, for example with one or more substituents. Alkenyl groups can include, for example, vinyl, allyl, 1-butenyl, and 2-hexenyl. One double bond carbon may optionally be the point of attachment of the alkenyl substituent.

  The term “alkynyl” refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon triple bonds. An alkynyl group can be optionally substituted, for example, with one or more substituents. Alkynyl groups can include, for example, ethynyl, propargyl, and 3-hexynyl. One triple bond carbon can optionally be the point of attachment of the alkynyl substituent.

The term “heterocyclyl” is independently selected from O, N (it is understood that one or two additional groups may be present to satisfy the nitrogen valence and / or to form a salt) or S A fully saturated monocyclic, bicyclic, tricyclic or other polycyclic ring system having one or more constituent heteroatoms as ring atoms. A heteroatom or ring carbon can be the point of attachment between the heterocyclyl substituent and another moiety. Any atom may be optionally substituted, for example with one or more substituents. Heterocyclyl groups can include, for example, tetrahydrofuryl, tetrahydropyranyl, piperidyl (piperidino), piperazinyl, morpholinyl (morpholino), pyrrolinyl and pyrrolidinyl. For example, “a heterocyclic ring containing 5-6 ring atoms, wherein 1 to 2 of the ring atoms are N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ — C ₆ alkyl), O and S are independently selected and the heterocyclic ring is optionally substituted by 1 to 3 independently selected R ^a , Tetrahydropyranyl, piperidyl (piperidino), piperazinyl, morpholinyl (morpholino), pyrrolinyl and pyrrolidinyl.

  The term “heterocycloalkenyl” is present for one or more (eg 1 to 4) O, N (1 or 2 additional groups to satisfy the nitrogen valence and / or to form a salt. A partially unsaturated monocyclic, bicyclic, tricyclic or other polycyclic hydrocarbon group having a ring atom which is a heteroatom independently selected from S) Say. A ring carbon (eg, saturated or unsaturated) or heteroatom can be the point of attachment of the heterocycloalkenyl substituent. Any atom may be optionally substituted, for example with one or more substituents. Heterocycloalkenyl groups are, for example, dihydropyridyl, tetrahydropyridyl, dihydropyranyl, 4,5-dihydrooxazolyl, 4,5-dihydro-1H-imidazolyl, 1,2,5,6-tetrahydro-pyrimidinyl and 5 , 6-dihydro-2H- [1,3] oxazinyl.

  The term “cycloalkyl” refers to a fully saturated monocyclic, bicyclic, tricyclic or other polycyclic hydrocarbon group. Any atom may be optionally substituted, for example with one or more substituents. The ring carbon serves as a point of attachment for the cycloalkyl group and other moieties. Cycloalkyl moieties can include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and norbornyl (bicycle [2.2.1] heptyl).

  The term “cycloalkenyl” refers to a partially unsaturated monocyclic, bicyclic, tricyclic or other polycyclic hydrocarbon group. A ring carbon (eg, saturated or unsaturated) is the point of attachment of a cycloalkenyl substituent. Any atom may be optionally substituted, for example with one or more substituents. Cycloalkenyl moieties can include, for example, cyclohexenyl, cyclohexadienyl, or norbornenyl.

  As used herein, the term “cycloalkylene” refers to a divalent monocyclic cycloalkyl group having the indicated number of ring atoms.

  As used herein, the term “heterocycloalkylene” refers to a divalent monocyclic heterocyclyl group having the indicated number of ring atoms.

  The term “aryl” refers to an aromatic monocyclic, bicyclic (2 fused ring) or tricyclic (3 fused ring) or polycyclic (> 3 fused ring) hydrocarbon ring system. One or more of the ring atoms may be optionally substituted, for example with one or more substituents. Aryl moieties include, for example, phenyl and naphthyl.

  The term “heteroaryl” is understood to be one or more O, N (one or two additional groups may be present to satisfy the nitrogen valence and / or to form a salt) or S Aromatic monocyclic, bicyclic (2 fused rings), tricyclic (3 fused rings) or polycyclic (> 3 fused rings) carbonizations having ring atoms which are heteroatoms independently selected from Refers to a hydrogen group. One or more ring atoms may be optionally substituted, for example with one or more substituents.

  Examples of heteroaryl groups are 2H-pyrrolyl, 3H-indolyl, 4H-quinolidinyl, acridinyl, benzo [b] thienyl, benzothiazolyl, β-carbolinyl, carbazolyl, coumarinyl, chromenyl, cinnolinyl, dibenzo [b, d] furanyl, flazanil , Furyl, imidazolyl, imidazolyl, indazolyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenalsadinyl, phenazinyl, phenothiazinyl, phenoxatinyl Nyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyro Including, but not limited to, tolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl and xanthenyl.

  The terms “arylcycloalkyl” and “arylheterocyclyl” refer to bicyclic, tricyclic, or other polycyclic ring systems containing an aryl ring fused to cycloalkyl and heterocyclyl, respectively. Similarly, the terms “heteroarylheterocyclyl” and “heteroarylcycloalkyl” refer to bicyclic, tricyclic, or other polycyclic ring systems comprising a heteroaryl ring fused to a heterocyclyl and cycloalkyl, respectively. Any atom may be substituted with, for example, one or more substituents. For example, arylcycloalkyl may include indanyl and arylheterocyclyl may include 2,3-dihydrobenzofuryl, 1,2,3,4-tetrahydroisoquinolyl and 2,2-dimethylchromanyl.

   The description “C═O” or “C (O)” refers to a carbon atom bonded to an oxygen atom by a double bond.

The term “oxo” refers to a double bonded oxygen when it is a substituent on carbon. When oxo is the substituent on the nitrogen or sulfur, respectively obtained groups N → O ^- is understood to have and S (O) of and SO ₂ structure.

  The term “cyano” as used herein, whether used alone or in combination with other terms, means a group of formula —CN, wherein the carbon and nitrogen atoms are bonded to each other by a triple bond. Yes.

  In general, when the definition of a particular variable has the possibility of both hydrogen and non-hydrogen (halo, alkyl, aryl, etc.), the term “substituent other than hydrogen” refers to non-hydrogen for that particular variable Comprehensive possibilities.

  The term “substituent” refers to “substituted” on any atom of this group, for example on an alkyl, haloalkyl, cycloalkyl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, aryl or heteroaryl group. Refers to the group. In one aspect, a substituent on a group is independently any one or combination of any two or more of the permissible mono- or multi-atom groups defined for the substituent. In other aspects, the substituents may themselves be substituted with any one or more of the above substituents.

  Furthermore, as used herein, the expression “optionally substituted” means unsubstituted (eg, substituted with H) or substituted. As used herein, the term “substituted” means that a hydrogen atom has been removed and replaced with a substituent. It is understood that substitution at an atom is limited by valence.

Expressions such as “C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 independently selected R ^b ” (such as) include unsubstituted C ₆ -C ₁₀ aryl groups and 1 to It is intended to include both four independently selected C ₆ -C ₁₀ aryl groups substituted with R ^b . A substituent (group) such as alkyl without an adjective such as “optionally substituted” or “substituted” is understood to mean that that particular substituent is not substituted. However, the use of “haloalkyl” without an adjective such as “optionally substituted” or “substituted” is still taken to mean an alkyl group in which at least one hydrogen atom is replaced with halo. .

In certain embodiments, R ^b can be as defined in any one, two, three or all of (aa)-(dd). For example, R ^b can be as defined in (aa) and (bb) or combinations thereof.

The description “Cy is a saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring system” in the definition of R ^e is interpreted to include any of the rings defined above (eg, , Cy may be a ring element of coumarinyl or biotin which may be optionally substituted as defined herein.

  Details of one or more embodiments are given below. Other features and advantages of the embodiments disclosed herein will be apparent from the description and the claims.

It is a pulse chase analysis of BrdU labeling that identifies the intensity and timing of cell death after birth of new neurons in the dentate gyrus. Twelve-week-old wild-type male C57 / B6 mice were individually housed without turning and using a car, and BrdU (50 mg / kg, ip) was injected on day 0. Nerve progenitor cell proliferation in the dentate gyrus (DG) subgranular zone (SGZ) and granule layer (GL), followed by day 1, day 5, day 10, day 15, day 20 and On the 25th day, follow-up was performed by immunohistochemistry for BrdU. Four mice were evaluated at each time point, and 25-30 adjacent coronal sections from each mouse via the hippocampus (upper cone lobe and lower cone lobe joined at the apical region, and the dentate gyrus was connected to the corpus callosum (Proceed to the rear side from the point oriented horizontally downward). On days 1 and 5, nearly 100% BrdU positive cells in DG were localized to SGZ. The total number of cells decreased by about 40% between days 1-5, following the appearance of apoptotic cell bodies in SGZ. By day 10, some of the BrdU positive cells had migrated to GL without a significant change in the total number of BrdU positive cells in the DG. By day 15, BrdU positive cells in GL remained constant, whereas BrdU positive cells in SGZ decreased, somewhat out of SGZ and moved to GL between days 10-15 This suggests that some cells have undergone apoptosis. This trend continued during days 20-25. These results show that daily injections of BrdU with one week of continuous molecular infusion, a period in which 40% of the neoplastic cells in the SGZ normally die, detect compounds that promote the growth or survival of the dentate gyrus neoplastic cells. Indicates that it will be possible.

Cannula and pump surgical placement did not affect hippocampal neurogenesis or neonatal neuron survival on the other side of the brain. Infusion over 7 days with a surgically implanted Alzet osmotic minipump (vehicle infusion, n = 5) of vehicle (artificial cerebrospinal fluid) was the same in treated mice (no surgery, n = 4) and no difference in hippocampal neural progenitor cell proliferation as assessed by BrdU incorporation normalized to dentate gyrus volume. However, when Alzet osmotic minipumps were loaded with fibroblast growth factor 2 (FGF-2; 10 mg / mL) (n = 5), hippocampal neural progenitor cell proliferation nearly doubled relative to the other two groups ( *, P <0.001, Student's t-test).

The ectopic incorporation of BrdU helped exclude the molecule from further consideration. As shown on the left side, immunohistochemical staining of BrdU in the hippocampus is usually limited to SGZ of the dentate gyrus. The in vivo neurogenic screen used was designed to detect small molecules that selectively stimulate BrdU incorporation into replicating cells in SGZ. Rarely, as shown on the right, there were compounds that showed nonspecific BrdU incorporation in ectopic regions such as CA3, CA1, cortex and striatum. Any molecule that showed ectopic uptake of BrdU was excluded from the study.

Screening 100 pools of 10 compounds identified 10 pools with the ability to promote neurogenesis. The total number of BrdU-labeled cells in the subdentate gyrus granule cell zone (SGZ) was determined based on fibroblast growth factor 2 (FGF-2; for mice injected with vehicle (artificial cerebrospinal fluid (aCSF) (n = 5)). (10 mg / mL) (n = 5) Almost doubled on day 7. Injection Each pool of 10 compounds was tested in 2 separate mice for the ability to promote neurogenesis at a concentration of 10 μM of each compound for 7 days. , 14, 18, 19, 41, 53, 54, 61, 69 and 70 showed stimulation of neural progenitor cell proliferation equivalent to FGF-2 injection, most of the pool had no effect on hippocampal neural progenitor cell proliferation It was.

Re-evaluation of the positive pool confirmed a statistically significant difference in enhanced BrdU incorporation. After initial identification, pools 7, 14, 18, 19, 41, 53, 54, 61, 69 and 70 were re-evaluated in 2 mice each. The results shown are the average and SEM of all 4 mice that evaluated each compound. All pools significantly stimulated neural progenitor cell proliferation in the hippocampal dentate gyrus SGZ (*, P <0.001, Student's t test) compared to vehicle controls.

In order to identify individual pro-neurogenesis compounds, the pro-neurogenesis pool was degraded. Figure 6A-In vivo evaluation of 10 independent compounds comprising pool # 7, compound # 3 stimulates proliferation or survival of neural progenitor cells in SGZ, but not the remaining individual compounds in pool # 7 Prove that. This molecule is referred to herein interchangeably as “P7C3” or “Compound of Example 45”. Each compound was injected into each of two mice at two concentrations (100 μM (A and B) and 10 μM (C and D)). The compound of Example 45 showed proneurogenesis or neuroprotective activity at both concentrations. Below the graph is a typical result of BrdU incorporation in SGZ, which was significantly greater in animals injected with Pool # 7 or the compound of Example 45. Figure 6B-Molecular formula and molecular weight of individual neurogenesis-promoting compounds identified in in vivo screening. FIG. 6C—Refeeded compounds are evaluated at 10 μM concentration in 3 mice per compound, and the neurogenesis or neuroprotective effect on neural stem cells is not an artifact of the storage conditions of the UTSWMC chemical compound library It was confirmed. The re-fed compound was confirmed to be 99% pure by mass spectrometry and was shown to maintain pro-proliferative or neuroprotective properties in neural stem cells in vivo. All compounds significantly stimulated neural progenitor cell proliferation in hippocampal dentate gyrus SGZ (*, P <0.001, Student's t test) compared to vehicle controls.

The neurogenic potency of the compound of Example 45 administered orally was dose-related. In the top graph, the concentration of the compound of Example 45 in the brain tissue of mice administered with the compound by daily oral gavage for 7 consecutive days correlated with the dose of the compound of Example 45 administered. The lower graph shows that the proneurogenic or neuroprotective efficacy of the compound of Example 45 was approximately double that of the vehicle control at doses ranging from 5 to 40 mg / kg. When the dose of the compound of Example 45 was reduced, neurogenesis was correspondingly reduced until it became no greater than the vehicle control with a dose of the compound of less than 1.0 mg / kg. The results shown are average values obtained from analysis at each dose of 5 adult wild-type male mice.

Analysis of a molecule structurally similar to the compound of Example 45 (P7C3) revealed the site of the compound that could be chemically modified without loss of in vivo activity. In vivo SAR studies were performed using 37 analogs of the compound of Example 45 and evaluated in 4 or 5 adult C57 / B6 male mice, respectively. Some analogs showed activity comparable to the parent compound, while others showed significantly reduced activity or demonstrated a neurogenesis-promoting effect intermediate between the vehicle and the FGF control. This trial allowed the identification of the region of the parent compound that would be chemically modified without loss of activity. As an example, the compound of Example 62 maintained strong activity by replacing the aniline ring of the compound of Example 45 with anisidine. Using this derivative compound, a coumarin moiety was bonded to the N-phenyl ring to produce a fluorescent derivative.

The activity of the compound of Example 62 is enantiomer specific. FIG. 9A—The (+) and (−) enantiomers of the compound of Example 62 were prepared. FIG. 9B—Evaluation of the enantiomers of the compound of Example 62 showed that the in vivo neurogenesis or neuroprotective efficacy was completely retained in the (+) enantiomer in a dose-dependent manner (−) Enantiomers showed decreased activity. Each enantiomer was evaluated in 3 month old adult wild type male C57 / B6 mice at 3-5 doses.

The compound of Example 45 enhanced the survival of new neurons in the dentate gyrus. FIG. 10A— Immunohistochemical staining of doublecortin (DCX), an antigen that is specifically and transiently expressed in proliferating hippocampal neural progenitor cells when irreversibly restricted to neuronal differentiation, is media only The compound of Example 45 (20 mg / kg) was substantially increased in newborn neurons in mice administered daily by gavage for 30 days, compared to that seen in mice receiving These results were representative of 10 sections from 5 mice in each group, indicating that the compound of Example 45 specifically promotes hippocampal neurogenesis. FIG. 10B—The compound of Example 45 enhances hippocampal neurogenesis by promoting the survival of neoplastic neurons. Three month old wild type C57 / B6 male mice are exposed to orally delivered Example 45 compound or vehicle for 30 days (n = 5 animals / group) and administered a single pulse of BrdU by IP injection (150 mg / kg). And were sacrificed after 1 hour, 1 day, 5 days or 30 days for immunohistochemical detection of BrdU incorporation into cells localized in the granular cell sublayer of the dentate gyrus. Although no significant difference was observed at 1 hour or 1 day, BrdU ⁺ cells tended to increase in the compound-treated group of Example 45 on the first day. Usually, at day 5 when 40% of newborn neurons die, animals receiving the compound of Example 45 were statistically significant (*, P <0.001, Student t) compared to vehicle-only control group. Assay) showed a 25% increase in BrdU ⁺ cells. This difference between groups spreads with time, with mice receiving daily oral administration of the compound of Example 45 for 30 days starting at 24 hours after BrdU pulse administration, BrdU ⁺ in the dentate gyrus compared to vehicle-only control. The amount of cells increased 5-fold. In this long-term study, BrdU ⁺ cells were found in both SGZ and granule layer of the dentate gyrus.

Quantification of short-term (1-hour pulse) BrdU incorporation and cleaved caspase 3 (CCSP3) formation in the dentate gyrus shows that NPAS3-deficient mice have the same growth rate of nascent cells as wild-type littermates (BrdU) However, the level of programmed cell death (CCSP3) was shown to be approximately double (*, P <0.01, Student's t-test). Three 6-week-old male mice (NPAS3-deficient or wild type littermates) in each group were evaluated.

Granule cell neurons in the dentate gyrus of NPAS3-deficient mice showed morphological defects in dendritic branching and spine density. FIG. 12A-Golgicox staining of dentate gyrus shows that dendritic branches of dentate gyrus granule cell neurons of npas 3 ^{− / −} mice are substantially less developed than wild-type littermates. The results shown are representative of 15 sections from 5 12-14 week old adult male mice of each genotype. FIG. 12B—In addition to the apparently reduced dendritic length and branching, the spinal density of the granular neurons in the dentate gyrus of npas 3 ^{− / −} mice was significantly reduced compared to wild-type littermates ( *, P <0.00011, Student's t test). These genotype-specific differences were not shown in neurons in the hippocampal CA1 region.

In hippocampal slice specimens from npas3 ^{− / −} mice, synaptic transmission is observed both in the outer molecular layer of the dentate gyrus (FIG. 13A) and in the CA1 region of the hippocampus (FIG. 13B) compared to hippocampal slices from wild-type mice. Increased in Long-term treatment with the compound of Example 45 normalized the synaptic response in the dentate gyrus, but not in the CA1 region of npas 3 ^{− / −} mice. Long-term treatment with the compound of Example 45 did not affect the wild-type response. Data are shown as mean ± SEM. Each group consists of 1 or 2 slices from each of 5 mice.

The compound of Example 45 has a proneurogenic or neuroprotective effect in the dentate gyrus of NPAS3-deficient animals. Six 12-week-old npas 3 ^{− / −} mice were orally administered vehicle or the compound of Example 45 (20 mg / kg / day) for 12 days, and BrdU (50 mg / kg) was also injected every day. At the end of day 12, mice were sacrificed and tissues were stained with BrdU and doublecortin (DCX). BrdU staining showed that the compound of Example 45 increased the neurogenesis intensity of npas3 ^{− / −} mice approximately 4-fold as indicated by the graph (*, P <0.001, Student t-test). ). DCX staining shows that the compound of Example 45 also promotes much broader process formation in the differentiated neurons of the adult dentate gyrus in npas3 ^{− / −} mice.

Golgicox staining of neurons in the dentate gyrus shows that long-term daily treatment daily treatment with the compound of Example 45 (20 mg / kg / day) in npas 3 ^{− / −} mice enhances dendritic branching. A high-power photomicrograph is shown at the top, and a low-power photomicrograph showing the entire dentate gyrus is shown below.

Of hippocampal subregions from one mouse of npas3 ^{− / −} and wild type littermates treated daily from fetal day 14 to 3 months of age with compound of Example 45 (20 mg / kg / day) or vehicle For the measurement of the thickness, the compound of Example 45 selects the thickness of the dentate gyrus granular cell layer to a level approaching that of the wild type without affecting the thickness of the cone cell layer in the CA1 region or CA3 region. Increase (*, P <0.01, Student's t-test).

Immunohistochemical detection of cleaved caspase 3 (CCSP3), a marker of apoptosis, showed an increase in the level of programmed cell death in the dentate gyrus of NPAS3-deficient animals. Apoptosis in NPAS3-deficient animals was blocked by treatment with the compound of Example 45 (20 mg / kg / day, p.o., 12 days), whereas similar treatment with vehicle alone had no effect. The images shown are representative of 10-12 sections evaluated per animal with 3-5 8 week old male NPAS3-deficient mice per group.

The compound of Example 45 acts mechanistically in mitochondria. FIG. 18A—The compound of Example 45 is calcium ionophore A23187 in a dose-dependent manner as judged by fluorescence imaging of TMRM dye, a cell penetrating, cationic red-orange fluorescent dye that is readily captured by intact mitochondria. Protected the mitochondrial membrane potential after exposure to. FIG. 18B—The protective effect of the compound of Example 62 was enantiomer specific, with the (+) enantiomer retaining activity much longer than the (−) enantiomer.

The compound of example 45 compared to a known agent. The compound of Example 45 and the antihistamine dimebon (FIG. 19A) enhanced hippocampal neurogenesis (FIG. 19B) and protected mitochondria from lysis following toxic exposure to the calcium ionophore A23187 (FIG. 19C). In the neurogenesis in vivo assay, the compound of Example 45 had a higher upper limit of effect than the antihistamine dimebon. In all three assays, the compound of Example 45 acted with greater relative potency than the antihistamine dimebon.

Effect of the compound of Example 45 in aged rats. FIG. 20A—The compound of Example 45 (20 mg / kg / day, ip) and BrdU (50 mg / kg, ip) were administered to 12-18 month old Fisher 344 rats for 7 days (n = Each group 4). P7C3 enhanced neural progenitor cell proliferation about 5-fold compared to vehicle (* p <0.001, Student's t-test). DCX staining showed P7C3 neuronal differentiation and dendritic branch-specific promotion. These photomicrographs were taken at the same magnification. Scale bar = 50 mm. Data are expressed as mean ± SEM. Delay time to finding a hidden platform in the Morris water maze task (FIG. 20B) and old rats treated with P7C3 or vehicle both before treatment and 2 months after treatment (FIG. 20C) Swimming speed and locomotor activity (FIG. 20D) was not different between groups. Data are expressed as mean ± SEM. (FIG. 20E) Quantified dietary dose (upper panel) and fasting blood glucose levels in aged rats were not different depending on whether the rats were administered P7C3 or vehicle. Data are expressed as mean ± SEM.

The compound of Example 45 promotes hippocampal neurogenesis in terminally aged rats, reduces cognitive decline, and prevents weight loss. (FIG. 21A) Before treatment, both groups (n = each group 23) had the same frequency of passing through the target platform. After 2 months of treatment, however, the compound treated rats of Example 45 had a statistically significant increase in passage through the target platform area relative to vehicle treated rats. (FIG. 21B) The compound-treated rats of Example 45 significantly enhanced hippocampal neurogenesis as assessed by BrdU incorporation compared to vehicle-treated rats. Much more of the BrdU-labeled cells have been shown to migrate to the granule layer of the compound-treated rats of Example 45 compared to vehicle-treated animals, and into the dentate gyrus as appropriately wired neurons Consistent with its functional uptake. The scale bar represents 50 mM. (FIG. 21C) Compared to vehicle-treated animals, the compound-treated rat of Example 45 has a significantly lower number of cleaved caspase 3-positive cells in the dentate gyrus, indicating that P7C3 can inhibit apoptosis in the aged rat brain. The scale bar represents 50 mM. (FIG. 21D) Compared to vehicle-treated animals, the compound-treated rats of Example 45 were observed to maintain a stable body weight in response to end-stage aging. In all graphs, data are expressed as mean ± SEM.

The compound of Example 45 maintains mitochondrial membrane potential in parallel with neurogenic promoting activity. U2OS cells were loaded with tetramethylrhodamine methyl ester (TMRM) dye and exposed to calcium ionophore A23187 in the presence or absence of the test compound. The compound of Example 45 (FIG. 22A) maintains mitochondrial membrane potential in a dose-dependent manner after exposure to calcium ionophore A23187. The protective effect of P7C3 was enantiomer specific. The (R) enantiomer of other compounds (FIG. 22B) blocked dye release at concentrations as low as 1 nM, while the (S) enantiomer (FIG. 22C) did not block dye release at the highest drug dose tested (100 nM). . The neurogenic promoting compound P7C3A20 (FIG. 22D) shows pigment release protection at all doses tested, and compounds with low neurogenic promoting activity (FIGS. 22E and 22F) are mitochondria at all tested doses. The effect on membrane potential protection was low. Each compound was evaluated three times with comparable results.

The compound of Example 45 protects the mitochondrial membrane potential of cultured primary cortical neurons. Tetramethylrhodamine methyl ester (TMRM) dye was added to cortical neurons cultured from rats on fetal day 14 after maturation for 6 days. The upper panel (calcium-free ionophore) showed that this dye alone had no effect on neuronal health. The remaining panel is from cells exposed to calcium ionophore A23187 at 0. The vehicle alone rapidly lost cortical neuronal mitochondrial membrane potential after ionophore exposure. Increasing the compound of Example 45 (FIG. 23A) protected the mitochondrial membrane potential after calcium ionophore A23187 exposure in a dose-dependent manner, with complete protection achieved at 1 mM. The low activity compound (FIG. 23B) was less effective at protecting mitochondrial membrane potential at all concentrations tested. The results shown are representative examples of 10 regions analyzed in 2 experiments for all conditions.

The compound of Example 45 (P7C3) provides a therapeutic effect in an amyotrophic lateral sclerosis (ALS) animal model. Female G93A SOD1 mice (n = 30 each group, all mouse siblings matched across all treatment groups) were treated with vehicle or P7C3 (10 mg / kg ip twice a day) starting at 40 days of age. did. P7C3-treated mice showed significant disease progression delay, as evidenced by a late age of 10% below maximum body weight (FIG. 24A). P7C3-treated mice also reached a neurological severity score of 2 at a later age than vehicle-treated mice (FIG. 24B), similarly indicating that P7C3-treated delays disease progression. This score is determined as follows: '0' = When the tail of the test mouse is lifted, the hind limbs are fully extended away from the lateral midline, maintained for 2 seconds, lifted 2-3 times; '1' = tail Collapse or partial collapse (weakening) or hindlimb tremor toward the median midline while hanging on the heel; '2' = at least two rounds of feet or cage bottom / table while walking 12 inches Dragging any part of the limb along with '3' = strong paralysis or minimal movement of joints, no leg used to move forward; and '4' = mouse within 30 seconds from either side Cannot return to the correct position. As disease further progressed, vehicle-treated mice showed an expected decrease in retention time with accelerating rotarod, showing the retention time averaged over 4 trials (FIG. 24C, white bars). However, P7C3-treated mice showed a consistent improvement trend of the challenge after the onset of disease (FIG. 24C, black bars), with statistically significant improvements on days 131, 138 and 145 (* , P <0.001, Student's t-test). All graph data shown above are standard ± SEM with statistical analysis performed using Student's t-test. As another indicator of disease progression, pacing was evaluated. FIG. 24D is footprint data for two sisters (VEH and P7C3) on day 92 (before disease onset) and day 118 (after disease onset). Immerse the front legs in red ink and the rear legs in black ink. VEH-treated mice showed a decrease in pace as expected on day 188 after disease onset, and their P7C3-treated sisters maintained normal pace on day 118. All analyzes were performed blinded to treatment groups.

The compound of Example 6a (P7C3A20) provides a therapeutic effect in an animal model of Parkinson's disease. Mice were treated with MPTP (30 mg / kg i.p.) or vehicle alone for 5 days and analyzed 21 days later for immunohistochemical staining for tyrosine hydroxylase staining (TH) (FIG. 25A). Treatment with MPTP and vehicle (n = 6) reduced the number of substantia nigra TH ⁺ neurons (FIG. 25B) by approximately 50% compared to mice that received vehicle alone (n = 8). (*, P = 0.0002, Student's t-test). Substantia nigra MPTP-mediated cell death was significantly attenuated in mice that further received P7C3A20 (10 mg / kg ip twice a day) (n = 5) (**, p = 0.005). All mice 'substantia nigra TH ⁺ neurons were counted by two investigators using the Image J software, blinded to treatment groups, and the results averaged.

The compound of Example 45 (P7C3) provides a therapeutic effect in an animal model of Huntington's disease. Forty female R6 / 2 mice were included in each of the VEH (vehicle) and P7C3 (10 mg / kg P7C3 ip twice daily) groups and treatment was initiated at 6 weeks of age. (FIG. 26A) Treatment with P7C3 statistically significantly extended the lifespan of R6 / 2 mice (p <0.001, Gehan Breathlow Wilcoxon test). (FIG. 26B) At 14 weeks of age, the objective index of general condition of P7C3-treated R6 / 2 mice also improved significantly (low score correlates with good general condition, * p <0.0001, Student's t-test ). All measurements were performed blind to genotype and treatment group.

The compound of Example 45 (P7C3) enhances hypothalamic neurogenesis. Administration of P7C3 for 1 month enhances the proliferation of hypothalamic neural progenitor cells (shown in red) in the arcuate nucleus (ARC), hypothalamic dorsolateral (DMH) and hypothalamic ventral medulla (VMH). The photomicrographs shown are representative of staining every 3 sections in the hypothalamus of 4-6 mice in each treatment group.

Neuroprotective efficacy of P7C3, P7C3A20 and Dimebon for newborn neurons in the adult hippocampus. Test compounds were evaluated by a dose response assay for the ability to block normal apoptotic cell death of neoplastic progenitor cells in the adult dentate gyrus. P7C3A20 shows the ceiling of maximum efficacy and effect, and Dimebon is the lowest. P7C3 is between both measurements. Six animals were tested per group. The dose was expressed as total mg / day and the compound was administered intraperitoneally in two divided doses per day. Data are expressed as mean ± SEM. P7C3 and P7C3A20 values were compared to vehicle (VEH) and Dimebon values were compared to saline (SAL).

Neuroprotective efficacy of P7C3 and P7C3A20 from MPTP toxicity against SNc dopaminergic neurons. FIG. 29A—Test compounds were evaluated by a dose response assay for their ability to block MPTP neurotoxicity in SNc. P7C3A20 showed greater potency and CoE than P7C3 and Dimebon showed no protective efficacy. Fifteen animals were tested per group. The VEH group included 30 animals, 15 animals receiving P7C3A20 / P7C3 vehicle and 15 animals receiving Dimebon vehicle (saline). These two control groups were not different in the number of viable TH ⁺ neurons and were therefore integrated. A representative immunohistochemical diagram of SNc TH staining is shown at the bottom of the graph. The dose was expressed as total mg / day and was administered intraperitoneally in divided doses twice a day. Data are expressed as mean ± SEM. FIG. 29B-Representative diagram of TH staining from the striatum of individual animals shows that after 3 weeks of daily administration of MPTP for 5 days, P7C3 and P7C3A20 prevent loss of dopaminergic axon ends. P7C3A20 did so with great effect and Dimebon did not protect. The striatum section was obtained from the same mice used in FIG. 2, and the compound-treated group was obtained from mice administered a dose of 20 mg / kg / day.

Brain and blood levels of P7C3, P7C3A20 and Dimebon 3 weeks after MPTP administration. The relative neuroprotective activity within the test compound correlates with the brain concentration of the compound, and the brain concentration correlates with the blood concentration of the test compound. Compared to P7C3, only about 1/10 of the amount of P7C3A20 accumulated in the brain. Dimebon's brain accumulation was comparable to P7C3. Data are expressed as mean ± SEM. Three animals per group were tested.

Neuroprotective efficacy of P7C3 and P7C3A20 against MPP ⁺ toxicity in dopaminergic neurons in nematodes. Parasites were treated with 5 mM MPP ⁺ for 40 hours and preincubated with various concentrations of test compound or vehicle for 30 minutes. VEH animals not exposed to MPP ⁺ showed normal GFP expression in dopaminergic neurons (black arrows). In contrast, GFP expression was lost after 40 hours of MPP ⁺ exposure (white arrows). Both P7C3A20 and P7C3 protected dopaminergic neurons from MPP ⁺ toxicity in a dose-dependent manner, with P7C3A20 showing a great potency and effect ceiling. Twenty parasites were analyzed per group and each group was performed three times. Data are expressed as mean ± SEM.

Protective efficacy of P7C3 and P7C3A20 against MPP ⁺ induced mobility in nematodes. The top panel shows a parasite with a green dot on the head. The second row of the panel shows the path of each parasite for 10 seconds and was determined by tracking the green dots. The chase was visualized to start in blue and turned white by the completion of 10 seconds. The green dot was used to determine locomotion, and the parasite head was defined as 10 seconds travel distance divided by body length. The scale bar indicates 70 μM. Quantitative analysis of locomotor activity showed that the value for the untreated VEH control was 16.2 ± 0.49 (n = 30). When parasites were treated with MPP ⁺ , locomotor activity was reduced by more than 50% (7.2 ± 0.68; n = 31, p <0.0001). 10 μM P7C3A20 protected migration to approximately 80% of normal (12.8 ± 0.81; n = 34, * p <0.01), 10 μM P7C3 protected almost 60% (9.6 ± 0.0. 72 mi; n = 28, * p <0.05). 10 μM Dimebon did not protect (7.7 ± 1.0; n = 30). Experiments were performed 3 times and data are expressed as mean ± SEM.

The effect of the novel P7C3 analog in the in vivo hippocampal neurogenesis assay correlates with activity in the in vivo MPTP neuroprotection assay. FIG. 33A—P7C3-S7 differs from P7C3 in that aniline NH is replaced with a sulfide linker. P7C3-S8 differs from P7C3 in that the aniline phenyl ring is replaced with a pyrimidine. P7C3-S25 differs from P7C3 in that the aniline moiety is replaced with dimethylpyrazole. P7C3-S40 and S41 differ in that P7C3 and aniline NH are replaced with oxygen linkers, which are single R and S enantiomers, respectively. P7C3-S54 differs from P7C3 mainly by the addition of a methyl group to the central carbon of the propyl linker and the addition of an OMe group to aniline. P7C3-S165 differs from P7C3 in that the aniline and carbinol fragments are replaced with carboxylic acids. P7C3-S184 differs from P7C3 in that the bromine of carbazole is replaced with chlorine and aniline is replaced with naphthylamine. Figure 33B-Novel analogues of P7C3 were subjected to in vivo testing in hippocampal neurogenesis (4 mice each) and MPTP protection (10 mice each) assay. The results correlate the activity of these two assays so that in vivo neurogenesis screening is useful as a predictor of neuroprotective efficacy of dopaminergic neurons in the substantia nigra of the P7C3 analog. LC / MS / MS assays of blood and brain concentrations of all compounds administered at once to C57BL / 6 mice at 10 mg / kg (ip) show that after intraperitoneal administration they cross the blood brain barrier. Indicates.

P7C3A20 and P7C3 block motor neuron death in the spinal cord when administered to G93A-SOD1 mutant mice at disease onset. Treatment of G93A-SOD1 mutant mice with P7C3A20, P7C3 or Dimebon or appropriate vehicle at 20 mg / kg / day began on day 80. Five mice from each group were sacrificed on days 90, 100, 110 and 120. The number of spinal motor neurons per millimeter of lumbar spinal cord was determined by immunohistochemical staining for ChAT and quantified with NIH Image J software. All images were analyzed blind to treatment group. The spinal motor neurons of G93A-SOD1 mutant mice died over time as expected. Spinal motor neuron death was blocked by administration of P7C3A20. P7C3 protection was moderate and Dimebon had no neuroprotective efficacy. (FIG. 34A) Representative staining of day 110 ChAT of one anterior horn of each of 5 mice from each treatment group. FIG. 34B is a graph display.

P7C3A20 retains the ability in the accelerated rotarod test when administered to G93A-SOD1 mutant mice at disease onset. Treatment of G93A-SOD1 mutant mice with P7C3A20, P7C3 or Dimebon or appropriate vehicle 20 mg / kg / day started on day 80, with 20 mice in each group. All compounds were administered in divided doses at 20 mg / kg / day ip. Each compound-treated mouse had homosexual siblings that received vehicle. Only sibling pairs were analyzed at each time point. By 16 weeks, 13 compound-vehicle pairs remained in each group. All vehicle-treated mice showed a decrease in retention time on the accelerating rotarod over time, as expected, and the P7C3 and Dimebon groups did not differ in retention time compared to the vehicle group. Mice treated with P7C3A20 showed significantly longer retention times with rotarod at weeks 13, 14, 15, and 16. All tests and analyzes were performed blind to treatment groups.

P7C3A20 kept pace when administered to G93A-SOD1 mutant mice at disease onset. FIG. 36A—schematic diagram shows the parameters used to measure the pace. Forelimb and hindlimb stride lengths were collected as a straight line from the hindlimb footprint to the next footprint. The back-front distance was collected as a straight line from the back footprint to the corresponding front footprint. Twenty measurements (10 on each side) of each parameter were measured per mouse and 20 mice per group were evaluated at 90 and 118 days. All measurements were performed blinded to treatment groups and Student's t-test was used for statistical comparison between treatment groups and their matched vehicle groups. FIG. 36B-On day 90, there was no difference in hindlimb stride, forelimb stride, and back-front distance between any groups. On day 118, all mice in the vehicle group and the P7C3 treated group and the Dimebon treated group showed significant differences in these measurements reflecting disease progression. The hindlimb and forelimb strides were maintained at near normal levels on day 118 in P7C3A20 treated mice. On day 132, P7C3 and Dimebon treated mice were too severe to participate in this task. At this point, P7C3A20 treated mice continued to show normal hindlimb and forelimb stride levels.

Plasma, brain and spinal cord concentrations of P7C3A20, P7C3 and Dimebon. Five mice for each compound group were treated with 20 mg / kg / day of the compound for 21 days starting on day 85. Blood, brain and spinal cord were collected 6 hours after the last injection and compound concentrations were measured by LC / MS / MS. Concentrations are expressed as mean ± SEM.

DETAILED DESCRIPTION Embodiments disclosed herein generally involve stimulating neurogenesis (eg, postnatal neurogenesis, eg, postnatal hippocampus and / or hypothalamic neurogenesis) and / or inhibiting neuronal cell death. It relates to promoting the survival of existing neurons.

In one aspect of the compounds, the embodiments disclosed herein are represented by the general formula (I)
Characterized by a compound having
Here and throughout the specification, R ¹ , R ² , R ³ , R ⁴ , R, R ′, L ¹ , L ² , A and Z may be as defined herein.

  Of course, for clarity, certain features of the embodiments disclosed herein that are described in the context of another embodiment can also be combined in one embodiment. Conversely, for simplicity, the various features of the embodiments disclosed herein that are described in the context of one embodiment can be provided separately or in any appropriate subcombination.

Therefore, for ease of explanation, when a variable (eg, R ¹ ) is defined herein as “as defined herein” (such as), that particular variable is It is also understood that it is defined by the broadest general definition given first and the subgroups and specific definitions of any general definition given elsewhere in this specification.

Variable groups R ¹ , R ² , R ³ , R ⁴
In some embodiments, one or more of R ¹ , R ² , R ^3, and R ⁴ (eg, one, eg, R ³ ) is halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thio. _alkoxy, C 1 -C _{6 haloalkoxy,} C 1 -C _{6 thiohaloalkoxy,} C 1 -C _{6 alkyl,} C 1 -C ₆ haloalkyl, _{cyano, -NH 2, -NH (C 1} -C 6 alkyl), Selected from N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro, the other is hydrogen.

In some embodiments, one or more of R ¹ , R ² , R ³ and R ⁴ (eg, one, eg, R ³ ) is halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C _{6 alkyl,} C 1 -C ₆ haloalkyl, are cyano and nitro selected, the other is hydrogen.

In some embodiments, one or more of R ¹ , R ² , R ^3, and R ⁴ (eg, one, eg, R ³ ) is selected from halo, C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl, while Is hydrogen.

In some embodiments, one or more of R ¹ , R ² , R ^3, and R ⁴ (eg, one, eg, R ³ ) is halo and C ₁ -C ₆ alkyl selected and the other is hydrogen.

In some embodiments, one or more (eg, one, eg, R ³ ) of R ¹ , R ² , R ^3, and R ⁴ is halo (eg, bromo or chloro) and C ₁ -C ₆ alkyl, Is hydrogen.

In some embodiments, one or more of R ¹ , R ² , R ^3, and R ⁴ (eg, one, eg, R ³ ) is bromo and the other is hydrogen.

In some embodiments, R ³ is halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C _{6. alkyl,} C 1 -C ₆ haloalkyl, _{cyano, -NH 2, -NH (C 1} -C 6 alkyl), N _(C 1 -C _{6 alkyl) 2, -NHC (O) (} C 1 -C 6 alkyl) And each of R ¹ , R ² and R ⁴ may be as defined herein.

In some embodiments, R ³ is halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C _{6. alkyl,} C 1 -C ₆ haloalkyl, _{cyano, -NH 2, -NH (C 1} -C 6 alkyl), N _(C 1 -C _{6 alkyl) 2, -NHC (O) (} C 1 -C 6 alkyl) And R ¹ , R ² and R ⁴ are each hydrogen.

In some embodiments, R ³ is selected from halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cyano and nitro, and R ¹ , R ² And each of R ⁴ can be as defined herein.

In some embodiments, R ³ is selected from halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cyano and nitro, and R ¹ , R ² And each of R ⁴ is hydrogen.

In certain embodiments, R ³ is selected from halo, C ₁ -C ₆ alkyl, and C ₁ -C ₆ haloalkyl, wherein each of R ¹ , R ^2, and R ⁴ can be as defined herein.

In some embodiments, R ³ is selected from halo, C ₁ -C ₆ alkyl, and C ₁ -C ₆ haloalkyl, and each of R ¹ , R ^2, and R ⁴ is hydrogen.

In certain embodiments, R ³ is selected from halo and C ₁ -C ₆ alkyl, and each of R ¹ , R ^2, and R ⁴ can be as defined herein.

In certain embodiments, R ³ is selected from halo and C ₁ -C ₆ alkyl, and each of R ¹ , R ^2, and R ⁴ is hydrogen.

In certain embodiments, R ³ is halo (eg, bromo or chloro) and each of R ¹ , R ^2, and R ⁴ can be as defined herein.

In certain embodiments, R ³ is halo (eg, bromo or chloro) and each of R ¹ , R ^2, and R ⁴ is hydrogen.

In certain embodiments, R ³ is bromo and each of R ¹ , R ^2, and R ⁴ can be as defined herein.

In some embodiments, R ³ is bromo and each of R ¹ , R ^2, and R ⁴ is hydrogen.

In some ^embodiments, each of R ^1, R 2, ^{R 3} and ^{R 4} are independently selected from hydrogen, halo and _C 1 -C ₆ alkyl.

In some embodiments, each of R ¹ , R ² , R ³ and R ⁴ is independently selected from hydrogen and halo (eg, bromo or chloro).

In certain embodiments, each of R ¹ , R ² , R ³ and R ⁴ is hydrogen.

In certain embodiments, when any one or more of R ¹ , R ² , R ^3, and R ⁴ can be a substituent other than hydrogen, the substituent or each of the substituents is other than C ₁ -C ₆ alkyl. (Eg, other than C ₁ -C ₃ alkyl, eg, other than CH ₃ ).

Variable group L ¹
In some embodiments, L ¹ is C ₁ -C ₃ (eg, C ₁ -C ₂ ) linear alkylene, optionally substituted with 1 to 2 independently selected R ^c. Good.

In some embodiments, L ¹ is methylene (ie, —CH ₂ —). In other embodiments, L ¹ is methylene substituted with 1 or 2 (eg, 1) independently selected R ^c . In some embodiments, R ^c is C ₁ -C ₆ alkyl (eg, C ₁ -C ₃ alkyl, eg, CH ₃ ).

In some embodiments, L ¹ is ethylene (ie, —CH ₂ CH ₂ —). In another embodiment, L ¹ is ethylene substituted with 1 or 2 (eg 1) independently selected R ^c . In some embodiments, R ^c is C ₁ -C ₆ alkyl (eg, C ₁ -C ₃ alkyl, eg, CH ₃ ).

Variable group L ²
In some embodiments, L ² is C ₁ -C ₃ (eg, C ₁ -C ₂ ) linear alkylene, optionally substituted with 1 to 2 independently selected R ^c. Good.

In some embodiments, L ² is methylene (ie, —CH ₂ —). In other embodiments, L ¹ is methylene substituted with 1 or 2 (eg, 1) independently selected R ^c . In some embodiments, R ^c is C ₁ -C ₆ alkyl (eg, C ₁ -C ₃ alkyl, eg, CH ₃ ). In some embodiments, R ^c is C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy or C ₁ -C ₆ thiohaloalkoxy. For example, R ^c can be C ₁ -C ₆ (eg, C ₁ -C ₃ ) thioalkoxy, such as —SCH ₃ .

In some embodiments, L ² is ethylene (ie, —CH ₂ CH ₂ —). In other embodiments, L ² is ethylene substituted with 1 or 2 (eg, 1) independently selected R ^c . For example, the carbon close to Z in the formula (I) of ethylene can be substituted as described in the previous paragraph.

In some embodiments, L ² is a bond that directly links A of formula (I) and Z of formula (I).

Non-limiting combinations of the variables L ¹ and L ^{2 In} certain embodiments, each of L ¹ and L ² is independently C ₁ -C ₃ alkylene, optionally having 1 to 2 independently It may be substituted with a selected R ^c .

In some embodiments, each of L ¹ and L ² is CH ₂ .

In some embodiments, one of L ¹ and L ² (eg, L ¹ ) is CH ₂ and the other (eg, L ² ) is 1 or 2 (eg, 1) with independently selected R ^c. ) Substituted methylene, where R ^c can be as defined herein.

In certain embodiments, each of L ¹ and L ² is methylene substituted with 1 or 2 (eg, 1) independently selected R ^c , wherein R ^c is as defined herein. It may be as defined in.

In some embodiments, L ¹ is C ₁ -C ₃ (eg, C ₁ -C ₂ ) linear alkylene, optionally substituted with 1 to 2 independently selected R ^c. Well and L ² is a bond directly linking A of formula (I) and Z of formula (I). In some embodiments, L ¹ is, for example, methylene (ie, —CH ₂ —) or independently selected R ^c (eg, C ₁ -C ₆ alkyl, eg, C ₁ -C ₃ alkyl, eg, CH ₃ ) may be methylene substituted one or two (eg one).

Variable group A
[I] In some embodiments, A is
(i) CR ^A1 R ^A2 wherein each of R ^A1 and R ^A2 is independently selected from hydrogen, halo, C ₁ -C ₃ alkyl or OR ⁹ ; or
(ii) C = O; or
(iv) a heterocycloalkylene containing 3 to 5 ring atoms, wherein 1 to 2 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; The heterocycloalkylene is (a) substituted with 1 oxo; and (b) optionally further substituted with 1 to 4 independently selected R ^a )
It is.

In some embodiments, A is CR ^A1 R ^A2 , wherein each of R ^A1 and R ^A2 is independently hydrogen, halo, C ₁ -C ₃ alkyl or OR ⁹ (eg, hydrogen, halo or OR ^9).

In certain embodiments, A can be CR ^A1 R ^A2 , where each of R ^A1 and R ^A2 is independently hydrogen, halo, or C ₁ -C ₃ alkyl.

In certain embodiments, A can be CR ^A1 R ^A2 , wherein one of R ^A1 and R ^A2 is halo (eg, fluoro) and the other of R ^A1 and R ^A2 is independently hydrogen, halo, or C ₁ -C ₃ alkyl (eg, hydrogen).

In some embodiments, one of R ^A1 and R ^A2 is hydrogen. In certain embodiments, one of R ^A1 and R ^A2 is halo or OR ⁹ and the other is hydrogen.

In certain embodiments, one of R ^A1 and R ^A2 can be OR ⁹ . In certain embodiments, the other of R ^A1 and R ^A2 can be as defined herein; for example, the other of R ^A1 and R ^A2 can be hydrogen or C ₁ -C ₃ alkyl. For example, one of R ^A1 and R ^A2 can be OR ⁹ and the other of R ^A1 and R ^A2 can be hydrogen. In some embodiments, R ⁹ can be hydrogen, or R ⁹ can be C ₁ -C ₃ alkyl (eg, CH ₃ ).

In certain embodiments, one of R ^A1 and R ^A2 can be halo. In certain embodiments, the other of R ^A1 and R ^A2 can be as defined herein; for example, the other of R ^A1 and R ^A2 can be hydrogen, C ₁ -C ₃ alkyl, or halo. For example, one of R ^A1 and R ^A2 can be halo (eg, fluoro) and the other of R ^A1 and R ^A2 can be hydrogen.

In certain embodiments, one of R ^A1 and R ^A2 is halo or OR ⁹ and the other is hydrogen.

For example, one of R ^A1 and R ^A2 can be OR ⁹ and the other can be hydrogen. In certain embodiments, R ⁹ can be hydrogen. R ⁹ may be C ₁ -C ₃ alkyl (eg, CH ₃ ).

As another example, one of R ^A1 and R ^A2 can be halo (eg, fluoro) and the other can be hydrogen.

In other embodiments, each of R ^A1 and R ^A2 is a substituent other than hydrogen.

For example, each of R ^A1 and R ^A2 can be halo (eg, fluoro).

As another example, one of R ^A1 and R ^A2 can be OR ⁹ (eg, where R ⁹ is hydrogen) and the other can be C ₁ -C ₃ alkyl (eg, CH ₃ ).

As yet another example, each of R ^A1 and R ^A2 can be C ₁ -C ₃ alkyl (eg, CH ₃ ).

In yet other embodiments, each of R ^A1 and R ^A2 is hydrogen.

  Embodiments can further include any one or more of the following characteristics.

When the carbon attached to R ^A1 and R ^A2 is substituted with 4 different substituents, the carbon attached to R ^A1 and R ^A2 can have the R configuration.

When the carbon attached to R ^A1 and R ^A2 is substituted with 4 different substituents, the carbon attached to R ^A1 and R ^A2 can have the S configuration.

[II] In some embodiments, A is C = O.

In [III] some embodiments, A is heterocycloalkylene containing 3-5 ring atoms, wherein 1-2 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), O, and S And the heterocycloalkylene is (a) substituted with 1 oxo (eg, 1 oxo on the ring carbon); and (b) optionally 1-4 independently. And may be further substituted with R ^a selected.

In some embodiments, A is a heterocycloalkylene containing 5 ring atoms, wherein 1 to 2 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S. And the heterocycloalkylene is (a) substituted with 1 oxo; and (b) optionally further substituted with 1 to 4 independently selected R ^a . For example, A is
It can be.

Non-limiting combinations of variables L ¹ , L ² and A In some embodiments, A is (i) CR ^A1 R ^A2 , wherein each of R ^A1 and R ^A2 is hydrogen, halo, C ₁ -C ₃ alkyl Or independently selected from OR ⁹ ; or (ii) C = O;
Each of L ¹ and L ² is independently C ₁ -C ₃ alkylene, which is optionally substituted with ₁ to 2 independently selected R ^c .

In some embodiments, A is CR ^A1 R ^A2 , wherein each of R ^A1 and R ^A2 is independently selected from hydrogen, halo, C ₁ -C ₃ alkyl, or OR ⁹ ;
Each of L ¹ and L ² is independently C ₁ -C ₃ alkylene, which is optionally substituted with ₁ to 2 independently selected R ^c .

Aspects can include one or more of the following characteristics.
Each of R ^A1 and R ^A2 can be as defined herein.
Each of L ¹ and L ² is CH ₂ .

One of L ¹ and L ² (eg, L ¹ ) is CH ₂ and the other (eg, L ² ) is substituted with 1 or 2 (eg, 1) independently selected R ^c Wherein R ^c can be as defined herein. For example: L ¹ may be CH ₂ ;
One of R ^A1 and R ^A2 is hydrogen;
· L ² is one or two (e.g. one) methylene substituted with ^{R c} a is independently selected (e.g., _C 1 -C ₆ such as CH _{3 (e.g.,} C 1 -C ₃ ) Alkyl; or C ₁ -C ₆ (eg, (C ₁ -C ₃ ) thioalkoxy such as —SCH ₃ ).

Each of L ¹ and L ² is methylene substituted with 1 or 2 (eg 1) independently selected R ^c , where R ^c is as defined herein. It can be. For example: • Each of R ^A1 and R ^A2 may be a substituent other than hydrogen (eg, one of which is CH ₃ ),
Each of L ¹ and L ² is methylene substituted with a C ₁ -C ₃ alkyl such as CH ₃ .

In some embodiments, A is a heterocycloalkylene containing 3-5 (eg, 5) ring atoms, wherein 1-2 of the ring atoms are N, NH, N (C ₁ -C ₃ alkyl), O and Independently selected from S; and the heterocycloalkylene is (a) substituted with 1 oxo; and (b) optionally further substituted with 1 to 4 independently selected R ^a. Can be;
L ¹ is a C ₁ -C ₃ (eg C ₁ -C ₂ ) linear alkylene, optionally substituted with 1 to 2 independently selected R ^c ,
L ² is a bond that directly connects A of formula (I) and Z of formula (I).

Variable group Z
[I] In some embodiments, Z is
(i) -NR ¹⁰ R ^11; or
^{(ii) -C (O) NR} 10 R 11; or
(iii) ^{-OR 12;} or
(iv) -S (O) _n R ¹³ where n is 0, 1 or 2; or
(v) heterocycloalkenyl including 5-6 ring atoms (wherein 1 to 3 ring atoms are _{N, NH, N (C 1} -C 6 _{alkyl), NHC (O) (C} 1 -C 6 alkyl ), O and S; and the heterocycloalkenyl may be optionally substituted with 1 to 4 independently selected R ^a );
(vi) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 independently selected R ^b ; or
(vii) a heteroaryl containing 5 to 14 ring atoms, wherein 1 to 6 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; (Heteroaryl may be optionally substituted with 1-4 independently selected R ^b )
It is.

  In certain embodiments, Z is as defined in (i), (iii), (iv), (v), (vi) or (vii) of the previous paragraph.

  In certain embodiments, Z is as defined in (i), (iii), (iv), (v) or (vii) of the previous paragraph.

  In certain embodiments, Z is as defined in (i), (iii), (v) or (vii) of the previous paragraph.

  In certain embodiments, Z is as defined in (i), (iii) or (iv) of the previous paragraph.

In some embodiments, Z is
(i) -NR ¹⁰ R ^11; or
(iii) ^{-OR 12;} or
(v) a heterocycloalkenyl including 5-6 ring atoms, wherein 1-3 is N, NH ring atoms, N _(C 1 -C _{6 alkyl), NC (O) (C} 1 -C ₆ alkyl), are independently selected from O and S; and said heterocycloalkenyl may optionally be substituted with R ^a chosen 1-4 independently.

In some embodiments, Z is (i) —NR ¹⁰ R ¹¹ ; or (iii) —OR ¹² .

In some embodiments, Z is (i) —NR ¹⁰ R ¹¹ ; or (iv) —S (O) _n R ¹³ , where n is 0, 1 or 2.

In some embodiments, Z is (iii) —OR ¹² ; or (iv) —S (O) _n R ¹³ , where n is 0, 1 or 2.

  In certain embodiments, Z does not include heterocyclyl (eg, nitrogen-containing heterocyclyl, such as piperazinyl or piperidinyl) as part of its structure (eg, as bonded to a fused ring or other ring).

In some embodiments, Z is other than heterocycloalkenyl containing 5-6 ring atoms, wherein 1-3 of the ring atoms are N, NH, N (C ₁ -C ₆ alkyl), NC (O) ( C ₁ -C ₆ alkyl), are independently selected from O and S; and said heterocycloalkenyl may optionally be substituted with R ^a chosen 1-4 independently.

In some embodiments, Z is other than heteroaryl containing 5-14 ring atoms, wherein 1-6 of the ring atoms are independent of N, NH, N (C ₁ -C ₃ alkyl), O and S. And the heteroaryl may be optionally substituted with 1-4 independently selected R ^b (eg other than pyridyl).

[II] In some embodiments, Z is —NR ¹⁰ R ¹¹ .

[A] In some embodiments, one of R ¹⁰ and R ¹¹ is hydrogen and the other of R ¹⁰ and R ¹¹ is a substituent other than hydrogen.

In some embodiments, one of R ¹⁰ and R ¹¹ is hydrogen or a substituent other than hydrogen, and the other of R ¹⁰ and R ¹¹ is a substituent other than hydrogen.

In some embodiments, each of R ¹⁰ and R ¹¹ is a substituent other than hydrogen.

In some embodiments, each of R ¹⁰ and R ¹¹ is hydrogen.

[B] In some embodiments, one of R ¹⁰ and R ¹¹ is the following (b), (c), (g)-(k) and (l)
(b) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ;
(c) 5 to 14 heteroaryl containing a ring atom (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl is optionally substituted with 1 to 4 R ^b );
(g) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a );
(h) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a );
(i) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a );
(j) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a );
(k) C ₃ -C ₈ cycloalkyl or C ₃ -C ₈ cycloalkenyl optionally substituted with 1 to 4 independently selected R ^a ; and
(l) C ₇ -C ₁₂ aralkyl (wherein the aryl moiety may be optionally substituted with 1 to 4 R ^b , independently selected)
Are independently selected from the substituents shown collectively, and the other of R ¹⁰ and R ¹¹ can be as defined herein.

In some ^{embodiments, R 10} and ^{R 11} is a _C 3 -C ₈ cycloalkyl or _C 3 -C ₈ cycloalkenyl must not, each of which is selected 1-4 independently optionally ^{R a} May be substituted.

In some embodiments, one of R ¹⁰ and R ¹¹ is independently selected from the substituents collectively set forth in (b), (c), (g)-(j) and (l) above, and R ¹⁰ and The other of R ¹¹ can be as defined herein.

In some embodiments, one of R ¹⁰ and R ¹¹ is independently selected from the substituents set forth collectively in (b), (c) and (g)-(j) above, and the other of R ¹⁰ and R ¹¹ May be as defined herein.

In some embodiments, one of R ¹⁰ and R ¹¹ is independently
(b) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ;
(c) heteroaryl containing 5 to 14 ring atoms, wherein 1 to 6 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; And the heteroaryl may optionally be substituted with 1 to 4 R ^b ;
Selected from
The other of R ¹⁰ and R ¹¹ can be as defined herein.

In some embodiments, one of R ¹⁰ and R ¹¹ is C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 (eg, 1 to 3, 1 to 2, or 1) R ^b ( For example, C ₆ ) and the other of R ¹⁰ and R ¹¹ can be as defined herein.

In certain embodiments, each R ^b is halo; or C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ thiohaloalkoxy; C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) optionally substituted with independently selected R ^e Independently selected from ₂ and —NHC (O) (C ₁ -C ₆ alkyl).

In certain embodiments, R ^b is each substituted with C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thioalkoxy; and optionally 1-3 independently selected R ^e . Independently selected from C ₁ -C ₆ thiohaloalkoxy. In certain embodiments, R ^b can further comprise halo.

In some embodiments, ^{R b} are each independently selected from _C 1 -C ₆ alkoxy and _C 1 -C ₆ haloalkoxy, substituted in each of which is selected 1-3 independently optionally ^{R e} May have been. In certain embodiments, R ^b can further comprise halo.

In certain embodiments, each R ^b is independently selected from C ₁ -C ₆ alkoxy, each of which is optionally substituted with 1 to 3 independently selected R ^e . In some embodiments, R ^b is C ₁ -C ₆ alkoxy (eg, OCH ₃ ). In certain embodiments, R ^b can further comprise halo.

In certain embodiments, one of R ¹⁰ and R ¹¹ is unsubstituted phenyl and the other of R ¹⁰ and R ¹¹ can be as defined herein.

In certain embodiments, one of R ¹⁰ and R ¹¹ can be phenyl substituted with one R ^b and the other of R ¹⁰ and R ¹¹ can be as defined herein. R ^b can be as defined herein (eg, R ^b can be C ₁ -C ₆ alkoxy, eg, OCH ₃ ). For example, one of R ¹⁰ and R ¹¹ can be 3-methoxyphenyl. In certain embodiments, R ^b can further comprise halo.

[C] In one embodiment, when one of R ¹⁰ and R ¹¹ is independently selected from the substituents collectively shown in (b), (c), (g) to (k) and (l) above , R ¹⁰ and R ¹¹ are
(a) hydrogen; or
(d) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl (eg, C ₁ -C ₆ alkyl), each of which is optionally substituted with 1 to 3 R ^d ; or
_{(e) -C (O) (} C 1 -C 6 _{alkyl), - C (O) (} C 1 -C 6 haloalkyl) or _{-C (O) O (C 1} -C 6 alkyl); or
(f) may be C ₂ -C ₆ alkenyl or _C 2 -C ₆ alkynyl.

In some embodiments, the other of R ¹⁰ and R ¹¹ is
(a) hydrogen; or
(d) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl (eg, C ₁ -C ₆ alkyl), each of which is optionally substituted with 1 to 3 R ^d ; or
(e) —C (O) (C ₁ -C ₆ alkyl), —C (O) (C ₁ -C ₆ haloalkyl) or —C (O) O (C ₁ -C ₆ alkyl)
It is.

In some embodiments, the other of R ¹⁰ and R ¹¹ is
(a) hydrogen; or
(d) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl (eg, C ₁ -C ₆ alkyl), each of which is optionally substituted with 1 to 3 R ^d ; or
_{(e) -C (O) (} C 1 -C 6 alkyl), or-C (O) (C 1 -C 6 haloalkyl)
It is.

In some embodiments, the other of R ¹⁰ and R ¹¹ is
(a) hydrogen; or
(d) C ₁ -C ₆ alkyl (eg, C ₁ -C ₃ alkyl, eg, CH ₃ ) optionally substituted with 1 to 3 R ^d ; or
(e) —C (O) (C ₁ -C ₆ alkyl), eg, C ₁ -C ₃ alkyl, eg, CH ₃
It can be.

In some embodiments, the other of R ¹⁰ and R ¹¹ is
(a) hydrogen; or
(d) C ₁ -C ₆ alkyl optionally substituted with 1 to 3 R ^d (eg, C ₁ -C ₃ alkyl, eg, CH ₃ ).
It can be.

In certain embodiments, the other of R ¹⁰ and R ¹¹ can be hydrogen.

In certain embodiments, the other of R ¹⁰ and R ¹¹ can be (d) or (e) or any subgroup thereof.

[E] In some embodiments, one of R ¹⁰ and R ¹¹ is C ₆ -C ₁₀ (eg, C ₆ ) aryl optionally substituted with 1 to 4 R ^b , and the other is hydrogen or C ₁ -C ₆ alkyl _(e.g., C 1 -C ₃ alkyl, e.g., CH ₃₎ which is.

In certain embodiments, one of R ¹⁰ and R ¹¹ is C ₆ -C ₁₀ (eg, C ₆ ) aryl optionally substituted with 1 to 4 R ^b , and the other is hydrogen.

In some embodiments, one of R ¹⁰ and R ¹¹ is unsubstituted phenyl and the other is hydrogen.

In some embodiments, one of R ¹⁰ and R ¹¹ is phenyl substituted with 1 R ^b , and the other is hydrogen. In some embodiments, R ^b is C ₁ -C ₆ alkoxy (eg, C ₁ -C ₃ alkoxy, eg, OCH ₃ ). For example, one of R ¹⁰ and R ¹¹ is 3-methoxyphenyl and the other is hydrogen.

[F] In some embodiments, each of R ¹⁰ and R ¹¹ must not be an optionally substituted naphthyl (eg, each of R ¹⁰ and R ¹¹ must not be an unsubstituted naphthyl). In certain embodiments, when R and R ′ are defined according to the definitions in definitions (1), (2) and (4), other than optionally substituted naphthyl (eg, unsubstituted naphthyl); A Is CR ^A1 R ^A2 (eg, CHOR ⁹ , eg, CHOH), and each of L ¹ and L ² is C ₁ -C ₃ alkylene (eg, each of L ¹ and L ² is CH ₂ ).

[G] In some embodiments, one of R ¹⁰ and R ¹¹ is hydrogen and the other is heteroaryl containing 5-14 ring atoms, wherein 1-6 of the ring atoms are N, NH, N ( C ₁ -C ₃ alkyl), independently selected from O and S; and the heteroaryl is optionally substituted with 1 to 4 R ^b .

In some embodiments, one of R ¹⁰ and R ¹¹ is hydrogen and the other is heteroaryl containing 5-6 ring atoms, wherein 1-2 of the ring atoms are N, NH, N (C _1- C ₃ alkyl), independently selected from O and S; and the heteroaryl may be optionally substituted with 1 to 2 R ^b .

In [III] an aspect, Z is ^{-OR 12.}

In certain embodiments, R ¹² is C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl, each of which is optionally substituted with 1 to 3 R ^c .

In certain embodiments, R ¹² is C ₁ -C ₆ alkyl, which is optionally substituted with 1 to 3 R ^c .

In some embodiments, R ¹² is C ₁ -C ₆ alkyl (eg, C ₁ -C ₃ alkyl, eg, CH ₃ ).

In certain embodiments, R ¹² is C ₁ -C ₆ alkyl (eg, C ₁ -C ₃ alkyl, eg, CH ₃ ), optionally 1-3 of (eg, 1 or 2, eg, it may be substituted with R ^c of 1). In some embodiments, each of R ^c is independent of —NH ₂ , —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ and —NHC (O) (C ₁ -C ₆ alkyl). Can be selected.

In certain embodiments, R ¹² is C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 (eg, 1 to 3, 1 to 2, or 1) R ^b .

In some embodiments, each R ^b is halo; or C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ thiohaloalkoxy; C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ optionally substituted with independently selected R ^e And —NHC (O) (C ₁ -C ₆ alkyl).

In certain embodiments, R ^b is each substituted with C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thioalkoxy; and optionally 1-3 independently selected R ^e . Independently selected from C ₁ -C ₆ thiohaloalkoxy.

In some embodiments, ^{R b} are each independently selected from _C 1 -C ₆ alkoxy and _C 1 -C ₆ haloalkoxy, substituted in each of which is selected 1-3 independently optionally ^{R e} May have been.

In certain embodiments, each R ^b is independently selected from C ₁ -C ₆ alkoxy, each of which is optionally substituted with 1 to 3 independently selected R ^e . In some embodiments, R ^b is C ₁ -C ₆ alkoxy (eg, OCH ₃ ).

In certain embodiments, R ^b can further comprise halo.

In certain embodiments, R ¹² is unsubstituted phenyl.

In certain embodiments, R ¹² is phenyl substituted with 1 R ^b . R ^b can be as defined herein (eg, R ^b can be C ₁ -C ₆ alkoxy, eg, OCH ₃ ). For example, R ¹² can be 3-methoxyphenyl.

[IV] In some embodiments, Z is —S (O) _n R ¹³ , where n can be 0, 1, or 2.

In certain embodiments, R ¹³ is C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 (eg, 1 to 3, 1 to 2, or 1) R ^b .

In some embodiments, each R ^b is halo; or C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ thiohaloalkoxy; C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ optionally substituted with independently selected R ^e And —NHC (O) (C ₁ -C ₆ alkyl).

In certain embodiments, R ^b is each substituted with C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thioalkoxy; and optionally 1-3 independently selected R ^e . Independently selected from C ₁ -C ₆ thiohaloalkoxy.

In some embodiments, ^{R b} are each independently selected from _C 1 -C ₆ alkoxy and _C 1 -C ₆ haloalkoxy, substituted in each of which is selected 1-3 independently optionally ^{R e} May have been.

In certain embodiments, each R ^b is independently selected from C ₁ -C ₆ alkoxy, each of which is optionally substituted with 1 to 3 independently selected R ^e . In an embodiment, R ^b is C ₁ -C ₆ alkoxy (eg, OCH ₃ ).

In certain embodiments, R ^b can further comprise halo.

In certain embodiments, R ¹³ is unsubstituted phenyl.

In certain embodiments, R ¹³ is phenyl substituted with 1 R ^b . R ^b can be as defined herein (eg, R ^b can be C ₁ -C ₆ alkoxy, eg, OCH ₃ ). For example, R ¹³ can be 3-methoxyphenyl.

In certain embodiments, the R ¹² and / or R ¹³ substitution must not be phenyl. In certain embodiments, when R and R ′ are defined according to the definition of definition (1), R ¹² and / or R ¹³ must not be substituted phenyl; CR ^A1 R ^A2 (eg, CHOR ⁹ , eg, , CHOH) and each of L ¹ and L ² is C ₁ -C ₃ alkylene (eg, each of L ¹ and L ² is CH ₂ ).

In [V] some embodiments, Z is heterocycloalkenyl containing 5-6 ring atoms, wherein 1-3 ring atoms are _{N, NH, N (C 1} -C 6 alkyl), NC (O ) (C ₁ -C ₆ alkyl), independently selected from O and S; and the heterocycloalkenyl is optionally substituted with 1 to 4 independently selected R ^a .

In some embodiments, Z is a heterocycloalkenyl containing 6 ring atoms, wherein 1-3 of the ring atoms are N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C _1- C ₆ alkyl), independently selected from O and S; and the heterocycloalkenyl is optionally substituted with 1 to 4 independently selected R ^a .

In some embodiments, 1 to 3 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₆ alkyl) and NC (O) (C ₁ -C ₆ alkyl).

In certain embodiments, R ^a is each independently selected from oxo, thioxo, ═NH and ═N (C ₁ -C ₆ alkyl), eg, ═NH.

For example, Z is
It can be.

In some embodiments, Z is heteroaryl containing 5-14 ring atoms, wherein 1-6 of the ring atoms are independently from N, NH, N (C ₁ -C ₃ alkyl), O and S. And the heteroaryl may be optionally substituted with 1 to 4 R ^b .

In some embodiments, Z is heteroaryl containing 5-6 ring atoms, wherein 1-4 of the ring atoms are independently selected from N, NH and N (C ₁ -C ₃ alkyl); and The heteroaryl may be optionally substituted with 1 to 2 ^Rb .

Variable groups R and R ′
[I] In some embodiments, R and R ′ are each united with C ₂ and C ₃ to form a compound of formula (II)
Form a phenyl ring of
Here, each of R ⁵ , R ⁶ , R ⁷ and R ⁸ is hydrogen, halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C _1. -C ₆ halo _{thioalkoxyalkyl,} C 1 -C _{6 alkyl,} C 1 -C ₆ haloalkyl, _cyano, -NH 2, -NH _(C 1 -C ₆ alkyl), N _(C 1 -C _{6 alkyl)} 2, - Independently selected from NHC (O) (C ₁ -C ₆ alkyl) and nitro.

For clarity, compounds in which R and R ′ together with C ₂ and C ₃ , respectively, form a fused phenyl ring having the formula (II) have the following general formula:
[Wherein R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² , A and Z may be as defined herein. ]
To be interpreted as corresponding to a compound having

In certain embodiments, one of R ⁵ , R ⁶ , R ⁷ and R ⁸ (eg, one, eg, R ⁶ ) is halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy. , _C 1 -C _{6 haloalkoxy,} C 1 -C _{6 thiohaloalkoxy,} C 1 -C _{6 alkyl,} C 1 -C ₆ haloalkyl, _{cyano, -NH 2, -NH (C 1} -C 6 alkyl), N Selected from (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro, the other being hydrogen.

In some embodiments, one of R ⁵ , R ⁶ , R ⁷ and R ⁸ (eg, one, eg, R ⁶ ) is halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C _1- C ₆ alkyl, C ₁ -C ₆ haloalkyl, cyano and nitro are selected, the other being hydrogen.

In some embodiments, one of R ⁵ , R ⁶ , R ⁷ and R ⁸ (eg, one, eg, R ⁶ ) is selected from halo, C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl, the other Hydrogen.

In certain embodiments, one (eg, one, eg, R ⁶ ) of R ⁵ , R ⁶ , R ^7, and R ⁸ is selected as halo and C ₁ -C ₆ alkyl and the other is hydrogen.

In certain embodiments, one (eg, one, eg, R ⁶ ) of R ⁵ , R ⁶ , R ^7, and R ⁸ is halo (eg, bromo or chloro) and C ₁ -C ₆ alkyl, the other Hydrogen.

In some embodiments, one of R ⁵ , R ⁶ , R ⁷ and R ⁸ (eg, one, eg, R ⁶ ) is bromo and the other is hydrogen.

In some embodiments, R ⁶ is halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C _{6. alkyl,} C 1 -C ₆ haloalkyl, _{cyano, -NH 2, -NH (C 1} -C 6 alkyl), N _(C 1 -C _{6 alkyl) 2, -NHC (O) (} C 1 -C 6 alkyl) And each of R ⁵ , R ⁷ and R ⁸ can be as defined herein.

In some embodiments, R ⁶ is halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C _{6. alkyl,} C 1 -C ₆ haloalkyl, _{cyano, -NH 2, -NH (C 1} -C 6 alkyl), N _(C 1 -C _{6 alkyl) 2, -NHC (O) (} C 1 -C 6 alkyl) And R ⁵ , R ⁷ and R ⁸ are each hydrogen.

In some embodiments, R ⁶ is selected from halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cyano and nitro, and R ¹ , R ² And each of R ⁴ can be as defined herein.

In some embodiments, R ⁶ is selected from halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cyano and nitro, and R ⁵ , R ⁷ And each of R ⁸ is hydrogen.

In certain embodiments, R ⁶ is selected from halo, C ₁ -C ₆ alkyl, and C ₁ -C ₆ haloalkyl, and each of R ⁵ , R ^7, and R ⁸ can be as defined herein.

In some embodiments, R ⁶ is selected from halo, C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl, and each of R ⁵ , R ⁷ and R ⁸ is hydrogen.

In certain embodiments, R ⁶ is selected from halo and C ₁ -C ₆ alkyl, and each of R ⁵ , R ^7, and R ⁸ can be as defined herein.

In certain embodiments, R ⁶ is selected from halo and C ₁ -C ₆ alkyl, and each of R ⁵ , R ^7, and R ⁸ is hydrogen.

In certain embodiments, R ⁶ is halo (eg, bromo or chloro) and each of R ⁵ , R ^7, and R ⁸ can be as defined herein.

In some embodiments, R ⁶ is halo (eg, bromo or chloro) and each of R ⁵ , R ^7, and R ⁸ is hydrogen.

In certain embodiments, R ⁶ is bromo and each of R ⁵ , R ^7, and R ⁸ can be as defined herein.

In some embodiments, R ⁶ is bromo and each of R ⁵ , R ^7, and R ⁸ is hydrogen.

In some ^embodiments, each of R ^5, R 6, ^{R 7} and ^{R 8} are independently selected from hydrogen, halo and _C 1 -C ₆ alkyl.

In certain embodiments, each of R ⁵ , R ⁶ , R ⁷ and R ⁸ is independently selected from hydrogen and halo (eg, bromo or chloro).

In some embodiments, each of R ⁵ , R ⁶ , R ⁷ and R ⁸ is hydrogen.

In certain embodiments, when any one or more of R ⁵ , R ⁶ , R ⁷ and R ⁸ can be a substituent other than hydrogen, the substituent or each of the substituents is other than C ₁ -C ₆ alkyl ( For _example, C 1 -C ₃ alkyl, for example, a CH _3).

  Embodiments can include any one or more of the characteristics described herein, including but not limited to the following.

{A}
Each of R ¹ , R ² , R ³ and R ⁴ can be as defined herein.

R ³ is halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C ₁ Selected from —C ₆ haloalkyl, cyano, —NH ₂ , —NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro Each of R ¹ , R ² and R ⁴ can be as defined herein (eg, each of R ¹ , R ² and R ⁴ is hydrogen).

R ³ is selected from halo and C ₁ -C ₆ alkyl, and each of R ¹ , R ² and R ⁴ can be as defined herein (eg, each of R ¹ , R ² and R ⁴ Is hydrogen).

R ³ is halo (eg, bromo or chloro) and each of R ¹ , R ² and R ⁴ can be as defined herein (eg, each of R ¹ , R ² and R ⁴ is Hydrogen).

R ³ is bromo and each of R ¹ , R ² and R ⁴ can be as defined herein (eg, each of R ¹ , R ² and R ⁴ is hydrogen).

Each of R ¹ , R ² , R ³ and R ⁴ is independently selected from hydrogen and halo (eg, bromo or chloro).

Each of R ¹ , R ² , R ³ and R ⁴ is hydrogen.

{B}
Each of L ¹ and L ² is independently C ₁ -C ₃ alkylene, which is optionally substituted with ₁ to 2 independently selected R ^c .

Each of L ¹ and L ² is CH ₂ .

One of L ¹ and L ² (eg, L ¹ ) is CH ₂ and the other (eg, L ² ) is substituted with 1 or 2 (eg, 1) independently selected R ^c Wherein R ^c can be as defined herein.

Each of L ¹ and L ² is methylene substituted with 1 or 2 (eg 1) independently selected R ^c , where R ^c is as defined herein. It can be.

L ¹ is a C ₁ -C ₃ (eg C ₁ -C ₂ ) linear alkylene, which is optionally substituted with 1 to 2 independently selected R ^c and L ² Is a bond directly linking A in formula (I) and Z in formula (I).

{C}
One of R ^A1 and R ^A2 is OR ⁹ and the other is hydrogen. In certain embodiments, R ⁹ can be hydrogen. R ⁹ may be C ₁ -C ₃ alkyl (eg, CH ₃ ).

One of R ^A1 and R ^A2 can be halo (eg, fluoro) and the other can be hydrogen.

Each of R ^A1 and R ^A2 can be a substituent other than hydrogen. For example, each of R ^A1 and R ^A2 can be halo (eg, fluoro). As another example, one of R ^A1 and R ^A2 can be OR ⁹ (eg, where R ⁹ is hydrogen) and the other is C ₁ -C ₃ alkyl (eg, CH ₃ ).

Each of R ^A1 and R ^A2 is hydrogen.

A is CR ^A1 R ^A2 , wherein each of R ^A1 and R ^A2 is independently selected from hydrogen, halo, C ₁ -C ₃ alkyl or OR ⁹ ; and each of L ¹ and L ² is Independently C ₁ -C ₃ alkylene, which is optionally substituted with ₁ to 2 independently selected R ^c .

{D}
Z is —NR ¹⁰ R ¹¹ , where R ¹⁰ and R ¹¹ can be as defined herein.

One of R ¹⁰ and R ¹¹ is C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b . In some embodiments, the other of R ¹⁰ and R ¹¹ is hydrogen or C ₁ -C ₃ alkyl (eg, CH ₃ ). In certain embodiments, the other of R ¹⁰ and R ¹¹ is hydrogen.

In some embodiments, one of R ¹⁰ and R ¹¹ is unsubstituted phenyl and the other is hydrogen.

In some embodiments, one of R ¹⁰ and R ¹¹ is phenyl substituted with 1 R ^b , and the other is hydrogen. In some embodiments, R ^b is C ₁ -C ₆ alkoxy (eg, C ₁ -C ₃ alkoxy, eg, OCH ₃ ). For example, one of R ¹⁰ and R ¹¹ is 3-methoxyphenyl and the other is hydrogen.

Z is —OR ¹² or —S (O) _n R ¹³ , where R ¹² and R ¹³ can be as defined herein.

  Aspects can include characteristics from any one, two, three, or four of {A}, {B}, {C}, and {D}, or any combination thereof.

In some embodiments, R ³ is a substituent other than hydrogen (eg, halo and C ₁ -C ₆ alkyl; eg, halo, eg, bromo); each of R ¹ , R ^2, and R ^{4 is} as defined herein. As defined (eg, each of R ¹ , R ² and R ⁴ is hydrogen);
R ⁶ is a substituent other than hydrogen (eg, halo and C ₁ -C ₆ alkyl; eg, halo, eg, bromo); each of R ⁵ , R ^7, and R ⁸ is as defined herein. (Eg, each of R ⁵ , R ⁷ and R ⁸ is hydrogen).

In some embodiments, R ³ is a substituent other than hydrogen (eg, halo and C ₁ -C ₆ alkyl; eg, halo, eg, bromo); each of R ¹ , R ^2, and R ^{4 is} as defined herein. As defined (eg, each of R ¹ , R ² and R ⁴ is hydrogen);
R ⁶ is a substituent other than hydrogen (eg, halo and C ₁ -C ₆ alkyl; eg, halo, eg, bromo); each of R ⁵ , R ^7, and R ⁸ is as defined herein. (Eg, each of R ⁵ , R ⁷ and R ⁸ is hydrogen);
A is CR ^A1 R ^A2 , wherein each of R ^A1 and R ^A2 is independently selected from hydrogen, halo, C ₁ -C ₃ alkyl or OR ⁹ ; and each of L ¹ and L ² is Independently C ₁ -C ₃ alkylene, which is optionally substituted with ₁ to 2 independently selected R ^c .

  Embodiments can include any one or more properties described herein (eg, as described under {B} and {C} above).

In some embodiments, R ³ is a substituent other than hydrogen (eg, halo and C ₁ -C ₆ alkyl; eg, halo, eg, bromo); each of R ¹ , R ^2, and R ^{4 is} as defined herein. As defined (eg, each of R ¹ , R ² and R ⁴ is hydrogen);
R ⁶ is a substituent other than hydrogen (eg, halo and C ₁ -C ₆ alkyl; eg, halo, eg, bromo); each of R ⁵ , R ^7, and R ⁸ is as defined herein. (Eg, each of R ⁵ , R ⁷ and R ⁸ is hydrogen);
A is CR ^A1 R ^A2 , wherein each of R ^A1 and R ^A2 is independently selected from hydrogen, halo, C ₁ -C ₃ alkyl or OR ⁹ ; and each of L ¹ and L ² is Independently C ₁ -C ₃ alkylene, which may optionally be substituted with 1 to 2 independently selected R ^c ; and Z is —NR ¹⁰ R ¹¹ , wherein , R ¹⁰ and R ¹¹ may be as defined herein.

  Embodiments can include any one or more of the properties described herein (eg, as described under {B}, {C}, and {D} above).

In some embodiments, each of L ¹ and L ² is CH ₂ .
A is CR ^A1 R ^A2 where one of R ^A1 and R ^A2 is OR ⁹ and the other is hydrogen;
Z is —NR ¹⁰ R ¹¹ ;
Each of R ¹⁰ and R ¹¹ is independently
(a) hydrogen;
(b) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ;
(d) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl optionally substituted with 1 to 3 R ^d ;
(f) a C ₂ -C ₆ alkenyl or _C 2 -C ₆ alkynyl.

  Embodiments can include any one or more of the properties described herein (eg, as described under {A}, {C}, and {D} above).

In some embodiments, A is CR ^A1 R ^A2 , wherein each of R ^A1 and R ^A2 is independently hydrogen, halo, or C ₁ -C ₃ alkyl; or A is CR ^A1 R ^A2 , where Wherein one of R ^A1 and R ^A2 is halo (eg, fluoro) and the other of R ^A1 and R ^A2 is independently hydrogen, halo, or C ₁ -C ₃ alkyl (eg, hydrogen); or A Is CR ^A1 R ^A2 , wherein one of R ^A1 and R ^A2 is halo (eg, fluoro), the other of R ^A1 and R ^A2 is hydrogen; and R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² and Z may be as defined herein; or a salt thereof (eg, a pharmaceutically acceptable salt).

  Aspects can include characteristics from any one, two, three, or four of {A}, {B}, {C}, and {D}, or any combination thereof.

In some embodiments, one of R ^A1 and R ^A2 can be OR ⁹ . In certain embodiments, the other of R ^A1 and R ^A2 can be as defined herein; for example, the other of R ^A1 and R ^A2 can be hydrogen or C ₁ -C ₃ alkyl. For example, one of R ^A1 and R ^A2 can be OR ⁹ and the other of R ^A1 and R ^A2 can be hydrogen. In certain embodiments, R ⁹ can be hydrogen;
R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² and Z may be as defined herein; or a salt thereof (eg, a pharmaceutically acceptable salt).

In certain embodiments, for example, when A is CHOH and Z is NR ¹⁰ R ¹¹ , one or more of the following applies: • each of R ³ and R ⁶ is CH ₃ ; and / or R ³ And each of R ⁶ is bromo and / or each of R ³ and R ⁶ is chloro; and / or one of R ³ and R ⁶ (eg, R ⁶ ) is CH ₃ and the other (eg, R ³ ) Is bromo;
Each of R ¹⁰ and R ¹¹ is other than hydrogen;
Each of R ¹⁰ and R ¹¹ is hydrogen;
One of R ¹⁰ and R ¹¹ is heteroaryl as defined herein;
L ¹ and / or L ² is C ₂ -C ₃ alkylene (optionally substituted);
• (B) and / or (C) applies.

  Aspects can include characteristics from any one, two, three, or four of {A}, {B}, {C}, and {D}, or any combination thereof.

In some embodiments, Z is other than NR ¹⁰ R ¹¹ ; R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² , Z and A may be as defined herein; or A salt thereof (for example, a pharmaceutically acceptable salt). In certain embodiments, (B) and / or (C) is applied. Aspects can include characteristics from any one, two, three, or four of {A}, {B}, {C}, and {D}, or any combination thereof.

In some embodiments, Z is —OR ¹² and / or —S (O) _n R ¹³ ; R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² and A are as defined herein. Or a salt thereof (eg, a pharmaceutically acceptable salt). In certain embodiments, (B) and / or (C) is applied. Aspects can include characteristics from any one, two, three, or four of {A}, {B}, {C}, and {D}, or any combination thereof.

In some embodiments, A is (ii) C = O; and / or (iv) a heterocycloalkylene containing 3-5 ring atoms, wherein 1-2 of the ring atoms are N, NH, N (C ₁ -C ₃ alkyl), are independently selected from O and S; and the heterocycloalkylene is optionally substituted with (a) 1 oxo; and (b) if 1-4 independently by May be further substituted with ^a selected R ^a ; and R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² and Z may be as defined herein; or a salt thereof (Eg, a pharmaceutically acceptable salt). Aspects can include characteristics from any one, two, three, or four of {A}, {B}, {C}, and {D}, or any combination thereof.

[II] In some embodiments, each of R and R ′ is independently hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

  In certain embodiments, R and R 'may be the same or different.

In certain embodiments, each of R and R ′ is independently C ₁ -C ₆ alkyl, for example, each of R and R ′ is CH ₃ .

  In other embodiments, each of R and R 'is hydrogen.

  Embodiments can include any one or more of the properties described herein, including but not limited to those described in conjunction with Formula (III).

[III] In some embodiments, R and R ′ are each joined with C ₂ and C ₃ to form a fused heterocyclic ring containing 5 to 6 ring atoms, wherein 1 to 2 of the ring atoms Are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S; and the heterocyclic ring is optionally 1-3 Optionally substituted by independently selected R ^a . For clarity and explanation, non-limiting examples of these compounds are described below (formula (IV))
[Wherein R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² , A and Z may be as defined herein. ]. Here, R and R ′ together with C ₂ and C ₃ respectively form a fused heterocyclic ring containing 5-6 ring atoms.

Embodiments can include any one or more of the properties described herein, including but not limited to those described in conjunction with Formula (III). In some embodiments, R ⁶³ can be hydrogen or C ₁ -C ₃ alkyl (eg, CH ₃ ).

In certain embodiments, the following are provided.
(i) When A is CH ₂ , each of L ¹ and L ² must be C ₁ -C ₃ alkylene, optionally with 1 to 2 independently selected R ^c May be substituted; or
(ii) Z is 5-14 (e.g., 5-6 or 6) must be other than heteroaryl containing ring atoms, wherein 1-6 ring atoms are _{N, NH, N (C 1} - C ₃ alkyl), independently selected from O and S; and the heteroaryl may be optionally substituted with 1-4 independently selected R ^b ; for example, other than substituted pyridyl, such as Other than pyridyl substituted with C ₁ -C ₃ alkyl (eg, CH ₃ ), eg, other than 2- or 6-methylpyridyl.

[IV] In some embodiments, R and R ′ are each taken together with C ₂ and C ₃ to form a fused C ₅ -C ₆ cycloalkyl ring, which is optionally selected from 1 to 4 independently selected. R ^a may be substituted. For clarity and explanation, non-limiting examples of such compounds are shown below (formula (V))
[Wherein R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² , A and Z may be as defined herein. ]. Here, R and R ′ together with C ₂ and C ₃ respectively form a fused C ₆ cycloalkyl ring. Embodiments can include any one or more of the properties described herein, including but not limited to those described in conjunction with Formula (III).

In [V] some embodiments, taken with R and R 'together with each C ₂ and C ₃ form a fused heteroaryl ring containing 5-6 ring atoms, wherein 1-2 ring atoms Independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; and the heteroaryl ring is optionally substituted by 1 to 3 independently selected R ^b Good. See, for example, the title compound of Example 13. Embodiments can include any one or more of the properties described herein, including but not limited to those described in conjunction with Formula (III).

  Any compound group, subgroup, or specific compound described herein may include one or more of the stereochemical properties described herein (eg, as outlined).

Compound Forms and Salts Compounds of the embodiments disclosed herein may contain one or more asymmetric centers and are therefore racemic and racemic mixtures, enantiomeric mixtures, single enantiomers, individual diastereomers and diastereomers. Present as a mixture. All such isomeric forms of these compounds are expressly included in the embodiments disclosed herein. The compounds of the embodiments disclosed herein may also contain bonds (eg, carbon-nitrogen bonds such as carbon-carbon bonds, amide bonds), wherein bond rotation is limited with respect to particular bonds, eg Caused by a ring or double bond. Accordingly, all cis / trans and E / Z isomers and rotamers are expressly included in the embodiments disclosed herein. The compounds of the disclosed embodiments can also be represented in tautomeric forms, in which case the disclosed embodiments are described herein even though they represent only a single tautomeric form. All tautomeric forms of the compound are expressly included. All such isomeric forms of such compounds are expressly included in the embodiments disclosed herein.

  Optical isomers can be obtained in pure form by conventional methods known to those skilled in the art including, but not limited to, diastereomeric salt formation, kinetic resolution and asymmetric synthesis. For example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); each incorporated herein by reference in its entirety; Wilen, SH, et al., Tetrahedron 33: 2725 (1977) ); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. Of Notre Dame Press, Notre Dame, IN (1972). Embodiments disclosed herein include all possible positional isomers and mixtures thereof, including but not limited to standard chromatography known to those skilled in the art, including but not limited to column chromatography, thin layer chromatography, and high performance liquid chromatography. Can be obtained by various separation methods.

The compounds of the embodiments disclosed herein include the compound itself and, where appropriate, salts and prodrugs thereof. A salt can be formed, for example, between an anion and a positively charged substituent (eg, amino) on the compounds described herein. Suitable anions include chloride, bromide, iodide, sulfuric acid, nitric acid, phosphoric acid, citric acid, methanesulfonic acid, trifluoroacetic acid and acetic acid. Similarly, a salt can be formed between a cation and a negatively charged substituent (eg, a carboxylate salt) on a compound described herein. Suitable cations include ammonium cations such as sodium ions, potassium ions, magnesium ions, calcium ions, tetramethylammonium ions. Examples of prodrugs include C _1-6 alkyl esters of carboxylic acid groups that can provide the active compound upon administration to a subject.

  Pharmaceutically acceptable salts of the compounds of the presently disclosed embodiments include those derived from pharmaceutically acceptable inorganic and organic acids and bases. As used herein, the term “pharmaceutically acceptable salt” includes salts formed by the addition of pharmaceutically acceptable acids or bases to the compounds disclosed herein. As used herein, the term “pharmaceutically acceptable” refers to a substance that is acceptable for use in pharmaceutical applications from the standpoint of toxicity and does not adversely interact with the active ingredient.

Suitable acid salts are acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorsulfonate, camphorsulfonate, diglucon Acid salt, dodecyl sulfate, ethane sulfonate, formate, fumarate, glucoheptanoate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, iodine Hydrohalide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmate, pectate, Persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionic acid, salicylate, succinate, sulfate, tartrate, thiocyanate Salt, tosylate and undecanoate. Other acids such as oxalic acid are not pharmaceutically acceptable per se, but can be used in the preparation of salts useful as intermediates to obtain the compounds of the embodiments disclosed herein and pharmaceutically acceptable acid addition salts thereof. . Salts derived from appropriate bases include alkali metal (eg, sodium), alkaline earth metal (eg, magnesium), ammonium and N- (alkyl) ₄ ⁺ salts. The embodiments disclosed herein also contemplate quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Such quaternization may yield a product that is soluble or dispersible in water or oil. Here, the salt form of any compound of the formula may be an amino acid salt of a carboxyl group (for example, a salt of L-arginine, -lysine, -histidine).

  A list of suitable salts, each of which is incorporated herein by reference in its entirety, is Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; Journal of Pharmaceutical Science, 66. , 2 (1977); and "Pharmaceutical Salts: Properties, Selection, and Use A Handbook; Wermuth, CG and Stahl, PH (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN 3-906390-26-8] It can be seen.

  The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but in other respects the salt is equivalent to the parent form of the compound for purposes of the embodiments disclosed herein. is there.

  In addition to salt forms, the embodiments disclosed herein provide compounds that are in a prodrug form. Prodrugs of the compounds described herein are those compounds that undergo chemical changes under physiological conditions to provide the compounds of the disclosed embodiments. Additionally, prodrugs can be converted to the compounds of the presently disclosed embodiments by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the presently disclosed embodiments when placed in a transdermal patch reservoir with a suitable enzyme or chemical. Prodrugs are often useful because in some situations they may be easier to administer than the parent drug. They may have better bioavailability by oral administration than the parent drug, for example. Prodrugs can also improve solubility in pharmacological compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that utilize hydrolytic cleavage or oxidative activation of the prodrug. An example of a prodrug is, but is not limited to, a compound of the embodiments disclosed herein that is administered as an ester ("prodrug") and then hydrolyzed metabolically to the active body carboxylic acid. Further examples include peptidyl derivatives of the compounds of the embodiments disclosed herein.

  Embodiments disclosed herein also include various hydrate and solvate forms of the present compounds.

The compounds of the embodiments disclosed herein may also differ from nature in the atomic isotope ratio of one or more atoms that constitute such compounds. For example, compounds, tritium ⁽³ H), may be radioactively labeled by radioactive isotopes such as iodine--125 ⁽¹²⁵ I) or carbon -14 ⁽¹⁴ C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are intended to be included within the scope of the disclosed embodiments.

Synthesis Compounds of the embodiments disclosed herein can be prepared according to the procedures outlined in the Examples section, from standard starting materials, compounds known in the literature or readily prepared intermediates, known to those skilled in the art. It can be conveniently prepared using methods and procedures. Standard synthetic methods and procedures for producing organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. When indicating typical or preferred processing conditions (i.e. reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), it is understood that other processing conditions may be used unless otherwise indicated. I will. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented may vary in order to optimize the formation of the compounds described herein.

  Synthetic chemical transformations (including protecting group methodologies) useful for the synthesis of the compounds described herein are known in the art, for example, RC Larock, Comprehensive Organic Transformations, 2d.ed., Wiley-VCH Publishers (1999) PGM Wuts and TW Greene, Protective Groups in Organic Synthesis, 4th Ed., John Wiley and Sons (2007); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); And L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and their subsequent editions.

The methods described herein can be monitored according to suitable methods known in the art. For example, spectroscopic means such as nuclear magnetic resonance spectroscopy (eg, ¹ H or ¹³ C), infrared spectroscopy (FT-IR), spectrophotometry (eg, UV-visible), or mass spectroscopy (MS) Or the formation of the product can be monitored by chromatography, eg high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

  The manufacture of the compounds can include protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of the protecting groups can be found in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991, which is hereby incorporated by reference in its entirety.

  The methods described herein can be performed in a suitable solvent that can be readily selected by one skilled in the art of organic synthesis. A suitable solvent is substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction takes place, i.e., at a temperature that can range from the freezing point of the solvent to the boiling point of the solvent. It can be. Certain reactions can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, an appropriate solvent for the particular reaction step can be selected.

Resolution of a racemic mixture of compounds can be performed by any of a number of methods known in the art. Examples of methods include the preparation of the corresponding alcohol or amine Mosher ester or amide, respectively. The absolute configuration of the ester or amide is determined by proton and / or ¹⁹ F NMR spectroscopy. An example of the method includes fractional recrystallization using a “chiral resolving acid” which is an optically active salt-forming organic acid. Resolving agents suitable for the fractional recrystallization method are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids. D and L form. Resolution of the racemic mixture can also be performed by elution on a column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

  The compounds of the embodiments disclosed herein can be prepared, for example, using the reaction pathways and techniques described below.

A series of carbazole 1,2-aminoalcohol compounds of formula 3 can be prepared by the method outlined in Scheme 1. 9-oxiranylmethyl-9H-carbazole of formula 2 can be prepared from an appropriately substituted carbazole of formula 1 and epichlorohydrin in the presence of a strong base such as sodium hydride.

  The oxiranyl ring of formula 2 can be opened in the presence of a primary or secondary amine to produce a 1,2-amino alcohol of formula 3. Such reactive primary or secondary amines can be, but are not limited to, phenethylamine, 3-phenylallylamine, N-substituted piperazines, and the like.

Alternatively, various carbazole 1,2-aminoalcohol compounds of formula 8 can be prepared by the method outlined in Scheme 2 and epoxides of 9-oxiranylmethyl-9H-carbazole of formula 2 can be converted to H ₂ which is the primary amine. Ring opening at NR ¹⁰ affords a secondary amino alcohol of formula 4 which is then protected with an amine protecting group (P) such as tert-butoxycarbonyl (Boc) to give a protected amino alcohol of formula 5 can get. The hydroxyl group of formula 5 can then be alkylated with a strong base such as sodium hydride and an alkylating agent (RX) such as an alkyl halide, tosylate, triflate or mesylate to produce an ether of formula 6. . Removal of the amine protecting group in the presence of a suitable acid provides the desired OR ether compound of formula 7. Finally, reductive alkylation of the secondary amine of formula 7 is achieved in the presence of a reducing agent such as an aldehyde and sodium cyanoborohydride (NaCNBH ₃ ) to give a tertiary 1,2-amino alcohol of formula 8 Can be obtained.

A series of substituted indole compounds of formula 11 and 12 can be prepared by the method outlined in Scheme 3 below. A compound of formula 11 is prepared using a strong base such as potassium hydroxide (KOH) or n-butyllithium (n-BuLi) using an indole of formula 9 with epoxide A, for example epichlorohydrin or epibromohydrin. It can be prepared by alkylation in the presence of an oxiranylindole of formula 10. The ring opening of the epoxide of the compound of formula 10 with a strong base or weak Lewis acid such as lithium bromide (LiBr) or bismuth chloride (BiCl ₃ ) in the presence of a primary amine, substituted alcohol or thiol then Eleven alcohols can be obtained. Furthermore, the compound of formula 12 can be prepared by ring opening of epoxide B using the indole nitrogen of formula 9 at a position with less hindrance.

In addition, a variety of epoxide derivatives can be prepared according to the method outlined in Scheme 4. The secondary alcohol of the compound of formula 11 can be oxidized by use of an oxidant or under Swan-like oxidation conditions to give a ketone of formula 13, which is further subjected to reductive amination to give 14 amines. A compound can be obtained. Alternatively, secondary alcohols are converted to esters using carboxylic anhydrides (where Z = R ″ C (O)) or ethers (where Z = alkyl) using standard alkylation conditions; A compound of formula 15 can be obtained A fluorine compound of formula 16 can be prepared by reaction of an alcohol of formula 11 with a fluorinating agent such as diethylaminosulfur trifluoride (DAST) Nitrogen heteroarylation of formula 17 Compounds can be prepared starting from compounds of formula 11 where Y = N, in the presence of catalytic amounts of copper iodide and heteroaryl iodide, and finally, sulfoxides and sulfones of formula 18 are prepared Starting from 11 sulfides (where Y = S), it can be prepared under oxidative conditions, for example in the presence of m-chloroperoxybenzoic acid (m-CPBA).

The pharmaceutical composition term “pharmaceutically acceptable carrier” can be administered to a subject (eg, a patient) with a compound of the embodiments disclosed herein, and when administered at a dosage sufficient to deliver a therapeutic amount of the compound. , Refers to a carrier or adjuvant that does not destroy its pharmacological activity and is non-toxic.

  Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the compositions of the disclosed embodiments include ion exchangers, alumina, aluminum stearate, lecithin, d-α-tocopherol phenylethylene glycol 1000 succinate. Surfactants used in pharmaceutical dosage forms such as self-emulsifier delivery systems (SEDDS), tween or other similar polymer delivery matrices, serum proteins such as human serum albumin, phosphate, glycine, sorbic acid, sorbine Buffer substances such as potassium acid, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica , Magnesium trisilicate, polyvinyl Including, but not limited to, pyrrolidone, cellulosic materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, polyethylene glycol, and wool oil. Chemically modified derivatives such as cyclodextrins such as α-, β- and γ-cyclodextrins or hydroxyalkyl cyclodextrins including 2- and 3-hydroxypropyl-β-cyclodextrins, or other soluble derivatives Can also be advantageously used to enhance delivery of compounds of the formulas described herein.

  Compositions for administration can take the form of bulk liquid solutions or suspensions or bulk powders. More generally, however, the composition is presented in unit dosage form to facilitate accurate dosing. The term “unit dosage form” refers to a physically discrete unit suitable as a single dosage for human subjects and other mammals, each unit, together with suitable pharmaceutical additives, producing the desired therapeutic effect. Containing a predetermined amount of active substance calculated as follows. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions or, in the case of solid compositions, pills, tablets, capsules, lozenges and the like. In such compositions, the compound will usually be a minor component (about 0.1 to about 50% by weight or preferably 1 to about 40% by weight) with the remainder being various media or carriers and the desired dosage form. It is a processing aid that helps to form.

  The dosage is generally determined empirically in routine trials depending on the compound formulation, route of administration, etc., and will necessarily vary depending on the target, host, route of administration and the like. In general, the amount of active compound in a unit dose of the formulation can vary or be adjusted from about 1 mg, 3 mg, 10 mg or 30 to about 30 mg, 100 mg, 300 mg or 1000 mg, depending on the particular application. In certain embodiments, packed into multiple packs adapted for continuous use, such as blister packs, which comprise at least 6, 9, or 12 unit dosage form sheets. The actual dosage used may vary depending on the requirements of the patient and the severity of the condition being treated. Determining the appropriate dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with lower dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the entire daily dose may be divided and administered several times during the day if desired.

The following are examples of capsule formulations (formulations 1 to 4).

Preparation of Solid Solution Crystalline carbazole (80 g / batch) and povidone (NF g 29/32 at 160 g / batch) are dissolved in methylene chloride (5000 mL). The solution is dried using a suitable solvent spray dryer and the residue is reduced to fine particles by grinding. Next, it is passed through a 30-mesh sieve and confirmed to be amorphous by X-ray analysis.

  Mix the solid solution, silicon dioxide and magnesium stearate with a suitable mixer for 10 minutes. The mixture is compressed with a suitable roller compressor and milled using a suitable mill adapted to a 30 mesh screen. Croscarmellose sodium, Pluronic F68 and silicon dioxide are added to the milled mixture and stirred for an additional 10 minutes. A premix is made with a mixture of magnesium stearate and the same amount. Add the premix to the rest of the mixture, mix for 5 minutes, and encapsulate the mixture in a hard gelatin capsule shell.

In one aspect of use , treating one or more diseases, disorders or conditions caused by or related to abnormal (eg, insufficient) neurogenesis or accelerated neuronal cell death in a subject in need of treatment (Eg, controlling, mitigating, improving, reducing, or delaying progression) or preventing (eg, delaying its onset or reducing the risk of occurrence). The method comprises subject to a compound of formula (I) as defined herein (and / or any compound of any other formula described herein) or a salt thereof (eg, a pharmaceutically acceptable salt). ) In an effective amount.

  In other aspects, treatment (eg, control, alleviate) of one or more diseases, disorders or conditions caused by or related to abnormal (eg, insufficient) neurogenesis or exacerbated neuronal cell death. A compound of formula (I) as defined herein (and / or in the manufacture of a medicament for improving, reducing or delaying progression) or prevention (e.g. delaying its onset or reducing the risk of occurrence) Or a compound of any of the other formulas described herein) or a salt thereof (eg, a pharmaceutically acceptable salt), or the use of a compound therefor.

  In certain embodiments, the one or more diseases, disorders or conditions may include neuropathy, neurotrauma and neurodegenerative diseases. In some embodiments, the one or more diseases, disorders, or conditions are abnormal (e.g., insufficient) neurogenesis (e.g., abnormal hippocampal neurogenesis as thought to occur in a neuropsychiatric disorder) or of existing neurons. It can be a disease, disorder or condition caused by or associated with accelerated death. Examples of one or more neuropsychiatric and neurodegenerative diseases include schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, posttraumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down's syndrome, Spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiotherapy, chronic stress and neurostimulant drugs (e.g. alcohol, opiates, methamphetamine, phencyclidine and cocaine), retinal degeneration, Including but not limited to spinal cord injury, peripheral nerve injury, physiological weight loss associated with various conditions and cognitive decline associated with normal aging, radiation therapy and chemotherapy. The resulting promotion of neurogenesis or survival of existing neurons (i.e. survival, proliferation, development, promotion and / or development of the resulting neurons) is due to abnormal neurogenesis or survival of existing neurons May be detected directly, indirectly or speculatively from an improvement or improvement in one or more symptoms of a disease or disorder that becomes or is associated with. Appropriate assays for directly or jointly detecting neuronal survival, proliferation, development, function and / or development are known in the art and include axonal regeneration in rat models (eg Park et al., Science. 2008 Nov 7; 322: 963-6), nerve regeneration in a rabbit facial nerve injury model (e.g. Zhang et al., J Transl Med. 2008 Nov 5; 6 (1): 67), regeneration of the sciatic nerve in a rat model (e.g. Sun et al. al., Cell Mol Neurobiol. 2008 Nov 6), protection against motor neurodegeneration in mice (eg Poesen et al., J. Neurosci. 2008 Oct 15; 28 (42): 10451-9); rat model of Alzheimer's disease ( Xuan et al., Neurosci Lett. 2008 Aug 8; 440 (3): 331-5), animal models of depression (e.g. Schmidt et al., Behav Pharmacol. 2007 Sep; 18 (5-6): 391-418 Krishnan et al., Nature 2008, 455, 894-902); and / or those exemplified herein.

Administration Compounds and compositions described herein, for example, from about 0.01 mg / kg to about 1000 mg / kg (eg, from about 0.01 to about 100 mg / kg, from about 0.1 to about 100 mg / kg, from about 1 to about Doses in the range of 100 mg / kg, about 1 to about 10 mg / kg) orally, parenterally (eg, subcutaneously, skin every 4 to 120 hours or according to specific drug requirements (Intravenous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and by intracranial injection or infusion), by inhalation spray, It can be administered topically, rectally, nasally, buccally, vaginally, via an implant reservoir, subcutaneously, intraperitoneally, by transmucosal injection, or in an ophthalmic formulation. The correlation between animal and human doses (based on milligrams per square meter of body surface) is described in Freireich et al., Cancer Chemother. Rep. 50, 219 (1966). Roughly determined from body surface area, patient height and weight. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). In certain embodiments, the composition is administered orally or by injection. The methods herein contemplate administration of an effective amount of the compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of the embodiments disclosed herein may be administered from about 1 to about 6 times daily or as a continuous infusion. Such administration can be used as a chronic or acute therapy.

  Lower or higher doses than those described above may be required. The specific dosage and treatment regimen for a particular patient will depend on the activity, age, weight, general health status, sex, dietary habits, administration time, excretion rate, concomitant medications, disease, condition or symptoms of the specific compound used. Depends on a variety of factors, including patient severity and severity of the course, disease, condition or symptoms and the judgment of the treating physician

  As the patient's condition improves, maintenance doses of the compounds, compositions or combinations disclosed herein may be administered as needed. Thereafter, when the symptoms are improved to a desired level, the dose and / or frequency of administration may be reduced to a level that maintains an improved state depending on the symptoms. However, patients may require long-term intermittent treatment due to recurrence of disease symptoms.

  In certain embodiments, the compounds described herein can be used in combination with one or more other therapeutic agents. In certain embodiments, the additional agent is separated from the compound of the presently disclosed embodiments separately as part of a multiple dosage regimen (e.g., one or more compounds of formula (I) (any sub-formula or specific compound thereof) (E.g., differently and sequentially on an overlapping schedule). In other embodiments, these agents can be part of a single dosage form mixed with a compound of the embodiments disclosed herein in one composition. In yet another embodiment, these agents are administered separately at about the same time as one or more compounds of formula (I) (including any subformula or specific compound thereof) are administered (eg, one And can be co-administered with the compounds of formula (I) above (including any sub-formula or specific compound). When a composition of the disclosed embodiments includes a compound of the formulas described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent are normally administered in a monotherapy regimen. It can be present at a dosage of about 1-100%, more preferably about 5-95% of the dosage.

  The compositions of the embodiments disclosed herein can comprise any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or vehicle. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.

  The composition may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oily suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents (eg, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the manufacture of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially polyoxyethylated forms thereof. These oil solutions or suspensions are also long chain alcohol diluents or dispersants or carboxymethylcellulose or similar dispersions commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and / or suspensions. Agents can be included. Other commonly used surfactants such as Tweens or Spans and / or other similar emulsifiers or bioavailability enhancers commonly used in the production of pharmaceutically acceptable solid, liquid or other dosage forms It can be used for formulation purposes.

  Compositions of the embodiments disclosed herein are orally administered in orally acceptable dosage forms including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. Good. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. A lubricant such as magnesium stearate is also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and / or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

  Compositions of the embodiments disclosed herein can also be administered in the form of suppositories for rectal administration. These compositions are prepared by mixing the compounds of the presently disclosed embodiments with a suitable nonirritating additive that is solid at room temperature but liquid at rectal temperature and therefore dissolves in the rectum to release the active ingredient. it can. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

  Topical administration of the compositions of the embodiments disclosed herein is useful when the desired treatment involves areas or organs that are easily accessible by topical application. For topical application to the skin, the composition should be formulated as a suitable ointment containing the active component suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the presently disclosed embodiments include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the composition can be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The compositions of the embodiments disclosed herein can also be applied topically to the lower gastrointestinal tract by rectal suppository formulation or a suitable enema formulation.

  In certain embodiments, topical administration of the compounds and compositions described herein may be presented in the form of an aerosol, semi-solid pharmaceutical composition, powder or solution. The term “semi-solid composition” includes ointments, creams, salves, jellies or other pharmaceutical compositions of substantially similar years suitable for administration to the skin. Examples of semi-solid compositions are described in Chapter 17 of The Theory and Practice of Industrial Pharmacy, Lachman, Lieberman and Kanig, published by Lea and Febiger (1970) and Remington's Pharmaceutical Sciences, 21st Edition, which are incorporated herein by reference in their entirety. (2005) Published by Mack Publishing Company

  Topically transdermal patches are also included in the embodiments disclosed herein. Also within the scope of the embodiments disclosed herein are patches for delivering active chemotherapeutic combinations herein. The patch includes a material layer (eg, polymer, cloth, gauze, bandage) and a compound of the formula shown herein. One side of the material layer may have an adhered protective layer that prevents the passage of the compound or composition. The patch can further include an adhesive to secure the patch to the subject in place. An adhesive is a composition, including one of natural or synthetic origin, that temporarily contacts the skin when in contact with the subject's skin. It can be waterproof. The adhesive can be placed on the patch to maintain contact with the subject's skin for an extended period of time. Adhesives are composed of sticky or adhesive strength that keeps the device in incidental contact with the subject, but by aggressive action (e.g. tearing off, peeling, or other intentional removal) The adhesive yields to external pressure on the device or the adhesive itself, allowing the adhesive contact to break. The adhesive may be pressure sensitive, i.e. placing the adhesive (and the device attached to the skin) against the skin by applying pressure (e.g. pressing, rubbing) on the adhesive or device. Enable.

  The compositions of the embodiments disclosed herein can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical formulation art and are known to be benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and / or the art. Other solubilizers or dispersants may be used and prepared as a solution in saline.

  A composition comprising a compound of the formula herein and an additional agent (eg, a therapeutic agent) can be administered using any route of administration described herein. In certain embodiments, a composition comprising a compound of the formula herein and an additional agent (eg, a therapeutic agent) can be administered using an implantable device. Implant devices and related techniques are known in the art and are useful as delivery meters when continuous or sustained release delivery of the compounds or compositions described herein is desired. In addition, implantable device delivery systems are useful for targeting specific points of compound or composition delivery (eg, localization sites, organs). Negrin et al., Biomaterials, 22 (6): 563 (2001). Sustained release techniques including alternate delivery methods can also be used in the embodiments disclosed herein. For example, sustained release formulations based on polymer techniques, sustained release techniques and encapsulation techniques (eg, polymers, liposomes) can also be used to deliver the compounds and compositions described herein.

  The embodiments disclosed herein are further described in the following examples. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the embodiments disclosed herein in any way.

Examples 1a and 1b. P7C3-S16 and P7C3-S17: S- and R-1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propane-2 -All

Typical method 1.
Step 1. Synthesis of 3,6-dibromo-9- (oxiran-2-ylmethyl) -9H-carbazole (epoxide 2-A)
According to literature methods (Asso, V .; Ghilardi, E .; Bertini, S .; Digiacomo, M .; Granchi, C .; Minutolo, F .; Rapposelli, S .; Bortolato, A .; Moro, S. Macchia, M. ChemMedChem, 2008, 3, 1530-1534), powdered KOH (0.103 g, 1.85 mmol) was added to a solution of 3,6-dibromocarbazole (0.500 g, 1.54 mmol) in DMF (1.5 mL). And stirred at ambient temperature for 30 minutes until dissolved. Epibromohydrin (0.32 mL, 3.8 mmol) was added via syringe and the reaction was stirred at room temperature overnight. Upon completion, the solution was partitioned between EtOAc and _{H 2} O. The aqueous layer was washed 3 times with EtOAc, and the combined organic layers were washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was recrystallized from EtOAc / hexanes to give the desired product (389 mg, 66%).
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.10 (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), 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] ⁺ , C ₁₅ H ₁₂ Br ₂ NO calculated 379.9)

Typical method 2
Step 2. Synthesis of 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol
According to literature methods (Asso, V .; Ghilardi, E .; Bertini, S .; Digiacomo, M .; Granchi, C .; Minutolo, F .; Rapposelli, S .; Bortolato, A .; Moro, S. Macchia, M. ChemMedChem, 2008, 3, 1530-1534), m-anisidine (1.0 mL, 8.95 mmol) was added to a suspension of epoxide 2-A (3.02 g, 7.92 mmol) in cyclohexane (73 mL). . BiCl ₃ (0.657 g, 2.08 mmol) was added and the mixture was refluxed overnight. Upon completion, the reaction was partitioned between EtOAc and _{H 2} O. The aqueous layer was washed 3 times with EtOAc, and the combined organic layers were washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was chromatographed _(SiO 2, _0~50% EtOAc / hexanes) to give the desired alcohol as an opaque yellow solid (998 mg, 25%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 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, 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, 2.4 Hz), 4.34-4.39 (m, 3H), 4.00 (br s, 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 (br s, 1H)
¹³ C NMR (CDCl ₃ , 100 MHz) δ 161.0, 149.2, 139.9 (2C), 130.4 (2C), 129.5 (2C), 123.8 (2C), 123.5 (2C), 112.8, 111.0 (2C), 106.7, 103.8 , 99.8, 69.5, 55.3, 48.0, 47.4
ESI m / z 502.9 ([M + H] ⁺ , C ₂₂ H ₂₁ Br ₂ N ₂ O ₂ calculated 503.0)

Step 3. 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-yl 3,3,3-trifluoro-2-methoxy-2- Synthesis of phenylpropanoate
1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol (0.150 g, 0.298 mmol) was dissolved in anhydrous dichloromethane (6 mL). And cooled to 0 ° C. Pyridine (0.053 mL, 0.655 mmol) followed by S-(+)-α-methoxy-α-trifluoromethylphenylacetyl chloride (S-mosher acid chloride, 0.083 mL, 0.446 mmol) and dimethylaminopyridine (0.004 g, 0.030 mmol) was added. The reaction was warmed to room temperature over 4 hours and then quenched by the addition of saturated aqueous NaHCO ₃ solution. The mixture was extracted three times with EtOAc and the combined organic layers were washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was chromatographed _(SiO 2, _0~50% EtOAc / hexanes) to give the ester both and possible amide mixture of the two ⁽⁵ in 1 H NMR: 1 ester: amide ratio 132 mg, 64%). Separation of the mixture using HPLC (Phenomenex SiO ₂ Luna, 21 × 250 mm, 15% EtOAc / hexane, 16 mL / min; HPLC retention time: 25.6 min (ester 1) and 41.2 min (ester 2)) I went.
Ester 1: ¹ H NMR (CDCl ₃ , 500 MHz) δ 8.11 (d, 2H, J = 2.0 Hz), 7.45 (dd, 2H, J = 8.5 Hz), 7.24 (m, 2H), 7.22 (m, 4H ), 7.05 (t, 1H, J = 8.0 Hz), 6.32 (dd, 1H, J = 2.0, 8.0 Hz), 6.12 (dd, 1H, J = 2.0, 8.0 Hz), 6.05 (dd, 1H, J = 2.0, 2.5 Hz), 5.59 (m, 1H), 4.54 (d, 2H, J = 6.5 Hz), 3.71 (br s, 1H), 3.69 (s, 3H), 3.43 (m, 1H), 3.29 (ddd , 1H, J = 5.5, 13.5 Hz), 3.19 (s, 3H)
Ester 2: ¹ H NMR (CDCl ₃ , 500 MHz) δ 8.08 (d, 2H, J = 2.0 Hz), 7.42 (dd, 2H, J = 2.0, 9.0 Hz), 7.28 (m, 2H), 7.24 (m , 4H), 7.04 (t, 1H, J = 8.0 Hz), 6.31 (dd, 1H, J = 2.0, 8.5 Hz), 6.11 (dd, 1H, J = 2.0, 8.0 Hz), 6.01 (dd, 1H, J = 2.0, 2.5 Hz), 5.63 (m, 1H), 4.49 (d, 2H, J = 6.5 Hz), 3.82 (dd, 1H, J = 5.5, 6.0 Hz), 3.66 (s, 3H), 3.42 ( s, 3H), 3.39 (m, 1H), 3.28 (dd, 1H, J = 5.0, 13.5 Hz)

Step 4. Synthesis of S- and R-1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol
According to literature methods (Abad, JL .; Casas, J .; Sanchez-Baeza, F .; Messeguer, AJ Org. Chem. 1995, 60, 3648-3656), ester 1 of Example 3 (0.011 g, 0. 015 mmol) was dissolved in degassed Et ₂ O (0.150 mL) and cooled to 0 ° C. Lithium aluminum hydride (1M in THF, 0.018 mL, 0.018 mmol) was added via syringe and the reaction was stirred for 20 minutes. After confirming the completion of the reaction by TLC, the reaction was stopped by the addition of MeOH and stirred for 45 minutes. The mixture was partitioned between EtOAc and _{H 2} O. The aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was chromatographed _(SiO 2, _0~30% EtOAc / hexanes) to give the desired alcohol (4.7 mg, 64%).
(From ester 1): [α] _D = + 10 ° (c = 0.1, CH ₂ Cl ₂ ); Example 1a
(From ester 2): [α] _D = −14 ° (c = 0.1, CH ₂ Cl ₂ ); Example 1b

Example 2. P7C3-S5: 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (2-iminopyridin-1 (2H) -yl) propan-2-ol
The compound of Example 2 was prepared according to Exemplary Method 2, except for a reaction time of 80 ° C. for 2 days. The crude product was used without further purification.
¹ H NMR (CDCl ₃ , 400 MHz) d = 8.14 (2H, J = 1.9 Hz), 7.55 (dd, 2H, J = 1.9, 8.8 Hz), 7.35 (d, 2H, J = 8.7 Hz), 6.83 ( t, 1H, J = 7.6 Hz), 6.37 (d, 1H, J = 6.8), 6.32 (d, 1H, J = 9.1 Hz), 5.65 (t, 1H, J = 6.7 Hz), 4.39 (dm, 5H ), 3.54 (d, 1H, J = 13.9 Hz) .MS (ESI), m / z: Measured value 473.9 (M + 1) ⁺ ([M + 1] + calculation of C ₂ 0H ₁₈ Br ₂ N ₃ O (Value 474.0)

Example 3a. P7C3-S7: 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylthio) propan-2-ol
Benzenethiol (30 μl, 0.29 mmol) was added to 3,6-dibromo-9- (oxiran-2-ylmethyl) -9H-carbazole (epoxide 2-A, 101.6 mg, 0.27 mmol) in MeOH (5.0 ml). ) Added to the solution at room temperature. The reaction mixture was heated to 80 ° C. and stirred overnight at the same temperature. The reaction was monitored at lc / ms by consumption of starting material. The reaction was cooled, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.03 (d, 2H, J = 2.1 Hz), 7.48 (dd, 2H, J = 2.0, 8.7 Hz), 7.33-7.20 (m, 7H), 4.33 (dd, 1H, J = 4.3, 14.9 Hz), 4.20 (dd, 1H, J = 6.9, 14.9 Hz), 4.00-4.12 (m, 1H), 3.05 (dd, 1H, J = 5.3, 13.9 Hz), 2.93 (dd , 1H, J = 7.2, 13.9 Hz), 2.51 (bs, 1H); ¹³ C NMR (CDCl ₃ , 126 MHz) δ 139.9, 134.5, 130.4, 129.6, 129.4, 127.4, 123.8, 123.4, 112.7, 111.1, 69.3 , 48.1, 39.4; MS (ESI), m / z: Found: 505.9 [M + O-1] ^- ([M + O-1] -calculated value of C ₂₁ H ₁₇ Br ₂ NOS 504.9; MS conditions Under oxidation; NMR is inconsistent with sulfoxide)

Example 3b. P7C3-S39: 1- (3,6-dibromo-9H-carbazol-9-yl) -3-phenoxypropan-2-ol
Following representative method 1, the title compound of Example 3b was obtained in 61% yield from dibromocarbazole and phenoxymethyloxirane.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.14 (d, 2H, J = 1.9 Hz), 7.51 (dd, 2H, J = 1.9, 8.7 Hz), 7.36 (d, 2H, J = 8.8 Hz), 7.127 -7.32 (m, 2H), 7.00 (t, 1H, J = 7.3 Hz), 6.87 (dd, 2H, J = 0.8, 8.9 Hz), 4.58 (dd, 1H, J = 7.9, 16.7 Hz), 4.41- 4.49 (m, 2H), 4.00 (dd, 1H, J-4.4, 9.6 Hz), 3.89 (dd, 1H, J = 4.5, 9.5 Hz), 2.38 (d = 1H, J = 5.7 Hz). MS (ESI ), m / z: 517.9 [ M + HCOO] - ( of _{C 21 H 17 Br 2 NO 2} [M + HCOO] - calculated 518.0

Example 3c. P7C3-S27: 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylsulfinyl) propan-2-ol
NaIO ₄ (5.14 g) in water was added to silica gel (20 g) and shaken until it became a free flowing solid. Thio-ether (1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylthio) propan-2-ol, (0.0120 g, 0.0244 mmol) and NaIO ₄ / silica gel (0.0 1018 g NaIO ₄ , 0.122 mmol) was suspended in CH ₂ Cl ₂ (1 mL) The white suspension was heated at 50 ° C. in a sealed vial for 4 h until TLC showed complete consumption of starting material. The reaction mixture was chromatographed on silica gel using hexane / EtOAc (1: 9) to give 0.0081 g of white solid as product, with 65.4% 1: 1 of diastereomers. Obtained as a mixture.
¹ H NMR (CDCl ₃ , 400 MHz) δppm = 2.39 (dd, J = 13.7, 1.7 Hz, 1 H diastereomer A) 2.83 (dd, J = 13.2, 2.9 Hz, 1 Dias. B) 2.97 (dd, J = 13.2, 8.6 Hz, 1 H Diast. B) 3.15 (dd, J = 13.7, 9.3 Hz, 1 H Diast. A) 3.90 (d, J = 1.7 Hz, 1 H Dias. B) 3.96 (d, J = 2.6 Hz, 1 H Diast. A), 4.24 (dd, J = 15.0, 6.3 Hz, 1H Dias A), 4.30 (dd, J = 15.2, 6.7, 1H Diast. B), 4.35 (dd, J = 15.2 , 6.0 Hz, 1 H Diast. B), 4.45 (dd, J = 15.1, 6.4 Hz, 1H Diast. B), 4.65-4.55 (m, 1 H Diast. A) 4.87-4.76 (m, 1 H Diast. B) 7.16 (d, J = 8.7 Hz, 2 H Diast. A) 7.34 (d, J = 8.8 Hz, 2H Diast B) 7.60-7.30 (m, 7 H Diast A +7 H Dast. B) 8.08 (d , J = 1.9 Hz, 2 H Diast. A) 8.13 (d, J = 1.9 Hz, 2 H Diast B). MS (ESI) m / z: 549.9 [M + HCOO] ^- (C ₂₁ H ₁₇ Br ₂ NO of ₂ S [M + CHOO] ^- calculated 549.9)

Example 3d. P7C3-S28: 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylsulfonyl) propan-2-ol
Thio-ether (1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylthio) propan-2-ol, (0.0113 g, 0.0230 mmol) of CH ₂ Cl ₂ (0. To the solution was added dropwise a solution of mCPBA (ca. 77% purity, 0.0129 g, 0.0575 mmol) in CH ₂ Cl ₂ (0.5 mL) The mixture was stirred overnight at room temperature The crude reaction mixture was Et _3. Neutralized with N (9 mL), stirred for 30 min, diluted with EtOAc (30 mL) and washed with saturated NaHCO ₃ (3 × 30 mL) and brine (1 × 30 mL) The organic layer was dried over anhydrous Na ₂ SO ₄ . Drying and evaporation gave the crude product, which was subjected to silica gel chromatography using hexane / EtOAc (3: 7) to give a white solid as product (0.0120 g, yield). 99.7%).
¹ H NMR (CDCl ₃ , 400 MHz) δ ppm 3.15 (dd, J = 14.2, 3.0 Hz, 1 H) 3.21-3.31 (m, 2 H) 4.38 (d, J = 6.3 Hz, 2 H) 4.60-4.76 (m, 1 H) 7.25-7.31 (m, 2 H) 7.47-7.56 (m, 4 H) 7.60-7.70 (m, 1H) 7.79 (dd, J = 8.4, 1.2 Hz, 2 H) 8.11 (d, J = 1.9 Hz, 2 H) ; MS (ESI) m / z: 565.9 [M + HCOO]; 543.7 [M + Na] + ([M + HCOO] of _{C 21 H 17 Br 2 NO 3} S - calculated 595.9; [M + Na] + calculated value 543.9)

Example 4. P7C3-S9: N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -N- (3-methoxyphenyl) acetamide
According to literature methods (Morcuende et al., J. Org. Chem. 1996, 5264-5270), triethylamine (14 μl, 0.10 mmol) and acetyl chloride (8 μl, 0.11 mmol) in anhydrous toluene (1.5 ml). 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol (53 mg, 0.11 mmol) and dibutyltin oxide (5.5 mg, 0.022 mmol) ) To the heterogeneous mixture. The reaction vessel was vented with nitrogen, sealed, and heated at 150 ° C. for 9 minutes under microwave irradiation. The reaction was monitored at lc / ms and all starting material was consumed. The heterogeneous solution was filtered under reduced pressure to give a white solid. The crude product was used without further purification.
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.09 (2H, J = 1.6 Hz), 7.52 (dd, 2H, J = 1.8, 8.7 Hz), 7.29 (d, 2H, J = 8.8 Hz), 7.26 (t , 1H, J = 8.2 Hz), 6.86 (dd, 1H, J = 2.5, 8.4 Hz), 6.68 (dd, 1H, J = 1.3, 7.7 Hz), 6.62 (s, 1H,), 4.33-4.40 (m , 1H), 4.29 (dd, 2H, J = 2.6, 6.0 Hz), 3.94 (d, 1H, J = 4.1 Hz), 3.76 (s, 3H), 3.51 (dd, 1H, J = 2.3, 14.0 Hz) , 1.9 (s, 3H);
¹³ C NMR (CDCl3, 126 MHz) δ 173.6, 160.9, 144.5, 139.9, 131.0, 129.4, 123.8, 123.4, 119.7, 113.9, 113.5, 112.6, 111.1, 70.9, 55.7, 55.2, 46.0, 22.8
MS (ESI), m / z: 544.9 (M + 1) ⁺ ([M + 1] of C ₂₄ H ₂₂ Br ₂ N ₂ O ₃ ⁺ calculated value 545.0)

Example 5. P7C3-S12: 5-((3,6-dibromo-9H-carbazol-9-yl) methyl) -3- (3-methoxyphenyl) -oxazolidine-2-one
Methyl chloroformate (10 μl, 0.13 mmol) was added to a stirred solution of jn-128-186 (55.0 mg, 0.11 mmol) and indium powder (3.5 mg, 0.030 mmol) in acetonitrile (3.0 ml). And the reaction mixture was stirred overnight at room temperature. An additional 3.1 mg (0.027 mmol) of indium and 20 μl (2.6 equivalents) of methyl chloroformate were added. After several hours, the reaction was diluted with ethyl acetate and washed with water followed by brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The methyl carbonate was purified by flash chromatography with 20-40% ethyl acetate / hexane. Sodium methoxide (3.0 ml) was added to a solution of carbonic acid (21.3 mg, 0.038 mmol) and methanol (1.0 ml). After 1 hour at ambient temperature, the solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine and concentrated.
¹ H NMR (CD ₃ COCD ₃ , 500 MHz) δ8.40 (s, 2H), 7.78 (d, 2H, J = 8.5 Hz), 7.64 (d, 2H, J = 8.9 Hz), 7.23-7.28 (m , 2H), 7.05 (d, 1H, J = 8.3 Hz), 6.70 (d, 1H, J = 8.3 Hz), 5.24-5.31 (m, 1H), 5.00 (dd, 1H, J = 7.9, 15.7 Hz) , 4.91 (dd, 1H, J = 3.2, 15.8 Hz), 4.38 (t, 1H, J = 9.3 Hz), 4.05 (m, 1H), 3.78 (s, 3H);
¹³ C NMR (CDCl3, 126 MHz) δ 160.4, 153.9, 140.3, 140.2, 129.8, 129.4, 124.0, 123.5, 112.4, 112.1, 110.3, 109.0, 104.4, 71.9, 54.9, 47.9, 46.6
MS (ESI), m / z: 528.9 (M + 1) ⁺ ([M + 1] of C ₂₃ H ₁₉ Br ₂ N ₂ O ₃ ⁺ calculated value 529.0)

Example 6a. 7C3-S10: N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline (also known as “P7C3A20”)

Representative Method 3: Epoxide Ring Opening with N-Protected Aniline N- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -N- (3-methoxyphenyl)- 4-nitrobenzenesulfonamide
A heterogeneous mixture of N- (4-methoxyphenyl) -4-nitrobenzenesulfonamide (100.2 mg, 0.32 mmol) in toluene (2.5 ml, 0.13 M) was added to a dry ice / acetone bath under N ₂ atmosphere. N-Butyllithium (200 μl 1.78 M in hexane, 0.36 mmol) was added dropwise. The reaction was stirred at −78 ° C. for 10 minutes and carbazole epoxide 2-A was added. The heterogeneous mixture was stirred at room temperature for 5 minutes and heated at 100 ° C. for 48 hours. The cooled reaction was diluted with EtOAc, washed 3 times with 5% acetic acid solution and washed with brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude mixture was purified with 100% dichloromethane. Yield = 88%.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.23 (d, 2H, J = 8.5 Hz), 8.06 (d, 2H, J = 1.9 Hz), 7.65 (d, 2H, J = 8.5 Hz), 7.46, ( dd, 2H, J = 8.6, 1.9 Hz), 7.22 (d, 2H, J = 8.8 Hz), 6.94 (d, 2H, 8.8 Hz), 6.83 (d, 2H, 9.1 Hz), 4.44 (dd, 1H, J = 14.9, 3.6 Hz), 4.26-4.34 (m, 1H), 4.17-4.24 (bs, 1H), 3.81 (s, 3H), 3.62-3.75 (m, 2H). MS (ESI), m / z ^{: 732.0 [(M + HCOO -} ); C 28 H 23 Br 2 N 3 O 6 S (M) calcd 687]

Representative Method 4: Fluorinated N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -N- (3-methoxyphenyl) -4-nitrobenzene of secondary alcohol Sulfonamide
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -N- (3-methoxyphenyl) -4-nitrobenzenesulfonamide (18.3 mg, 0.027 mmol; An oven-dried 20 ml scintillation vial containing the above representative method 3) was aerated with N ₂ and charged with anhydrous dichloromethane (1.5 ml, 0.018M). The sealed vial was cooled with a dry ice / acetone bath and diethylaminosulfur trifluoride (DAST, 7 μl, 0.053 mmol) was added dropwise. The reaction temperature was maintained at −78 ° C. for 1 hour, then slowly warmed to room temperature and stirred overnight. The reaction was quenched with saturated NaHCO ₃ solution (2.0 ml), diluted with CH ₂ Cl ₂ (6 ml) and extracted three times. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was then used. Quantitative yield.
Alternatively, morpholino sulfur trifluoride (MORPHO-DAST) may be used at room temperature.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.28 (d, 2H, J = 8.0 Hz), 8.13 (s, 2H), 7.72 (d, 2H, J = 8.7 Hz), 7.54, (d, 2H, J = 8.0 Hz), 7.21 (d, 3H, J = 8.1 Hz), 6.89 (dd, 1H, 8.3, 2.4 Hz), 6.67 (t, 1H, J = 2.0 Hz), 6.55 (d, 1H, J = 8.0 Hz) 4.93 (m, 1H), 4.43-4.68 (m, 2H), 4.20 (t, 1H, J = 6.2 Hz), 3.81-3.99 (m, 2H), 3.75 (s, 3H)
MS (ESI), m / z : Calculated 688.96, Found 733.9 (M + HCOO ^-)

Typical method 5: Nosyl group deprotection (see Fukuyama, T .; Jow, C.-K .; Cheung, M. Tetrahedron Lett. 1995, 36, 6373-6374)
N- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -N- (3-methoxyphenyl) -4-nitrobenzenesulfonamide (21.0 mg, 0.030 mmol; To a vial containing representative method 4) lithium hydroxide (3.2 mg, 0.134 mmol), dimethylformamide (0.5 ml, 0.06 M) and mercaptoacetic acid (4.2 μl, 0.060 mmol) were added. . After stirring at room temperature for 1 hour, the reaction mixture was diluted with EtOAc and washed successively with water, saturated sodium bicarbonate solution, water (3 ×) and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude reaction mixture was purified with 30% EtOAc / hexane (+ 0.2% TEA) and 13.6 mg was isolated. Yield = 88%

Further Representative Methods DAST [(Et ₂ NSF ₃ ) 0.12 ml, 0.916 mmol] was converted to 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propane- To a solution of 2-ol (0.102 g, 0.203 mmol) in anhydrous DCM (6.0 ml) was added dropwise at -78 ° C. The reaction was stirred at −78 ° C. for 1 hour and slowly warmed to 0 ° C. over 5 hours. The reaction was quenched with phosphate buffer (pH = 8) and extracted with DCM. The aqueous layer was extracted twice with DCM (10 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude reaction was purified by flash chromatography on SiO ₂ (20% EtOAc / hexane / 0.2% TEA). The fraction containing the desired fluorinated product was further purified with 40% EtOAc / hexanes (+ 0.1% TEA). 5.7 mg of the desired product was isolated.

Analytical data for the title compound of Example 6a
¹ H NMR (CDCl ₃ , 500 MHz) δ8.16 (2H, J = 2.0 Hz), 7.56 (dd, 2H, J = 1.9, 8.7 Hz), 7.31 (d, 2H, J = 8.6 Hz), 7.11 ( t, 1H, J = 8.1 Hz), 6.36 (dd, 1H, J = 2.2, 8.1 Hz), 6.23 (dd, 1H, J = 2.0, 8.0 Hz), 6.15 (t, 1H, J = 2.3 Hz), 5.11 (dddd, 1H, J = 4.6, 5.8, 10.4, 47.7 Hz), 4.60 (m, 2H), 4.39 (dm, 2H), 3.95 (t, 1H, J = 6.3 Hz), 3.75 (s, 3H)
MS (ESI), m / z: 504.9 (M + 1) ^+. ([M + 1] ⁺ calculated value 505.0 of C ₂₂ H ₁₉ Br ₂ FN ₂ O)

P7C3-S10 (also known as P7C3A20) gram scale synthesis 3,6-dibromo-9- (oxiran-2-ylmethyl) -9H-carbazole
Two sets of reactions were set up. 3,6-Dibromocarbazole (49.61 and 51.98 g, 152.6 and 159.9 mmol, respectively) and crushed potassium hydroxide pellets (11.1 and 10.6 g, 197.8 and 188.9 mmol, respectively) Formamide (1 L each) was stirred for 1 hour and epibromohydrin (32 and 35 ml, 386.6 and 422.9 mmol, respectively) was added. The reaction was stirred overnight. Each reaction was worked up by dilution with EtOAc and washed several times with water followed by brine. The organic layer was dried over MgSO ₄ , filtered and concentrated. The off-white solid was washed with a minimum amount of EtOAc to give 95.2 g of epoxide in 80% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.15 (d, J = 1.9 Hz, 2H), 7.58 (dd, J = 8.6, 2.0 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 4.66 (dd, J = 16.0, 2.7 Hz, 1H), 4.29 (dd, J = 15.9, 5.1 Hz, 1H), 3.33 (ddd, J = 6.7, 5.2, 2.8 Hz, 1H), 2.82 (t, J = 4.3 Hz, 1H), 2.50 (dd, J = 4.7, 2.6 Hz, 1H)

1,1,1-trifluoro-N- (3-methoxyphenyl) methanesulfonamide
A solution of trifluoromethanesulfone anhydride (45 ml, 26.7 mmol) in methylene chloride (250 ml) was added to ice-cooled m-anisidine (25 ml, 22.3 mmol) and triethylamine (39 ml, 28.0 mmol) in methylene chloride (1.25 L). ) Added to the solution. The reaction was stirred overnight at room temperature. The post-treatment was performed in two parts. Each of the two parts was basified by the addition of 2.5N NaOH solution (250 ml) and MeOH (625 ml). The aqueous layer was extracted three times with methylene chloride (100 ml each) to remove unreacted aniline or doubly triflated product. The aqueous layers were combined, the aqueous layers were combined, acidified to pH 2 with 18% HCl, and extracted again with methylene chloride three times. The organic layer is dried over MgSO ₄ , filtered and concentrated to produce 17.69 g of a brown solid in 77% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.48-7.13 (m, 1H), 6.97-6.61 (m, 3H), 3.82 (m, 3H).
MS (ESI), m / z: Calculated 255.21, Measured 255.9 (M + 1) ⁺

N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -1,1,1-trifluoro-N- (3-methoxyphenyl) methanesulfonamide (P7C3- (S244)
1,1,1-trifluoro-N- (3-methoxyphenyl) methanesulfonamide (22.07 g, 86.5 mmol) in N-butyllithium (2.5 M in hexane, 48 ml) in ice-cold ( 145 ml) solution was added dropwise over 40 minutes. The solution was stirred at room temperature for 15 minutes and 3,6-dibromo-9- (oxiran-2-ylmethyl) -9H-carbazole (25.05 g, 65.7 mmol) was added and heated at 90 ° C. for 1 hour. These conditions were optimized for maximum conversion while minimizing the formation of aziridene byproducts. The reaction was cooled to room temperature, diluted with ethyl acetate (1.2 L), washed several times with water and finally with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated to give an orange viscous mixture. To this mixture was added 60% methylene chloride / hexane (150 ml) and the solution was concentrated to give a yellow foam (perhaps this step helps remove residual ethyl acetate and / or dioxane). Further 60% methylene chloride / hexane (150 ml) was added and stirred overnight. The mixture was filtered and washed several times with 60% methylene chloride / hexanes until the solid was white to give 20.1 g of 99% purity. The second crystal obtained 2.98 g with 91% purity. The resulting mixture of filtrate and washings contained SM: product: aziridene byproduct at 2: 2.6: 1. This mixture was subjected to amination conditions in which a mixture (24 g of about 2 equivalents) was heated overnight in a sealed pressure tube at 100 ° C. in a solution of ammonia in methanol (7 N, 11 and 8 ml each). Epoxide SM is converted to β-hydroxyamine (MacMillan et al., J. Am. Chem. Soc. 2011, 133, 1428), which facilitates chromatographic purification. An additional 9.7 g of product was obtained by column chromatography with 80% DCM / hexane. The total yield was 32.78 g, and the yield was 78%.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.13 (d, J = 1.9 Hz, 2H), 7.54 (dd, J = 8.7, 1.9 Hz, 2H), 7.33 (t, J = 8.1 Hz, 1H), 7.22 (d, J = 8.7 Hz, 2H), 6.95 (dd, J = 8.4, 2.3 Hz, 2H), 6.88 (s, 1H), 4.56- 4.10 (m, 4H), 3.99 (m, 1H), 3.81 ( s, 3H), 1.98 (d, J = 4.2 Hz, 1H)
MS (ESI), m / z: Calculated value 633.94, Actual value 678.6 (M + HCOO) ^-

3,6-Dibromo-9-((1- (3-methoxyphenyl) aziridin-2-yl) methyl) -9H-carbazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (d, J = 1.9 Hz, 2H), 7.40 (dd, J = 8.7, 1.9 Hz, 2H), 7.26 (d, J = 8.7 Hz, 2H), 6.84 (t, J = 8.1 Hz, 1H), 6.31 (dd, J = 8.2, 2.4 Hz, 1H), 6.12- 5.94 (m, 1H), 5.84 (t, J = 2.2 Hz, 1H), 4.42 (dd, J = 15.4, 2.8 Hz, 1H), 3.94 (dd, J = 15.4, 8.0 Hz, 1H), 3.33 (s, 3H), 2.22 (dq, J = 8.7, 3.0 Hz, 1H), 2.16 (d, J = 3.3 Hz, 1H), 2.02 (d, J = 6.3 Hz, 1H)
MS (ESI), m / z: Calculated 483.98, Measured 484.7 (M + 1) ⁺

N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -1,1,1-trifluoro-N- (3-methoxyphenyl) methanesulfonamide (P7C3- S241)
Morpholinosulfur trifluoride (14.0 ml, 115 mmol) was added to N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -1,1,1-trifluoro- N- (3-Ethoxyphenyl) methanesulfonamide (20.6 g, 32.4 mmol) was added to a solution of anhydrous methylene chloride (315 ml) and stirred overnight. The solution was neutralized by dropwise addition of a solution in a water bath at ambient temperature, saturated bicarbonate solution (375 ml). The biphasic mixture was extracted twice with methylene chloride. The combined organic layers were dried over MgSO ₄ , filtered and concentrated to give 21.5 g of off-white foam in quantitative yield.
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.15 (d, J = 1.9 Hz, 2H), 7.56 (dd, J = 8.7, 1.9 Hz, 2H), 7.32 (t, J = 8.2 Hz, 1H), 7.21 (d, J = 8.6 Hz, 2H), 6.99- 6.90 (m, 2H), 6.86 (m, 1H), 5.08- 4.86 (dm, 1H), 4.57- 4.44 (m, 2H), 4.09 (m, 2H ), 3.79 (s, 3H)
MS (ESI), m / z: Calculated value 635.93, Actual value 680.6 (M + HCOO ^- ) ^-

P7C3-S10 (P7C3A20): N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -1,1,1-trifluoro-N- (3-methoxyphenyl) methanesulfonamide (5. A two-necked flask containing 00 g, 7.83 mmol) was bubbled with N ₂ and degassed xylene (52.0 ml) was added. The solution was cooled in a dry ice / acetone bath, was added dropwise Red-Al ^(R) (sodium bis (2-methoxyethoxy) 65% wt toluene solution of aluminum hydride, 11.0 ml, 36.1 mmol), and the internal between The temperature was maintained between -50 and -40 ° C. The cooling bath was removed immediately after completion of the Red-Al addition. The reaction was slowly warmed to about −23 ° C. at which point the reaction flask was transferred to a heating block. The reaction flask was heated to an internal temperature of 59.3-62.0 ° C. Heating was continued for 1 hour and the mixture was cooled to ambient temperature over 30 minutes. Analysis by HPLC / MS-ESI confirmed the following. 92% consumption of starting material, 75% product was obtained (N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline), 1% carbazole And 7% des-bromo degradation product, 3% N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -1,1,1-trifluoro-N- (3-Methoxyphenyl) methanesulfonamide and less than 5% elimination product were obtained (P7C3-S179). The reaction mixture was diluted with EtOAc and washed with water until no white solid Al salt was observed. The organic layer was washed several times with 6M HCl until a yellow precipitate formed. The hydrochloride salt was collected by filtration to give 3.60 g (85% yield). This salt formation removed carbazole decomposition products, unreacted starting materials and certain elimination products from the crude reaction mixture. The salt was made the free base by vigorous stirring in a 1: 1 mixture of methylene chloride and saturated bicarbonate solution until a translucent bilayer mixture was obtained. The organic layer was separated and the aqueous layer was extracted 3 times with methylene chloride. The combined organic layers were dried over MgSO ₄ , filtered and concentrated to give a solid that contained the des-brominated product as a minor impurity (about 3%). The solid was washed overnight by stirring several times in 40% Et ₂ O / hexane and 30% DCM / hexane and the solid was filtered. For final purification, the solids obtained in 3 reactions (total 19.5 g triflate SM) were combined to give a 96% pure solid. The solid was stirred overnight in 30% DCM / hexane and filtered to give 10.6 g of product in 98% purity, 69% yield.
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.16 (d, J = 2.0 Hz, 2H), 7.56 (dd, J = 1.9, 8.7 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H), 7.11 (t, J = 8.1 Hz, 1H), 6.36 (dd, J = 2.2, 8.1 Hz, 1H), 6.23 (dd, J = 2.0, 8.0 Hz, 1H), 6.15 (t, J = 2.3 Hz, 1H) , 5.11 (dddd, J = 4.6, 5.8, 10.4, 47.7 Hz, 1H), 4.60 (dm, 2H), 3.95 (t, J = 6.3 Hz, 1H), 3.75 (s, 3H), 4.39 (dm, 2H )
¹³ C NMR (CDCl ₃ , 100.5 MHz) δ 161.0, 148.6, 139.6, 130.4, 129.6, 123.9, 123.5, 112.9, 110.6 (d, ⁴ J = 2.0 Hz), 106.5, 103.9, 99.7, 90.7 (d, ¹ J = 176.9 Hz), 55.3, 45.6 (d, ² J = 22.1 Hz), 45.1 (d, ² J = 25.1 Hz),
MS (ESI), m / z: Calculated value 503.98, Actual value 504.9 (M + 1) ⁺

(E) -N- (3- (3,6-Dibromo-9H-carbazol-9-yl) prop-1-en-1-yl) -1,1,1-trifluoro-N- (3-methoxy Phenyl) methanesulfonamide (P7C3-S179).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.13 (d, J = 1.9 Hz, 2H), 7.55 (dd, J = 8.6, 2.0 Hz, 2H), 7.32 (t, J = 8.2 Hz, 1H), 7.21 (d, J = 8.7 Hz, 2H), 7.01 (d, J = 13.4 Hz, 1H [olefin CH]), 6.98-6.93 (m, 1H), 6.80 (dd, J = 7.9, 1.9 Hz, 1H), 6.73 (t, J = 2.3 Hz, 1H), 4.83 (d, J = 6.7 Hz, 2H), 4.76 (ddd, J = 12.8, 7.2, 5.4 Hz, 1H), 3.75 (s, 3H)
MS (ESI), m / z: Calculated value 615.93, Actual value 660.5 (M + HCOO) ^-

Example 6b. P7C3-S11: N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxy-N-methylaniline
The title compound of Example 6b was used except that 1- (3,6-dibromo-9H-carbazol-9-yl) -3-((3-methoxyphenyl) (methyl) -amino) propan-2-ol was used. Prepared according to the method described in representative method 4 (see example 23).
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.13 (d, 2H, J = 1.9 Hz), 7.54 (dd, 2H, J = 1.9, 8.8 Hz), 7.23 (d, 2H, J = 8.7 Hz), 7.12 (t, 1H, J = 8.2 Hz), 6.32 (dd, 1H, J = 2.2, 8.1 Hz), 6.26 (dd, 1H, J = 2.3, 8.0 Hz), 6.17 (t, 1H, J = 2.4 Hz) , 5.10 (dddd, 1H, J = 4.6, 6.4, 10.7, 48.5 Hz), 4.37-4.48 (m, 2H), 3.72 (s, 3H), 3.60-3.71 (m, 1H), 3.53 (td, 1H, J = 6.9, 15.9 Hz), 2.99 (s, 3H)
MS (ESI), m / z: 518.9 [M + 1] ⁺ ([M + H] for C ₂₃ H ₂₁ Br ₂ FN ₂ O ⁺ calculated value 519.0)

Example 7a. P7C3-S3: 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-one
Triethylamine (1.65 ml, 11.8 mmol) was added to 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol (1. 02 g, 2.02 mmol) in DMSO (21 ml). The solution was stirred for 30 minutes and sulfur trioxide pyridine complex (0.659 g, 4.14 mmol) was added. After stirring overnight, more triethylamine (1.0 ml, 7.17 mmol) was added followed by sulfur trioxide pyridine complex (0.663 mg, 4.17 mmol) after 1 hour. After stirring for 1 hour, the orange solution was diluted with ethyl acetate (˜150 ml) and washed several times with water followed by brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give a brown foam. Flash chromatography on SiO ₂ 100% (CH ₂ Cl ₂ + 0.2% TEA) gave high R _f value ketone (thioether, 18%) and low R _f value ketone (yield = 40%).
Large products: ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.18 (2H, J = 1.9 Hz), 7.56 (dd, 2H, J = 1.9, 8.7 Hz), 7.11 (d, 2H, J = 8.8 Hz) , 7.06 (t, 1H, J = 8.1 Hz), 6.30 (dd, 1H, J = 2.3, 8.2 Hz), 6.07 (dd, 1H, J = 2.0, 8.0 Hz), 6.11 (t, 1H, J = 2.2 Hz), 5.08 (s, 2H,), 4.41 (t, 1H, J = 4.8 Hz), 3.90 (d, 2H, J = 5.1 Hz), 3.72 (s, 3H)
¹³ C NMR (CDCl ₃ , 126 MHz) δ = 202.9, 161.1, 147.9 (2 C), 139.5, 130.6 (2 C), 129.9 (2 C), 124.1 (2 C), 123.9 (2 C), 113.5, 110.1 (2 C), 103.7, 99.3, 55.4, 51.9, 51.0
MS (ESI), m / z: 500.9 (M + 1) ⁺ ([M + 1] of C ₂₂ H ₁₈ Br ₂ N ₂ O ₂ ⁺ calculated value 501.0)

Example 7b. P7C3-S4: 3- (3,6-dibromo-9H-carbazol-9-yl) -1- (3-methoxyphenylamino) -1- (methylthio) propan-2-one
The title compound of Example 7b was obtained as a minor product in the preparation of the title compound of Example 7a.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.16 (d, 2H, J = 2.0 Hz), 7.55 (dd, 2H, J = 1.7, 8.8 Hz), 7.25 (d, J = 8.8 Hz, 2H), 7.12 (t, 1H, J = 8.4 Hz), 6.39 (dd, 1H, J = 2.2, 8.2 Hz), 6.33 (dd, 1H, J = 2.2, 8.0 Hz), 6.29 (t, 1H, J = 2.2 Hz ), 5.50 (d, 1H, J = 18.0 Hz), 5.22 (d, 1H, J = 18.4 Hz), 5.25 (d, J = 8.0 Hz, 1H), 4.50 (d, J = 8.0 Hz, 1H, exchange Possible), 3.76 (s, 3H), 1.74 (s, 3H)
¹³ C NMR (CDCl ₃ , 126 MHz) δ = 193.2, 160.9, 143.9 (2 C), 139.8 (2C), 130.4, 129.8 (2C), 124.1, 123.7 (2C), 113.4 (2C), 110.3 (2C) , 107.8, 104.7, 101.0, 60.3, 55.4, 48.9, 9.0
ESI m / z 498.9 [M-SMe + H] ⁺ (C ₂₃ H ₂ 0Br ₂ N ₂ O ₂ S [M-SMe + H] ⁺ calculated 499.0
HRMS m / z: 546.9675 [M + H] ⁺ (C ₂₃ H ₂ 0Br ₂ N ₂ O ₂ S [M + H] ⁺ calculated value 545.9612

Example 8. P7C3-S13: N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-methoxypropyl) -3-methoxyaniline
Sodium hydride (9.0 mg, 0.23 mmol) was stirred with 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol ( 99.3 mg, 0.20 mmol) in DMF (0.5 ml, 0.39 M) was added. The solution was stirred at room temperature for about 70 minutes and a solution of methyl iodide (14 ml, 0.22 mol) in DMF (1.0 ml) was added dropwise. The reaction was monitored in lc / ms for consumption of starting material and the appearance of O and N-methyl products. After stirring for 2.5 hours at room temperature, the conversion was about 30% and about 5% N-methyl product had formed. The reaction was stopped when an increase in N-Me relative to O-Me was observed, and the conversion was about 50%. The brown solution was diluted with ethyl acetate and washed several times with water and finally with brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The mixture was purified by preparative TLC (30% EtOAc / hexane).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.13 (s, 2H), 7.51 (dd, 2H, J = 1.8, 8.8 Hz), 7.31 (d, 2H, J = 8.7 Hz), 7.09 (t, 1H , J = 8.2 Hz), 6.33 (dd, 1H, J = 2.3, 8.3 Hz), 6.21 (dd, 1H, J = 2.1, 8.0 Hz), 6.12 (m, 1H), 4.42 (m, 1H), 4.03 (bs, 1H), 3.85 (m, 1H), 3.74 (s, 3H), 3.29 (s, 3H), 3.09 (m, 2H)
¹³ C NMR (CDCl ₃ , 126 MHz) δ 161.0, 149.4, 139.8, 130.4, 129.5, 123.8, 123.5, 112.7, 110.9, 106.7, 103.6, 99.7, 78.2, 58.3, 55.3, 45.3, 44.3
MS (ESI), m / z: 516.9 (M + 1) ⁺ ([M + 1] of C ₂₃ H ₂₂ Br ₂ N ₂ O ₂ ⁺ calculated value 517.0)

Example 9. P7C3-S2: 1- (3,6-Dimethyl-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol
Step 1. Synthesis of 3,6-dimethyl-9- (oxiran-2-ylmethyl) -9H-carbazole
According to representative method 1, 3,6-dimethylcarbazole (Beyer et al., OJ Org. Chem. 20003, 68, 2209-2215) was added to epichlorohydrin to give 69% yield.
¹ H NMR (CDCl ₃ , 500 MHz) δ7.84 (d, 2H, J = 1.0 Hz), 7.30 (d, 2H, J = 8.5 Hz), 7.26 (dd, 2H, J = 1.0, 8.5 Hz), 4.54 (dd, 1H, J = 3.5, 16.0 Hz), 4.35 (dd, 1H, J = 4.5, 16.0 Hz), 3.30 (m, 1H), 2.76 (dd, 1H, J = 4.0, 5.0 Hz), 2.52 (s, 6H), 2.51 (m, 1H)

Step 2. Synthesis of 1- (3,6-dimethyl-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol
According to representative method 2, 1- (3,6-dimethyl-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol is converted to 3,6-dimethyl-9- (oxirane- 2-ylmethyl) -9H-carbazole, 22% after purification by preparative TLC.
¹ H NMR (CDCl ₃ , 500 MHz) δ 7.84 (d, 2H, J = 0.5 Hz), 7.30 (d, 2H, J = 8.0 Hz), 7.23 (d, 2H, J = 8.0 Hz), 7.05 (t , 1H, J = 8.0 Hz), 6.28 (dd, 1H, J = 2.5, 8.0 Hz), 6.21 (dd, 1H, J = 2.5, 8.0 Hz), 6.12 (dd, 1H, J = 2.0, 2.5 Hz) , 4.39 (m, 3H), 4.01 (br s, 1H), 3.68 (s, 3H), 3.31 (dd, 1H, J = 3.0, 11.5 Hz), 3.17 (dd, 1H, J = 6.5, 13.0 Hz) , 2.51 (s, 6H), 2.13 (br s, 1H)
¹³ C NMR (CDCl ₃ , 125 MHz) δ 161.0, 149.5, 139.5 (2C), 130.3 (2C), 128.7, 127.3 (2C), 123.2 (2C), 120.5 (2C), 108.7 (2C), 106.7, 103.7 , 99.5, 69.7, 55.2, 48.0, 47.4, 21.6 (2C)
ESI m / z 375.2 ([M + H] ⁺ , C ₂₄ H ₂₇ N ₂ O ₂ calculated 375.2)

Example 10. P7C3-S14: 1- (3-Bromo-6-methyl-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol
Step 1. Synthesis of 3-bromo-6-methyl-9- (oxiran-2-ylmethyl) -9H-carbazole
According to representative method 2, Example 14 was obtained in 74% yield.
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.13 (d, 1H, J = 1.5 Hz), 7.80 (d, 1H, J = 1.0 Hz), 7.50 (dd, 1H, J = 2.0, 8.5 Hz), 7.33 -7.28 (m, 3H), 4.57 (dd, 1H, J = 3.0, 15.5 Hz), 4.29 (dd, 1H, J = 5.0, 15.5 Hz), 3.29 (m, 1H), 2.77 (dd, 1H, J = 4.0, 4.5 Hz), 2.51 (s, 3H), 2.48 (dd, 1H, J = 2.5, 4.5 Hz)

Step 2. Synthesis of 1- (3-Bromo-6-methyl-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol
Following representative method 2, Example 15 was obtained in 41% yield from 3-bromo-6-methyl-9- (oxiran-2-ylmethyl) -9H-carbazole.
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.14 (d, 1H, J = 2.0 Hz), 7.81 (s, 1H), 7.48 (dd, 1H, J = 2.0, 8.5 Hz), 7.31 (d, 1H, J = 5.0 Hz), 7.29 (br s, 1H), 7.06 (t, 1H, J = 8.5 Hz), 6.29 (dd, 1H, J = 2.0, 8.0 Hz), 6.21 (dd, 1H, J = 2.0, 8.0 Hz), 6.11 (t, 1H, J = 2.0 Hz), 4.37 (m, 3H), 3.99 (br s, 1H), 3.70 (s, 3H), 3.30 (dd, 1H, J = 3.5, 13.5 Hz ), 3.16 (dd, 1H, J = 6.5, 13.5 Hz), 2.51 (s, 3H), 2.14 (br s, 1H)
¹³ C NMR (CDCl ₃ , 125 MHz) δ 161.0, 149.4, 139.8, 139.5, 130.3, 129.4, 128.5, 128.2, 124.7, 123.2, 122.3 120.7, 112.1, 110.6, 109.0, 106.7, 103.7, 99.6, 69.5, 55.3, 47.9, 47.4, 21.5
ESI m / z 439.1 ([M + H] ⁺ , C ₂₃ H ₂₄ BrN ₂ O ₂ calculated 439.1)

Example 11 P7C3-S15: 1- (3,6-dichloro-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol
Step 1. Synthesis of 3,6-dichloro-9- (oxiran-2-ylmethyl) -9H-carbazole
According to representative method 1, 3,6-dichloro-9- (oxiran-2-ylmethyl) -9H-carbazole was obtained in 23% yield.
¹ H NMR (CDCl ₃ , 600 MHz) δ 7.92 (d, 2H, J = 1.8 Hz), 7.40 (dd, 2H, J = 1.8, 9.0 Hz), 7.32 (d, 2H, J = 9.0 Hz), 4.59 (dd, 1H, J = 3.0, 16.2 Hz), 4.22 (dd, 1H, J = 5.4, 16.2 Hz), 3.27 (m, 1H), 2.78 (dd, 1H, J = 4.2, 4.8 Hz), 2.46 ( (dd, 1H, J = 2.4, 4.8 Hz)

Step 2. Synthesis of 1- (3,6-dichloro-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol
According to representative method 2, 1- (3,6-dichloro-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol is converted to 3,6-dichloro-9- (oxirane- Obtained in 37% yield from 2-ylmethyl) -9H-carbazole.
¹ H NMR (CDCl ₃ , 500 MHz) δ 7.95 (d, 2H, J = 2.0 Hz), 7.38 (dd, 2H, J = 2.0, 8.5 Hz), 7.33 (d, 2H, J = 9.0 Hz), 7.06 (t, 1H, J = 8.0 Hz), 6.30 (dd, 1H, J = 2.0, 8.0 Hz), 6.20 (dd, 1H, J = 2.0, 8.0 Hz), 6.11 (dd, 1H, J = 2.0, 2.5 Hz), 4.30-4.35 (m, 3H), 3.70 (s, 3H), 3.28 (dd, 1H, J = 3.5, 13.0 Hz), 3.13 (dd, 1H, J = 6.5, 13.0 Hz)
¹³ C NMR (CDCl ₃ , 150 MHz) δ 161.0, 149.3, 139.7, 130.4 (2C), 126.9 (2C), 125.5 (2C), 123.4 (2C), 120.4 (2C), 110.5 (2C), 106.7, 103.8 , 99.8, 69.6, 55.3, 48.0, 47.5
ESI m / z 415.0 ([M + H] ⁺ , C ₂₂ H ₂ 0Cl ₂ N ₂ O ₂ calculated 415.1)

Example 12. P7C3-S18: 1- (5-Bromo-2,3-dimethyl-1H-indol-1-yl) -3- (phenylamino) propan-2-ol
Step 1. Synthesis of 5-bromo-2,3-dimethyl-1H-indole
According to published methods (Gundersen, EG, US Patent Publication No. 2005/070592)) 2-butanone (0.11 mL, 1.278 mmol) was added to 4-bromophenylhydrazine hydrochloride (0.300 g, 1.342 mmol). To the EtOH (3.8 mL) solution was added. The mixture was heated to reflux for 22 hours, concentrated under reduced pressure, and partitioned between EtOAc and 1N HCl. The organic layer was washed with H ₂ O and saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was chromatographed _(SiO 2, 0-20% EtOAc / hexanes) to give the desired indole as a pink powder (200 mg, 67%).
¹ H NMR (CDCl ₃ , 500 MHz) δ 7.69 (br s, 1H), 7.55 (d, 1H, J = 2.0 Hz), 7.15 (dd, 1H, J = 2.0, 8.5 Hz), 7.09 (dd, 1H , J = 0.5, 8.5 Hz), 2.34 (s, 3H), 2.15 (d, 3H, J = 0.5 Hz). ESI m / z 224.0 ([M + H] ⁺ , C ₁ 0H ₁₁ BrN calculated 224.0)

Step 2. Synthesis of 5-bromo-2,3-dimethyl-1- (oxiran-2-ylmethyl) -1H-indole
According to representative method 1, 5-bromo-2,3-dimethyl-1- (oxiran-2-ylmethyl) -1H-indole was obtained in 48% yield of 5-bromo-2,3-dimethyl-1H-indole. It was.
¹ H NMR (CDCl ₃ , 500 MHz) δ 7.58 (d, 1H, J = 2.0 Hz), 7.20 (dd, 1H, J = 2.0, 8.5 Hz), 7.10 (d, 1H, J = 8.5 Hz), 4.35 (dd, 1H, J = 3.0, 16.0 Hz), 4.09 (dd, 1H, J = 4.5, 16.0 Hz), 3.17 (m, 1H), 2.72 (t, 1H, J = 4.5 Hz), 2.35 (dd, 1H, J = 3.0, 5.0 Hz), 2.33 (s, 3H), 2.19 (s, 3H). ESI m / z 280.0 ([M + H] ⁺ , C ₁₃ H ₁₅ BrNO calculated 280.0)

Step 3. Synthesis of 1- (5-bromo-2,3-dimethyl-1H-indol-1-yl) -3- (phenylamino) propan-2-ol
According to representative method 2, 1- (5-bromo-2,3-dimethyl-1H-indol-1-yl) -3- (phenylamino) propan-2-ol is converted to 5-bromo-2,3-dimethyl- 1- (oxiran-2-ylmethyl) -1H-indole was obtained in 39% yield.
¹ H NMR (CDCl ₃ , 500 MHz) δ 7.58 (d, 1H, J = 2.0 Hz), 7.17 (dd, 2H, J = 7.0, 8.5 Hz), 7.11 (d, 1H, J = 8.5 Hz), 6.75 (t, 1H, J = 7.0 Hz), 6.60 (d, 2H, J = 8.5 Hz), 4.17 (m, 1H), 4.15 (m, 2H), 3.27 (dd, 1H, J = 3.0, 8.5 Hz) , 3.12 (dd, 1H, J = 7.0, 13.0 Hz), 2.34 (s, 3H), 2.19 (s, 3H)
¹³ C NMR (CDCl ₃ , 125 MHz) δ 147.9, 135.1, 134.3, 130.6, 129.6 (2C), 123.6, 120.9, 118.6, 113.7 (2C), 112.5, 110.5, 107.1, 69.9, 47.7, 47.4, 10.7, 9.0 ESI m / z 373.0 ([M + H] ⁺ , C ₁₉ H ₂₂ BrN ₂ O calculated 373.1)

Example 13 P7C3-S26: 1- (3,6-Dibromo-9H-pyrido [3,4-b] indol-9-yl) -3- (phenylamino) propan-2-ol
Step 1. Synthesis of 3,6-dibromo-β-carboline
According to literature methods (Ponce, MA; Erra-Balsells, RJ Heterocyclic Chem. 20001, 38, 1087), β-carboline (0.100 g, 0.595 mmol) and SiO ₂ (1.00 g) in CH ₂ Cl ₂ (15 mL ). N-bromosuccinimide (0.212 g, 1.189 mmol was dissolved in CH ₂ Cl ₂ (15 mL) and the solution was slowly added to the carboline mixture by syringe, protected from light. The reaction was stirred at ambient temperature for 2.5 hours. The silica gel was then filtered off and washed 3 times with CH ₂ Cl _{2. The} combined organic layers were extracted with 0.1M NaOH and saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. . the crude product was purified by chromatography _(SiO 2, _0~100% EtOAc / hexanes) to afford the desired 3,6-dibrominated carboline (25 mg, 13%) and 6,8-dibrominated carboline (15 mg 8%) and tribrominated carboline (36 mg, 19%).
¹ H NMR (d ₆ -DMSO, 500 MHz) δ 8.72 (s, 1H), 8.58 (d, 1H, J = 1.5 Hz), 8.48 (s, 1H), 7.70 (dd, 1H, J = 1.5, 9.0 Hz), 7.58 (d, 1H, J = 9.0 Hz). ESI m / z 326.9 ([M + H] ⁺ , C ₁₁ H ₇ Br ₂ N ₂ calculated 326.9)

Step 2. Synthesis of 3,6-dibromo-9- (oxiran-2-ylmethyl) -9H-pyrido [3,4-b] indole
According to representative method 1, 3,6-dibromo-9- (oxiran-2-ylmethyl) -9H-pyrido [3,4-b] indole was obtained in 3,6-dibromo-9-carboline in 73% yield. It was.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.62 (d, 1H, J = 0.8 Hz), 8.17 (d, 1H, J = 2.0 Hz), 8.02 (d, 1H, J = 1.2 Hz), 7.69 (dd , 1H, J = 2.0, 8.8 Hz), 7.41 (d, 1H, J = 8.8 Hz), 5.34 (br s, 1H), 4.73 (dd, 1H, J = 2.4, 16.0 Hz), 4.27 (dd, 1H , J = 5.2, 16.0 Hz), 3.32 (m, 1H), 2.83 (dd, 1H, J = 4.0, 4.4 Hz), 2.49 (dd, 1H, J = 2.4, 4.4 Hz)
ESI m / z 382.9 ([M + H] ⁺ , C ₁₄ H ₁₁ Br ₂ N ₂ O calculated 382.9)

Step 3. Synthesis of 1- (3,6-dibromo-9H-pyrido [3,4-b] indol-9-yl) -3- (phenylamino) propan-2-ol
According to representative method 2, 1- (3,6-dibromo-9H-pyrido [3,4-b] indol-9-yl) -3- (phenylamino) propan-2-ol is converted to 3,6-dibromo- 9- (oxiran-2-ylmethyl) -9H-pyrido [3,4-b] indole was prepared and was 14% yield after purification by preparative TLC.
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.64 (s, 1H), 8.18 (d, 1H, J = 2.0 Hz), 7.99 (s, 1H), 7.66 (dd, 1H, J = 1.5, 9.0 Hz) , 7.40 (d, 1H, J = 9.0 Hz), 7.18 (dd, 2H, J = 7.5 Hz), 6.76 (t, 1H, J = 7.5 Hz), 6.63 (d, 2H, J = 8.5 Hz), 5.33 (br s, 1H), 4.38-4.49 (m, 3H), 3.37 (dd, 1H, J = 4.0, 13.0 Hz), 3.21 (dd, 1H, J = 7.0, 13.0 Hz)
¹³ C NMR (CDCl ₃ , 125 MHz) δ 147.7, 141.2, 137.0, 132.6, 132.5, 130.9, 130.1, 129.7 (2C), 125.0, 122.0, 119.0, 118.6, 113.8 (2C), 113.4, 111.9, 69.6, 48.1 , 47.9. ESI m / z 475.9 ([M + H] ⁺ , C ₂ 0H ₁₈ Br ₂ N ₃ O calculated 476.0)

Example 14. P7C3-S36: 1- (3-azidophenylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol
Following representative method 2, Example 14 was obtained in 14% yield.
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.13 (d, 2H, J = 2.0 Hz), 7.53 (dd, 2H, J = 2.0, 8.5 Hz), 7.31 (d, 2H, J = 8.5 Hz), 7.12 (t, 1H, J = 8.0 Hz), 6.44 (dd, 1H, J = 1.5, 8.0 Hz), 6.36 (dd, 1H, J = 1.5, 8.0 Hz), 6.20 (dd, 1H, J = 2.0 Hz) , 4.35-4.41 (m, 3H), 4.10 (br s, 1H), 3.31 (dd, 1H, J = 3.0, 13.0 Hz), 3.17 (dd, 1H, J = 6.5, 13.0 Hz), 2.11 (br s , 1H)
ESI m / z 513.9 ([M + H] ⁺ , C ₂₁ H ₁₈ Br ₂ N ₅ O calculated 514.0)

Example 15. P7C3-S34: 1,3-bis (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol
3,6-Dibromocarbazole (0.050 g, 0.154 mmol) was cooled to DMF (1.5 mL) and cooled to 0 ° C. NaH (60% dispersion in mineral oil, 0.007 g, 0.169 mmol) was added and the reaction was stirred for 45 minutes at 0 ° C. 3,6-Dibromo-9- (oxiran-2-ylmethyl) -9H-carbazole (0.059 g, 0.154 mmol) was added and the reaction was stirred at ambient temperature for 24 hours. TLC was confirmed by the consumption of starting material, the reaction was partitioned between EtOAc and _{H 2} O. The aqueous layer was washed 3 times with EtOAc, and the combined organic layers were washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was chromatographed _(SiO 2, _0~50% EtOAc / hexanes) to give the desired product (37 mg, 34%).
¹ H NMR (acetone-d ₆ , 400 MHz) δ 8.36 (d, 4H, J = 2.0 Hz), 7.64 (d, 4H, J = 8.8 Hz), 7.56 (dd, 4H, J = 2.0, 8.8 Hz) , 4.72 (m, 5H), 2.78 (br s, 1H)
¹³ C NMR (acetone-d ₆ , 100 MHz) δ 141.2 (4C), 129.8 (4C), 124.6 (4C), 124.1 (4C), 112.9 (4C), 112.7 (4C), 70.3, 48.3 (2C). ESI m / z 747.0 ([M + CO ₂ H] ^- , C ₂₈ H ₁₉ Br ₄ N ₂ O ₃ calculated 746.8)

Example 16. P7C3-S35: 1- (9H-carbazol-9-yl) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol
According to the method used for the preparation of the compound of Example 15, Example 16 was obtained in 48% yield.
¹ H NMR (acetone-d ₆ , 400 MHz) δ 8.36 (m, 2H), 8.14 (d, 2H, J = 8.0 Hz), 7.63 (d, 2H, J = 8.4 Hz), 7.55 (s, 2H) , 7.42 (dt, 2H, J = 1.2, 7.2 Hz), 7.20 (dt, 2H, J = 0.8, 7.2 Hz), 4.76 (m, 1H), 4.64-4.72 (m, 4H), 2.77 (br s, 1H)
¹³ C NMR (acetone-d ₆ , 100 MHz) δ 142.0 (2C), 141.0 (2C), 129.8 (2C), 126.6 (2C), 124.5 (2C), 124.1 (2C), 123.8 (2C), 121.0 ( 2C), 119.9 (2C), 112.7 (2C), 112.6 (2C), 110.5 (2C), 70.3, 48.4, 48.1
ESI m / z 591.0 ([M + CO ₂ H] ^- , C ₂₈ H ₂₁ Br ₂ N ₂ O ₃ calculated 591.0)

Example 17 P7C3-S31: 3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxy-N- (3-methoxyphenyl) -propanamide
Step 1. Synthesis of methyl 3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropanoate
3,6-Dibromocarbazole (0.300 g, 0.923 mmol) was dissolved in DMF (1.2 mL) and cooled to 0 ° C. NaH (60% dispersion in mineral oil, 0.074 g, 1.846 mmol) was added and the reaction was stirred for 1 hour at 0 ° C. Methyl glycidate (0.471 g, 4.615 mmol) was added and the reaction was stirred for 3.5 hours and allowed to warm to ambient temperature. Once the reaction was confirmed complete by TLC, the reaction mixture was partitioned between EtOAc and H ₂ O. The aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was chromatographed _(SiO 2, _0~30% EtOAc / hexanes) to give the desired product (125 mg, 32%).
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.10 (d, 2H, J = 2.0 Hz), 7.53 (dd, 2H, J = 2.0, 9.0 Hz), 7.36 (d, 2H, J = 9.0 Hz), 4.63 -4.55 (m, 3H), 3.69 (s, 3H), 2.94 (d, 1H, J = 5.5 Hz)
ESI m / z 425.8 ([M + H] ⁺ , C ₁₆ H ₁₄ Br ₂ NO ₃ calculated 425.9)

Step 2. Synthesis of 3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropanoic acid
NaOH (0.64 mL, 1 M solution in H ₂ O) was added to methyl 3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropanoate (0.055 g, 0.129 mmol) in EtOH. (2.6 mL) was added to the suspension and the reaction was stirred at ambient temperature for 2.5 hours. The reaction was concentrated under reduced pressure and the residue was acidified with 1N aqueous HCl. The mixture was extracted with EtOAc (3 ×) and the combined organic layers were washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the desired product as a white solid. (53 mg, 99%).
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.10 (d, 2H, J = 1.5 Hz), 7.52 (dd, 2H, J = 1.5, 8.5 Hz), 7.40 (d, 2H, J = 9.0 Hz), 4.68 (m, 2H), 4.60 (dd, 1H, J = 6.5, 15.5 Hz)
ESI m / z 411.9 ([M + H] ⁺ , C ₁₅ H ₁₂ Br ₂ NO ₃ calculated 411.9)

Step 3. Synthesis of 3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxy-N- (3-methoxyphenyl) -propanamide
3- (3,6-Dibromo-9H-carbazol-9-yl) -2-hydroxypropanoic acid (0.025 g, 0.061 mmol) was suspended in anhydrous CH ₂ Cl and cooled to 0 ° C. Thionyl chloride (0.005 mL, 0.073 mmol) was added dropwise and the reaction was stirred at 0 ° C. for 1 hour. m-anisidine (0.008 mL, 0.073 mmol) and Et ₃ N (0.010 mL, 0.073 mmol) were added and the reaction was allowed to warm to ambient temperature over 2.5 hours. Upon completion, the solution was partitioned between EtOAc and _{H 2} O. The aqueous layer was washed 3 times with EtOAc, and the combined organic layers were washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was chromatographed _(SiO 2, _0~30% EtOAc / hexanes) to give the desired product (15 mg, 48%).
¹ H NMR (acetone-d ₆ , 500 MHz) δ 9.22 (br s, 1H), 8.34 (d, 2H, J = 1.5 Hz), 7.65 (d, 2H, J = 8.5 Hz), 7.59 (dd, 2H , J = 4.0, 8.5 Hz), 7.42 (dd, 1H, J = 2.0 Hz), 7.24 (m, 1H), 7.20 (dd, 1H, J = 8.0 Hz), 6.67 (dd, 1H, J = 2.0, 8.0 Hz), 5.56 (br s, 1H), 4.82 (m, 1H), 4.73 (m, 2H), 3.77 (s, 3H)
¹³ C NMR (CDCl ₃ , 100 MHz) δ 170.9, 161.1, 141.1, 140.3, 130.3 (2C), 129.8 (2C), 124.6 (2C), 124.0 (2C), 113.1 (2C), 112.8 (2C), 112.7 , 110.5, 106.4, 72.7, 55.6, 48.4
ESI m / z 514.9 ([MH] ^- , C ₂₂ H ₁₇ Br ₂ N ₂ O ₃ calculated 515.0)

Example 18. Ethyl 5- (2-hydroxy-3- (3-methoxyphenylamino) propyl) -8-methyl-3,4-dihydro-1H-pyrido [4,3-b] indole-2 (5H) Carboxylate
Step 1. Synthesis of ethyl 8-methyl-3,4-dihydro-1H-pyrido [4,3-b] indole-2 (5H) -carboxylate
According to literature methods (Harbert et al., J. Med. Chem. 1980, 23, 635-643), p-tolylhydrazine hydrochloride (0.500 g, 3.15 mmol) and 1-carboethoxy-4-piperidone (0 .18 mL, 1.17 mmol) was suspended in EtOH (0.880 mL) and heated to reflux for 2 hours. The reaction mixture was removed from the heat source and left overnight at ambient temperature. The resulting mixture was filtered and washed with 50% aqueous EtOH to give the desired product as a beige powder (259 mg, 86%).
¹ H NMR (CDCl ₃ , 500 MHz) δ 7.73 (br s, 1H), 7.23 (s, 1H), 7.18 (d, 1H, J = 8.0 Hz), 6.96 (d, 1H, J = 8.0 Hz), 4.64 (br s, 2H), 4.18 (q, 2H, J = 7.0 Hz), 3.85 (m, 2H), 2.81 (br s, 2H), 2.42 (s, 3H), 1.28 (t, 3H, J = 7.0 Hz)

Step 2. Synthesis of ethyl 8-methyl-5- (oxiran-2-ylmethyl) -3,4-dihydro-1H-pyrido [4,3-b] indole-2 (5H) -carboxylate
Ethyl 8-methyl-3,4-dihydro-1H-pyrido [4,3-b] indole-2 (5H) -carboxylate (0.025 g, 0.097 mmol) was dissolved in anhydrous degassed THF and -78 Cooled to ° C. A solution of n-BuLi (0.082 mL, 1.78 M in hexane) was added dropwise and the reaction was stirred at −78 ° C. for 30 minutes. Epibromohydrin (0.016 mL, 0.194 mmol) was added and the reaction was slowly warmed to ambient temperature. After 3.5 hours, epibromohydrin (0.008 mL, 0.097 mmol) was added and the reaction was stirred overnight at ambient temperature. Upon completion, the reaction was quenched by the addition of saturated aqueous NH ₄ Cl and the mixture was extracted with EtOAc (3 ×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was chromatographed _(SiO 2, _0~50% EtOAc / hexanes) to give the desired product (15 mg, 49%).
¹ H NMR (CDCl ₃ , 500 MHz) δ 7.19 (m, 1H), 7.00 (d, 1H, J = 8.5 Hz), 4.65 (br s, 2H), 4.32 (dd, 1H, J = 3.0, 15.5 Hz ), 4.18 (q, 2H, J = 7.0 Hz), 4.08 (dd, 1H, J = 5.0, 15.5 Hz), 3.85 (m, 2H), 3.18 (m, 1H), 2.81 (br s, 2H), 2.73 (dd, 1H, J = 4.0, 4.5 Hz), 2.44 (s, 3H), 2.38 (br s, 1H), 1.29 (t, 3H, J = 7.0 Hz)

Step 3. Ethyl 5- (2-hydroxy-3- (3-methoxyphenylamino) propyl) -8-methyl-3,4-dihydro-1H-pyrido [4,3-b] indole-2 (5H)- Carboxylate synthesis
According to literature methods (Chakraborti et al., Eur. J. Org. Chem. 20004, 3597-3600), LiBr (0.001 g, 0.010 mmol) and m-anisidine (0.011 mL, 0.102 mmol) were added to ethyl 8 -Methyl-5- (oxiran-2-ylmethyl) -3,4-dihydro-1H-pyrido [4,3-b] indole-2 (5H) -carboxylate (0.032 g, 0.102 mmol) was added. Stir vigorously overnight at ambient temperature. After completion, the reaction was partitioned between EtOAc / H ₂ O and the organic layer was concentrated to an orange oil. The crude residue was chromatographed _(SiO 2, _0~50% EtOAc / hexanes) to give the desired product (30 mg, 67%).
¹ H NMR (CDCl ₃ , 500 MHz) δ 7.23 (br s, 1H), 7.17 (d, 1H, J = 8.0 Hz), 7.05 (dd, 1H, J = 8.0 Hz), 6.97 (d, 1H, J = 8.5 Hz), 6.28 (dd, 1H, J = 1.5, 8.0 Hz), 6.19 (d, 1H, J = 8.0 Hz), 6.11 (br s, 1H), 4.64 (br s, 2H), 4.18 (m , 1H), 4.16 (q, 2H, J = 7.5 Hz), 4.12 (m, 1H), 3.80 (br s, 2H), 3.71 (s, 3H), 3.23 (dd, 1H, J = 3.5, 13.0 Hz ), 3.07 (dd, 1H, J = 7.5, 13.0 Hz), 2.83 (m, 1H), 2.76 (m, 1H), 2.42 (s, 3H), 1.27 (t, 3H, J = 7.0 Hz)
ESI m / z 438.2 ([M + H] ⁺ , C ₂₅ H ₃₂ N ₃ O ₄ calculated 438.2)

Example 19. P7C3-S26: 4- (3,6-dibromo-9H-carbazol-9-yl) -1- (phenylamino) butan-2-ol
Step 1. Synthesis of 3,6-dibromo-9- (2- (oxiran-2-yl) ethyl) -9H-carbazole
Crushed KOH (0.0054 g, 0.0954 mmol, 1.2 eq) was added to a solution of 3,6-dibromocarbazole (0.0258 g, 0.0795 mmol, 1 eq) in DMF (0.5 mL) and the mixture was added to 30 mL. Stir for minutes. A solution of 1-bromo-3,4-epoxybutane (0.0300 g, 0.199 mmol) in DMF (0.5 mL) was added dropwise to the mixture and stirred overnight at ambient temperature. The crude reaction was diluted with EtOAc (20 mL) and washed with water (5 × 10 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give 31.2 mg of white solid as product in 97.9% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ ppm 1.65-1.81 (m, 1H) 2.13-2.27 (m, 1H) 2.34 (dd, J = 4.88, 2.64 Hz, 1H) 2.64 (dd, J = 4.78, 4.05 Hz, 1H) 2.69-2.80 (m, 1H) 4.26-4.54 (m, 2H) 7.27 (d, J = 8.69 Hz, 2H) 7.50 (dd, J = 8.69, 1.90 Hz, 2H) 8.08 (d, J = 1.90 Hz, 2H)

Step 2. Synthesis of 4- (3,6-dibromo-9H-carbazol-9-yl) -1- (phenylamino) butan-2-ol
Following representative method 2, Example 19 was isolated as a white solid in 31% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ ppm 1.87-1.98 (m, 1H) 2.05-2.14 (m, 1H) 2.99-3.07 (dd, J = 13.24, 3.43 Hz, 1H) 3.09-3.17 (dd, J = 13.24, 8.27 Hz, 1H) 3.60-3.74 (m, 1H) 4.39-4.48 (m, 1H) 4.51-4.60 (m, 1H) 6.57 (d, J = 7.71 Hz, 2H) 6.74 (t, J = 7.34 Hz, 1H) 7.15 (dd, J = 8.27, 7.59 Hz, 2H) 7.38 (d, J = 8.69 Hz, 2H) 7.56 (dd, J = 8.69, 1.90 Hz, 2H) 8.14 (d, J = 1.85 Hz, 2H)
¹³ C NMR (CDCl ₃ , 500 MHz) δ = 148.1, 139.6, 129.6, 129.4, 123.8, 123.6, 118.7, 113.6, 112.4, 110.8, 67.7, 51.0, 39.9, 33.7
m / z (ESI): 486.9 (M + H ⁺ ) ([M + 1] calculated for C ₂₂ H ₂ 0Br ₂ N ₂ O 467.0)

Example 20. P7C3-S33: N- (3- (3,6-dibromo-9H-carbazol-9-yl) propyl) aniline
Step 1. Synthesis of 3,6-dibromo-9- (3-bromopropyl) -9H-carbazole
Crushed KOH (0.0673 g, 1.20 mmol, 1.2 eq) was added to a solution of 3,6-dibromocarbazole (0.3250 g, 1.00 mmol) in DMF (2 mL) and the mixture was stirred for 30 min. A solution of 1,3-dibromopropane (0.5047 g, 2.50 mmol, 2.5 eq) in DMF (3 mL) was added dropwise to the mixture and stirred overnight at room temperature. The crude reaction mixture was diluted with EtOAc (30 mL) and washed with 1M HCl (2 × 10 mL) and water (3 × 10 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was subjected to silica gel chromatography using hexane / EtOAc to give 0.1275 g of colorless oil as product. The yield was 28.6%.
¹ H NMR (CDCl ₃ , 400 MHz) δ ppm 2.24-2.44 (m, 2H) 3.29 (t, J = 6.05 Hz, 2H) 4.33 (t, J = 6.59 Hz, 2H) 7.26 (d, J = 8.83 Hz , 2H) 7.51 (dd, J = 8.69, 1.95 Hz, 2H) 8.02 (d, J = 1.71 Hz, 2H)

Step 2. Synthesis of N- (3- (3,6-dibromo-9H-carbazol-9-yl) propyl) -2-nitro-N-phenylbenzenesulfonamide
Crushed KOH (0.0028 g, 0.0431 mmol) was added to a solution of 2-nitro-N-phenylbenzenesulfonamide (0.0100 g, 0.0359 mmol) in DMF (0.2 mL) and the mixture was stirred for 30 minutes. A solution of 3,6-dibromo-9- (3-bromopropyl) -9H-carbazole (Example 35, 0.0240 g, 0.0538 mmol) in DMF (0.3 mL) was added dropwise to the mixture and stirred at room temperature overnight. . The crude reaction mixture was diluted with EtOAc (20 mL) and washed with water (5 × 10 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was subjected to silica gel chromatography using hexane / EtOAc to give 0.0008 g white solid as impure product. , Purity 66.9% (impurity is Ns-aniline; used without further purification), yield 35.5%.
¹ H NMR (CDCl ₃ , 400 MHz) δ ppm 1.89-2.01 (m, 2H) 3.95 (t, J = 6.61 Hz, 2H) 4.32-4.38 (m, 2H) 7.15 (s, 1H) 7.17 (s, 1H ) 7.18-7.25 (m, 3H) 7.32 (d, J = 3.66 Hz, 2H) 7.41-7.44 (m, 2H) 7.51 (dd, J = 8.69, 1.95 Hz, 2H) 7.59-7.71 (m, 2H) 8.09 (d, J = 1.90 Hz, 2H)

Step 3. Synthesis of N- (3- (3,6-dibromo-9H-carbazol-9-yl) propyl) aniline
N- (3- (3,6-dibromo-9H-carbazol-9-yl) propyl) -2-nitro-N-phenylbenzenesulfonamide (0.0378 g, 0.0588 mmol, 1 eq), cesium carbonate (0 0.0574 g, 0.176 mmol, 3 eq) and benzenethiol (0.0194 g, 0.176 mmol) were mixed in anhydrous THF (1 mL). The mixture was stirred at room temperature for 3 hours. THF was removed under reduced pressure and the residue was purified by silica gel chromatography using hexane / EtOAc to give 0.0164 g of colorless oil as product in 60.9% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ ppm 2.08-2.29 (m, 2H) 3.09 (t, J = 6.56 Hz, 2H) 3.55 (br. S., 1H) 4.37 (t, J = 6.69 Hz, 2H ) 6.53 (dd, J = 8.56, 0.95 Hz, 2H) 6.73 (t, J = 7.32 Hz, 1H) 7.16 (dd, J = 8.49, 7.37 Hz, 2H) 7.25 (d, J = 8.69 Hz, 2H) 7.51 (dd, J = 8.69, 1.95 Hz, 2H) 8.12 (d, J = 1.85 Hz, 2H)
¹³ C NMR (CDCl ₃ , 400 MHz) δ = 148.0, 139.5, 129.6, 129.4, 123.7, 123.6, 118.2, 113.3, 112.4, 110.5, 41.4, 40.9, 28.9
MS (ESI), m / z: 456.9 [M + H] ⁺ ([M + H] of C ₂₁ H ₁₈ Br ₂ N ₂ ⁺ calculated value 457.0)

Example 21. P7C3-S32: 1- (3,6-dibromo-9H-carbazol-9-yl) -4- (phenylamino) butan-2-ol
Step 1. Synthesis of N- (but-3-enyl) -2-nitro-N-phenylbenzenesulfonamide
Crushed KOH (0.0484 g, 0.862 mmol, 1.2 eq) was added to a solution of 2-nitro-N-phenylbenzenesulfonamide (0.200 g, 0.719 mmol) in DMF (1 mL) and the mixture was added for 30 min. Stir. A solution of 4-bromo-1-butene (0.2426 g, 1.80 mmol) in DMF (2 mL) was added dropwise to the mixture and stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (30 mL) and washed with 1M HCl (2 × 10 mL) and water (3 × 10 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was subjected to silica gel chromatography using hexane / EtOAc to give 0.1546 g of white solid, yield 63. 5% was obtained.
¹ H NMR (CDCl ₃ , 400 MHz) δ ppm 2.20 (q, J = 6.90 Hz, 2H) 3.83 (t, J = 7.15 Hz, 2H) 5.00 (d, J = 4.39 Hz, 1H) 5.03 (s, 1H ) 5.64-5.83 (m, 1H) 7.14-7.21 (m, 3H) 7.30 (d, J = 1.85 Hz, 2H) 7.42-7.46 (m, 2H) 7.52-7.58 (m, 1H) 7.60-7.66 (m, 1H)

Step 2. Synthesis of 2-nitro-N- (2- (oxiran-2-yl) ethyl) -N-phenylbenzenesulfonamide
mCPBA (77%, 0.0550 g, 0.246 mmol) in N- (but-3-enyl) -2-nitro-N-phenylbenzenesulfonamide (0.0653 g, 0.196 mmol) in CHCl ₃ (1 mL). Added at 0 ° C. The mixture was stirred at 0 ° C. for 30 minutes, gradually warmed to room temperature and continued to stir for 18 hours. After TLC showed disappearance of the starting material, the reaction mixture was diluted with a 1: 1 mixture of water and saturated NaHCO ₃ (2 × 10 mL) and water (10 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was subjected to silica gel chromatography using hexane / EtOAc to give 0.0662 g of colorless oil as product. The yield was 96.9%.
¹ H NMR (CDCl ₃ , 400 MHz) δ ppm 1.66-1.79 (m, 2H) 2.46 (dd, J = 4.95, 2.66 Hz, 1H) 2.70-2.80 (m, 1H) 2.93-3.03 (m, 1H) 3.87 -4.07 (m, 2H) 7.19-7.23 (m, 2H) 7.28-7.34 (m, 3H) 7.43-7.47 (m, 2H) 7.57-7.66 (m, 2H)
MS (ESI) m / z: 371.0 (M + Na ⁺ ) ([M + Na] ⁺ calculated value 371.1 of C ₁₆ H ₁₆ N ₂ O ₅ S)

Step 3. Synthesis of N- (2- (oxiran-2-yl) ethyl) aniline
Prepared from 2-nitro-N- (2- (oxiran-2-yl) ethyl) -N-phenylbenzenesulfonamide according to the method used for preparing the compound of Example 20.
¹ H NMR (CDCl ₃ , 400 MHz) δ ppm 1.64-1.79 (m, 1H) 1.98-2.15 (m, 1H) 2.55 (dd, J = 4.90, 2.71 Hz, 1H) 2.79 (t, J = 4.44 Hz, 1H) 3.00-3.10 (m, 1H) 3.31 (t, J = 6.64 Hz, 2H) 3.87 (br. S., 1H) 6.62 (d, J = 7.71 Hz, 2H) 6.71 (t, J = 7.32 Hz, 1H) 7.18 (dd, J = 8.49, 7.37 Hz, 2H)
MS (ESI) m / z: 164.1 (M + H ⁺ ) ([M + 1] of C ₁ 0H ₁₃ NO ⁺ calculated value 164.1)

Step 4. Synthesis of 1- (3,6-dibromo-9H-carbazol-9-yl) -4- (phenylamino) butan-2-ol
NaH (60% dispersion in mineral oil, 0.0019 g, 0.0452 mmol) was dissolved in anhydrous THF (0.5 mL) of 3,6-dibromocarbazole (0.0147 g, 0.0452 mmol) and the mixture was stirred for 15 minutes. did. A solution of N- (2- (oxiran-2-yl) ethyl) aniline (0.000067 g, 0.0410 mmol) in anhydrous THF (1.5 mL) was added dropwise and the resulting mixture was stirred at 60 ° C. overnight. THF was removed under reduced pressure and the residue was dissolved in EtOAc (10 mL) and washed with water (2 × 5 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was subjected to silica gel chromatography using hexane / EtOAc to give 0.0115 g oil; yield 57.5%.
¹ H NMR (CDCl ₃ , 400 MHz) δ ppm 1.76-1.95 (m, 2H) 3.22-3.41 (m, 2H) 4.20-4.38 (m, 3H) 6.63 (d, J = 8.49 Hz, 2H) 6.76 (t , J = 7.32 Hz, 1H) 7.18 (t, J = 7.95 Hz, 2H) 7.31 (d, J = 8.74 Hz, 2H) 7.54 (dd, J = 8.69, 1.95 Hz, 2H) 8.12 (d, J = 1.95 (Hz, 2H)
¹³ C NMR (CDCl ₃ , 400 MHz) δ = 148.1, 139.9, 129.6, 129.5, 123.8, 123.5, 118.7, 113.9, 112.7, 111.1, 70.7, 50.0, 42.2, 34.1
MS (ESI) m / z: 531.0 [M + HCOO] - 486.9 [M + H] + (C 22 H 2 0Br 2 N 2 O of the [M ⁺ H] + calcd 487.0)

Example 22. P7C3-S38: 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (pyridin-2-ylamino) propan-2-ol
Step 1. Synthesis of 1-amino-3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol
NH ₃ (MeOH 7M in the 9.4 mL, 65.6 mmol) solution of 3,6-dibromo-9- (oxiran-2-ylmethyl) -9H- carbazole (0.500 g, 1.31 mmol) was added to. The vial was sealed and the reaction mixture was heated to 100 ° C. and stirred for 1 hour. Volatile components were removed under reduced pressure. The residue was suspended in CH ₂ Cl ₂ and the white precipitate was filtered. The filtrate was pooled and CH ₂ Cl ₂ was removed under reduced pressure to give 0.3413 g of a white solid as a crude product, which contained about 50% undetermined by-product. This crude product was used directly in the next step without further purification. Purification by flash silica gel chromatography gave pure material.
¹ H NMR (CDCl ₃ , 400 MHz) δ ppm 2.61 (dd, J = 12.66, 7.78 Hz, 1H) 2.90 (dd, J = 12.52, 4.03 Hz, 1H) 3.96-4.06 (m, 1H) 4.32 (d, J = 5.81 Hz, 2H) 7.36 (d, J = 8.74 Hz, 2H) 7.55 (dd, J = 8.69, 1.95 Hz, 2H) 8.13 (d, J = 1.90 Hz, 2H)
MS (ESI) m / z: 396.9 (M + H ⁺ ) ([M + H] ⁺ calculated value 397.0 of C ₁₅ H ₁₄ Br ₂ N ₂ O)

Step 2. Synthesis of 5-((3,6-dibromo-9H-carbazol-9-yl) methyl) oxazolidin-2-one
Triphosgene (0.0890g, 0.300mmol, 0.35 eq) in anhydrous _CH 2 Cl ₂ and (2 mL) solution of 1-amino-3- (3,6-dibromo -9H- carbazol-9-yl) propane To a solution of 2-ol (0.3413 g, 0.857 mmol) and Et ₃ N (0.1909 g, 1.886 mmol) in CH ₂ Cl ₂ (1 mL) was added dropwise at 4 ° C. under N ₂ atmosphere. The reaction mixture was stirred for 15 minutes at 4 ° C., warmed to room temperature and stirred for 1 hour. CH ₂ Cl ₂ was removed under reduced pressure. Saturated NH ₄ Cl (5 mL) and EtOAc (10 mL) were added to the residue and stirred for 20 minutes. The aqueous layer was separated and the organic layer was washed with water (2 × 10 mL). The combined aqueous layers were extracted with EtOAc, dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was subjected to silica gel chromatography using CH ₂ Cl ₂ / EtOAc to give 0 0.173 g of white solid was obtained in 2 steps with a yield of 20.0%.
¹ H NMR (CDCl ₃ , 400 MHz) δ ppm 3.37 (dd, J = 8.98, 6.34 Hz, 1H) 3.67 (t, J = 8.49 Hz, 1H) 4.54 (dd, J = 5.22, 1.81 Hz, 2H) 5.02 (br. s., 1H) 5.05-5.14 (m, 1H) 7.31 (d, J = 8.69 Hz, 2H) 7.58 (dd, J = 8.69, 1.85 Hz, 2H) 8.14 (d, J = 1.85 Hz, 2H )
MS (ESI) m / z: 466.9 [M + HCOO] - ([M + HCOO] of _{C 16 H 12 Br 2 N 2} O 2 - Calculated 466.9)

Step 3. Synthesis of 5-((3,6-dibromo-9H-carbazol-9-yl) methyl) -3- (pyridin-2-yl) oxazolidine-2-one
5-((3,6-dibromo-9H-carbazol-9-yl) methyl) oxazolidin-2-one (0.0195 g, 0.0460 mmol), 2-iodopyridine (0.0209 g, 0.102 mmol), CuI A mixture of (0.0009 g, 0.000046 mmol) and K ₂ CO ₃ (0.0054 g, 0.0418 mmol) in DMSO (0.5 mL) was sealed in a vial and heated at 130 ° C. for 12 hours. The reaction mixture was cooled, diluted with EtOAc (20 mL) and washed with water (5 × 10 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was subjected to silica gel chromatography using CH ₂ Cl ₂ / EtOAc as eluent to give 0.0183 g of white. The solid was obtained as a product in a yield of 79.4%.
¹ H NMR (CDCl ₃ , 400 MHz) δ ppm 4.04 (dd, J = 10.79, 7.08 Hz, 1H) 4.36 (dd, J = 10.69, 8.74 Hz, 1H) 4.60 (d, J = 5.03 Hz, 2H) 5.02 -5.16 (m, 1H) 7.02 (t, J = 6.08 Hz, 1H) 7.35 (d, J = 8.69 Hz, 2H) 7.59 (dd, J = 8.66, 1.73 Hz, 2H) 7.68 (t, J = 7.88 Hz , 1H) 8.11 (s, 1H) 8.13 (d, J = 1.32 Hz, 2H) 8.25 (d, J = 4.93 Hz, 1H)
MS (ESI) m / z: 543.9 [M + HCOO] - ([M + HCOO] of _{C 21 H 15 Br 2 N 3} O 2 - Calculated 544.0)

Step 4. Synthesis of 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (pyridin-2-ylamino) propan-2-ol
LiOH.H ₂ O (0.0075 g, 0.182 mmol, 10 eq) was converted to 5-((3,6-dibromo-9H-carbazol-9-yl) methyl) -3- (pyridin-2-yl) oxazolidine- 2-one (0.00091 g, 0.0182 mmol) was added to a mixture of THF (208 μL) and H ₂ O (23 μL) (v / v = 9: 1). The mixture was stirred at room temperature for 7 days. The reaction mixture was purified by silica gel chromatography using CH ₂ Cl ₂ / EtOAc as eluent to give 0.0017 g of white solid as product in 41.0% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ ppm 2.27-2.44 (m, 1H) 3.15-3.32 (m, 1H) 3.44 (dd, J = 15.23, 5.03 Hz, 1H) 4.26-4.41 (m, 3H) 4.52 (t, J = 5.00 Hz, 1H) 6.46 (d, J = 8.00 Hz, 1H) 6.66 (t, J = 6.20 Hz, 1H) 7.37 (d, J = 8.74 Hz, 2H) 7.40-7.48 (m, 1H ) 7.56 (dd, J = 8.69, 1.90 Hz, 2H) 8.04 (d, J = 4.49 Hz, 1H) 8.14 (d, J = 1.85 Hz, 2H)
¹³ C NMR (CDCl ₃ , 400 MHz) δ = 158.6, 146.7, 139.5, 138.1, 129.2, 123.6, 123.3, 113.9, 112.3, 110.9, 109.6, 70.5, 47.4, 46.8
MS (ESI) m / z: 518.0 [M + HCOO] - ( a _{C 2 0H 17 Br 2 N 3} O [M + HCOO] - Calculated 518.0)

Example 23 P7C3-S1: 1- (3,6-Dibromo-9H-carbazol-9-yl) -3-((3-methoxyphenyl) (methyl) -amino) propan-2-ol
The synthesis was performed using a synthesis method according to the method of representative method 2.

Example 25. P7C3-S6: 3-amino-1- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) pyridinium
The compound of Example 25 was synthesized using a synthetic method according to the method of Representative Method 2.

Example 26. P7C3-S8: 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (pyrimidin-2-ylamino) propan-2-ol
To a 4 ml vial was added the corresponding primary amine (34.8 mg, 0.087 mmol), 2-chloropyrimidine (10.3 mg, 0.090 mmol) and dimethylformamide (1.5 ml, 0.058 M). The reaction was heated at 100 ° C. overnight. The cooled reaction mixture was diluted with EtOAc and washed several times with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude mixture was subjected to silica gel chromatography (20% MeOH / CH ₂ Cl ₂ ).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.26 (d, 2H, J = 4.94 Hz), 8.14 (d, 2H, J = 1.88 Hz), 7.56 (dd, 2H, J = 6.7, 1.9 Hz), 7.37 (d, 2H, J = 8.7 Hz), 6.63 (t, 1H, J = 4.9 Hz), 5,43 (t, 1H, J = 5.71 Hz), 4.36 (s, 3H), 3.56 (m, 1H) , 3.30-3.38 (m, 1H)
¹³ C NMR (CDCl ₃ , 126 MHz) δ 139.4, 29.5 (2C), 129.3 (2C), 123.7 (2C), 123.4 (2C), 118.6 (2) (2 C), 113.5 (2C), 112.3, 110.7 (2 C), 67.6, 50.9, 33.6
MS (ESI) m / z: 474.9 [(M + 1) ⁺ ; C19H16Br ₂ N4O (M) calculated 474)]

  The title compound of Example 26 can also be synthesized using synthetic methods analogous to those described in Representative Method 2.

Example 28. P7C3-S19: 1- (3,6-dibromo-9H-carbazol-9-yl) -3-methoxypropan-2-ol
Following representative method 1, Example 28 was prepared from dibromocarbazole and methoxymethyloxirane.

Example 29. P7C3-S21: 1- (3,6-dibromo-9H-carbazol-9-yl) -4-phenylbutan-2-ol
Following representative method 1, Example 29 was prepared from dibromocarbazole and 2-phenethyloxirane.

Example 30 P7C3-S22: 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (1H-indol-1-yl) propan-2-ol
Following representative method 1, Example 30 was prepared from dibromocarbazole and 1- (oxiran-2-ylmethyl) -1H-indole.

Example 31. P7C3-S23: 3- (1- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -1H-1,2,3-triazole-4- Yl) propan-1-ol
The compound of Example 31 was synthesized using a synthetic method according to the method of Representative Method 2.

Example 32. P7C3-S24: 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-ethoxyphenylamino) propan-2-ol
The compound of Example 32 was synthesized using a synthetic method according to the method of Representative Method 2.

Example 33. P7C3-S25: 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3,5-dimethyl-1H-pyrazol-1-yl) propan-2-ol
The compound of Example 33 was synthesized using a synthetic method according to the method of Representative Method 2.

Example 36. P7C3-S29: 1- (3-bromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol
Step 1. 3-Bromo-9- (oxiran-2-ylmethyl) -9H-carbazole
The title compound of Example 36, Step 1, was prepared using a method analogous to that described in Exemplary Method 1.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 2.52 (dd, J = 4.6, 2.6 Hz, 1H) 2.80 (t, J = 4.3 Hz, 1H) 3.33 (td, J = 5.3, 2.2 Hz, 1H) 4.34 (dd, J = 15.9, 4.9 Hz, 1H) 4.64 (dd, J = 15.9, 2.9 Hz, 1H) 7.26 (t, J = 7.3 Hz, 1H) 7.35 (d, J = 8.7 Hz, 1H) 7.58-7.42 (m, 3H) 8.02 (d, J = 5.1 Hz, 1H) 8.19 (d, J = 1.7 Hz, 1H)

Step 2. The title compound was prepared from 3-bromo-9- (oxiran-2-ylmethyl) -9H-carbazole using a method analogous to that described in Representative Method 2.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 2.13 (d, J = 3.0 Hz, 1H) 3.21 (dd, J = 13.0, 6.5 Hz, 1H) 3.35 (dd, J = 13.0, 3.2 Hz, 1H) 3.72 (s, 3H) 4.03 (s, br, 1H) 4.50-4.36 (m, 3H) 6.15 (t, J = 2.3 Hz, 1H) 6.24 (dd, J = 8.0, 2.2 Hz, 1H) 6.32 (dd, J = 8.2, 2.3 Hz, 1H) 7.08 (t, J = 8.1 Hz, 1H) 7.30-7.24 (m, 1H) 7.36 (d, J = 8.7 Hz, 1H) 7.51-7.44 (m, 2H) 7.53 (dd, J = 8.7, 1.9 Hz, 1H) 8.05 (d, J = 7.9 Hz, 1H) 8.21 (d, J = 1.9 Hz, 1H)
¹³ C NMR (CDCl ₃ , 400 MHz) δ = 161.0, 149.4, 141.2, 139.6, 130.4, 128.8, 126.9, 125.0, 123.3, 122.2, 120.8, 120.1, 112.4, 110.7, 109.4, 106.7, 103.8, 99.7, 69.6, 55.3, 48.0, 47.4
ESI m / z: 425.0 [(M + H ⁺ ), C ₂₂ H ₂₁ BrN ₂ O ₂ (M) calculated 421.1]

Example 37. P7C3-S37: N- (5- (3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylamino) phenoxy) pentyl) -2- (7 -(Dimethylamino) -2-oxo-2H-chromen-4-yl) acetamide
Coumarin was coupled to the compound of Example 62 using known methods (Alexander, et al., ChemBioChem, 20006, 7, 409-416).

Example 39. P7C3-S43: N- (2- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropoxy) ethyl) -acetamide
Step 1. 2- (2- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-hydroxypropoxy) ethyl) isoindoline-1,3-dione
Sodium hydride dispersion (31.6 mg, 0.79 mmol) was added to a solution of N- (2-hydroxyethyl) -phthalimide (153.7 mg, 0.80 mmol) in anhydrous THF (1.2 ml, 0.67 M). did. The suspension is stirred for 15 minutes and carbazole epoxide 2-A is added. The reaction was stirred at room temperature for 5 minutes and then at 60 ° C. for 1 hour. The cooled reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted and the combined organic layers were filtered through a celite pad. The crude product was used without further purification. Yield = 44%
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.12 (s, 2H), 7.85 (s, 2H), 7.72 (m, 2H), 7.55 (d, 2H, J = 8.5 Hz), 7.33 (d, 2H, J = 8.7 Hz), 4.64 (d, 1H, J = 16.1 Hz), 4.27 (d, 1H), 3.88 (m, 4H), 3.31 (bs, 1H), 2.80 (m, 1H), 2.48 (m, 1H), 2.04 (s, 1H)
MS (ESI), m / z: 614.9 [(M + HCOO) ⁻ ; C25H ₂ 0Br ₂ N ₂ O ₄ (M) Calculated 570]

Step 2. 1- (2-Aminoethoxy) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol
Hydrazine hydrate (400 μl, 8.22 mmol) was added to a solution of phthalimide (53 mg, 0.093 mmol) prepared in Step 1 above in ethanol (2.0 ml, 0.046 M). The reaction was stirred overnight, concentrated and purified with 5-10% MeOH / DCM.
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.11 (s, 2H), 7.53 (dd, 2H, J = 8.7, 1.8 Hz), 7.38 (d, 2H, J = 8.5 Hz), 4.37 (dm, 5H) , 4.05 (t, 1H, J = 6.8 Hz), 2.84 (m, 2H), 2.62 (m, 1H)
MS (ESI), m / z: 440.9 [(M + 1) ⁺ ; C17H ₁₈ Br ₂ N ₂ O ₂ (M) calculated 440.0]

Step 3. The title compound of Example 39 was prepared as follows. Triethylamine (33.5 μl, 0.26 mmol) and acetic anhydride (17 μl, 0.18 mmol) were added to a solution of amine XIII (71 mg, 0.16 mmol) in THF (3.0 ml, 0.053 M). The reaction was stirred overnight. The reaction mixture was diluted with EtOAc, washed with water, dried over Na ₂ SO ₄ , filtered and concentrated. The crude mixture was subjected to flash chromatography (5% MeOH / CH ₂ Cl ₂ ).
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.13 (d, 2H, J = 1.7 Hz, 7.55 (dd, 2H, J = 8.7, 1.8 Hz), 7.34 (d, 2H, 9.1 Hz), 5.78 (bs, 1H), 4.35 (ddd, 3H, J = 6.2, 6.8 Hz), 4.22 (m, 1H), 3.46 (m, 4H), 3.33 (dd, 1H, J = 9.7, 5.4 Hz), 2.80 (bs, 1H ), 1.98 (s, 3H)
MS (ESI), m / z: 482.9 [(M + 1) ⁺ ; C ₁₉ H ₂ 0Br ₂ N ₂ O ₃ (M) calculated 482.0]

Example 40. P7C3-S44: 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (pyridin-3-ylamino) propan-2-ol
Step 1. 5-((3,6-Dibromo-9H-carbazol-9-yl) methyl) -3- (pyridin-3-yl) oxazolidine-2-one
Corresponding N-H oxazolidinone (0.0390g, 0.0920mmol), 3- iodopyridine (0.0419g, 0.204mmol), CuI ( 0.0018g, 0.00920mmol) and _K 2 CO _{3 (0.0116g,} A mixture of 0.0837 mmol) in DMSO (0.5 mL) was heated in a sealed vial at 130 ° C. for 12 hours. The reaction mixture was cooled, diluted with EtOAc (20 mL), washed with water (2 × 10 mL) and brine 2 × 10 mL. The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product (0.0383 g white solid, yield 83.7%), which was used without further purification.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 3.82 (dd, J = 9.1, 6.6 Hz, 1H) 4.12 (dd, J = 10.0, 7.9 Hz, 1H) 4.72-4.55 (m, 2H) 5.15 (td, J = 11.8, 5.4 Hz, 1H) 7.27 (dd, J = 8.3, 4.9 Hz, 1H) 7.34 (d, J = 8.7 Hz, 2H) 7.59 (dd, J = 8.7, 1.9 Hz, 2H) 8.03 (ddd, J = 8.5, 2.6, 1.2 Hz, 1H) 8.14 (d, J = 1.9 Hz, 2H) 8.37 (d, J = 4.2 Hz, 1H) 8.44 (s, 1H). ESI m / z: 543.9 [(M + ^{_{HCOO -); C 21 H 15}} Br 2 N 3 O 2 (M) calcd 499]

Step 2. The title compound of Example 40 was prepared as follows. LiOH.H ₂ O (0.00097 g, 0.231 mmol) was added to 5-((3,6-dibromo-9H-carbazol-9-yl) methyl) -3- (pyridin-3-yl) oxazolidine-2- On (0.0116 g, 0.0231 mmol) in THF (265 μL) and H ₂ O (29 μL) (v / v = 9: 1) was added to the mixture. The mixture was stirred at room temperature for 7 days. The reaction mixture was purified by silica gel chromatography using CHCl ₃ / MeOH as the eluent to give 0.0008 g of white solid as product in 79.3% yield.
¹ H NMR (CDCl ₃ , 600 MHz) δ = 3.15 (dd, J = 12.6, 6.2 Hz, 1H) 3.30 (d, J = 11.8 Hz, 1H) 4.45-4.33 (m, 3H) 6.81 (d, J = 7.4 Hz, 1H) 7.02 (s, br, 1H) 7.32 (d, J = 8.7 Hz, 2H) 7.52 (dd, J = 8.7, 1.8 Hz, 2H) 7.83 (s, br, 2H) 8.11 (d, J = 1.6 Hz, 2H)
¹³ C NMR (CDCl ₃ , 400 MHz) δ = 139.8, 139.5, 136.2, 130.0, 129.5, 124.1, 123.8, 123.5, 119.7, 112.8, 110.9, 69.0, 47.6, 47.3
ESI m / z: 517.9 [(M + HCOO ⁻ ); C ₂ 0H17Br ₂ N ₃ O (M) calculated 473]

Example 41 P7C3-S45: 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (pyridin-4-ylamino) propan-2-ol
Step 1. 5-((3,6-Dibromo-9H-carbazol-9-yl) methyl) -3- (pyridin-4-yl) oxazolidine-2-one
Corresponding N-H oxazolidinone (0.0195g, 0.0460mmol), 4- iodopyridine (0.0209g, 0.102mmol), CuI ( 0.0009g, 0.00460mmol) and _K 2 CO _{3 (0.0058g,} A mixture of 0.0418 mmol) in DMSO (0.5 mL) was heated in a sealed vial at 130 ° C. for 12 hours. The reaction mixture was cooled, diluted with EtOAc (20 mL) and washed with brine (3 × 10 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was further triturated with hexane from the CH ₂ Cl ₂ suspension to give 0.0187 g of white solid as product. The yield was 74.6%.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 3.77 (dd, J = 9.4, 6.8 Hz, 1H) 4.08 (t, J = 9.0 Hz, 1H) 4.64 (d, J = 4.6 Hz, 2H) 5.23-5.10 (m, 1H) 7.34 (d, J = 8.7 Hz, 2H) 7.37 (s, br, 2H) 7.61 (dd, J = 8.6, 1.8 Hz, 2H) 8.16 (d, J = 1.8 Hz, 2H) 8.55 ( s, br, 2H)
ESI m / z: 544.0 [(M + HCOO ⁻ ); C ₂₁ H ₁₅ Br ₂ N ₃ O ₂ (M) Calculated 499]

Step 2. The title compound of Example 41 was prepared as follows. LiOH.H ₂ O (0.0157 g, 0.373 mmol) was added to 5-((3,6-dibromo-9H-carbazol-9-yl) methyl) -3- (pyridin-4-yl) oxazolidine-2- On (0.0187 g, 0.0373 mmol) in THF (428 μL) and H ₂ O (48 μL) (v / v = 9: 1) was added to the mixture. The mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with EtOAc (30 mL) and washed with brine 3 × 30 mL. The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which did not require purification (0.0001 g white solid, 7.3%).
¹ H NMR (d ₆ -acetone, 400 MHz) δ = 3.33 (dd, J = 13.1, 6.4 Hz, 1H) 3.49 (dd, J = 13.2, 4.4 Hz, 1H) 4.41 (td, J = 7.6, 4.1 Hz , 1H) 4.51 (dd, J = 15.0, 7.6 Hz, 1H) 4.61 (dd, J = 14.8, 3.4 Hz, 1H) 6.61 (s, 2H) 7.56 (d, J = 8.6 Hz, 2H) 7.62 (d, J = 8.7 Hz, 2H) 8.10 (s, br, 2H) 8.37 (s, 2H)
¹³ C NMR (d ₆ -acetone, 400 MHz) δ = 179.0, 149.6, 140.4, 129.0, 123.8, 123.3, 112.1, 111.8, 107.8, 68.8, 47.6, 46.4
ESI m / z: 517.9 [(M + HCOO ⁻ ); C ₂ 0H ₁₇ Br ₂ N ₃ O (M) calculated 473]

Example 42 P7C3-S46: 1- (2,8-dimethyl-3,4-dihydro-1H-pyrido [4,3-b] indol-5 (2H) -yl) -3- (phenylamino) propane -2-ol
The compound of Example 42 was synthesized using a synthetic method according to the method of Representative Method 2.

Example 43 P7C3-S59: N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2,2-difluoropropyl) -3-methoxyaniline
Step 1. N- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-oxopropyl) -N- (3-methoxyphenyl) -4-nitrobenzenesulfonamide
The nosylate of the title compound of Example 62 (prepared according to the method described herein) was oxidized with Dess-Martin periodinane using a method analogous to that described in Example 103. Quantitative yield.
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.24 (d, 2H, J = 8.9 Hz), 8.14 (s, 2H), 7.68 (d, 2H, J = 9.1 Hz), 7.53 (d, 2H, J = 8.6 Hz), 7.18 (t, 1H, J = 8.7 Hz), 7.05 (t, 2H, J = 8.1 Hz), 6.87 (dd, 1H, J = 8.3, 2.5 Hz) 5.21, (s, 2H), 4.30 (s, 2H), 2.48 (s, 3H). MS (ESI), m / z: 683.9 [(M-1) ^- ; C ₂₈ H ₂₁ Br ₂ N ₃ O ₆ S (M) calculated 685.0]

Step 2. N- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2,2-difluoropropyl) -N- (3-methoxyphenyl) -4-nitrobenzenesulfonamide
The title compound of Example 43, Step 2 was prepared from the ketone prepared in Step 1 above using a method analogous to that described in Example 103. The yield is quantitative and the crude product is used without further purification.
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.31 (d, 2H, J = 8.9 Hz), 8.11 (s, 2H), 7.77 (d, 2H, J = 8.9 Hz), 7.55 (dd, 2H, J = 8.7, 1.8 Hz), 7.25 (m, 3H), 6.92 (dd, 1H, J = 8.3, 2.0 Hz), 6.73 (m, 1H) 6.61, (d, 1H, J = 7.7 Hz), 4.78 (t, 2H, T = 14.7 Hz), 4.18 (t, 2H, J = 11.2 Hz), 3.78 (s, 3H)
MS (ESI), m / z: 751.9 [(M + HCOO) ^- ; C ₂₈ H ₂₁ Br ₂ F ₂ N ₃ O5S (M) calculated 707.0]

Step 3. The title compound of Example 43 was prepared as follows. The nosyl group of N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2,2-difluoropropyl) -N- (3-methoxyphenyl) -4-nitrobenzenesulfonamide is represented by Removed using the method described in Method 5.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.11 (d, 2H, J = 1.6 Hz), 7.49 (dd, 2H, J = 8.7, 2.0 Hz), 7.32 (d, 2H, J = 8.9 Hz), 7.11 (t, 1H, J = 8.2 Hz) 6.39 (dd, 1H, J = 8.2, 2.3 Hz), 4.68 (t, 2H, J = 13.2 Hz), 3.89 (t, 1H, J = 7.0 Hz), 3.74 ( s, 3H), 3.47 (m, 2H)
MS (ESI), m / z: 566.9 [(M + HCOO) ⁻ ; C ₂₂ H ₁₈ Br ₂ F ₂ N ₂ O (M) calculated 522.0]

Example 45. P7C3: 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 46. 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (o-tolylamino) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 47. 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (m-tolylamino) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 48. 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (2-methoxyphenylamino) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 50 1- (4-Bromophenylamino) -3- (3,6-dichloro-9H-carbazol-9-yl) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 51 1- (4-Bromophenylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 52. 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (4-ethoxyphenylamino) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 53. 1- (4-Chlorophenylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 54 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (phenethylamino) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 55. 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (2-hydroxyethylamino) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 56. 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (2,4-dimethoxyphenylamino) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 57. 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (2,3-dimethylphenylamino) propan-2-ol
This compound can be purchased from ChemDiv, Inc.

Example 58. 1- (2-Chlorophenylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol
This compound can be purchased from ChemDiv, Inc.

Example 59. 1- (tert-Butylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol
This compound can be purchased from ChemDiv, Inc.

Example 60. 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (isopropylamino) propan-2-ol
This compound can be purchased from ChemDiv, Inc.

Example 61. 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (4-methoxyphenylamino) propan-2-ol
This compound can be purchased from ChemDiv, Inc.

Example 62. 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol
This compound can be purchased from ChemDiv, Inc.

Example 63. 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (m-tolylamino) propan-2-ol
This compound can be purchased from ChemDiv, Inc.

Example 64. 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (3,5-dimethylphenylamino) propan-2-ol
This compound can be purchased from ChemDiv, Inc.

Example 65. 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (3,4-dimethylphenylamino) propan-2-ol
This compound can be purchased from ChemDiv, Inc.

Example 66. 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (3,4-dimethylphenylamino) propan-2-ol
This compound can be purchased from ChemDiv, Inc.

Example 67. 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (2,5-dimethylphenylamino) propan-2-ol
This compound can be purchased from ChemDiv, Inc.

Example 68 1- (4-Bromophenylamino) -3- (2,3-dimethyl-1H-indol-1-yl) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 69. 1- (2,3-Dimethyl-1H-indol-1-yl) -3- (4-methoxyphenylamino) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 70 1- (2,3-Dimethyl-1H-indol-1-yl) -3- (4-ethoxyphenylamino) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 71 1- (2,3-Dimethyl-1H-indol-1-yl) -3- (p-tolylamino) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 72. 1- (2,3-Dimethyl-1H-indol-1-yl) -3- (phenylamino) propan-2-ol oxalate
This compound can be purchased from ChemBridge Corporation.

Example 73. 1- (1H-Indol-1-yl) -3- (4-methoxyphenylamino) propan-2-ol hydrochloride
This compound can be purchased from ChemBridge Corporation.

Example 74. 1- (1H-Indol-1-yl) -3- (phenylamino) propan-2-ol oxalate
This compound can be purchased from ChemBridge Corporation.

Example 75. 1- (3,4-Dihydro-1H-carbazol-9 (2H) -yl) -3- (m-tolylamino) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 76. P7C3-S229: 1- (9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol
This compound can be purchased from ChemBridge Corporation.
Another batch was also synthesized independently. Specifically, according to representative method 2, 1- (9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol was obtained in 80% yield.
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.09 (d, J = 7.7 Hz, 2H), 7.45 (q, J = 8.2 Hz, 4H), 7.24 (d, J = 6.6 Hz, 2H), 7.17 (t , J = 7.6 Hz, 2H), 6.80 (t, J = 7.5 Hz, 2H), 6.71 (d, J = 7.8 Hz, 2H), 4.49 (s, 1H), 4.46 (d, J = 5.1 Hz, 2H ), 3.40 (d, J = 12.9 Hz, 1H), 3.28 (dd, J = 12.3, 7.5 Hz, 1H). ESI m / z: 317.1 ([M + H] ⁺ , C ₂₁ H ₂ 0N ₂ O calculation (Value 317.16)

Example 77. 1- (3,6-Dichloro-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 78. 1- (9H-carbazol-9-yl) -3- (p-tolylamino) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 79. 1- (3,6-Dichloro-9H-carbazol-9-yl) -3- (p-tolylamino) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 80 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (p-tolylamino) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 81 N- (4- (3- (9H-carbazol-9-yl) -2-hydroxypropoxy) phenyl) acetamide
This compound can be purchased from ChemBridge Corporation.

Example 82. 1- (9H-carbazol-9-yl) -3-phenoxypropan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 83. 1- (9H-carbazol-9-yl) -3- (4-methoxyphenylamino) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 84 1- (Benzylamino) -3- (9H-carbazol-9-yl) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 85. Methyl 4- (3- (9H-carbazol-9-yl) -2-hydroxypropoxy) benzoate
This compound can be purchased from ChemBridge Corporation.

Example 86 1- (9H-carbazol-9-yl) -3- (4-methoxyphenoxy) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 87. P7C3-S20: 1-amino-3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol
This compound can be purchased from ChemBridge Corporation.

Example 88a. P7C3-S40: (S) -1- (3,6-dibromo-9H-carbazol-9-yl) -3-phenoxypropan-2-ol
Example 88b. P7C3-S41: (R) -1- (3,6-Dibromo-9H-carbazol-9-yl) -3-phenoxypropan-2-ol The title compound of Examples 88a and 88b was prepared from the epoxide starting material. Prepared according to the method described in Example 3b except using the appropriate commercially available optically active phenoxymethyloxirane as the material.

Example 89. P7C3-S42: 3,6-dibromo-9- (2-fluoro-3-phenoxypropyl) -9H-carbazole
The title compound of Example 89 was prepared according to the method described in Representative Method 4 except that the title compound of Example 3b was used as the starting material. The crude mixture was purified with 100% DCM (+ 0.2% TEA). Isolated yield = 97%.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.13 (d, 2H, J = 1.7 Hz), 7.51 (dd, 2H, J = 8.7, 1.9 Hz), 7.29-7.35 (m, 4H), 7.01 (t, 1H, J = 7.5 Hz), 6.91 (d, 1H, J = 7.8 Hz), 5.16 (dddd, 1H, J = 4.5, 5.4, 9.7, 46.0 Hz), 4.59-4.79 (m, 2H), 4.03-4.17 (m, 2H)
MS (ESI), m / z: 519.9 [(M + HCOO) ⁻ ; C ₂₁ H16Br ₂ FNO (M) calculated 475.0]

Example 90. P7C3-S54: 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -2-methylpropan-2-ol
Process 1. Chlorohydrin-19
m-anisidine (0.18 mL, 1.62 mmol) was added to a solution of 2-chloromethyl-2-methyloxirane (0.154 mL, 1.62 mmol) in acetic acid (2 mL) and the mixture was heated to 75 ° C. Upon completion, the reaction was neutralized to pH 7 with saturated sodium bicarbonate, extracted 3 times with EtOAc, washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was chromatographed _(SiO 2, _0~25% EtOAc / hexanes) to give the desired alcohol (332 mg, 89%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.08 (t, 1H, J = 8.1 Hz), 6.29 (m, 2H), 6.23 (t, 1H, J = 2.3 Hz), 3.95 (s, NH), 3.77 (s, 3H), 3.60 (dd, 2H, J = 35.1, 11.0 Hz), 3.25 (dd, 2H, J = 44.8, 13.0 Hz), 2.31 (apparent d, OH), 1.36 (s, 3H) ESI m / z 230.1 ([M + H] ⁺ )

Process 2. Epoxide-20
Chlorohydrin-19 (0.166 g, 0.722 mmol) was dissolved in dioxane (1 mL) and added to KOH (0.168 mgs, 3.0 mmol) pre-solution. The reaction was followed by TLC (20% EtOAc / hexanes) until the starting material was consumed to give a low polarity product. After aqueous workup, the crude product was used without further purification.
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.07 (t, 1H, J = 8.1 Hz), 6.27 (dd, 1H, J = 8.2, 0.8 Hz), 6.22 (dd, 1H, J = 8.2, 0.8 Hz) , 6.16 (t, 1H, J = 2.3 Hz), 3.83 (s, NH), 3.32 (br s, 2H), 2.82 (d, 1H, J = 4.5 Hz), 2.63 (d, 1H, J = 4.5 Hz )
Reference: Chemistry of Heterocyclic Compounds volume 41, No 4, 2005, pg 426.

Step 3. The title compound of Example 90 was obtained in 83% yield using 3,6-dibromocarbazole, sodium hydride (NaH) and epoxide 20. See, for example, the method described in Example 21, Step 4.
¹ H NMR (CDCl ₃ , 400 MHz): δ 8.14 (s, 2H), 7.53 (d, 2H, J = 8.9 Hz), 7.42 (d, 2H, J = 8.4 Hz), 7.09 (t, 1H, J = 8.4 Hz), 6.33 (d, 1H, J = 6.3 Hz), 6.27 (d, 1H, J = 6.3 Hz), 6.18 (s, 1H), 4.41 (d, 1H, J = 15.3 Hz), 4.32 ( d, 1H, J = 15.3 Hz) 3.74 (s, NH), 3.49 (s, 3H), 3.28 (d, 1H, 12.4 Hz), 3.22 (d, 1H, 12.4 Hz), 2.03 (s, OH), 1.33 (s, 3H) ESI m / z 518.9 ([M + H] ⁺ )
¹³ C NMR (CDCl ₃ , 100 MHz) δ 161.0, 149.8, 140.6 (2C), 130.4 (2C), 129.4 (2C), 123.8 (2C), 123.2 (2C), 112.8, 111.8 (2C), 106.9, 103.8 , 99.8, 75.0, 55.4, 52.5, 51.5, 25.1
ESI m / z 516.9 ([M + H] ⁺ , C ₂₃ H ₂₂ Br ₂ N ₂ O ₂ calculated 516.04

Example 91. 1- (2,8-Dimethyl-3,4-dihydro-1H-pyrido [4,3-b] indol-5 (2H) -yl) -3- (3-methoxyphenylamino) propane- 2-ol
According to literature methods (Zoidis et al., Bioorg. Med. Chem. 20009, 17, 1534-1541), the title compound of Example 18 (0.015 g, 0.034 mmol) was dissolved in anhydrous THF (0.34 mL). And cooled to 0 ° C. LAH (0.10 mL, 1.0 M in THF) solution was added dropwise and the reaction was stirred for 2 h at 0 ° C. MeOH was added to consume the remaining LAH and after 45 minutes the mixture was partitioned between EtOAc / H ₂ O. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 ×) and the combined organic layers were washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated. Crude residue was purified by column chromatography _(SiO 2, 0-20% MeOH / acetone + 1% Et ₃ N), followed by purification by PTLC (10% MeOH / acetone + 1% Et ₃ N) and the desired product Obtained (0.6 mg, 5%).
¹ H NMR (CDCl ₃ , 500 MHz) δ = 7.14 (m, 2H), 7.04 (dd, 1H, J = 8.0, 8.0 Hz), 6.98 (d, 1H, J = 8.5 Hz), 6.27 (d, 1H , J = 8.0 Hz), 6.18 (d, 1H, J = 8.0 Hz), 6.12 (s, 1H), 4.14 (m, 1H), 4.10 (m, 1H), 4.01 (m, 1H), 3.72 (s , 3H), 3.20 (m, 1H), 3.06 (m, 1H), 2.72 (s, 3H), 2.41 (s, 3H)
ESI m / z 380.2 ([M + H] ⁺ , C ₂₃ H ₃ 0N ₃ O ₂ calculated 380.2)

Example 92. P7C3-S48: 1- (4-azidophenylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol
4-azidoaniline (0.038 g, 0.283 mmol) was added 3,6-dibromo-9- (oxiran-2-ylmethyl) -9H-carbazole (0.100 g, 0.262 mmol) in THF (0.10 mL). To the solution. LiBr (0.001 g, 0.013 mmol) was added and the reaction was stirred at room temperature for 3 days. The reaction was chromatographed _(SiO 2, _0~25% EtOAc / hexanes) to give the desired product (31 mg, 23%).
¹ H NMR (d ₆ -acetone, 500 MHz) δ = 8.36 (d, 2H, J = 2.0 Hz), 7.61 (m, 2H), 7.55 (m, 2H), 6.85 (m, 2H), 6.74 (m , 2H), 5.19 (br s, 1H), 4.61 (dd, 1H, J = 4.0, 15.0 Hz), 4.56 (br s, 1H), 4.50 (dd, 1H, J = 8.0, 15.0 Hz), 4.39 ( m, 1H), 3.39 (dd, 1H, J = 4.5, 13.0 Hz), 3.25 (dd, 1H, J = 6.5, 13.0 Hz)
¹³ C NMR (acetone-d ₆ , 100 MHz) δ = 147.7, 141.1, 129.8 (2C), 128.9, 124.5, 124.0 (2C), 120.7 (2C), 114.9 (2C), 112.8 (2C), 112.6, 111.9 , 69.6, 48.5, 48.4
ESI m / z 513.9 ([M + H] ⁺ , C ₂₁ H ₁₈ Br ₂ N ₅ O calculated 514.0)

Example 93 P7C3-S47: 1- (3-azido-6-bromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol
Step 1. 3-Azido-6-bromo-9H-carbazole
3,6-dibromo-carbazole _{(0.500g, 1.538mmol), NaN 3} (0.120g, 1.846mmol), CuI (0.029g, 0.154mmol), L- proline (0.053 g, 0.461 mmol ) And NaOH (0.019 g, 0.461 mmol) were dissolved in 7: 3 EtOH / H ₂ O (3.0 mL) and heated at 95 ° C. for 24 hours under N ₂ atmosphere. The completed reaction was partitioned between EtOAc / H ₂ O (3 ×) and the combined organic layers were washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was chromatographed _(SiO 2, 0-15% EtOAc / toluene), followed by _{HPLC (Phenomenex SiO 2 Luna 10μ,} 250 × 21.2mm column, 50% EtOAc / hexane, 21 mL / min, retention time = 48 To give the desired product.
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.14 (s, 1H), 8.08 (br s, 1H), 7.64 (s, 1H), 7.50 (d, 1H, J = 8.5 Hz), 7.38 (d, 1H , J = 9.0 Hz), 7.29 (d, 1H, J = 8.5 Hz), 7.10 (d, 1H, J = 9.0 Hz)
ESI m / z 285.0 ([MH] ^- , C ₁₂ H ₆ BrN ₄ calculated 285.0)

Step 2. The title compound of Example 93 was obtained in 46% yield from 3-azido-6-bromo-9H-carbazole using a method analogous to that described in Example 90, Step 3.
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.14 (d, 1H, J = 1.5 Hz), 7.64 (d, 1H, J = 2.0 Hz), 7.52 (dd, 1H, J = 1.5, 8.5 Hz), 7.40 (d, 1H, J = 9.0 Hz), 7.31 (d, 1H, J = 8.5 Hz), 7.12 (dd, 1H, J = 2.0, 8.5 Hz), 7.07 (dd, 1H, J = 8.0, 8.0 Hz) , 6.31 (dd, 1H, J = 2.0, 8.0 Hz), 6.21 (dd, 1H, J = 1.5, 8.0 Hz), 6.13 (dd, 1H, J = 2.0, 2.5 Hz), 4.39-4.35 (m, 3H ), 3.71 (s, 3H), 3.31 (dd, 1H, J = 3.5, 13.0 Hz), 3.16 (dd, 1H, J = 7.0, 13.0 Hz), 2.17 (br s, 1H)
ESI m / z 466.0 ([M + H] ⁺ , C ₂₂ H ₂₁ BrN ₅ O ₂ calculated 466.1)

Example 94. P7C3-S49: 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (4-methoxyphenoxy) propan-2-ol
The title compound of Example 93 was obtained in 47% yield from dibromocarbazole and (p-methoxyphenyl) -glycidyl ether using a method analogous to that described in Example 90, Step 3 and Example 93, Step 2. Got in.
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.12 (d, 2H, J = 2.0 Hz), 7.50 (dd, 2H, J = 2.0, 8.5 Hz), 7.34 (d, 2H, J = 8.5 Hz), 6.81 (m, 2H), 6.79 (m, 2H), 4.56 (m, 1H), 4.42 (m, 3H), 3.93 (dd, 1H, J = 4.5, 9.5 Hz), 3.81 (dd, 1H, J = 4.5 , 9.5 Hz), 3.76 (s, 3H), 2.39 (d, 1H, J = 6.0 Hz)
¹³ C NMR (acetone-d ₆ , 100 MHz) δ 155.2, 153.8, 141.2 (2C), 129.8 (2C), 124.5 (2C), 124.0 (2C), 116.4 (2C), 115.5 (2C), 112.9 (2C ), 112.5 (2C), 71.1, 69.8, 55.9, 47.4
ESI m / z 547.9 ([M + CO ₂ H] ^- , C ₂₃ H ₂ 0Br ₂ NO ₅ calculated 548.0)

Example 95. P7C3-S52: 1- (3,6-dichloro-9H-carbazol-9-yl) -3- (phenylsulfonyl) propan-2-ol
Step 1. 1- (3,6-Dichloro-9H-carbazol-9-yl) -3- (phenylthio) propan-2-ol
Prepared using a method analogous to that described in Example 95, step 1, title compound Example 3a (white solid, 0.0293 g, 99.0% yield).
¹ H NMR (CDCl ₃ , 400 MHz) δ = 2.55 (s, 1H) 2.97 (dd, J = 13.8, 7.2 Hz, 1H) 3.09 (dd, J = 13.9, 5.2 Hz, 1H) 4.20-4.06 (m, 1H) 4.28 (dd, J = 15.0, 7.0 Hz, 1H) 4.41 (dd, J = 15.0, 4.1 Hz, 1H) 7.46-7.14 (m, 9H) 7.93 (d, J = 1.8 Hz, 2H)
¹³ C NMR (CDCl ₃ , 400 MHz) δ = 139.7, 134.5, 130.3, 129.5, 127.3, 126.8, 125.4, 123.3, 120.4, 110.6, 69.3, 48.2, 39.4
ESI m / z: 446.0, 436.0 [(M + HCOO -), (M + Cl -); C 21 H 17 Cl2NOS (M) calcd 401.0]

Step 2. The title compound of Example 95 was prepared as follows. To a solution of 1- (3,6-dichloro-9H-carbazol-9-yl) -3- (phenylthio) propan-2-ol (0.0081 g, 0.0201 mmol) in CH ₂ Cl ₂ (0.2 mL), A solution of mCPBA (77%, 0.0113 g, 0.0503 mmol) in CH ₂ Cl ₂ (0.2 mL) was added dropwise. The mixture was sealed and stirred overnight at room temperature. The crude reaction was diluted with EtOAc (30 mL) and washed with saturated NaHCO ₃ (3 × 30 mL) and brine (1 × 30 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was subjected to silica gel chromatography using hexane / EtOAc to give a white solid as product (0. 0080 g, yield 91.3%).
¹ H NMR (CDCl ₃ , 400 MHz) δ = 3.17 (dd, J = 14.2, 3.0 Hz, 1H) 3.28 (dd, J = 14.3, 8.3 Hz, 1H) 3.29 (d, J = 2.9 Hz, 1H) 4.39 (d, J = 6.3 Hz, 2H) 4.67 (dtt, J = 8.7, 5.9, 3.0 Hz, 1H) 7.31 (d, J = 8.7 Hz, 2H) 7.40 (dd, J = 8.7, 2.0 Hz, 2H) 7.52 (t, J = 7.9 Hz, 2H) 7.66 (t, J = 7.5 Hz, 1H) 7.80 (d, J = 7.3 Hz, 2H) 7.96 (d, J = 2.0 Hz, 2H)
¹³ C NMR (CDCl ₃ , 400 MHz) δ = 139.6, 138.8, 134.5, 129.8, 128.0, 127.0, 125.7, 123.5, 120.5, 110.5, 65.8, 60.0, 48.5
ESI m / z: 477.9 [(M + HCOO ⁻ ); C ₂₁ H ₁₇ Cl ₂ NO ₃ S (M) calculated 433.0]

Example 96. P7C3-S53: 3,6-dibromo-9- (2-fluoro-3- (phenylsulfonyl) propyl) -9H-carbazole
Step 1. 3,6-Dibromo-9- (2-fluoro-3- (phenylthio) propyl) -9H-carbazole
The title compound of Example 96, Step 1, was prepared by fluorination of the title compound of Example 31 using a method analogous to that described in Representative Method 4.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 3.09 (ddd, J = 14.2, 11.3, 8.4 Hz, 1H) 3.37-3.23 (m, 1H) 4.53 (ddd, J = 20.8, 15.9, 6.7 Hz, 1H) 4.66 (ddd, J = 26.6, 15.9, 2.8 Hz, 1H) 5.04-4.81 (m, 1H) 7.36-7.27 (m, 5H) 7.42 (dt, J = 3.2, 2.0 Hz, 2H) 7.54 (dd, J = 8.7, 1.9 Hz, 2H) 8.13 (d, J = 1.9 Hz, 2H)
¹³ C NMR (CDCl ₃ , 400 MHz) δ = 139.8, 134.3, 129.6, 129.5, 127.6, 123.9, 123.4, 112.9, 110.91 (d, J = 2.1 Hz, 1C) 92.2, 90.4, 46.16 (d, J = 22.8 Hz, 1C) 35.63 (d, J = 23.3 Hz, 1C)

Step 2. The title compound of Example 96 was prepared as follows. To a solution of 3,6-dibromo-9- (2-fluoro-3- (phenylthio) propyl) -9H-carbazole (0.0143 g, 0.0290 mmol) in CH ₂ Cl ₂ (0.5 mL) was added mCPBA (77% , 0.0162 g, 0.0725 mmol) in CH ₂ Cl ₂ (0.5 mL) was added dropwise. The mixture was sealed and stirred overnight at room temperature. The crude reaction was diluted with EtOAc (30 mL) and washed with saturated NaHCO ₃ (3 × 30 mL) and brine (1 × 30 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was subjected to silica gel chromatography using hexane / EtOAc as eluent to give a white solid as product. (0.0114 g, 74.8% yield).
¹ H NMR (CDCl ₃ , 400 MHz) δ = 3.61-3.40 (m, 2H) 4.56 (ddd, J = 22.4, 16.0, 6.6 Hz, 1H) 4.72 (dd, J = 26.8, 15.9 Hz, 1H) 5.38 ( dd, J = 47.1, 5.9 Hz, 1H) 7.34 (d, J = 8.7 Hz, 2H) 7.63-7.53 (m, 4H) 7.68 (t, J = 7.4 Hz, 1H) 7.90 (d, J = 8.0 Hz, 2H) 8.12 (s, J = 2.0 Hz, 2H)
¹³ C NMR (CDCl ₃ , 400 MHz) δ = 139.8, 134.7, 129.84, 129.79, 128.2, 124.1, 123.5, 113.3, 110.91, 110.89, 88.1, 86.3, 58.4, 58.1, 47.3, 47.1
ESI m / z: 557.9 [(M + Cl ⁻ ); C ₂₁ H ₁₆ Br ₂ FNO ₂ S (M) calculated 522.9]

Example 97a. P7C3-S50: (S) -1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylsulfonyl) propan-2-ol
Example 97b. P7C3-S51: (R) -1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylsulfonyl) propan-2-ol
A method analogous to that described in Example 3d from the title compound of Examples 97a and 97b from (S)-or (R) -3,6-dibromo-9- (oxiran-2-ylmethyl) -9H-carbazole. Manufactured using.

Preparation of (S) -3,6-dibromo-9- (oxiran-2-ylmethyl) -9H-carbazole [(S) -epoxide A]
To a solution of 3,6-dibromocarbazole (0.2194 g, 0.675 mmol) and triphenylphosphine (0.1770 g, 0.675 mmol) in THF (5.4 mL) was added S-(−)-glycidol (44.8 μL, 0.0500 g, 0.675 mmol) was added. The reaction mixture was cooled in an ice bath and diethyl azodicarboxylate (106.3 μL, 0.1175 g, 0.675 mmol) was added. The reaction mixture was warmed to room temperature and stirred overnight. THF was removed under reduced pressure and the residue was dissolved in EtOAc (30 mL) and washed with brine (3 × 30 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was subjected to silica gel chromatography using hexane / EtOAc to give a white solid as product (0. 0514 g, yield 20.0%).

Example 98. P7C3-S62: 1- (3,6-dicyclopropyl-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol
Step 1. tert-Butyl 3,6-dibromo-9H-carbazole-9-carboxylate
A solution of 3,6-dibromocarbazole (0.8288 g, 2.55 mmol) in THF (20 mL) was added to a suspension of NaH (60%, 0.1122 g, 2.81 mmol) in THF (10 mL) at −78 ° C. did. After stirring for 1 hour, (Boc) ₂ O anhydride (0.6122 g, 2.81 mmol) in THF (20 mL) was added dropwise to the mixture. The reaction was warmed to room temperature and stirred overnight. The THF was removed under reduced pressure and the residue was dissolved in EtOAc (30 mL) and washed with 1M HCl (2 × 30 mL) and brine (1 × 30 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , evaporated and the crude product was subjected to silica gel chromatography using hexane / EtOAc to give a white solid as product (0.9890 g, yield 91 .7%).
¹ H NMR (CDCl ₃ , 400 MHz) δ = 1.75 (s, 9H) 7.58 (dd, J = 8.9, 2.0 Hz, 1H) 8.05 (d, J = 1.8 Hz, 1H) 8.16 (d, J = 8.9 Hz , 1H)
¹³ C NMR (CDCl ₃ , 400 MHz) δ = 150.5, 137.5, 130.5, 126.3, 122.6, 117.9, 116.4, 84.9, 28.5

Step 2. tert-Butyl 3,6-dicyclopropyl-9H-carbazole-9-carboxylate
According to literature methods (Petit et al., ChemMedChem 20009, 4, 261-275), tert-butyl 3,6-dibromo-9H-carbazole-9-carboxylate (0.0200 g, 0.0470 mmol), cyclopropylboronic acid (0.0202 g, 0.235 mmol), palladium acetate (10 mol%, 0.0001 g, 0.000047 mmol), tricalcium phosphate (0.0350 g, 0.165 mmol), tricyclohexylphosphine (0.0026 g, 0.0091 mmol). ), Water (12.2 μL) and a stir bar were combined in a sealed vial. The vial was aerated with N ₂ and degassed toluene (0.22 mL) was added. The mixture was stirred at 100 ° C. for 65 hours. The crude reaction mixture was diluted with EtOAc (10 mL) and washed with brine (3 × 10 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product that was used as such without further purification.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 0.82-0.76 (m, 4H) 1.02 (ddd, J = 8.4, 6.4, 4.4 Hz, 4H) 1.74 (s, 9H) 2.11-2.01 (m, 2H) 7.19 (dd, J = 8.6, 1.9 Hz, 2H) 7.65 (d, J = 1.7 Hz, 2H) 8.14 (d, J = 8.5 Hz, 2H)

Step 3. 3,6-Dicyclopropyl-9H-carbazole
Corresponding N-Boc carbazole (0.0163g, 0.0469mmol) in _{CH 2} Cl 2 (1mL) solution was added dropwise TFA (144.8μL, 1.876mmol). The mixture was sealed and stirred at room temperature for 6 hours. CH ₂ Cl ₂ and TFA were removed under reduced pressure. The residue was diluted with EtOAc (30 mL) and washed with saturated NaHCO ₃ (3 × 30 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was subjected to silica gel chromatography using hexane / EtOAc as eluent to give a white solid as product. (0.0139 g).
¹ H NMR (CDCl ₃ , 400 MHz) δ = 0.77 (dt, J = 6.4, 4.5 Hz, 4H) 0.99 (ddd, J = 8.4, 6.2, 4.4 Hz, 4H) 2.13-2.03 (m, 2H) 7.16 ( dd, J = 8.4, 1.7 Hz, 2H) 7.28 (d, J = 8.4 Hz, 2H) 7.76 (d, J = 1.1 Hz, 2H) 7.83 (s, br, 1H)

Step 4. 3,6-Dicyclopropyl-9- (oxiran-2-ylmethyl) -9H-carbazole
The title compound of Example 98, Step 4, was prepared from 3,6-dicyclopropyl-9H-carbazole using a method analogous to that described in Representative Method 1.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 0.81-0.74 (m, 4H) 1.03-0.96 (m, 4H) 2.09 (ddd, J = 14.4, 8.9, 5.6 Hz, 2H) 2.53 (dd, J = 4.8 , 2.6 Hz, 1H) 2.77 (t, J = 4.3 Hz, 1H) 3.30 (dt, J = 7.4, 3.9 Hz, 1H) 4.35 (dd, J = 15.8, 4.6 Hz, 1H) 4.54 (dd, J = 15.8 , 3.4 Hz, 1H) 7.22 (dd, J = 8.4, 1.7 Hz, 2H) 7.31 (d, J = 8.4 Hz, 2H) 7.78 (d, J = 1.1 Hz, 2H)

Step 5. The title compound of Example 98 was prepared from 3,6-dicyclopropyl-9- (oxiran-2-ylmethyl) -9H-carbazole using a method analogous to that described in Representative Method 2. .
¹ H NMR (CDCl ₃ , 600 MHz) δ = 0.79-0.75 (m, 4H) 0.99 (td, J = 6.2, 4.6 Hz, 4H) 2.08 (ddd, J = 13.6, 8.5, 5.1 Hz, 2H) 3.21 ( dd, J = 12.9, 5.6 Hz, 1H) 3.35 (d, J = 13.8 Hz, 1H) 4.39 (s, J = 23.7 Hz, 3H) 6.62 (d, J = 8.4 Hz, 2H) 6.75 (t, J = 7.3 Hz, 1H) 7.17 (t, J = 7.9 Hz, 2H) 7.20 (dd, J = 8.4, 1.1 Hz, 2H) 7.32 (d, J = 8.4 Hz, 2H) 7.78 (s, 2H)
¹³ C NMR (CDCl ₃ , 500 MHz) δ = 148.2, 139.8, 134.9, 129.6, 124.8, 123.2, 118.5, 117.5, 113.7, 108.8, 69.8, 48.0, 47.6, 15.7, 9.1
ESI m / z: 441.2 [(M + HCOO ⁻ ); C ₂₇ H ₂₈ N ₂ O (M) calculated 396.2]

Example 99. P7C3-S63: 1- (3,6-diiodo-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol
Step 1. 3,6-Diiodo-9- (oxiran-2-ylmethyl) -9H-carbazole
The title compound of Example 99, Step 1 was used in a manner analogous to that described in Representative Method 1 from 3,6-diiodocarbazole (Maegawa et al., Tetrahedron Lett. 2006, 47, 6957-6960). Manufactured.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 2.48 (dd, J = 4.6, 2.6 Hz, 1H) 2.80 (t, J = 4.3 Hz, 1H) 3.37-3.24 (m, 1H) 4.28 (dd, J = 16.0, 5.1 Hz, 1H) 4.64 (dd, J = 15.9, 2.7 Hz, 1H) 7.24 (d, J = 8.6 Hz, 2H) 7.73 (dd, J = 8.6, 1.6 Hz, 2H) 8.33 (d, J = (1.7 Hz, 2H)
¹³ C NMR (CDCl ₃ , 500 MHz) δ = 140.0, 135.0, 129.5, 124.3, 111.3, 82.6, 50.6, 45.2, 44.9

Step 2. The title compound of Example 99 was prepared from 3,6-diiodo-9- (oxiran-2-ylmethyl) -9H-carbazole using a method analogous to that described in Representative Method 1.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 2.92 (s, br, 1H) 3.19 (dd, J = 12.8, 6.1 Hz, 1H) 3.33 (d, J = 10.9 Hz, 1H) 4.49-4.29 (m, 3H) 6.63 (d, J = 8.3 Hz, 2H) 6.78 (t, J = 7.3 Hz, 1H) 7.20 (t, J = 7.7 Hz, 2H) 7.28 (d, J = 2.5 Hz, 2H) 7.72 (d, J = 8.6 Hz, 2H) 8.35 (s, 2H)
¹³ C NMR (CDCl ₃ , 400 MHz) δ = 147.9, 140.1, 135.1, 129.65, 129.63, 124.4, 118.9, 113.7, 111.5, 82.6, 69.6, 48.0, 47.3
ESI m / z: 613.0 [(M + HCOO ⁻ ); C ₂₁ H ₁₈ I ₂ N ₂ O (M) calculated 568.0]

Example 100. P7C3-S64: 1- (3,6-diethynyl-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol
Step 1. 1- (3,6-Bis ((triisopropylsilyl) ethynyl) -9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol
The title compound of Example 62 (0.0112 g, 0.0222 mmol), bis (benzonitrile) dichloropalladium (3 mol%, 0.0003 g, 0.0007 mmol), [(tBu) ₃ PH] BF ₄ (6.2 mol%). , 0.0004 g, 0.0013 mmol), copper (I) iodide (2 mol%, 0.0001 g, 0.0004 mmol), DABCO (0.0006 g, 0.0533 mmol) were combined under N ₂ atmosphere. Degassed dioxane (0.1 mL) was added and the resulting solution was stirred at room temperature for 10 minutes. Trimethylsilylacetylene (11.8 μL, 0.0533 mmol) was added to the mixture via a microsyringe. The mixture was stirred overnight at room temperature. The crude reaction mixture was diluted with EtOAc (10 mL) and washed with brine (3 × 10 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was subjected to silica gel chromatography using hexane / EtOAc to give a colorless oil as product (0 0.015 g, yield 96.8%).
¹ H NMR (CDCl ₃ , 400 MHz) δ = 1.22-1.13 (m, 42H) 2.24 (s, br, 1H) 3.17 (dd, J = 12.6, 6.7 Hz, 1H) 3.31 (d, J = 12.1 Hz, 1H) 3.71 (s, 3H) 4.48-4.31 (m, 3H) 6.12 (t, J = 2.1 Hz, 1H) 6.22 (dd, J = 8.0, 1.8 Hz, 1H) 6.31 (dd, J = 8.1, 2.1 Hz , 1H) 7.07 (t, J = 8.1 Hz, 1H) 7.37 (d, J = 8.5 Hz, 2H) 7.58 (dd, J = 8.5, 1.5 Hz, 2H) 8.22 (d, J = 1.4 Hz, 2H)
¹³ C NMR (CDCl ₃ , 400 MHz) δ = 171.5, 161.0, 149.3, 140.9, 130.6, 130.4, 124.9, 122.7, 115.1, 109.3, 108.2, 106.7, 103.9, 99.7, 88.7, 69.5, 55.3, 47.4, 19.0, 11.6

Step 2. The title compound of Example 100 was prepared as follows. Of 1- (3,6-bis ((triisopropylsilyl) ethynyl) -9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol (0.0152 g, 0.0215 mmol) To a solution of anhydrous THF (200 μL) was added TBAF solution in THF (1M, 64.5 μL, 0.0645 mmol) and acetic acid (2.5 μL, 0.0430 mmol). The mixture was sealed and stirred under N ₂ atmosphere at room temperature for 27 hours until TLC showed complete disappearance of starting material. The crude reaction was diluted with EtOAc (10 mL) and washed with saturated NaHCO ₃ (3 × 10 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was subjected to silica gel chromatography using hexane / EtOAc to give a white solid as product (0. 0061 g, yield 71.9%).
¹ H NMR (CDCl ₃ , 400 MHz) δ = 2.24 (s, br, 1H) 3.09 (s, 2H) 3.20 (s, br, 1H) 3.32 (s, br, 1H) 3.72 (s, 3H) 4.48- 4.27 (m, 3H) 6.14 (s, 1H) 6.23 (dd, J = 8.0, 1.4 Hz, 1H) 6.32 (dd, J = 8.2, 1.8 Hz, 1H) 7.08 (t, J = 8.1 Hz, 1H) 7.40 (d, J = 8.5 Hz, 2H) 7.59 (dd, J = 8.5, 1.4 Hz, 2H) 8.21 (d, J = 1.1 Hz, 2H)
¹³ C NMR (CDCl ₃ , 500 MHz) δ = 161.1, 149.3, 141.2, 130.7, 130.4, 125.0, 122.7, 113.6, 109.6, 106.7, 103.8, 99.8, 84.7, 76.0, 69.6, 55.3, 48.0, 47.4
ESI m / z: 439.1 [(M + HCOO ⁻ ); C ₂₆ H ₂₂ N ₂ O ₂ (M) calculated 394.2]

Example 101. P7C3-S65: 9- (2-hydroxy-3- (3-methoxyphenylamino) propyl) -9H-carbazole-3,6-dicarbonitrile
According to literature method (Weissman et al., J. Org. Chem. 20005, 70, 1508-1510), the title compound of Example 62 (0.0252 g, 0.05 mmol), potassium hexacyanoferrate (II) trihydrate Product (0.0106 g, 0.025 mmol), sodium bicarbonate (0.0106 g, 0.1 mmol) and palladium acetate (1 mol%, 0.0001 g) were combined under N ₂ atmosphere. Anhydrous dimethylacetamide (0.1 mL) was added and the reaction mixture was stirred at 120 ° C. overnight. The crude reaction mixture was diluted with EtOAc (10 mL) and washed with water (2 × 10 mL) and brine (1 × 30 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was subjected to silica gel chromatography using hexane / EtOAc to give a white solid as product (0. 0110 g, yield 54.6%).
¹ H NMR (d ₆ -acetone, 400 MHz) δ = 2.81 (s, 1 H) 3.36-3.28 (m, 1H) 3.50-3.43 (m, 1H) 3.71 (s, 3 H) 4.44 (s, br, 1 H) 4.66 (dd, J = 15.0, 8.5 Hz, 1 H) 4.77 (dd, J = 15.1, 3.4 Hz, 1 H) 5.16 (t, J = 5.8 Hz, 1H) 6.22 (dd, J = 8.1, 2.1 Hz, 1H) 6.27 (t, J = 2.0 Hz, 1H) 6.31 (dd, J = 8.1, 1.2 Hz, 1H) 7.01 (t, J = 8.1 Hz, 1H) 7.84 (dd, J = 8.6, 1.2 Hz , 2H) 7.91 (d, J = 8.6 Hz, 2H) 8.74 (s, 2H)
¹³ C NMR (d ₆ -acetone, 500 MHz) δ = 161.3, 150.4, 143.9, 130.02, 129.95, 126.0, 122.4, 119.8, 112.0, 106.0, 103.3, 102.5, 98.9, 69.0, 54.5, 48.0, 47.7
ESI m / z: 441.1 [( M + HCOO -); C 24 H 2 0N 4 O 2 (M) calcd 396.2)

Example 102. P7C3-S55: N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) aniline
Step 1. N- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -4-nitro-N-phenylbenzenesulfonamide
The title compound of Example 102, Step 1, was prepared from epoxide 2-A and Ns-aniline using methods analogous to those described in Representative Methods 3 and 4. The crude mixture was purified with 40% EtOAc / hexanes (+ 0.1% TEA). The isolation yield was 60%.
¹ H NMR ((CD ₃ ) ₂ CO) ₃ , 400 MHz) δ 8.37 (m, 2H), 7.90 (m, 2H), 7.68 (m, 1H), 7.53-7.60 (m, 6H), 7.32-7.40 (m, 5H), 5.03 (dm, 1H), 4.71-4.93 (m, 2H), 4.27-4.41 (m, 2H)
MS (ESI), m / z: 703.9 [(M + HCOO) ⁻ ; C ₂₇ H ₂ 0Br ₂ FN ₃ O ₄ S (M) calculated 659.0]

Step 2. The title compound of Example 102 was prepared as follows. Cesium carbonate (11.5 mg, 0.036 mmol), nosylate prepared in step 1 above (7.9 mg, 0.012 mmol), THF (0.7 ml, 0.017 M) and benzenethiol (3.8 μl, 0.037 mmol) ) And stirred overnight. The crude reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. Chromatographic purification on SiO ₂ (20% EtOAc / hexane (0.2% TEA)) gave 74% (4.2 mg).
¹ H NMR (CDCl ₃ , 500 MHz) δ = 8.16 (s, 2H), 7.56 (d, 2H, J = 8.5 Hz), 7.31 (d, 2H, J = 8.5 Hz), 7.21 (t, 2H, J = 7.4 Hz), 6.80 (t, 1H, J = 7.3 Hz), 6.62 (d, 2H, J = 8.5 Hz), 5.11 (dddd, 1H, J = 5.4, 5.4, 10.4, 47.4 Hz), 4.52-4.68 (m, 2H), 3.94 (t, 1H, J = 6.02 Hz), 3.30-3.51, (dm, 2H)
MS (ESI), m / z: 475.0 [(M + 1)-; C ₂₁ H ₁₇ Br ₂ FN ₂ (M) calculated 474.0]

Example 103. P7C3-S56: 3,6-dibromo-9- (2,2-difluoro-3-phenoxypropyl) -9H-carbazole
Step 1. 1- (3,6-Dibromo-9H-carbazol-9-yl) -3-phenoxypropan-2-one
Dess-Martin periodinane (58.2 mg, 0.137 mmol) was added to a solution of the title compound of Example 3b (45.0 mg, 0.095 mmol) in dichloromethane (1.0 ml, 0.095 M). After 2 hours, the reaction mixture was diluted with EtOAc and washed with saturated sodium thiosulfate solution, water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was used without further purification. Yield = 74%
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.15 (d, 2H, J = 1.9 Hz), 7.52 (dd, 2H, J = 8.6, 1.9 Hz) 7.35 (m, 2H), 7.08 (t, 1H, J = 7.3 Hz), 7.04 (d, 2H, J = 8.9 Hz), 6.91 (m, 2H), 5.29 (s, 2H), 4.68 (m, 2H)
MS (ESI), m / z: 469.9 [(M-1) ^- ; C ₂₁ H ₁₅ Br ₂ NO ₂ (M) calculated 570.9]

Step 2. The title compound of Example 103 was prepared as follows. Diethylaminosulfur trifluoride (39 μl, 0.30 mmol) was added to 1- (3,6-dibromo-9H-carbazol-9-yl) -3-phenoxypropan-2-one (33.3 mg, 0.070 mmol). It was added dropwise to a solution of anhydrous dichloromethane (1.5 ml, 0.047 M). The reaction was quenched with saturated sodium bicarbonate solution and extracted three times with dichloromethane. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude mixture was purified on SiO ₂ (10% EtOAc / hexane + 0.2% TEA). The isolation yield was 69%.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.09 (d, 2H, J = 1.9 Hz), 7.48 (dd, 2H, J = 8.7, 1.8 Hz) 7.30-7.4 (m, 4H), 7.06 (t, 1H , J = 7.3 Hz), 6.91 (d, 2H, J = 7.9 Hz), 4.79 (t, 2H, J = 12.4 Hz), 4.07 (t, 2H, J = 11.1 Hz)
MS (ESI), m / z: 537.9 [(M + HCOO) ^- ; C ₂₁ H ₁₅ Br ₂ F ₂ NO (M) calculated 492.9]

Example 104. P7C3-S60: N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -4-methoxyaniline
Step 1. N- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -N- (4-methoxyphenyl) -4-nitrobenzenesulfonamide
The title compound of Example 104, Step 1, was prepared from epoxide 2-A and Ns-anisidine according to Representative Method 3. Yield = 71%
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.29 (d, 2H, J = 8.7 Hz), 8.11 (d, 2H, J = 1.9 Hz), 7.71 (, 2H, J = 8.6 Hz), 7.52 (dd, 2H, J = 8.6, 1.9 Hz), 7.23 (d, 2H, J = 8.9 Hz), 6.94 (d, 2H, J = 8.9 Hz), 6.82 (d, 2H, J = 8.9 Hz), 4.44 (dd, 1H, J = 14.8, 3.8 Hz), 4.30 (m, 1H), 4.21 (bs, 1H), 3.81 (s, 3H), 3.69 (m, 2H)
MS (ESI), m / z: 732.0 [(M + HCOO ⁻ ); C ₂₈ H ₂₃ Br ₂ N ₃ O ₆ S (M) calculated 687.0]

Step 2. N- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -N- (4-methoxyphenyl) -4-nitrobenzenesulfonamide
The title compound of Example 104, Step 2, was prepared according to Representative Method 4 from the nosylate prepared in Step 1 above.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.27 (m, 2H), 8.09 (m, 2H), 7.71 (d, 2H, J = 7.41 Hz), 7.53 (m, 2H), 7.19 (m, 2H) , 6.95 (d, 2H, J = 8.8 Hz), 6.82 (d, 2H, J = 8.8 Hz), 4.92 (dm, 1H, J _d = 48.3 Hz), 4.55 (m, 2H), 3.88 (m, 2H ), 3.79 (s, 3H)
MS (ESI), m / z: 734.0 (M + HCOO) ^- ; C ₂₈ H ₂₂ Br ₂ FN ₃ O ₅ S (M) calculated 689.0]

Step 3. The title compound of Example 104 was prepared according to Representative Method 5. Isolated yield 70%.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.14 (m, 2H0, 7.53 (dt, 2H, J = 8.8, 1.6 Hz), 7.30 (d, 2H, 8.6 Hz), 6.78 (d, 2H, J = 7.9 Hz), 6.57 (d, 2H, J = 7.9 Hz), 5.07 (dddd, 1H, J = 4.7, 6.1, 9.4, 47.7), 4.58 (m, 2H), 3.75 (s, 3H), 3.32 (m, 2H)
MS (ESI), m / z: 549.0 ((M + HCOO) ^- ; C ₂₂ H ₁₉ Br ₂ FN ₂ O (M) calculated 505.0)

Example 105. P7C3-S67: N- (2-bromo-3- (3,6-dibromo-9H-carbazol-9-yl) propyl) -N- (4-methoxyphenyl) -4-nitrobenzenesulfonamide
Step 1. N- (2-Bromo-3- (3,6-dibromo-9H-carbazol-9-yl) propyl) -N- (4-methoxyphenyl) -4-nitrobenzenesulfonamide
A solution of the title compound Example 104, Step 1 (20.5 mg, 0.030 mmol) in anhydrous dichloromethane (1.0 ml, 0.03 M) was cooled in an ice bath and BBr ₃ (7 μl, 0.074 mmol) was added. After 1 hour the reaction was diluted with EtOAc and washed twice with water, saturated sodium bicarbonate solution and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude mixture was purified with 100% CH ₂ Cl ₂ (+ 0.2% TEA). Isolated yield = 56%.
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.26 (d, 2H, J = 8.9 Hz), 8.12 (d, 2H, J = 1.7 Hz), 7.60 (d, 2H, J = 8.8 Hz) 7.53 (dd, 2H, J = 8.7, 1.9 Hz), 7.18 (d, 2H, J = 8.7 Hz), 6.89 (d, 2H, J = 8.9 Hz) 6.81 (d, 2.H, J = 9.0 Hz), 4.86 (dd , 1H, J = 15.6, 5.4 Hz), 4.57 (m, 1H), 4.44 (m, 1H), 3.92 (m, 2H), 3.82 (s, 3H). MS (ESI), m / z: 747.9 [ (M-1) ^- ; C ₂₈ H ₂₂ Br ₃ N ₃ O ₅ S (M) Calculated 748.9]

Step 2. The title compound of Example 105 was prepared from the nosylate prepared in Step 1 above according to Representative Method 5. Isolation yield = 43% at about 90% purity.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.14 (d, 2H, J = 1.7 Hz), 7.51 (dd, 2H, J = 8.6, 1.9 Hz), 7.28 (d, 2H, J = 8.7 Hz), 6.71 (d, 2H, J = 8.9 Hz), 6.41 (d, 2H, J = 8.8 Hz), 4.84 (m, 1H), 4.63 (m, 3H), 3.82 (m, 1H), 3.73 (s, 3H) MS (ESI), m / z: 564.8 [(M + 1) ⁺ ; C ₂₂ H ₁₉ Br ₃ N ₂ O calculated 563.9]

  The title compounds of Examples 106-109 can be prepared using the methods described herein and / or using conventional synthetic methods.

Example 106. P7C3-S61: ethyl 2- (4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropylamino) phenoxy) acetate

Example 107. P7C3-S66: N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -4- (2- (2-methoxyethoxy) ethoxy) aniline
Step 1. N- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -N- (4-methoxyphenyl) -4-nitrobenzenesulfonamide
The title compound was prepared according to Representative Method 3.

Step 2. N- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -N- (4-hydroxyphenyl) -4-nitrobenzenesulfonamide
Boron tribromide (290 μl, 3.06 mmol) was added at 0 ° C. to a solution of step 1 product (598 mg, 0.87 mmol) in anhydrous dichloromethane (17.0 ml). The reaction mixture was concentrated, diluted with ethyl acetate and washed with water, saturated sodium bicarbonate, water and brine. The pure product was isolated by column chromatography of the crude mixture with 1% MeOH / DCM. Yield = 59%
¹ H NMR (CD ₃ ) ₂ CO, 500 MHz) δ 8.42 (d, 2H, J = 8.8 Hz), 8.35 (s, 2H), 7.87 (d, 2H, J = 8.8 Hz), 7.56 (dd, 2H , J = 1.7, 8.8 Hz), 7.49 (d, 2H, J = 8.9 Hz) 7.05 (d, 2H, J = 8.7 Hz), 6.81 (d, 2H, J = 8.6 Hz), 4.59 (dd, 1H, J = 2.9, 15.2 Hz), 4.53 (d, 1H, J = 5.5 Hz), 4.15 (m, 1H), 3.87 (m, 1H)

Step 3. N- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -N- (4-hydroxyphenyl) -4-nitrobenzenesulfonamide
The product of step 2 was fluorinated according to representative method 4. The pure product was obtained after column chromatography with 1% MeOH / DCM (+ 0.2% TEA). Yield = 89%.
¹ H NMR (CD ₃ ) ₂ CO, 400 MHz) δ 8.48 (d, 2H, J = 9.0 Hz), 8.41 (d, 2H, J = 1.7 Hz), 7.94 (d, 2H, J = 8.6 Hz), 7.66 (dd, 2H, J = 1.9, 8.8 Hz), 7.60 (d, 2H, J = 8.8 Hz), 7.10 (d, 2H, J = 9.0 Hz), 6.89 (d, 2H, J = 8.8 Hz), 5.10 (dm, 1H), 4.74-4.94 (m, 2H), 4.20-4.32 (m, 2H)

Step 4. N- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -N- (4- (2- (2-methoxyethoxy) ethoxy) phenyl) -4 -Nitrobenzenesulfonamide
The product of step 3 was obtained (15.9 mg, 0.023 mmol), potassium carbonate (13.6 mg, 0.098 mmol) and 1-bromo-2- (2-methoxyethoxy) ethane (8.5 mg, 0.03 mmol). 041 mmol) in dimethylformamide (1.0 ml) was heated at 70 ° C. overnight. The reaction was diluted with EtOAc and washed several times with water and then with brine. Column chromatography with 100% DCM (+ 0.2% TEA) -1% MeOH / DCM (+ 0.2% TEA) gave the pure product. Yield = 43%.
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.30 (d, 2H, J = 8.9 Hz), 8.14 (d, 2H, J = 1.7 Hz), 7.72 (d, 2H, J = 8.8 Hz), 7.56 (dd , 2H, J = 1.8, 8.6 Hz), 7.23 (d, 2H, J = 8.8 Hz), 6.95 (d, 2H, J = 8.7 Hz), 6.85 (d, 2H, J = 8.7 Hz), 4.93 (dm , 1H), 4.46-4.69 (m, 2H), 4.13 (t, 2H, J = 5.2 Hz), 3.85-3.91 (m, 3H), 3.72 (m, 2H), 3.58 (m, 2H), 3.46- 3.50 (m, 1H), 3.39 (s, 3H) .MS (ESI), m / z: 824.0 (M + HCOO) ^-

Step 5. P7C3-S66: N- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -4- (2- (2-methoxyethoxy) ethoxy) aniline
The nitrosulfonyl group was removed from the product of Step 4 by representative method 5. The pure product was isolated after preparative TLC. Yield = 92%
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.15 (d, 2H, J = 1.8 Hz), 7.55 (dd, 2H, J = 1.9, 8.7 Hz), 7.30 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J = 8.9 Hz), 6.57 (d, 2H, J = 9.2 Hz), 5.08 (dm, 1H, ¹ J _{HF =} 47.8 Hz), 4.50-4.69 (m, 2H), 4.08 (m, 2H), 3.84 (m, 2H), 3.66-3.75 (m, 2H), 3.59 (m, 2H), 3.40 (s, 3H), 3.27-3.45 (m, 2H). MS (ESI), m / z : Calculated value 594.31, Actual value 595 (M + 1) ⁺

Example 108. P7C3-S68: N- (2- (2- (4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropylamino) phenoxy) acetamido) ethyl) -5- (2-oxohexahydro-1H-thieno [3,4-d] imidazol-4-yl) pentanamide
The title compound of Example 108 (P7C3-S68) was prepared by alkylation of the product of Step 107 of Example 107 compound (P7C3-S66) with ethyl iodoacetate followed by amidation and desulfonylation. The product was purified by preparative TLC with 10% MeOH / CH ₂ Cl ₂ (+ 0.2% TEA).
¹ H NMR (CD ₃ OD, 500 MHz) δ = 8.23 (s, 2H), 7.51 (dd, 4H, J = 31.0, 8.8, Hz), 6.84 (d, 2H, J = 8.9 Hz) 6.67 (d, 2H, J = 8.6 Hz), 5.04 (dm, 1H, J = 48.9 Hz), 4.69 (d, 1H, J = 5.2 Hz) 4.65 (m, 1H), 3.37-3.42 (m, 3H), 4.17 (m , 1H), 3.42-3.52 (m, 1H), 3.37 (m, 4H) 3.05 (m, 1H), 2.82 (dm, 1H), 2.69 (m, 1H), 2.63 (d, 1H, J = 12.7 Hz ), 2.13-2.18 (m, 2H) , 1.15-1.69 (m, 6H). 13 C NMR (CDCl 3, 126 MHz) δ = 176.6, 166.0, 151.7, 144.6, 141.2, 130.3, 124.9, 124.1, 117.1, 115.5, 113.4, 112.4, 106.2, 92.6 (d, ¹ J = 176.7 Hz), 69.2, 63.3, 61.6, 56.9, 47.2 (d, ² J = 22.2 Hz), 46.1 (d, ² J = 24.1 Hz), 41.0 , 40.2, 39.7, 36.8, 29.7, 29.4, 26.8.MS (ESI), m / z: Calculated 816.11, Measured 817.1 (M + 1) ⁺

Example 109. P7C3-S57

Example 110. P7C3-S70: 2- (4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropylamino) phenoxy) -N, N-dimethylacetamide
The title compound was prepared according to P7C3-S66.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 8.04 (d, 2H, J = 8.6 Hz), 7.45 (dd, 2H, J = 1.9, 8.6 Hz), 7.20 (d, 2H, J = 9.7 Hz), 6.75 (d, 2H, J = 8.8 Hz), 6.47 (d, 2H, J = 9.1 Hz), 4.97 (dm, 1H, ¹ J _HF = 47.2 Hz), 4.53 (s, 2H), 4.38-4.60 (m , 2H), 3.11-3.36 (m, 2H), 3.00 (s, 3H), 2.89 (s, 3H). 13 C NMR (CDCl 3, 100 MHz) δ = 184.0, 168.3, 151.4, 142.0, 139.6, 129.5 , 123.4, 116.1, 112.9, 110.7 (d, ⁴ J = 1.8 Hz), 90.8 (d, ¹ J = 175.5 Hz), 68.4, 46.4 (d, ² J = 24.7 Hz), 45.0 (d, ² J = 92.3 Hz), 29.8, 32.9.MS (ESI), m / z: Calculated value 575.02, Actual value 622.0 (M + HCOO) ^-

Example 111. P7C3-S71: 2- (4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropylamino) phenoxy) -N- (2-hydroxyethyl) acetamide
The title compound was prepared according to P7C3-S66 and purified by silica gel chromatography (5% MeOH / DCM + 0.2% TEA).
¹ H NMR (CDCl ₃ , 400 MHz) δ = 12.07 (bs, 1H), 8.15 (d, 2H), 7.55 (dd, 2H, J = 2.0, 8.5 Hz), 7.31 (d, 2H, J = 8.8 Hz ), 7.06 (bm, 1H), 6.80 (d, 2H, J = 9.1 Hz), 6.57 (d, 2H, 9.2 Hz), 5.09 (dm, 1H, ¹ J _HF = 47.2 Hz), 4.51-4.68 (m , 2H), 4.51-4.68 (m, 2H), 4.45 (s, 2H), 3.78 (t, 3H, J = 4.9 Hz), 3.53 (q, 2H, J = 5.4 Hz), 3.22-3.45 (m, 2H), 2.57 (bs, 1H ). 13 C NMR (CDCl 3, 100 MHz). δ = 169.9, 150.5, 142.5, 139.7, 129.6, 123.5, 116.2, 110.7 (d, 4 J = 1.2 Hz), 90.8 ( d, ¹ J = 176.5 Hz), 68.3, 62.4, 46.3 (d, ² J = 21.8 Hz), 45.0 (d, ² J = 25.7 Hz), 42.2.MS (ESI), m / z: Calculated 591.02, Actual value 638.0 (M + HCOO) ^-

Example 112. P7C3-S72: 1- (bis (4-bromophenyl) amino) -3- (phenylamino) propan-2-ol
P7C3-S72 was prepared from di- (4-bromophenyl) amine, epibromohydrin and aniline according to representative methods 1 and 2.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 7.38 (d, 4H, J = 8.8 Hz), 7.19 (d, 2H, J = 7.4 Hz), 6.95 (d, 4H, J = 8.8 Hz), 6.76 ( t, 1H, J = 7.4 Hz), 6.62 (d, 2H, J = 7.9 Hz), 4.17 (bm, 1H), 3.89 (dd, 1H, J = 4.3, 15.2 Hz), 3.72-3.81 (m, 1H ), 3.32 (dd, 1H, J = 3.2, 12.8 Hz), 3.08-3.18 (m, 1H). 13 C NMR (CDCl 3, 100 MHz) δ = 148.0, 147.0, 132.6, 129.5, 123.1, 118.4, 114.9 , 113.5, 67.9, 56.6, 47.8.MS (ESI), m / z: Calculated value 473.99, Actual value 521 (M + HCOO) ^-

Example 113. P7C3-S73: (E) -3,6-dibromo-9- (3-phenoxyallyl) -9H-carbazole and (E) -3,6-dibromo-9- (3-phenoxyprop-1 -En-1-yl) -9H-carbazole.
Step 1. 3,6-Dibromo-9- (2-bromo-3-phenoxypropyl) -9H-carbazole
To a solution of ice-cooled P7C3-S39 (95.0 mg, 0.20 mmol, 1 eq) and triphenylphosphine (78.7 mg, 0.30 mmol, 1.5 eq) in dichloromethane (0.6 mL) was added tetrabromomethane (0.6 mL). 73.0 mg, 0.22 mmol, 1.1 eq) was added. The mixture was stirred at room temperature for 3 hours. Dichloromethane was and the crude residue was purified by silica gel chromatography using 9% EtOAc / Hex to give 7.4 mg of white solid as product in 6.9% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 4.22-4.11 (m, 2H) 4.61 (dt, J = 12.2, 6.2 Hz, 1H) 4.68 (dd, J = 15.2, 6.4 Hz, 1H) 4.98 (dd, J = 15.2, 7.1 Hz, 1H) 6.88 (d, J = 7.8 Hz, 2H) 7.02 (t, J = 7.4 Hz, 1H) 7.37-7.26 (m, 4H) 7.49 (dd, J = 8.7, 1.8 Hz, 2H) 8.12 (d, J = 1.8 Hz, 2H)

Step 2. P7C3-S73. (E) -3,6-Dibromo-9- (3-phenoxyallyl) -9H-carbazole and (E) -3,6-dibromo-9- (3-phenoxyprop-1- En-1-yl) -9H-carbazole
In a 4 mL vial, the product of step 1, kryptofix 222 (4.8 mg, 0.0130 mmol, 1 eq), KF (0.5 mg, 0.0090 mmol, 0.7 eq), K ₂ CO ₃ (0.3 mg, 0.0019 mmol, 0.15 eq) and acetonitrile (0.15 mL) were added. The vial was sealed and heated at 80 ° C. for 20 minutes. The crude reaction was purified by silica gel chromatography using 9% EtOAc / Hex to give 4.9 mg of white solid in one fraction as a mixture of these two olefins in a 45:55 ratio for a total yield of 83. Obtained at 6%.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 4.51 (dd, J = 6.5, 1.4 Hz, 0.45 × 1H) 4.83 (dd, J = 6.2, 1.2 Hz, 0.55 × 1H) 6.21 (dt, J = 8.0, (6.6 Hz, 0.45 × 1H) 6.31 (dt, J = 14.2, 6.1 Hz, 0.55 × 1H) 6.74 (d, J = 7.9 Hz, 1H) 6.94-6.85 (m, 1H) 7.05-6.98 (m, 2H) 7.38 -7.15 (m, 4H) 7.49 (d, J = 8.7 Hz, 1H) 7.57 (ddd, J = 8.6, 4.1, 1.9 Hz, 2H) 8.14 (dd, J = 13.0, 1.8 Hz, 2H)

Example 114. P7C3-S75: 1- (3,6-bis (trifluoromethyl) -9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol Step 1. 4- (Trifluoro Methyl) phenyl trifluoromethanesulfonate
To a solution of 4-trifluoromethylphenol (324.2 mg, 2.0 mmol, 1 eq) in dichloromethane (1.2 mL) was added pyridine (194.1 μL, 2.4 mmol, 1.2 eq). A solution of triflic anhydride (370.1 μL, 2.2 mmol, 1.1 eq) in dichloromethane (1.2 mL) was added dropwise at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 2.5 hours. The reaction was quenched with water (1 mL). The organic layer was washed with saturated NaHCO ₃ , 1M HCl and brine, dried over MgSO ₄ and concentrated to give the crude product. This was further purified by silica gel chromatography using 5% EtOAc / Hex to give 449.4 mg colorless oil as product in 76.4% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 7.42 (d, J = 8.8 Hz, 2H) 7.75 (d, J = 9.0 Hz, 1H)

Step 2. 3,6-Bis (trifluoromethyl) -9H-carbazole
According to the method of Watanabe et al., J. Org. Chem. 2009, 74, 4720-4726, the product of step 1 was obtained (29.4 mg, 0.10 mmol, 1 eq), 4- (trifluoromethyl) Aniline (17.7 mg, 0.11 mmol, 1.1 eq), Pd (OAc) ₂ (2.2 mg, 0.01 mmol, 0.1 eq), XPhos (7.2 mg, 0.015 mmol, 0.15 eq) ) And Cs ₂ CO ₃ (39.1 mg, 0.12 mmol, 1.2 eq) were added toluene (0.2 mL) under an argon atmosphere. The mixture was stirred at 100 ° C. for 1.5 hours. After cooling, the crude mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over MgSO ₄ and concentrated. The crude product was further purified by silica gel chromatography using 0-5% EtOAc / Hex to give 22.2 mg of diarylamine as a colorless oil in 69.2% yield. To this intermediate was added acetic acid (0.8 mL) and Pd (OAc) ₂ (2.5 mg). The mixture was heated at 90 ° C. under an oxygen balloon for 12 hours. The reaction was stopped by adding solid NaHCO ₃ . The mixture was diluted with ethyl acetate and washed with NaHCO ₃ . The organic layer was dried over MgSO ₄ and concentrated to give the crude product. This was further purified by silica gel chromatography using 25% EtOAc / Hex to give 9.2 mg of white solid in 41.7% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 7.54 (d, J = 8.6 Hz, 2H) 7.72 (dd, J = 8.6, 1.5 Hz, 2H) 8.38 (s, 2H) 8.47 (s, br, 1H) . ESI (m / z): 302.0 (MH ⁺ )

Step 3. 1-Chloro-3- (phenylamino) propan-2-ol
Acetic acid (0.56 mL), aniline (456 μL, 5.0 mmol, 1 eq) and epichlorohydrin (469 μL, 6.0 mmol, 1.2 eq) were combined and stirred in a sealed vial at 75 ° C. for 3 hours. The reaction was quenched with solid NaHCO ₃ (0.8218 g) and the mixture was diluted with ethyl acetate and washed with saturated NaHCO ₃ . The combined organic extracts were dried over MgSO ₄ and concentrated to give the crude product. This was further purified by silica gel chromatography using 30% EtOAc / Hex to give 495.5 mg colorless oil as product in 53.4% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 2.10 (d, J = 0.9 Hz, 1H) 3.25 (dd, J = 13.3, 7.1 Hz, 1H) 3.39 (dd, J = 13.3, 4.5 Hz, 1H) 3.77 -3.56 (m, 2H) 4.17-4.03 (m, 1H) 6.67 (dd, J = 8.6, 1.0 Hz, 2H) 6.76 (tt, J = 7.4, 1.0 Hz, 1H) 7.20 (dd, J = 8.5, 7.4 . Hz, 2H) ESI (m / z): 186.1 (M + H +); 230.1 (M + HCOO -)

Step 4. N- (oxiran-2-ylmethyl) aniline
The product of step 3 was obtained (185.7 mg, 1.0 mmol, 1 eq) in 1,4-dioxane (3.3 mL) and KOH powder (67.3 mg, 1.2 mmol, 1.2 eq). Was added. The mixture was stirred at room temperature for 24 hours. The mixture was diluted with EtOAc and washed with 1M HCl and brine. The organic layer was dried over MgSO ₄ and concentrated to give the crude product. This was further purified by silica gel chromatography using 20% EtOAc / Hex to give 141.8 mg of colorless oil as product in 95.0% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 2.70 (dd, J = 4.9, 2.3 Hz, 1H) 2.87-2.77 (m, 1H) 3.23-3.18 (m, 1H) 3.26 (t, J = 4.9 Hz, 1H) 3.59-3.48 (m, 1H) 3.87 (s, 1H) 6.64 (d, J = 7.7 Hz, 2H) 6.73 (t, J = 7.3 Hz, 1H) 7.18 (dd, J = 8.3, 7.5 Hz, 2H )

Step 5. P7C3-S75: 1- (3,6-bis (trifluoromethyl) -9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol
The product of step 2 was obtained (4.6 mg, 0.0152 mmol, 1 eq) in THF (0.25 mL) in NaH (60% dispersion in mineral oil, 0.7 mg, 0.0167 mmol, 1.1 eq). ) Was added and the mixture was stirred at room temperature for 15 minutes. The product of step 4 was obtained (2.7 mg, 0.0182 mmol, 1.2 eq) and the resulting mixture was stirred at room temperature overnight and heated at 65 ° C. for 4 hours. Brine was added and the crude reaction was extracted 3 times with EtOAc. The combined organic extracts were dried over MgSO ₄ and concentrated to give the crude product. This was further purified by silica gel chromatography using 30% EtOAc / Hex to give 4.1 mg of white solid as product in 59.6% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 2.33 (s, 1H) 3.25 (dd, J = 13.1, 7.1 Hz, 1H) 3.40 (dd, J = 13.1, 4.0 Hz, 1H) 4.43 (ddd, J = 11.3, 6.8, 4.6 Hz, 1H) 4.62-4.46 (m, 2H) 6.64 (d, J = 8.3 Hz, 2H) 6.79 (t, J = 7.3 Hz, 1H) 7.23-7.12 (m, 2H) 7.60 (d , J = 8.6 Hz, 2H) 7.75 (dd, J = 8.6, 1.4 Hz, 2H) 8.41 (s, 2H). 13 C NMR (CDCl 3, 400 MHz) δ = 147.8, 143.1, 129.7, 123.9 (dd, J = 7.0, 3.5 Hz, 1C), 123.0, 122.7, 122.5, 119.0, 118.5 (q, J = 4.2 Hz, 1C), 113.8, 110.0, 69.7, 48.1, 47.5. ESI (m / z): 497.1 (M + HCOO ^-)

Example 115. P7C3-S77: 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylthio) propan-2-ol
Prepared according to Example 3a. Chromatography (0-50% EtOAc in hexanes) gave 242 mg (88% yield) of an off-white foam.
¹ H NMR (CDCl ₃ , 500 MHz) δ = 8.01 (d, J = 1.5 Hz, 2H), 7.46 (dd, J = 1.5, 8.5 Hz, 2H), 7.21 (d, J = 9.0 Hz, 2H), 7.14 (dd, J = 8.0, 8.0 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 6.80 (m, 1H), 6.72 (dd, J = 2.0, 8.0 Hz, 1H), 4.32 (dd , J = 4.0, 15.0 Hz, 1H), 4.20 (dd, J = 7.0, 15.0 Hz, 1H), 4.09 (m, 1H), 3.69 (s, 3H), 3.03 (dd, J = 5.0, 14.0 Hz, 1H), 2.91 (dd, J = 7.5, 14.0 Hz, 1H), 2.55 (d, J = 3.0 Hz, 1H). 13 C NMR (CDCl 3, 125 MHz) δ = 160.1, 139.7, 135.7, 130.3, 129.3 (2C), 123.6, 123.3 (2C), 122.0, 115.4, 112.7, 112.6, 111.0 (2C), 69.2, 55.4, 48.0, 39.0. ESI m / z: 563.6 ([M + HCOO] ^- )

Example 116. P7C3-S78: 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (4-methoxyphenylthio) propan-2-ol
Prepared according to Example 3a. Chromatography (0-50% EtOAc in hexanes) gave 263 mg (96% yield) of an off-white solid.
¹ H NMR (CDCl ₃ , 500 MHz) δ = 8.02 (d, J = 2.0 Hz, 2H), 7.47 (dd, J = 2.0, 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 9.0 Hz, 2H), 6.77 (d, J = 9.0 Hz, 2H), 4.31 (dd, J = 4.0, 15.0 Hz, 1H), 4.18 (dd, J = 7.0, 15.5 Hz, 1H ), 4.01 (m, 1H), 3.75 (s, 3H), 2.93 (dd, J = 5.0, 14.0 Hz, 1H), 2.79 (dd, J = 7.5, 13.5 Hz, 1H), 2.6 (d, J = 3.5 Hz, 1H). ¹³ C NMR (CDCl ₃ , 125 MHz) δ = 159.7, 139.8 (2C), 133.9 (2C), 129.3 (2C), 124.4, 123.6 (2C), 123.3 (2C), 115.1 (2C ), 112.6 (2C), 111.0 (2C), 69.1, 555.5, 48.0, 41.3. ESI m / z: 563.5 ([M + HCOO] ^- )

Example 117. P7C3-S79: 3,6-dibromo-9- (2-fluoro-3- (3-methoxyphenylthio) propyl) -9H-carbazole
Prepared according to Example 96 from P7C3-S77. Chromatography (0-5% EtOAc in hexanes) gave 32 mg (32% yield) of an off-white solid.
¹ H NMR (CDCl ₃ , 500 MHz) δ = 8.07 (d, J = 1.5 Hz, 2H), 7.50 (dd, J = 1.5, 8.5 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 7.21 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.92 (br s, 1H), 6.77 (dd, J = 2.0, 8.5 Hz, 1H), 4.90 (dm, J = 47.5 Hz, 1H), 4.59 (ddd, J = 2.5, 16.0, 26.5 Hz, 1H), 4.45 (ddd, J = 7.0, 16.0, 22.0 Hz, 1H), 3.76 (s, 3H), 3.26 (ddd , J = 4.5, 15.0, 15.0 Hz, 1H), 3.06 (m, 1H). 13 C NMR (CDCl 3, 125 MHz) δ = 160.2, 139.8 (2C), 135.5, 130.5, 129.5 (2C), 123.9 ( 2C), 123.4 (2C), 122.2 (2C), 115.8, 113.0, 112.9, 110.9 (d, J = 2.1 Hz, 2C), 104.9, 91.3 (d, J = 180 Hz), 55.5, 46.1 (d, J = 22.9 Hz), 35.4 (d, J = 23.9 Hz). ESI m / z: 565.7 ([M + HCOO] ^- )

Example 118. P7C3-S80: 3,6-dibromo-9- (2-fluoro-3- (4-methoxyphenylthio) propyl) -9H-carbazole
Prepared according to Example 96 from P7C3-S78. Chromatography (0-5% EtOAc in hexanes) gave 23 mg (23% yield) of an off-white solid.
¹ H NMR (CDCl ₃ , 500 MHz) δ = 8.08 (d, J = 1.5 Hz, 2H), 7.52 (dd, J = 1.5, 8.5 Hz, 2H), 7.39 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 4.83 (dm, J = 48.0 Hz, 1H), 4.58 (ddd, J = 2.5, 15.5, 27.0 Hz, 1H ), 4.45 (ddd, J = 7.0, 16.0, 20.5 Hz, 1H), 3.78 (s, 3H), 3.13 (ddd, J = 4.5, 14.5, 14.5 Hz, 1H), 2.96 (m, 1H). 13 C NMR (CDCl ₃ , 125 MHz) δ = 159.9, 134.2, 129.5, 124.4, 123.9, 123.4, 115.2, 112.9, 110.9 (d, J = 2.1 Hz, 2C), 104.9, 91.5 (d, J = 179.6 Hz), 55.6, 46.1 (d, J = 22.6 Hz), 37.6 (d, J = 22.4 Hz) ESI m / z:. 565.7 ([M + HCOO] - 565.9)

Example 119. P7C3-S81: 3,6-dibromo-9- (2-fluoro-3- (3-methoxyphenylsulfonyl) propyl) -9H-carbazole
Prepared according to Example 96 from P7C3-S77. Chromatography (0-30% EtOAc in hexanes) gave 17.7 mg (84% yield) of an off-white solid.
¹ H NMR (CDCl ₃ , 500 MHz) δ = 8.11 (d, J = 1.5 Hz, 2H), 7.55 (dd, J = 1.5, 8.5 Hz, 2H), 7.43 (m, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.33 (m, 1H), 7.16-7.14 (m, 1H), 5.34 (dm, J = 49.0 Hz, 1H), 4.71 (ddd, J = 2.5, 16.0, 26.5 Hz, 1H) , 4.56 (ddd, J = 7.0 , 16.0, 22.5 Hz, 1H), 3.81 (s, 3H), 3.48 (m, 2H). 13 C NMR (CDCl 3, 125 MHz) δ = 160.4, 140.0, 139.7 (2C ), 130.9, 129.7 (2C), 124.0 (2C), 123.5 (2C), 121.1 (2C), 120.2, 113.2, 112.6, 110.9 (d, J = 2.1 Hz, 2C), 87.1 (d, J = 181.3 Hz ), 58.1 (d, J = 23.4 Hz), 56.0, 47.1 (d, J = 22.0 Hz). ESI m / z: 531.7 ([MH ₂ F] ^- )

Example 120. P7C3-S82: 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylsulfonyl) propan-2-ol
Prepared according to Example 3d from P7C3-S77. Chromatography (0-25% EtOAc in hexanes) gave 30 mg (94% yield) of an off-white solid.
¹ H NMR (CDCl ₃ , 500 MHz) δ = 8.06 (d, J = 2.0 Hz, 2H), 7.49 (dd, J = 2.0, 9.0 Hz, 2H), 7.36 (apparent t, J = 8.0 Hz, 1H ), 7.31 (m, 1H), 7.22 (d, J = 9.0 Hz, 2H), 7.20 (m, 1H), 7.10 (m, 1H), 4.61 (m, 1H), 4.33 (m, 2H), 3.78 (s, 3H), 3.32 (br s, 1H), 3.23 (dd, J = 8.0, 14.0 Hz, 1H), 3.12 (dd, J = 3.0, 14.5 Hz, 1H). ¹³ C NMR (CDCl ₃ , 125 MHz) δ = 160.3, 139.7, 139.6 (2C), 130.8, 129.6 (2C), 123.8, 123.4 (2C), 120.8, 119.9, 113.0 (2C), 112.3 (2C), 110.9 (2C), 65.6, 59.9, 55.9, 48.2. ESI m / z: 595.6 ([M + HCOO] ^- )

Example 121. P7C3-S83: 3,6-dibromo-9- (2-fluoro-3- (4-methoxyphenylsulfonyl) propyl) -9H-carbazole
Prepared according to Example 96 from P7C3-S78. Chromatography (0-30% EtOAc in hexanes) gave 18.9 mg (89% yield) of an off-white solid.
¹ H NMR (CDCl ₃ , 500 MHz) δ = 8.10 (d, J = 2.0 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.54 (dd, J = 1.5, 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 5.32 (dm, J = 47.5 Hz, 1H), 4.69 (ddd, J = 2.5, 16.0, 27.0 Hz, 1H ), 4.54 (ddd, J = 7.0, 16.0, 22.5 Hz, 1H), 3.85 (s, 3H), 3.49-3.42 (m, 2H). 13 C NMR (CDCl 3, 125 MHz) δ = 164.5, 139.7 ( 2C), 130.5 (2C), 130.3, 129.7 (2C), 124.0 (2C), 123.5 (2C), 114.9 (2C), 113.2 (2C), 110.9 (d, J = 2.25 Hz, 2C), 87.4 (d , J = 181.1 Hz), 58.5 (d, J = 23.1 Hz), 56.0, 47.2 (d, J = 22.0 Hz). ESI m / z: 531.5 ([MH ₂ F] ^-

Example 122. P7C3-S84: 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (4-methoxyphenylsulfonyl) propan-2-ol
Prepared according to Example 3d from P7C3-S78. Chromatography (0-30% EtOAc in hexanes) gave 27 mg (85% yield) of an off-white solid.
¹ H NMR (CDCl ₃ , 500 MHz) δ = 8.09 (d, J = 2.0 Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.50 (dd, J = 2.0, 9.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 4.61 (m, 1H), 4.36 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.35 (d, J = 2.5 Hz, 1H), 3.20 (dd, J = 8.5, 14.0 Hz, 1H), 3.10 (dd, J = 2.5, 14.0 Hz, 1H). ¹³ C NMR (d ₆ -acetone, 125 MHz) δ = 164.7, 141.0 (2C), 132.8, 131.2 (2C), 129.8 (2C), 124.5 (2C), 124.0 (2C), 115.2 (2C), 112.74 (2C), 112.68 (2C), 66.6, 61.0, 56.3, 49.7. ESI m / z: 595.6 ([M + HCOO] ^- )

Example 123. P7C3-S91: 3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylthio) phenol
Prepared according to Example 3a. By chromatography on silica (0-40% EtOAc in hexane) followed by HPLC purification (75% MeCN / H ₂ O + 0.1% HCO ₂ H, Phenomenex C18 Luna, 10 × 250 mm, 3 mL / min), 9.9 mg ( (21% yield) of off-white solid.
¹ H NMR (d ₆ -acetone, 400 MHz) δ = 8.35 (br s, 2H), 7.56 (m, 4H), 7.13 (obvious t, J = 8.0 Hz, 1H), 6.94 (br s, 1H) , 6.88 (d, J = 7.6 Hz, 1H), 6.69 (dd, J = 1.6, 8.0 Hz, 1H), 4.66 (dd, J = 3.2, 15.2 Hz, 1H), 4.47 (dd, J = 8.4, 14.8 . Hz, 1H), 4.26 ( m, 1H), 3.22 (d, J = 6.4 Hz) 13 C NMR (d 6 - acetone, 125 MHz) δ = 158.8, 141.1 (2C), 138.2, 130.9, 129.7 (2C ), 124.4 (2C), 124.0 (2C), 120.7 (2C), 116.5, 114.2, 112.8 (2C), 112.5, 70.2, 49.2, 38.5. ESI m / z: 549.7 ([M + HCOO] ^- )

Example 124. P7C3-S92: 4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylthio) phenol
Prepared according to Example 3a. Chromatography (0-3% acetone in dichloromethane) followed by HPLC purification (75% MeCN / H ₂ O + 0.1% HCO ₂ H, Phenomenex C18 Luna, 10 × 250 mm, 3 mL / min) gave 11.4 mg (25 % Yield) of off-white solid.
¹ H NMR (d ₆ -acetone, 500 MHz) δ = 8.64 (br s, 1H), 8.34 (s, 2H), 7.56 (m, 4H), 7.36 (d, J = 8.5 Hz, 2H), 6.82 ( d, J = 8.5 Hz, 2H), 4.62 (dd, J = 3.5, 15.0 Hz, 1H), 4.54 (br s, 1H), 4.43 (dd, J = 8.5, 15.0 Hz, 1H), 4.16 (m, . 1H), 3.09 (d, J = 6.5 Hz, 2H) 13 C NMR (d 6 - acetone, 125 MHz) δ = 158.0, 141.1 (2C), 134.3 (2C), 129.7 (2C), 125.3, 124.4 ( 2C), 124.0 (2C), 117.1 (2C), 112.9 (2C), 112.5 (2C), 70.3, 49.1, 41.2. ESI m / z: 503.6 ([MH] ^- , C ₂₁ H ₁₆ Br ₂ NO ₂ S (Calculated value 503.9)

Example 125. P7C3-S93: 3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylsulfonyl) phenol
Prepared from P7C3-S91 according to Example 3d. Chromatography (0-40% EtOAc in hexanes) followed by HPLC purification (75% MeCN / H ₂ O + 0.1% HCO ₂ H, Phenomenex C18 Luna, 10 × 250 mm, 3 mL / min) gave 9.9 mg (46 % Yield) of off-white solid.
¹ H NMR (d ₆ -acetone, 500 MHz) δ = 9.28 (br s, 1H), 8.36 (s, 2H), 7.59 (m, 4H), 7.44 (obvious t, J = 8.0 Hz, 1H), 7.43 (m, 1H), 7.38 (br s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 4.72 (br s, 1H), 4.64 (dd, J = 2.5, 14.0 Hz, 1H), 4.76 (m, 1H), 4.54 (dd, J = 8.5, 14.0 Hz, 1H), 3.66 (dd, J = 5.0, 14.5 Hz, 1H), 3.58 (dd, J = 6.5, 14.5 Hz, 1H). ¹³ C NMR (d ₆ -acetone, 125 MHz) δ = 158.9, 142.5, 141.0 (2C), 131.4, 129.8 (2C), 124.5 (2C), 124.1 (2C), 121.7, 119.8, 115.3, 112.8 (2C), 112.7 (2C), 66.5, 60.7, 49.7. ESI m / z: 535.5 ([MH] ^- , C ₂₁ H ₁₆ Br ₂ NO ₄ S calculated 535.9)

Example 126. P7C3-S94: 4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylsulfonyl) phenol
Prepared according to Example 3d from P7C3-S92. Chromatography (0-40% EtOAc in hexanes) gave 5.5 mg (23% yield) of an off-white solid.
¹ H NMR (d ₆ -acetone, 500 MHz) δ = 8.36 (s, 2H), 7.79 (d, J = 9.0 Hz, 2H), 7.60 (m, 4H), 7.01 (d, J = 9.0 Hz, 2H ), 4.66-4.50 (m, 3H), 3.61 (dd, J = 5.0, 14.5 Hz, 1H), 3.52 (dd, J = 6.0, 14.5 Hz, 1H). ¹³ C NMR (d ₆ -acetone, 125 MHz ) δ = 163.2, 141.0 (2C), 131.7, 131.4 (2C), 129.8 (2C), 124.5 (2C), 124.0 (2C), 116.7 (2C), 112.8 (2C), 112.7 (2C), 66.6, 61.1 , 49.7. ESI m / z: 535.5 ([MH] ^- , C ₂₁ H ₁₆ Br ₂ NO ₄ S calculated 535.9)

Example 127. P7C3-S95: 1- (3-aminophenylthio) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol
Prepared according to Example 3a. Chromatography (0-50% EtOAc in hexanes) gave 5.5 mg (23% yield) of an off-white solid.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 8.08 (s, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H), 7.01 (apparent t, J = 8.0 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.49 (m, 2H), 4.39 (dd, J = 4.8, 15.2 Hz, 1H), 4.27 (dd, J = 6.8, 15.6 Hz , 1H), 4.13 (m, 1H), 3.58 (br s, 2H), 3.01 (dd, J = 5.2, 14.0 Hz, 1H), 2.88 (dd, J = 7.6, 14.0 Hz, 1H), 2.53 (br ¹³ C NMR (CDCl ₃ , 125 MHz) δ = 147.3, 139.8 (2C), 135.2, 130.3 (2C), 129.4 (2C), 123.7, 123.4 (2C), 120.0 (2C), 116.1, 114.0, 112.7, 111.1 (2C), 69.2, 48.1, 39.0. ESI m / z: 504.6 ([M + H] ⁺ , C ₂₁ H ₁₉ Br ₂ N ₂ OS calculated 505.0)

Example 128. P7C3-S96: 1- (4-aminophenylthio) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol
Prepared according to Example 3a. Chromatography (0-50% EtOAc in hexanes) gave 31 mg (23% yield) of an off-white solid.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 8.09 (s, 2H), 7.50 (d, J = 8.8, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz , 2H), 6.55 (d, J = 8.4 Hz, 2H), 4.36 (dd, J = 4.0, 15.6 Hz, 1H), 4.23 (dd, J = 6.8, 15.2 Hz, 1H), 4.03 (m, 1H) , 3.73 (br s, 2H), 2.91 (dd, J = 5.2, 14.0 Hz, 1H), 2.75 (dd, J = 8.0, 13.6 Hz, 1H), 2.59 (br s, 1H). ¹³ C NMR (CDCl ₃ , 125 MHz) δ = 146.9, 139.9 (2C), 134.6 (2C), 129.3 (2C), 123.7, 123.3 (2C), 121.0 (2C), 115.9 (2C), 112.6 (2C), 111.2 (2C) , 69.1, 48.1, 41.9. ESI m / z: 504.7 ([M + H] ⁺ , C ₂₁ H ₁₉ Br ₂ N ₂ OS calculated 505.0)

Example 129. P7C3-S97: 1- (3,6-Dibromo-9H-carbazol-9-yl) -3-phenoxypropan-2-amine Step 1. 1- (3,6-Dibromo-9H-carbazole- 9-yl) -3-phenoxypropan-2-one
To a solution of P7C3-S39 (87.2 mg, 0.1835 mmol, 1 eq) in CHCl ₃ (3 mL) was added Dess-Martin periodinane (DMP, 77.8 mg, 0.1835 mmol, 1 eq). The mixture was stirred at room temperature. After 1 hour, a second portion of DMP (31.1 mg, 0.0734 mmol, 0.4 mmol) was added to the reaction mixture and stirred for an additional 4 hours. The solvent was removed under reduced pressure and the crude residue was purified by silica gel chromatography using 28% EtOAc to give 31.7 mg of white solid as product in 36.9% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 4.69 (s, 2H) 5.30 (s, 2H) 6.92 (d, J = 8.7 Hz, 2H) 7.04 (d, J = 8.6 Hz, 2H) 7.08 (t, J = 8.7 Hz, 1H) 7.36 (t, J = 8.0 Hz, 2H) 7.53 (d, J = 8.7 Hz, 2H) 8.16 (s, 2H)

Step 2. (Z) -1- (3,6-Dibromo-9H-carbazol-9-yl) -3-phenoxypropan-2-one O-benzyloxime
The product of Step 1 was obtained (17.7 mg, 0.0374 mmol, 1.0 equiv) in THF (400 μL) in 2,6-lutidine (4.4 μL, 0.0374 mmol, 1.0 equiv), O-benzylhydroxylamine hydrochloride (14.3 mg, 0.0898 mmol, 2.4 eq) and 4A molecular sieves (15.8 mg) were added. The mixture was stirred for 12 hours until TLC showed complete consumption of starting material. The reaction mixture was quenched with saturated NaHCO ₃ and extracted three times with dichloromethane. The combined organic extracts were dried over MgSO ₄ and concentrated to give the crude product. This was further purified by silica gel chromatography (5-10% EtOAc / Hex) to give 20.2 mg of white solid as product in 93.4% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 4.68 (s, 2H) 5.00 (s, 2H) 5.14 (s, 2H) 6.72 (d, J = 8.2 Hz, 2H) 6.94 (t, J = 7.3 Hz, 1H) 7.47-7.16 (m, 11H) 8.06 (s, 2H)

Step 3. P7C3-S97: 1- (3,6-Dibromo-9H-carbazol-9-yl) -3-phenoxypropan-2-amine
The stirred Step 2 product was obtained (5.8 mg, 0.01 mmol, 1 eq) in anhydrous THF (0.2 mL) at 0 ° C. with borane-THF complex (1 M in THF, 150 μL, 0.0 15 mmol, 15.0 equiv) was added. The mixture was stirred overnight at room temperature. The reaction mixture was quenched with methanol and concentrated under reduced pressure. 10% Pd-C (4.0 mg) and anhydrous methanol were added and the mixture was stirred under a hydrogen balloon for 5 hours at room temperature. The mixture was filtered through a silica gel plug and the NaHCO ₃ was further purified by silica gel chromatography (1-5% MeOH / 0.2% Et ₃ N / dichloromethane) to yield 4.1 mg of white solid as product. Obtained at 58.1%.
¹ H NMR (CD ₃ OD, 500 MHz) δ = 3.61 (td, J = 9.7, 4.0 Hz, 1H) 3.72 (dd, J = 9.6, 4.0 Hz, 1H) 3.89 (dd, J = 9.5, 4.2 Hz, 1H) 4.39 (dd, J = 14.9, 5.9 Hz, 1H) 4.59 (dd, J = 14.9, 8.2 Hz, 1H) 6.88 (d, J = 8.0 Hz, 2H) 6.94 (t, J = 7.4 Hz, 1H) 7.26 (t, J = 8.0 Hz, 2H) 7.46 (dd, J = 8.8, 1.7 Hz, 2H) 7.49 (d, J = 8.7 Hz, 2H) 8.21 (s, 2H). ¹³ C NMR (CD ₃ OD, 500 MHz) δ = 159.8, 141.0, 130.5, 130.2, 124.9, 124.2, 122.2, 115.5, 113.3, 112.2, 69.8, 51.2, 46.9 ESI (m / z): 472.7 (M + H ⁺ )

Example 130. P7C3-S98: N-benzyl-2- (3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylthio) -phenoxy) acetamide
It manufactured according to P7C3-S66 from P7C3-S91. Chromatography (0-50% EtOAc in hexanes) gave 6.6 mg (23% yield) of an off-white solid.
¹ H NMR (CDCl ₃ , 500 MHz) δ = 8.05 (d, J = 1.5 Hz, 2H), 7.47 (dd, J = 1.5, 8.5 Hz, 2H), 7.30-7.23 (m, 5H), 7.18-7.15 (m, 2H), 6.92 (d, J = 7.5 Hz, 1H), 6.81 (br s, 1H), 6.72-6.69 (m, 2H), 4.43 (s, 2H), 4.41-4.35 (m, 3H) , 4.28 (dd, J = 7.0, 15.0 Hz, 1H), 4.12 (m, 1H), 3.04 (dd, J = 6.0, 14.0 Hz, 1H), 2.97 (dd, J = 7.0, 14.0 Hz, 1H), 2.75 (br s, 1H). 13 C NMR (CDCl 3, 125 MHz) δ = 169.3, 168.1, 157.7, 139.8, 137.7, 136.7, 130.6, 129.4, 129.0, 127.92, 127.90, 123.8, 123.4, 123.2, 115.5, 113.2, 112.7, 111.1, 69.3, 67.5, 48.1, 43.2, 38.7. ESI m / z: 696.6 ([M + HCOO] ^-

Example 131. P7C3-S99: N-benzyl-2- (4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylthio) -phenoxy) acetamide
Manufactured according to P7C3-S66 from P7C3-S92. Chromatography (0-70% EtOAc in hexane followed by 0-10% EtOAC in dichloromethane) gave 8.7 mg (22% yield) of an off-white solid.
¹ H NMR (CDCl ₃ , 500 MHz) δ = 8.10 (s, 2H), 7.50 (dd, J = 1.5, 8.5 Hz, 2H), 7.32-7.26 (m, 8H), 6.79 (m, 3H), 4.51 (d, J = 6.0 Hz, 2H), 4.48 (s, 2H), 4.40 (dd, J = 4.5, 15.0 Hz, 1H), 4.29 (dd, J = 7.0, 15.5 Hz, 1H), 4.07 (m, 1H), 2.99 (dd, J = 5.0, 14.0 Hz, 1H), 2.85 (dd, J = 7.5, 13.5 Hz, 1H), 2.54 (br s, 1H). ¹³ C NMR (CDCl ₃ , 125 MHz) δ = 167.8, 157.0, 139.9, 133.7, 129.4, 129.0, 128.0, 127.9, 123.9, 123.8, 123.5, 115.8, 112.7, 111.1, 69.2, 67.6, 48.1, 43.2, 41.1. ESI m / z: 696.5 ([M + HCOO ] ^- , C ₃₁ H ₂₇ Br ₂ N ₂ O ₅ S calculated 697.0)

Example 132. P7C3-S100
Amine-terminated P7C3 analog (prepared by alkylation of phenol according to P7C3-S66) (5.0 mg, 0.0008 mmol) in DMF (300 μl) was added to 4,4-difluoro-5,7-dimethyl-4-bora. -3a, 4a-diaza-s-indacene-3-propionic acid succinimidyl ester (Bodipy-OSu, 4.0 mg, 0.010 mmol) was added followed by diisopropylethylamine (25 μl, 0.14 mmol). . The reaction was stirred overnight protected from light. The reaction was diluted with EtOAc and washed several times with water followed by brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude mixture was purified by preparative TLC with 100% EtOAc protected from light to give the desired product. Yield = 54%. MS (ESI), m / z: Calculated 848.18, Found 848.7 (M + 1) ⁺

Example 133. P7C3-S101: 3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropylsulfonyl) phenol
Prepared from P7C3-S91 according to Example 96. Chromatography (0-50% EtOAc in hexane) followed by HPLC purification (30% EtOAc / hexane, Phenomenex Silica Luna, 10 × 250 mm, 3 mL / min) gave 13.9 mg (14% yield) of a pale yellow solid Got.
¹ H NMR (d ₆ -acetone, 500 MHz) δ = 9.41 (br s, 1H), 8.38 (s, 2H), 7.60 (m, 4H), 7.45 (obvious t, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.35 (br s, 1H), 7.16 (dd, J = 2.0, 8.0 Hz, 1H), 5.42 (dm, J = 47.0 Hz, 1H), 4.89-4.78 ( . m, 2H), 3.92 ( d, J = 5.5 Hz, 1H), 3.87 (m, 1H) 13 C NMR (d 6 - acetone, 125 MHz) δ = 159.0, 142.2, 140.8, 131.5, 130.1, 124.7, 124.3, 122.0, 119.8, 115.4, 113.2, 112.5 (d, J = 1.75 Hz), 88.6 (d, J = 178.8 Hz), 58.5 (d, J = 21.8 Hz), 47.1 (d, J = 21.1 Hz). ESI m / z: 537.7 ([MH] ^-

Example 134. P7C3-S102: N-benzyl-2- (3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylsulfonyl) -phenoxy) acetamide
Prepared from P7C3-S93 according to P7C3-S66. Chromatography (0-50% acetone in hexane) gave 10.1 mg (20% yield) of an off-white solid.
¹ H NMR (d ₆ -acetone, 500 MHz, 45 ° C) δ = 8.32 (s, 2H), 8.00 (br s, 1H), 7.57 (s, 3H), 7.55-7.52 (m, 2H), 7.32- 7.30 (m, 1H), 7.29 (m, 2H), 7.22 (m, 1H), 4.65 (s, 2H), 4.63-4.60 (m, 2H), 4.53 (m, 1H), 4.47 (d, J = . 6.0 Hz, 1H), 3.61 (m, 2H), 3.32 (d, J = 5.5 Hz, 1H) 13 C NMR (d 6 - acetone, 125 MHz) δ = 168.1, 159.0, 142.7, 141.0, 140.2, 131.5 , 129.9, 129.2, 128.4, 127.8, 124.5, 124.1, 121.7, 121.0 115.2, 112.8, 112.7, 68.3, 66.5, 60.7, 49.6, 43.1. ESI m / z: 728.5 ([M + HCOO] ^-

Example 135. P7C3-S103: 4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropylsulfonyl) phenol
Prepared from P7C3-S94 according to Example 96. HPLC purification (40% EtOAc / hexane, Phenomenex Silica Luna, 21.2 × 250 mm, 13.5 mL / min) gave 11.4 mg (16% yield) of an off-white solid.
¹ H NMR (d ₆ -acetone, 500 MHz) δ = 8.39 (s, 2H), 7.76 (d, J = 8.5 Hz, 2H), 7.60 (m, 4H), 7.00 (d, J = 8.5 Hz, 2H ), 5.39 (dm, J = 51.5 Hz, 1H), 4.89-4.81 (m, 2H), 3.85 (m, 1H), 3.80 (d, J = 5.5 Hz). ¹³ C NMR (d ₆ -acetone, 125 MHz) δ = 163.5, 140.8 (2C), 131.5 (2C), 131.3, 130.1 (2C), 124.7 (2C), 124.3 (2C), 116.8 (2C), 113.2 (2C), 112.5 (d, J = 1.9 Hz, 2C), 88.8 (d, J = 178.5 Hz), 58.8 (d, J = 21.6 Hz), 47.2 (d, J = 21.3 Hz). ESI m / z: 537.6 ([MH] ^-

Example 136. P7C3-S104: 5- (5- (3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylamino) phenoxy) pentylcarbamoyl) -2- ( 6-hydroxy-3-oxo-3H-xanthen-9-yl) benzoic acid
The title compound was synthesized according to P7C3-S100. MS (ESI), m / z: Calculated 933.1, Actual 931.6 (M) ⁺

Example 137. P7C3-S105: 1- (8-bromo-3,4-dihydro-1H-pyrido [4,3-b] indol-5 (2H) -yl) -3-phenoxypropan-2-ol step 1. tert-Butyl 8-bromo-3,4-dihydro-1H-pyrido [4,3-b] indole-2 (5H) -carboxylate
8-Bromo-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole (813 mg, 3.2 mmol), dimethylaminopyridine (53.5 mg, 0.14 mmol) and di-dicarbonate A solution of tert-butyl (1.46 g, 6.7 mmol) in methylene chloride (10 ml) and methanol (5.0 ml) and triethylamine (0.95 ml, 6.8 mmol) were stirred overnight. The reaction was concentrated to give a deep red semi-solid that was diluted with methylene chloride. The organic layer was washed twice with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude reaction product was purified with 50% EtOAc / hexanes to give 931.8 mg of product (82%).
¹ H NMR (CDCl ₃ , 500 MHz) δ = 7.88 (bs, 1H), 7.58 (s, 1H), 7.22 (dd, 2H, J = 8.3, 28.1 Hz), 4.58 (s, 2H), 3.82 (s , 2H), 2.83 (s, 2H), 1.51 (s, 9H). (ESI (m / z): 350.8 (M + 1) ⁺

Step 2. tert-Butyl 8-bromo-5- (2-hydroxy-3-phenoxypropyl) -3,4-dihydro-1H-pyrido [4,3-b] indole-2 (5H) -carboxylate
tert-Butyl 8-bromo-3,4-dihydro-1H-pyrido [4,3-b] indole-2 (5H) -carboxylate (449.7 mg, 1.28 mmol) and powdered potassium hydroxide (86.9 mg) A solution of 1.54 mmol) in acetone (4.0 ml) was stirred for 15 min and 2- (phenoxymethyl) oxirane (254 mg, 1.69 mmol) was added. After 1 hour the reaction was concentrated, diluted with EtOAc and washed twice with water followed by brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude mixture was purified by silica gel chromatography (1% MeOH / CH ₂ Cl ₂ + 0.1% Et ₃ N). Yield = 21%. ESI (m / z): 546.6 (M + CHCOO -)

Step 3. P7C3-S105: 1- (8-Bromo-3,4-dihydro-1H-pyrido [4,3-b] indol-5 (2H) -yl) -3-phenoxypropan-2-ol
Trifluoroacetic acid (31 μl, 0.40 mmol) was added to a solution of the product of Step 2 (20.1 mg, 0.04 mmol) in methylene chloride (0.3 ml). After 100 minutes, the reaction mixture was concentrated and purified by preparative TLC (10% MeOH / CH ₂ Cl ₂ ). Yield = 96%.
¹ H NMR (CDCl ₃ , 400 MHz)) δ = 7.43 (s, 1H), 7.27 (s, 1H), 7.17 (dd, 2H, J = 8.5, 26.7 Hz), 6.97 (t, 1H, 4.58 J = 7.0 Hz), 6.86 (d, 2H, J = 6.9 Hz), 4.24 (dm, 5H), 4.06 (m, 1H), 3.88 (m, 2H), 3.34 (m, 2H), 3.16 (m, 1H) , 2.96 (m, 1H). ESI (m / z): 400.8 (M + 1) ⁺

Example 138. P7C3-S106: 1- (8-bromo-2-cyclopropyl-3,4-dihydro-1H-pyrido [4,3-b] indol-5 (2H) -yl) -3-phenoxypropane -2-ol
According to literature methods (Barta, Thomas E. et al. WO2003 / 091247A2), ethoxycyclopropyl-oxytrimethylsilane (30 μl, 0.15 mmol) was added to P7C3-S105 (45.9 mg, 0.114 mmol) in methanol (1.0 ml). ) And acetic acid (70 μl, 1.2 mmol) solution. The reaction was stirred for 10 minutes and sodium cyanoborohydride (37.0 mg, 0.59 mmol) was added. The sealed vial was heated to reflux for 2.5 hours, then concentrated, diluted with EtOAc, and washed with 1N NaOH solution, water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. Purification by preparative TLC (5% MeOH / CH ₂ Cl ₂ ) gave the product in 8% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.54 (s, 1H), 7.30 (t, 1H, J = 7.7 Hz), 7.18 (s, 2H), 7.00 (t, 1H, J = 7.3 Hz), 6.88 (d, 2H, J = 8.4 Hz), 4.29 (m, 2H), 4.15 (m, 1H), 3.92 (m, 4H), 3.00 (m, 4H), 1.98 (bs, 1H), 1.33 (m, 1H), 0.6 (m, 4H ). 13 C NMR (CDCl 3, 126 MHz) δ 158.1, 135.7, 125.2, 129.8, 127.6, 123.9, 121.7, 120.5, 114.6, 112.7, 110.7, 69.6, 38.8, 50.8, 49.6 , 45.7, 45.7, 38.0, 8.7, 6.4. ESI (m / z): Calculated 440.11, Measured 440.9 (M + 1) ⁺

Example 139. P7C3-S107: 8-bromo-5- (2-hydroxy-3-phenoxypropyl) -3,4-dihydro-1H-pyrido [4,3-b] indole-2 (5H) -carbonitrile
According to literature methods (Kong, Chan Chun et al .; WO 2004/52885), cyanogen bromide (5.0 M in CH ₃ CN, 44 μl) was added to P7C3-S105 (88.1 mg, 0.22 mmol) and potassium carbonate (45 0.4 mg, 0.33 mmol) in methylene chloride (2.1 ml) was added. The reaction was stirred at ambient temperature and then refluxed overnight. The cooled reaction mixture was filtered through a small celite plug and placed directly into a separatory funnel. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated. Silica gel chromatography (1% MeOH / CH ₂ Cl ₂ ) gave the purified product. Yield = 12%
¹ H NMR (CDCl ₃ , 400 MHz)) δ = 7.52 (s, 1H), 7.32 (t, 1H, J = 8.2 Hz), 7.25 (m, 2H), 7.02 (t, 1H, J = 7.3 Hz) , 6.90 (d, 2H, J = 7.8 Hz), 4.46 (s, 2H), 4.34 (m, 2H), 4.19 (m, 1H), 4.00 (dd, 1H, J = 4.4, 9.5 Hz), 3.87 ( dd, 1H, J = 4.8, 9.7 Hz), 3.55 (m, 2H), 3.01 (m, 2H) 2.49 (bs, 1H). 13 C NMR (CDCl 3, 126 MHz) δ 160.0, 125.4, 133.9, 129.9 , 124.9, 120.5, 118.2, 113.3, 111.0, 104.8, 69.5, 68.8, 46.7, 46.3, 45.9, 22.1
ESI (m / z): Calculated value 425.07, Measured value 471.8 (M + CH ₃ COO) ^-

Example 140 P7C3-S108: 8-bromo-5- (2-fluoro-3-phenoxypropyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole Step 1. tert -Butyl 8-bromo-5- (2-fluoro-3-phenoxypropyl) -3,4-dihydro-1H-pyrido [4,3-b] indole-2 (5H) -carboxylate
The title compound was synthesized from the product of Step 2 of P7C3-S105 according to representative method 4. The crude reaction product was used without purification.

Step 2. P7C3-S108: 8-Bromo-5- (2-fluoro-3-phenoxypropyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole
Trifluoroacetic acid (15 μl, 0.20 mmol) was added to a solution of step 1 product (20.6 mg, 0.04 mmol) in methylene chloride (0.4 ml). After an additional 3 hours, trifluoroacetic acid (25 μl, 0.32 mmol) was added. The reaction was diluted with methylene chloride and washed twice with water and twice with 10% NaCl solution. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude reaction was purified by preparative TLC (7% MeOH / DCM + 0.15% TEA) and isolated in quantitative yield.
¹ H NMR (CD ₃ OD, 500 MHz)) δ = 7.62 (m, 1H), 7.38 (d, 1H, J = 9.9 Hz), 7.25 (m, 3H), 6.92 (m, 2H), 5.06 (dm , 1H), 4.56 (m, 2H), 4.37 (s, 2H), 4.08-4.24 (m, 2H), 3.57 (m, 2H), 3.27 (m, 1H), 3.18 (m, 2H). ¹³ C NMR (CD ₃ OD, 126 MHz) δ = 159.7, 137.1, 134.5, 130.7, 126.0, 121.4, 115.6, 114.3, 112.6, 103.2, 91.7 (d, ¹ J = 177.1 Hz), 68.0 (d, ² J = 23.5 Hz), 47.9, 45.0 (d, ² J = 22.9 Hz), 42.9, 41.9, 20.8, 9.2.MS (ESI), m / z: Calculated value 402.07, Measured value 402.8 (M + 1) ⁺

Example 141. P7C3-S109: 1- (cyclohexylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol
Heterogeneous solution of cyclohexylamine (152 μl, 1.3 mmol) in 3,6-dibromo-9- (oxiran-2-ylmethyl) -9H-carbazole (102.5 mg, 0.27 mmol) in ethanol (2.6 ml). Added to. The reaction mixture was heated to reflux for 1 hour and concentrated to give the pure desired product. Yield = 97%.
¹ H NMR (CDCl ₃ , 500 MHz)) δ 8.13 (d, 2H, J = 1.5 Hz), 7.55 (dd, 2H, J = 1.8, 8.6 Hz), 7.36 (d, 2H, J = 8.8 Hz), 4.28 (d, 2H, J = 5.5 Hz), 4.01 (m, 1H), 2.81 (dd, 1H, J = 3.5, 12.0 Hz), 2.50 (m, 1H), 2.29 (m, 1H), 1.77 (d , 2H, J = 11.4 Hz) , 1.63 (m, 3H), 0.84-1.28 (m, 6H). 13 C NMR (CDCl 3, 500 MHz) δ 140.0, 129.3, 123.7, 123.3, 112.4, 111.1, 69.2, 56.8, 50.0, 47.6, 34.1, 33.7, 26.0, 25.1 ESI (m / z): Calculated value 478.03, Actual value 524.7 (M + CHCOO) ^-

Example 142. P7C3-S110: (9- (2-hydroxy-3- (phenylthio) propyl) -9H-carbazole-3,6-dicarbonitrile
Prepared according to Example 101 in 5.3% yield from P7C3-S7.
¹ H NMR (d ₆ -acetone, 400 MHz) δ = 3.40-3.24 (m, 2H) 4.30 (tdd, J = 9.0, 6.1, 2.9 Hz, 1H) 4.66 (dd, J = 15.1, 8.7 Hz, 1H) 4.74 (d, J = 5.1 Hz, 1H) 4.82 (dd, J = 15.1, 3.0 Hz, 1H) 7.22 (t, J = 7.4 Hz, 1H) 7.33 (t, J = 7.6 Hz, 2H) 7.47 (dd, J = 8.3, 1.0 Hz, 2H) 7.92-7.77 (m, 4H) 8.73 (s, 2H) ¹³ C NMR (d ₆ -acetone, 500 MHz) δ = 143.8, 136.3, 130.1, 129.4, 129.2, 126.4, 126.0 , 122.4, 119.8, 111.9, 103.2 , 69.4, 48.7, 37.9 ESI (m / z): 427.8 (M + HCOO -)

Example 143. P7C3-S111: 9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3,6-dicarbonitrile
Prepared according to Example 101 in 16.5% yield from P7C3-S39.
¹ H NMR (d ₆ -acetone, 400 MHz) δ = 4.15 (d, J = 5.4 Hz, 2H) 4.56 (dt, J = 9.2, 5.1 Hz, 1H) 4.76 (dd, J = 15.1, 7.6 Hz, 1H ) 4.86 (dd, J = 15.1, 3.9 Hz, 1H) 6.98 (dd, J = 16.4, 8.0 Hz, 3H) 7.31 (t, J = 8.0 Hz, 2H) 7.85 (dd, J = 8.6, 1.4 Hz, 2H) ) 7.96 (d, J = 8.6 Hz, 2H) 8.75 (s, 1H) 13 C NMR (d 6 -. acetone, 500 MHz) δ = 158.9, 143.9, 130.1, 129.7, 126.0, 122.5, 121.2, 119.7, 114.7 , 112.0, 103.3, 69.7, 69.0 , 46.9 ESI (m / z): 411.9 (M + HCOO -).

Examples 144a and 144b. P7C3-S113 and P7C3-S114: N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline (R- and S) (Enantiomer)
Step 1. (2R) -N- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3,3,3-trifluoro-2-methoxy-N- ( 3-methoxyphenyl) -2-phenylpropanamide
To a solution of P7C3-S10 (20.0 mg, 0.0395 mmol, 1.0 equiv) in dichloromethane (790 μL) was added NaH (60% dispersion in mineral oil, 0.9 mg, 0.0395 mmol, 1.0 equiv). The mixture was stirred at room temperature for 15 minutes. (S)-(+)-α-methoxy-α-trifluoromethyl-phenylacetyl chloride (14.8 μL, 0.0790 mmol, 2.0 eq) was added dropwise to the reaction mixture. 4- (Dimethylamino) pyridine (DMAP, catalyst) was added to the above mixture after 1 hour. The mixture was stirred at room temperature overnight and quenched with water. The crude reaction was diluted with ethyl acetate and washed with brine. The organic layer was dried over MgSO ₄ and concentrated to give the crude product. This was further purified by silica gel preparative HPLC (20-25% EtOAc / Hex) to yield 10.1 mg of the white solid quickly eluting diastereomer and 6.8 mg of the white solid eluting diastereomer. Yield 59.2%.
¹ H NMR (CDCl ₃ , 400 MHz) Fast eluting diastereomer: δ = 3.39 (s, 3H) 3.54 (s, 3H) 3.70-3.61 (m, 1H) 4.34 (dd, J = 30.0, 14.2 Hz, 1H) 4.61-4.44 (m, 2H) 5.24 (d, J = 50.4 Hz, 1H) 6.66 (d, J = 8.1 Hz, 1H) 7.40-7.23 (m, 10H) 7.54 (d, J = 8.6 Hz, 2H ) 8.12 (s, 2H).
Slowly eluting diastereomers: δ = 3.25 (s, 3H) 3.50 (s, 3H) 3.61-3.53 (m, 1H) 4.27 (dd, J = 32.4, 14.4 Hz, 1H) 4.61-4.40 (m, 2H) 5.32 (d, J = 50.3 Hz, 1H) 6.65 (d, J = 7.9 Hz, 1H) 7.42-7.20 (m, 10H) 7.56 (d, J = 8.6 Hz, 2H) 8.12 (s, 2H)
P7C3-S113 (see below) was derived from a diastereomer that eluted faster on reverse phase HPLC (C18 column) and slower on normal phase (silica gel) HPLC.

Step 2. P7C3-S113 and P7C3-S114: N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline (absolute chemistry unassigned)
Anhydrous and degassed diethyl ether (206 μL) was obtained in a dried, nitrogen-vented vial containing another Step 1 product (4.0 mg, 0.0054 mmol, 1 eq). The suspension was cooled to 0 ° C. Lithium aluminum hydride solution (1M in THF, 60 μL, 0.06 mmol, 3 eq) was added to the cooled suspension. The mixture was stirred in an ice bath for 1 hour and further at room temperature for 1 hour. Water (0.4 μL), 15% NaOH (0.4 μL) and water (1.2 μL) were added sequentially to the mixture to stop the reaction. The crude reaction was diluted with ethyl acetate and washed with brine. The organic layer was dried over MgSO ₄ and concentrated. This was further purified by silica gel chromatography (30% EtOAC / Hex) to give 1.5 mg of white solid as product in 50-55% yield. P7C3-S113 and -S114 showed the same LC / MS chromatogram and NMR spectrum as P7C3-S10. P7C3-S113 was determined to be> 99% ee by HPLC (Chiralcel OD-H, 1 mL / min, 100% acetonitrile t _S113 = 5.45 min, t _S114 = 5.74 min). P7C3-S114 was measured as 79% ee.

  As will be appreciated by those skilled in the art, different enantiomers may have different activities, as is generally known. One enantiomer may be more active than the other enantiomer. The combination of the two enantiomers can have a different level of activity than any substantially pure enantiomer. Preliminary experiments show that P7C3-S113 is more active than P7C3-S114 in promoting neurogenesis and / or anti-apoptotic activity in an in vivo assay in which 12-week-old live male C57 / B16 mice were treated with 10 μM of any compound. It has been suggested. It should be noted that such differences in enantiomeric activity can also be observed with other compounds of the embodiments disclosed herein. It should also be noted that such activity depends on the assay mode, compound concentration, compound purity, compound stability, and other parameters. When tested at different concentrations, the activity of low activity enantiomers may increase and vice versa.

Example 145. P7C3-S115: N- (2- (3,6-Dibromo-9H-carbazol-9-yl) ethyl) aniline Step 1. Ethyl 2- (3,6-dibromo-9H-carbazole-9- Yl) acetate
To a solution of 3,6-dibromocarbazole (325.0 mg, 1.0 mmol, 1 eq) in anhydrous N, N-dimethylformamide (5 mL) was added crushed KOH (67.3 mg, 1.2 mmol, 1.2 eq). did. The mixture was stirred for 30 minutes. Ethyl bromide acetate (277.2 μL, 2.5 mmol, 2.5 eq) was added to the mixture and it was stirred at room temperature overnight. The crude reaction was diluted with ethyl acetate (30 mL) and washed with 1M HCl and water. The organic layer was dried over MgSO ₄ and concentrated to give 396.3 mg of white solid as product (96.4%).
¹ H NMR (CDCl ₃ , 400 MHz) δ = 1.22 (t, J = 7.1 Hz, 3H) 4.20 (q, J = 7.1 Hz, 2H) 4.94 (s, 2H) 7.21 (d, J = 8.7 Hz, 2H 7.57 (dd, J = 8.6, 1.1 Hz, 2H) 8.16 (s, 2H). ESI (m / z): 407.6 (MH ⁺ )

Step 2. 2- (3,6-Dibromo-9H-carbazol-9-yl) acetic acid
The product of step 1 was obtained (41.1 mg, 0.1 mmol, 1 eq) in THF-methanol-water (3: 2: 1, 1.2 mL total) in LiOH (12.0 mg, 0.5 mmol). 5 equivalents) was added. The mixture was stirred at room temperature for 1 hour. The reaction was diluted with 1M HCl (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed twice with water (10 mL) and dried over MgSO ₄ to give 38.3 mg of white solid as product in 99% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 5.02 (s, 2H) 7.22 (d, J = 8.8 Hz, 2H) 7.58 (dd, J = 8.7, 1.2 Hz, 2H) 8.16 (d, J = 1.6 Hz , 2H). ESI (m / z): 379.6 (MH ⁺ )

Step 3. 2- (3,6-Dibromo-9H-carbazol-9-yl) -N-phenylacetamide
To a solution of the product of step 3 (9.6 mg, 0.025 mmol, 1 eq) in anhydrous dichloromethane (1.5 mL) was added N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (EDC, 5. 8 mg, 0.03 mmol, 1.2 eq), 1-hydroxybenzotriazole hydrate (HOBt, 4.1 mg, 0.03 mmol, 1.2 eq) and 4- (dimethylamino) pyridine (DMAP, 1 crystal) Was added. After the mixture was stirred at room temperature for 20 minutes, aniline (3.4 μL, 0.0375 mmol, 1.5 eq) was added and the resulting mixture was heated at 80 ° C. overnight. The reaction mixture was diluted with ethyl acetate (20 mL) and washed sequentially with 1M NaOH, 1M HCl and water. The organic layer was dried over MgSO ₄ and concentrated to give a sparingly soluble white solid that was pure enough to be used in the next step.
¹ H NMR (d ₆ -DMSO, 400 MHz) δ = 5.29 (s, 2H) 7.06 (t, J = 7.3 Hz, 1H) 7.31 (t, J = 7.8 Hz, 2H) 7.66-7.55 (m, 6H) 8.50 (s, 2H) 10.55 (s, 1H). ESI (m / z): 454.6 (MH ⁺ )

Step 4. P7C3-S115. N- (2- (3,6-Dibromo-9H-carbazol-9-yl) ethyl) aniline
To a dried and nitrogen-vented vial containing the product of Step 3 (9.2 mg, 0.02 mmol, 1 eq) was added anhydrous and degassed diethyl ether (750 μL). The suspension was cooled to 0 ° C. Lithium aluminum hydride (1M in THF, 60 μL, 0.06 mmol, 3 eq) was added and the mixture was stirred in an ice bath for 1 hour and then at room temperature overnight. Water (3.6 μL), 15% NaOH (3.6 μL) and water (10.8 μL) were added sequentially to the mixture to stop the reaction. The crude mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over MgSO ₄ and concentrated to give the crude product. This was further purified by silica gel chromatography (60% dichloromethane / Hex) to give 2.7 mg of white solid as product in 28.8% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ = 3.70-3.56 (m, 2H) 4.46 (t, J = 5.5 Hz, 2H) 6.55 (d, J = 7.8 Hz, 2H) 6.76 (t, J = 7.4 Hz , 1H) 7.16 (d, J = 8.8 Hz, 2H) 7.20 (t, J = 7.9 Hz, 2H) 7.50 (dd, J = 8.7, 1.9 Hz, 2H) 8.14 (d, J = 1.7 Hz, 2H). _{^{. 13 C NMR (CDCl 3,}} 500 MHz) δ = 146.8, 139.5, 129.7, 129.4, 123.7, 123.5, 118.4, 113.1, 112.6, 110.5, 42.7, 42.5 ESI (m / z): 486.7 (M + HCOO -) ; 476.7 (M + Cl ^-)

Example 146. P7C3-S129: 2- (6-Amino-3-imino-3H-xanthen-9-yl) -4- (6- (5- (3- (3- (3,6-dibromo-9H) -Carbazol-9-yl) -2-hydroxypropylamino) phenoxy) pentylamino) -6-oxohexylcarbamoyl) benzoic acid and 2- (6-amino-3-imino-3H-xanthen-9-yl) -5 -(6- (5- (3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylamino) phenoxy) pentylamino) -6-oxohexylcarbamoyl) benzoic acid
Manufactured according to P7C3-S100. HPLC purification (45% MeCN / H ₂ O + 0.1% HCO ₂ H, Phenomenex C18 Luna, 10 × 250 mm, 3 mL / min) afforded 1.7 mg (50% yield) as a mixture of isomers. ESI m / z: 1043.2 ([M + H] ⁺ , C ₅₃ H ₅₃ Br ₂ N ₆ O ₇ calculated 1043.2)

Example 147. P7C3-S130
Prepared from P7C3-S94 according to Example P7C3-S66. Chromatography (1% MeOH in dichloromethane) followed by trituration with hexanes gave 1.2 mg (5.3% yield) of an off-white solid.
¹ H NMR (CDCl ₃ , 500 MHz) δ = 8.12 (s, 2H), 7.71 (d, J = 7.0 Hz, 2H), 7.54 (d, J = 9.0 Hz, 2H), 7.29 (m, 2H), 6.98 (d, J = 7.0 Hz, 2H), 4.62 (br s, 1H), 4.39 (s, 2H), 4.19 (s, 2H), 3.88 (s, 2H), 3.72 (m, 11H), 3.42 ( s, 1H), 3.23 (d, J = 5.0 Hz, 1H), 3.16 (s, 1H), 2.49 (t, J = 14.0 Hz, 2H), 1.43 (s, 9H). ESI m / z: 841.6 ( [M + HCOO] ^- , C ₃₅ H ₄₂ Br ₂ NO ₁₁ S calculated 842.1)

Example 148. P7C3-S131: 1- (8-bromo-2-methyl-3,4-dihydro-1H-pyrido [4,3-b] indol-5 (2H) -yl) -3-phenoxypropane- 2-ol
Powdered KOH (13.6 mg, 0.24 mmol) was added to 8-bromo-2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole (Boekelheide, V .; Ainsworth, CJ Am. Chem. Soc. 1950, 72, 2134) (52.5 mg, 0.20 mmol) in DMF (1.0 mL) was added and stirred at ambient temperature for 30 minutes until dissolved. 2- (phenoxymethyl) oxirane was added via syringe and the reaction was stirred at room temperature overnight. Upon completion, the solution was diluted with EtOAc. The mixture was washed with H ₂ O and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography to give the product as a white foam (35.3 mg, 43%).
¹ H NMR (CDCl ₃ ) δ = 7.49 (s, 1H), 7.27 (t, J = 7.9 Hz, 2H), 7.18-7.15 (m, 2H), 6.98 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 8.0 Hz, 2H), 4.23 (dd, J = 14.6, 4.5 Hz, 1H), 4.15-4.08 (m, 1H), 4.03 (dd, J = 14.6, 7.1 Hz, 1H), 3.83- 3.75 (m, 2H), 3.53-3.43 (m, 2H), 2.85-2.63 (m, 4H), 2.47 (s, 3H). 13 C NMR (CDCl 3, 126 MHz) δ = 158.0, 135.4, 135.0, 123.6, 121.3, 114.4, 110.7, 107.7, 69.1, 68.9, 52.2, 51.3, 46.0, 45.6, 23.0. ESI m / z: 414.8 ([M + H] ⁺ , C ₂₁ H ₂₃ BrN ₂ O ₂ calculated 415.0)

Example 149. Synthesis of P7C3-S137: 1- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) pyridin-2 (1H) -one
n-BuLi (2.5 M in hexane, 80 μl, 0.2 mmol) was added to a solution of 3,6-dibromo-9H-carbazole (32.1 mg, 0.10 mmol) in THF (1.0 mL) at −78 ° C. And stirred for 30 minutes. 1- (oxiran-2-ylmethyl) pyridin-2 (1H) -one ¹ was added at −78 ° C. and the reaction was stirred at room temperature overnight. Upon completion, the solution was quenched with H ₂ O. CH ₂ Cl ₂ was added and the mixture was washed with H ₂ O and saturated aqueous NaCl. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography to give the product as a white solid (42.2 mg, 89%).
¹ H NMR (d ₆ -DMSO, 500 MHz) δ 8.47 (s, 2H), 7.64-7.53 (m, 5H), 7.40 (t, 1H, J = 7.2 Hz), 6.35 (d, 1H, J = 9.0 Hz), 6.19 (t, 1H, J = 6.2 Hz), 5.33 (d, 1H, J = 5.5 Hz), 4.44 (d, 1H, J = 14.8 Hz), 4.35 (dd, 1H, J = 7.9, 14.8 Hz), 4.28 (d, 1H, J = 13.0 Hz), 4.25-4.17 (m, 1H), 3.74 (dd, 1H, J = 8.8, 12.5 Hz). MS (ESI) m / z: 474.6 ([M + H] ⁺ , C ₂₀ H ₁₇ Br ₂ N ₂ O ₂ calculated 475.0)

Example 150. P7C3-S138: 9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3-carbonitrile Step 1. Synthesis of 9H-carbazole-3-carbonitrile
A solution of 3-bromo-9H-carbazole (123.4 mg, 0.50 mmol) and CuCN (49.9 mg, 0.56 mmol) in N-methyl-pyrrolidone (2 mL) was heated at 200 ° C. for 5 hours. The cooled reaction mixture was poured into water and the precipitate was filtered and washed with ethyl acetate. The filtrate was extracted with ethyl acetate and the combined ethyl acetate extracts were washed with water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography to give the product as a white solid (84.7 mg, 88%).
¹ H NMR (CD ₃ OD, 500 MHz) δ 8.46 (s, 1H), 8.13 (d, 1H, J = 7.9 Hz), 7.65 (d, 1H, J = 8.4 Hz), 7.55 (d, 1H, J = 8.4 Hz), 7.51 (d, 1H, J = 8.1 Hz), 7.47 (t, 1H, J = 7.5 Hz), 7.24 (t, 1H, J = 7.5 Hz), 3.35 (s, 1H). MS ( ESI) m / z: 193.0 ([M + H] ⁺ , C ₁₃ H ₉ N ₂ calculated 193.1)

Step 2. Synthesis of 9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3-carbonitrile
P7C3-S138 was synthesized according to P7C3-S137 except that 9H-carbazole-3-carbonitrile and 2- (phenoxymethyl) oxirane were used and was isolated in 61% yield.
¹ H NMR (CD ₃ OD, 400 MHz) δ 8.45 (s, 1H), 8.14 (d, 1H, J = 7.8 Hz), 7.73-7.56 (m, 3H), 7.47 (t, 1H, J = 7.7 Hz ), 7.27 (td, 3H, J = 2.0, 7.9 Hz), 6.94 (t, 3H, J = 8.6 Hz), 4.66 (dd, 1H, J = 5.0, 15.0 Hz), 4.52 (dd, 1H, J = 6.8, 15.0 Hz), 4.43-4.34 (m, 1H), 3.99 (dd, 1H, J = 5.4, 9.8 Hz), 3.93 (dd, 1H, J = 4.6, 9.8 Hz). MS (ESI) m / z : 342.9 ([M + H] ⁺ , C ₂₂ H ₁₉ N ₂ O ₂ calculated 343.1)

Example 151 P7C3-S141: tert-butyl (5- (4-((3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) sulfonyl) phenoxy) pentyl) carbamate
The title compound was synthesized according to P7C3-S98.
MS (ESI) m / z: 766.6 [M + formic acid] ^- , C ₃₁ H ₃₆ Br ₂ N ₂ O ₆ S calculated 722.1

Example 152. P7C3-S142: 6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3-carbonitrile
N-bromosuccinimide (8.0 mg, 0.09 mmol) was added to a solution of P7C3-S138 (14.0 mg, 0.04 mmol) in toluene (0.7 mL) and ethyl acetate (0.3 mL) at room temperature. The reaction was stirred at 70 ° C. for 2 days and cooled to room temperature at which time more N-bromosuccinimide (8.1 mg, 0.09 mmol) was added. The reaction was further stirred at 70 ° C. for 2 days. ^When the reaction was complete as monitored by ¹ H NMR, the suspension was washed with water, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography to give the product as a white solid (9.7 mg, 56%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.31 (s, 1H), 8.20 (d, 1H, J = 1.7 Hz), 7.66 (d, 1H, J = 8.6 Hz), 7.63-7.53 (m, 2H) , 7.43 (d, 1H, J = 8.7 Hz), 7.31 (t, 2H, J = 8.0 Hz), 7.02 (t, 1H, J = 7.4 Hz), 6.89 (d, 2H, J = 8.6 Hz), 4.63 (dd, 1H, J = 5.0, 14.4 Hz), 4.57-4.41 (m, 2H), 4.04 (dd, 1H, J = 4.5, 9.4 Hz), 3.91 (dd, 1H, J = 4.5, 9.4 Hz), 2.49 (d, 1H, J = 5.6 Hz). MS (ESI) m / z: 420.8 ([M + H] ⁺ , C ₂₂ H ₁₈ BrN ₂ O ₂ calculated 421.1)

Example 153. P7C3-S146: 6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3-carboxamide
A mixture of P7C3-S142 (4.5 mg, 0.01 mmol), 50% hydrogen peroxide (0.008 mL) and 1N aqueous NaOH (0.007 mL) in ethanol (1 mL) was stirred at 30 ° C. for 30 h. Further 50% hydrogen peroxide (0.008 mL) and 1N aqueous NaOH (0.007 μL) were added and the reaction was complete after 15 hours at 30 ° C. The solution was concentrated and the crude residue was purified by preparative thin layer chromatography to give the product (3.9 mg, 72%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.48 (s, 1H), 8.19 (d, 1H, J = 1.6 Hz), 7.86 (dd, 1H, J = 1.6, 8.6 Hz), 7.58-7.46 (m, 2H), 7.40 (d, 1H, J = 8.7 Hz), 7.33-7.28 (m, 2H), 7.01 (t, 1H, J = 7.4 Hz), 6.90 (d, 2H, J = 7.8 Hz), 6.08 ( s, 1H), 5.61 (s, 1H), 4.61 (t, 1H, J = 8.5 Hz), 4.55-4.40 (m, 2H), 4.03 (dd, 1H, J = 4.6, 9.5 Hz), 3.93 (dd , 1H, J = 4.6, 9.5 Hz), 2.73 (s, 1H). MS (ESI) m / z: 438.8 ([M + H] ⁺ , C ₂₂ H ₂₀ BrN ₂ O ₃ calculated 439.1)

Example 154. P7C3-S147: 1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (pyridin-2-yloxy) propan-2-ol Step 1. 3- (Pyridin-2- Synthesis of (Iloxy) propane-1,2-diol
According to literature method ² , a solution of solketal (1.25 mL, 0.01 mol) in THF (20 mL) is stirred, cooled to 0 ° C. under N ₂ and KO ^t Bu (1.349 g, 0.012 mol) is added. did. The mixture was stirred for 15 minutes, it was added 2-bromopyridine (1.1 mL, 0.011 mol), the mixture 18 h, stirred at room temperature, diluted with _{H 2} O, and extracted with _CH 2 C1 _2. The combined extracts were dried (Na ₂ SO ₄ ), filtered and evaporated to give the crude title product (288.1 mg, 17%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.98 (d, 1H, J = 3.2 Hz), 7.50 (t, 1H, J = 6.8 Hz), 6.81 (t, 1H, J = 5.8 Hz), 6.69 (d , 1H, J = 8.3 Hz), 4.35 (d, 2H, J = 4.5 Hz), 4.09 (s, 1H), 3.95-3.83 (m, 1H), 3.63-3.46 (m, 2H), 2.81 (s, MS (ESI) m / z: 170.0 ([M + H] ⁺ , C ₈ H ₁₂ NO ₃ calculated value 170.1)

Step 2. 1- (Mesityloxy) -3- (pyridin-2-yloxy) propan-2-ol
2-mesitylenesulfonyl chloride (10.8 mg, 0.55 mmol), Bu ₂ SnO (63.1 mg, 0.25 mmol), DMAP (61.9 mg, 0.51 mmol) and Et ₃ N (1 mL) were added to 3- ( To a solution of pyridin-2-yloxy) propane-1,2-diol (83.7 mg, 0.50 mmol) in toluene (5 mL). The reaction mixture was stirred at room temperature for 2 hours. After the addition of water, the mixture was extracted with CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography to give the title product (123.9 mg, 71%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.05 (dd, 1H, J = 1.9, 5.1 Hz), 7.65-7.56 (m, 1H), 7.01-6.87 (m, 3H), 6.74 (d, 1H, J = 7.8 Hz), 4.98 (s, 1H), 4.43 (qd, 2H, J = 4.1, 12.2 Hz), 4.15 (s, 1H), 4.02 (d, 2H, J = 5.6 Hz), 2.61 (s, 6H ), 2.27 (s, 3H). MS (ESI) m / z: 351.9 ([M + H] ⁺ , C ₁₇ H ₂₂ SNO ₅ calculated 352.1)

Step 3. Synthesis of 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (pyridin-2-yloxy) propan-2-ol (P7C3-S147)
According to representative method 1, 1,3,6-dibromo-9H-carbazole (32.4 mg, 0.10 mmol) in dry DMF (0.5 mL) was added KOH (10.2 mg, 0.15 mmol) and 1- (mesityloxy). ) -3- (Pyridin-2-yloxy) propan-2-ol (47.5 mg, 0.14 mmol) in dry DMF (1.0 mL) gave the title product (34.1 mg, 72%).
¹ H NMR (d ₆ -DMSO, 400 MHz) δ 8.46 (d, 2H, J = 1.8 Hz), 8.15-8.10 (m, 1H), 7.79-7.67 (m, 1H), 7.62 (d, 2H, J = 8.8 Hz), 7.56 (dd, 2H, J = 1.9, 8.7 Hz), 7.04-6.93 (m, 1H), 6.86 (d, 1H, J = 8.3 Hz), 5.39 (d, 1H, J = 3.6 Hz ), 4.53 (dd, 1H, J = 3.6, 14.8 Hz), 4.44 (dd, 1H, J = 6.9, 14.8 Hz), 4.31-4.19 (m, 3H). MS (ESI) m / z: 474.7 ([ M + H] ⁺ , C ₂₀ H ₁₇ Br ₂ N ₂ O ₂ calculated 475.0)

Example 155. P7C3-S150: 1- (3-Bromo-9H-carbazol-9-yl) -3-phenoxypropan-2-ol
According to representative method 1, a solution of bromocarbazole (24.7 mg, 0.10 mmol) in dry DMF (0.6 mL) was added KOH (10.0 mg, 0.15 mmol) and 2- (phenoxymethyl) oxirane (30.8 mg, Treatment with 0.21 mmol) of dry DMF (0.4 mL) gave the title product (10.5 mg, 31%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.19 (d, 1H, J = 1.8 Hz), 8.03 (d, 1H, J = 7.8 Hz), 7.54-7.42 (m, 3H), 7.36 (d, 1H, J = 8.7 Hz), 7.34-7.21 (m, 3H), 7.00 (t, 1H, J = 7.4 Hz), 6.89 (d, 2H, J = 7.8 Hz), 4.60 (dd, 1H, J = 8.1, 16.1 Hz), 4.53-4.43 (m, 2H), 4.01 (dd, 1H, J = 4.2, 9.5 Hz), 3.91 (dd, 1H, J = 4.5, 9.5 Hz), 2.44 (d, 1H, J = 5.6 Hz ). MS (ESI) m / z: 395.8 ([M + H] ⁺ , C ₂₁ H ₁₉ BrNO ₂ calculated 396.1)

Example 156. P7C3-S151: Methyl 6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3-carboxylate Step 1. 6-Bromo-9- (2-hydroxy-3- Synthesis of phenoxypropyl) -9H-carbazole-3-carboxylic acid
Concentrated HCl (773 μL) was added to a solution of P7C3-S142 (10.8 mg, 0.026 mmol) in dioxane (3.1 mL) at room temperature. The mixture was crude in a microwave reactor at 150 ° C. for 4 hours. Upon completion, 1N aqueous NaOH was added to reach a pH value of about 4. The solution was diluted with EtOAc. The mixture was washed with H ₂ O and saturated aqueous NaCl. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude title product.

Step 2. Synthesis of methyl 6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3-carboxylate (P7C3-S151)
Concentrated H ₂ SO ₄ (20 μL) was added to a solution of the above crude acid in MeOH (1 mL) at room temperature. The solution was stirred at 70 ° C. overnight. Upon completion, the solution was concentrated under reduced pressure. The crude residue was purified by flash column chromatography to give the product (5.8 mg, 50% over 2 steps).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.75 (s, 1H), 8.25 (d, J = 1.7 Hz, 1H), 8.13 (dd, J = 8.7, 1.5 Hz, 1H), 7.54 (dd, J = 8.7, 1.9 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.31 (t, J = 8.0 Hz, 2H), 7.01 (t, J = 7.3 Hz, 1H), 6.89 (d, J = 7.9 Hz, 2H), 4.70-4.57 (m, 1H), 4.56-4.40 (m, 2H), 4.04 (dd, J = 9.6, 4.4 Hz, 1H), 4.00-3.86 (m, 4H), 2.51 (d, J = 5.2 Hz, 1H). MS (ESI) m / z: 453.8 ([M + H] ⁺ , C ₂₃ H ₂₁ BrNO ₄ calculated 454.1)

Example 157. P7C3-S153: 6-Bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3-carboxylic acid
LiOH.H ₂ O was added to a 2 mL THF / H ₂ O / MeOH (v / v / v = 3/1/1) solution of P7C3-S151 at room temperature, and the mixture was stirred at 60 ° C. for 3 hours. Upon completion, the solution was treated with 1.0 N HCl to a pH value of about 3. The mixture was extracted with ethyl acetate and the ethyl acetate extract was washed with H ₂ O and saturated aqueous NaCl. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by preparative thin layer chromatography to give the product as a white solid (2.2 mg, 67%).
¹ H NMR (d ₆ -DMSO, 400 MHz) δ 8.84 (d, 1H, J = 1.3 Hz), 8.54 (d, 1H, J = 1.8 Hz), 8.03 (dd, 1H, J = 1.6, 8.7 Hz) , 7.68 (dd, 2H, J = 8.8, 14.4 Hz), 7.59 (dd, 1H, J = 1.9, 8.7 Hz), 7.33-7.26 (m, 2H), 6.99-6.91 (m, 3H), 5.45 (s , 1H), 4.61 (dd, 1H, J = 4.1, 14.7 Hz), 4.49 (dd, 1H, J = 4.1, 14.8 Hz), 4.31-4.22 (m, 1H), 4.05-3.93 (m, 2H). MS (ESI) m / z: 437.8 ([MH] ^- , C ₂₂ H ₁₇ BrNO ₄ calculated 438.0)

Examples 158a and 158b. P7C3-S154: 6-Bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [2,3-b] indole-3-carbonitrile and P7C3-S155: 9- (2-Hydroxy-3-phenoxypropyl) -9H-pyrido [2,3-b] indole-3-carbonitrile Step 1. Synthesis of 6-amino-5-bromonicotinonitrile
Br ₂ (0.52 mL, 0.01 mol) was added to a solution of 6-aminonicotinonitrile (1.1901 g, 0.01 mol) in AcOH (10 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was purified by flash column chromatography to give the title product (980.0 mg, 49%).
¹ H NMR (d ₆ -DMSO, 400 MHz) δ 8.36 (s, 1H), 8.19 (s, 1H), 7.33 (bs, 2H). MS (ESI) m / z: 197.9 ([M + H] ⁺ , C ₆ H ₅ BrN ₃ calculated 198.0)

Step 2. Synthesis of 5,6-dibromonicotinonitrile
^t -BuONO ^(77.4mg, 0.75mmol) in anhydrous CuBr ₂ (135.2mg, 0.61mmol) was added at room temperature to _CH 3 CN (3mL) solution of. The mixture was heated to 65 ° C. and a suspension of 6-amino-5-bromonicotinonitrile (98.1 mg, 0.50 mmol) in CH ₃ CN (2 mL) was added. The mixture was stirred at 65 ° C. for 3 hours. The mixture was poured into 3M HCl and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography to give the title product (81.0 mg, 62%).
¹ H NMR (CD ₃ OD, 400 MHz) δ 8.70 (d, 1H, J = 2.0 Hz), 8.53 (d, 1H, J = 2.0 Hz) .MS (ESI) m / z: 260.7 ([M + H ] ⁺ , C ₆ H ₃ Br ₂ N ₂ calculated 260.9)

Step 3. Synthesis of 5-bromo-6-((4-bromophenyl) amino) nicotinonitrile
According to literature methods ³ , 2,4-bromoaniline (59.0 mg, 0.34 mmol), 5,6-dibromonicotinonitrile (81.0 mg, 0.31 mmol), Pd (OAc) ₂ (3.6 mg) _{, 0.016mmol), PPh 3 (8.2mg} , 0.03mmol) and ^NaO t -Bu ^(36.1mg, mixture of about 5 minutes in 0.38 mmol) of o- xylene (3mL), _{N 2} at room temperature In a N ₂ atmosphere and heated in a screw-cap sample vial at 120 ° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by flash column chromatography to give the product as a white solid (56.4 mg, 52%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.41 (d, 1H, J = 1.7 Hz), 7.94 (d, 1H, J = 1.7 Hz), 7.55-7.46 (m, 4H), 7.34 (s, 1H) MS (ESI) m / z: 351.7 ([M + H] ⁺ , C ₁₂ H ₈ Br ₂ N ₃ calculated 351.9)

Step 4. Synthesis of mixture bromo and des-bromocarboline
According to literature method ³ , Pd (OAc) ₂ (1.3 mg, 0.006 mmol), PCy ₃ (3.3 mg, 0.012 mmol) and DBU (16.0 mg, 0.11 mmol) were treated with 5-bromo-6. -((4-Bromophenyl) amino) nicotinonitrile (36.0 mg, 0.10 mmol) was added to a solution of DMA (2 mL) at room temperature. The reaction mixture was bubbled for about 5 minutes, placed under a N ₂ atmosphere and heated at 145 ° C. for about 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate while heating to 40-50 ° C. The mixture was washed several times with water followed by brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography to give 6-bromo-9H-pyrido [2,3-b] indole-3-carbonitrile and 9H-pyrido [2,3-b] indole-3-carbonitrile (5 9.9 mg) of mixture and recovered 5-bromo-6-((4-bromophenyl) amino) nicotinonitrile (19.8 mg).

Step 5. 6-Bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [2,3-b] indole-3-carbonitrile (P7C3-S154) and 9- (2-hydroxy-3) Synthesis of -phenoxypropyl) -9H-pyrido [2,3-b] indole-3-carbonitrile (P7C3-S155)
MeLi (1.6 M in Et ₂ O, 108 μl, 0.17 mmol) was added to 6-bromo-9H-carbazole-3-carbonitrile and 9H-carbazole-3-carbonitrile (24.1 mg) in THF (1.0 mL). ) Was added at −78 ° C. and stirred for 40 minutes. Phenyl glycidyl ether (24.1 mg, 0.16 mmol) was added at −78 ° C. and the reaction was stirred at 45 ° C. overnight. Upon completion, the solution was quenched with H ₂ O. Ethyl acetate was added and the mixture was washed with H ₂ O and saturated aqueous NaCl. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. A small amount was purified by reverse phase HPLC to give the title products P7C3-S154 and P7C3-S155.
P7C3-S154: ¹ H NMR (d ₆ -DMSO, 400 MHz) δ 9.13 (d, 1H, J = 1.9 Hz), 8.91 (d, 1H, J = 1.9 Hz), 8.55 (d, 1H, J = 1.7 Hz), 7.81 (d, 1H, J = 8.8Hz), 7.74 (dd, 1H, J = 1.9, 8.8Hz), 7.27 (t, 2H, J = 7.9 Hz), 6.93 (t, 1H, J = 7.3 Hz), 6.88 (d, 2H, J = 8.0 Hz), 5.42 (s, 1H), 4.68 (dd, 1H, J = 4.8, 14.3 Hz), 4.61 (dd, J = 1H, 7.7, 14.2 Hz), 4.41-4.32 (m, 1H), 4.04 (dd, 1H, J = 4.9, 9.9 Hz), 3.98 (dd, 1H, J = 5.5, 9.9 Hz) .MS (ESI) m / z: 421.8 ([M + H] ⁺ , C ₂₁ H ₁₇ BrN ₃ O ₂ calculated 422.1)
P7C3-S155: ¹ H NMR (d ₆ -DMSO, 400 MHz) δ 9.11 (d, 1H, J = 2.0 Hz), 8.87 (d, 1H, J = 2.0 Hz), 8.29 (d, 1H, J = 8.0 Hz), 7.82 (d, 1H, J = 8.3 Hz), 7.60 (dt, 1H, J = 0.8, 7.6 Hz), 7.38 (t, 1H, J = 7.5 Hz), 7.29-7.23 (m, 2H), 6.92 (t, 1H, J = 7.3 Hz), 6.88 (d, 2H, J = 7.8 Hz), 5.41 (s, 1H), 4.68 (dd, 1H, J = 5.2, 14.3 Hz), 4.62 (dd, 1H , J = 7.4, 14.3 Hz), 4.44-4.34 (m, 1H), 4.04 (dd, 1H, J = 4.8, 9.9 Hz), 3.98 (dd, 1H, J = 5.4, 9.9 Hz). MS (ESI) m / z: 343.8 ([M + H] ⁺ , C ₂₁ H ₁₈ N ₃ O ₂ calculated 344.1)

Example 159. P7C3-S157: tert-butyl 3- (2- (2- (2- (3-((3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) Amino) phenoxy) ethoxy) ethoxy) ethoxy) propanoate
The title compound was synthesized according to P7C3-S219 (see below).
MS (ESI) m / z: 748.7 [M + H] ⁺ , C ₃₄ H ₄₂ Br ₂ N ₂ O ₇ calculated 748.1

Example 160. P7C3-S159: 1- (3-Bromo-6-methoxy-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol Representative method 6: heterocycle bromination step 1. Synthesis of 3-bromo-6-methoxy-9H-carbazole
3-Methoxy-9H-carbazole (Bedford, RB; Betham, MJ Org. Chem. 2006, 71, 9403-9410) (0.029 g, 0.147 mmol) was dissolved in dry DMF (0.28 mL) and NBS ( 0.026 g, 0.147 mmol) was added to the solution. The reaction mixture was stirred for 2 hours at room temperature, protected from light. The solution was poured into water (2 mL), filtered and washed with water. The title compound was isolated as a gray solid (0.033 g, 82%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.13 (s, 1H), 7.91 (brs, 1H), 7.50-7.43 (m, 2H), 7.30 (d, 1H, J = 8.7 Hz), 7.25 (d, 1H, J = 5.6 Hz), 7.08 (d, 1H, J = 8.7 Hz), 3.91 (s, 3H). MS (ESI) m / z 276.9 [M + H] ⁺ ([M + H] ⁺ , C ₍₁₃ H ₁₁ BrNO calculated value 276.0)

Representative Method 7: Alkylation of carbazole with NaH 2. 1- (3-Bromo-6-methoxy-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol (P7C3-S159) )
NaH (0.0025 g of a 60% suspension in oil, 0.093 mmol) was added 3-bromo-6-methoxy-9H-carbazole (0.014 g, 0.052 mmol) in anhydrous THF (0.1 mL). At 0 ° C. and stirred for 30 minutes. N- (oxiran-2-ylmethyl) aniline (0.0093 g, 0.062 mmol) in anhydrous THF (0.1 mL) was added dropwise to the reaction mixture. The reaction was warmed to room temperature and stirred for 48 hours. The reaction was quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc. Concentration of the combined organic layer, chromatography _(SiO 2, _0~30% EtOAc / hexanes) to give the title compound (0.007 g, 25%).
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.15 (s, 1H), 7.56-7.44 (m, 2H), 7.33 (dd, 2H, J = 8.8, 22.6 Hz), 7.19 (t, 2H, J = 7.7 Hz,), 7.11 (dd, 1H, J = 2.2, 8.8 Hz), 6.80 (t, 1H, J = 7.3 Hz), 6.67 (d, 2H, J = 7.8 Hz), 4.41 (m _c , 1H), 4.39 (m _c , 2H), 3.91 (s, 3H), 3.34 (dd, 1H, J = 3.0, 12.9 Hz), 3.20 (dd, 1H, J = 6.9, 12.9 Hz). MS (ESI) m / z 424.8 [M + H] ⁺ ([M + H] ⁺ , C ₂₂ H ₂₂ BrN ₂ O ₂ calculated 425.0)

Example 161. P7C3-S160: 1- (3,6-dibromo-1,4-dimethoxy-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol
Representative Method 8: Synthesis of carbazole via sequential amination and C—H activation 1. Synthesis of 1,4-dimethoxy-9H-carbazole
According to published methods (Bedford, RB; Betham, MJ Org. Chem. 2006, 71, 9403-9410), NaOtBu (0.754 g, 7.84 mmol), Pd (OAc) ₂ (0.014 g, 0.06 mmol) ) And [HPtBu ₃ ] [BF ₄ ] (0.023 g, 0.078 mmol) were suspended in dry toluene (5 mL) in a microwave vial. 2-Chloroaniline (0.165 mL, 1.567 mmol) and 2-bromo-1,4-dimethoxybenzene (0.240 mL, 1.598 mmol) were added and the vial was sealed. The reaction was heated in a microwave reactor at 170 ° C. for 4 hours, cooled and quenched by the addition of 1M HCl. The aqueous layer was extracted with CH ₂ Cl ₂ and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude mixture chromatographed _(SiO 2, _0~10% EtOAc / hexanes) to give the title product (0.193 g, 55%).
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.19 (d, 1H, J = 7.8 Hz), 8.15 (brs, 1H), 7.29-7.22 (m, 2H), 7.10 (t, 1H, J = 7.2 Hz) , 6.63 (d, 1H, J = 8.4 Hz), 6.38 (d, 1H, J = 8.4 Hz), 3.88 (s, 3H), 3.81 (s, 3H). MS (ESI) m / z 228.0 [M + H] ⁺ ([M + H] ⁺ , C ₁₄ H ₁₄ NO ₂ calculated 228.2)

Step 2. Synthesis of 3,6-dibromo-1,4-dimethoxy-9H-carbazole
According to representative method 6, 1,4-dimethoxy-9H-carbazole (0.050 g, 0.22 mmol) was treated with a solution of NBS (0.078 g, 0.44 mmol) in dry CH ₂ Cl ₂ (11 mL), The title compound was obtained (0.073 g, 88%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.33 (brs, 1H), 8.31 (d, 2H, J = 1.8 Hz), 7.52 (dd, 1H, J = 1.8, 8.6 Hz), 7.32 (d, 1H, J = 8.6 Hz), 6.99 (s, 1H), 4.03 (s, 3H), 3.97 (s, 3H). MS (ESI) m / z 383.7 [MH] ^- ([MH] ^- , C ₁₄ H ₁₀ Br ₍₂ NO ₂ calculated value 384.0)

Step 3. Synthesis of 1- (3,6-dibromo-1,4-dimethoxy-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol
Following representative method 7, the title compound was obtained in 46% yield.
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.32 (s, 1H), 7.54 (dd, 1H, J = 1.7, 8.8 Hz), 7.39 (d, 1H, J = 8.8 Hz), 7.19 (t, 2H, J = 7.8 Hz), 7.01 (s, 1H), 6.75 (t, 1H, J = 7.3 Hz), 6.64 (d, 2H, J = 7.8 Hz), 4.76 (dd, 1H, J = 3.9, 14.7 Hz) , 4.55 (dd, 1H, J = 7.8, 14.7 Hz), 4.37 (m _c , 1H), 4.01 (s, 3H), 3.94 (s, 3H), 3.35 (dd, 1H, J = 3.8, 13.0 Hz) , 3.20 (dd, 1H, J = 7.4, 13.0 Hz) .MS (ESI) m / z 534.7 [M + H] ⁺ ([M + H] ⁺ , C ₂₃ H ₂₃ Br ₂ N ₂ O ₃ calculated 535.2 )

Example 162. P7C3-S161: 1- (3,6-dibromo-1,8-dimethyl-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol
The title compound was prepared according to P7C3-S160.
¹ H NMR (CDCl ₃ , 500 MHz) δ 7.97 (s, 2H), 7.29 (s, 2H), 7.13 (t, 2H, J = 7.7 Hz), 6.73 (t, 1H, J = 7.3 Hz), 6.43 (d, 2H, J = 8.1 Hz), 4.85 (dd, 1H, J = 8.1, 15.6 Hz), 4.74 (dd, 1H, J = 4.7, 15.6 Hz), 3.92 (m _c , 1H), 3.86 (m _c , 1H), 3.00 (dd, 1H, J = 3.4, 13.2 Hz), 2.94 (dd, 1H, J = 7.2, 13.2 Hz), 2.73 (s, 6H). MS (ESI) m / z 502.7 [M + H] ⁺ ([M + H] ⁺ , C ₂₃ H ₂₃ Br ₂ N ₂ O calculated 503.2)

Example 163. P7C3-S164: ethyl 2- (3,6-dibromo-9H-carbazol-9-yl) acetate
Sodium hydride was added to a stirring solution of 3,6-dibromocarbazole (250 mg, 0.77 mmol) in DMF (4 ml). The solution was stirred for 30 minutes and ethyl chloroacetate was added dropwise. After 12 hours, water was added and a pale white precipitate formed, which was filtered and rinsed with water and hexanes to give the desired ethyl ester in 93% yield.
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.15 (s, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 4.94 (s, 2H), 4.20 (q, J = 6.3 Hz, 2H), 1.26-1.18 (m, 3H). ESI m / z: 409.7 ([M + H] ⁺ , C ₁₆ H ₁₃ Br ₂ NO ₂ calculated 409.9)

Example 164. P7C3-S165: 2- (3,6-dibromo-9H-carbazol-9-yl) acetic acid
Ethyl 2- (3,6-dibromo-9H-carbazol-9-yl) acetate (50 mg, 0.12 mmol) was dissolved in THF (0.6 ml). To this stirring solution was added methanol (0.4 ml), water (0.2 ml) and lithium hydroxide (14.5 mg, 0.6 mmol). After 1 hour all starting material was consumed. The solution was acidified with 1N HCl. When the pH was about 4, a precipitate formed and was collected and rinsed with fresh water to give the desired acid in 95% yield.
¹ H NMR (500 MHz, acetone-d ₆ ) δ 8.41 (s, 2H), 7.62 (dt, J = 8.6, 1.7 Hz, 2H), 7.58 (dd, J = 8.7, 1.5 Hz, 2H), 5.31 ( d, J = 1.6 Hz, 2H). ESI m / z: 381.7 ([M + H] ⁺ , C ₁₄ H ₉ Br ₂ NO ₂ calculated 381.9)

Example 165. P7C3-S166: 1- (6-Bromo-3-methoxy-1-methyl-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol
The title compound was prepared according to P7C3-S160.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.13 (d, 1H, J = 1.9 Hz), 7.47 (dd, 1H, J = 1.9, 8.7 Hz), 7.34 (d, 1H, J = 2.5 Hz), 7.30 (d, 1H, J = 8.7 Hz), 7.21-7.15 (m, 2H), 6.86 (d, 1H, J = 1.9 Hz), 6.75 (t, 1H, J = 7.3 Hz), 6.60 (d, 2H, J = 7.7 Hz), 4.65 (dd, 1H, J = 8.3, 15.4 Hz), 4.56 (dd, 1H, J = 4.4, 15.4 Hz), 4.31 (m _c , 1H), 3.89 (s, 3H), 3.30 (dd, 1H, J = 3.8, 13.0 Hz), 3.21 (dd, 1H, J = 7.2, 13.0 Hz), 2.76 (s, 3H). MS (ESI) m / z 440.9 [M + H] ⁺ ([[ M + H] ⁺ , C ₂₃ H ₂₄ BrN ₂ O ₂ calculated 440.3)

Example 166. P7C3-S167: 1- (4,6-Dibromo-3-methoxy-1-methyl-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol
The title compound was synthesized according to P7C3-S160.
¹ H NMR (CDCl ₃ , 400 MHz) δ 9.03 (d, 1H, J = 1.9 Hz), 7.53 (dd, 1H, J = 1.9, 8.8 Hz), 7.29 (d, 1H, J = 8.8 Hz), 7.22 -7.15 (m, H), 6.86 (s, 1H), 6.76 (t, 1H, J = 7.3 Hz), 6.60 (d, 2H, J = 7.7 Hz), 4.65 (dd, 1H, J = 8.4, 15.4 Hz), 4.53 (dd, 1H, J = 4.1, 15.4 Hz), 4.27 (m _c , 1H), 3.94 (s, 3H), 3.29 (dd, 1H, J = 3.9, 13.1 Hz), 3.20 (dd, 1H, J = 7.2, 13.1 Hz), 2.77 (s, 3H). MS (ESI) m / z 518.7 [M + H] ⁺ ([M + H] ⁺ , C ₂₃ H ₂₃ Br ₂ N ₂ O ₂ calculation (Value 519.2)

Example 167. P7C3-S168: 1- (3,6-dibromo-4-methoxy-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol
The title compound was synthesized according to P7C3-S160.
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.46 (s, 1H), 7.62-7.47 (m, 2H), 7.44 (d, 1H, J = 8.7 Hz), 7.18 (t, 2H, J = 7.6 Hz) , 6.75 (t, 1H, J = 7.2 Hz), 6.64 (d, 2H, J = 8.2 Hz), 6.60 (d, 1H, J = 8.5 Hz), 5.04 (dd, 1H, J = 4.1, 15.2 Hz) , 4.68 (dd, 1H, J = 8.1, 15.2 Hz), 4.51 (m _c , 1H), 4.07 (s, 3H), 3.39 (dd, 1H, J = 3.1, 13.0 Hz), 3.24 (dd, 1H, J (7.5, 13.0 Hz). MS (ESI) m / z 504.7 [M + H] ⁺ ([M + H] ⁺ , C ₂₂ H ₂₁ Br ₂ N ₂ O ₂ calculated 505.2)

Example 168 P7C3-S172: 9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylic acid Step 1. Ethyl 9- (2-hydroxy-3- Phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylate
According to Representative Method 1, the title compound ethyl 9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylate is converted to ethyl 9H-pyrido [3,4-b]. Obtained in 67% yield from indole-3-carboxylate and phenoxymethyloxirane.
¹ H NMR (500 MHz, DMSO-d ₆ ) d 9.12 (s, 1H), 8.92 (s, 1H), 8.43 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H) , 7.66 (t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.30 (t, J = 7.6 Hz, 2H), 6.96 (dd, J = 12.0, 8.0 Hz, 3H) , 5.50 (s, 1H), 4.75 (dd, J = 14.8, 3.4 Hz, 1H), 4.64 (dd, J = 14.8, 7.3 Hz, 1H), 4.38 (dd, J = 14.2, 7.1 Hz, 1H), 4.31 (s, 1H), 4.03 (p, J = 9.7 Hz, 2H), 1.41-1.32 (m, 3H). ESI m / z: 390.9 ([M + H] ⁺ , C ₂₃ H ₂₂ N ₂ O ₄ (Calculated value 391.16)

Step 2: P7C3-S172: 9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylic acid
Ethyl 9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylate (42 mg, 0.107 mmol) was suspended in 10% NaOH (aq) for 3 hours. Heated to reflux. Upon completion, the reaction was cooled to room temperature and acidified with ice cold HCl (conc.). The temperature was maintained at 0 ° C. and stirred for 1 hour. The precipitate was filtered, rinsed with water and dried under reduced pressure to give the desired compound in 92% yield.
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.16 (s, 1H), 9.00 (s, 1H), 8.48 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H) , 7.66 (t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.30 (t, J = 7.6 Hz, 2H), 6.96 (dd, J = 12.0, 8.0 Hz, 3H) , 5.52 (s, 1H), 4.78 (dd, J = 14.8, 3.4 Hz, 1H), 4.68 (dd, J = 14.8, 7.3 Hz, 1H), 4.31 (s, 1H), 4.03 (p, J = 9.7 ESI m / z: 362.9 ([M + H] ⁺ , C ₂₁ H ₁₈ N ₂ O ₄ calculated 363.13)

Example 169. P7C3-S173: 6-Bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylic acid Step 1. Ethyl 6-bromo-9H Synthesis of pyrido [3,4-b] indole-3-carboxylate
According to the method of Chem. Bio. Chem, 2009, 10, 889-895, N-bromosuccinimide (37 mg, 0.208 mmol) was added to ethyl 9H-pyrido [3,4-b] indole-3-carboxylate (50 mg, 0 .208 mmol) in acetic acid (1.5 ml) and stirred at room temperature. After 45 minutes, acetic acid was removed and the solid was partitioned between EtOAc and NaHCO ₃ . The organic layer was washed with water and brine and dried over Na ₂ SO ₄ to give the desired compound in 98% yield.
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.99 (d, J = 3.4 Hz, 2H), 8.70 (s, 1H), 7.67 (dd, J = 24.8, 8.5 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). ESI m / z: 318.8 ([M + H] ⁺ , C ₁₄ H ₁₁ BrN ₂ O ₂ calculated 319.0)

Step 2. Ethyl 6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylate (P7C3-S174)
According to representative method 1, the title compound ethyl 6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylate is converted to ethyl 6-bromo-9H- Obtained in 71% yield from pyrido [3,4-b] indole-3-carboxylate and phenoxymethyloxirane.
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.26 (s, 1H), 9.19 (s, 1H), 8.87 (s, 1H), 7.90-7.80 (m, 2H), 7.30 (t, J = 6.6 Hz, 2H), 6.96 (d, J = 7.5 Hz, 3H), 4.81 (d, J = 14.9 Hz, 1H), 4.73 (dd, J = 15.7, 8.6 Hz, 1H), 4.44 (dd, J = 13.8 , 6.8 Hz, 2H), 4.29 (s, 1H), 4.03 (s, 2H), 1.40 (td, J = 7.0, 2.6 Hz, 3H). ESI m / z: 468.8 ([M + H] ⁺ , C ₍₂₃ H ₂₁ BrN ₂ O ₄ calculated 469.07)

Step 3. P7C3-S173: 6-Bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylic acid
P7C3-S173 was synthesized according to P7C3-S172 except that ethyl 6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylate was used did.
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.35 (s, 1H), 9.27 (s, 1H), 8.91 (s, 1H), 7.90 (dd, J = 24.1, 9.5 Hz, 2H), 7.30 ( t, J = 7.4 Hz, 2H), 6.96 (d, J = 7.4 Hz, 3H), 4.89-4.73 (m, 3H), 4.29 (s, 1H), 4.04 (d, J = 4.2 Hz, 2H). ESI m / z: 440.8 ([M + H] ⁺ , C ₂₁ H ₁₇ BrN ₂ O ₄ calculated 441.0)

Example 170. P7C3-S174: ethyl 6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylate
P7C3-S174 was a synthetic intermediate of P7C3-S173.

Example 171. P7C3-S175: 9- (2-Fluoro-3-phenoxypropyl) -9H-carbazole-3,6-dicarbonitrile
The title compound was prepared according to the method described in Representative Method 4 using Morpho-Dast, except that P7C3-S111 was used as the starting material. The crude mixture was purified on silica gel with 100% DCM (+ 0.2% TEA). Isolation yield = 75%.
¹ H NMR (THF-d ₈ , 400 MHz) δ 8.62 (s, 2H), 7.80 (s, 4H), 7.27 (t, J = 8.2 Hz, 2H), 6.84 (dm, 1H, J _{HF =} 47.3 Hz .), 4.84-5.04 (m, 2H ), 4.16-4.34 (m, 2H) MS (ESI), m / z: calculated 369.13, Found 413.9 (M + HCOO ^-)

Example 172. P7C3-S176: 1- (cyclopentylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol
A solution of 3,6-dibromo-9- (oxiran-2-ylmethyl) -9H-carbazole (153 mg, 0.40 mmol) and cyclopentylamine (200 μl, 2.02 mmol) in ethanol (4.0 ml) was added at 80 ° C. for 3 hours. Heated. The reaction was cooled and concentrated to give the desired one in quantitative yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.15 (d, J = 1.9 Hz, 2H), 7.56 (dd, J = 8.7, 2.0 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H), 4.32 (d, J = 5.6 Hz, 2H), 4.11-4.00 (m, 1H), 3.75 (q, J = 6.6 Hz, 1H), 3.06-2.95 (m, 1H), 2.79 (dd, J = 12.1, 3.7 Hz, 1H), 2.52 (dd, J = 12.0, 8.8 Hz, 1H), 1.90-1.39 (m, 6H), 1.32-1.17 (m, 2H). MS (ESI), m / z: Calculated value 464.01, Found 508.7 (M + HCOO ^-)

Example 173. P7C3-S177: 9- (2-Hydroxy-2-methyl-3-phenoxypropyl) -9H-carbazole-3,6-dicarbonitrile Step 1. 1- (3,6-Dibromo-9H- Carbazol-9-yl) -2-methyl-3-phenoxypropan-2-ol
Example 103, Step 1 title compound, 1- (3,6-dibromo-9H-carbazol-9-yl) -3-phenoxypropane in ice-cooled methylmagnesium bromide (92 μl, 3.0 M in THF) To a solution of 2-one (86 mg, 0.18 mmol) in anhydrous THF (1.8 ml) was added. The reaction was stirred for 6 hours with gentle warming in an ice bath and quenched by the addition of water. The crude mixture was diluted with EtOAc and washed with saturated sodium bicarbonate, water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. Some unreacted starting material precipitated from ˜50% acetone / hexane. The concentrated filtrate was then used. Yield = 89%. MS (ESI), m / z: calc. 486.98, found 531.7 (M + HCOO ⁻ ).

Step 2. 9- (2-Hydroxy-2-methyl-3-phenoxypropyl) -9H-carbazole-3,6-dicarbonitrile (P7C3-S177)
An oven-dried vial was charged with 1- (3,6-dibromo-9H-carbazol-9-yl) -2-methyl-3-phenoxypropan-2-ol (79.5 mg, 0.16 mmol), copper iodide (16 mg). 0.08 mmol), sodium cyanide (22 mg, 0.45 mmol) and potassium iodide (16 mg, 0.10 mmol) were added. The sealed vial was filled with nitrogen three times, evacuated, and N, N-dimethyl-1,2-ethanediamine (22.5 μl, 0.21 mmol) and anhydrous toluene (75 μl) were added. The reaction was heated at 100 ° C. for more than 60 hours. The cooled mixture was diluted with EtOac and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude mixture was purified on silica gel with 40% THF / hexane. Yield = 34%.
¹ H NMR (THF-d ₈ , 400 MHz) δ 8.49 (d, J = 1.0 Hz, 2H), 7.79 (d, J = 8.6 Hz, 2H), 7.60 (dd, J = 8.7, 1.5 Hz, 2H) , 7.17 (d, J = 8.0 Hz, 2H), 6.89-6.74 (m, 3H), 4.46-4.70 (m, 2H), 371-3.89 (m, 2H), 1.32 (s, 3H). MS (ESI ), m / z: calculated 381.15, Found 425.9 (M + HCOO ^-)

Example 174. P7C3-S178: 1- (cyclohexyloxy) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol
A previous amount of spatula sodium hydride (60% suspension in mineral oil) was added to 6-dibromo-9- (oxiran-2-ylmethyl) -9H-carbazole (epoxide 2-A) (145 mg, 0.38 mmol). To a cyclohexanol (10 ml) solution. The reaction was stirred at 60 ° C. overnight. The mixture was washed with water and dried under reduced pressure for several days. Yield = 45%
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.14 (d, J = 1.9 Hz, 2H), 7.56 (dd, J = 8.7, 1.9 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 4.43 (dd, J = 15.0, 6.8 Hz, 1H), 4.32 (dd, J = 14.9, 5.7 Hz, 1H), 4.18 (m, 1H), 3.49 (dd, J = 9.4, 4.1 Hz, 1H), 3.27 ( m, 2H), 2.53 (d, J = 6.0 Hz, 1H), 1.89 (m, 2H), 1.79-1.69 (m, 2H), 1.56 (m, 2H), 1.40-1.17 (m, 4H). MS (ESI), m / z: calculated 479.01, Found 523.7 (M + HCOO ^-)

Example 175. P7C3-S179: (E) -N- (3- (3,6-dibromo-9H-carbazol-9-yl) prop-1-en-1-yl) -1,1,1-tri Fluoro-N- (3-methoxyphenyl) methanesulfonamide
The title compound is N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -1,1,1-trifluoro-N- (3-methoxyphenyl) methanesulfone It was isolated as a reaction product of amide (P7C3-S241) in toluene and Red-Al at 80 ° C. This was purified by column chromatography with 10% EtOAc / hexane.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.13 (d, J = 1.9 Hz, 2H), 7.55 (dd, J = 8.6, 2.0 Hz, 2H), 7.32 (t, J = 8.2 Hz, 1H), 7.21 (d, J = 8.7 Hz, 2H), 7.01 (d, J = 13.4 Hz, 1H), 6.98-6.93 (m, 1H), 6.80 (dd, J = 7.9, 1.9 Hz, 1H), 6.73 (t, J = 2.3 Hz, 1H), 4.83 (d, J = 6.7 Hz, 2H), 4.76 (ddd, J = 12.8, 7.2, 5.4 Hz, 1H), 3.75 (s, 3H). MS (ESI), m / z: calculated 615.93, Found 660.5 (M + HCOO ^-)

Example 176. P7C3-S180: 1- (9H-carbazol-9-yl) -3- (naphthalen-1-ylamino) propan-2-ol
The title compound was prepared using representative method 2 and 9- (oxiran-2-ylmethyl) -9H-carbazole. Chromatography with 10% EtOAc / hexanes gave 49% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.13 (d, J = 7.7 Hz, 2H), 7.83 (ddd, J = 9.7, 6.8, 3.0 Hz, 2H), 7.57-7.43 (m, 6H), 7.37- 7.27 (m, 4H), 6.58 (dd, J = 6.6, 2.0 Hz, 1H), 4.77 (s, 1H), 4.68-4.50 (m, 3H), 3.55 (dd, J = 12.6, 3.6 Hz, 1H) , 3.41 (dd, J = 12.7, 6.9 Hz, 1H), 2.23 (s, 1H) .MS (ESI), m / z: calculated value 366.17, actual value 367.0 (M + 1)

Example 177. P7C3-S183: 1- (8-Bromo-5H-pyrido [4,3-b] indol-5-yl) -3-phenoxypropan-2-ol
The title compound was synthesized according to P7C3-S160 using phenylglycidyl ether and the appropriate carboline (Sako, K. et al. Bioorg. Med. Chem. 2008, 16, 3780-3790).
¹ H NMR (CDCl ₃ -MeOD [4: 2], 500 MHz) δ 8.98 (s, 1H), 8.25 (d, 1H, J = 5.9 Hz), 8.12 (d, 1H, J = 1.5 Hz), 7.46 (d, 1H, J = 8.6 Hz), 7.40-7.33 (m, 2H), 7.19 (t, 2H, J = 7.8 Hz), 6.88 (t, 1H, J = 7.3 Hz), 6.81 (d, 2H, J = 8.5 Hz), 4.52 (dd, 1H, J = 4.9, 14.8 Hz), 4.36 (dd, 1H, J = 6.4, 14.8 Hz), 4.30 (m _c , 1H), 3.85 (m _c , 2H). MS (ESI) m / z 398.8 [M + H] ⁺ ([M + H] ⁺ , C ₂₀ H ₁₈ BrN ₂ O ₂ calculated 398.2)

Example 178. P7C3-S184: 1- (3,6-dichloro-9H-carbazol-9-yl) -3- (naphthalen-1-ylamino) propan-2-ol
The title compound was prepared according to P7C3-S180. Chromatography with 10% EtOAc / hexanes gave the desired in 59% yield.
¹ H NMR (400 MHz, acetone-d6) δ 8.22 (d, J = 2.0 Hz, 2H), 8.17-7.96 (m, 1H), 7.88-7.73 (m, 1H), 7.68 (d, J = 8.8 Hz , 2H), 7.59-7.34 (m, 4H), 7.26 (m, 1H), 7.21 (d, J = 8.1 Hz, 1H), 6.61 (d, J = 7.4 Hz, 1H), 5.63 (d, J = 5.1 Hz, 1H), 4.71 (m, 1H), 4.60 (m, 2H), 3.58 (dm, 3H) .MS (ESI), m / z: Calculated value 434.10, Measured value 434.9 (M-1)

Example 179. P7C3-S186: 1- (6-Bromo-9H-pyrido [2,3-b] indol-9-yl) -3-phenoxypropan-2-ol
The title compound was synthesized according to P7C3-S160 using α-carboline (Sako, K. et al. Bioorg. Med. Chem. 2008, 16, 3780-3790) and phenyl glycidyl ether.
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.46 (d, 1H, J = 4.7 Hz), 8.29 (d, 1H, J = 7.6 Hz), 8.15 (s, 1H), 7.55 (d, 1H, J = 8.7 Hz), 7.42 (d, 1H, J = 8.7 Hz), 7.27 (t, 2H, J = 7.9 Hz), 7.23 (dd, 1H, J = 5.0, 7.5 Hz), 6.96 (t, 1H, J = 7.3 Hz), 6.88 (d, 2H, J = 8.1 Hz), 4.73 (dd, 1H, J = 2.6, 14.9 Hz), 4.66 (dd, 1H, J = 5.6, 14.9 Hz), 4.53 (m _c , 1H ), 4.07 (dd, 1H, J = 5.1, 9.1 Hz), 3.86 (dd, 1H, J = 7.6, 9.1 Hz). MS (ESI) m / z 397.8 [M + H] ⁺ ([M + H] ⁺ , C ₂₀ H ₁₈ BrN ₂ O ₂ calculated 398.2)

Example 180. P7C3-S187: 1- (3,6-dibromo-9H-pyrido [2,3-b] indol-9-yl) -3-phenoxypropan-2-ol
The title compound was synthesized according to P7C3-S186 except that excess NBS was used for bromination.
¹ H NMR (CDCl ₃ -MeOD [4: 2], 500 MHz) δ 8.39 (s, 1H), 8.33 (s, 1H), 8.05 (s, 1H), 7.52-7.43 (m, 1H), 7.43- 7.32 (m, 1H), 7.18 (t, 2H, J = 7.1 Hz), 6.87 (t, 1H, J = 7.3 Hz), 6.78 (d, 2H, J = 7.9 Hz), 4.60 (dd, 1H, J = 4.6, 14.7 Hz), 4.53 (dd, 1H, J = 6.0, 14.7 Hz), 4.38 (m _c , 1H), 3.89 (m _c , 2H). MS (ESI) m / z 476.7 [M + H] ⁺ ([M + H] ⁺ , C ₂₀ H ₁₇ Br ₂ N ₂ O ₂ calculated 477.1)

Example 181. P7C3-S188: 1- (3,6-dibromo-9H-carbazol-9-yl) -3-((6-methoxypyridin-2-yl) amino) propan-2-ol
The title compound was prepared according to P7C3-S10 (also known as P7C3A20).
MS (ESI) m / z: 503.7 [M + H] ⁺ , C ₂₁ H ₁₉ Br ₂ N ₃ O ₂ calculated 503.0

Example 182. P7C3-S190: 1- (6-Bromo-3-methyl-9H-pyrido [3,4-b] indol-9-yl) -3-phenoxypropan-2-ol
Step 1. 6-Bromo-9H-pyrido [3,4-b] indol-3-yl) methanol (P7C3-S204)
Ethyl 6-bromo-9H-pyrido [3,4-b] indole-3-carboxylate (141 mg, 0.44 mmol) and lithium borohydride (19 mg, 0.88 mmol) were dissolved in THF (2 ml) and 60 ° C. And stirred overnight. Upon completion, the reaction was quenched with 1N HCl. The mixture was extracted with CH ₂ Cl ₂ (3 ×), washed with brine and H ₂ O and dried over Na ₂ SO ₄ . This material was used in the next step without further purification.
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.05 (s, 1H), 8.99 (s, 1H), 8.74 (s, 1H), 8.65 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 4.90 (s, 2H). ESI m / z: 276.8 ([M + H] ⁺ , C ₁₂ H ₉ BrN ₂ O calculated 276.99)

Step 2. 6-Bromo-9H-pyrido [3,4-b] indole-3-carbaldehyde
According to published methods (J. Med. Chem., 1982, 25, 1081), 6-bromo-9H-pyrido [3,4-b] indol-3-yl) methanol (253 mg, 1.27 mmol) and MnO ₂ (300 mg, 3.44 mmol) were combined in acetonitrile (5 ml) and stirred at reflux overnight. The material was cooled to room temperature and filtered through a celite pad. This was rinsed with CH ₃ CN to give the desired aldehyde in 58% yield.
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.36 (s, 1H), 10.11 (s, 1H), 9.10 (s, 1H), 8.90 (s, 1H), 8.73 (s, 1H), 7.75 ( d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H). ESI m / z: 274.8 ([M + H] ⁺ , C ₁₂ H ₇ BrN ₂ O calculated 274.97)

Step 3. 6-Bromo-3-methyl-9H-pyrido [3,4-b] indole (P7C3-S226)
According to published methods (Tetrahedron, 2002, 5251), 6-bromo-9H-pyrido [3,4-b] indole-3-carbaldehyde (40 mg, 0.145 mmol), hydrazine hydrate (51 mg, 1. 02 mmol) and KOH (29 mg, 0.509 mmol) were combined with ethylene glycol (0.5 mL) and heated at 150 ° C. overnight. The reaction was cooled to room temperature. Ice pieces were added and the mixture was stirred in an ice bath for 1 hour. A white precipitate was formed, which was filtered and dried to give the desired compound in 73% yield.
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.59 (s, 1H), 8.77 (s, 1H), 8.42 (s, 1H), 7.97 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 2.58 (s, 3H). ESI m / z: 260.8 ([M + H] ⁺ , C ₁₂ H ₉ BrN ₂ calculated 260.99)

Step 4. P7C3-S190: 1- (6-Bromo-3-methyl-9H-pyrido [3,4-b] indol-9-yl) -3-phenoxypropan-2-ol
According to Representative Method 1, the title compound 1- (6-bromo-3-methyl-9H-pyrido [3,4-b] indol-9-yl) -3-phenoxypropan-2-ol is converted to 6-bromo-3. -Obtained from methyl-9H-pyrido [3,4-b] indole and phenoxymethyloxirane in 78% yield after precipitation from isopropanol.
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.93 (s, 1H), 8.47 (s, 1H), 8.01 (s, 1H), 7.70-7.61 (m, 2H), 7.30 (t, J = 7.7 Hz, 2H), 6.95 (d, J = 7.1 Hz, 3H), 5.47 (s, 1H), 4.63 (d, J = 15.7 Hz, 1H), 4.51 (dd, J = 15.3, 6.7 Hz, 1H), 4.26 (s, 1H), 4.02-3.91 (m, 2H), 2.60 (s, 3H). ESI m / z: 410.8 ([M + H] ⁺ , C ₂₁ H ₁₉ BrN ₂ O ₄ calculated 411.06)

Example 183. P7C3-S191: 6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxamide
6-Bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylic acid (P7C3-S174) (30 mg, 0.068 mmol) was added to CH ₂ Cl ₂ (0.5 mL) was added along with a catalytic amount of DMF. Oxalyl chloride (60 μl, 0.68 mmol) was added and the solution was stirred for 1 hour at room temperature. The reaction was concentrated to remove the solvent and NH ₃ in dioxane was added. When the reaction was complete, the solvent was removed under reduced pressure to give the desired compound in 92% yield.
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.06 (s, 1H), 8.90 (s, 1H), 8.66 (s, 1H), 7.98 (s, 1H), 7.73 (dt, J = 8.8, 5.3 Hz, 2H), 7.34 (s, 1H), 7.33-7.25 (m, 2H), 6.96 (d, J = 8.5 Hz, 3H), 5.41 (s, 1H), 4.73 (dd, J = 15.0, 3.9 Hz , 1H), 4.63 (dd, J = 15.0, 7.4 Hz, 1H), 4.31 (s, 1H), 4.03 (d, J = 5.4 Hz, 2H). ESI m / z: 439.8 ([M + H] ⁺ , C ₂₁ H ₁₈ BrN ₃ O ₃ calculated 440.05)

Example 184. P7C3-S192: 6-Bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carbonitrile Step 1. 6-Bromo-9H- Pyrido [3,4-b] indole-3-carbonitrile (P7C3-S221)
6-Bromo-9H-pyrido [3,4-b] indole-3-carbaldehyde (30 mg, 0.11 mmol) was suspended in 100 μl of THF. Ammonium hydroxide (1 mL) and iodine (31 mg, 0.12 mmol) were added and the mixture was stirred at room temperature for 1 hour. When complete, Na ₂ S ₂ O ₃ (5 ml) was added and extracted three times with diethyl ether. This material was used in the next step without further purification.
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.26 (s, 1H), 9.05 (s, 1H), 8.92 (s, 1H), 8.62 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H). ESI m / z: 271.8 ([M + H] ⁺ , C ₁₂ H ₆ BrN ₃ calculated 271.97)

Step 2. 6-Bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carbonitrile (P7C3-S192)
6-Bromo-9H-pyrido [3,4-b] indole-3-carbonitrile (21.3 mg, 0.785 mmol) was placed in the flask and bubbled with nitrogen. THF was added and the solution was cooled to -78 ° C. Methyl lithium (1.6M in Et ₂ O) (1.1 eq) was added and stirred for 30 minutes. 1,2-Epoxy-3-phenoxypropane (0.011 mL, 0.824 mmol) was added while gradually warming to 45 ° C. Upon completion, the reaction was quenched with 1N HCl and extracted three times with EtOAc. The organic layer was washed with H ₂ O, brine and dried over Na ₂ SO ₄ . The crude mixture was purified by SiO ₂ (0~50% EtOAc / hexanes) in 90% yield of the desired product.
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.24 (s, 1H), 8.94 (s, 1H), 8.66 (s, 1H), 7.86-7.77 (m, 2H), 7.30 (d, J = 3.9 Hz, 2H), 6.95 (d, J = 3.4 Hz, 3H), 5.50 (s, 1H), 4.77 (d, J = 15.1 Hz, 1H), 4.71-4.62 (m, 1H), 4.28 (s, 1H ), 4.01 (s, 2H). ESI m / z: 421.8 ([M + H] ⁺ , C ₂₁ H ₁₈ BrN ₃ O ₃ calculated 422.04)

Example 185. P7C3-S194: 1- (8-bromo-5H-pyrido [3,2-b] indol-5-yl) -3-phenoxypropan-2-ol
The title compound was synthesized according to P7C3-S186.
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.57 (d, 1H, J = 4.5 Hz), 8.51 (d, 1H, J = 1.6 Hz), 7.85 (d, 1H, J = 8.3 Hz), 7.59 (dd , 1H, J = 1.8, 8.7 Hz), 7.48 (d, 1H, J = 8.7 Hz), 7.38-7.31 (m, 1H), 7.31-7.26 (m, 1H), 7.23-7.17 (m, 1H), 7.04 (t, 1H, J = 7.3 Hz), 6.94 (d, 2H, J = 8.0 Hz), 5.50 (m _c , 1H), 4.76 (dd, 1H, J = 6.5, 15.2 Hz), 4.62 (dd, 1H, J = 5.9, 15.2 Hz), 4.07 (dd, 1H, J = 4.8, 10.4 Hz), 3.98 (dd, 1H, J = 3.5, 10.4 Hz). MS (ESI) m / z 398.8 (M + H ] ⁺ ([M + H] ⁺ , C ₂₀ H ₁₈ BrN ₂ O ₂ calculated 398.2)

Example 186. P7C3-S195: 8-bromo-5- (2-hydroxy-3-phenoxypropyl) -5H-pyrido [4,3-b] indole 2-oxide
To a stirring solution of P7C3-S183 (0.029 g, 0.073 mmol) in CHCl ₃ : EtOH (1: 1) (0.072 mL) was added mCPBA (0.057 g, 0.252 mmol). The mixture was stirred at reflux for 30 minutes. The cooled reaction was treated with 2M NaOH and the mixture was stirred for 30 minutes at room temperature. The aqueous layer was extracted with CH ₂ Cl ₂ and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude mixture chromatographed _{(SiO 2, 0~10% MeOH /} CH 2 Cl 2) to give the title compound (0.029g, 90%).
¹ H NMR (CDCl ₃ -MeOD [4: 2], 500 MHz) δ 8.82 (s, 1H), 8.12 (d, 1H, J = 1.5 Hz), 8.09 (d, 1H, J = 6.9 Hz), 7.55 (dd, 1H, J = 1.7, 8.8 Hz), 7.52 (d, 1H, J = 7.1 Hz), 7.41 (d, 1H, J = 8.8 Hz), 7.26-7.21 (m, 2H), 6.93 (t, 1H, J = 7.3 Hz), 6.85 (d, 2H, J = 8.1 Hz), 4.57 (dd, 1H, J = 3.9, 15.1 Hz), 4.41 (dd, 1H, J = 6.7, 15.1 Hz), 4.21 ( m _c , 1H), 3.93 (dd, 1H, J = 4.3, 9.5 Hz), 3.86 (dd, 1H, J = 7.0, 9.5 Hz). MS (ESI) m / z 414.8 [M + H] ⁺ ([ M + H] ⁺ , C ₂₀ H ₁₈ BrN ₂ O ₃ calculated 414.2)

Example 187. P7C3-S198: 8-Bromo-5- (2-hydroxy-3-phenoxypropyl) -5H-pyrido [3,2-b] indole 1-oxide
P7C3-S198 was synthesized according to P7C3-S195 except that P7C3-S194 was used and was isolated in 53% yield.
¹ H NMR (CDCl ₃ -MeOD [4: 2], 500 MHz) δ 8.68 (s, 1H), 7.99 (s, 1H), 7.57 (m _c , 1H), 7.48 (d, 1H, J = 8.7 Hz ), 7.35 (d, 1H, J = 8.7 Hz), 7.18 (m _c , 1H), 7.14 (t, 2H, J = 7.6 Hz), 6.82 (t, 1H, J = 7.1 Hz), 6.76 (d, 2H, J = 8.4 Hz), 4.51 (dd, 1H, J = 3.7, 15.1 Hz), 4.35 (dd, 1H, J = 6.5, 15.1 Hz), 4.24 (m _c , 1H), 3.86-3.74 (m, 2H). MS (ESI) m / z 412.8 [MH] ^- ([MH] ^- , C ₂₀ H ₁₈ BrN ₂ O ₃ calculated 412.2)

Example 188. P7C3-S204: (6-Bromo-9H-pyrido [3,4-b] indol-3-yl) methanol
The title compound was an intermediate in the synthesis of P7C3-S190.

Example 189. P7C3-S205: Ethyl 6-bromo-9H-pyrido [3,4-b] indole-3-carboxylate
The title compound was an intermediate in the synthesis of P7C3-S173.

Example 190. P7C3-S208: tert-butyl (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) carbamate Step 1. 1-azido-3- (3,6- Dibromo-9H-carbazol-9-yl) propan-2-ol
3,6-Dibromo-9- (oxiran-2-ylmethyl) -9H-carbazole (500 mg, 1.3 mmol), NaN ₃ (111 mg, 1.7 mmol), NH ₄ Cl (91 mg, 1.7 mmol) were added to EtOH ( 4 ml) and H ₂ O (1 ml) and heated at 80 ° C. overnight. Upon completion, evaporate the EtOH, the mixture was partitioned between EtOAc and _{H 2} O. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. This material was used in the next step without further purification.
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.14 (s, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 4.35 (d, J = 5.9 Hz , 1H), 4.25 (dd, J = 9.9, 4.9 Hz, 1H), 3.49 (dt, J = 12.4, 4.5 Hz, 1H), 3.38-3.30 (m, 1H), 2.15 (s, 1H). ESI m / z: 466.7 ([M + HCOO] ^- , C ₁₂ H ₇ BrN ₂ O ₂ calculated 424.1)

Step 2. 9- (3-Azido-2-fluoropropyl) -3,6-dibromo-9H-carbazo
Synthesized according to representative method 4 except that 1-azido-3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol was used.
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.15 (s, 2H), 7.59 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 5.08-4.90 (m, 1H) , 4.55 (dt, J = 9.5, 5.1 Hz, 2H), 3.62-3.52 (m, 1H), 3.39 (ddd, J = 24.1, 13.7, 4.7 Hz, 1H). ESI m / z: 469.6 ([M + HCOO] ^- , C ₂₀ H ₁₁ Br ₂ FN ₄ Calculated 423.94)

Step 3. 3- (3,6-Dibromo-9H-carbazol-9-yl) -2-fluoropropan-1-amine
9- (3-azido-2-fluoropropyl) -3,6-dibromo-9H-carbazole (60 mg, 0.14 mmol) and triphenylphosphine (44 mg, 0.168 mmol) were combined with THF (0.5 mL), Stir overnight at 60 ° C. When complete, H ₂ O (1 ml) was added and the mixture was stirred for 1 hour. The mixture was extracted with EtOAc. The organic layer was washed with H ₂ O, brine, dried over Na ₂ SO ₄ and concentrated to give a white foam. This material was used in the next step without further purification.
¹ H NMR (500 MHz, MeOH-d ₄ ) δ 8.29 (s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.53 (s, 1H), 5.16 (d, J = 50.4 Hz, 1H) , 4.73 (dd, J = 23.1, 5.3 Hz, 1H), 3.43 (d, J = 14.2 Hz, 1H), 3.24-3.11 (m, 1H). ESI m / z: 398.7 ([M + H] ⁺ , (C ₁₅ H ₁₃ Br ₂ FN ₂ calculated 398.94)

Step 4. P7C3-S208: tert-butyl (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) carbamate
3- (3,6-Dibromo-9H-carbazol-9-yl) -2-fluoropropan-1-amine (21 mg, 0.0524 mmol) was dissolved in THF (500 μl) and cooled to 0 ° C. Boc anhydride (12.6 mg, 0.0576 mmol) was dissolved in THF and added dropwise. The reaction was stirred overnight at room temperature. Upon completion, the substance was concentrated to remove excess THF, and partitioned between EtOAc and _{H 2} O. The organic layer was washed with brine and dried over Na ₂ SO ₄ . The crude mixture was purified by SiO ₂ (0~50% EtOAc / hexanes), was obtained in 42% yield of the desired product.
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.15 (s, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 4.94 (d, J = 57.3 Hz , 2H), 4.59-4.39 (m, 2H), 3.68-3.52 (m, 1H), 3.30 (ddd, J = 21.4, 13.4, 6.2 Hz, 1H), 1.46 (s, 9H). ESI m / z: 498.8 ([M + H] ⁺ , C ₂₀ H ₂₁ Br ₂ FN ₂ O ₂ calculated 499.0)

Example 191. P7C3-S213: 2- (3,6-dibromo-9H-carbazol-9-yl) acetamide
Ethyl 2- (3,6-dibromo-9H-carbazol-9-yl) acetate (P7C3-S164) (10 mg, 0.024 mmol) and ammonium hydroxide (100 μl) were stirred at 60 ° C. overnight. Upon completion, the reaction was filtered and rinsed with H ₂ O to give the desired product in quantitative yield.
¹ H NMR (500 MHz, acetone-d ₆ ) δ 8.40 (d, J = 1.9 Hz, 2H), 7.61 (dd, J = 8.7, 1.9 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H) , 7.07 (s, 1H), 6.64 (s, 1H), 5.08 (s, 2H). ESI m / z: 424.7 ([M + HCOO] ^- , C ₁₄ H ₁₀ Br ₂ FN ₂ O calculated 378.92)

Example 192 P7C3-S214: 2- (3,6-dibromo-9H-carbazol-9-yl) -N-methylacetamide
2- (3,6-Dibromo-9H-carbazol-9-yl) acetic acid (P7C3-S165) (50 mg, 0.13 mmol) was added to dichloromethane (1 ml). Methylamine (2.0 M in THF) (0.144 mmol) was added followed by a catalytic amount of dimethylaminopyridine. The mixture was cooled to 0 ° C. in an ice bath and a solution of dicyclohexylcarbodiimide (1 ml) in dichloromethane was added dropwise. The mixture was stirred overnight at room temperature. Upon completion, the DCM mixture was washed with H ₂ O, brine, dried over Na ₂ SO ₄ and concentrated. The crude mixture was purified on SiO ₂ (0-50% EtOAc / hexane) followed by precipitation from MeOH / H ₂ O to give the desired product in 42% yield.
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.19 (s, 2H), 7.61 (d, J = 8.6 Hz, 2H), 7.23 (s, 2H), 5.37 (s, 1H), 4.89 (s, 2H) , 2.72 (d, J = 4.9 Hz, 3H). ESI m / z: 439.7 ([M + HCOO] ^- , C ₁₅ H ₁₂ Br ₂ N ₂ O calculated 392.93)

Example 193. P7C3-S215: 2- (3,6-Dibromo-9H-carbazol-9-yl) -N, N-dimethylacetamide
Synthesized according to P7C3-S214 except that dimethylamine was used.
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.15 (s, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H), 5.01 (s, 2H), 3.09 (s, 3H), 2.99 (s, 3H). ESI m / z: 452.6 ([M + HCOO] ^- , C ₁₆ H ₁₄ Br ₂ N ₂ O calculated 406.95)

Example 194. P7C3-S217: 3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropan-1-amine hydrochloride
The free base P7C3-S217 was an intermediate in the synthesis of P7C3-S208. The HCl salt was formed by adding 1M HCl at 0 ° C. to a CH ₂ Cl ₂ solution of the free base. The white solid was collected by filtration and washed with CH ₂ Cl ₂ .

Example 195. P7C3-S218: N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) acetamide
3- (3,6-Dibromo-9H-carbazol-9-yl) -2-fluoropropan-1-amine hydrochloride (P7C3-S217) (25 mg, 0.057 mmol) in dichloromethane (2 mL) and triethylamine (12 mg, 0.12 mmol). The solution was cooled to 0 ° C. and acetyl chloride (4.49 mg, 0.057 mmol) was added. The desired product precipitated out of solution and the reaction was complete within 10 minutes. The precipitate was filtered, rinsed with H ₂ O and dried under reduced pressure.
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.15 (d, J = 1.7 Hz, 2H), 7.57 (dd, J = 8.7, 1.8 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 5.75 (s, 1H), 4.98 (dddd, J = 13.1, 9.5, 6.6, 2.6 Hz, 1H), 4.58-4.41 (m, 2H), 3.83 (dddd, J = 29.0, 14.6, 6.9, 2.6 Hz, 1H) , 3.36-3.23 (m, 1H), 2.03 (s, 3H). ESI m / z: 440.7 ([M + H] ⁺ , C ₁₇ H ₁₅ Br ₂ FN ₂ O calculated 440.95)

Example 196. P7C3-S219: N- (5- (3-((3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) amino) phenoxy) pentyl) -5- (2-Oxohexahydro-1H-thieno [3,4-d] imidazol-4-yl) pentanamide
The title compound was used and synthesized according to biotin N-succinimidyl ester P7C3-S100. The mixture was chromatographed _{5~10% MeOH / CH 2 Cl 2} . Isolation yield = 37%.
MS (ESI), m / z: Calculated value 799.1, Actual value 799.7 (M + 1) ⁺

Example 197. P7C3-S220: 2- (3,6-dibromo-9H-carbazol-9-yl) propanamide
The title compound was prepared according to P7C3-S213.
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.18 (s, 2H), 7.58 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 5.58 (s, 1H), 5.42 (s, 1H), 5.27 (q, J = 7.1 Hz, 1H), 1.74 (d, J = 7.1 Hz, 3H). ESI m / z: 394.7 ([M + H] ⁺ , C ₁₅ H ₁₂ Br ₂ (N ₂ O calculated 394.93)

Example 198. P7C3-S221: 6-Bromo-9H-pyrido [3,4-b] indole-3-carbonitrile
The title compound was an intermediate in the synthesis of P7C3-S192.

Example 199. P7C3-S226: 6-Bromo-3-methyl-9H-pyrido [3,4-b] indole
The title compound was an intermediate in the synthesis of P7C3-S190.

Example 200. P7C3-S233: 9-((1H-tetrazol-5-yl) methyl) -3,6-dibromo-9H-carbazole
According to published methods (JOC, 1993, 4139-4141), 2- (3,6-dibromo-9H-carbazol-9-yl) acetonitrile (P7C3-S235) (75 mg, 0.123 mmol) and azidotrimethylsilane ( A solution of 32 μl, 0.24 mmol) in toluene (500 μL) was added to dibutyltin oxide (3 mg, 0.012 mmol) and heated to reflux overnight. The reaction was cooled to room temperature, concentrated to remove toluene, and partitioned between EtOAc and 10% NaHCO _{3 (aq)} . The aqueous layers were combined, acidified to pH 2 and extracted with EtOAc (2x). The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude material was purified by SiO ₂ (0~50% EtOAc / hexanes).
¹ H NMR (500 MHz, acetone-d ₆ ) δ 8.43 (s, 2H), 7.69 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 6.11 (s, 2H) ESI m / z: 403.5 ([MH] ⁺ , C ₁₄ H ₉ Br ₂ N ₅ calculated 403.92)

Example 201. P7C3-S234: methyl (2- (3,6-dibromo-9H-carbazol-9-yl) acetyl) carbamate
According to published methods (PCT International Application 2011054851), 2- (3,6-Dibromo-9H-carbazol-9-yl) acetamide (P7C3-S213) (50 mg, 0.13 mmol) was dissolved in THF (1 ml). And cooled to 0 ° C. Methyl chloroformate (12 μL, 0.157 mmol) was added followed by the slow addition of LiO ^t Bu (25 mg, 0.31 mmol) in THF (1 ml). Upon completion, the mixture was partitioned between 2N HCl and EtOAc. Addition of EtOAc formed a precipitate that was filtered, rinsed with H ₂ O and hexane, and dried under reduced pressure.
¹ H NMR (500 MHz, THF-d8) δ 12.71 (s, 1H), 10.14 (s, 2H), 9.36 (d, J = 8.7 Hz, 2H), 9.22 (d, J = 8.7 Hz, 2H), 7.45 (s, 2H), 5.66 (s, 3H). ESI m / z: 436.6 ([MH] ⁺ , C ₁₆ H ₁₂ Br ₂ N ₂ O ₃ calculated 436.92)

Example 202. P7C3-S241: N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -1,1,1-trifluoro-N- (3-methoxy Phenyl) methanesulfonamide
P7C3-S244 was fluorinated according to representative method 4 to give the title compound.
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.15 (d, J = 1.9 Hz, 2H), 7.56 (dd, J = 8.7, 1.9 Hz, 2H), 7.32 (t, J = 8.2 Hz, 1H), 7.21 (d, J = 8.6 Hz, 2H), 6.99-6.90 (m, 2H), 6.86 (m, 1H), 5.08-4.86 (dm, 1H), 4.57-4.44 (m, 2H), 4.09 (m, 2H ), 3.79 (s, 3H) .MS (ESI), m / z: Calculated value 635.93, measured value 680.6 (M + HCOO ^- ) ^-

Example 203. P7C3-S243: N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -6-methoxypyridin-2-amine
2- (Dicyclohexylphosphino) -3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl (BrettPhos, 35.6 mg, 0.066 mmol) and chloro [2 -(Dicyclohexylphosphino) -3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl] [2- (2-aminoethyl) phenyl] palladium (II) (52.8 mg, 0.066 mmol) was placed in a vial containing P7C3-S217 free amine (116.8 mg, 0.29 mmol). The vial was bubbled with nitrogen for 10 minutes and 1,4-dioxane (4.75 ml) was added followed by lithium bis (trimethylsilyl) amide solution (1.0 M solution in THF, 610 μl). The reaction was heated at 100 ° C. for 5.5 hours. The mixture was cooled and centrifuged to separate the solid. The filtrate was loaded directly onto a silica gel column and purified with 80% DCM / hexane (+ 0.1% TEA). The highest purity fraction (80-90% purity) was treated with DCM / hexane and the solid pellet contained the desired product.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.16 (d, J = 1.9 Hz, 2H), 7.56 (d, J = 1.9 Hz, 2H), 7.35- (t, J = 7.8 Hz, 1H), 7.30 ( d, J = 8.7 Hz, 1H), 6.04 (dd, J = 32.7, 8.0 Hz, 2H), 5.29-5.02 (dm, 1H), 4.65-4.46 (m, 3H), 3.87-3.74 (m, 1H) , 3.70 (s, 3H), 3.66-3.49 (m, 1H) .MS (ESI), m / z: Calculated value 504.98, Actual value 506.7 (M + 1)

Example 204. P7C3-S244: N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -1,1,1-trifluoro-N- (3-methoxy Phenyl) methanesulfonamide Step 1. 1,1,1-trifluoro-N- (3-methoxyphenyl) methanesulfonamide
To a solution of trifluoromethanesulfone anhydride (45 ml, 26.7 mmol) in methylene chloride (250 ml) was added ice-cooled m-anisidine (25 ml, 22.3 mmol) and triethylamine (39 ml, 28.0 mmol) in methylene chloride (1.25 L). ) The solution was added dropwise. The reaction was stirred overnight at ambient temperature. The post-treatment was performed little by little. Each of the two parts was basified by the addition of 2.5N NaOH solution (250 ml) and MeOH (625 ml). The aqueous layer was extracted three times with methylene chloride (100 ml each). The aqueous layers were combined, acidified with 18% HCl to pH 2, and extracted again with methylene chloride three times. The organic layer is dried over MgSO ₄ , filtered and concentrated to give 17.69 g of a brown solid in 77% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.48-7.13 (m, 1H), 6.97-6.61 (m, 3H), 3.82 (s, 3H). MS (ESI), m / z: calculated value 255.21, measured Value 255.9 (M + 1) ⁺

Step 2. N- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -1,1,1-trifluoro-N- (3-methoxyphenyl) methanesulfonamide (P7C3-S244)
1,1,1-trifluoro-N- (3-methoxyphenyl) methanesulfonamide (22.07 g, 86.5 mmol) in N-butyllithium (2.5 M in hexane, 48 ml) in ice-cold ( 145 ml) solution was added dropwise over 40 minutes. The solution was stirred at ambient temperature for 15 minutes and 3,6-dibromo-9- (oxiran-2-ylmethyl) -9H-carbazole (25.05 g, 65.7 mmol) was added and heated at 90 ° C. for 1 hour. The reaction was cooled and diluted with ethyl acetate (1.2 L) and washed several times with water and finally with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated to give an orange viscous mixture. The residue was dissolved in 60% methylene chloride / hexane (150 ml) and concentrated to give a yellow foam, to which was further added 60% methylene chloride / hexane (150 ml) and stirred overnight. The mixture was filtered and washed several times with 60% methylene chloride / hexanes until the solid was white to give 20.1 g of 99%.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.13 (d, J = 1.9 Hz, 2H), 7.54 (dd, J = 8.7, 1.9 Hz, 2H), 7.33 (t, J = 8.1 Hz, 1H), 7.22 (d, J = 8.7 Hz, 2H), 6.95 (dd, J = 8.4, 2.3 Hz, 2H), 6.88 (s, 1H), 4.56-4.10 (m, 4H), 3.99 (m, 1H), 3.81 ( s, 3H), 1.98 (d, J = 4.2 Hz, 1H) .MS (ESI), m / z: Calculated value 633.94, measured value 678.6 (M + HCOO) ^-

Example 205. P7C3-S255: 1- (3,6-dibromo-9H-carbazol-9-yl) -3-((4-methoxybenzyl) (3-methoxyphenyl) amino) propan-2-ol
P7C3-S255 was synthesized according to P7C3-S244 using representative method 3 and 3-methoxy-N- (4-methoxybenzyl) aniline. Yield = 31%
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.07 (d, J = 2.0 Hz, 2H), 7.50 (dd, J = 8.7, 2.0 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.12 -7.04 (m, 3H), 6.81 (d, J = 8.6 Hz, 2H), 6.36 (ddd, J = 12.7, 8.1, 2.4 Hz, 2H), 6.28 (t, J = 2.4 Hz, 1H), 4.48 ( d, J = 2.7 Hz, 2H), 4.35-4.27 (m, 1H), 4.28-4.10 (m, 2H), 3.78 (s, 3H), 3.65 (s, 3H), 3.54-3.34 (m, 2H) , 2.22 (s, 1H) .MS (ESI), m / z: Calculated value 622.05, Actual value 666.7 (M + HCOO) ^-

Example 206. P7C3-S261: N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -2,2,2-trifluoroacetamide
TFAA (78 μL, 0.5526 mmol) was added to 1-amino-3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol (100 mg, 0.2518 mmol) and pyridine (61 μL, 0.7536 mmol). ) In DCM (1.7 mL). After 30 minutes, TLC showed complete consumption of starting material. The reaction mixture was separated using NaHCO ₃ . The aqueous layer was washed with DCM. The combined organic layers were dried and concentrated to give the crude material as a tan solid. The crude material was dissolved in hot CHCl ₃ and triturated with hexane. 50.6 mg (40.8% yield) of clear product was collected by suction filtration.
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.16 (d, J = 1.7 Hz, 2H), 7.59 (dd, J = 8.7, 1.8 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 6.71 (s, 1H), 4.41-4.28 (m, 2H), 3.79 (dd, J = 13.1, 6.7 Hz, 1H), 3.49 (s, 1H), 3.46-3.39 (m, 1H). MS (ESI) m / z = 492.6 ([M + H] ⁺ , C17H13Br ₂ F3N ₂ O ₂ calculated 499.13)

Example 207. P7C3-S263: tert-butyl (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) carbamate
Boc anhydride (82.4 mg, 0.3777 mmol) was added to 1-amino-3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol (100 mg, 0.2518 mmol) and triethylamine (70 μL). , 5036 mmol) in DCM (1.7 mL). The reaction was stirred overnight at room temperature. The reaction mixture was separated with brine and the aqueous layer was washed twice with DCM. The combined organic layers were dried and concentrated to give the crude material as an off-white solid. This was subjected to column chromatography using DCM / MeOH to give 4.6 mg (3.7% yield) product as a white solid.
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.14 (d, J = 1.9 Hz, 3H), 7.56 (dd, J = 8.6, 1.9 Hz, 3H), 7.34 (d, J = 8.7 Hz, 3H), 4.86 (s, 1H), 4.31 (d, J = 6.2 Hz, 3H), 3.40-3.25 (m, 1H), 3.09-2.97 (m, 1H), 1.45 (s, 13H), 3.25-3.09 (m, 2H ). MS (ESI) m / z = 440.7 ([M-Boc] ⁺ , C ₂₀ H ₂₂ Br ₂ N ₂ O ₃ calculated 496.00

Example 208. P7C3-S271: 5- (2-hydroxy-3-phenoxypropyl) -5H-pyrimido [5,4-b] indole-2-carboxylic acid
The title compound was synthesized according to Representative Method 7 from P7C3-S262 (0.028 g, 0.117 mmol) and 2- (phenoxymethyl) oxirane (24 μL, 0.175 mmol) (0.030 g, 70%).
¹ H NMR (CDCl ₃ -MeOD [4: 2], 500 MHz) δ 9.02 (s, 1H), 8.35 (d, 1H, J = 7.9 Hz), 7.49 (d, 2H, J = 3.7 Hz), 7.22 (dt, 1H, J = 4.0, 7.9 Hz), 7.08 (t, 2H, J = 8.0 Hz), 6.77 (t, 1H, J = 7.4 Hz), 6.72 (d, 2H, J = 8.0 Hz), 4.59 (dd, 1H, J = 4.4, 15.1 Hz), 4.45 (dd, 1H, J = 6.5, 15.1 Hz), 4.25 (m _c , 1H), 3.81 (dd, 1H, J = 4.4, 9.5 Hz), 3.76 (dd, 1H, J = 6.5, 9.5 Hz). MS (ESI) m / z 363.9 [M + H] ⁺ ([M + H] ⁺ , C ₂₀ H ₁₈ N ₃ O ₄ calculated 364.4)

Example 209. P7C3-S273: N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) acetamide
A solution of acetic anhydride (29 μL, 0.302 mmol) in DCM (0.7 mL) was added to 1-amino-3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol (100 mg, 0.3 mL). 2518 mmol) and triethylamine (42 μL, 0.3022 mmol) in DCM (1 mL) was added at 0 ° C. After stirring overnight, the reaction mixture was diluted with DCM and washed with 18% HCl, brine and NaHCO ₃ . The organic layer was dried and concentrated to give the crude material as a pink-light solid. Preparative TLC using 5% MeOH / DCM as the eluent gave 6.5 mg (5.9% yield) of product as a white solid.
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.15 (d, J = 2.5 Hz, 2H), 7.59-7.54 (m, 2H), 7.34 (dd, J = 8.9, 4.2 Hz, 2H), 5.77 (s, 1H), 4.31 (q, J = 5.5, 4.3 Hz, 2H), 4.26 (s, 2H), 3.57 (d, J = 3.8 Hz, 1H), 3.46-3.26 (m, 3H), 2.01 (d, J = 4.3 Hz, 3H). MS (ESI) m / z = 438.7 ([M + H] ⁺ , C17H ₁₆ Br ₂ N ₂ O ₂ calculated 437.96

Example 210. P7C3-S274: ethyl (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) carbamate
The title compound was prepared according to P7C3-S218. The crude material was chromatographed using 5% MeOH / DCM as eluent. 24.5 mg (20.7% yield) of product was obtained as a white solid.
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.15 (s, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.33 (dd, J = 8.6, 1.6 Hz, 2H), 4.98 (s, 1H) , 4.31 (d, 2H), 4.26 (s, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.45-3.36 (m, 1H), 3.29-3.17 (m, 1H), 3.01 (s, 1H ), 1.26 (t, J = 7.9, 3.7 Hz, 3H) .MS (ESI) m / z = 468.7 ([M + H] ⁺ , C18H ₁₈ Br ₂ N ₂ O ₃ calculated 467.97

Example 211. P7C3-S278: 6-bromo-9- (3- (4-bromophenoxy) -2-hydroxypropyl) -9H-carbazole-3-carbonitrile Step 1. 9H-carbazole-3-carbonitrile
3-Bromo-9H-carbazole (4.00 g, 16.3 mmol, 1 eq) in N-methyl-2-pyrrolidinone (40 mL) was added to copper (I) cyanide (1.6012 g, 17.9 mmol, 1.1). Equivalent) was added. The mixture was sealed and heated at 200 ° C. until TLC showed no starting material. The reaction solution was cooled and water (60 mL) was added. The off-white precipitate was filtered off and washed with EtOAc (3 × 20 mL). The filtrate was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL) and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give a red-brown oil. Methanol was added to the crude oil to give 0.8251 g of an off-white precipitate as a pure product. The mother liquor from the methanol precipitate was concentrated and purified by chromatography (25% EtOAc / Hex) to give 0.28 g of an off-white solid. The combined yield was 35.5%.
¹ H NMR (CD ₃ OD, 400 MHz) δ ppm 7.26 (ddd, J = 8.0, 6.9, 1.3 Hz, 1H) 7.54-7.45 (m, 2H) 7.57 (dd, J = 8.4, 0.6 Hz, 1H) 7.67 (dd, J = 8.5, 1.6 Hz, 1H) 8.18-8.12 (m, 1H) 8.49 (dd, J = 1.5, 0.6 Hz, 1H). MS (ESI) m / z = 192.9 ([M + H] ⁺ ), C ₁₃ H ₈ N ₂ Calculated 192.07

Step 2. 9- (2-Hydroxy-3-phenoxypropyl) -9H-carbazole-3-carbonitrile
To a solution of 3-cyano-9H-carbazole (0.4998 g, 2.6 mmol, 1 eq) in THF (40 mL) was added ⁿ BuLi (1.6 M in hexane, 3.25 mL, 5.2 mmol, 2 eq). . The mixture was stirred at -78 ° C for 2 hours. 1,2-Epoxy-3-phenoxypropane (0.7809 g, 5.2 mmol, 2 eq) was added and the mixture was stirred at 45 ° C. overnight. Water (50 mL) was added and the mixture was extracted with dichloromethane (3 × 30 mL). The combined dichloromethane layers were washed with brine (2 × 30 mL) and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the product was chromatographed on silica gel with dichloromethane to give 0.77736 g of a white foamy solid (86%).
¹ H NMR (CD ₃ OD, 400 MHz) δ ppm 3.95 (dd, J = 9.8, 4.6 Hz, 1H) 4.02 (dd, J = 9.8, 5.4 Hz, 1H) 4.46-4.35 (m, 1H) 4.57 (dd , J = 15.0, 6.9 Hz, 1H) 4.70 (dd, J = 15.2, 5.0 Hz, 1H) 7.00-6.88 (m, 3H) 7.34-7.21 (m, 3H) 7.49 (t, J = 7.8 Hz, 1H) 7.65 (d, J = 8.3 Hz, 2H) 7.72 (d, J = 8.5 Hz, 1H) 8.17 (d, J = 7.8 Hz, 1H) 8.49 (s, 1H). MS (ESI) m / z = 342.9 ( [M + H] ⁺ ), 364.9 ([M + Na] ⁺ ), C ₂₂ H ₁₈ N ₂ O ₂ calculated 342.14

Step 3. 6-Bromo-9- (3- (4-bromophenoxy) -2-hydroxypropyl) -9H-carbazole-3-carbonitrile (P7C3-S278)
To a solution of the product of step 2 (0.7736 g, 2.26 mmol, 1 eq) in THF (8 mL) was added N-bromosuccinimide (0.8043 g, 4.52 mmol, 2 eq). The mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and the crude residue was purified by silica gel chromatography (30% ethyl acetate in hexane) to give 1.0230 g of white solid as product in 90.5% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ ppm 3.88 (dd, J = 9.5, 4.7 Hz, 1H) 3.99 (dd, J = 9.5, 4.7 Hz, 1H) 4.69-4.38 (m, 3H) 6.81-6.70 ( m, 2H) 7.44-7.35 (m, 3H) 7.54 (t, J = 6.5 Hz, 1H) 7.59 (dd, J = 8.7, 1.9 Hz, 1H) 7.66 (d, J = 8.6 Hz, 1H) 8.20 (d , J = 1.3 Hz, 1H) 8.31 (s, 1H) .MS (ESI) m / z = 498.7 ([M + H] ⁺ ), C ₂₂ H ₁₉ Br ₂ N ₃ O ₂ Calculated 497.96

Example 212. P7C3-S279: methyl 9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylate
To a solution of P7C3-S172 (10.9 mg, 0.03 mmol, 1 eq) in DMF (0.5 mL) was added iodomethane (6.4 mg, 0.045 mmol, 1.5 eq) and potassium carbonate (12.4 mg, 0.5 eq). 09 mmol, 3 eq) was added. The mixture was sealed and stirred overnight at room temperature in 4 mL vials. The crude reaction was diluted with dichloromethane (3 mL) and washed with brine (3 × 3 mL). The organic layer was dried over Na ₂ SO ₄ and dichloromethane was removed under reduced pressure to give a yellow crude oil. This was further purified by silica gel chromatography using 10% dichloromethane in methanol as eluent to give 8.6 mg of white solid as product in 82.0% yield.
¹ H NMR (CDCl ₃ , 400 MHz) δ ppm 3.64 (s, 3H) 4.14 (ddd, J = 15.8, 9.3, 5.6 Hz, 2H) 4.58 (dd, J = 14.6, 7.3 Hz, 1H) 4.68 (d, J = 4.4 Hz, 1H) 4.76 (dd, J = 14.6, 3.3 Hz, 1H) 6.98 (dd, J = 13.9, 7.6 Hz, 3H) 7.31 (dd, J = 8.5, 7.5 Hz, 2H) 7.36 (td, J = 7.5, 3.4 Hz, 1H) 7.62 (d, J = 3.7 Hz, 2H) 8.14 (d, J = 7.8 Hz, 1H) 8.57 (s, 1H) 9.00 (s, 1H). MS (ESI) m / z = 377.1 ([M + H] ⁺ ), C ₂₂ H ₂₀ N ₂ O ₄ Calculated 376.14

Example 213. P7C3-S282: 1- (3,6-dimethoxy-9H-carbazol-9-yl) -3-phenoxypropan-2-ol
According to representative method 7, the title compound was prepared from 3,6-dimethoxy-9H-carbazole (Hsieh, BB; Litt, MH Macromolecules, 1986, 19, 516-520) (0.030 g, 0.01717 mmol) and 2- (phenoxy Synthesized from a solution of methyl) oxirane (19 μL, 0.128 mmol) in dry THF: DMF (1: 1) (0.459 mL) (0.028 g, 81%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.51 (s, 2H), 7.35 (d, 2H, J = 8.6 Hz), 7.29 (d, 2H, J = 8.6 Hz), 7.05 (dd, 2H, J = 2.4, 8.8 Hz), 6.98 (t, 1H, J = 7.4 Hz), 6.88 (d, 2H, J = 7.9 Hz), 4.52 (m _c , 1H), 4.46 (m _c , 2H), 4.00-3.85 ( m, 8H). MS (ESI) m / z 378.2 [M + H] ⁺ ([M + H] ⁺ , C ₂₃ H ₂₄ NO ₄ calculated 378.4)

Example 214. P7C3-S283: 2-chloro-N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) acetamide
P7C3-S38 (0.134 g, 0.337 mmol) was dissolved in CH ₂ Cl _{2 /} MeCN (9: 1, 5.6 mL) and treated with Et ₃ N (70 μL, 0.50 mmol) at 0 ° C. Chloroacetyl chloride (29 μL, 0.370 mmol) was added dropwise. After stirring at room temperature for 45 minutes, the reaction was quenched with 1N HCl solution. The organic layer was separated, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude mixture chromatographed _(SiO 2, 0-80% EtOAc / hexanes) to give the title compound (0.091 g, 60%).
¹ H NMR (acetone-d ₆ , 400 MHz) δ 8.36 (s, 2H), 7.74-7.51 (m, 4H), 4.65 (d, 1H, J = 4.7 Hz), 4.49 (dd, 1H, J = 3.4 , 15.0 Hz), 4.41 (dd, 1H, J = 8.3, 15.0 Hz), 4.29 (m _c , 1H), 4.13 (s, 2H), 3.63-3.50 (m, 1H), 3.43 (dt, 1H, J = 5.7, 12.8 Hz). MS (ESI) m / z 474.6 [M + H] ⁺ ([M + H] ⁺ , C ₁₇ H ₁₆ Br ₂ ClN ₂ O ₂ calculated 475.5)

Example 215. P7C3-S284: 2-chloro-N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) acetamide
According to the reported method (Metro, TX; Pardo, DG; Cossy, JJ Org. Chem. 2008, 73, 707-710), P7C3-S283 (0.091 g, 0.192 mmol) in iPrOH (7.7 mL) Dissolved and treated at 0 ° C with a solution of tBuOK (0.054 g, 0.48 mmol) in iPrOH (1.9 mL). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with 1N HCl and concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude mixture was purified by chromatography _(SiO 2, EtOAc), to give the title compound (0.060g, 72%).
¹ H NMR (d ₆ -DMSO, 400 MHz) δ 8.47 (d, 2H, J = 1.9 Hz), 7.67 (d, 2H, J = 8.7 Hz), 7.60 (dd, 2H, J = 1.9, 8.7 Hz) , 4.55 (d, 2H, J = 5.5 Hz), 4.10 (m _c , 1H), 3.98-3.77 (m, 2H), 3.18 (t, 2H, J = 11.3 Hz). MS (ESI) m / z 438.6 [M + H] ⁺ ([M + H] ⁺ , C ₁₇ H ₁₄ Br ₂ N ₂ O ₂ calculated 439.1), 460.6 [M + Na] ⁺ ([M + Na] ⁺ , C ₁₇ H ₁₃ Br ₂ (N ₂ NaO ₂ calculated 460.1)

Example 216. P7C3-S287: 2- (3-bromo-6-methyl-9H-carbazol-9-yl) -N- (phenylsulfonyl) acetamide
The title compound was prepared according to P7C3-S232. Column chromatography (1: 4 THF: hexane) gave 86.7 mg (35.5% yield) of product as a white solid.
¹ H NMR (400 MHz, acetone-d ₆ ) δ 8.23 (d, J = 1.9 Hz, 1H), 7.97 (d, J = 1.1 Hz, 1H), 7.95 (d, J = 1.5 Hz, 1H), 7.94 (s, 1H), 7.65-7.60 (m, 1H), 7.56-7.50 (m, 2H), 7.45 (dd, J = 8.7, 2.0 Hz, 1H), 7.34-7.28 (m, 1H), 7.26 (d , J = 0.7 Hz, 1H), 7.24 (dd, J = 8.4, 1.6 Hz, 1H), 5.12 (s, 2H), 2.47 (s, 3H). MS (ESI) m / z = 457.0 ([M + H] ⁺ , C ₂₁ H ₁₇ BrN ₂ O ₃ S calculated 456.01)

Example 217. P7C3-S288: 2- (3-Bromo-6-methyl-9H-carbazol-9-yl) acetamide
The title compound was prepared according to P7C3-S213.
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19 (d, J = 1.9 Hz, 1H), 7.86 (s, 1H), 7.57 (dd, J = 8.6, 1.9 Hz, 1H), 7.36 (dd, J = 8.3, 1.6 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.24 (s, 1H), 5.34 (d, J = 31.8 Hz, 2H), 4.88 (s, 2H), 2.54 (s, 3H). MS (ESI) m / z = 317.0 ([M + H] ⁺ , C ₁₅ H13BrN ₂ O calculated 316.02)

Example 218. P7C3-S294: 2- (3-Bromo-6-methyl-9H-carbazol-9-yl) ethanol
The title compound was prepared according to P7C3-S171.
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.17 (d, J = 1.9 Hz, 1H), 7.84 (s, 1H), 7.52 (dd, J = 8.6, 2.0 Hz, 1H), 7.38-7.28 (m, 3H), 4.44 (t, J = 5.4 Hz, 2H), 4.05 (q, J = 5.5 Hz, 2H), 2.53 (s, 3H), 1.47 (t, J = 6.0 Hz, 1H)
MS (APCI) m / z = 304.0 ([M + H] ⁺ , C ₁₅ H ₁₄ BrNO calculated value 303.03)

Example 219. P7C3-S295: N- (3- (3-Bromo-6-methyl-9H-carbazol-9-yl) -2-fluoropropyl) -6-methoxypyridin-2-amine
S286 (50.5 mg, 0.13 mmol), 2-iodo-6-methoxypyridine (29.6 mg, 0.13 mmol), chloro [2- (dicyclohexylphosphino) -3,6-dimethoxy-2'-4 ' -6′-tri-i-propyl-1,1′-biphenyl] [2- (2-aminoethyl) phenyl] palladium (II) (BrettPhos palladacycle, 10.8 mg, 0.014 mmol) and 2- (dicyclohexylphosphine) Fino) A vial containing 3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl (BrettPhos, 6.8 mg, 0.013 mmol) was aerated with nitrogen for 20 minutes. Dioxane (2.45 ml) was added and LHMDS (1.0 M in THF, 0.5 mmol) was added dropwise. The reaction was stirred for 1 hour and centrifuged. The supernatant was chromatographed on silica gel with 10-30% THF / hexane. Yield = 25%
¹ H NMR (400 MHz, (CD ₃ ) ₂ CO) δ 8.27 (dd, J = 1.7, 0.9 Hz, 1H), 7.98 (dt, J = 1.9, 0.9 Hz, 1H), 7.53 (t, J = 1.4 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.35-7.26 (m, 2H), 6.92 (s, 1H), 6.14 (d, J = 8.0 Hz, 1H), 5.91 (dd, J = 7.8, 0.7 Hz, 1H), 5.33-5.04 (m, 1H), 4.77 (dd, J = 5.5, 3.8 Hz, 1H), 4.71 (d, J = 5.5 Hz, 1H), 3.86-3.76 (m, 1H), 3.74-3.64 (m, 1H), 3.60 (s, 3H), 2.49 (s, 3H) .MS (ESI), m / z: Calculated 441.09, Found 442.0 (M + 1)

  Additional compounds of the embodiments disclosed herein can be synthesized by schemes and methods according to the above.

Pro-neurogenesis / neuroprotective activity of various compounds The compounds were tested in vivo for dose response neurotrophic efficacy. The results are shown in Table 1.

  In our standard in vivo assay, compounds were evaluated for their ability to promote neurogenesis / neuroprotection in four 12 week old adult male C57 / B16 mice at a concentration of 10 μM.

  The (+) (dextrorotatory) enantiomer of 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol described herein is highly active showed that.

  The (−) (left-handed) enantiomer of 1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol described herein has low activity. Indicated.

  A commercial sample of P7C3-S229 was previously tested in a neurogenesis assay and found to be indistinguishable from the vehicle when administered intracranial with a 10 micromolar solution (MacMillan etal., J. Am. Chem. Soc , 2011; (133): 1428-1437). Subsequently, another sample was synthesized separately and tested in the same manner and found to be active. There are many reasons for this discrepancy, but we do not want to be bound by theory, and it is hypothesized that possible explanations include: 1) The same commercial sample was not strictly identified; it may have been a different material. 2) The purity of the commercial sample was not strictly confirmed; impurities may interfere with the neurogenesis promoting activity of the commercial sample. 3) P7C3-S229 has low solubility. Slight differences in the formulation of different samples or physical properties of the samples (eg, crystalline versus amorphous solids) can lead to differences in exposure in in vivo experiments.

  Based on its structure, P7C3-S295 (Example 219) is believed to have high biological activity (eg, pro-neoplastic efficacy / neuroprotection assay in the mouse model described herein). Further experiments (in vitro and in vivo) are ongoing to further characterize the effects of P7C3-S295 in the disease models described herein.

Identification of a neurogenesis-promoting or neuroprotective compound:
In an attempt to identify compounds that would promote the birth of new neurons or protect new neurons from cell death, a library of 1,000 compounds was screened using in vivo assays. In the initial screening, compounds were randomly pooled into groups of 10 and administered intraventricularly at a constant rate for 7 days into the left ventricle of surviving mice with an Alzet osmotic minipump. The compound was administered at a concentration of 10 μM per molecule, for a total solute concentration of 100 μM. After 7 days of infusion at a constant rate of 0.5 μL / hour, a total volume of 84 μL should have exited the pump (0.0008 μMoles) and entered the cerebrospinal fluid. The average brain volume of 12 week old male C57 / B6 mice is 500 mm ³ in our study. The maximum amount of drug that could be present in the brain was estimated considering the extreme and impossible scenario of 100% absorption of drug into brain tissue and 0% clearance during the 7 day infusion period. Under these conditions, each compound should be present at a concentration of 1.7 μMolar at the end of one week of injection. Since the actual amount of chemical in the brain is probably part of this expected level, it is reasonable to estimate that the compound was administered in the mid to low nanomolar range.

During compound infusion, the thymidine analog bromodeoxyuridine (BrdU) was injected intraperitoneally (IP) as a means of scoring the birth and survival of proliferating neural progenitor cells in the hippocampus. Because both social interactions and locomotor activity are known to stimulate hippocampal neurogenesis, mice were bred individually and not utilized during the screening phase. After a one week period of compound administration, the animals were perfused and sacrificed. Dissected brain tissue is fixed, embedded, sectioned, stained with antibodies against BrdU, and nerves of neoplastic progenitor cells localized in the granule cell sublayer of the dentate gyrus in the opposite hemisphere of the minipump cannula It was evaluated with a light microscope as a quantitative means of newborn and survival. Every 5 sections ranging from the entire head to caudal range of the hippocampus were analyzed and normalized to the volume of the dentate gyrus where the total number of BrdU ⁺ cells was measured. Since an increase in both neonatal neuron proliferation and survival is an important screening parameter, screening was carried out for 7 days to cast a broad network of molecules that would enhance either process. Selection of screening parameters is based on a single-chase pulse chase experiment with BrdU under the same conditions used for our screening, 40% of the neoplastic cells in the dentate gyrus die within the first 5 days after birth This was confirmed (FIG. 1). Intracranial injection of fibroblast growth factor 2 (FGF-2) or artificial cerebrospinal fluid (aCSF) medium in the same one week long protocol was used as a positive and negative control. There was no difference in the number of BrdU-labeled cells in the dentate gyrus between mice subjected to surgical pump implantation and vehicle injection and mice that did not undergo surgery (FIG. 2). This confirmed the effectiveness of an in vivo approach to assess the ability of intracerebroventricular injection compounds to enhance hippocampal neurogenesis in the contralateral hemisphere.

  Neuronal stimulation induced by any compound is at a level that is enhanced in response to healthy activities such as sprinting in wheelchairs, access to rich environments or access to social interactions It appears to be important to localize in the exact region of the brain known to produce For this reason, attention was directed only to compound pools that stimulate BrdU incorporation only into the subgranular zone of the dentate gyrus. Do significant non-specific uptake of BrdU in ectopic regions such as CA3, CA1, cortex or striatum reflect pathological inflammation, as proliferating cells incorporate BrdU into DNA synthesis, Or it was hypothesized that the cells take up BrdU during DNA repair and thus show other forms of toxicity. Any compound pool that produced ectopic BrdU incorporation was excluded from the screen. See FIG. 3 for an example.

  Each of the 100 pools was tested with 2 independent mice. As shown in FIG. 4, 10 out of 100 test pools were observed to enhance dentate gyrus-specific neurogenesis roughly as much as FGF-2. Each pool that was determined to be positive in the first 2 test animals was subsequently re-evaluated in 2 additional mice, and all 10 pools may exhibit a statistically significant difference in neurogenesis. It became clear (FIG. 5). To identify a single proneogenic compound, the positive pool was broken down into its 10 component molecules, each of which was injected individually into 2 mice at each concentration at 2 concentrations (10 μM and 100 μM). . FIG. 6A shows the results of a degradation assay for pool # 7, where it was discovered that neurogenesis was selectively stimulated by one of the component compounds in the pool (compound # 3) and had no effect on other compounds in the pool. This molecule was named the compound of Example 45 or P7C3. In the degradation of 10 positive pools, 8 pools yielded a single neurogenesis promoting compound (FIG. 6B). Since the proliferative or neuroprotective effect on neural stem cells is not an artifact of the storage conditions of the UTSWMC chemical compound library, the refeed compound was confirmed to be 99% pure by mass spectrometry and 4 mice Of mice, each tested at a concentration of 10 μM, showed retention of proliferative or neuroprotective properties against neural stem cells (FIG. 6C).

  Pharmacokinetic analysis of the compound of Example 45 in plasma and whole brain tissue was performed after a single IV, IP and oral gavage. The compound of Example 45 was orally bioavailable, was able to easily cross the blood brain barrier, and was shown to contribute with a plasma terminal half-life of 6.7 hours after IP delivery. These advantageous pharmacological properties prompted a dose response experiment in which daily oral administration of the compound of Example 45 to adult mice was monitored both in terms of the brain concentration of the compound and the ability to promote neurogenesis (FIG. 7). . Maximum ability to promote neurogenesis was confirmed at the oral dose of 5 mg / kg transfer, and a gradual decrease in efficacy was observed at the 2.5 mg / kg and 1 mg / kg doses. Liquid chromatography-mass spectrometry analysis of brain concentrations of the compound of Example 45 in the dose ranges of 1 mg / kg, 2.5 mg / kg and 5 mg / kg was 213 nM (101 ng / g brain tissue) 5 hours after administration. Corresponding compound concentrations of 1.13 μM (534 ng / g brain tissue) and 1.35 μM (640 ng / g brain tissue) were confirmed.

Enantioselective activity of the compound derivative of Example 45:
To further study the compound of Example 45, an in vivo structure activity relationship (SAR) study was conducted using a 37-chemical derivative of the compound directly administered to the adult mouse brain via an Alzet minipump to promote neurogenesis. Performed in activity. Compounds were administered at 10 μM per week to 4 mice per compound with daily IP injection of BrdU. Following compound administration, animals were perfused, sacrificed, sectioned, stained and subjected to light microscopy to monitor hippocampal neurogenesis localization to the granular cell sublayer of the dentate gyrus. Roughly 10% of the deformed compound retained the same neurogenesis promoting activity as the parent compound. Nearly the same number of compounds produced slightly lower activity, but the majority of variants were significantly reduced in activity (Figure 8). For example, a variant of the compound of Example 45 having a methoxy substitution on the aniline ring (the compound of Example 62) was re-tested for proneurogenic activity via direct administration to the adult mouse brain via an Alzet minipump. The compound was administered at 10 μM per week to 4 mice injected daily with BrdU. Following compound administration, animals were perfused, sacrificed, sectioned, stained, and subjected to light microscopy to monitor hippocampal neurogenesis localization to the granular cell sublayer of the dentate gyrus. The methoxy derivative showed the same activity as the compound of Example 45. Subsequently, the (+) and (−) enantiomers of the compound of Example 62 were prepared (FIG. 9A). Two enantiomers were evaluated in an in vivo neurogenesis assay. The (+) enantiomer of the compound of Example 62 retained potent pro-neurogenesis activity and the (−) enantiomer showed a decrease in activity (FIG. 9B). Other derivatives were also resynthesized as described above and retested.

The compound of Example 45 enhances the survival of neoplastic neurons:
The properties of the cells produced in the subgranular zone of the dentate gyrus when the compound of Example 45 was administered as follows were evaluated. Animals were orally administered the compound of Example 45 for 30 days. The brain tissue is then transiently expressed in newly formed neurons during the period between birth and final maturity, but is not expressed in glial cells, thereby acting as a marker of neurogenesis in the dentate gyrus. Immunohistochemical staining was performed with an antibody against the tube-associated protein doublecortin (DCX) (Brown et al., 2003). As shown in FIG. 10A, the relative abundance of doublecortin positive neurons increased dramatically in response to long-term exposure to the compound of Example 45. This observation does not exclude the possibility that the compound also enhances glial cell formation, but clearly shows that the compound of Example 45 enhances the formation of cells destined to become neurons.

For neurogenesis mediated by the compound of Example 45, this is then due to either increased cell proliferation or protection from neonatal cell death from birth to final uptake into the granule layer of the dentate gyrus. Tested to see what could be done. This was achieved by comparing the ability of the compound of Example 45 to enhance the short-term or long-term increase in BrdU incorporation into the dentate gyrus (FIG. 10B). Animals that were orally delivered with the compound or vehicle of Example 45 for 30 days were administered a single pulse of BrdU by IP injection. The short-term effect on neuronal cell birth was determined by immunohistochemical detection of BrdU incorporation into cells localized in the subcellular granule cells of the dentate gyrus, following sacrifice of animals 1 hour after BrdU injection, followed by tissue fixation and sectioning. Monitored by Compound administration of Example 45 did not result in increased levels of BrdU positive cells relative to vehicle in this short-term assay. One day after BrdU administration, there was no statistically significant difference in the number of BrdU ⁺ cells in the dentate gyrus between the two groups. In contrast, in our assay, 40% of the neoplastic cells usually die (FIG. 1). At 5 days, animals receiving the compound of Example 45 were statistically significant compared to the vehicle-only control group. Showed a 25% increase in BrdU ⁺ cells. This difference between groups spreads with time, with mice receiving daily oral administration of the compound of Example 45 for 30 days starting at 24 hours after BrdU pulse administration, BrdU ⁺ in the dentate gyrus compared to vehicle-only control. The amount of cells increased 5-fold. Remarkably, in this long-term study, BrdU positive cells were observed not only along the granular cell sublayer of the dentate gyrus where new neurons are known to be born, but also within the granular layer itself. . These cells were hypothesized to represent adult neurons that migrate to the granule layer, perform the differentiation process, and are themselves taken up by the dentate gyrus as properly wired neurons. Observations that direct this interpretation are presented in the next section of this document. In summary, these experiments provide evidence that the compound of Example 45 enhances neuronal cell formation in the adult hippocampus and that its mechanism of action appears at some point after its birth.

  One skilled in the art will recognize that the above cell proliferation test can also be used to test other compounds of the embodiments disclosed herein.

The compound of Example 45 normalizes dentate gyrus apoptosis and improves morphological and electrophysiological defects in NPAS3-deficient mice:
Both copies of the gene encoding neuronal PAS domain protein 3 (NPAS3) each have severe dysfunction in adult neurogenesis (Pieper et al., Proc. Natl. Acad. Sci. USA 2005, 102, 14052-14057). By evaluation of BrdU incorporation in a short-term assay of neurogenesis by sacrifice of animals 1 hour after BrdU pulse, NPAS3-deficient animals were observed to have no detectable defect in the birth of neurons beneath the granule cell layer of the dentate gyrus (Fig. 11). This is in contrast to our previous observation that BrdU labeling in the dentate gyrus of NPAS3-deficient animals was significantly reduced when BrdU was administered long-term (12 days) (Pieper et al., Proc. Natl. Acad Sci. USA 2005, 102, 14052-14057). From the knowledge that NPAS3 transcription factor requires fibroblast growth factor receptor 1 (FGFR1) in the hippocampus for proper expression (Pieper et al., Proc. Natl. Acad. Sci. USA 2005, 102, 14052-14057), inhibition of growth factor signaling may be due to impairment of the trophic environment important for neoplastic neuron survival in the dentate gyrus. As a first test of this hypothesis, brain tissues prepared from NPAS3-deficient animals were compared with wild-type littermates for cleaved caspase 3 (CCSP3) positive cells in the granular cell sublayer of the dentate gyrus. A statistically significant 2-fold increase in CCSP3-positive (apoptotic) cells was seen in the dentate gyrus of NPAS3-deficient animals (FIG. 11). This high rate of programmed cell death is probably due, at least in part, to the almost complete loss of adult neurogenesis in mice lacking the NPAS3 transcription factor (Pieper et al., Proc. Natl. Acad. Sci. USA 2005, 102, 14052-14057).

In addition to this quantitative deficiency of adult neurogenesis, abnormalities in both morphology and electrophysiology have been observed in granular neurons of the dentate gyrus of NPAS3-deficient animals. Compared to wild-type animals, Golgicox staining showed a severe decrease in dendritic branch and spine density of dentate gyrus granule neurons in NPAS3-deficient animals (FIGS. 12A and 12B). In contrast, genotype-dependent differences were not seen in these indices in the hippocampal CA1 region cone cells. Compared to wild-type littermates, an equivalent specific defect was observed in electrophysiological records in NPAS3-deficient animals (FIGS. 13A and 13B). Full field recording of excitatory post-synaptic potential (fEPSP) showed a significant deficiency in NPAS3-deficient animals compared to wild-type littermates. In the dentate gyrus, the stimulating electrode and the recording electrode were placed on the surface of the molecular layer that is innervated by the axons of the penetrating pathway originating from the olfactory cortex. In the CA1 region of the hippocampus, the stimulating electrode and recording electrode were placed in a radial layer innervated by Schaffer side branch axons of CA3 pyramidal cells. Stimulation intensity was raised in 5 μA increments, the slope of the decreasing portion of the electric field potential was measured, and fEPSP was quantified with respect to the amplitude of the fiber firing, representing action potential firing in presynaptic axons. This analysis confirmed the abnormal excitability of synaptic transmission in both the outer molecular layer and CA1 region of the dentate gyrus in npas 3 ^{− / −} mice (FIGS. 13A and 13B).

With these genotype and region-specific deficiencies in both neuronal morphology and electrophysiological activity, whether long-term administration of the compound of Example 45 advantageously repairs any deficiency in NPAS3-deficient animals Tested. Prior to addressing this study, the compound of Example 45 was demonstrated by demonstrating that the compound of Example 45 enhanced both BrdU incorporation of neoplastic neurons as well as doublecortin expression in the dentate gyrus of npas 3 ^{− / −} mice. Was first confirmed to be able to enhance hippocampal neurogenesis in NPAS3-deficient mice (FIG. 14). From the knowledge that the formation of the dentate gyrus begins in late prenatal mouse embryos around fetal day 14 (Stanfield and Cowan, 1988, The development of the hippocampal region. In Cerebral Cortex, EG Jones and A. Peters, eds (New York: Plenum Press), pp. 91-131), animals were exposed to the compound of Example 45 for as long as possible in order to obtain the greatest opportunity for the compound to exert its beneficial effects. After gavage administration to pregnant female mice, embryos on day 14 were collected, cut, and treated with acetonitrile: water extraction so that the compound concentration of Example 45 in the embryonic brain could be measured. Daily administration of 20 mg / kg of the compound of Example 45 to pregnant females resulted in appreciable levels of the compound in the brain tissue of the developing embryo. It was also observed that oral administration of the compound to lactating females resulted in delivery of the compound of Example 45 to weaned pup brain tissue. In all cases, LC / MS-based quantification of the compound of Example 45 confirmed a level of compound accumulation above the 1.35 μM limit necessary to indicate adult neurogenesis (FIG. 7). Furthermore, daily IP administration of weaned pups at 20 mg / kg of the compound of Example 45 is sufficient to produce brain concentrations of the compound of Example 45 above levels necessary for enhanced adult neurogenesis. Was observed.

  Mouse heterozygous females at the NPAS3 locus were mated with heterozygous males. Two weeks after mating, females were orally administered daily by gavage with the compound of Example 45 at 20 mg / kg or vehicle alone. Administration continued during the last trimester of pregnancy as well as during the two-week lactation period after birth. After weaning, the pups were administered IP daily with 20 mg / kg of the compound of Example 45 or vehicle control. At 7 weeks of age, mice were switched to gavage delivery of the same amount of the compound of Example 45. When mice reached 3 months of age, they were sacrificed, brain tissue was cut and subjected to Golgicox staining or electrophysiological recording. As shown in FIG. 15, long-term exposure to the compound of Example 45 strongly repaired the morphological defect of dendritic branches in the dentate gyrus granule neurons in NPAS3-deficient mice. Furthermore, as shown in FIG. 13A, electrophysiological defects in the dentate gyrus of NPAS3-deficient mice were also corrected by prolonged exposure of the mouse to the compound of Example 45. However, the corresponding electrophysiological deficits in the CA1 region of the hippocampus were not affected (FIG. 13B), highlighting the specificity of the compound of Example 45 for improving dentate gyrus function in this animal model.

  Even more strikingly, administration of the compound of Example 45 did not affect any health aspects of maternal, embryo, weanling or young adult mice compared to vehicle-only controls. Macroscopic histology of brain tissue was normal in both compound-treated and vehicle-treated animals, and there was no evidence of neuronal cell loss or degenerative changes (cytoplasmic eosinophilia, vacuolation or nuclear enrichment) . The only morphological change other than normalization of the dendritic branches of the granular neurons of the dentate gyrus was a compound-dependent increase in the thickness of the granule layer itself of the dentate gyrus (FIG. 16). The granule layer thickness of the dentate gyrus is approximately 40% thinner in NPAS3-deficient animals than wild-type littermates. Long-term administration of the compound of Example 45 during late embryonic development, early postnatal development and 2 months after weaning significantly corrected this defect without affecting the thickness of other hippocampal layers in NPAS3-deficient mice ( FIG. 16).

  Recognizing that the decreased granule layer thickness of the dentate gyrus of NPAS3-deficient animals is due to increased levels of apoptosis of neonatal hippocampal neural progenitor cells, the therapeutic effect of the compound of Example 45 on apoptosis in the hippocampus of NPAS3-deficient animals was demonstrated. Tested via immunohistochemical staining of cleaved caspase 3 (CCSP3). As shown in FIG. 17, treatment for 12 days with oral delivery of the compound of Example 45 (20 mg / kg) to adult NPAS3-deficient animals significantly reduced CCSP3 staining in the dentate gyrus, whereas vehicle treatment was effective. There wasn't. Thus, it was proposed that the compound of Example 45 promoted restoration of the granular layer of the dentate gyrus of NPAS3-deficient mice by improving genotype-specific exacerbations of programmed cell death.

  One skilled in the art will recognize that the apoptosis test described above can also be used to test other compounds of the embodiments disclosed herein.

The compound of Example 45 protects mitochondrial integrity:
Extensive evidence that Xiaodong Wang's laboratory is a pioneer indicates that the intrinsic pathway leading to programmed cell death begins in mitochondria (Liu et al., Cell 1996, 86, 147-157; Yang et al. Science 1997, 275, 1129-1132). With the help of Wang's laboratory, an assay was established to test whether the compound of Example 45 protects mitochondria from calcium-induced lysis (Distelmaier et al., Cytometry A 2008, 73, 129- 138). Tetramethylrhodamine methyl ester (TMRM) is a cell-permeable, cationic red-orange fluorescent dye that is easily captured by active mitochondria. When loaded with TMRM dye, vehicle-only treated cells release the dye within 15 minutes of exposure to calcium ionophore A23187. In contrast, pigment release was blocked intracellularly with exposure to only 10 ng of the compound of Example 45 (FIG. 18A). Similar to the in vivo neurogenesis assay and in vitro protection of cultured cortical neurons from Aβ _(25-35) mediated toxicity, protection of the mitochondrial membrane potential in this assay was only seen with the (+) enantiomer of the compound of Example 62 ( FIG. 18B).

  One skilled in the art will recognize that the mitochondrial integrity test can be used to test other compounds of the embodiments disclosed herein.

Comparison of the compound of Example 45 and Dimebon:
The compound having structural similarity to the compound of Example 45 is 2,3,4,5-tetrahydro-2,8-dimethyl-5- (2- (6-methyl-3-pyridyl) ethyl) -1H-pyrido ( 4,3-b) indole (FIG. 19A). Antihistamine, a trade name of Dimebon, has been known as an anecdote for several decades to improve dementia symptoms (O'Brien, Lancet Neurol. 2008, 7, 768-769; Burns and Jacoby, Lancet 2008, 372, 179-180). Recently, a US biotechnology company called Medivation has started a clinical trial to formally test whether Dimebon improves symptoms in patients with Alzheimer's disease. The results of an FDA-funded phase II clinical trial in Alzheimer's disease have recently been published and favorable response rates have been reported (Doody et al., Lancet 2008, 372, 207-215). The compound of Example 45 and Dimebon were compared in three functional assays. In vivo studies of the effect on hippocampal neurogenesis demonstrated the activity of both compounds, with the compound of Example 45 showing a 10-30 fold higher level of potency and about 40% higher efficacy ceiling than the antihistamine (Figure 19B). ). Dimebon has been linked to mitochondrial protection (Bachurin et al., Ann. NY Acad. Sci. 2001, 939, 425-435; Bachurin et al., Ann. NY Acad. Sci. 2003, 993, 334-344 , discussion 345-349). Therefore, Dimebon was compared to the compound of Example 45 in a calcium-induced mitochondrial lysis assay. Both compounds were observed to be active, and it was also observed that the relative potency of the compound of Example 45 was higher than Dimebon (FIG. 19C). Mitochondrial permeability protection was lost at 10-1 nM dose with the compound of Example 45 and 10-1 μM with Dimebon.

The compound of Example 45 and Dimebon were tested for binding to the H1 histamine receptor. Although Dimebon showed high affinity for this receptor (IC ₅₀ <100 nM), both enantiomers of the compound of Example 45 had low H1 affinity (IC ₅₀ > 10 μM).

  Those skilled in the art will recognize that the binding activity test can also be used to test other compounds of the embodiments disclosed herein.

Effect of the compound of Example 45 on aged rats:
Next, older Fisher rats were used as a means of conducting a behavioral test that could assess the potential benefit of the compound of Example 45 on hippocampal dependent learning. It is well established that normal rodent aging is accompanied by an attenuation of hippocampal neurogenesis (Kuhn et al., J. Neurosci. 1996, 16, 2027-2033; Driscoll et al., Neuroscience 2006, 139 , 1173-1185). Reduced neurogenesis in older rats may be associated with increased neuronal apoptosis in older rat brain (Martin et al., J. Biol. Chem. 2002, 277, 34239-34246; Kim et al., Exp. Gerontol. 2010, 45, 357-365). These changes are hypothesized to contribute to cognitive decline in response to terminal aging.

  Whether the compound of Example 45 enhances hippocampal neurogenesis in elderly rats as in adult mice was evaluated for the first time. Rats were administered IP daily with 10 mg / kg of the compound or vehicle of Example 45 along with daily administration of BrdU and sacrificed 7 days later for immunohistochemistry. As shown in FIG. 20A, compound treated animals demonstrated a 500% increase in BrdU labeling of the dentate gyrus compared to vehicle treated controls. Immunohistochemical staining with antibodies against doublecortin similarly demonstrated a robust, compound-specific enrichment of this newborn neuronal marker. Since the neurogenic promoting potency of the compound of Example 45 in this short-term assay was observed, it was determined whether 18-month-old rats were able to determine whether long-term administration of the compound of Example 45 reduced age-related cognitive decline. Tested by daily administration of the compound of Example 45 or vehicle alone at 10 mg / kg for 2 months. Both groups of animals received weekly IP administration of BrdU (50 mg / kg) for further hippocampal neurogenesis immunohistochemistry. As a control, both the compound treatment and vehicle treatment groups of Example 45 are shown as a decrease in latency to find a hidden platform through a 5-day training period, both before and after 2 months of treatment. It was confirmed that the participants showed physically equivalent ability for participation in the task and learning of the task (FIG. 20B). Furthermore, neither swimming speed (FIG. 20C) nor locomotor activity (FIG. 20D) were different by age or treatment paradigm.

  Two months after compound or vehicle administration, cognitive ability was tested blind to treatment groups by removing the target platform. The animals in the compound-treated group of Example 45 retained a statistically significant improvement in their ability to progress to the area of the lost platform, as evidenced by their ability in probe testing. As shown in FIG. 21A, when the platform was removed from the maze, rats treated with the compound of Example 45 passed through that position where the platform was previously included significantly more frequently than vehicle-treated rats. Furthermore, rats treated with the compound of Example 45 spend a significantly higher percentage of time than the vehicle-treated rats in the general target zone, defined as the quadrant in which the platform was previously included (35. 5% ± 2.2% eg 45 compound treatment, 28.1% ± 2.6% for vehicle treatment, Student's t-test, p <0.02.

  After behavioral testing, animals were sacrificed for immunohistochemical detection of BrdU and CCSP3. As shown in FIG. 21B, the dentate gyrus of rats exposed to the compound of Example 45 showed 3 times higher levels of BrdU positive neurons than the vehicle group. Furthermore, animals treated with the compound of Example 45 had a statistically significant decrease in the number of CCSP3-positive cells compared to vehicle control (FIG. 21C). Unexpectedly, administration of the compound of Example 45 helped maintain a stable body weight as the rats became older, in contrast to vehicle-treated rats that lost weight with age (FIG. 21D). The effect on body weight mediated by the compound of Example 45 was independent of food intake (FIG. 20E), and treatment of elderly rats with the compound of Example 45 had no effect on fasting blood glucose levels (FIG. 20E). Next, it was tested whether weight maintenance in aged rats mediated by the compound of Example 45 operates via a central or peripheral mechanism of action.

  One skilled in the art will recognize that the above in vivo testing in rats or other animal models can also be used to test other compounds in the embodiments disclosed herein.

The compound of Example 45 enhances hypothalamic neurogenesis:
The hypothalamus, located directly under the thalamus and forming the floor and lower sidewall of the third ventricle, controls the autonomic nervous system and emotions through extensive neuronal connections to the pituitary, thalamus, midbrain and cerebral cortex It consists of multiple cell groups that also control behavior. These functions include water balance, biorhythms, feeding and drinking drive, sexual activity, pituitary function and temperature control. Adult brain neural stem cells are located in the walls of the third ventricle, rapidly increasing the response to various stimuli, and formation of new neurons in the hypothalamus is also observed in the hypothalamus parenchyma. Administration of trophic factors such as brain-derived neurotrophic factor and ciliary neurotrophic factor enhances neurogenesis in the rodent hypothalamus. In addition, adult hypothalamic neonatal neurons are taken up by existing hypothalamic neural circuits and express neuronal markers such as POMC (Phosphorylation Signal Transducer of Transcription Activator), Neuropeptide Y, Ocytocin and Vasopressin. During hypothalamic development, POMC-expressing progenitor cells differentiate into two groups of cells with an antagonistic role that express either POMC or neuropeptide Y, which exerts the opposite effect on energy balance control. The differential control of postnatally produced neurons in the hypothalamus is hypothesized to form the basis for the development of new treatments for the control of food intake behavior. This hypothesis is dictated by the observation that acute removal of new hypothalamic neurons leads to severe eating disorders and weight loss.

  Administration of vehicle or P7C3 (10 mg / kg twice a day, ip) starting 2 days prior to implantation of a 7-day Alzet osmotic minipump (model 1007d) filled with BrdU (1 mg / kg) resulted in 9 Whether to enhance hypothalamic neurogenesis in aged male C57BL / 6 mice was evaluated. The pump was connected to a cannula that delivered BrdU to the left ventricle at a constant rate for 7 days, during which time the animal continued to receive vehicle or P7C3. The pump was surgically removed at the end of the 7 day period of action and the mice were allowed to survive for an additional 4 weeks, during which time medium or P7C3 administration continued. At the end of this 4-week period, deep anesthesia was given with an intraperitoneal (ip) injection of an anesthetic cocktail for mice and transmucosed with 4% paraformaldehyde (PFA) in phosphate buffered saline (pH 7.4). Cardiac perfusion. The brains were then dissected and post-fixed overnight in 4% PFA at 4 ° C. and antifreeze treated with 30% sucrose in PBS. The fixed brain was embedded in OCT and cut with a cryostat to a thickness of 20 μm. According to our standard method, every third section was stained for BrdU (Accurate, rat anti-Brdu 1: 400) immunohistochemically. Anti-rat Dylight 596 was used for visualization of BrdU incorporation. As seen in FIG. 27, treatment with P7C3 significantly enhanced hypothalamic neurogenesis in the rodent brain, with a significant increase in the amount of BrdU positive staining.

  One skilled in the art will recognize that the hypothalamic neurogenesis test can also be used to test other compounds of the embodiments disclosed herein.

  Since P7C3 (and its derivatives and analogs) can enhance hypothalamic neurogenesis, compounds of the embodiments disclosed herein are such as water balance, biological rhythms, feeding and drinking drives, sexual activity, pituitary function and temperature control. Can be useful for controlling hypothalamic function. For example, in view of the role of P7C3 in maintaining a stable body weight in aging rats, the compounds of the embodiments disclosed herein are normal aging, radiation therapy, chemotherapy, eating disorders, cachexia, diabetes, stress, substance abuse It can provide a therapeutic effect on patients whose physiological weight loss is predicted for various reasons, such as dementia, stroke, cancer, infection, and other diseases and / or conditions.

The compound of Example 45 protects mitochondria:
Since P7C3 improves dentate gyrus neuronal death in surviving mice, its function may be related to mitochondrial integrity. An assay was established to test whether P7C3 protects cultured U2OS cells from calcium-induced mitochondrial lysis (Distelmaier et al., Cytometry A 2008, 73, 129-138). Tetramethylrhodamine methyl ester (TMRM) dye was captured by active mitochondria and when treated with TMRM, vehicle-treated cells released the dye within 15 minutes of exposure to calcium ionophore A23187. In contrast, pigment release was completely blocked in cells exposed to as little as 10 nM P7C3 (FIG. 22A). Compounds known to be less active in vivo were also less active in this assay (not shown). Protection of mitochondrial membrane potential in this assay was observed in Example 1b, the R enantiomer of P7C3-OMe (FIG. 22B), but not in Example 1a, the S enantiomer (FIG. 22C). Furthermore, protection of mitochondrial membrane permeability was observed with the compound variant P7C3A20 (Example 6a), which also showed a high level of neurogenic promoting activity (FIG. 22D). Derivatives with less neurogenic promoting activity than P7C3, such as Example 33 (FIG. 22E) and Example 21 (FIG. 22F), have a lower protective effect on protecting mitochondrial integrity at doses tested in cultured primary cortical neurons. It was.

  Whether the compound of Example 45 protected mitochondrial membrane potential in cultured primary cortical neurons was also examined (FIG. 23). Tetramethylrhodamine methyl ester (TMRM) dye was added to cortical neuron cultures from fetal day 14 rats after maturation for 6 days. The upper panel (calcium-free ionophore) showed that this dye alone had no effect on neuronal health. The remaining panel is from cells exposed to calcium ionophore A23187 at 0:00. The vehicle alone rapidly lost cortical neuronal mitochondrial membrane potential after ionophore exposure. Increasing the mitochondrial membrane potential of the compound of Example 45 protected the mitochondrial membrane potential after calcium ionophore A23187 exposure in a dose-dependent manner, and complete protection was achieved at 1 mM. The low activity compound (Example 33) was less effective at protecting mitochondrial membrane potential at all concentrations tested. The results shown are representative examples of 10 regions analyzed in 2 experiments for all conditions.

  Those skilled in the art will recognize that the mitochondrial test can be used to test other compounds of the embodiments disclosed herein.

The compound of Example 45 normalizes high levels of hippocampal apoptosis in npas 3 ^{− / −} mice:
Recognizing that the decreased thickness of the npas3 ^{− / −} dentate gyrus granule layer is due to increased apoptosis of proliferating neural progenitor cells, the compound of Example 45 (P7C3) treatment for apoptosis in the hippocampus of npas3 ^{− / −} mice Was tested through immunohistochemical staining for CCSP3. As shown in FIG. 17, a statistically significant decrease in CCSP3 staining was observed in the dentate gyrus after 12 days of oral delivery of the compound of Example 45 (20 mg / kg) to adult npas 3 ^{− / −} mice. Therefore, it is proposed that the compound of Example 45 promotes the repair of the granular layer of the dentate gyrus of npas 3 ^{− / −} mice by overcoming the genotype-specific enhancement of apoptosis.

  Those skilled in the art will recognize that the mouse model and other animal models can also be used to test other compounds of the embodiments disclosed herein.

The compound of Example 45 (P7C3 provides a therapeutic effect in an animal model of amyotrophic lateral sclerosis (ALS):
ALS, also known as Lou Gehrig's disease, is due to selective degeneration of upper (cortical layer V in the primary motor cortex) and lower (spinal spinal) motor neurons, which are central nervous system neurons that control spontaneous muscle movement. One adult-onset (typically 40-70 years), rapidly progressing, fatal disease. An estimated 5000 people in the United States are diagnosed with ALS each year. This disorder causes muscle weakness and atrophy throughout the body, and patients with ALS eventually lose the ability to initiate and control all spontaneous movements. The part of the body that is most affected by ALS reflects the motor nerve that was initially damaged. About 75% of patients experience symptoms on the arms or legs as manual dexterity or difficulty in walking, while about 25% suffer from ALS 'medullary onset'-clear difficulty in swallowing or swallowing experience. A small portion of patients develop ALS in the respiratory system in the form of weakened intercostal muscles that support breathing. Regardless of the onset area, as the disease progresses, muscle weakness and atrophy consistently spread to other parts of the body. Most patients have difficulty moving, dysphagia (dysphagia), dysarthria (difficulty speaking or speaking) and upper motor nerves (muscle spasticity, hyperreflexia and hyperemetic reflex) and lower motor nerves (muscle weakness) Develop a group of symptoms, including classic manifestation of loss of muscle atrophy, muscle spasm and bundling). Sensory and autonomic nervous systems are usually preserved but may be included in some patients. About 20% of ALS patients also develop frontotemporal dementia (FTLD), and 30-50% of patients develop slight cognitive changes that can be observed with detailed neuropsychological examinations. About 15-45% of ALS patients also develop what is called a “pseudomedullary effect” —a form of emotional instability that causes the patient to develop laughing, crying or smile attacks that cannot be controlled intermittently. This symptom domain is thought to be associated with degeneration of the upper medullary motor nerves, resulting in emotional hypermotility. Although the progression of the disease varies from person to person, most patients will eventually be unable to stand or walk, go in and out of bed, or use their hands and arms. Chewing and swallowing difficulties further promote weight loss and increase the risk of asphyxiation and aspiration pneumonia. Most patients require ventilator assistance as the diaphragm and intercostal muscles weaken toward the final stage of the disease. ALS patients generally die within 2-5 years of diagnosis due to respiratory failure or pneumonia.

  Ninety-five percent of ALS cases develop sporadically (SALS) and there is no identifiable cause or family history of the disease. The remaining 5% of cases are inherited, known as family-based ALS (FALS). Because FALS and SALS are clinically and neuropathologically similar, the pathogenesis of these forms of ALS can be converged to a common pathogenic pathway. Approximately 20% of FALS and 3% of SALS cases have an autosomal dominant mutation in the SOD1 gene on chromosome 21, and about 150 different mutations distributed throughout this gene have been identified in FALS. SOD1 encodes cytoplasmic Cu / Zn superoxide dismutase, an antioxidant enzyme that protects cells by converting superoxide (a toxic free radical produced through normal mitochondrial metabolic activity) to hydrogen peroxide. Free free radicals accumulate and damage both mitochondrial and nuclear DNA and cellular proteins. In ALS associated with SOD1 mutation, motor neuron cytotoxicity appears not to be due to loss of dismutase activity, but to toxic SOD1 function gain. Although the exact molecular mechanism underlying toxicity is unknown, it is known that mutagenic conformational changes in SOD1 result in misfolding and subsequent cytotoxic aggregation of mutant SOD1 in cell bodies and axons . Aggregate accumulation of mutant SOD1 is thought to interfere with cell function and induce neuronal cell death by damaging mitochondria, proteasomes, protein folding chaperones or other proteins.

  Transgenic animal models of mutant SOD1, such as the G93A-SOD1 mutant mouse, are currently being used to study the pathogenic mechanisms believed to be widespread in ALS. Mice hemizygous for the G93A-SOD1 transgene express 18 ± 2.6 copies of the form of SOD1 found in some FALS patients (glycine to alanine substitution at codon 93). This is the first mutant form of SOD1 expressed in mice and the most widely used and well characterized mouse model of ALS. The superoxide dismutase activity of these mice remains such that the pathogenic effect of the mutant transgene appears to gain function, as is believed to occur in human patients. In these mice, death of motor nerve cells in the anterior horn of the spinal cord and loss of myelinated axons in the ventral motor root lead to paralysis and muscle atrophy. In these mice, upper cortical motor neurons also die as the disease progresses, and protein aggregates of mutant SOD1 are only found in affected tissues, and a large amount is seen during motor neurodegeneration. At about 100 days of age, G93A-SOD1 mice are paralyzed on one or more limbs, with paralysis due to motor nerve loss from the spinal cord. This paralysis spreads rapidly throughout the body, resulting in the death of 50% of mice in 128.9 ± 9.1 days.

  P7C3 was administered intraperitoneally to female G93A-SOD1 transgenic mice using a 10 mg / kg P7C3 ip twice daily treatment paradigm starting at 40 days of age compared to vehicle. This treatment scheme was selected based on the standard protocol for initial proof-of-concept screening in these mice. As a control for transgene copy number, mouse siblings are matched between treatment groups according to standard protocols. After the start of P7C3 or vehicle treatment, the day of disease onset is determined by the peak in body weight, and the initial progression of the disease is defined as the day when mice are 10% below their maximum body weight. Mice are also evaluated daily by a standard measurement of neurological severity score, and a score of 2 or worse for 2 consecutive days serves as an additional marker of disease progression. This score is determined blind to the treatment group with scoring as described in the figure legend. As shown in FIG. 24A, P7C3 treatment delays the onset of disease by delaying the disease progression of G93A-SOD1 mice by 10% below the maximum body weight of the mice. As shown in FIG. 24B, treatment with P7C3 also significantly delays the age at which G93A-SOD1 mice reach another marker of disease progression, neurological severity score 2. Furthermore, P7C3 treatment significantly improves the ability of the accelerated rotarod task associated with the disease in these mice, suggesting a delay in the progression of the motor dysfunction of the disease process, as shown in FIG. 24C. This protective effect of P7C3 on motor performance in G93A-SOD1 mice is also observed in pacing ink footprint analysis, as shown in FIG. 24D.

  Those skilled in the art will recognize that the ALS model and other animal models can also be used to test other compounds of the embodiments disclosed herein.

The compound of Example 6a (P7C3A20) provides a therapeutic effect in an animal model of Parkinson's disease:
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the death of dopaminergic neurons in the substantia nigra projected onto the striatum to control normal movement. Although one of the most common neurological disorders in the elderly, the cause of PD remains uncertain. Symptoms in the early stages of the disease are related to exercise, including tremors, stiffness, slowness of movement and dyskinesias. Further progression of the disease stage typically involves cognitive and behavioral problems including dementia. Early motor symptoms are managed in part by administration of drugs that enhance dopaminergic signaling. However, as the disease progresses and as the substantia nigra dopaminergic neurons continue to die, patients reach a point where these drugs become ineffective in the treatment of symptoms, and the complication of dyskinesia Cause symptoms. Effective prevention of nigral dopaminergic neuronal cell death is therefore an ideal treatment approach for PD patients.

  MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a potent neurotoxin that selectively kills substantia nigra dopaminergic neurons in both mice and monkeys; Causes a clinical picture similar to PD. Therefore, the MPTP toxicity model is used for the study of dopaminergic neuronal cell death aimed at developing new treatments for PD based on neuroprotective strategies that would prove to be effective in these neurons it can. Developed by Tatton and Kish (1997), Neuroscience 77: 1037-1048, and Jakson-Lewis et al. (2007), Nature Protocols 2: 141-151 to determine whether P7C3A20 is substantia nigra and neuroprotective Use well-characterized and popular MPTP dosing regimens. Here, 12 week old wild type male C57BL / 6 mice were treated with P7C3A20 (10 mg / kg ip twice a day) or vehicle for 3 days and on day 4 30 mg / kg / day ip. A 5-day regimen of free base MPTP was started. Mice continued to receive P7C3A20 or vehicle for 5 days after this MPTP administration. Mice continued to receive the same dose of P7C3A20 or vehicle daily for an additional 21 days, at which time they were sacrificed by transcardial perfusion with 4% paraformaldehyde. The brain was fixed with 4% paraformaldehyde overnight at 4 ° C. and antifreeze treated with 30% sucrose in phosphate buffered saline. Fixed brains were cut to 30 microns with a sliding microtome and stained every fourth section (120 microns apart) with an antibody against tyrosine hydroxylase (TH) (Abcam, rabbit anti-TH, 1: 2500). TH positive cells were counted in the substantia nigra region. As shown in FIGS. 25A and 25B, treatment with P7C3A20 significantly attenuated MPTP-mediated killing of nigrodopaminergic neurons. These observations suggest that P7C3A20 and related compounds may form the basis of a novel neuroprotective strategy for prevention or delay of Parkinson's disease progression.

  Those skilled in the art will recognize that the PD model and other animal models can also be used to test other compounds of the embodiments disclosed herein.

The compound of Example 45 provides a therapeutic effect in an animal model of Huntington's disease:
Huntington's disease (HD) is an autosomal dominant neurodegeneration characterized by an insidious and progressive onset of mood disorders, behavioral changes, involuntary chorea-like movements (constant limbs, complex stroking movements) and cognitive impairment Is a disease. The prevalence of HD is about 1 in 10,000 in the United States, and is due to polyglutamine elongation exceeding 36 repeats at the N-terminus of the protein huntingtin (Htt). There are currently no treatments that delay the appearance or progression of the disease. HD is pathologically characterized by the dramatic loss of neurons in the striatum and cerebral cortex, and therapeutic strategies that protect these neurons from death should provide patients with new treatment options. Physical symptoms of HD typically begin at 35 to 44 years of age, but there are reports of onset ranging from infancy to age. The exact method by which HD affects each person varies and can vary even within the same family, but symptom progression is predictable in most cases. The earliest symptoms are general loss of coordination and unsteady pace, and as the disease progresses, uncoordinated and jerky body movements become more apparent. More advanced stages of intelligence are typically associated with behavioral and mental problems such as anxiety, severe depression, emotional dullness, self-centeredness, aggression and alcoholism, compulsive behavior such as gambling or hypersexuality. With observable decline. Over time, physical ability declines until coordination becomes extremely difficult, and intelligence generally declines to dementia. Complications such as pneumonia, heart disease, weight loss and physical injuries resulting from falls leading to malnutrition and reduced life expectancy until about 20 years after onset of symptoms. There is no cure for HD, and 24-hour care is required later in the disease.

  Htt is a large cytoplasmic protein that interacts with more than 100 other proteins and has multiple biological functions. The behavior of mutant Htt (mHtt) proteins is not fully understood but is known to be toxic to neurons. Injuries occur primarily in the striatum, but in later stages other areas of the brain, such as the cerebral cortex, are also attacked. As nerve cell death progresses, symptoms related to the function of the affected area of the brain appear. For example, exercise planning and adjustment is the primary function of the striatum, and impairment of these tasks is frequent in the early symptoms of HD. Disease initiation and progression is largely related to polyglutamine elongation, protein-protein interaction abnormalities, abnormal nuclear and cytoplasmic protein aggregation, and proteolytic changes in the conformation of the mHtt protein, followed by transcriptional dysregulation, excitement It is thought that toxicity, mitochondrial dysfunction and neuronal apoptosis can occur. In addition to the role of mHtt in acquiring new toxicological properties in HD pathology, there is increasing evidence that loss of wild-type Htt function also contributes to pathogenesis. For example, an essential role for Htt in spindle formation and mammalian neurogenesis has recently been identified.

  One animal model of HD that can be used to screen potential therapeutic agents is the R6 / 2 transgenic mouse. These mice contain a variant exon 1 of the human huntingtin gene that has been engineered to contain about 145 to 155 CAG repeat extensions. R6 / 2 mice phenotype most of clinical HD neuropathology (striatal and cortical neuronal death) and behavioral signs. They are associated with progressive motor and cognitive dysfunction, ubiquitinated nuclear and cytoplasmic inclusion of mutant Htt, weight loss, reduction of striatum and brain size, abnormal levels of neurotransmitters and their receptors and premature death Indicates. They exhibit motor impairment at an early stage of 5-6 weeks of age, exhibit behavioral abnormalities manifested at 8-9 weeks of age, and typically die at 11-13 weeks of age. R6 / 2 mice also have significantly lower levels of adult hippocampal neurogenesis compared to wild-type littermates even before onset of symptoms.

  In one hypothesis, P7C3 (and its derivatives) can enhance mature hippocampal neurogenesis by preventing death rather than promoting the growth of these cells. As such, P7C3 is “proneurogenic” in terms of its neuroprotective activity. P7C3 (and its derivatives) may prevent cell death and promote cell proliferation. It was evaluated whether P7C3 provides a therapeutic effect for R6 / 2 mice. P7C3 (10 mg / kg ip twice a day, starting at 6 weeks of age) or vehicle was administered to 40 female R6 / 2 mice. As shown in FIG. 26A, 50% of vehicle-treated R6 / 2 mice died at about 15 weeks of age, and treatment with P7C3 delayed animal death for about 3 weeks. At 14 weeks of age, treatment with R6 / 2 mice P7C3 showed an improvement in overall status score and appearance as shown in FIG. 26B compared to vehicle-treated littermates. The general condition score is determined by a three-point scoring performed blindly on the genotype and treatment group (score 0 = appearing fur, normal posture (no curvature), clear eyes, agility; score 1 = Hair begins to stand upside, slightly curved; score 2 = raised hair (hair that was sloped), no hair care, bends in back or neck area, cortical eyes). Mortality is monitored twice a day, when the animal's death is found or when placed on its back, it is not in the correct posture, with movements that begin by gently poking for 30 seconds. From the overall appearance of hair condition, grooming and locomotor activity, treatment with R6 / 2 mice P7C3 also appears to be qualitatively better than VEH-treated R6 / 2 mutant mice (shown) Absent).

  Those skilled in the art will recognize that the HD model and other animal models can also be used to test other compounds of the embodiments disclosed herein.

Neuroprotective efficacy of aminopropylcarbazole in a Parkinson's disease mouse model:
Parkinson's disease (PD) is characterized by the death of dopaminergic neurons in the substantia nigra (SNc), a region of the brain that controls motor activity by projecting dopaminergic axons onto the striatum. It is an incurable progressive neurodegenerative disorder of primarily idiopathic origin (Lees AJ, Hardy J., Revesz T (2012) Parkinson's disease. Lancet 373: 2055-2066). The initial symptoms of PD are movement related, including tremors, stiffness, slowness of movement and hypoactivity, tremors and gait disturbances. More advanced stages of PD involve cognitive and behavioral problems including dementia. Current treatments for PD consist primarily of partial management of early motor symptoms with drugs that enhance dopaminergic signaling such as L-DOPA or dopamine receptor agonists. Unfortunately, as the number of killed dopaminergic neurons in SNc increases, these drugs cannot alleviate symptoms and further cause dyskinesia. Therefore, there is a significant unmet need for new pharmacological strategies that slow PD progression, such as drugs that can block the death of SNc dopaminergic neurons.

  We have previously reported the identification of aminopropylcarbazole (P7C3) discovered through unbiased, in vivo screening for small molecules that can enhance postnatal hippocampal neurogenesis. P7C3 exhibits enhanced neurogenesis by enantioselective stabilization of mitochondrial membrane potential and prevention of apoptosis of new neurons in the dentate gyrus (Pieper AA, et al. (2010) Discovery of a Proneurogenic, Neuroprotective Chemical. Cell 142 : 39-51). Long-term oral or intraperitoneal (ip) administration of P7C3 to rodents safely improved hippocampal function. For example, administration of P7C3 to mice with pathologically high levels of neuronal apoptosis in the dentate gyrus or to mice lacking neuronal PAS domain protein 3 (NPAS3) (Pieper AA, et al. (2005) The neuronal PAS domain protein 3 transcription factor controls FGF-mediated adult hippocampal neurogenesis in mice.Proc Natl Acad Sci USA 102: 14052-14057), restored hippocampal structure and function without apparent physiological side effects (Pieper AA, et al. (2010) Discovery of a Proneurogenic, Neuroprotective Chemical. Cell 142: 39-51). Furthermore, extensive administration of P7C3 to elderly rats safely prevented hippocampal cell death and retained cognitive ability in response to terminal aging (Pieper AA, et al. (2010) Discovery of a Proneurogenic, Neuroprotective Chemical. Cell 142: 39-51).

  Through in vivo structure-activity relationship (SAR) studies, we have identified P7C3 analogs with increased or decreased activity. In particular, the chemical variant known as P7C3A20 was observed to have greater potency and efficacy than P7C3. P7C3A20 differs from P7C3 in that the hydroxyl group at the chiral center of the linker is substituted with fluorine and a methoxy group is added to the aniline ring. This analog shows a more advantageous toxicity profile than P7C3 and is not toxic to hERG channel binding, histamine receptor binding or HeLa cells. In the same biological assay that Dimebon, a long-expanded antihistamine in Russia said to have anti-apoptotic and mitochondrial protective properties, used to discover and characterize P7C3 and P7C3A20 It was also found to show moderate efficacy. Although the chemical structure of dimebon is similar to the P7C3 group of aminopropylcarbazole, the order of activity for chemical derivatives of P7C3 is very low. Here we report that the neuroprotective activity of these agents is beyond the promotion of long-term survival of neoplastic cells in the adult hippocampus. Specifically, we have shown that most active mutants of P7C3 show strong protection of mature dopaminergic neurons in both mouse and parasite models of neurodegeneration, and substituted carbazole is a treatment for treating Parkinson's disease We propose to represent an attractive chemical framework for agent optimization.

Results Neuroprotective efficacy of P7C3, P7C3A20 and Dimebon on neonatal hippocampal neurons Adult hippocampal neurogenesis in mice is a one month long process, during which surviving cells functionally enter the central nervous system Because of the transition through a “differentiated gauntlet” that lasts about a month before being wired, most of the neoplastic cells die. We have previously discovered that about 40% of these neoplastic cells die in the first week after birth in the subgranular zone of the dentate gyrus. P7C3 was originally discovered by a one week long in vivo screening design to identify small molecules that enhance the growth or survival of neonatal hippocampal neural progenitor cells. Subsequently, bromodeoxyuridine (BrdU) pulse chase labeling confirmed that P7C3 did not affect neural progenitor proliferation, but instead enhanced neoplastic cell survival by blocking apoptosis. P7C3A20 is active at lower doses than P7C3 and has a high effect ceiling (CoE) in this 7-day in vivo assay, while Dimebon is shown to be substantially less potent and effective than P7C3 It was done.

  To more carefully compare the neuroprotective efficacy of these compounds in assisting hippocampal neurogenesis, we conducted a 30 day BrdU pulse chase survival assay dose response study (FIG. 28). Briefly, neoplastic cells were labeled with a single intraperitoneal (ip) injection of BrdU (150 mg / kg) and daily treatment of the three test compounds was started the next day. After 30 days of compound administration, mice were transcardially perfused with 4% paraformaldehyde, brains cut, viable immunohistochemical detection of BrdU following normal microscopic imaging and normalization to dentate gyrus volume Was used for quantification. As shown in FIG. 28, P7C3A20 increased neuronal survival almost 100% at the lowest dose tested (5 mg / kg / day). In contrast, neither P7C3 nor Dimebon had an effect at this dose. At the next highest dose (10 mg / kg / day), P7C3 and Dimebon showed 65% and 15% neuroprotective efficacy, respectively, while P7C3A20 showed about 175% neuroprotective ceiling (CoE). . All three compounds show their respective maximum CoE at the two highest concentrations tested (20 or 40 mg / kg / day), with the highest CoE for P7C3A20 (≈230% increase in survival) and P7C3 CoE Was intermediate (survival ≈130% increase) and Dimebon CoE was the lowest (survival ≈30%).

Efficacy assay of P7C3, P7C3A20 and Dimebon against protection from MPTP toxicity in dopaminergic neurons in mice The protective efficacy of the three test compounds against neonatal hippocampal neurons in a 30-day survival assay indicates that they are matured outside the hippocampus Inspired to test whether neurons also have neuroprotective efficacy. To study this hypothesis, we used a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of neuronal cell death. MPTP is a powerful toxin that selectively kills neurons in the substantia nigra of both rodents and primates and causes clinical symptoms similar to PD (Fukuda T. (2001) Neurotoxicity of MPTP. Neuropathology 21 : 323-332). MPTP is lipophilic and easily enters the brain where it is metabolized by the glial cell monoamine oxidase B to the highly toxic cation 1-methyl-4-phenylpyridinium (MPP ⁺ ). MPP ⁺ is selectively enriched in SNc dopaminergic neurons by high affinity to the plasma membrane dopamine transporter, and toxicity is further enhanced by the binding of MPP ⁺ to melamine in these cells. Create a depot mechanism that maintains a long-term high intracellular concentration of ⁺ . MPTP toxicity is routinely used in the study of dopaminergic neuronal cell death as a potential means of discovering new treatments for PD based on neuroprotective strategies that have proven effective in this model.

We compared the protective efficacy of our drugs with Tatton and Kish models of MPTP, which induces long-term apoptotic death of SNc dopaminergic neurons that last about 3 weeks after daily administration of short-term MPTP. Mice were treated with 30 mg / kg / day free base MPTP daily for 5 days. On day 6, 24 hours after receiving the fifth MPTP administration, daily treatment with P7C3, P7C3A20, Dimebon or vehicle was started. This test paradigm ensures that any activity observed with P7C3 or its analogs is due to neuroprotective effects, not MPTP uptake or metabolic disruption. Dose response studies were performed in mice dosed twice daily with each compound (or vehicle) and continued for 21 days (FIG. 29A). The treatment group consisted of 15 animals each. At the end of the 21-day treatment, mice were sacrificed by transcardial perfusion with 4% paraformaldehyde and the fixed brain was cut through the striatum and SNc at 30 μM intervals. Every fourth section (120 μM apart) was stained with an antibody specific for tyrosine hydroxylase (TH) (Abcam, rabbit anti-TH, 1: 2500). The TH enzyme catalyzes the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), which acts as a precursor to dopamine. TH staining therefore provides a means to immunohistochemically identify dopaminergic neurons. By counting the number of TH ⁺ cells in SNc, we were able to protect the neuroprotective efficacy of the three compounds after MPTP exposure. All microscopic analyzes were performed by two researchers blinded to treatment groups

As others have observed, MPTP administration reduces the number of SNc TH ⁺ neurons by approximately 50% (VEH) (FIG. 29A). This neurotoxicity was blocked to varying degrees by both P7C3 and P7C3A20. P7C3 enhanced survival about 40% over VEH at the 5 mg / kg / day dose, with the highest dose of P7C3 (20 mg / kg / day) providing nearly 60% protection compared to the vehicle. In contrast, the 20 mg / kg / day dose of P7C3A20 protected SNc dopaminergic neurons up to about 85% seen in normal mice not exposed to MPTP. At all doses tested, P7C3A20 provided better protection than P7C3. The CoE and potency of P7C3A20 was higher than P7C3, and the efficacy of P7C3A20 (over 30% over VEH) was expressed at a dose of 1 mg / kg / day. Dimebon was unable to protect MPTP at any dose to a measurable extent.

  In addition to enabling quantification of dopaminergic cells in SNc, TH staining is also routinely used to visualize the integrity of dopaminergic axonal protection from SNc cell bodies to striatum. . FIG. 29B shows that the highest dose of P7C3A20 (20 mg / kg / day) almost completely prevented the depletion of dopaminergic axons in the striatum after MPTP exposure. The highest dose of P7C3 was also found to provide significant qualitative protection. In contrast, Dimebon did not provide protection for dopaminergic axons in the striatum, corresponding to its lack of neuroprotective efficacy in SNc. As shown in FIG. 30, LC / MS / MS quantification of brain and blood concentrations of P7C3A20 and P7C3 confirmed that the neuroprotective efficacy of each compound correlated with the brain and blood concentration of each compound. . Remarkably, P7C3A20 showed significantly greater protective efficacy than P7C3 despite the fact that P7C3A20 accumulates in brain tissue at a concentration of less than 1/10 of P7C3. Dimebon, which did not show neuroprotective efficacy in the MPTP model of dopaminergic neuronal cell death, showed brain accumulation at a level comparable to P7C3A20.

Efficacy assay of P7C3, P7C3A20 and Dimebon against protection from MPP ⁺ toxicity in dopaminergic neurons in nematodes Genes, metabolic signaling pathways, neurotransmitters and receptor pharmacology are advanced in nematodes and vertebrates It has been reported that exposure of nematodes to MPP ⁺ selectively kills dopaminergic neurons and impairs mobility. To test the neuroprotective efficacy of P7C3A20, P7C3 and Dimebon from MPP ⁺ toxicity in nematodes, we dopaminergic neurons are driven by the dopaminergic neuron-specific promoter dat-1 Dopaminergic cell death was monitored in transgenic species of parasites that developed a green color due to GFP expression. As shown in FIG. 31, incubation of synchronized L1 larvae with 40 mM, 5 mM MPP ⁺ induced a substantially complete destruction of all four head sensory dopaminergic dendrites. For this evaluation, GFP fluorescence was observed in 20 parasites per group and performed in triplicate. Head sensory dopaminergic dendrites were observed at 40x magnification (AMG, Evos fl microscope) and GFP signal was followed from the nerve ring to the tip of the nose according to established protocols. If any part of the dendrite was missing as assessed by loss of GFP signal, it was counted as degradation. All analyzes were performed blind to treatment groups.

Combined treatment of MPP ⁺ exposed parasites with 10 μM P7C3A20 resulted in 80% protection. In comparison, the neuroprotective efficacy of the same dose of P7C3 was only about 50%. The neuroprotective efficacy of both agents decreased with decreasing drug doses. From these measurements, P7C3A20 showed greater potency than P7C3, with 30% neuroprotective efficacy starting at the 0.1 μM dose. In comparison, P7C3 was not effective (35%) until 1.0 μM was administered. Administration of the highest dose (10 μM) of Dimebon failed to protect parasite dopaminergic neurons from MPP ⁺ -induced toxicity.

P7C3, P7C3A20 and Dimebon efficacy assay for protection from MPP ⁺ -induced mobility deficits in nematodes Parasite mobility was measured 32 hours after MPP ⁺ exposure as a behavioral indicator of toxicity. To quantify parasite locomotion, video representations were recorded for 10 seconds using a Nikon Eclipse 80i microscope at 4x magnification. Each video segment contained 160 frames, and each parasite head (10-20 parasites per group, triplicate) was manually associated using Imera software. The body of each parasite was also measured with Imera software. The ratio of distance traveled to body length was used to determine the motor index, defined as spontaneous motion, as previously established (Wang J., et al. (2009) An ALS-linked mutant SOD1 produces a locomotor defect associated with aggregation and synaptic dysfunction when expressed in neurons of Caenorhabditis elegans. PLoS Genetics e10003350). As shown in FIG. 32, locomotor activity was reduced by 50% in nematodes 32 hours after exposure to 5 mM MPP ⁺ . Co-incubation of 10 μM P7C3A20 with MPP ⁺ exposed parasites resulted in 80% conservation of locomotor activity, 10 μM P7C3 protected to about 60% of normal levels. Dimebon did not provide protective efficacy in this behavioral assay.

Correlation of efficacy of novel analogs of P7C3 in in vivo hippocampal neurogenesis assay and neuroprotective efficacy in MPTP-mediated dopaminergic cell death In the past two years we have improved the potency, efficacy and physical properties of the P7C3 series of molecules In order to eliminate real or perceived chemical disadvantages, exhaustive structure-activity relationship (SAR) studies were conducted. To date, we have synthesized over 300 P7C3 analogs, all of which have been evaluated in primary screening in an in vivo hippocampal neurogenesis assay. Our attempts include, but are not limited to, removal of bromine and aniline rings, increased biological activity, decreased lipophilicity, elimination of toxicity such as hERG channel binding, increased solubility and decreased molecular weight. Here we show the results of evaluation of 8 of these novel analogs (FIG. 33A) hippocampal neurogenesis assay (4 mice each compound) and MPTP protection assay (10 mice each compound) (FIG. 33B). All analyzes were performed blinded to treatment groups.

  With respect to the original P7C3 skeleton, P7C3-S7 differs in that aniline NH is replaced with a sulfide linker, P7C3-S8 differs in that the aniline phenyl ring is replaced with pyrimidine, and P7C3-S25 replaces the aniline moiety with dimethylpyrazole. It differs in the point (FIG. 33A). As shown in FIG. 33B, all eight test molecules crossed the blood brain barrier. P7C3-S7 and P7C3-S25 were active in both hippocampal neurogenesis assay and MPTP protection assay. In contrast, P7C3-S8 lacked activity in both assays. We also tested the potency of members of the new enantiomer pair in these assays. P7C3-S40 and P7C3-S41 differ in that P7C3 and aniline NH are replaced with oxygen linkers (FIG. 33A). P7C3S40 and P7C3S41 are single enantiomers of R and S, respectively, and FIG. 33B shows that the neuroprotective activity in both assays is exclusively in the S enantiomer. P7C3-S54 differs from P7C3 mainly by the addition of a methyl group to the central carbon of the propyl linker and the addition of an OMe group to aniline (FIG. 33A). This analog was observed to retain neuroprotective activity in both assays. P7C3-S165 differs from P7C3 in that the aniline and carbinol fragments are replaced with carboxylic acids, a change that dramatically increases polarity (FIG. 33A). To be inspired, neuroprotection was observed in both assays (FIG. 33B).

  Finally, P7C3-S184 differs from P7C3 in that carbazole bromine is replaced with chlorine and aniline is replaced with naphthylamine (FIG. 33A). This molecule was inactive in both in vivo assays. P7C3-S184 has been reported as a β-secretase (BACE1) inhibitor (Asso V., et al. (2008) alpha-naphthylaminopropan-2-ol derivatives as BACE1 inhibitors. ChemMedChem 3: 1530-1534). BACE1 is an aspartate proteolytic enzyme that catalyzes the formation of Aβ peptide from amyloid precursor protein, and has been proposed as a therapeutic target for Alzheimer's disease. By analysis of BACE1 inhibition using our P7C3 series of multiple molecules, we found no correlation between neuroprotective efficacy and BACE1 inhibition in our in vivo model (data not shown).

Discussion The results of unbiased screening, independent of the target of 1,000 chemically different drug-like compounds, led to the identification of aminopropylcarbazole conferred with the ability to enhance adult neurogenesis. This compound, designated P7C3, was found to act by blocking the death of newborn neurons in the dentate gyrus of adult mice. Here we asked for an answer to a simple question. If P7C3 can protect the death of newborn neurons during hippocampal neurogenesis in adult mice, this compound may also protect against the death of neurons that are present in animal models of neurodegenerative diseases. More specifically, we administered MPTP to mice as a means of killing dopamine neurons. Twenty-four hours after the toxin was removed, mice were treated with the three compounds for 3 weeks at various doses. The mice were then sacrificed and assayed for evidence of neuroprotective efficacy. As a second, relevant animal model of neuronal cell death, nematode parasites were co-treated with MPP ⁺ as a means of assessing neuroprotective activity, various doses of P7C3, P7C3A20 and Dimebon.

  Three compounds, P7C3, its structure-related analog P7C3A20, and Dimebon were selected for large-scale testing because of their knowledge that they exhibit characteristic proneogenic activity. Among the many P7C3 chemical analogs evaluated in the first reported study in this category of pro-neurogenesis compounds, P7C3A20 showed the highest potency and ceiling of neurogenesis. In addition to the P7C3 and P7C3A20 compounds, we added Dimebon to this study for two reasons. First, even though both P7C3 and Dimebon contain tricyclic heterocycles, Dimebon was found to show significantly lower levels of potency and efficacy compared to P7C3 in our original studies. Its neurogenesis-promoting activity in the adult mouse hippocampus was only seen at relatively high doses, and the ceiling of the effect was clearly lower compared to both P7C3 and P7C3A20. Similarly, when tested for the ability to protect mitochondrial membrane integrity after exposure of cultured cells to calcium ionophore, Dimebon showed 100-1,000 times lower protective efficacy than P7C3. Second, Dimebon has been subjected to extensive clinical trials in both Alzheimer's disease and Huntington's disease. Despite early signs of efficacy in Phase II trials for Alzheimer's disease (Doody RS, et al. (2008) Effect of Dimebon on cognition, activities of daily living, behavior, and global function in patients with mild-to -moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled study. Lancet 372: 207-215), Dimebon failed in two phase III trials. Neuroprotective efficacy of the first (P7C3A20) having a very advantageous potency profile as a neurogenesis-promoting compound, the second (P7C3) having an intermediate potency profile and the third (Dimebon) having a much weaker potency profile By testing the properties of these three compounds in this sex study, we tested whether this hierarchy of activity remains.

  Inspired, we observed that the A20 chemical variant of P7C3 showed significant neuroprotective efficacy in the MPTP model of both rodent and parasite dopaminergic neuronal cell death. P7C3, a parent compound discovered in an unbiased screening of 1,000 drug-like compounds for proneurogenic activity, is a lower level of neuroprotective activity than P7C3A20 in mice and parasite models of dopaminergic neuronal cell death showed that. In contrast, Dimebon did not show protective activity in any assay. Although some have reported that treatment of an Alzheimer's disease mouse model (TgCRND8 mouse) with Dimebon improves memory and reduces the accumulation of insoluble Aβ42 in the brain, Dimebon is a Parkinson that we use. The activity providing neuroprotection in the disease model appeared to be too weak.

  We concluded that P7C3 and P7C3A20 have a hierarchy of activities similar to their ability to protect dopaminergic neurons from MPTP-induced cell death and protect newborn hippocampal neurons from cell death. If true, this interpretation is a relatively straightforward we use to monitor the activity of hundreds of chemical variants of P7C3, which monitors adult neurogenesis over 7 days after direct administration of test compounds to the adult mouse brain. The possibility arises that the assay may represent a reliable surrogate for the refinement of drug-like compounds with broad neuroprotective activity. In fact, we have now observed this correlation in an unbiased, blinded analysis of nine P7C3 analogs. Five of these molecules show significant potency in our standard in vivo hippocampal neurogenesis assay, and the same five molecules also show significant neuroprotective efficacy from MPTP-mediated neurotoxicity of dopaminergic neurons. It was. The four analogs that were inactive in in vivo neurogenesis also showed no efficacy in the in vivo MPTP neurotoxicity assay. Taken together, these results indicate that a relatively fast evaluation of a new molecule in an in vivo neurogenesis assay is predictive of its neuroprotective efficacy in an MPTP assay

  Our ongoing SAR efforts using in vivo neurogenesis assays with our P7C3 series of molecules are certified as a fast and accurate way to refine this series of molecules into Parkinson's disease neuroprotective agents it is conceivable that. In this situation, some of the analogs shown in FIG. 33 showed potential improvements from P7C3. We were initially concerned about the presence of the aniline ring as a functional group that could be associated with toxicity. Inspired, three of the analogs (P7C3S7, -S41 and -S165) lacked an aniline ring and showed potency comparable to or greater than P7C3 in both in vivo assays. We have further recognized that P7C3 was originally identified as a racemic mixture and that this racemic mixture may require further characterization during clinical development. P7C3S41 and P7C3S165 addressed this limitation because the former is a single enantiomer and the latter lacks any stereochemistry. In addition, we sought to reduce the polarity and molecular weight of these neuroprotective compounds. P7C3S165 (mw = 383 Da vs. 474 Da of P7C3) is significantly lighter than P7C3 and is substantially much more polar with carboxylic acids. These results suggested that the physical properties of these analogs could be further improved in an attempt to optimize derivatives suitable for clinical trials.

  The interpretation that the activity of P7C3 analogs in the in vivo neurogenesis assay correlates with neuroprotective efficacy in mature neurons was consistent with the assay results for P7C3, P7C3A20 and Dimebon in a mouse model of amyotrophic lateral sclerosis. In this model, using mice expressing high levels of the human transgene encoding a mutagenized variant of the gene encoding human Cu, Zn superoxide dismutase, we have P7C3A20 active and P7C3 medium. The same hierarchy of activity was observed, with a degree of activity and dimebon inactive. The more active variants of this group of compounds actually have neuroprotective properties, and we have conducted a relatively fast in vivo assay for enhanced neurogenesis to rank compounds for structure-activity relationship (SAR) scoring. If it can be relied on, it should be possible to optimize the variant with the goal of selecting a properly qualified compound to proceed to human testing. To date, there are no safe tolerated neuroprotective compounds available for the treatment of any of a wide range of neurodegenerative diseases including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Based on the observations reported here, we propose that a properly optimized variant of the P7C3 class of promoting neurogenesis, a neuroprotective compound, is promising for the treatment of neurodegenerative diseases.

Materials and Methods The animal experiments described here were approved by the University of Texas Southwestern Medical Center Institutional Animal Care and Use Committee.
Statistics: All p values were obtained using Student's t-test.

Neonatal hippocampal neuronal 30-day survival assay: Because both social activity and locomotor activity enhance hippocampal neurogenesis, they were individually housed without using a wheel during the entire process, and bromodeoxyuridine (BrdU, (Sigma-Aldrich) started one week before labeling. During the test, mice had free access to food and water. BrdU was injected intraperitoneally at 150 mg / kg ip, and administration of test compound or vehicle was started 24 hours later. P7C3 and P7C3A20 were dissolved in 5% dextrose (pH 7.0) containing 2.5% DMSO and 10% Cremaphor EL (Sigma, C5135). Dimebon was dissolved in normal saline. The compounds were compared to each control and tested for 30 days at 2.5 mg / kg, 5 mg / kg, 10 mg / kg and 20 mg / kg twice daily (ip). The injection site was alternated between the right side and the left side. Each group consisted of 6 12-week-old adult male C57 Bl / 6 mice. Animals were monitored daily for general health and weight loss. The cage was changed according to general scheduling. After 30 days of compound administration, mice were sacrificed by transcardial perfusion with 4% paraformaldehyde, pH 7.4, and their brains were processed for immunohistochemical detection of BrdU incorporated into the dentate gyrus. Dissected brains were soaked in 4% paraformaldehyde overnight at 4 ° C., antifreeze treated with sucrose, and sliced into 40 μM thick floating sections coronally with a Leica SM2000R sliding microtome. BrdU antigen unmasking was accomplished by washing tissue sections in 50% formamide / 2X SSC for 2 hours at 65 ° C followed by 5 minutes 2X SSC wash followed by 30 minutes incubation at 37 ° C with 2M HCl. Sections were processed for immunohistochemical staining with mouse monoclonal anti-BrdU (1: 100, Roche). Diaminobenzidine was used as a chromogen and tissues were counterstained with hematoxylin as an aid in visualization in neuroanatomy. Images were analyzed with a Nikon Eclipse 90i motorized research microscope equipped with a Plan Apo lens connected to Metamorph Image Acquisition software (Nikon). All staining quantification was performed blinded to treatment groups. The number of BrdU ⁺ cells in all the dentate gyrus, and quantitated by counting BrdU ⁺ cells 5 in the dentate gyrus each section of the entire hippocampus, and normalized to the dentate gyrus volume.

P7C3-S7, -S8, -S40, -S41, -S54, -S165 and -A20 were synthesized as described above.
P7C3-S184 was synthesized as previously described in Asso et al. (2008) alpha-naphthylaminopropan-2-ol derivatives as BACE1 inhibitors. ChemMedChem 3: 1530-1534.

Pharmacokinetic analysis: C57BL / 6 mice were treated with MPTP, and 21-day IP administration of compounds was used for pharmacokinetic (PK) analysis of total levels of P7C3, P7C3A20 and Dimebon in plasma and brain. In another set of experiments designed to test the ability of new P7C3 analogs to cross the blood brain barrier, C57BL / 6 mice were dosed once at 10 mg / kg IP. P7C3, P7C3A20 and Dimebon were formulated for administration as described above. Analogs were formulated in 5% dextrose, pH 7.4, containing 5% DMSO and 10% Cremophor EL, except that P7C3-S8 is 10% DMSO and 20% Cremophor dissolved in 5% dextrose for delivery. Needed EL. Six hours after the final dose, the animals were inhaled with an excessive amount of CO ₂ and whole blood and brain were collected. Plasma was prepared from blood and stored at −80 ° C. with brain tissue until analyzed. Brain homogenates were prepared by homogenizing the tissue with 3 volumes of PBS. Whole brain homogenate volume was estimated as mL of brain volume plus PBS. 100 mL of plasma or brain homogenate is treated with the addition of methanol or acetonitrile containing 2-fold or 4-fold excess formic acid and internal standard (IS), N-benzylbenzamide (Sigma-Aldrich, lot # 02914LH) Tissue protein was precipitated to release the bound drug. The final formic acid concentration was 0.1% and the final IS concentration was 25 ng / ml. Extraction conditions were optimized prior to PK analysis for efficient and reproducible recovery over a 3 log range of concentrations. Samples were vortexed for 15 seconds, incubated for 10 minutes at room temperature, and spun at 2 × 16,100 g in a standard refrigerated centrifuge. The supernatant was analyzed by LC / MS / MS. A standard curve was prepared by adding the appropriate compound to plasma or brain homogenate. The value of signal more than 3 times that of blank plasma or brain homogenate was designated as the limit of detection (LOD). The limit of quantification (LOQ) was defined as the lowest concentration at which the back calculation yielded a concentration that exceeded the LOD signal within 20% of the theoretical value. Plasma and brain LOQ values ranged from 0.5 to 500 ng / ml, but were well below the concentrations measured at 6 hours for all compounds. Compound levels were monitored by LC / MS / MS using an AB / Sciex (Framingham, Mass.) 3200 Qtrap mass spectrometer coupled with Shimadzu (Columbia, MD) Prominence LC. The compound is a mass spectrometer in MRM (multiple reaction monitoring) mode, from precursor to fragment ion transition, P7C3 474.9 → 337.8 (pos. Mode; M + H ⁺ ), P7C3A20 507.0 → 204.1 (pos. mode; M + H ⁺ ), 320.3 → 277.3 for Dimebon (pos. mode; M + H ⁺ ), 381.9 → 80.7 (neg. mode; M−H ⁺ ) for P7C3-S165, P7C3 -S54 at 519.0 → 338.0 (pos. Mode; M + H ⁺ ), P7C3-S7 at 536.0 → 536.0 (redundant MRM) (neg. Mode; M + HCOO ⁻ ), P7C3-S41 at 520.0 → 520.0 (neg. Mode; M + HCOO ⁻ ); 520.1 → 520.1 (neg. Mode; M + HCOO ⁻ ) in P7C3-S40, 477.1 → 138.2 (pos. Mode; M + H in P7C3-S8) ^+), in the P7C3-S25 478.0 → 53.2 (. Pos mode; M + H +) and in P7C3-S184 435.2 → 248.2 (pos mode;. M + H +) was detected in accordance with. The IS, N-benzylbenzamide, was monitored using the 212.1 → 91.1 transition (pos. Mode; M + H ⁺ ). An Agilent (Santa Clara, CA) XDB C18 column (50 × 4.6 mm, 5 micron packing) was used for chromatography with the following conditions: Buffer A: dH20 + 0.1% formic acid, Buffer B: Methanol + 0.1 % Formic Acid, 0-1.5 min 0% B, 1.5-2.5 min gradient to 100% B, 2.5-3.5 min 100% B, 3.5-3.6 min 0% Gradient to B, 3.6-4.5 min 0% B. Chromatographic conditions were the same for all compounds except the initial and final concentrations of Buffer B set at 0% for P7C3 and P7C3A20 and 3% for Dimebon and all other P7C3 analogs.

Nematode maintenance: Nematodes were grown on nematode growth medium (NGM) agar at 20 ° C. in 60 mm Petri dishes according to standard protocols. The parasite bait was E. coli fortified strain HB101. All experiments were performed using BZ555 [Pdat-1 :: GFP] obtained from the Ceanorhabditis Genetics Center at the University of Minnesota, USA. BZ555 is an integrated transgenic strain (chromosome IV) that expresses GFP under the control of the dopamine neuron-specific promoter dat-1. In order to obtain first stage synchronized larvae (L1's), the spawning adults are treated with alkaline hypochlorite solution, washed 3 times with M9 buffer according to standard protocols, to 6 ml of M9. Suspended and shaken at room temperature for 12-14 hours. Compound testing was performed in a 12-well plate (BD Falcon; Thermo Fisher Scientific Inc.) with a HB101 bacterial density of 2 with compound and OD600 at 500 μl in PBS.

Evaluation of MPTP-mediated neurotoxicity to mouse SNc neurons: 15 adult male C57B1 / 6 mice were individually housed for 1 week and treated with 30 mg / kg / day (ip) free base MPTP (Sigma) for 5 days. Injections were made every day. On day 6, treatment with P7C3, P7C3A20, Dimebon or vehicle was started on the fifth, ie 24 hours after the last MPTP administration. Mice were housed in disposable cages and safety equipment and precautions were implemented in accordance with UT Southwestern Medical Center policy. Dose response studies were performed in mice injected intraperitoneally with twice daily doses of each compound (or vehicle), after which the mice were sacrificed by transcardial perfusion with 4% paraformaldehyde. Brains were dissected and fixed with 4% paraformaldehyde overnight and antifreeze treated for freezing with sucrose according to standard methods. Frozen brains were cut from the striatum to SNc at 30 μM intervals and every fourth section (120 μM apart) was stained with an antibody against tyrosine hydroxylase (TH) (Abcam, rabbit anti-TH, 1: 2500). . Diaminobenzidine was used as a chromogen and tissues were counterstained with hematoxylin as an aid in visualization in neuroanatomy. Images were analyzed with a Nikon Eclipse 90i motorized research microscope equipped with a Plan Apo lens connected to Metamorph Image Acquisition software (Nikon). TH ⁺ neurons were counted by two researchers in each section in a blinded manner with Image J software (NIH), the results averaged, and section intervals multiplied to give the total number of TH ⁺ neurons per SNc. Were determined.

Evaluation of MPP ⁺ dopaminergic neurocytotoxicity in nematodes: Synchronized L1 larvae containing PBS, vehicle or compound in the presence or absence of 5 mM MPP ⁺ iodide (Sigma) freshly diluted in PBS 12 Well plates (about 400 larvae / well) were seeded. DMSO was used as vehicle (VEH) and the concentration in the treatment group was kept below 1%. The assay solution (500 ml) was incubated for 40 hours at 20 ° C. The parasite was washed with dH ₂ O and the supernatant was aspirated. To test for dopaminergic neurocytotoxicity, the parasites were anesthetized for 5 minutes (0.1% tricaine, 0.01% tetramisole), transferred to a microscope slide and covered with a cover slide. Images were taken at 40x magnification (AMG, Evos fl microscope). Each experiment was performed in triplicate with a count of 10-20 parasites per condition. For quantification, researchers were blinded to treatment conditions. Quantification was performed by observing all four head sensilla (CEP) dendrites according to standard protocols. Briefly, GFP fluorescence was visualized from the neural ring to the tip of the nose and if any part of the dendrite was missing, it was counted as degradation.

Nematode locomotor analysis: A video-based assay was used to assess swimming speed, distance traveled and parasite length. After 32 hours exposure to MPP ⁺ , the parasites were washed, resuspended in M9 buffer (500 μl) and transferred to a microscope slide. A 10-second video was taken at 4x magnification using a Nikon Eclipse 80i microscope. Each animation consisted of 160 frames, and the distance traveled by each parasite head was manually tracked in each frame using Imera software. This software was also used to measure parasite length. Following a standard protocol, exercise distance versus body length was used as an exercise index and defined as spontaneous exercise.

Neuroprotective efficacy of aminopropylcarbazole in a mouse model of amyotrophic lateral sclerosis ALS, also known as Lou Gehrig's disease, is a relatively rare, adult-onset, rapidly developing, including spinal motor nerve degeneration It is a fatal disease (Tandan R, Bradley WG (1985) Amyotrophic lateral sclerosis. Part 1. Clinical features, pathology, and ethical issues in management. Ann Neurol 18: 271-280). This disorder causes muscle weakness and atrophy throughout the body, and patients with ALS eventually lose all spontaneous movement. The part of the body that is most affected by ALS reflects the motor nerve that was initially damaged. Regardless of the onset area, as the disease progresses, muscle weakness and atrophy consistently spread to other parts of the body. Although the progression of the disease varies from person to person, most patients will eventually be unable to stand or walk, go in and out of bed, or use their hands and arms. Chewing, swallowing and respiratory problems lead to progressive weight loss and increased risk of asphyxiation and aspiration pneumonia. Most patients require ventilator assistance as the diaphragm and intercostal muscles weaken toward the final stage of the disease. Patients with ALS most commonly die within 2-5 years after diagnosis due to respiratory failure or pneumonia. There is currently no treatment for ALS.

  About 20% of inherited cases of ALS and 3% of sporadic cases are associated with autosomal dominant mutations in the SOD1 gene on chromosome 21, and to date about 150 mutations have been identified in this gene. SOD1 encodes cytoplasmic Cu / Zn superoxide dismutase, an antioxidant enzyme that protects cells by converting superoxide (a toxic free radical produced through normal mitochondrial metabolic activity) to hydrogen peroxide. Free, free radicals damage both mitochondrial and nuclear DNA and cellular proteins. In ALS associated with SOD1 mutations, motor neuronal cytotoxicity appears not to be due to loss of dismutase activity, but to toxic SOD1 function gain. The exact molecular mechanism underlying toxicity is unknown, but mutagenic conformational changes in SOD1 result in misfolding followed by cytotoxic aggregation of cell body and axon mutant SOD1. Aggregate accumulation of mutant SOD1 is thought to interfere with cell function and induce neuronal cell death by damaging mitochondria, proteasomes, protein folding chaperones or other proteins.

  It is currently used to study pathogenic mechanisms that are believed to be widespread in transgenic animal models ALS of mutant SOD1, such as G93A-SOD1 mutant mice. Mice hemizygous for the G93A-SOD1 transgene express 18 ± 2.6 copies of the form of SOD1 found in some FALS patients (glycine to alanine substitution at codon 93). This is the first mutant form of SOD1 expressed in mice and the most widely used and well characterized mouse model of ALS. The superoxide dismutase activity of these mice remains such that the pathogenic effect of the mutant transgene appears to gain function, as is believed to occur in human patients. In these mice, motor neuron death occurs in the anterior horn of the spinal cord leading to paralysis and muscle atrophy. At about 100 days of age, G93A-SOD1 mice characteristically experience more than one limb paralysis due to loss of spinal motor neurons. Paralysis spreads rapidly throughout the body, resulting in the death of 50% of mice within 7 weeks of disease onset.

  We have reported a proneurogenic, neuroprotective aminopropylcarbazole (P7C3) discovered through in vivo screening that does not depend on the target of postnatal hippocampal neurogenesis (Pieper et al. (2010) Discovery of a Proneurogenic). , Neuroprotective Chemical. Cell 142: 39-51). Long-term administration of P7C3 to mice with pathologically high levels of neuronal apoptosis in the dentate gyrus restored hippocampal structure and function without obvious physiological side effects. Furthermore, extensive administration of P7C3 to elderly rats prevented hippocampal cell death and retained cognitive ability in response to terminal aging.

  We have synthesized and characterized a variant of P7C3 known as P7C3A20 that has greater potency and ability to promote neurogenesis than the parent compound. P7C3A20 is structurally different in that the hydroxyl group at the chiral center of the linker is substituted with fluorine and a methoxy group is added to the aniline ring. P7C3A20 also showed a more favorable toxicity profile than P7C3, with no hERG channel binding, histamine receptor binding or toxicity to HeLa cells. We have reported that Dimebon, an antihistamine that is chemically related to P7C3 and reported to have anti-apoptotic and mitochondrial protective properties, is moderate in the same biological assay used to discover and characterize P7C3 and P7C3A20. Found to have efficacy. However, this effect was a substantially low potency and effect ceiling (CoE).

  Using three related compounds, one with very high proneurogenic activity (P7C3A20), one with moderate activity (P7C3) and one with weak activation (Dimebon), we Efficacy studies were initiated with two animal models of degenerative disease. We have reported evidence of significant neuroprotective activity of P7C3A20 above in a rodent model of Parkinson's disease (PD). P7C3 showed moderate activity in the PD animal model and there was no evidence of efficacy at Dimebon. The correlated activity of compounds tested in neurogenesis and PD assay was extended to 8 analogs of P7C3. In all cases, the derivative of P7C3 that was active in the neurogenesis assay was also active in the animal model of PD, and the inactive variant was inactive in both assays.

  Here we scored the activities of P7C3A20, P7C3 and Dimebon in the model of neuronal cell death outside the brain using the same technique. To address this challenge, we used G93A-SOD1 mutant mice, a model of amyotrophic lateral sclerosis (ALS), characterized by spinal motor neuron death with reduced motor function. Here we report strong activity of P7C3A20, moderate activity of P7C3 and inactivity of Dimebon in the G93A-SOD1 mouse model of ALS, as seen in the rodent model of PD.

Results Efficacy of early administration of P7C3 to G93A-SOD1 mutant mice prior to disease onset As the first test of efficacy in this disease model, we started at 40 days of age, 20 mg / kg / day Using the P7C3 treatment paradigm, female G93A-SOD1 transgenic mice were administered P7C3 intraperitoneally and vehicle was administered to the siblings. This treatment scheme was selected based on a standard protocol for initial proof-of-concept screening in G93A-SOD1 mutant mice. As a control for transgene copy number, mouse siblings were matched between treatment groups according to standard protocols, and quantitative PCR was performed to confirm that copy number was maintained within the normal range. After initiation of P7C3 or vehicle treatment, the day of disease onset was determined by peak body weight, and the initial progression of the disease was defined as the day when mice were 10% below maximum body weight. Mice are also evaluated daily by standard measurements of neurological severity scores ranging from 0-4, with high numbers reflecting large neurological dysfunction. In addition to weight loss, a score of 2 or worse for 2 consecutive days was also used as an indicator of disease progression.

  P7C3 treatment delays the onset of disease by delaying disease progression in G93A-SOD1 mice 10% below the maximum body weight of the mice. Treatment with P7C3 also significantly delays the age at which G93A-SOD1 mice reach neurological severity score 2, another marker of disease progression. Furthermore, P7C3 treatment significantly improves the performance of the accelerated rotarod task associated with disease in these mice, suggesting a delay in the progression of motor dysfunction in the disease process. This delayed effect of disease progression was not reflected in increased animal survival and was consistent with other studies where there was a reduction in disease symptoms in a rodent model of ALS without improved survival.

Efficacy of administration of P7C3A20, P7C3 and Dimebon on disease development by preventing spinal motor neuron death in G93A-SOD1 mutant mice Based on the promising results of early (day 40) administration of P7C3 to G93A-SOD1 mutant mice, Next, we attempted to determine whether P7C3A20, P7C3 or Dimebon can protect anterior horn spinal motor neurons when administered when disease onset is predicted (day 80). We started to administer P7C3, P7C3A20 or Dimebon at a dose of 20 mg / kg / day, respectively, and motor neuron survival was analyzed by lumbar spinal cord section staining for choline acetyltransferase (ChAT). ChAT, an enzyme that synthesizes the neurotransmitter acetylcholine, serves as a marker for spinal motor neurons. All sections were counted blinded to treatment groups for quantification of motor neuron survival, and 5 mice in each treatment group were analyzed on days 90, 100, 110 and 120 did. Each treatment group was compared to a sibling match group that received the corresponding vehicle.

  As shown in FIG. 34, the wild-type bar represents the average number of spinal motor neurons of one mouse among 110 days old, vehicle-treated, wild-type littermates. Since motor neuron survival was not different in the various vehicle treatment groups at any time, the results were integrated for ease of explanation. For animals expressing the G93A-SOD1 transgene, the number of spinal motor neurons decreased consistently between 90 and 120 days (FIG. 34). At all time points, treatment with P7C3A20 provided significant protection from spinal motor neuron death (FIG. 34). Treatment with Dimebon showed motor neuron loss rates indistinguishable from the vehicle treatment group. P7C3, in contrast, provided moderate protection on day 100 (p = .048) and day 110 (p = .01). However, before the mice reached 120 days of age, the P7C3 treated group had similar motor neuron loss to the vehicle and Dimebon treated groups. Representative immunohistological staining of the spinal cord section is shown in FIG. 34 from each of the 5 mice tested on day 110. Taken together, these results demonstrate that daily administration of P7C3A20 starting at disease onset effectively blocks spinal motor neuron death in G93A-SOD1 mutant mice. P7C3 activity was lower than P7C3A20 from these measurements, and Dimebon was completely devoid of neuroprotective activity.

Comparison of efficacy of administration of P7C3A20, P7C3 and Dimebon at disease onset for protection of rotarod ability in G93A-SOD1 mutant mice. As evidence of compound-mediated protection of spinal motor neurons was observed, we It was investigated whether or not the mice were protected. Motor performance was monitored by an accelerated rotarod task that is typically used in the evaluation of ALS rodent models. We again started P7C3, P7C3A20 or Dimebon on day 80 at 20 mg / kg / day with a minimum of 20 mice per treatment group. Each animal in each group had its sibling match vehicle control and the study was performed blind to the treatment group. Rotarod training was started on day 50 for 2 days and weekly replicates were performed every 7 days thereafter. Each mouse was tested 4 times for each 600 seconds, with a 20 minute recovery time during the test. Latency to fall is an average over 4 tests.

  As shown in FIG. 35, the ability of all treatment groups was comparable at 10 and 11 weeks. Treatment with the test compound started on day 80 between weeks 11 and 12, with no significant difference between groups at week 12. However, at week 13, P7C3A20 treated mice showed significantly better performance than the corresponding vehicle treated group (p = 0.019). The following week, P7C3 and Dimebon, and the entire vehicle group, continued to decline at a constant rate in this task, and P7C3A20 treated mice behaved significantly better at each time point. Rotarod data was not collected after week 16 because too few animals survived to make a reasonable comparison between groups.

  As indicated by the early onset of P7C3 administration (day 40), this intervention improved rotarod performance but did not extend mouse survival. Also, despite the improvement in rotarod performance of P7C3A20 treated mice when daily treatment was started on day 80, no delay was observed with other indicators of disease progression (neurology score or weight loss). This observation may reflect the increased efficacy burden associated with compound administration at the onset of disease. Taken together, our results indicate that administration of P7C3A20, the most potent member of the P7C3 series of neuroprotective agents, at disease onset significantly improves the ability of G93A-SOD1 mice in the accelerated rotarod test. . Both P7C3 and Dimebon had insufficient motor function protection activity in the accelerated rotarod task at 20 mg / kg / day when administration was started at the onset of disease.

Comparison of efficacy of administration of P7C3A20, P7C3 and Dimebon at disease onset for protection of gait in G93A-SOD1 mutant mice. Analysis of gait is a second tool to assess limb strength and coordination in ALS rodent models It is. We performed this analysis on the same mice used for the accelerated rotarod task at three time points on days 90, 118 and 132. Briefly, the front paws of each test mouse were soaked in orange tempera paint and the hind paws were soaked in blue tempera paint. The mice were then guided into a bisected PVC tube placed on artists easel paper to allow the mice to walk a distance of 30 inches and leave a footprint on the paper. Footprint key parameters were poisoned manually as described in the method. These parameters include forelimb and hindlimb stride length, front and back width, and forelimb to hindlimb distance (FIG. 36A).

  A total of 20 measurements (10 on each side) were recorded for each parameter per mouse, and 20 mice per group were measured at 90 and 118 days. All measurements were performed blind to the treatment group. By day 132, forelimb and hindlimb widths were not different as a function of treatment group or disease progression, at which time P7C3A20 treatment was observed to protect hindlimb stride. Three of the measured parameters (hindlimb stride, hind-front distance and forelimb stride) showed significant improvement as a function of treatment with P7C3A20 early in disease progression, and these in pacing analysis at 20 mg / kg / day None of the parameters improved significantly with treatment with P7C3 or Dimebon (FIG. 36B).

  The hindlimb stride is defined as the distance between each successive hindlimb footprint on one side, and one of the first characteristics of the disease in G93ASOD1 mutant mice is hindlimb muscle weakness. As the disease progresses, the mouse cannot move the hind limbs equal to each stride and the hind stride distance decreases. This was evident on day 118 when the P7C3, Dimebon and all vehicle treatment groups showed a decrease in hindlimb stride length (FIG. 36B). Measurements of hind limb stride were significantly (p = .0016) maintained at near normal levels in P7C3A20 treated mice (FIG. 36B). Forelimb stride is similarly defined as the distance between each successive forelimb footprint on one side, and this measure also prevents the mouse from moving longer distances for each stride as the disease progresses. Shortens as a result of the decrease in stride of each hind limb. Thus, the loss of forelimb stride length confirmed the deficit associated with hindlimb stride length and we observed that at day 118 this measurement was actually reduced in the P7C3, Dimebon and all vehicle treatment groups, P7C3A20 treated mice were still maintained at near normal levels (FIG. 36B).

  On day 132, the number of mice in the P7C3-VEH and Dimebon-VEH groups that could participate in this task was insufficient due to complete paralysis of limb abnormalities in most of the original study group. However, in the A20-VEH group, 10 P7C3A20 mice were still able to walk across the paper. Here we observed that improvements in hindlimb and forelimb stride are protected, but there is no longer a difference in hind-front distance. The back-front distance is defined as the distance between the hindlimb footprint and the forelimb footprint on the same side. As the disease progresses early in this animal model of ALS, the hind-front distance is normal for the forelimbs, but the hindlimbs are not strong enough to create the appropriate stride, which is the forelimb footprint. To reach the landing of the rear leg on the top, it stretches constantly. Assayed on day 118, it is demonstrated in FIG. 36B that treatment with P7C3A20 attenuates this post-previous distance increase. However, on day 132, there was no difference in the back-to-front distance of VEH-treated and P7CA20-treated mice. At this stage, the disease has progressed considerably and this measurement reflects a further complication of weakening of the forelimbs that prevents the mice from extending their forelimbs normally. As a result, the back-front distance decreased and there was no difference between the P7C3A20 group and its sibling match media group. Taken together, the results of our pacing analysis show that treatment with P7C3A20 at disease onset helps protect the pacing of the ALS G93A-SOD1 mouse model.

Analysis of plasma, brain and spinal levels of P7C3, P7C3A20 and Dimebon LC / MS / MS quantification of brain and blood concentrations of P7C3, P7C3A20 and Dimebon allows all three compounds to enter the brain and spinal cord It was confirmed that there was (FIG. 37). Remarkably, P7C3A20 shows significantly greater protective efficacy compared to the other two compounds, despite the fact that P7C3A20 accumulates less than 1/20 of P7C3 concentration in spinal cord tissue. Dimebon, which did not show protective efficacy in G93A-SOD1 mice, showed a level of spinal cord accumulation comparable to P7C3A20. These results are comparable to the observations observed in evaluating the neuroprotective efficacy of these same three compounds in MPTP-treated mice.

Discussion The results of unbiased screening of 1,000 chemically different drug-like compounds led to the identification of aminopropylcarbazole conferred with the ability to enhance adult neurogenesis. This compound, designated P7C3, was found to act by blocking the death of newborn neurons in the dentate gyrus of adult mice. We have also discovered that P7C3, P73A20 and other active analogs protect nigrodopaminergic neurons from MPTP-induced neurotoxicity. Here we sought to determine whether a class of proneurogenic compounds would also block neuronal cell death outside the brain.

  When we assayed the protection of neonatal hippocampal or mature dopaminergic neurons from apoptotic cell death following MPTP toxicity, we demonstrated a characteristic level of proneural neurogenesis, neuroprotective activity, and therefore P7C3, P7C3A20 and Dimebon was selected for testing. P7C3A20 showed the highest potency and effect ceiling among these three molecules. We selected Dimebon for its extensive similarity in chemical structure with P7C3 and extensive studies in human clinical trials. When tested for its ability to protect mitochondrial membrane integrity after exposure of cultured cells to calcium ionophore, Dimebon showed 100-1,000 fold lower protective efficacy than P7C3. Similarly, weak activity was observed when Dimebon was assayed in our standard model of hippocampal neurogenesis. The low potency and effectiveness of Dimebon was further confirmed by its inability to protect nigrodopaminergic neurons from MPTP toxicity. In addition, Dimebon has been extensively tested in human clinical trials for both Alzheimer's and Huntington's disease. Early signs in Phase II findings suggested that Dimebon was effective in Alzheimer's disease, but the drug failed in two Phase III trials. By testing the properties of these three related compounds in this study of protective efficacy in animal models of ALS, we tested whether this hierarchy of activity remains.

  Inspired, we observed that P7C3A20 significantly blocked spinal motor neuron death in the G93A-SOD1 mouse model of ALS. Importantly, this protective effect is observed when the compound is administered at the onset of disease and correlates with the preservation of muscle strength and coordination, as assessed through accelerated rotarod testing and pace analysis. P7C3 provides moderate protection from cell death when administered at disease onset. Long-term administration of P7C3 by initiating treatment much faster (day 40) was assayed with an accelerated rotarod task to protect motor function. Dimebon did not provide protection in any of these measurements. Although the effectiveness of Dimebon in an animal model of Alzheimer's disease (TGCRND8) mice has recently been reported, this drug appeared to be too weak in providing protection in the G93A-SOD1 mutant mouse model of ALS.

  We have shown that P7C3A20 and P7C3 protect newborn hippocampal neurons from cell death, block MPTP-mediated death of mature substantia nigra dopaminergic neurons and kill spinal motor neurons in G93A-SOD1 mutant mice It was concluded that it shows a hierarchy of activities similar to its ability to protect. These collective observations show that a relatively direct assay that monitors adult hippocampal neurogenesis over 7 days after direct administration of a novel analog of P7C3 to the adult mouse brain is a refinement of drug-like compounds with neuroprotective activity. The possibility that it can represent a reliable substitute for the optimization. In the past two years, we have conducted comprehensive structure-activity relationship (SAR) studies to improve the chemical skeleton of the P7C3 series of molecules. To date, we have synthesized over 250 P7C3 analogs, all of which have been evaluated in an in vivo hippocampal neurogenesis assay. Our goal in these efforts to develop the discovery of neuroprotective agents is to maximize neuroprotective effectiveness and eliminate real or perceived chemical disadvantages. These attempts include, but are not limited to, removal of carbazole bromine, removal of the aniline ring, increased biological activity, decreased lipophilicity, elimination of toxicity such as hERG channel binding, increased solubility and decreased molecular weight. Using an in vivo hippocampal neurogenesis assay, these ongoing SAR attempts with P7C3 analogs are an efficient way to guide the optimization of this series of molecules towards neuroprotectant candidates.

  There are no safely tolerated, neuroprotective compounds available for the treatment of all forms of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Based on the observations reported here, we propose that a properly optimized variant of the P7C3 class of promoting neurogenesis, a neuroprotective compound, may be a valuable candidate for the treatment of neurodegenerative diseases.

Materials and Methods The animal experiments described here were approved by the University of Texas Southwestern Medical Center Institutional Animal Care and Use Committee.
Statistics: Total p-values were obtained using treatment of the treatment group and individual sibling-matched vehicle treatment group using Student's t-test.

Analysis of motor neuron survival in the spinal cord: After transcardial perfusion with 4% paraformaldehyde (PFA), the lumbar spinal cord was cut, fixed overnight with 4% PFA, and antifreeze treated at 4 ° C with 30% sucrose. Then, it was embedded in OCT and sliced to a thickness of 30 μM with Thermo-Fisher cryostat (HM550). Every seventh section was immunohistochemically stained with goat anticholine acetyltransferase (ChAT) (Millipore). Briefly, in _1% H _{2 O} 2 sections, 45 minutes, incubated at room temperature, washed with Tris-buffered saline (TBS), was treated with 0.1% Triton-TBS, 60 minutes, 3 Blocked with TBS solution of% BSA, 5% donkey serum, 0.3% triton-100. Sections were incubated with goat anti-ChAT (1: 100) in the same blocking solution overnight at 4 ° C. The next day, sections were washed with TBS and incubated with donkey anti-goat biotin (1: 200, Jackson Immune). The signal was amplified with Vector Labs ABC kit and diaminobenzidine was used as the chromogen. The immunostained tissue was photographed 4 times using a Nikon Eclipse 90i motorized microscope and the number of ChAT positive neurons was counted in a blinded fashion by two researchers and normalized to the frontal volume. .

Rotarod: Starting on day 50, mice were trained with accelerating rotarod using Colombia Instruments Rotamex-5. Training consisted of placing the mouse on a rotarod moving at 300 rpm for 5 seconds. The mouse is trained to stay on the rotarod for a total of 300 seconds. When the mouse fell, it was returned to the rotarod and the test was started again for 300 seconds. Training was conducted for two consecutive days. On day 52, mice underwent the first complete rotarod test as described in Current Protocols for Neuroscience. The rotarod started at 4 rpm, increased by 1.25 rpm every 20 seconds, and accelerated to 40 rpm in 600 seconds. Time to fall was recorded automatically. Each test was spaced 20 minutes to allow the mice to rest and each mouse participated 4 times. Mice were tested every 7 days until they could not stay on the rotarod for more than 10 seconds in 3 tests.

Footprint analysis: Five measurements were taken: forelimb and hindlimb stride, forelimb and hindlimb width and forelimb to hind distance as described in Current Protocols for Neuroscience. A total of 20 measurements were taken for each measurement. Forelimb and hindlimb stride lengths were collected as a straight line from one footprint to the next. The distance from forelimb to hindlimb was collected as a straight line from the hind footprint to the corresponding forefoot footprint. The response was based on the nearest forefoot footprint. The width from the footprint was measured by drawing a line at a 90 ° angle from the line connecting the previous step and the leg being analyzed. The distance was recorded as the length of the line from the leg to the stride line of the reverse footprint. Mice that reached a score of 3 were excluded from the analysis because they were unable to take paw measurements that were not used for forward movement.

  Footprints were taken at 90, 118 and 132 days of age. A 6 "x 42" PVC pipe cut in half length was placed on easyl paper (27 "x 30 1/4"). Each mouse's paw was covered with non-toxic tempera paint (front orange, back blue) and placed on one end of the pipe. The mouse ran quickly to the other end of the pipe when released, and this process was repeated until 10 distinct back and front footprints were made on each side while the subject was running. Footprints were scanned with a hand scanner and visualized for scoring with Nikon Metamorph software. Measurements were based on established guidelines.

Neurological scoring: Neurological scores were determined daily as starting on day 80 of compound treatment and were determined as follows: '0' = hind limb separated from lateral midline when tail of test mice was lifted Fully stretched, maintained for 2 seconds, lifted 2-3 times; '1' = collapse or partial collapse (weakening) or hindlimb tremor of limb extension toward the lateral midline while lifting at the tail; 2 '= at least 2 rounded toes or drag any part of the limb along the cage bottom / table while walking 12 inches;' 3 '= strong paralysis or minimal joint movement, forward movement Do not use the leg; and '4' = the mouse cannot return to the correct position within 30 seconds from either side. When score 2 was reached, the animals were given 1 fresh petri dish with wet food daily. When mice reached a score of 4 for 2 consecutive days, they were sacrificed.

Body weight data: Mice were weighed daily starting from the compound administration start date to assess disease progression and readjust the compound dose. A digital balance in increments of 0.01 g was used and when weighing, the mouse was placed in a small plastic container on the scale. Body weight was measured daily between 11 am and 1 pm.

Quantitative PCR: Quantitative PCR was performed according to guidelines established by the Jackson Laboratory protocol for SOD1-G93A mice.

Synthesis and preparation of P7C3A20: Prepare compound as described above.

Pharmacokinetic analysis of P7C3, P7C3A20 and Dimebon: Compound analysis as described above.

Other Embodiments This application claims the benefit of US Provisional Application No. 61 / 143,755, which is hereby incorporated by reference in its entirety. The disclosure of US Provisional Application No. 61 / 143,755 includes tautomers, stereoisomers and pharmaceutically acceptable salts thereof,
[Where,
R _{1 to} R ₈ are each hydrogen, heteroatoms, heteroatom functional groups and optionally substituted, optionally heteroatom lower (C ₁ -C ₆ ) alkyl;
R ₉ is hydrogen or optionally substituted, optionally a heteroatom lower (C ₁ -C ₆ ) alkyl;
R ¹⁰ and R ¹¹ are each independently hydrogen, optionally substituted, optionally heteroatom C ₁ -C ₆ alkyl, optionally substituted, optionally heteroatom C ₂ -C ₆ alkenyl, It is optionally selected from the optionally substituted heteroatom C ₂ -C ₆ alkynyl and the optionally substituted heteroatom C ₆ -C ₁₄ aryl. ]
Including, but not limited to, methods of promoting postnatal mammalian neuroprotection in patients determined to be in need of treatment, including administering to the patient an effective amount of a neurotrophic carbazole compound.

  Unless otherwise stated, all structures described herein include interchangeable tautomers as if each were described separately.

Embodiments disclosed herein include all alternative combinations of particular embodiments.
-Where R ₁ -R ₈ are each independently selected from hydrogen and halide;
Where R ₁ , R ₂ , R ₄ , R ₅ , R ₇ and R ₈ are hydrogen and R ³ and R ⁶ are halides such as Cl, Br, I and F;
-Where R ⁹ is hydrogen;
-Where R ¹⁰ is hydrogen and R ¹¹ is optionally substituted, optionally a heteroatom C ₆ -C ₁₄ aryl;
-Where R ¹⁰ and R ¹¹ together form a 5-7 membered optionally substituted heterocyclic ring;
-Where R ¹⁰ and R ¹¹ together form an optionally substituted pyrrolidine or piperidine;
-Where R ¹⁰ is hydrogen and R ¹¹ is a substituted phenyl, such as a halide- or C ₁ -C ₆ alkoxy-phenyl, containing para-, meta- or ortho-positions;
-Where R ¹⁰ is hydrogen and R ¹¹ is naphthyl;
The compound has the formula of Table 1 (here) or Table 2 (here);
Where the compound is of formula 2
Having:
Wherein (a) at least one of R _{1 to} R ₈ is a heteroatom, optionally substituted or optionally a heteroatom lower (C ₁ -C ₆ ) alkyl and at least one of R _{1 to} R ₄ Or at least one of R _{5 to} R ₈ is different; or (b) R ₉ is optionally substituted, optionally a heteroatom lower (C ₁ -C ₆ ) alkyl;
-Further comprising detection of the obtained neuroprotective effect, in particular neurogenesis; and / or It includes a precursor process that determines whether a disorder is present, in particular by detecting and / or diagnosing it.

  The embodiments disclosed herein also include the disclosed neurotrophic carbazole or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable pharmacological, particularly neurogenic, activity that was not previously known or suggested. Also provided are novel medicaments, particularly novel neurogenic, compositions, comprising acceptable additives.

  The embodiments disclosed herein also provide the disclosed novel neurotrophic carbazole and pharmaceutically acceptable salts thereof.

US Provisional Application No. 61 / 143,755 further discloses:
As used herein, the term “heteroatom” generally means any atom other than carbon and hydrogen. Preferred heteroatoms include oxygen (O), phosphorus (P), sulfur (S), nitrogen (N), silicon (S), arsenic (As), selenium (Se) and halogen, preferred heteroatom functional groups Haloformyl, hydroxyl, aldehyde, amine, azo, carboxyl, cyanyl, thiocyanyl, carbonyl, halo, hydroperoxyl, imine, aldimine, isocyanide, isocyanate, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl , Sulfo and sulfhydryl.

The term “alkyl”, either by itself or as part of another substituent, means a straight or branched chain or cyclic hydrocarbon group or combinations thereof, unless otherwise specified, which are fully saturated, Contains the specified number of carbon atoms (ie C ₁ -C ₈ means 1 to 8 carbons). Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, such as n-pentyl, n-hexyl. N-heptyl, homologues and isomers of n-octyl, and the like.

The term “alkenyl”, either by itself or as part of another substituent, means a straight or branched chain or cyclic hydrocarbon group or combinations thereof, which may be mono- or polyunsaturated, specified number of carbon atoms (i.e. C ₂ -C ₈ meaning that 2 to 8 carbon) and a one or more double bonds. Examples of alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl) and higher homologs and isomers thereof. .

The term “alkynyl”, either by itself or as part of another substituent, means a straight or branched chain hydrocarbon group or a combination thereof, which may be mono- or polyunsaturated and specified. The number of carbon atoms (ie C ₂ -C ₈ means 2 to 8 carbons) and one or more triple bonds. Examples of alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl and its higher homologues and isomers.

The term “alkylene” by itself or as part of another substituent means a divalent group derived from alkyl, for example —CH ₂ —CH ₂ —CH ₂ —CH ₂ —. Typically, an alkyl (or alkylene) group has 1 to 24 carbon atoms, and such groups of 10 or fewer carbon atoms are preferred in the embodiments disclosed herein. “Lower alkyl” or “lower alkylene” refers to a short chain alkyl or alkylene group, generally having eight or fewer carbon atoms.

  The terms “alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy) are used in their conventional sense and refer to an alkyl group attached to the rest of the molecule by an oxygen, amino or sulfur atom, respectively.

The term “heteroalkyl”, either by itself or as part of another substituent, is selected from the group consisting of the stated number of carbon atoms and 1 to 3 O, N, Si and S, unless otherwise specified. A stable straight chain or branched chain or cyclic hydrocarbon group or a combination thereof, wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom is optionally quaternized. May have been. The heteroatoms O, N and S can be present at any internal position of the heteroalkyl group. The heteroatom Si can be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the rest of the molecule. Examples _{-CH 2 -CH 2 -O-CH 3} , -CH 2 -CH 2 -NH-CH 3, -CH 2 -CH 2 -N (CH 3) -CH 3, -CH 2 -S-CH 2 _{-CH 3, -CH 2 -CH 2,} -S (O) -CH 3, -CH 2 -CH 2 -S (O) 2 -CH 3, -CH = CH-O-CH 3, -Si (CH _{3) 3,} including _-CH 2 _-CH = N-OCH ₃ and -CH = CH-N (CH3) -CH 3. For example, up to _two heteroatoms may be consecutive, as in —CH ₂ —NH—OCH ₃ and —CH ₂ —O—Si (CH ₃ ) ₃ .

Similarly, the term “heteroalkylene”, by itself or as part of another substituent, includes —CH ₂ —CH ₂ —S—CH ₂ —CH ₂ — and —CH ₂ —S—CH ₂ —CH _2. It means a divalent group derived from heteroalkyl, as exemplified by —NH—CH ₂ —. For heteroalkylene groups, the heteroatom may occupy one or both ends of the chain end (eg, alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.

The terms “cycloalkyl” and “heterocycloalkyl” by themselves or in combination with other terms refer to cyclic versions of “alkyl” and “heteroalkyl”, respectively, unless otherwise specified. Thus, a cycloalkyl group has the specified number of carbon atoms (ie, C ₃ -C ₈ means 3-8 carbons) and may also contain one or two double bonds. A heterocycloalkyl group consists of a specified number of carbon atoms and 1 to 3 heteroatoms selected from the group consisting of O, N, Si and S, wherein the nitrogen and sulfur atoms are optionally oxidized. The nitrogen heteroatom may optionally be quaternized. Further, for heterocycloalkyl, the heteroatom can occupy the position at which the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl are 1- (1,2,5,6-tetrahydropyrid-yl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl , Tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl and the like.

The terms “halo” and “halogen” by themselves or as part of other substituents, unless otherwise stated, mean a fluorine, chlorine, bromine or iodine atom. Furthermore, terms such as “haloalkyl” may be the same or different, depending on the halogen atom in a number ranging from 1 to (2m ′ + 1), where m ′ is the total number of carbon atoms in the alkyl group. It is meant to include substituted alkyl. For example, the term “halo (C ₁ -C ₄ ) alkyl” is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Therefore, the term “haloalkyl” refers to monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (where m ′ is the total number of carbon atoms in the alkyl group) ranging from 2 to (2m ′ + 1). Alkyl substituted with a halogen atom. The term “perhaloalkyl”, unless stated otherwise, means an alkyl substituted with (2m ′ + 1) halogen atoms, where m ′ is the total number of carbon atoms in the alkyl group. For example, the term “perhalo (C ₁ -C ₄ ) alkyl” is intended to include trifluoromethyl, pentachloroethyl, 1,1,1-trifluoro-2-bromo-2-chloroethyl, and the like.

  The term “acyl” refers to a group derived from an organic acid by removal of the hydroxy portion of the acid. Thus, acyl is intended to include, for example, acetyl, propionyl, butyryl, decanoyl, pivaloyl, benzoyl, and the like.

  The term “aryl” refers to polyunsaturated, usually aromatic hydrocarbon substituents, which can be monocyclic or polycyclic fused together or covalently linked (up to three rings), unless otherwise specified. means. Examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl and 1,2,3,4-tetrahydronaphthalene.

  The term “heteroaryl” refers to an aryl group (or ring) containing from 0 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms may be optionally oxidized. The nitrogen heteroatom may optionally be quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Examples of heteroaryl groups are 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5 -Oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl including.

  For brevity, the term “aryl” when used in combination with other terms (eg, aryloxy, arylthioxy, arylalkyl) includes both the above aryl and heteroaryl rings. Thus, the term “arylalkyl” refers to an alkyl group (eg, phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) in which a carbon atom is replaced by, for example, an oxygen atom (eg, a methylene group). It is intended to include radicals in which an aryl group is linked to an alkyl group, including propyl, etc.

  Each of the above terms (eg, “alkyl”, “heteroalkyl”, “aryl” and “heteroaryl”) is intended to include both substituted and unsubstituted forms of the indicated group. Preferred substituents for each type of group are shown below.

Substituents on alkyl and heteroalkyl groups (as well as groups called alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) are -OR ', = O, = NR ′, ═N—OR ′, —NR′R ″, —SR ′, halogen, —SiR′R ″ R ′ ″, —OC (O) R ′, —C (O) R ′, —CO ₂ R ', -CONR'R ", - OC ( O) NR'R", - NR "C (O) R', - NR'-C (O) NR" R '", - NR'-SO 2 NR'_{",-NR" CO 2 R '} , - NH-C (NH 2) = NH, -NR'C (NH 2) = NH, -NH-C (NH 2) = NR', - S (O) R _{', -SO 2 R', -} SO 2 NR'R ", - NR" SO 2 R, a variety of groups selected from -CN and -NO ₂ A 0-3, 0, those groups having one or two substituents being particularly preferred. R ′, R ″ and R ′ ″ are each independently hydrogen, unsubstituted (C ₁ -C ₈ ) alkyl and heteroalkyl groups, unsubstituted aryl groups, aryl substituted with 1 to 3 halogens Means a group, an unsubstituted alkyl group, an alkoxy or thioalkoxy group or an aryl- (C ₁ -C ₄ ) alkyl group. When R ′ and R ″ are attached to the same nitrogen atom, they may be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, —NR′R ″ is 1- Intended to include pyrrolidinyl and 4-morpholinyl. Typically, an alkyl or heteroalkyl group has 0 to 3 substituents, and those groups having 2 or fewer substituents are preferred in the embodiments disclosed herein. More preferably, the alkyl or heteroalkyl group is unsubstituted or monosubstituted. Most preferably, the alkyl or heteroalkyl group is unsubstituted. From the above discussion of substituents, one of ordinary skill in the art will understand that the term “alkyl” is intended to include groups such as trihaloalkyl (eg, —CF ₃ and —CH ₂ CF ₃ ).

Preferred substituents for the alkyl group and heteroalkyl group m are —OR ′, ═O, —NR′R ″, —SR ′, halogen, —SiR′R ″ R ′ ″, —OC (O) R ′, — C (O) R ′, —CO ₂ R ′, —CONR′R ″, —OC (O) NR′R ″, —NR ″ C (O) R ′, —NR ″ CO ₂ R ′, —NR ′ Selected from —SO ₂ NR ″ R ′ ”, —S (O) R ′, —SO ₂ R ′, —SO ₂ NR′R ″, —NR ″ SO ₂ R, —CN and —NO ₂ , wherein , R ′ and R ″ are as defined above. Further preferred substituents are —OR ′, ═O, —NR′R ″, halogen, —OC (O) R ′, —CO ₂ R ′, —CONR′R ″, —OC (O) NR′R ″. , -NR "C (O) R ', - NR" CO 2 R', - NR'-SO 2 NR "R '", - SO 2 R', - SO 2 NR'R ", - NR" SO 2 R, is selected from -CN and -NO _2.

Similarly, substituents for aryl groups and heteroaryl groups are also miscellaneous, and are halogen, —OR ′, —OC (O) R ′, —NR′R ″, —SR ′, —R ′, —CN, —NO ₂ , —CO ₂ R ′, —CONR′R ″, —C (O) R ′, —OC (O) NR′R ″, —NR ″ C (O) R ′, —NR ″ CO ₂ R ′, -NR'-C (O) NR " R '", - NR'-SO 2 NR "R'", - NH-C (NH 2) = NH, -NR'C (NH 2) = NH, -NH _{-C (NH 2) = NR '} , - S (O) R', - SO 2 R ', - SO 2 NR'R ", - NR" SO 2 R, -N 3, -CH (Ph) 2, Selected from perfluoro (C ₁ -C ₄ ) alkoxy and perfluoro (C ₁ -C ₄ ) alkyl, ranging from 0 to the total number of open valences of the aromatic ring system, individually R ′, R ″ and R ′ "is hydrogen, _(C 1 -C ₈₎ alkyl and het Alkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl) - (C ₁ -C ₄₎ alkyl and (unsubstituted aryl) oxy -. Is (C ₁ -C ₄₎ are independently selected from alkyl aryl group 1 , 2,3,4-tetrahydronaphthalene, it may be substituted with a substituted or unsubstituted (C ₃ -C ₇ ) spirocycloalkyl group, an outer (C ₃ -C ₇ ) spirocycloalkyl group. May be substituted as defined for “cycloalkyl.” Typically, an aryl or heteroaryl group has 0 to 3 substituents and contains 2 or fewer substituents. These groups are preferred in the embodiments disclosed herein: In one embodiment, the aryl or heteroaryl group is unsubstituted or mono-substituted. There are, aryl or heteroaryl group is unsubstituted.

Preferred substituents for the aryl group and heteroaryl group are halogen, —OR ′, —OC (O) R ′, —NR′R ″, —SR ′, —R ′, —CN, —NO ₂ , —CO _2. R ′, —CONR′R ″, —C (O) R ′, —OC (O) NR′R ″, —NR ″ C (O) R ′, —S (O) R ′, —SO ₂ R ′ , —SO ₂ NR′R ″, —NR ″ SO ₂ R, —N ₃ , —CH (Ph) ₂ , perfluoro (C ₁ -C ₄ ) alkoxy and perfluoro (C ₁ -C ₄ ) alkyl; Wherein R ′ and R ″ are as defined above. Further preferred substituents are halogen, —OR ′, —OC (O) R ′, —NR′R ″, —R ′, —CN, — NO ₂ , —CO ₂ R ′, —CONR′R ″, —NR ″ C (O) R ′, —SO ₂ R ′, —SO ₂ NR′R ″, —NR ″ SO ₂ R, perfluoro (C ₁ -C ₄₎ Al Selected from oxy and perfluoro (C ₁ -C ₄ ) alkyl.

Here, the substituent —CO ₂ H used includes its bioequivalent substituents; for example, The Practice of Medicinal Chemistry; Wermuth, CG, Ed .; Academic Press: New York, 1996; p. 203 checking ...

Two aryl rings, or substituents on adjacent atoms on the heteroaryl ring is optionally formula -T-C (O) - ( CH 2) may be replaced by q-U- substituents, wherein, T And U are independently —NH—, —O—, —CH ₂ — or a single bond, and q is an integer of 0-2. Alternatively, two of the substituents on adjacent atoms on the aryl or heteroaryl ring may optionally may be replaced in the formula -A- (CH ₂₎ r-B- substituents, wherein, A and B Independently —CH ₂ —, —O—, —NH—, —S—, —S (O) —, —S (O) ₂ —, —S (O) ₂ NR′— or a single bond, r is an integer of 1 to 3. One single bond of the new ring may be replaced with a double bond if desired. Alternatively, two of the substituents on adjacent atoms on the aryl or heteroaryl ring may optionally be replaced by substituents of the formula — (CH ₂ ) sX— (CH ₂ ) t—, where s and t are each independently an integer of 0 to 3, and X is —O—, —NR′—, —S—, —S (O) —, —S (O) ₂ — or —S (O). ₂ NR′−. The substituent R ′ of —NR′— and —S (O) ₂ NR′— is selected from hydrogen or unsubstituted (C ₁ -C ₆ ) alkyl.

Claims (20)

Formula (I)
[Where,
Each of R ¹ , R ² , R ³ and R ⁴ is independently hydrogen, halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C _{6 thiohaloalkoxy,} C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 2 -C ₆ alkynyl, cyclopropyl, -N _3, a _{cyano, -NH 2, -NH (C 1} -C 6 alkyl ), —N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro;
R and R ′ are the following (1), (2), (3) or (4)
(1) R and R ′ are combined with C ₂ and C ₃ respectively to form the formula (II)
Form a fused phenyl ring
(Wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen, halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ halo. _alkoxy, C 1 -C _{6 thiohaloalkoxy,} C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 2 -C ₆ alkynyl, cyclopropyl, -N _3, a _cyano, -NH _2, -NH _{(C 1} -C ₆ alkyl), - N _(C 1 -C _{6 alkyl)} 2, is selected from _{-NHC (O) (C 1 -C} 6 alkyl) and nitro); or
(2) R and R ′ together with C ₂ and C ₃ respectively form a fused heteroaryl ring containing 6 ring atoms (wherein 1-2 of the independently selected ring atoms are N And the heteroaryl ring may optionally be substituted with 1 to 2 independently selected R ^b ); or
(3) R and R ′ together with C ₂ and C ₃ respectively form a condensed heterocyclic ring containing 5 to 6 ring atoms (where 1 to 2 ring atoms are N, NH N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S; and the heterocyclic ring is optionally selected from 1 to 3 independently Optionally selected R ^a ); or
(4) each of R and R ′ is independently hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;
Are defined according to:
Each of L ¹ and L ² is independently C ₁ -C ₃ alkylene, which may optionally be substituted with 1 to 2 independently selected R ^c ;
A is
(i) CR ^A1 R ^A2 where each of R ^A1 and R ^A2 is hydrogen, halo, C ₁ -C ₃ alkyl, OR ⁹ (where R ⁹ is hydrogen or optionally hydroxy or C ₁ -C ₃ alkoxy is or C ₁ -C ₃ alkyl optionally substituted with) or formed between one of a and L ¹ and L ² double bonds independently selected); or
(ii) C = O; or
(iii) C ₃ -C ₅ cycloalkylene (which is (a) substituted with one oxo; and (b) optionally further substituted with 1 to 4 independently selected R ^a). Or); or
(iv) a heterocycloalkylene containing 3 to 5 ring atoms, wherein 1 to 2 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; The heterocycloalkylene is (a) substituted with 1 oxo; and (b) optionally further substituted with 1 to 4 independently selected R ^a )
Is;
Z is
(i) -NR ¹⁰ R ^11; or
^{(ii) -C (O) NR} 10 R 11; or
(iii) ^{-OR 12;} or
(iv) -S (O) _n R ¹³ where n is 0, 1 or 2; or
(v) heterocycloalkenyl containing 5 to 6 ring atoms, wherein 1 to 3 ring atoms are N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl ), O and S; and the heterocycloalkenyl may be optionally substituted with 1 to 4 independently selected R ^a ); or
(vi) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 independently selected R ^b ; or
(vii) a heteroaryl containing 5 to 14 ring atoms, wherein 1 to 6 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; Heteroaryl may be optionally substituted with 1-4 independently selected R ^b ); or
(viii) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a ); or
(ix) arylheterocyclyls containing 8-14 ring atoms, where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(x) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(xi) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;
Each of R ¹⁰ and R ¹¹ is the following (a) to (l)
(a) hydrogen;
(b) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ;
(c) 5 to 14 heteroaryl containing a ring atom (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl is optionally substituted with 1 to 4 R ^b );
(d) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl optionally substituted with 1 to 3 R ^d ;
_{(e) -C (O) (} C 1 -C 6 _{alkyl), - C (O) (} C 1 -C 6 haloalkyl) or _{-C (O) O (C 1} -C 6 alkyl);
(f) C ₂ -C ₆ alkenyl or _C 2 -C ₆ alkynyl;
(g) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a );
(h) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a );
(i) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a );
(j) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a );
(k) C ₃ -C ₈ cycloalkyl or C ₃ -C ₈ cycloalkenyl optionally substituted with 1 to 4 independently selected R ^a ; and
(l) C ₇ -C ₁₂ aralkyl (wherein the aryl moiety may be optionally substituted with 1 to 4 R ^b , independently selected)
Wherein R ¹⁰ and R ¹¹ are independently selected from the substituents collectively described in (b), (c), (g), (h), (i), (j) And must be selected from (k);
R ¹² is
(i) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or
(ii) heteroaryl including 5-14 ring atoms (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl may optionally be substituted with 1 to 4 R ^b ); or
(iii) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl substituted with 1 to 3 R ^d ; or
(iv) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a ); or
(v) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vi) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vii) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;
R ¹³ is
(i) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or
(ii) heteroaryl including 5-14 ring atoms (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl may optionally be substituted with 1 to 4 R ^b ); or
(iii) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a ); or
(iv) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(v) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vi) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;
Each R ^a is halo, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, oxo, thioxo, = NH, = N (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) ₂ It is independently selected from _{-NHC (O) (C 1 -C} 6 alkyl), and cyano;
R ^b represents the following (aa) to (dd)
(aa) C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ thiohaloalkoxy; -O- (CH ₂ ) _1-3- [O (CH _{2) 1-3] 1-3 -H; -C} 1 -C 6 _alkyl, C 1 -C ₆ haloalkyl, -NH _(C 1 -C _{6 alkyl), - N (C 1 -C} 6 _alkyl) 2, —NHC (O) (C ₁ -C ₆ alkyl), wherein each of the alkyl moieties is optionally substituted with 1 to 3 independently selected R ^e ;
(bb) halo; hydroxy; cyano; nitro; -NH _2; azido; _sulfhydryl; C 2 -C _{6 alkenyl;} C 2 -C ₆ alkynyl; -C (O) H; -C (O) (C 1 -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); - C (O) OH ; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C _{(O) NH (C 1 -C} 6 alkyl); - C (O) N (C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH _(C 1 -C _{6 alkyl); - SO 2 N (C} 1 -C 6 _alkyl) 2;
(cc) C ₃ -C ₆ cycloalkyl or heterocyclyl containing 5-6 ring atoms, wherein 1 to 2 ring atoms of the heterocyclyl are N, NH, N (C ₁ -C ₆ alkyl), NC (O ) (C ₁ -C ₆ alkyl), independently selected from O and S; and each of the phenyl and heterocyclyl is optionally substituted with 1 to 3 independently selected R ^a ) ;and
(dd) phenyl or heteroaryl containing 5-6 ring atoms, wherein 1-2 of the heteroaryl ring atoms are independently N, NH, N (C ₁ -C ₃ alkyl), O and S Wherein each of the phenyl and heteroaryl is optionally halo; hydroxyl; cyano; nitro; —NH ₂ ; —NH (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) _{2 , -NHC (O) (C 1} -C 6 _alkyl), C 1 -C _{6 alkoxy;} C 1 -C _{6 haloalkoxy;} C 1 -C _{6 thioalkoxy;} C 1 -C ₆ thiohaloalkoxy; _{C 1} - Optionally substituted with 1 to 3 substituents independently selected from C ₆ alkyl and C ₁ -C ₆ haloalkyl)
Independently selected from the substituents described in;
R ^c is halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Selected;
R ^d represents hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Selected;
Each R ^e is hydroxyl, C ₁ -C ₆ alkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thiohaloalkoxy; -NH ₂ ; -NH (C _1- C _{6 alkyl); - N (C 1 -C} 6 _{alkyl) 2; -NHC (O) (} C 1 -C 6 alkyl); cyano; -C (O) H; -C (O) (C 1 -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); - C (O) OH ; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C _{(O) NH (C 1 -C} 6 alkyl); - C (O) N (C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH _(C 1 -C _{6 alkyl); - SO 2 N (C} 1 -C 6 _{alkyl) 2;} and ^{L 3} - _(C 1 -C ₆ alkylene) - are independently selected from biotin, where L ³ is -O -, - NH -, - NCH 3 -, - C (O) -, - C (O) NH -, - C (O) NCH 3 -, - NHC (O) - or -NCH ₃ C (O)-;
However,
When A is CH ₂ and R and R ′ are defined according to definition (1), both R ³ and R ⁶ must not be hydrogen;
When A is CH ₂ and R and R ′ are defined according to definition (2), R ³ must not be hydrogen;
When A is CH ₂ , R and R ′ are defined according to definition (1), Z is —OR ¹² and R ¹² is unsubstituted phenyl, then both R ³ and R ⁶ are chloro Must not;
A is CH ₂ , R and R ′ are defined according to definition (1), Z is —OR ¹² , R ¹² is phenyl substituted with pyridyl or alkyl substituted with 1 to 3 R ^e , Both R ³ and R ⁶ must not be bromo;
When A is CH (CH ₃ ), R and R ′ are defined according to definition (1), Z is NR ¹⁰ R ¹¹ , R ¹⁰ is CH ₃ and R ¹¹ is unsubstituted phenyl, Both R ³ and R ⁶ must not be hydrogen; and if A is CR ^A1 R ^A2 and R ^A1 and R ^A2 are OH, the other of R ^A1 and R ^A2 is C ₁ -C _3. Alkyl. ]
Or a pharmaceutically acceptable salt thereof. A is
(i) CR ^A1 R ^A2 , wherein each of R ^A1 and R ^A2 is hydrogen, halo, C ₁ -C ₃ alkyl, OR ⁹ (where R ⁹ is hydrogen or optionally hydroxy or Independently selected from C ₁ -C ₃ alkyl optionally substituted with C ₁ -C ₃ alkoxy) and a double bond formed between A and ^one of L ¹ and L ² ; or
(ii) A compound according to claim 1, wherein C = O. A is CR ^A1 R ^A2 , wherein each of R ^A1 and R ^A2 is independently hydrogen, halo, C ₁ -C ₃ alkyl, OR ⁹ or between A and ^one of L ¹ and L ² 2. A compound according to claim 1 which is a double bond formed. A is CR ^A1 R ^A2 where one of R ^A1 and R ^A2 is hydrogen, halo, C ₁ -C ₃ alkyl or OR ⁹ ; the other of R ^A1 and R ^A2 is halo, C ₁ -C ₃ alkyl or oR ^9, a compound according to claim 1. ^5. The compound of claim 4, wherein the carbon attached to R ^A1 and R ^A2 is substituted with 4 different substituents. ^6. The compound of claim 5, wherein the carbon attached to R ^A1 and R ^A2 is in the (R) or (S) configuration. (R) a carbon atom in which a compound having a configuration is bonded to R ^A1 and R ^A2 is substantially free from a compound having a configuration in (S), and a carbon in which a compound having a configuration (S) is bonded to R ^A1 and R ^A2 7. A compound according to claim 6, which is substantially free of compounds whose atoms are in the (R) configuration.   6. The compound of claim 5, wherein the compound is (+) (dextrorotatory) or (-) (left-handed).   A compound in which the (+) (dextrorotatory) compound is substantially free of (−) (left-handed) compound and a compound in which (−) (left-handed) compound is (+) (dextrorotatory) is substantially The compound of Claim 8 which is not contained in. R ³ is halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C ₁ -C _{6 haloalkyl,} C 2 -C ₆ alkynyl, cyclopropyl, -N _3, a _{cyano, -NH 2, -NH (C 1} -C 6 _{alkyl), - N (C 1 -C} 6 _alkyl) 2, -NHC (O) (C ₁ -C ₆ alkyl) is selected from nitro compound of claim 1. The compound of claim 1, wherein R ³ is halo or C ₁ -C ₆ alkyl. R and R ′ are combined with C ₂ and C ₃ respectively to form the formula (II)
The compound according to claim 1, which forms a phenyl ring of R ⁶ is halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C ₁ -C _{6 haloalkyl,} C 2 -C ₆ alkynyl, cyclopropyl, -N _3, a _{cyano, -NH 2, -NH (C 1} -C 6 _{alkyl), - N (C 1 -C} 6 _alkyl) 2, -NHC (O) (C ₁ -C ₆ alkyl) is selected from nitro compound of claim 12. R ⁶ is halo or _C 1 -C ₆ alkyl, A compound according to claim 12. Z is
(i) -NR ¹⁰ R ^11; or
^{(ii) -C (O) NR} 10 R 11; or
(iii) ^{-OR 12;} or
(iv) -S (O) _n R ¹³ (where n is 0, 1 or 2)
Is;
Here, each of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ is
(a) hydrogen;
(b) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or
(c) 5 to 14 heteroaryl containing a ring atom (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl may optionally be substituted with 1 to 4 R ^b )
Selected independently from;
Here, R ^b is the following (aa) to (dd)
(aa) C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ thiohaloalkoxy; -O (CH ₂ ) _1-3 [O (CH ₂ ) _1-3 ] _1-3 H; C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, —NH (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) ₂ , —NHC (O ) _(C 1 -C ₆ alkyl);
(bb) halo; hydroxy; cyano; nitro; -NH _2; azido; _sulfhydryl; C 2 -C _{6 alkenyl;} C 2 -C ₆ alkynyl; -C (O) H; -C (O) (C 1 -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); - C (O) OH ; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C _{(O) NH (C 1 -C} 6 alkyl); C (O) N ( C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH _(C 1 -C ₆ alkyl); - SO ₂ N _(C 1 -C _{6 alkyl)} 2;
(cc) C ₃ -C ₆ cycloalkyl or heterocyclyl containing 5-6 ring atoms, wherein 1 to 2 ring atoms of the heterocyclyl are N, NH, N (C ₁ -C ₆ alkyl), NC (O ) (C ₁ -C ₆ alkyl), independently selected from O and S); and
(dd) phenyl or heteroaryl containing 5-6 ring atoms, wherein 1-2 of the heteroaryl ring atoms are independently N, NH, N (C ₁ -C ₃ alkyl), O and S Wherein each of the phenyl and heteroaryl is optionally halo; hydroxyl; cyano; nitro; —NH ₂ ; —NH (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) _{2 , -NHC (O) (C 1} -C 6 _alkyl), C 1 -C _{6 alkoxy;} C 1 -C _{6 haloalkoxy;} C 1 -C _{6 thioalkoxy;} C 1 -C ₆ thiohaloalkoxy; _{C 1} - Optionally substituted with 1 to 3 substituents independently selected from C ₆ alkyl and C ₁ -C ₆ haloalkyl)
The compound according to claim 1, which is independently selected from the substituents described in 1 above. 2. A compound according to claim 1 selected from:
(R) -1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol;
(S) -1- (3,6-Dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (2-iminopyridin-1 (2H) -yl) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylthio) propan-2-ol;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -N- (3-methoxyphenyl) acetamide;
5-((3,6-dibromo-9H-carbazol-9-yl) methyl) -3- (3-methoxyphenyl) -oxazolidine-2-one;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-one;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-methoxypropyl) -3-methoxyaniline;
1- (3,6-dimethyl-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol;
1- (3-bromo-6-methyl-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -propan-2-ol;
1- (3,6-dichloro-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol;
1- (5-bromo-2,3-dimethyl-1H-indol-1-yl) -3- (phenylamino) propan-2-ol;
1- (3,6-dibromo-9H-pyrido [3,4-b] indol-9-yl) -3- (phenylamino) propan-2-ol;
1- (3-azidophenylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
1,3-bis (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
1- (9H-carbazol-9-yl) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxy-N- (3-methoxyphenyl) -propanamide;
Ethyl 5- (2-hydroxy-3- (3-methoxyphenylamino) propyl) -8-methyl-3,4-dihydro-1H-pyrido [4,3-b] indole-2 (5H) -carboxylate;
4- (3,6-dibromo-9H-carbazol-9-yl) -1- (phenylamino) butan-2-ol;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) propyl) aniline;
1- (3,6-dibromo-9H-carbazol-9-yl) -4- (phenylamino) butan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (pyridin-2-ylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3-((3-methoxyphenyl) (methyl) -amino) propan-2-ol;
3- (3,6-dibromo-9H-carbazol-9-yl) -1- (3-methoxyphenylamino) -1- (methylthio) propan-2-one;
3-Amino-1- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) pyridinium;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (pyrimidin-2-ylamino) propan-2-ol;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxy-N-methylaniline;
1- (3,6-dibromo-9H-carbazol-9-yl) -3-methoxypropan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -4-phenylbutan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (1H-indol-1-yl) propan-2-ol;
3- (1- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -1H-1,2,3-triazol-4-yl) propan-1-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-ethoxyphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3,5-dimethyl-1H-pyrazol-1-yl) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylsulfinyl) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylsulfonyl) propan-2-ol;
1- (3-bromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol;
N- (5- (3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylamino) phenoxy) pentyl) -2- (7- (dimethylamino) -2- Oxo-2H-chromen-4-yl) acetamide;
1- (3,6-dibromo-9H-carbazol-9-yl) -3-phenoxypropan-2-ol;
N- (2- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropoxy) ethyl) -acetamide;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (pyridin-3-ylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (pyridin-4-ylamino) propan-2-ol;
1- (2,8-dimethyl-3,4-dihydro-1H-pyrido [4,3-b] indol-5 (2H) -yl) -3- (phenylamino) propan-2-ol;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2,2-difluoropropyl) -3-methoxyaniline;
1- (3,6-dibromo-9H-carbazol-9-yl) -3-phenoxypropan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (o-tolylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (m-tolylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (2-methoxyphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (naphthalen-1-ylamino) propan-2-ol;
1- (4-bromophenylamino) -3- (3,6-dichloro-9H-carbazol-9-yl) propan-2-ol;
1- (4-bromophenylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (4-ethoxyphenylamino) propan-2-ol;
1- (4-chlorophenylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenethylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (2-hydroxyethylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (2,4-dimethoxyphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (2,3-dimethylphenylamino) propan-2-ol;
1- (2-chlorophenylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
1- (tert-butylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (isopropylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (4-methoxyphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (m-tolylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3,5-dimethylphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3,4-dimethylphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3,4-dimethylphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (2,5-dimethylphenylamino) propan-2-ol;
1- (4-bromophenylamino) -3- (2,3-dimethyl-1H-indol-1-yl) propan-2-ol;
1- (2,3-dimethyl-1H-indol-1-yl) -3- (4-methoxyphenylamino) propan-2-ol;
1- (2,3-dimethyl-1H-indol-1-yl) -3- (4-ethoxyphenylamino) propan-2-ol;
1- (2,3-dimethyl-1H-indol-1-yl) -3- (p-tolylamino) propan-2-ol;
1- (2,3-dimethyl-1H-indol-1-yl) -3- (phenylamino) propan-2-ol oxalate;
1- (1H-indol-1-yl) -3- (4-methoxyphenylamino) propan-2-ol hydrochloride;
1- (1H-indol-1-yl) -3- (phenylamino) propan-2-ol oxalate;
1- (3,4-dihydro-1H-carbazol-9 (2H) -yl) -3- (m-tolylamino) propan-2-ol;
1- (9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
1- (3,6-dichloro-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
1- (9H-carbazol-9-yl) -3- (p-tolylamino) propan-2-ol;
1- (3,6-dichloro-9H-carbazol-9-yl) -3- (p-tolylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (p-tolylamino) propan-2-ol;
N- (4- (3- (9H-carbazol-9-yl) -2-hydroxypropoxy) phenyl) acetamide;
1- (9H-carbazol-9-yl) -3-phenoxypropan-2-ol;
1- (9H-carbazol-9-yl) -3- (4-methoxyphenylamino) propan-2-ol;
1- (benzylamino) -3- (9H-carbazol-9-yl) propan-2-ol;
Methyl 4- (3- (9H-carbazol-9-yl) -2-hydroxypropoxy) benzoate;
1- (9H-carbazol-9-yl) -3- (4-methoxyphenoxy) propan-2-ol;
1-amino-3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
(S) -1- (3,6-dibromo-9H-carbazol-9-yl) -3-phenoxypropan-2-ol;
(R) -1- (3,6-dibromo-9H-carbazol-9-yl) -3-phenoxypropan-2-ol;
3,6-dibromo-9- (2-fluoro-3-phenoxypropyl) -9H-carbazole;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) -2-methylpropan-2-ol;
1- (2,8-dimethyl-3,4-dihydro-1H-pyrido [4,3-b] indol-5 (2H) -yl) -3- (3-methoxyphenylamino) propan-2-ol;
1- (4-azidophenylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
1- (3-azido-6-bromo-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (4-methoxyphenoxy) propan-2-ol;
1- (3,6-dichloro-9H-carbazol-9-yl) -3- (phenylsulfonyl) propan-2-ol;
3,6-dibromo-9- (2-fluoro-3- (phenylsulfonyl) propyl) -9H-carbazole;
(S) -1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylsulfonyl) propan-2-ol;
(R) -1- (3,6-dibromo-9H-carbazol-9-yl) -3- (phenylsulfonyl) propan-2-ol;
1- (3,6-dicyclopropyl-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
1- (3,6-diiodo-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
1- (3,6-diethynyl-9H-carbazol-9-yl) -3- (3-methoxyphenylamino) propan-2-ol;
9- (2-hydroxy-3- (3-methoxyphenylamino) propyl) -9H-carbazole-3,6-dicarbonitrile;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) aniline;
3,6-dibromo-9- (2,2-difluoro-3-phenoxypropyl) -9H-carbazole;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -4-methoxyaniline;
N- (2-bromo-3- (3,6-dibromo-9H-carbazol-9-yl) propyl) -N- (4-methoxyphenyl) -4-nitrobenzenesulfonamide;
Ethyl 2- (4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropylamino) phenoxy) acetate; and N- (3- (3,6-dibromo-9H- Carbazol-9-yl) -2-fluoropropyl) -4- (2- (2-methoxyethoxy) ethoxy) aniline;
N- (2- (2- (4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropylamino) phenoxy) acetamido) ethyl) -5- (2-oxohexa Hydro-1H-thieno [3,4-d] imidazol-4-yl) pentanamide;
2- (4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropylamino) phenoxy) -N, N-dimethylacetamide;
2- (4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropylamino) phenoxy) -N- (2-hydroxyethyl) acetamide;
(E) -3,6-dibromo-9- (3-phenoxyallyl) -9H-carbazole;
(E) -3,6-dibromo-9- (3-phenoxyprop-1-en-1-yl) -9H-carbazole;
1- (3,6-bis (trifluoromethyl) -9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
1- (2,8-dibromo-10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl) -3- (3-methoxyphenylamino) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylthio) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (4-methoxyphenylthio) propan-2-ol;
3,6-dibromo-9- (2-fluoro-3- (3-methoxyphenylthio) propyl) -9H-carbazole;
3,6-dibromo-9- (2-fluoro-3- (4-methoxyphenylthio) propyl) -9H-carbazole;
3,6-dibromo-9- (2-fluoro-3- (3-methoxyphenylsulfonyl) propyl) -9H-carbazole;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (3-methoxyphenylsulfonyl) propan-2-ol;
3,6-dibromo-9- (2-fluoro-3- (4-methoxyphenylsulfonyl) propyl) -9H-carbazole;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (4-methoxyphenylsulfonyl) propan-2-ol;
3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylthio) phenol;
4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylthio) phenol;
3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylsulfonyl) phenol;
4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylsulfonyl) phenol;
1- (3-aminophenylthio) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
1- (4-aminophenylthio) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3-phenoxypropan-2-amine;
N-benzyl-2- (3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylthio) -phenoxy) acetamide;
N-benzyl-2- (4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylthio) -phenoxy) acetamide;
3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropylsulfonyl) phenol; N-benzyl-2- (3- (3- (3,6-dibromo-9H- Carbazol-9-yl) -2-hydroxypropylsulfonyl) -phenoxy) acetamide;
4- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropylsulfonyl) phenol;
5- (5- (3- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-hydroxypropylamino) phenoxy) pentylcarbamoyl) -2- (6-hydroxy-3-oxo- 3H-xanthen-9-yl) benzoic acid;
1- (8-bromo-3,4-dihydro-1H-pyrido [4,3-b] indol-5 (2H) -yl) -3-phenoxypropan-2-ol;
1- (8-bromo-2-cyclopropyl-3,4-dihydro-1H-pyrido [4,3-b] indol-5 (2H) -yl) -3-phenoxypropan-2-ol;
8-bromo-5- (2-hydroxy-3-phenoxypropyl) -3,4-dihydro-1H-pyrido [4,3-b] indole-2 (5H) -carbonitrile;
8-bromo-5- (2-fluoro-3-phenoxypropyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole;
1- (cyclohexylamino) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
(9- (2-hydroxy-3- (phenylthio) propyl) -9H-carbazole-3,6-dicarbonitrile;
9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3,6-dicarbonitrile;
(R) -N- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline
(S) -N- (3- (3,6-Dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -3-methoxyaniline N- (2- (3,6-dibromo-9H-carbazole -9-yl) ethyl) aniline;
2- (6-Amino-3-imino-3H-xanthen-9-yl) -4- (6- (5- (3- (3- (3,6-dibromo-9H-carbazol-9-yl)- 2-hydroxypropylamino) phenoxy) pentylamino) -6-oxohexylcarbamoyl) benzoic acid and 2- (6-amino-3-imino-3H-xanthen-9-yl) -5- (6- (5- (5- 3- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropylamino) phenoxy) pentylamino) -6-oxohexylcarbamoyl) benzoic acid;
1- (8-bromo-2-methyl-3,4-dihydro-1H-pyrido [4,3-b] indol-5 (2H) -yl) -3-phenoxypropan-2-ol;
6-((4-Bromophenyl) (2-hydroxy-3-phenoxypropyl) amino) nicotinonitrile;
1- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) pyridin-2 (1H) -one;
9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3-carbonitrile;
tert-butyl (5- (4-((3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) sulfonyl) phenoxy) pentyl) carbamate;
6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3-carbonitrile;
6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3-carboxamide;
1- (3,6-dibromo-9H-carbazol-9-yl) -3- (pyridin-2-yloxy) propan-2-ol;
Methyl 6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3-carboxylate;
6-Bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-carbazole-3-carboxylic acid;
6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [2,3-b] indole-3-carbonitrile;
9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [2,3-b] indole-3-carbonitrile;
tert-butyl 3- (2- (2- (2- (3-((3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) amino) phenoxy) ethoxy) ethoxy) Ethoxy) propanoate;
1- (3,6-dibromo-1,4-dimethoxy-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
1- (3,6-dibromo-1,8-dimethyl-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
2- (3,6-dibromo-9H-carbazol-9-yl) acetic acid;
1- (6-Bromo-3-methoxy-1-methyl-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
1- (4,6-dibromo-3-methoxy-1-methyl-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
1- (3,6-dibromo-4-methoxy-9H-carbazol-9-yl) -3- (phenylamino) propan-2-ol;
9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylic acid;
6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylic acid;
Ethyl 6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylate;
9- (2-Fluoro-3-phenoxypropyl) -9H-carbazole-3,6-dicarbonitrile;
9- (2-hydroxy-2-methyl-3-phenoxypropyl) -9H-carbazole-3,6-dicarbonitrile;
1- (cyclohexyloxy) -3- (3,6-dibromo-9H-carbazol-9-yl) propan-2-ol;
(E) -N- (3- (3,6-Dibromo-9H-carbazol-9-yl) prop-1-en-1-yl) -1,1,1-trifluoro-N- (3-methoxy Phenyl) methanesulfonamide;
1- (3,6-dibromo-9H-pyrido [2,3-b] indol-9-yl) -3-phenoxypropan-2-ol;
1- (3,6-dibromo-9H-carbazol-9-yl) -3-((6-methoxypyridin-2-yl) amino) propan-2-ol;
1- (8-bromo-5H-pyrido [4,3-b] indol-5-yl) -3-phenoxypropan-2-ol;
6-bromo-9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxamide;
8-bromo-5- (2-hydroxy-3-phenoxypropyl) -5H-pyrido [4,3-b] indole 2-oxide;
8-bromo-5- (2-hydroxy-3-phenoxypropyl) -5H-pyrido [3,2-b] indole 1-oxide;
(6-Bromo-9H-pyrido [3,4-b] indol-3-yl) methanol;
Ethyl 6-bromo-9H-pyrido [3,4-b] indole-3-carboxylate;
tert-butyl (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) carbamate;
2- (3,6-dibromo-9H-carbazol-9-yl) -N-methylacetamide;
3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropan-1-amine hydrochloride;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) acetamide;
2- (3,6-dibromo-9H-carbazol-9-yl) propanamide;
6-bromo-9H-pyrido [3,4-b] indole-3-carbonitrile;
6-bromo-3-methyl-9H-pyrido [3,4-b] indole;
Methyl (2- (3,6-dibromo-9H-carbazol-9-yl) acetyl) carbamate;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -1,1,1-trifluoro-N- (3-methoxyphenyl) methanesulfonamide;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-fluoropropyl) -6-methoxypyridin-2-amine;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -1,1,1-trifluoro-N- (3-methoxyphenyl) methanesulfonamide;
1- (3,6-dibromo-9H-carbazol-9-yl) -3-((4-methoxybenzyl) (3-methoxyphenyl) amino) propan-2-ol;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) -2,2,2-trifluoroacetamide;
tert-butyl (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) carbamate;
5- (2-hydroxy-3-phenoxypropyl) -5H-pyrimido [5,4-b] indole-2-carboxylic acid;
N- (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) acetamide;
Ethyl (3- (3,6-dibromo-9H-carbazol-9-yl) -2-hydroxypropyl) carbamate;
6-bromo-9- (3- (4-bromophenoxy) -2-hydroxypropyl) -9H-carbazole-3-carbonitrile;
Methyl 9- (2-hydroxy-3-phenoxypropyl) -9H-pyrido [3,4-b] indole-3-carboxylate; and N- (3- (3-bromo-6-methyl-9H-carbazole- 9-yl) -2-fluoropropyl) -6-methoxypyridin-2-amine;
Or a pharmaceutically acceptable salt thereof.   A pharmaceutical composition comprising the compound or salt according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier.   18. A compound, salt or composition according to any of claims 1 to 17 for the treatment of a disease, disorder or condition caused by unwanted neuronal cell death or associated with insufficient neurogenesis.   Disease, disorder or condition is schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, posttraumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down's syndrome, spinocerebellar ataxia, amyotrophic lateral cord Sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, abuse of neurostimulants, retinal degeneration, spinal cord injury, peripheral nerve injury, physiological weight loss related to various conditions and normal aging and chemotherapy The compound, salt or composition according to claim 18, which is a neuropsychiatric and / or neurodegenerative disease selected from the group consisting of cognitive decline. Formula (I)
A method of treating a disease, disorder or condition caused by undesired neuronal cell death or associated with insufficient neurogenesis, comprising administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof ,
Each of R ¹ , R ² , R ³ and R ⁴ is independently hydrogen, halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C _{6 thiohaloalkoxy,} C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 2 -C ₆ alkynyl, cyclopropyl, -N _3, a _{cyano, -NH 2, -NH (C 1} -C 6 alkyl ), —N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and nitro;
R and R ′ are the following (1), (2), (3) or (4)
(1) R and R ′ are combined with C ₂ and C ₃ respectively to form the formula (II)
Form a fused phenyl ring
(Wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen, halo, hydroxyl, sulfhydryl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ halo. _alkoxy, C 1 -C _{6 thiohaloalkoxy,} C 1 -C _{6 alkyl,} C 1 -C _{6 haloalkyl,} C 2 -C ₆ alkynyl, cyclopropyl, -N _3, a _cyano, -NH _2, -NH _{(C 1} -C ₆ alkyl), - N _(C 1 -C _{6 alkyl)} 2, is selected from _{-NHC (O) (C 1 -C} 6 alkyl) and nitro); or
(2) R and R ′ together with C ₂ and C ₃ respectively form a fused heteroaryl ring containing 6 ring atoms (wherein 1-2 of the independently selected ring atoms are N And the heteroaryl ring may optionally be substituted with 1 to 2 independently selected R ^b ); or
(3) R and R ′ together with C ₂ and C ₃ respectively form a condensed heterocyclic ring containing 5 to 6 ring atoms (where 1 to 2 ring atoms are N, NH N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S; and the heterocyclic ring is optionally selected from 1 to 3 independently Optionally selected R ^a ); or
(4) each of R and R ′ is independently defined as being hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;
Each of L ¹ and L ² is independently C ₁ -C ₃ alkylene, which may optionally be substituted with 1 to 2 independently selected R ^c ;
A is
(i) CR ^A1 R ^A2 where R ^A1 and R ^A2 are each hydrogen, halo, C ₁ -C ₃ alkyl, OR ⁹ (where R ⁹ is hydrogen or optionally hydroxy or C ₁ -C ₃ alkoxy is or C ₁ -C ₃ alkyl optionally substituted with) or independently of the double bonds that are formed between one of a and L ¹ and L ² is selected); or
(ii) C = O; or
(iii) C ₃ -C ₅ cycloalkylene (which is (a) substituted with one oxo; and (b) optionally further substituted with 1 to 4 independently selected R ^a). Or); or
(iv) a heterocycloalkylene containing 3 to 5 ring atoms, wherein 1 to 2 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; The heterocycloalkylene is (a) substituted with 1 oxo; and (b) optionally further substituted with 1 to 4 independently selected R ^a )
Is;
Z is
(i) -NR ¹⁰ R ^11; or
^{(ii) -C (O) NR} 10 R 11; or
(iii) ^{-OR 12;} or
(iv) -S (O) _n R ¹³ where n is 0, 1 or 2; or
(v) heterocycloalkenyl containing 5 to 6 ring atoms, wherein 1 to 3 ring atoms are N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl ), O and S; and the heterocycloalkenyl may be optionally substituted with 1 to 4 independently selected R ^a ); or
(vi) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 independently selected R ^b ; or
(vii) a heteroaryl containing 5 to 14 ring atoms, wherein 1 to 6 of the ring atoms are independently selected from N, NH, N (C ₁ -C ₃ alkyl), O and S; Heteroaryl may be optionally substituted with 1-4 independently selected R ^b ); or
(viii) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a ); or
(ix) arylheterocyclyls containing 8-14 ring atoms, where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(x) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(xi) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;
Each of R ¹⁰ and R ¹¹ is the following (a) to (l)
(a) hydrogen;
(b) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ;
(c) 5 to 14 heteroaryl containing a ring atom (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl is optionally substituted with 1 to 4 R ^b );
(d) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl optionally substituted with 1 to 3 R ^d ;
_{(e) -C (O) (} C 1 -C 6 _{alkyl), - C (O) (} C 1 -C 6 haloalkyl) or _{-C (O) O (C 1} -C 6 alkyl);
(f) C ₂ -C ₆ alkenyl or _C 2 -C ₆ alkynyl;
(g) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a );
(h) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a );
(i) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a );
(j) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a );
(k) C ₃ -C ₈ cycloalkyl or C ₃ -C ₈ cycloalkenyl optionally substituted with 1 to 4 independently selected R ^a ; and
(l) C ₇ -C ₁₂ aralkyl (wherein the aryl moiety may be optionally substituted with 1 to 4 R ^b , independently selected)
Wherein R ¹⁰ and R ¹¹ are independently selected from the substituents collectively described in (b), (c), (g), (h), (i), (j) And must be selected from (k);
R ¹² is
(i) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or
(ii) heteroaryl including 5-14 ring atoms (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl may optionally be substituted with 1 to 4 R ^b ); or
(iii) C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl substituted with 1 to 3 R ^d ; or
(iv) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a ); or
(v) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vi) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a );
Or
(vii) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;
R ¹³ is
(i) C ₆ -C ₁₀ aryl optionally substituted with 1 to 4 R ^b ; or
(ii) heteroaryl including 5-14 ring atoms (wherein 1-6 ring atoms are _{N, NH, N (C 1} -C 3 alkyl), are independently selected from O and S; and wherein Heteroaryl may optionally be substituted with 1 to 4 R ^b ); or
(iii) C ₈ -C ₁₄ arylcycloalkyl (where
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) the cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a ); or
(iv) arylheterocyclyl containing 8-14 ring atoms, wherein
(1) The aryl moiety may be optionally substituted with 1-4 independently selected R ^b ;
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(v) a heteroarylheterocyclyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) 1-2 of the ring atoms of the heterocyclyl moiety are independently selected from N, NH, N (C ₁ -C ₆ alkyl), NC (O) (C ₁ -C ₆ alkyl), O and S And the heterocyclyl moiety may optionally be substituted with 1 to 3 independently selected R ^a ); or
(vi) a heteroarylcycloalkyl containing 8-14 ring atoms, wherein
(1) 1-2 is N ring atom of the heteroaryl portion, NH, N _(C 1 -C ₃ alkyl), are independently selected from O and S; and said heteroaryl moiety may optionally 1 to 3 Optionally substituted by independently selected R ^b ; and
(2) The cycloalkyl moiety is optionally substituted with 1 to 4 independently selected R ^a )
Is;
Each R ^a is halo, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, oxo, thioxo, = NH, = N (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) ₂ It is independently selected from _{-NHC (O) (C 1 -C} 6 alkyl), and cyano;
R ^b represents the following (aa) to (dd)
(aa) C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ thiohaloalkoxy; -O- (CH ₂ ) _1-3- [O (CH _{2) 1-3] 1-3 -H; -C} 1 -C 6 _alkyl, C 1 -C ₆ haloalkyl, -NH _(C 1 -C _{6 alkyl), - N (C 1 -C} 6 _alkyl) 2, —NHC (O) (C ₁ -C ₆ alkyl), wherein each of the alkyl moieties is optionally substituted with 1 to 3 independently selected R ^e ;
(bb) halo; hydroxy; cyano; nitro; -NH _2; azido; _sulfhydryl; C 2 -C _{6 alkenyl;} C 2 -C ₆ alkynyl; -C (O) H; -C (O) (C 1 -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); - C (O) OH ; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C _{(O) NH (C 1 -C} 6 alkyl); - C (O) N (C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH _(C 1 -C _{6 alkyl); - SO 2 N (C} 1 -C 6 _alkyl) 2;
(cc) C ₃ -C ₆ cycloalkyl or heterocyclyl containing 5-6 ring atoms, wherein 1 to 2 ring atoms of the heterocyclyl are N, NH, N (C ₁ -C ₆ alkyl), NC (O ) (C ₁ -C ₆ alkyl), independently selected from O and S; and each of the phenyl and heterocyclyl is optionally substituted with 1 to 3 independently selected R ^a ) ;and
(dd) phenyl or heteroaryl containing 5-6 ring atoms, wherein 1-2 of the heteroaryl ring atoms are independently N, NH, N (C ₁ -C ₃ alkyl), O and S Wherein each of the phenyl and heteroaryl is optionally halo; hydroxyl; cyano; nitro; —NH ₂ ; —NH (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) _{2 , -NHC (O) (C 1} -C 6 _alkyl), C 1 -C _{6 alkoxy;} C 1 -C _{6 haloalkoxy;} C 1 -C _{6 thioalkoxy;} C 1 -C ₆ thiohaloalkoxy; _{C 1} - Optionally substituted with 1 to 3 substituents independently selected from C ₆ alkyl and C ₁ -C ₆ haloalkyl)
Independently selected from the substituents described in;
R ^c is halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Selected;
R ^d represents hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ thiohaloalkoxy, C ₁ -C ₆ alkyl, C _{1-, respectively.} Independently from C ₆ haloalkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) ₂ , —NHC (O) (C ₁ -C ₆ alkyl) and cyano Selected;
Each R ^e is hydroxyl, C ₁ -C ₆ alkoxy; C ₁ -C ₆ thioalkoxy; C ₁ -C ₆ haloalkoxy; C ₁ -C ₆ thiohaloalkoxy; -NH ₂ ; -NH (C _1- C _{6 alkyl); - N (C 1 -C} 6 _{alkyl) 2; -NHC (O) (} C 1 -C 6 alkyl); cyano; -C (O) H; -C (O) (C 1 -C _{6 alkyl); - C (O) (} C 1 -C 6 haloalkyl); - C (O) OH ; -C (O) O (C 1 -C 6 _{alkyl); - C (O) NH} 2; -C _{(O) NH (C 1 -C} 6 alkyl); - C (O) N (C 1 -C 6 _{alkyl) 2; -SO 2 (C 1} -C 6 _{alkyl); - SO 2 NH 2;} -SO 2 NH _(C 1 -C _{6 alkyl); - SO 2 N (C} 1 -C 6 _{alkyl) 2;} and ^{L 3} - _(C 1 -C ₆ alkylene) - biotin, wherein, ^{L 3} is -O -, - N _{-, - NCH 3 -, -} C (O) -, - C (O) NH -, - C (O) NCH 3 -, - NHC (O) - or -NCH ₃ C (O) - independently from Selected;
However,
When A is CH ₂ and R and R ′ are defined according to definition (1), both R ³ and R ⁶ must not be hydrogen;
When A is CH ₂ and R and R ′ are defined according to definition (2), R ³ must not be hydrogen;
When A is CH ₂ , R and R ′ are defined according to definition (1), Z is —OR ¹² and R ¹² is unsubstituted phenyl, then both R ³ and R ⁶ are chloro Must not;
A is CH ₂ , R and R ′ are defined according to definition (1), Z is —OR ¹² , R ¹² is phenyl substituted with pyridyl or alkyl substituted with 1 to 3 R ^e , Both R ³ and R ⁶ must not be bromo;
When A is CH (CH ₃ ), R and R ′ are defined according to definition (1), Z is NR ¹⁰ R ¹¹ , R ¹⁰ is CH ₃ and R ¹¹ is unsubstituted phenyl, Both R ³ and R ⁶ must not be hydrogen; and if A is CR ^A1 R ^A2 and R ^A1 and R ^A2 are OH, the other of R ^A1 and R ^A2 is C ₁ -C _3. Alkyl. ].