WO2020051435A1

WO2020051435A1 - Neuroprotective agents for treatment of neurodegenerative diseases

Info

Publication number: WO2020051435A1
Application number: PCT/US2019/049927
Authority: WO
Inventors: Aloke K. Dutta
Original assignee: Wayne State University
Priority date: 2018-09-07
Filing date: 2019-09-06
Publication date: 2020-03-12
Also published as: EP3846816A1; CA3111561A1; EP3846816A4

Abstract

A compound having formula I is useful for treating a neurodegenerative disease: (I) or a pharmaceutically acceptable salt or ester thereof, wherein R₁, R₂, R₃, R₄, R5, R₆, R₇, R₈ are each independently hydroxyl, C_1-4 alkyl, C_1-4 alkoxyl, C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_4-8, are specified substituents.

Description

N EURO PROTECTIVE AGENTS FOR TREATMENT OF NEURO DEGENERATIVE DISEASES

CROSS-REFERENCE TO RELA TED APPLICA TIONS

[0001 I This application is a continuation-in-part of U.S. Serial No 16/124,974 filed September 7,

2018.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] The invention was made with Government support under Contract No. NS047198 awarded by the National Institutes of Health / National institute of Neurological Disorders and Stroke, The Government has certain rights to the invention

TECHNICAL FIELD

[0003[ The present invention relates to compounds for treating neurodegenerative diseases.

BACKGROUND OF THE INVENTION

[0004] Dopaminergic receptor systems have been targeted for the development of pharmaeotherapeulic agents for a number of CNS related disorders, including drug addiction, schizophrenia, depression, and Parkinson’s disease (PD). Dopamine (DA) receptor agonists have been employed more extensively in the treatment of Parkinson’s disease than any other type of pharmacotherapy. Levodopa (L-dopa), the immediate precursor to endogenous DA, is the current gold-standard treatment option for PD. DA receptors belong to the family of transmembrane proteins known as G-protein-coupled receptors (GPCRs). DA receptors are widely distributed in the CNS, are also present in the periphery, and are divided into five subtypes. On the basis of the stimulatory action on adenyiyl cyclase, Dl and D5 are grouped together as Dl type. D2-D4 receptors are classified as D2 type because of their inhibitory action on adeny!yl cyclase activity. Interestingly, the D3 receptor was found to have a distribution in the brain that is somewhat different from that of the D2 receptor. The highest levels of D3 receptor expression were found to be in the limbic region of the brain, while D2 receptor expression is most dense i n the striatum of the midbrain. D2 and D3 receptor subtypes occur post- and presynapiically. In the latter location they function as autoreceptors that regulate DA synthesis, metabolism, and release. It is noteworthy that D2 and D3

I receptor subtypes share 50% overall amino acid sequence homology and 75-80% in their agonist binding sites. As a result, development of ligands selective for either subtype is a challenging task.

(00051 Parkinson’s disease (PD) is a progressive, neurodegenerative disorder that results from the death of DA-producmg cells in the substantia nigra region of the midbrain. Common symptoms include resting tremor, muscular rigidity, bradykinesia, postural instability, and cognitive psychiatric complications. Although the etiology of PD is not yet clear and may be multi factorial, oxidative stress and mitochondrial dysfunction are thought to play a central role in the pathology of the disease. Recent studies on various genetic mutations have provided new insights into the disease process. Oxidative stress has been strongly implicated in midbrain dopaminergic cell death. Toxicity from endogenous and exogenous origins, caused by oxidative mechanisms, has been implicated as a fundamental process in progressive nigral cell loss. Along with motor fluctuations and wearing off after long-term treatment, side effects associated with L-dopa treatment and the eventual oxidation of DA derived from L-dopa have been speculated to produce further oxidative stress.

|00061 In addition, a-syrmciein, a presynaptic protein involved in fibril lization, has been implicated in the pathogenesis of PD. A recent report demonstrated that in cultured human dopaminergic neurons, accumulation of a-synuclein induces apoptosis in the presence of DA and reactive oxygen species. Furthermore, an interaction between calcium, cytosolic DA, and a-synuclein has been implicated in the loss of DA neurons in the substantia nigra. In this case, DAdependent neurotoxicity is mediated by a soluble protein complex containing a-synuclein, Therefore, a-synuclein, together with oxidized DA, could have synergistic effects in terms of disease susceptibility an progression.

100071 Accordingly, there is a need for dopamine improved D2/D3 agonist molecules, and in particular, for improved D2/D3 agonist molecules with a capacity to bind to iron.

7 SUMMARY OF THE INVENTION jjOOGSj In at least one embodiment, the present: invention solves one or more problems of the prior art by providing a compound having formula Ϊ for treating a neurodegenerative disease:

wherein:

R] is H, Ci-s alkyl, C₂-s alkenyl, C₄-s cydoaikyl, CU-s cycioalkenyi, Ce-io aryl, Ci -to alky!

C_ti-io aryl,

R₂, R_J, R₄, Rs are each independently H or OH wherein at least 2 of R₂, R₃, R₄, Rs are OH;

Re is an optionally substituted Ci-s alkyl, Ci-s alkoxyl, C₂-s alkenyl, C_2-8 alkynyl, Ci-s

R_? is an optionally substituted Ci-s alkyl. Cos alkoxyl, C_2-3 alkenyl, C_2-8 alkynyl. Ci-s cydoaikyl, Ci-s cydoalkenyi, or C_0-10 aryl;

Rs are each independently hydroxyl, CM alkyl, C alkoxyl. C alkyl, C_2-8 alkenyl. C_2-8 alkynyl, Ci-s cydoaikyl, Ci-s cycloalkenyl; C_MO aryl, ~NR or Cwo hydrocarbon groups optionally containing one or more G, N, S, or Se heteroatoms where R’ individually are H or organ yi groups (e,g., C alkyl, Cz-s alkenyl, C₂-s alkynyl, Ci-s cydoaikyl, Ci-s cycloalkenyl, or Ce-io aryl) and q is 2 or 3. with the proviso that when q is 3, the group bears a positive formal charge (with an appropriate counter ion (e.g,, halide) being present);

Z_m is absent or a divalent linking moiety in which Z is repeated m times;

0 is 0, 1, 2, 3, or 4; and

is 0, 1 , 2, 3, 4, or 5. In another embodiment, a compound having formula P for treating a neurodegenerative disease is provided:

or a pharmaceutically acceptable salt or ester thereof,

wherein:

A is an optionally substituted CV12 aryl or Ce-i2 heteroaryl;

R)4, R15 are each independently H, Ci-s alkyl, Ci-s alkyl, C2-8 alkenyl, C -8 eycloaikyi, C s cycloalkenyl, Ce-10 aryl, or Ci-io alkyl, or Ce-to aryl;

B j and B;> are each independently:

o is 0, 1 , 2. 3, or 4; and

Ru, is an optional substituent. BRIEF DESCRIPTIO OF THE DRA WINGS

JjOOiOj Exemplary embodiments of the present invention will become more fully understood from the detailed description and the accompanying drawings, wherein:

[00111 FIGURE 1. Synthetic Scheme 1 for compounds that are useful for treating a neurodegenerati ve disease.

[0012j FIGURES 2A-B. (A) Inhibition of aSN fibriliizaiion by D-687 and D-688 The drugs were incubated with aSN over a period of six days and the fibrilizaiioti was measured by ThT fluorescence assay. Data Values shown are means ± SEMs of three independent experiments. (B) PCI 2 cells were treated w ith 10 mM prefabricated aSN aggregates formed in presence of daigs collected at day 0 and day 6. Values shown are means ± SEMs of three independent experiments performed in 4-6 replicates. One way ANOVA analysis followed by Tukey's Multiple Comparison post hoc test were performed. (*p<0,01 compared to the control),

[0013J FIGURES 3 A and 38. Inhibition and dissociation of Abi-42 oligomer formation by : a) ThT fluorescence of Abi-4 (IOmM ) with or without incubation w ith test compounds (20mM) for 24 h. The ThT fluorescence of Abi-42 at Oh was taken as 100%. b) Abi-42 fibrils (ΊOmM) w'ere incubated with test compounds (20mM) for a period of 24h. The ThT fluorescence of Abi-« aggregates at Oh was considered as 100%

10014] FIGURE 4, Synthetic Scheme 2 for compounds that are useful for treating a neurodegenerative disease

[0015] FIGURE 5. Synthetic Scheme 3 for compounds that are useful for treating a neurodegenerative disease.

[00I6[ FIGURE 6. Synthetic Scheme 4 for compounds that are useful for treating a neurodegenerati ve disease.

DETAILED DESCRIPTION OF THE INVENTION

[00I7{ Reference will now' be made in detail to presently preferred compositions, embodiments and methods of the present invention, which constitute the best modes of practicing the invention presently known to the inventors. The Figures are not necessarily to scale. However, it is to be understood that the disclosed embodiments are merely exemplary of the invention that may be embodied in various and alternative forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for any aspect of the invention and or as a representative basis for teaching one skilled in the art to variously employ the present invention.

Except in the examples, or where otherwise expressly indicated, all numerical quantities in this description indicating amounts of material or conditions of reaction and/or use are to be understood as modified by the word "about" in describing the broadest scope of the invention. Practice within the numerical limits stated is generally preferred. Also, unless expressly stated to the contrary: all R groups (e.g. R where i is an integer) include hydrogen, alkyl, lower alkyl, C alkyl, CVJO aryl, CV_K> heteroaryl, -N<¼, -NH>, -N(R’R”), -N(R’R^MR^M,)^÷L-, Cl, F, Br, -CFj, -CCb, -CN, - SO H, -PO₃H₂, -COOH, -COsR’, -CORE -CBO, -OH, -OR’, -0/NG, -SOyAT, -POyM \ -COO NT, - CF₂H, -CFiRk -CF¾, and -CFR’R” where R R” and R”’ are Ci-io alkyl or Ce-is aryl groups (it should he appreciated that these groups can be in addition to other groups listed for a specific R groiup); single letters (e.g., "n" or "o" l are 1 , 2, 3, 4, or 5; in the compounds disclosed herein a CH bond can be substituted with alkyl, lower alkyl, C alkyl, CVJO aryl, Ce-io heteroaryl, -NO2, -N¾ - M(R/ R”), -N(R^,R”R^,,,)l·, Cl, F, Br, -CFj, -OCR, -CN, -SO₃H, -PO3H3, -COOH, -C(½R’, -COR/, - CHO, -OH, -OR/, -0 M⁺, -SOkMy -POs M , -COCrNT, -CF₂H, -CFhR’, ~CFH₂, and -CFR’R” where R’, R” and R’” are Ci-10 alkyl or Ce-is aryl groups; percent, "parts of," and ratio values are by weight; the term "polymer" includes "oligomer," "copolymer," "terpolymer," and the like; molecular weights provided for any polymers refers to weight average molecular weight unless otherwise indicated; the description of a group or class of materials as suitable or preferred for a given purpose in connection with the invention implies that mixtures of any two or more of the members of the group or class are equally suitable or preferred; description of constituents in chemical terms refers to he constituents at the time of addition to any combination specified in the description, and does not necessarily preclude chemical interactions among the constituents of a mixture once mixed; the first definition of an acronym or other abbreviation applies to ail subsequent uses herein of the same abbreviation and applies mutatis mutandis to normal grammatical variations of the initially defined abbreviation; and, unless expressly stated to the contrary, measurement of a property is determined by the same technique as previously or later referenced for the same property. It is also to be understood that this invention is not limited to the specific embodiments and methods described below, as specific component and/or conditions may, of course, vary. Furthermore, the terminology used herein is used only for the purpose of describing particular embodiments of the present invention and is not intended to be limiting in any way.

[0020) it must also be note that, as used in the specification and the appended claims, the singular for "a," "an_*" and "the" comprise plural referents unless the context clearly indicates otherwise. For example, reference to a component in the singular is intended to comprise a plurality of components.

[0021) The term “comprising” is synonymous with “including,” “having,” “containing,” or

“characterized by.” These terms are inclusive an open-ended and do not exclude additional, unrecited elements or method steps.

[0022) The phrase“consisting of’ excludes any element, step, or ingredient not specified in the claim. When this phrase appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth i that clause; other elements are not excluded from the claim as a whole.

[0023] The phrase“consisting essentially of’ limits the scope of a claim to the specified materials or steps, plus those that do not materially affect the basic and novel characteristic^) of the claimed subject matter

[0024) With respect to the terms“comprising,”“consisting of,” and“consisting essentially of,” where one of these three terms is used herein, the presently disclosed and claimed subject matter can incl ude the use of ei ther of the other t O terms.

J0025) It should also be appreciated that integer ranges explicitly include all intervening integers.

For example, the integer range 1 -10 explicitly includes 1 , 2, 3, 4, 5, 6, 7, 8, 9, and 10. Similarly, the range 1 to 100 includes 1, 2, 3, 4. . , 97, 98, 99, 100 Similarly, when any range is calle for, intervening numbers that are increments of fee difference between the upper limit an the lower limit divided by 10 can be taken as alternative upper or lower limits, For example, if the range is 1.1. to 2.1 the following numbers 1.2, 1.3, 1 4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.0 can be selected as lower or upper limits. In the specific examples set forth herein, concentrations, temperature, and reaction conditions (e.g. pressure, pH, etc.) can be practiced with plus or minus 50 percent of the values indicated rounded to three significant figures, in a refinement, concentrations, temperature, and reaction conditions (e.g., pressure, pH, etc.) can be practiced with plus or minus 30 percent of the values indicated rounded to three significant figures of fee value provided in the examples. In another refinement, concentrations, temperature, and reactio conditions (e.g., pH, etc.) can be practiced with pins or minus 10 percent of the values indicated rounded to three significant figures of the value provided in the examples.

[0026] in the examples set forth herein, concentrations, temperature, and reaction conditions (e.g,, pressure, pH, flow rates, etc.) can be practiced with plus or minus 50 percent of the values indicated rounded to or truncated to two significant figures of the value provide in the examples, hi a refinement, concentrations, temperature, and reaction conditions (e.g,, pressure, pH, How rates, etc.) can be practiced with plus or minus 30 percent of the values indicate rounded to or truncated to two significant figures of the value provided in the examples. In another refinement, concentrations, temperature, and reaction conditions (e.g., pressure, pH, flow rates, etc.) can be practiced with plus or minus 10 percent of the values indicated rounded to or truncated to two significant figures of the value provided in the examples,

[00271 Throughout this application, where publications are referenced, the disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which thi invention pertains,

[0028] In a variation, the term“organyl group” means any organic substituent group, regardless of functional type, having one free valence at a carbon atom. Examples of organyl group include but are not limited to Ci-s alkyl, C2-8 alkenyl, C2-8 alkynyi, C4-8 cycloalkyl, C4-8 cycloalkenyl, G no aryl, C2-10 aikanediyl, Ci-s alkoxy, Cue thioalkoxy, Cs-is cylcoalkyl, and the like. More specific examples Inc hides, but are not limited to methyl, ethyl, propyl, butyl, pyridinyi , 4-pyridylmeihyl, and the like,

[0029] in a variation, the term“alkyl” means a straight or branched hydrocarbon radical having from 1 to 10 carbon atoms and includes, for example, methyl, ethyl, n -propyl, isopropyl, n-butyi, sec-butyl, isobutyl, tert-butyl, n-pentyl, n~hexy1, n-heptyl, n-octyl, and the like.

[O030J In a variation, the term“aikanediyl” means a straight or branched hydrocarbo diradical having from 1 to 10 carbon atoms formed by removing 2 hydrogen atoms from an alkane,

[O031J In a variation, the term“alkoxy” and "thioalkoxy" are 0-alkyl or S-alkyl of fro 1 to 8 carbon atoms as defined above for "alkyl". [0032] In a variation, the term“eycloaSkyi” means a saturated hydrocarbon ring having 3 to 8 carbon atoms and includes, for example, cyclopropyl, eyclobutyl, cyelopentyl, cyclohexyl, cycloheptyl, cyclooctyl , and the like.

{00331 In a variation, the term“alkenyl” means a straight or branched unsaturated hydrocarbon radical having from 2 to 12 carbon atoms and includes, for example, ethenyl, 2-propenyl, 1 -bnteny!, 2-butenyl, l-pcntenyl, 2-pen Lenyl, 3-rnethyl-3-butenyl, 1-hexenyi, 2~hexenyi, 3-hcxcnyS, 3-heptenyl,

1-ocienyl, l-nonenyl, l -decenyi, l-undecenyi, l-dodecenyl, and the like

10034] In a variation, the term“alkenediyi” means a straight or branched hydrocarbon diradical having from 2 to 12 carbon atoms formed by removing 2 hydrogen atoms from a€2-12 alkene.

10035] in a variation, the term“alkynyl” means straight or branched triple bonded unsaturated hydrocarbon radical having from 2 to 12 carbon atoms and includes, for example, ethynyl, 2- propynyl, 3~butynyl, 4-penlynyl, 5-hexynyl, 6-hcptynyl, 7-octynyl, 8-nonynyi, 9-decynyl, 10- undecynyl, l l-dodecynyl, and the like.

[0036] In a variation, the term“alkynediyl” means a straight or branched hydrocarbon diradical having from 2 to 12 carbon atoms formed by removing 2 hydrogen atoms fro a€2-12 alkyne.

[0037] In a variation, the term“cycloalkyla!ky!” means a saturated hydrocarbon ring attached to an alkyl group wherein alkyl is as defined above. The saturated hydrocarbon ring contains from 3 to 12 carbon atoms. Examples of such are cyclopropylmethyi, cyclopentylmetbyl, cyciohexylmethyl, adamantylmethyl and the like.

[0038] In a variation, the term“heterocycloa!ky!” means a saturated hydrocarbon ring having 3 to 8 carbon atoms in which 1 or more carbon atoms are replaced by N, S, O, Se, etc. Examples includes

2- or 3 -tetrah drothieno, 2- or 3-tetrahydrofurano, 2- or 3-pyrroIidino, 2-, 4-, or 5-thiazolidino, 2-, 4- , or 5~oxazolidino, 2~, 3-, or 4-piperidino, N-morpholinyl or N-thiamorpholin l,

[0039] In a variation, the term“aryl” means an aromatic radical such as a phenyl group, a naphthyl group, a phenyl group substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, ihioalkoxy as defined above, hydroxy, halogen, iriiluoro methyl, amino, a!ky!amino as defined above for alkyl, dia!ky!amino as defined for alkyl, N -acetyl amino, cyano— SO2NH2, or nitro, or a naphthyl group substituted by 1 to 4 substituents as defined above for a phenyl group substituted by 1 to 4 substituents, in a refinement, aryl is a Q.- ai l .

|0040) in a variation, the term ^wheteroary!” means a C5-13 heteroaromatic radical such as 2- or 3- thienyl; 2~ or 3-furanyl; 1 -, 2- or 3-pyrrolyi; 1 ~, 2-, 4~, or 5-imidazoIyi; 1 ~, 3-, 4~, or 5-pyrazolyS; 2-, 4-, or 5~thiazoiyi; 3-, 4-, or S-isothiazol l; 2~, 4~, or 5-oxazolyS; 3~ 4-, or 5-isoxazolyl; 1~, 3-, or 5-

1.2.4-iriazolyl; 1-, 2-, 4-, or 5-l ,2,3-triazoly1; - or 5~tetrazolyl; 4-, or 5-l ,2,3~oxadiazoly1; 3-, or 5-

1.2.4-oxadiazolyl; 2-1 ,3,4-oxadiazolyl; 2-l ,3,4~thiadiazoyl; 2~i,3,5-iriazinyl; 3-pyridinyI; 3~, 4~„ or 5~pyridazinyl; 2-pyrazinyl; 2~, 4-, or 5-pyrimidinyl; unsubstituted or substituted by 1 to 2 substituents selected from NH_?, OH, S, halogen as defined hereinafter, alkyl as defined above, or alkoxy as defined above. In a refinement, heieroaryl is a C5.10 heteroaryl.

[0041] In a variation, the term“halogen” or“halo” means fluorine, chlorine, bromine, or iodine.

[0042] Abbreviations;

[0043] “BINAP” means 2,2'-bis(diphenylphosphino)-l ,G-binaphthyl

[0044] “DMSO” is dimethylsulfoxide;

[0045] “DA” means dopamine.

[0046] “et” is ethyl;

[0047] “me” is methyl ;

[0048] “h” is hour;

[0049] “L-DOPA” means (S)-(3,4-dihydroxyphenyI) alanine.

[0050] “NaBH(OAc)₃” means sodium triacetoxyborohydride.

[0051] “PD: Parkinson’s disease.

[0052] “Pd(OAc)2” means pailadium(II) acetate.

[0053] “s” i: s seconds;

[0054] “SCh.py” means sulfur trioxide pyridine. [0055] “ft” is room temperature;

[0056] TBAF” is tetra-ti-buiyiammonium fltoride;

|0057| “THF” is tetrahydrofuran;

[0058] “TBS” means iert-buty 1 dimethyl si! y 1.

[0059] In at least one embodiment, the present invention provides a compound having formula 1 for treating a neurodegenerative disease:

or a pharmaceutically acceptable salt or ester thereof,

wherein:

Ri is H, C^*i 8 alkyl C₂-8 alkenyl, C₄-s cycloalkyl C4-& cycloalkenyl, C<cio aryl, C’w« alkyl

R₂, R',, R₄, Ri are each independently H or OH wherei in a refinement at least 2 of R:>, R₂, R.₄, ₅ arc Oil In another refinement, 3 of R_?., Rs, R.s, Rs are OH. In still another refinement, each of (i.e , al! of) Rs, Rj, Ri, R5 are OH;

R , is H, an optionally substituted Ci^ alkyl, an optionally substituted Cue a!koxyl, an optionally substituted C . alkenyl, an optionally substituted C;vs alkynyl, an optionally substituted C_4-8 cycloaikyi, an optionally substituted C_4-8 cycloalkenyl, an optionall substituted Qcio aryl.

I I R? is H, an optionally substituted C_M alkyl, an optionally substituted Cos alkoxyi, an optionally substituted C_2-8 alkenyl, an optionally substituted C_2-8 alkynyl, an optionally substituted C_M cycloalkyl, an optional ly substituted C_4-8 eycloalkenyi, or an optionally substituted Cs-io aryl;

Rg are each independently hydroxyl, C_M alkyl, C_M alkoxyi, C_M alkyl, C2-8 alkenyl, C2-8 alkynyl, C_M cycloalkyl, CM eycloalkenyi; C_MO aryl, -NR³ _q or CM_O hydrocarbon groups optionally containing one or more O, N, S, or Se heteroatoms where R³ individually are H or organ yl groups and q is 2 or 3, with the proviso that when q is 3, the group bears a positive formal charge; and

Z_m is absent or a divalent linking moiety in which Z is repeated m times;

o is 0, 1 , 2, 3, or 4 (when o is 0 all substituents are hydrogen (H));and

m is an integer from 0 to 5. In a refinement, the compound of claim 1 wherein R_{; and R are each independently CM alkyl, C alkenyl, CM alkynyl, CM cycloalkyl, or C eycloalkenyi.

10060} In a refinement, R_? is substituted with a component selected from the group consisting of halogen, C alkyl, CM alkoxy, CM acyioxy, C_M acyl, -C(0)-R¾ , - Rio-NH-S0₂-N(R9)r , -Rto-NH- C(C))-Ry; - R;::-N(Ryt. and - Ri -Ar where:

Ry is H, C alkyl, C_M alkenyl, C cycloalkyl, CM cycloalkenyl, or Ce-io aryl;

Rio is C alkenyl;

r is 2 or 3; and

Ar is a _M 0 aryl ring system, optionally including one or more lieteroatoms or Cs-io heteroaryl; with the proviso that when r is 3, the nitrogen of the N(R9)_f group will bear a positive formal charge hi a further refinement, Ar is an optionally substituted phenyl, thienyl, pyridy!, bipyridyk biphenylyi, or naphthyl.

|0061} In another refinement, Rs are hydroxyl, C_M alkyl, C_M alkoxyi, C_M alkenyl, C2-8 alkynyl,

C4-8 cycloalkyl, CM eycloalkenyi; CMO aryl, -N(Rn)_¾ ~NH-C(0)~Rn, or -NH-C(0)-N(RI₂)2, where Ru individually are H, CM alkyl, C2.8 alkenyl, C>-io alkynyl, CM cycloalkyl. CM eycloalkenyi, or C_ft-io aryl where q is 2 or 3, with the proviso that when q is 3, the group bears a positive formal charge and wherein the hydrocarbon groups in each case are optionally substituted with -CN, CM alkyl, -ORu, -OH, halo, or -CF¾ where R e, is CM alkyl.

10062] When present, Z can be -CH.>-, -CHOHCH2-, -CHOHCH2CH2-, -CHOHCH2CH2CH2-, -CO-,

-N-CH2-, -N-CO-, -(Clh - , -CHOH(CHi)u-, -(Ok^CO-, -(CHS^NCOCCHJ _» Ci-io carboximido, Ci-io alkanediyl, C₂-io alkanediyl,€2-10 alkynediyl, and combinations thereof; m is 1 , 2, 3, 4, or 5, and n and k are each independently integers 0, 1, 2, 3, 4, 5 ,6, 7, or 8

|0063l in a variation, more specific compounds having formula 1 are provided by the following formula:

pharmaceutically acceptable salts and esters thereof.

In another variation, more specific compounds having formula I are provided by the following formula:

and pharmaceutically acceptable salts and esters thereof,

J0065] Specific useful compounds having formula Ϊ are the following compounds:

13b (D-687) ; and

13c (D-688) ; and pharmaceutically acceptable salts and esters thereof.

100661 In another embodiment, a compound having formula P for treating a neurodegenerative disease is provided:

or a pharmaceutical iy acceptable salt or ester thereof,

wherein:

A is an optionally substituted CM 2 aryl or Ce-i2 heteroaryl;

Ri4, Ris are each independently H, Ci s alkyl, C2-S alkenyl, C₄-s eycloalkyl, C₄-s cycloalkenyl, C_ft-to aryl, Ci-io alkyl, or CMO and;

B j and B;> are each independently

o is 0, 1 , 2, 3, or 4; and

R u, is an optional substituent as set forth above for example of R group substituents. (0067] in a variation of the compounds having formula 11. A is optionally substituted phenyl:

where Ri?, Ris, Riv, R₂₀ are each independently H, Cos alkyl, OH, or halide (e.g,, F, Ci, Br, 1) or any R group substituent set forth above. In a refinement, A is a substituted phenyl having 1, 2, 3, or 4 hydroxyl groups. In a further refinement, A is:

|0068) In another variation, more specific compounds having formula 11 are provided by the following formula:

eptable salts and esters thereof

10069] In another refinement, R ·.«·_> are H, hydroxyl, halogen, nitro, cyano, Cj-s alkyl, Cue alkoxyl, C₂- s alkenyl, C2-8 alkynyl, C4-8 cycloalkyl, C4-8 cycloalkenyl; Ce-to aryl, -N(Rn)_q -NH-C(0)-Ru, or - NH-€(0)-N(RI2)2, where Rn individually are H, Ci-& alkyl, C2-8 alkenyl, €_2-10 alkynyl, C₄-8 cycloalkyl, C_4-8 cycloalkenyl, or C-₆-io aryl where q is 2 or 3, with the proviso that when q is 3, the group bears a positive formal charge and wherein the hydrocarbon groups in each case are optionally substituted with -CN, Ci-s alkyl, -ORr_>, -OH, halo, or -CF3 where R is Cos alkyl.

100701 The compounds set forth herein may be used per se or as pharmaceutically accepta derivatives. The latter term includes salts, esters, and other derivatives generally considered acceptable by pharmaceutical standards. Useful derivatives, for example, include salts of organic and inorganic acids such as sulfates, phosphates, hydrohalide salts, carboxylaie salts, etc., as well as esters of carboxylic acid or hydroxyl substituents, ethers of hydroxyl substituents, amides of amino substituents, as well as carbamates, ureas, etc. Synthesis of these derivatives is conventional, and well known to those skilled in pharmaceutical chemistry. For example, compounds bearing hydroxyl groups may he converted to esters by customary techniques of organic chemistry, such as reaction with an acyl halide, carboxylic acid anhydride, or by esterification with an acid while removing byproduct water. In some cases, derivation may be desired to facilitate compounding of the pharmaceutical into an acceptable form such as tablets, powder, aqueous dispersion, capsule, etc , or may be useful in assi sting bioavailability of the drug following administration, for example, by rendering the compound more or less soluble. In many cases, such as, for example, esters, ureas,

I B carbamates, ethers, etc., the derivative may act as“prodrug,” which liberates the active form by biological transformation, i.e._t by enzymatic hydrolysis of an ester functionality, as is well known to the pharmaceutical chemist.

10071] In another embodiment, a method for treating a subject with a neurodegenerative disease.

The method includes a step of identifying a subject having a CMS disease. A therapeutic amount of a compound having formula 1 or 11 or any of the variation or refinements thereof is administered to the subject. Examples of such neurodegenerative diseases includes drug addiction, schizophrenia, depression, and Parkinson; s disease (PD). Typical dosages for mammalian subjects may vary from 0.001 mg Kg of body weight to about 100 mg Kg of body weight, preferably 0.01 nig-Kg to 5 mg/Kg Tire actual amount will vary depending upon the particular CNS activity desired to be altered, and the desired degree of alteration. The upper limits may, as with virtually ail drugs, be limited by toxicity of the drug or its metabolites, or by the presence of unwanted side effects. The drugs may be administered in any form, but preferably in the form of tablets or capsules with appropriate excipients. Dosages, forms of administration, etc., can be readily determined by those skilled in the art.

10072] Guidelines to the effective dosages in mammalian species are provided by the many known drugs commercially available which bind to CNS monoamine receptor sites, and by comparing the binding affinities of these pharmaceuticals with the target compounds of the subject invention by in vivo and in vitro studies, in addition to the utility of the subject invention compounds in treatment of diseases such as Parkinson's disease, schizophrenia, treatment for addiction such as cocaine addiction, and the like, die subject invention compounds are also useful, particularly in their radio labeled form, for clinical studies directed to distribution of monoamine receptor sites in the brain and the effect which compounds, such as cocaine, have on these sites.

100731 The following examples illustrate the various embodiments of the present invention, Those skilled i the art will recognize many variations that are within the spirit of the present invention and scope of the claims.

10074] Figure 1 provides a synthetic scheme for compounds having formula I.

10075] I, Scheme 1 (Figure 1)

10076] 1. ( 2- B r om o- e tho \ yHert-b u ty 1 -dime thy 1- silane |0077| A solution of bromoethanol 1 (1 mL, 14.1 mmol), imidazole (1.9 g, 27,9 mmol), and tert- butyldimetbyisilyl chloride (2.1 g, 13,9 mmol) in CH2CI2 (15 mL) was stirred at room temperature for 20 h. Alter the reaction was complete, water (20 mL) was added, and reaction mixture was extracted with CH2CI2 (3 x 50 mL), The CH2CI2 layer was dried over NaiSCL, filtered, and concentrated in vacuo. The resulting crude was purified by column chromatography using 5% ethyl acetate in hexanes to give compound 2 (2,85 g, 86%). ⁵H NMR (CDCL, 600 MHz): S ppm 0,09 (s, 6H), 0,91 (s, 9H), 3,40 (t, J = 6,6 Hz, 2H), 3.89 (t, J = 6,6 Hz, 2H).

100781 2. l- 2-(tert-Biityl-dimethyl-silanylox:y)-ethylj-piperazine

100791 A suspension of piperazine 3 (2.3 g, 26.7 tnmo!), intermediate 2 (2.55 g, 10.7 mmol), and potassium carbonate (11 g, 79,6 mmol) in acetonitrile (35 mL) was refluxed at 80-90 °C for overnight. The reaction mixture was filtered, and the filtrate was condensed in vacuo. The residue was then diluted with ether, washed with water, dried over Na^SCM, filtered, and concentrated to produce intermediate 4 (2.19 g, 84%). ^!H NMR (CDClj, 600 MHz): d ppm 0.06 (s, 6H), 0.89 (s, 9H), 2.49-2.53 (m, 6H), 2.89 (t, J - 4.8 Hz, 4M h 3.76 (t, J ~ 6.6 Hz, 2H).

|0080{ 3. 4^t-bromo-3,4-dimethoxy-l,l '-biphenyl

100811 Into a mixture of starting material 5 (5.96 g, 25.3 mmol), Pd(PPhO-s (0.73 g, 0.63 mmol), and

K2CCK (3,5 g, 25.3 mmol) in ioluene/HsO (20 mL, 10 mL), a suspension of boronic acid 6 (2.3 g, 12,6 mmol) in ethanol (10 mL) was added and stirred at room temperature for 10 min. The reaction mixture was refluxed at 85-90 °C for 3 h. The solvent was partially evaporated, and the mixture was extracted with ethyl acetate (3 x 100 mL), which was then concentrated in vacuo after dried over Na₂SC>4. The resulting crude was purified by column chromatography using 5-10% ethyl acetate in hexanes to give compound 7 (2.89 g, 78%). ^f H NMR (CDCb, 600 MHz): d ppm 3.93 (s, 3H), 3.95 (s, 3H), 6.94 (d, J = 8.4 Hz, 1H), 7.06 (d, ,/ = 1.8 Hz, 1H), 7.11 (dd, J = 8.4, 2.4 Hz, J H), 7.42-7.43 ( , 2H), 7.54 (dt, ,/= 8.4, 1.8 Hz, 2 H),

[0082 [ 4. l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(3^t,4^t-dimethoxy-[l,l '-biphenylj-4- yDpiperazine

|0 S3| The mixture of intermediate 4 (3.33 g, 13,6 mmol), intermediate 7 (2 g, 6.8 mmol), B1NAP

(0.425 g, 0,68 mmol ), and CS2CO3 (6,67 g, 20.5 mmol) in toluene (60 mL) was degassed by bubbling N₂ for 5 min. Then PdfOAcb (115 mg, 0.51 mmol) was added quickly followed by degassing for another 5 min. The reaction mixture was refluxed at 110 °C for 24 h under inert condition. Afterward, it was cooled to room temperature, filtered through a pad of eeliie, washe with CH2CI2_» and concentrated in vacuo. Hie resulting crude was purified by column chromatography using 10-30% ethyl acetate in hexanes to give compound 8 (2 4 g, 77%). ^lH NMR (CDCb, 600 MHz): d ppm 0 80 (s, 6H), 0 91 (s, 9H), 2.60 (t, J 6 6 Hz, 2H), 2 71 (t, J = 4.8 Hz, 4H), 3.24 (t, ,7= 4.8 Hz, 4H), 3.81 (t, J = 5.4 Hz, 2H), 3.91 (s, 3H), 3.94 (s, 3H), 6.91 (d, J = 7.8 Hz, IH), 6,97 (d, ,/ = 8,4 Hz, 2H), 7 07-7 11 (m, 2H), 7,46 (d, J = 7.8 Hz, 2H)

100841 5. 2-(4-(3\4'-dimethoxy-[I,l rtbiphenylM-yi)piperazin-l-yl)ethanol

|00851 Compound 8 (2 g, 4 4 mmol) was dissolved in THF (25 mL) and cooled to 0 °C TBAF (n- tetrabutylammonium fluoride) 1 M in THF (8 76 mL, 8.76 mmol) was added at 0 °C, and reaction stirred at room temperature for 2 h. After reaction was complete, saturated NaHCC solution (50 mL) was added, and reaction mixture was extracted with CH2CI2 (3 x 150 mL), which was then concentrated in vacuo. The resulting crude was purified by column chromatography using 0-5% methanol in CH.-Ch to give compound 9 ( 1 34 g, 89%).’FI NMR (CDCb, 600 MHz): _<5 ppm 2.63 (t, J 5.4 Hz, 2 I), 2.71 (t, J - 5.4 Hz, 4H), 3.26 (t, J - 4.8 Hz, 4H ), 3.68 (I, .7 - 5.4 Hz, 2H), 3.92 (s, 3H), 3.94 (s, 3H), 6.92 (d, ,7 - 8 4 Hz, HI), 6.86 f d. ,7 - 9 0 Hz, 2H), 7.07-7.1 1 (m, 2H), 7.47 (d, J - 9.0 Hz, 21 1 ).

10086] 6. 2-(4-(3',4'-tiimeth oxy- 11 ,G- biphenyl] -4- i)piperazln- 1 -yl)aeeta tdehyde

10087J A solution of DMSO (0 31 mL, 4 37 mmol) in CH2CI2 (2 mL) was added into a round- bottom flask containing a stirring solution of oxalyl chloride (0.21 mL, 2.41 mmol) in (U A L (2 mL) at -78 °C, The mixture was stirred for 0.5 h at the same temperature, and compound 9 (0.42 g, 1.23 mmol) in CH2G2 (3 mL) was added. The stirring of the reaction mixture was continued at -78 °C for another 0.5 h. Thereafter, EtsN (1 ,38 mL, 9.90 mmol) was added, and the reaction was allowed to warm to room temperature and continued for another 1 h. The reaction mixture was quenched by the addition of a saturated solution of NaliCOi at 0 °C and was extracted with CH2CI2 (3 x 100 mL). The combined organic layer was dried over NajSCL, and the solvent was removed in vacuo to produce the crude, which was purified by column chromatography using ethyl acetate to give compound 10 (0.379 g, 91%). ¾ NMR (600 MHz, CDCb): d ppm 2,73 (t, J = 4.8 Hz, 4H), 3.27 (s, 2FI), 3.30 (t, J 4.8 Hz, 4H ), 3.92 (s, 3H ), 3.94 (s, 3FI), 6.92 (d, J - 8.4 Hz, 1H), 6.98 (d, J- 9 Hz, 2 FI), 7.07-7.11 (m, 2H), 7.47 (d, J = 9.0 Hz, 2H), 9 76 (s, 1 11 ). |00S8| Procedure A. 1 a. 2-(4-(3\4¹ '-di methoxy-[ 1 ,1 '-bip hen !] -4-y t)piperazin-l-yl)-N,N- dieth lethanamine

100891 Into a stirring solution of amine 11a (38.4 pL, 0.37 mmol) in CH2G2 (10 mL) was added aldehyde 10 (127 mg, 0.37 mmol), and the mixture stirred for 1.5 h. NaBHfOAefi (0.158 g, 0.75 mmol) was then added portion-wise. The reaction was stirred for 48 h at room temperature. The reaction mixture was quenched with a sat, NaHCCb solution at 0 °C and extracted with CH2CI2 (3 x 30 mL). The combined organic layer was dried over NasSCfi, and solvent was removed under reduced pressure. The crude product was purified by column chromatography using 0-10% MeOH in CH2CI2 to give compound 12a (127 mg, 86%). ¾ NMR (600 MHz, CDClj): d ppm 1.08 (t, 7.2

Hz, 6H), 2.59-2.73 (m, 12 H), 3.25 (t J = 5.4 Hz, 4H), 3.91 (s, 3H), 3.94 (s, 3H), 6 91 (d, J = 8.4 Hz, 1 H), 6.96 (d, J - 8.4 Hz, 2H), 7.07-7.11 (m, 2H), 7.46 (d, J ~ 9.0 Hz, 2H ).

[0090| 1 h. N- (2-{4-{ ¹ , ' - di m et h o xy- [ 1 , 1’-biphenyl] -4-y i)piperazm-l-yI)ethyl)-N- isopropyipropan-2-amine

[0091 ] Aldehyde 10 (194 mg, 0.57 mmol), amine lib (80.5 mT, 0.57 mmol), and MaBH(OAc)₃

(0.242 g, 1.14 mmol) in CH2CI2 (10 mL) were reacted using procedure A, and the resulting crude was purified by column chromatography using 0-10% MeOH in CHAT to give compound 12b ( 1 17 mg, 48%) Ή NMR (600 MHz, CDCh): S ppm 1 ,08 (bs, 12B), 2.45-2.81 (m, 8H), 2.98-3.16 (m, 2H), 3.25 (t, J= 4.2 Hz, 4H), 3.92 (s, 3H), 3.94 (s, 3H), 6.91 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 7,07-7,10 (m, 2H), 7.46 (d, J= 8.4 Hz, 2H),

[0092] lc. 2-(4-(3(4’-diiiiethos;y-[l,l’-biphei3yl]-4-yl)pipetazln-l-yl)- -(4- fhiorobetzyl)ethanamine

[0093] Aldehyde 10 (185 mg, 0 54 mmol), amine lie (61.7 pL, 0.54 mmol), and NaBH(OAc);, (0.23 g, 1.09 mmol) in Cl bCT (10 mL) were reacted using procedure A, and die resulting cmde was purified by column chromatography using 0-10% MeOH in CH2CI2 to give compound 12c (73 mg, 30%). ^l H NMR (600 MHz, CDCh): ppm 2.59 (t, J 6.0 Hz, 6H), 2.75 (t, J - 6.6 Hz, 2H ), 3.22 (t, J ~ 4.8 Hz, 4H), 3.81 (s, 2H), 3.91 (s, 3H), 3.94 (s, 3H), 6.91 (d, J 8.4 Hz, 1 H), 6.97 (d, J- 8.4 Hz, 2H), 7,02 (t, j = 8,4 Hz, 2H), 7,07-7, 1 1 (m, 211), 7.31 (dd, J = 8.4, 5.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), [0094J Procedure B. 2a (D-690). 4'-[4-(2-DiethyIamiiio-ethyI)-piperaziii-l-yi]-biphenyl-3,4-dioI (D-690)

[0095] Compound 12» (44 mg, 0.11 mmol) was treated wit 48% hydrobromic acid (2,5 niL) and refluxed for 6 h, HBr was removed to obtain the residue, which was then dissolved in MeOH and filtered through cotton. The filtrate was concentrated and washed with ether for three times followed drying to give the hydrobromide salt of compound 13» (D-690) (63.5 mg, 89%). ¾ NMR (600 MHz, CD₃OD): S ppm 1 .40 (t, J = 7.2 Hz, 6H), 3.31 -3.94 (m, 16H), 6.78 (d, J = 7,8 Hz, IH), 6.91 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 2 4 Hz, 1H), 7.10-7.31 (m, 2H), 7,52 (d, ./ = 8.4 Hz, 2B). Mp 198-200 °C. Ana. (CaahHsBrjNiO^) C, H, N.

[0096] 13b (D-687). 4^,-i4-(2-Diisopr«pylamin«-ethyl)-piperazin-l-yl]-biphenyl-3,4-diol (D-687)

[0097] Compound 2b (41 mg, 0.096 mmol ) was treated with 48% hydrobromic acid (2 2 ml,) and refluxed for 6 h by following procedure B. The crude was washed with ether for three times followed drying to give the hydrobromide salt of compound 13b (D-687) (49.6 mg, 75%)’H NMR (600 MHz, CDsOD): d ppm 1.46 (s, 6H), 1.47 (s, 6H), 3.34-3.90 (m, !4H), 6.79 (d, J = 7.8 Hz, I H), 6 90 (d, J - 8.4 Hz, IH), 7.00 (s, I H), 7.18-7.28 (m, 2H), 7.51 (d, J - 8.4 Hz, 2H). Mp 168-171 °C. Ana. (GMH43B13N3O₁5) C, H, N.

I00981 2c (D-688). 4’- {4- [2-(4- Fluoro-benzyl aniin o)-ethyi [ -piperazin-l-yl} -b iphenyl-3,4-dioI (D-

688)

[0099] Compound 12c (63 mg, 0. 14 mmol) was treated with 48% hydrobromic acid (3.2 l.) and refluxed for 6 h by follow ing procedure B. The crude was washed with ether for three times followed drying to give the hydrobromide salt of compound 13c (D-688) (80.5 mg, 82%).’H NMR (600 MHz, CD₃OD): S ppm 3 59-3.72 (m, 12H), 4,39 (s, 2H), 6 82 (d, _<7 = 7.8 Hz, I H), 6 93 (d, J = 6.6 Hz, IH), 7.03 (d, J = 1.8 Hz, IH), 7.20-7.25 (m, 4H), 7,53 (d, J = 9,0 Hz, 2H), 7,69-7,71 (m, 2H). Mp 200-203 °C. Ana, (C_2i¾₅Br₃F ₃0₄) C, H, N.

[00100] Modulation of Alpha synuclein study

[00101] We assessed the ability of our compounds, D-687 and D-688, to alter aggregation and cytotoxicity after co-incubating oSN with these drugs for 6 days followed by evaluation of ThT fluorescence activity and cell viability experiment with the PC 12 cells. A total inhibition of ThT activity was observed at day 6 in the presence of these compounds compared to LJSN alone, indicating alteration of the aggregation process in the presence of drugs in order to maintain identical condition, cellular viability was determined by using samples from various experiments diluted to maintain final concentration of 10 mM of aSN and 20 mM of drugs. Treatment with preaggregated aSN alone showed a reduction of cell viability by -- 40%

100102] Figure 2 provides (A) inhibition of aSN tibrillization by D-687 and D-688. The drugs were incubated with aSN over a period of six days and the fibrilization was measured by ThT fluorescence assay. Data Values shown are means ± SEMs of three independent experiments, (B) PC 12 cells were treated with 10 mM prefabricated aSN aggregates formed in presence of drugs collected at day 0 and day 6. Values shown are means ± SEMs of three independent experiments performed in 4-6 replicates. One way ANOVA analysis followed by Tukey's Multiple Comparison post hoc test were performed. (*p<0.0l compared to the control).

|00103 j Modulation of amyloid beta aggregation:

|00104| We next evaluated effect of our compounds on modulation of aggregation and disaggregation activity of Ab 1-42 peptide.

100105] Figure 3 A and 3B show inhibition and dissociation of Ab oligomer formation by : a) ThT fluorescence of Ab 1-42 (10mM) with or without incubation with test compounds (20mM) for 24 h. The ThT fluorescence of Abi- 2 at Oh was taken as 100%. b) Abi-42 fibrils (10mM) were incubated with test compounds (20mM) for a period of 24h. The ThT fluorescence of Abi-42 aggregates at Oh was considered as 100%

100106] Similar to the effect of the drugs on a-syn, interaction of compounds with Abi-42 peptide clearly indicated a significant effect in inhibiting aggregation in a time dependent manner as indicated by decrease in ThT activity (Figure 3a). Similarly, test compounds were able to decrease ThT activity of preformed Ab aggregates in a time dependent manner, reflecting its effect in disrupting structure of aggregates (Figure 3b). On the other hand, incubation of aggregates itself led to a gradual increase in ThT activity (Figure 3b). Therefore, test compounds exhibited dual activity in inhibiting association of Ab_ί-42 to form aggregates and in dissociating the formed aggregates. jOOl 07] Conclusion: The overall results indicate the compounds D687, D688 and D690 potently inhibited aggregation of aSN protein and Abi-42 peptide and disaggregate Abh_{¾ .} 100108] IL Scheme 2

100109] L4-Bis(chloromethyl)-2,5-dimethoxybenzene (2): Paraformaldehyde (3.3 g, 108,6 mmol) was added to a slurry of compoun 1 (5.0 g, 36,2 mmol) in cone HC1 (15 mL) and acetic acid (15 mL) at rt under inert gas atmosphere. The mixture was sonicated for 2h, Hie mixture was filtered and the solid w¾s washed with hexane (3 X 50 mL) followed by acetone (15 mL). The crude product was purified by column chromatography using 5% ethyl acetate in hexane to affor compound 2 (5.53 g, 23.53 mmol, 65%) as white solid. ^JH NMR (600 MHz, CDCL): d 6.92 (s, 2H), 4.63 (s, 4H), 3.85 (s, 6H). fOOI 10] 2,2'-(2,5-Dmietho\y-l ,4-phenylene)diacetonitrile (3): To a mechanically stirred suspension of NaCN (3.45 g, 70.46 mmol) in anhydrous dimethyl sulfoxide was added in small portions of 2 (7.1 1 g, 30 24 mmol). The reaction mixture was stirred at 50 °C for !h. Temperature was increased to 85 °C and the reaction mixture was allowed to stir at that temperature for additional 5 minutes. The mixture was cooled to rt. The reaction mixture was diluted with water (100 ml.) and extracted with ethyl acetate (3 X 150 mL). The combined organic layer was washed with water, brine, dried over NajSOi, and solvent was removed under vacuum. Crude product was purified by column chromatography using 20% ethyl acetate in hexane to give compound 3 (4 57 g, 21.17 mmol, 70%) as white solid, ⁵H NMR (600 MHz, CDCb): 6 6,92 (s, 211 ), 3.85 (s, (41 ), 3.70 (s, 4H),.

|001H | 2,2'-(2,5-Dimethoxy-l,4-pheiiyIene)diaeetic add (4): To a suspension of compound 3 (0.40 g, 1.85 mmol) in cone. HC1 (10 mL) was added acetic acid (1 mL). The mixture was allowed to stir at 100 °C for 3 h. After completion of the reaction as indicated by TILL the mixture was cooled to rt. The mixture of acids was removed under low pressure. The crude residue was extracted with ethyl acetate (70 mL) and washed with water (3 X 20 mL) The organic layer was washed with brine and dried over NasSCL. The solvent was removed under vacuum. Crude product was purified by column chromatography using 10% methanol in dich loro me thane to give compound 4 (0.28 g, 1,1 1 mmol, 60%) as brown solid. ^!H NMR (600 MHz, %-D SOf. 5 12 14 (brs, 2H), 6.82 (s, 2H), 3.66 (s, 6H), 3.65 (s, 4H).

100112] Dimethyl 2,2^*-(2,5-dimethoxy-l,4-phenylene)diacetate (5): To a suspension of the acid 4 (.1.0 g, 3.93 mmol ) in methanol (25 mL) was slowly added thionyichloride (4,85 mL 66.86 mmol) at 0 °C The mixture was allowed to stir at that teperaiue for 1 h. Then the reaction temperature was graduall increased to it and the stirring was continued for 24h. Solvent and excess reagents were removed under low pressure. The crude residue was extracted with ethyl acetate (120 mL) and washed with saturated aqueous NaHCCb solution (40 iuL) The organic layer was washed with water (3 X 30 mL), brine and dried over Na₂S0₄. The solvent was removed under vacuum. Crude product was purified by column chromatography using 3% methanol in dichloromethane to give compound 5 (0.61 g, 2,16 mmol, 55%) as white solid. ^lE NMR (600 MHz, CDCb): 6 6.74 (s, 2H), 3.77 (s, 6H), 3.68 (s, 611 ), 3.61 (s, 414 ).

]001131 2,2^,-(2,5-Dimethoxy-l ,4-pheny lene)diethanol (6): To a stirring solution of the ester 5 (0,56 g, 2.0 mmol) in THF (20 mL) was added LiAlH₄ (0,30 g, 8.0 mmol) in portions at 0 °C under inert ga atmosphere and the stirring was continued for 1 h. The reaction temperature was increased to rt and the mixture was allowed to stir for overnight. The reaction was quenched with the addition of water (3 mL) fol lowed by 2 N aqueou NaOH (3-5 mL) at 0 °C. The mixture was filtered through cellte and the solid residue was washed with THF (2 X 20 mL) followed by hot ethyiacetaie (40 mL). The combined solution was evaporated under vacuum. Crude product was purified by column chromatography using 3% methanol in dichloromethane to give compound 6 (0.25 g. 1 10 mmol, 55%) as white solid ¾ NMR (600 MHz, CDCb): 6 6.71 (s, 2H), 3.82

6.6 Hz, 4 H), 3.78 (s, 6

H), 2.87 (t, J = 6.6 Hz, 4 H).

100114] 2,2'-(2,5-Dimethoxy- -phenylene)diacetaidehyde (7): To a stirring solution of 6 (50 g,

0.22 mmol) in DCM (10 mL) was added Dess-Martin periodinane (280 mg, 0.66 mmol) at rt. After stirring the reaction mixture for 4 h the volume of the mixture was reduced to half under low pressure. Ii was then passed through celite and the solid was washed with DCM (2 X 7 mL), The combine filtrate was evaporated to produce a soli residue which was purified by column chromatography using 25% ethySacetate in hexane to give compound 7 (29 mg, 0 13 mmol, 60%). lH NMR (600 MHz, CDCb): 6 9 68 (t, J = 1.8 Hz, 2H), 6 71 (s, 2H), 3 77 (s, 6H), 3.65 (d, J= 1.8 Hz, 411 ).

100115] (2,S^,,2^,A)-,V,A^,-((2.5-dimethoxy-L4-pheHylene)bis(ethane-2,l-diyl))his(5-metho\y-]N- propyl- 1,2, 3 ,4-tetrahydronaphthalen-2-a mine) (9): Into stirring solution of compound 7 (47 mg, 0.213 mmol) in DCM (6 mL), (S)-5 -methoxy- A^'-propyl - 3 ,2,3 A -tc trail ydronaphthal en-2 -amine (8) (93 mg, 0.422 mmol) was added at room temperature. The reaction mixture was stirred for 1 h, and then NaBH(OAc)i (161 mg, 0.759 mmol) was added into the solution. After stirring for 40 h, saturated solution of NaHCOj (6 mL) was added into the reaction mixture and the compound was extracted with DCM (3 x 10 mL) The combined organic layer was washed with water and brine and finally purified by silica gel column chromatography (60% EtOAc in hexane) to yield compound 9 (33 mg, 0.05 m ol, 25%.). Ή NMR (600 MHz, CDCh): 8 7 08 (dd, J¾ = 8.4 Hz, J₂ = 7.8 Hz, 2H), 6.71 (d, ./ = 7.8 Hz, 2H), 6.66 (s, 2H), 6,65 (d, J= 8.4 Hz, 2H), 3.80 (s, 6H), 3.77 (s, 6H), 3.01 -2.86 (m, 6H), 2 77-2 72 (m, 8H), 2.56-2.50 (m, 6H), 2.11 (m, 2H), 1.66-1 ,55 (m, 8H), 0,9! (t, ,/ = 7.2 Hz, 6H) ¹³C NMR (150 MHz, CDCh): 5 157.2, 151.3, 138.2, 127 4, 126.1 , 125.3, 121.6, 113.5, 106.8, 56.8, 56.1 , 55,2, 52.7, 51.1 , 32.5, 30.5, 25.8, 23.8, 22.1, 12.0.

[00116 j 2,5-Bis(2-(((S)-5-hydroxy-l ,2,3,4-tetrahydronaphthalen-2- yI)(propyl)amino)ethyl)benzene-l,4-diol (10): A mixture of compound 9 (30 mg, 0,048 mmol) an 48% aqueous HBr (6 mL) was refluxed for 6 h. The reaction mixture was then evaporated to dryness in vacuum. The crude mixture was then washed with diethyl ether to afford compound 10 as a brown solid (31 mg, 0.042 mmol, 88%). ^l H NMR (600 MHz, CD₃OD): 5 6.96 (t, J = 7.8 Hz, 2H), 6.70-6.69 (m, 2H), 6.63-6.60 (m, 4H), 3.79-3.76 (m, 2H), 3.52-3.46 (m, 2H), 3.39-3.32 (m, 4H), 3 24-3 16 (m, 4H), 3.09-2.95 (10H), 2.66-2.56 (m, 2H), 2.40-2.32 (m, 2H), 1.89-1.78 (m, 6H), 1.05 (t, J - 7.2 Hz, 8H).

|00117] C. Scheme 3 (Figure 5) fOOl lSj 2,2^,-(2,5-Dimetho\y-i,4-phenylene)diacetaldehyde (7), To a stirring suspension of alcohol

6 (0.12 g, 0.53 mmol) in CH2CI2 (10 mL) was added Dess-Marlin periodinane (0.675 g, 1.59 mmol) at room temperature. After stirring the reaction mixture for 4 h, it was filtered through a pad of eelite, washed with CH2CI2 and the combine filtrate was evaporated to produce a solid residue. The crude product was purified by silica gel column chromatography (hexane;ethyl acetate ^:::: 3:1 ) to give aldehyde 7 (0.1 g, 85%). The purified aldehyde was used immediately for next step. * H NMR (600 MHz, CDCh): d 9.69 (s, 1H), 6.73 (s, 2H), 3,78 (s, 6H), 3.66 (d, J = 1.8 Hz, 4H)

|00119j 2,5~bis(2-(((A)-2~amino-4,5,6,7-tetrahydrohenzo|f/3thiazol-6-yl)(propyl)amino>

ethyi)benzene-i,4-diol (11).

[001201 into a stirring solution of aldehyde 7 (0.09 g, 0.41 mmol ) in ChfiCfi (10 mL) was added (S)- L⁶ -propyl-4,5, 6, 7-tetrahydrobenzo[if|thiazoie-2, 6-diamine (0. 154 g, 0 73 mmol). Alter the mixture was stirred for 1.5 h, NaBH{OAcb (0.343 g, 1.62 mmol) was added portion wise and the mixture was stirred for 48 h at room temperature. The reaction mixture was quenched with a saturated solution of NaHCCh at 0 °C and extracted with CTfiCfi (3 * 40 mL). The combined organic layer was dried over NajSCh, and the solvent was removed under reduced pressure. Crude product was purified by column chromatograph (EtOAc/MeOH 8:1) to afford compound 11 (0.085 g, 34%). ¹H NMR (600 MHz, CDCh): S 6 65 (s, 2H)_S 5 19 (bs, 4H)_S 3 77 (s, 6H)_S 3 13-3 07 (m, 2H), 2.73-2,67 (m, 121 1 ). 2.59-2.49 (m, 8H), 2.01-1.99 (m, 21 1 ). 1.74-1.68 (m, 21 1 ). 1.54-1.48 (m, 4H), 0.90 (t, J = 7.2 Hz, 6H); °C NMR (150 MHz, CDCb): <5 165,91, 151.21 , 144,84, 127.20, 117 10, 1 13,45, 60,41 , 57.79, 56.08, 52 91, 51 .24, 30.71, 26.48, 25.94, 25.12, 22.15, 14 18, 1 1 .90; [a]o^2S- -55.2 (c=1 .0 in CH2CI2).

|00121 j 2,5-M$(2-(((^ 2-ammo-4,5,6,7-tetrahydrobenzo[i^thiazo!-0-yl)(propyi)amino)- ethyl)benzene- 1 ,4-diol (12) (D- 73), A mixture of compound 11 (0.075 g, 0.12 mmol) and 48% aqueous HBr (15 mL) was refluxed at 130 °C for 5 h. The reaction mixture was evaporated to dryness, washed with ether followed by vacuum drying to yield HBr salt of 12 (0.105 g, 95%).

NMR (600 MHz, CD₃OD): S 6.77 (s, 2H), 4.03 (s, 2H ), 3.55-3.33 (m, SH ), 3.27-3.23 (m, 2H ), 3.14 (i, J ^:- 10.2 Hz, 2H), 3.04 (t, J 7.8 Hz, 4H), 3.00-2.94 (m, 2H), 2.78 (bs, 4H), 2.47-2.41 (m, 2H), 2.18-2.11 (m, 2H), 1.94-1.83 (m, 4H), 1.04 (t, J - 7.2 Hz, 6H);“C NMR (150 MHz, CD3OD): <5 173.95, 151 .96, 136.64, 126.43, 120.98, 115.79, 63.10, 62.86, 57.37, 56.82, 54.90, 52.45, 29.99, 27.01, 26.16, 25.54, 22.26, 13.99; [ofo²⁵- -42.0 (c=1.0 in CH3OH); Anal. Calcd for IsiBrsNeOsSi: C, 35.77; H, 5.10; N, 8.34. Found: C, 36.08; H, 5.42; N, 8.27.

[001221 Table 1. Inhibition constants determined by competition experiments assessing j ³ II [spiroperidol binding to cloned Du and D receptors expressed in i lEK-293 cells'¹

‘“Results are the mean ± SEM of 3-6 experiments, each performed in triplicate.

|00123 j Table 2. Stimulation of [^3SS]GTPyS binding to clone human D2 and D? receptors expressed in CHO cells⁰

[00124] the concentration producing half maximal sti ulation. For each compound, maximal stimulation (£_max) is expressed as a percent of the £_{m ax} observed with I mM (Da) or 100 mM (Dy) of the full agonist DA (E_max., %). Results are the mean ± SEM for 3-6 experiments, each performed in triplicate. 00125j D, Scheme 4 (Figure 6)

[00126] Synthesis of P-679

[00127] iV-(2,5-Dioxo-tetrahydro-furan-3-yI)-2,2,,2-trifUioro-acetamide (1), Trifluoroacetic anhydride (13.12 mL, 93.91 mmol) was added to D-aspartic acid (5,0 g, 37.57 mmol) at -60 °C and stirred for 10 min. The reaction mixture was allowed to warm to room temperature and then to 40 °C during which a vigorous exothermic reaction took place. Trifluoroacetic acid (10 mL) was added next and the reaction mixture was stirred under refluxing condition for 2 h. After cooling, petroleum ether was added and the soli thus formed was collecte by filtration, washe successively with petroleum ether and ether and finally dried under vacuum to afford compound 1 (7 7 g, 97%), ¹H NMR (600 MHz, Acetone-D*): <5 9 41 (bs, I B), 5.30-5.26 (m, 1 H), 3.53 (q, J = 10.2 Hz, 1H), 3.27 (dd. J 12.0, 6.6 Hz, I B).

[00128] 4-(3,4-Dimethoxy-phenyI)-4-oxo-2-(2_>2,2-trif1uoro-acet\iamino)-hutyric acid (2). To a stirring suspension of compound 1 (4.0 g, 18.95 mmol ) and AlCh (6 3 g, 47.37 mmol ) in Cl LCl· (90 ml), verairole (3.62 mL, 28,42 mmol) was added an the reaction mixture was stirred at room temperature for 4 days. 6M HC1 was added to the reaction vessel and the layers were separated. Aqueous layer was extracted with ether (3 x 50 mL) and the combined organic portions were dried over Na^SCfi, filtered and evaporated under reduced pressure. The crude materia! was purified by silica gel column chromatography (hexane: EtO Ac 1 : 1) to give compound 2 (5.3 g, 80%). ¹H NMR (600 MHz, CDCb); S 7.61 (bs, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 7.48 (s, IH), 6.92 (d, J = 8.4 Hz, 1 H), 5.02-5.00 (m, 1H), 3.97 (s, 3i¾ 3.93 (s, 3H), 3.89-3.86 (m, IH), 3.58 (dd, J 14.4, 4.2 Hz, IH).

[00129] 4-(3,4-Dhnethoxy-phenyI)-2-(2,2.,2-trifluoro-acetyIaimno)-butyric acid (3). Triethylsilane

(9.7 mL, 60.7 mrnol) was added to a magnetically stirred solution ofketo acid 2 (5 3 g, 15,18 mmol) in trill uoroacetic acid (22.5 mL, 303.5 mmol). This solution was boiled under reflux under M? for 2 h after which it was cooled and carefully neutralized to pH 8 with NaHCCh solution at 0 °C. The aqueous solution was washed twice with Et₂0 and acidified (pH <5) b the dropwise addition of 6N HC1 at 0 °C. The product was extracte with EtiO (3 x 30 mL), the organic layers were dried over MgSCk, and the ether was removed by rotary evaporation to yield a yellow oil. which solidified on standing. This solid was recrystallized from EtO Ac/hexane to afford carboxylic acid 3 (4.7 g, 92%). ¾ NMR (600 MHz, CDCT): 0 6.81 (d, J = 8.4 Hz, IH), 6.74-6.71 (m, 2H), 6 70 (d, J = 1.2 Hz, IH), 4.73-4.70 (m, IH), 3.87 (s, 3H), 3.86 (s, 3H), 2.68 (t, J = 7.2 Hz, 2H), 2.37-2.31 (m, I H), 2.21- 2.15 (m, I H ).

[00130] A-(6,7-Diraethoxy-l-oxo-l,2,3_s4-tetrahydro-naphthaIen-2-yl)-2,2_s2-trifluoro-acetamide (4). To an ice-cooled solution of compound 3 (4.5 g, 13.42 mmol) in 40 ml. of O bC k was added solid PCI5 (3.35 g, 16.1 1 mmol). Stirring was continued for 1 h at 0 °C, and SnCU (3.14 mL, 26.84 mmol) was added. The mixture was stirred for 0.5 h at 0 °C and then allowed to warm to room temperature and stirred for an additional 4 h. The mixture was poured into ice water and vigorously stirred for 15 min. The layers were separated, and the aqueous phase was extracted with CH2CI2 (3 x 50 mL) The organic portions were dried over MgSCL and rotary evaporated to furnish white solid, which was purified by silica gel column chromatography (hexane:EtOAe = 3:2) to give colorless tetralone 4 (2.5 g, 59%). ^lH NMR (600 MHz, CDCh): d 7.58 (bs, 1H), 7.46 (dd, .7 = 3.6, 1.2 Hz, 1 H), 6.69 (s, 1H), 4.58-4,54 (m, 1 H), 3.96 (s, 3H), 3,93 (s, 3H), 3 26-3 20 (m, 1 H), 2.99-2.96 (m, I H). 2.89-2.85 (m, 1H), 1.95 (dq, ./ = 9.0, 4.8 Hz, 1H).

[00131] A'-(0,7-Dimethoxy-l,2,3,4-tetrahydro-naphthalen-2-yl)-2,2,2-tnfUioro-aeetamide (5).

Triethylsiiane (4.53 mL, 28.37 mmol) was added to a solution of compound 4 (2.25 g, 7.09 mmol ) in 17,5 mL (141.84 mmol) of Bfd.Et^O, and the resulting solution was stirred at room temperature under N2 for 48 h. Alter basification of the mixture by addition to saturated NaHCCh, the layers were separated, and the product was extracted with H O (3 x 50 mL). Tire combined organic layers were dried over NajSCL and concentrated on a rotary evaporator. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 7:3) to afford compound 5 (1.65 g, 77%). ^lH NMR (600 MHz, CDCh ): S 6.59 (s, IH), 6.55 (s, Hi), 6.34 (bs, IH), 4.37-4.30 (m, 111). 3,85 (s, 3H), 3.84 (s, 3H), 3.11 (dd, ./ - 1 1.4, 4.8 Hz, IH), 2.90-2.85 (m, IH), 2.83-2.78 (m, IH), 2.67 (dd, J = 8.4, 7.8 Hz, 1H), 2.1 1 -2.06 (m, 1 H), 1.91-1.85 (m, 1H). [00132] 6,7-Dimethoxy-l,2,3,4-tetraliydro-iiaphthalen-2-y!amlne (6). To a stirred suspension of

K2CO3 (1 37 g, 9 9 mmol) in 30 mL of MeOH containing 1.5 mL of H2O was added triiluoroacetamide 5 (1 ,0 g, 3.3 mmol), and the mixture was boiled under reflux for 4 h. The mixture was allowed to cool to room temperature, and the undissolve K2CO3 was removed by filtration through a cotton plug. The filtrate was concentrated in vacuo, and the dark residue was diluted with water. The product was extracted with EtOAc (3 x 40 mL), the organic layers were dried over NinSCfi and the volatiles were removed by rotary evaporator to furnish compound 6 (0 65 g, 95%). 'll NMR (600 MHz, CD OD): <5 6,62 (s, 1 H), 6,60 (s, IH), 4.87 (bs, 2H), 3.75 is, 611), 3.03-2.99 (m, IH), 2.88 (dd, /= 10.8, 4.8 Hz, 1 H), 2.79-2.72 (m, 2H), 2.45 (dd, J- 9.6, 6.0 Hz, 1 H), 2.00-1.95 (m, Hi), 1.55-1.49 (m, 1H).

[00133] A-{6,7-Dimethoxy-l,2,3,4-tetrahydro-naphthalen-2-yl)-2-nitro-benzenesulfonamkJe (7).

2-Nitroben enesulfony! chloride (0.64 g, 2.89 mmol) was dissolved in 20 mL of THE, and the solution was cooled to approximately -10°C. EfvN ( 1.82 mL, 13.03 mmol) and compound 6 (0 6 g, 2.89 mmol) were added and the resulting suspension was heated during mixing to approximately 25°C, and allowed to react for 1.5 h. Precipitated triethyiammonium chloride was filtered off, and the filtrate was concentrated. Water was added and extracted with EtOAc (3 x 30 mL). The combined organic layer was dried using Na?S0₄, and the solvent was removed under reduce pressure to obtain sulfonamide 7 (1,05 g, 93%). ^rH NMR (600 MHz, CDCh): *5 8.21 -8.19 (m, IH), 7.90-7.88 (m, IH), 7,78-7.74 (m, 2H), 6,54 (s, I H), 6.41 (s, IH), 5.40 (d, J = 7 2 Hz, IH), 3.83 (s, 3H), 3.80 (s, 3H), 2.95-2.9.1 (m, IH), 2.81 -2.74 (m, 2H), 2.69 -2.65 (m, I B), 2.01-1.97 (m, I H), 1.83-1.77

[00134] A^?-(6,7-Dmiethoxy-l,2,3,4-tetrahydro-naphthalen-2-yI)-2-nitro-A^?-propyI-benzene- sulfonamide (8). To a stirred suspension of 7 (1 ,0 g, 2.55 mmol) and potassium carbonate (2.47 g, 17.84 mmol) in acetonitrile (25 mL), 1 -bromopropane (0 69 mL, 7,65 mmol) was added and the reaction mixture was stirred at 40 °C for 48 h. The reaction mixture was cooled to room temperature, fi ltered off and the filtrate was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane:EtOAc - 7:3) to afford compound 8 (0.99 g, 89%). ^lH NMR (600 MHz, CDCH): S 8,09 (dd. J 6,0, 1.8 Hz, Hi), 7.71-7.66 (m, 2H). 7.63 (dd, J - 6.0, 1.8 Hz, I H), 6.55 (s, IH), 6.50 (s, 1 11). 4.12-4.06 (m, IH), 3.83 (s, 3H), 3.82 (s, 3H), 3.28 (t. J 7.8 Hz, 2H ), 2,96-2,78 (m, 111 ). 2.01-1.98 (m, I H), 1 87-1.80 (m, IH), 1.74-1.64 (m, 2H), 0.90 (t, J - 7.2 Hz, 3H); [a]»²⁵- +75.4 (c-1.0 in CH2CI2). [00135] {6,7-Dimethoxy-l,2,3_i4-tetrahydro-naphthaien-2-yl)-propyl-amlne (9)- Into a mixture of potassium carbonate (1 ,63 g, 11 ,81 mmol) in 20 mL of DMF, thioglycolie acid (0.47 mL, 6,56 mmol) was added slowly at 0 °C The mixture was stirred a room temperature for approximately 1 h, followed by addition of compound 8 (0.57 g, 1 ,31 mmol, in 10 mL of DMF), The reaction mixture was heated during stirring to about 50 °C and allowed to react for an additional 15 h, after which it was quenched by addition of 1N NaOH and extracted with EtOAc (4 x 25 mL). 'fhe combined organic layer was dried using Na₂S0₄, and the solvent was concentrated under reduced -pressure. The crude product was purified by silica gel column chromatography (0-10% MeOH in CH2CI2) to give compound 9 (0 22 g, 67%). Hi NMR (600 MHz, CDCh): S 6.56 (d, J === 5.4 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 2.99-2.91 (m, 2H), 2.82-2.76 (m, 2H), 2.71 (t, J - 7.8 Hz, 2H ), 2.60-2.56 (m, 2H), 2 08-2 06 (m, 1H), 1.66-1.55 (m, 3H), 0.95 (t, J- 7.2 Hz, 3H); a]_D ²⁵-+68.6 (c=L0 in CH2CI2).

|OOI36j Procedure A. (4-{i(5-Methoxy-l,2_»3 4-tetrahydro-naphthalen-2-yl)-propyl-carbamoyl]- methyl}-phenyl)-acetic acid (10). To a solution of 1 ,4-phenylenediacetic acid ( 1.0 g, 5.15 mmol) in DMF (20 mL) were added EDO (0.296 g, 1.54 mmol), HOB (0.21 g, 1 .54 mmol ) and Et.iN (0.25 mL, 1.80 mmol) and the resulting mixture was stirred at room temperature for 1 h. (5V5-me hoxy-V- propyl-l ,2,3,4-telrahydronaphthalen-2-amine (0.28 g, 1.29 mmol) in DMF (5 mL) was added next to the reaction mixture and stirred at room temperature for an additional 3 h after which DMF was evaporated under vacuum. Water was added and extracted with CH2O2 (3 ^x 25 mL). The combined organic layer was drie using Na?S0_4, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatograph (hexaneiEtOAe = 2:3) to yield compound 10 (0.325 g, 64%). ^lH NMR (600 MHz, CDCh): S 7.24-7.15 (m, 4H), 7.08 (q, ./ = 7.8 Hz, 1 H), 6.66-6.60 (m, 2H), 4.58-4.55 (m, 1H), 4,04-3.99 (m, 1 H), 3 80 (s, 3H), 3.75 (s, 1 H), 3.72 (s, 1H), 3.24-3.12 (m, 2H), 3.02-2.82 (m, 3H), 2.63-2.57 (m, 1 H), 2.40-2.34 (m, 1 H), 1.97-1.94 (m, 1 H), 1.74-1.59 (m, 3H), 0.91 -0.87 (m, 3H),

[00137] 2-(4-{|(6,7-Dimethoxy-l,2,3 4-tetrahydro-naphthaIen-2-yI)-propyI-carbamoyl]-methyI}- phenyI)- V-(5-methoxy-l,2,3,4-tetrahydro-naphthalen-2-yl)-A-propyI-acetaimde (11).

Compound 10 (0.28 g, 0.71 mmol), 9 (0.177 g, 0.71 mmol), EDO (0 136 g, 0.71 mmol), HOBl (0.096 g, 0 71 mmol) and EhN (0 1 mL, 0,71 mmol) were reacted in DMF (15 mL) overnight according to procedure A The crude product was purified by silica gel column chromatography (hexane: EtOAc - 2:3) to afford compound 11 (0 325 g, 73%).

NMR (600 MHz, CDCh): d 7.26- 7.17 (m, 4H), 7.1 1 -7.06 (m, 1 H), 6.67-6.61 (m, 2H), 6.56-6.50 (m, 2H), 4.63-4.57 (m, IH), 4.06-3.99 (m, 1 H), 3.83-3.78 (m, 9H), 3.76-3,71 (m, 411 ). 3.24-3.1 1 (m, 4H), 3.03-2.75 (m, 51 Gk 2.73-2.58 (m, 3H), 2 42-2 31 (m, 1H), 1.97-1.87 (m, 2H), 1.81-1 63 (m, 5H), 0.92-0.87 (m, 6H); [a]h²⁵= +12.4 (c= 1.0 in CH2CI2).

100138] (6,7-Diniethovy- 1.2,3,4-tetrahydro-naphthaien-2-yl)-|2-(4- {2- [(5-methoxy-l ,2.3,4- tetrahydro-naphtha]en-2-yl)-propyl-amino]-ethyl]-pheny])-ethylj-propyl-amine (12). To a solution of compound 11 (0,31 g, 0.5 mmol) in anhydrous THF (10 L), BH3.THF complex (4.95 niL, 4.95 mmol, 1.0 M in THF) was added dropwise at room temperature. Reaction temperature was raised to 55 °C and the mixture was stirred for 4 h, Alter cooling, water (1 mL) and concentrated HC1 (2 mL) were added at 0 °C and then THF was evaporated under vacuum. 25% NaOH solution (20 mL) was added to the aqueous phase and extracted with EtOAc (3 x 25 mL). The combined organic layer was dried using NaaSCU, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (hexane:EtOAc - 7:3) to furnish compound 12 (0.205 g, 69%) Ή NMR (600 MHz, CDCh): S 7.18 (s, 4H), 7.1 1 -7.08 (m, 1 H), 6.71 (q. ./ - 7.8 Hz, 1H), 6.65 (d, J 8.4 Hz, IK), 6.60-6.56 (m, 2H), 3.84-3.79 (m, 9H), 3.30-3.19 (m, 3H), 3.18-3.04 iroJH). 3.01 -2.73 (m, 10H), 2.57-2.38 (m, 3H), 1 .91-1 .71 (m, 7H), 0.97-0.93 (m, 6H); °C NMR (150 MHz, CDCh); d 157.09, 147.41, 137.12, 136.05, 129.24, 127.09, 126.66, 126.23, 124 19, 121.50, 1 12.03, 111 05, 107.27, 64.44, 64.05, 60.37, 58.72, 55,92, 55.25, 30 13, 29.63, 29.53, 29.45, 24.06, 23.51, 21.05, 16.42, 14.23, 1 1 .88;

100139] 6-{|2-(4-{2-[(5-Hydroxy-l,2,3,4-tetrahyclro-naphthalen-2-yl)-propyI-ammo]-ethyl}- phenyl)-ethyl]-propyl-amino}-5.6,7,8-tetrahydro-naphthalene-2,3-diol (13) (15-679). A mixture of compound 12 (0.2 g, 0,33 mmol) and 48% aqueous HBr (15 mL) was refluxed at 130 °C for 5 h. The reaction mixture was evaporated to dryness, washed with ether followed by vacuum drying to yield HBr salt of 13 (0 22 g, 89%), ¹ H NMR (600 MHz, CD₃OD): S 7.31 (i, J = 7.8 Hz, 4H), 6.85 (i, J= 7.2 Hz, l H), 6.63 (d, J = 7.8 Hz, 1H), 6.57-6.52 (m, 2H), 6.47 (s, 1 H), 3.64-3.62 (m, 2H), 3.46- 3.32 (m, 111 ), 3.27-3.13 (m, 9H), 3.01-2.88 (m, 4H), 2.68 (bs, 2H), 2.54-2.46 (m, 1 H), 2.32-2.26 (m, 2H), 1 .84-1 .76 (m, 6H), 1.02 (t, - 7.2 Hz, 6H); ^t3C NMR (150 MHz, CDiOD): d 154.53, 143.73, 143.41 , 135.52, 133.56, 129.27, 126.61 , 125.78, 122.99, 121.73, 120.09, 1 15.39, 1 14.66, 112.24, 60.88, 60.52, 52.57, 52,31, 52.14, 51.82, 30.46, 29.47, 28.66, 27.31, 24,11 , 23.48, 22.36, 18.54, 10.31; [a]tt% t-7.8 (c-0.5 in CH3OH); Anal. Calcd for CwHssBraNsC s: C, 57.99; H, 7.16; N, 3.76. Found: C, 57.94; H, 7.03; N, 3.81. ί00140| While embodiments of the invention have been illustrated and described it is not intended that these embodiments illustrate and describe all possible forms of the invention. Rather, the words used in the specification are words of description rather than limitation, and it is understood that various changes may be made without departing from the spirit an scope of the invention.

Claims

WHAT IS CLAIMED IS:

1 , A compound having formula Ϊ for treating a neurodegenerative disease:

or a pharmaceutically acceptable salt or ester thereof,

wherein:

Ri is H, Cj-8 alkyl, C₂-8 alkenyl, C₄-8 cycloalkyl, C4-8 cycloalkenyi, Ce-io aryl. Cj. to alkyl C*.

_JO aryl.

R₂, R , R₄, R$ are each independently H or OH wherein at least 2 of R₂, Rj, R4, R₅ arc OH; Rh is H, an optionally substituted Ci-s alkyl, an optionally substituted C₁-8 alkoxyl, an optionally substituted tb-s alkenyl, an optionally substituted C .x alkynyl, an optionally substituted

0..x cycloalkyl, an optionally substituted C.._x cycloalkenyi, an optionally substituted Cl -8 alkyl CL

_lo aryl, an optionally substituted CVio aryl,

R_? is H, an optionally substituted C_t-s alkyl, an optionally substituted Cue alkoxyl, an optionally substituted CLH alkenyl, an optionally substituted C₂-S alkynyl, an optionally substituted C_4-8 cycloalkyl, an optionally substituted C₄-s cycloalkenyi, an optionally substituted Cl -8 alkyl Ce- o aryl or an optionally substituted CS-JO aryl; Rg are each independently hydroxyl. Ci-4 alkyl, CM alkoxyl, Ci-s alkyl, C2-8 alkenyl, C2-3 alkynyl, CM eycloalkyl, CM cycloalkenyl; CS-JO aryl, -NR-’q or CMO hydrocarbon groups optionally containing one or more O, , S, or Se heteroatoms where R’ individuall are H or organyi groups and q is 2 or 3, with the proviso that when q is 3, the group bears a positive formal charge;

Z_¾Ts is absent or a divalent linking moiety in which Z is repeated m times;

o is 0. 1. 2, 3, or 4; and

m is Q, 1 , 2, 3, 4, or 5.

2 The compound of claim 1 wherein

3. The compound of claim 1 wherein

and R_? are each independently C alkyl, C->-s alkenyl. CM alkynyl, CM eycloalkyl, or CM cycloalkenyl, an optionally substituted C l -8 alkyl CGUO aryl.

4 The compound of claim 1 having a formula selected fro the group consisting of:

ceutically acceptable salts and esters thereof.

, The compound of claim 1 having a formula selected from the group consisting of:

and pharmaceutically acceptable salts and esters thereof.

6 The compound of claim 1 having the following formula:

13a (D-690) or a pharmaceutically acceptable sail: or ester thereof.

7. The compound of claim 1 having the fol lowing formula;

13b (D-687) or a pharmaceutically acceptable salt or ester thereof.

8. The compound of claim 1 having the following formula:

13c (D-688) or a pharmaceutically acceptable salt or ester thereof.

9. The compound of claim 1 wherein R_? is substituted with a component selected from the group consisting of, halogen, CM alkyl, Cj-s alkoxy, C acyloxy, CM acyl, -C(0)-R.9, -Rio-NH- SO_.i-Ni R / , , -Rjo-NH-C(0)-Ri»; -R i o-N(Ry)r. and -Ry-Ar where

R > is H, Ci-s alkyl, C_M alkenyl, C₄-s eycioaikyl, CU-s eycloalkenyl, or Cs-io aryl;

Rut is C -s alkenyl;

r is 2 or 3; and

Ar is a C*-io aryl ring system, optionally including one or more heteroatoms or Cs-io heteroaryl; with the proviso that when r is 3. the nitrogen of the CR»),- group will bear a positive formal charge.

10. The compound of claim 9 wherein Ar is an optionally substituted phenyl, thienyl, pyridyl, bipyridyl, biphenylyl, or naphthyl.

1 1. The compound of claim 1 wherein Rs are hydroxyl, halogen, C i -s alkyl, C_M alkoxyl, C2-8 alkenyl, C2-8 alkynyl, C_M cyeioalkyl, C_M eycloalkenyl; C_<s-io aryl, -N(Rn)₄ -NH-C(0)-Rn, or ~ NH-C(0)-N(Rj 2)2, where Rn individually are H, CM alkyl, C2-8 alkenyl, C2-10 alkynyl, CM cycloalkyl, CM eycloalkenyl, or GS-JO aryl where q is 2 or 3, with the proviso that when q is 3, the group bears a positive formal charge and wherein the hydrocarbon groups in each case are optionally substituted with -ON, CM alkyl, -ORn, -OH, halo, or -CFi where Ru is C alkyl.

12. The compound of clai 1 wherein Z is selected from the group consisting of-CTh-, -

CHOHCB2-, -CHOHCH2CH2-, -CHOHCH2CH2CH2-, -CO-, -N-CH2-, N-CO-, -(CH2 I :- , - CHOH(CH₂)_n-„ -f CH >),CO-, -(CHRNCOitTT)_k-. Cwo carboximido, 2I-JO alkanediyl, C200 alkanediyl,€ >-_HJ alkynediyl, and combinations thereof; m is L 2, 3, 4, or 5, and n and k are each independently integers 0, 1 , 2_» 3, 4, 5 ,6, 7, or 8,

13, A compound having formula 11 for treating a neurodegen erativc disease:

or a pharmaceutically acceptable salt or ester thereof,

wherein:

A is an optionally substituted C₆-i2 aryl or C₆-i2 heteroaryl;

Ri4, Rf s are each independently B. Ci-s alkyl, C2-_S alkenyl, Ci-s cycloalkyl, C4-8

cycloaikenyl, Cs-io aryl, Ci-10 alkyl or CTu> ryl;

Bt and B₂ are each independently

o is 0, 1 , 2, 3. or 4; and

Rj₆ is an optional substituent.

14. The compound of claim 13 wherein A is optionally substituted phenyl .

15. The compound of claim 14 wherein A is a substituted phenyl having 1, 2, 3. or 4 hydroxyl groups.

6. The compound of claim 13 wherein A is:

where Rn, Rie, i_¾ R20 are each independently H, Ci-g alkyl, OH, or halo (e.g., F, Cl, Br, 1).

17. The compound of claim 13 wherein A is:

18. The compound of claim 13 having the following formula:

19. The compound of claim 13 having the following formula:

pharmaceutically acceptable salt or ester thereof.

20. The compound of claim 13 having the following formula:

pharmaceutically acceptable salt or ester thereof.

21. The compound of claim 13 wherein Rtf, are hydroxyl, halogen, nitro, cyano, Cj-g alkyl, Ci-s alkoxyl, Ci-s alkenyl, C_2-8 alkynyl, C4-S cycloalkyl, C_4-8 cycloalkenyl; Cs-to aryl, ~N(Rj 3 )_q ~ NH~C(0)~Rn, or -NHC(0)-N(Ri2>2, where Rn individually are H, Ci-s alkyl, C2-8 alkenyl, C2-10 alkynyl, C_4-8 cycloalkyl, CU-s cycloalkenyl, or Ce-io aryl where q is 2 or 3, with the proviso that when is 3, the group bears a positive formal charge and wherein the hydrocarbon groups in each ease are optionally substituted with ~CN, Cj-s alkyl, -OR· n -OH, halo, or -CF where R_{J 3} is Ct-s alkyl.