WO2014046544A1

WO2014046544A1 - Substituted 3-heteroaryloxy-3-(hetero)aryl-propylamines as serotonin transporter and serotonin ht2c receptor modulators

Info

Publication number: WO2014046544A1
Application number: PCT/NL2013/050677
Authority: WO
Inventors: André Heeres; Cornelius Joannes GROL; Marcus Leonardus Gerardus BORST; Sandra WILLIGERS - Hogg
Original assignee: Aapa B.V.
Priority date: 2012-09-21
Filing date: 2013-09-23
Publication date: 2014-03-27

Abstract

The present invention relates to compounds compound according to Formula (1): and pharmaceutically acceptable salts, hydrates and solvates thereof. These compounds have serotonin (5-HT) transporter inhibitory effects and 5-HT 2C receptor antagonist or inverse agonist effects. The present invention also relates to pharmaceutical compositions comprising these compounds, and methods of using them for application in the prophylaxis or treatment of CNS disorders.

Description

SUBSTITUTED 3-HETEROARYLOXY-3-(HETERO)ARYL-PROPYLAMINES AS SEROTONIN

TRANSPORTER AND SEROTONIN HT2C RECEPTOR MODULATORS

Field of the invention

The present invention relates to the preparation of certain substituted phenyl propyl amine compounds possessing serotonin (5-HT) transporter inhibitory effects and 5-HT₂c receptor antagonist or inverse agonist effects, pharmaceutical compositions thereof, and methods of using them for application in the prophylaxis or treatment of CNS disorders.

Background of the invention

Serotonin re-uptake inhibitors (SSRI) such as fluoxetine, citalopram, sertraline and paroxetine act by blocking the serotonin transporter and are the first drugs of choice for the treatment of depression and other affective disorders such as major anxiety disorder and panic disorder. However, SSRI's are not optimal and patients using these drugs suffer from side effects including sexual dysfunction and sleeping problems. Moreover, a high percentage of the patients do not respond, or only poorly, to treatment with SSRI's. Furthermore, SSRI's have a rather slow onset of action (4-8 weeks) due to complicated neurobiological adaptive mechanisms. In order to shorten the on-set time several augmentation strategies have been proposed, which result in a more rapid increase in 5-HT (5-hydroxytryptamine) than SSRI's alone (A. Adell et al., Drug discovery Today, 2005, 578-585; incorporated by reference). One approach used is combining SSRI's with 5-HT₂c antagonists/inverse agonists (T.I.F.H. Cremers et al., Neurophsychopharmacology, 2004, 1782-1789; T.I.F.H. Cremers et al. Neurophsychopharmacology, 2007, 1550-1557; US 2002/0103249, US 2003/0032636, US 2007/0105843, US 2009/0176808; all incorporated by reference). US 2005/0070577, incorporated by reference, discloses compositions comprising a 5-HT₂A receptor antagonists and an SSRI.

Fluoxetine is disclosed in US 4.314.081, incorporated by reference, and has the formula:

Similar compounds are for example disclosed in US 4.956.388, US 5.145.870 and US 5.238.959, all incorporated by reference.

WO 02/14273, incorporated by reference, discloses certain indole derivatives which are 5-HT₂c receptor antagonists.

US 6.369.060, incorporated by reference, discloses pyridazine and pyridine indole carboxamides of the general formula:

These compounds are 5-HT₂c receptor antagonists.

US 2009/0258876, incorporated by reference, discloses indole carboxylic acid bispyridiyl carboxamide derivatives as 5-HT₂c receptor antagonists.

US 6.462.056, incorporated by reference, discloses oxazolidine derivatives of the general formula:

These compounds are 5-HT₂A receptor antagonists with a 5-HT reuptake- inhibiting effect. US 7.291.738, incorporated by reference, discloses compounds of the general formula:

wherein R¹ is for example (substituted) aryl, (substituted) heteroaryl. These compounds are 5-HT2c receptor ligands.

In order to avoid e.g. potential drug-drug interactions for drug combinations (2 tablets, 2 drugs) and fixed dose combinations (1 tablet, 2 drugs), compounds have been developed modulating the activity of multiple biological targets. Series of arylpiperazine pyrrole 3-carboxamides, pyrimidin 4-carboxamides and aryl piperazine purine derivatives were prepared for combined targeting of the serotonin transporter (5-

HTT) and the serotonin 5-HT_2a and 5-HT_2c receptors (S.Y. Kang et al., Bioorg. Med.

Chem.Lett., 2010, 1705-1711; J.Y. Kim et al., Bioorg. Med. Chem.Lett., 2010, 6439- 6442; S.Y. Kang et al., Bioorg. Med. Chem.Lett., 2010, 6156-6169; US 201 1/0178091;

WO 2011/005052; WO 2011/059207; all incorporated by reference).

However, there is still an unmet need for compounds that are potent serotonin 5-

HT_2c receptors and serotonin transporter modulators with desirable pharmaceutical properties.

Summary of the invention

The present invention relates to compounds according to Formula (1):

R¹ is selected from the group consisting of C₆ - C24 aryl and C4 - C24 heteroaryl;

R² and R³ are independently selected from the group consisting of hydrogen and Ci - C12 alkyl, or R² and R³ are -[C(R¹⁴)₂]_m- and form a heterocyclic ring with the N-atom to which they are attached, wherein m is 2, 3, 4, 5, 6 or 7;

R⁴ is -[C(R¹⁴)₂]„-, wherein n is 1, 2, 3, 4 or 5;

W¹ is C(R¹⁴)₂, NR¹⁴, O or S;

R⁵, R⁶, R⁷ and R⁸ are independently selected from the group consisting of hydrogen, halogen and Ci - C₁₂ alkyl;

U, X, Y and Z are independently C or N;

when U is N, R⁸ is absent;

when X is N, R⁷ is absent;

when Y is N, R⁶ is absent;

when Z is N, R⁵ is absent;

R⁹ is -V¹-[C(R¹⁴)₂]o or

wherein o is 0, 1 2, 3, 4 or 5, and wherein V¹ is

C(R¹⁴)₂, NR¹⁴, O or S;

W² is =0, =S, =N-CN, =C=C-N0₂ or =N-S0₂ H₂;

E is CR¹⁴, N or NR¹⁴, provided that when E is NR¹⁴, L is absent and M is R¹⁰;

L and M are C(R¹⁴)₂ when ¹³³³³³ represents a single bond, and L and M are CR¹⁴ when 3³³³³³ represents a double bond; R¹⁰, R¹¹, R¹² and R¹³ are independently selected from the group consisting of H, Ci - C₆ alkyl, C₂ - C₆ alkenyl, C₂ - C₆ alkynyl, OH, Ci - C₆ alkoxy, C₂ - C₆ alkenoxy, C₂ - C₆ alkynoxy, Ci - C₆ alkylthio, C₂ - C₆ alkenylthio, C₂ - C₆ alkynylthio, N(R¹⁴)₂, halogen, CN, S(0)pR¹⁴, S(0)₂N(R¹⁴)₂, C(0)R¹⁴, C(W²)OR¹⁴, C(W²)N(R¹⁴)₂, N0₂, N-C(0)R¹⁴, P(0)(R¹⁴)OH, P(0)(R¹⁴) H₂;

p is 0, 1 or 2;

R¹⁴ is independently selected from the group consisting of H, Ci - C₆ alkyl, halogen, OH, Ci - C₆ alkoxy, Ci - C₆ alkylthio, H₂, H(Ci - C₄ alkyl), N(Ci - C₄ alkyl)₂, or two groups R¹⁴ represent =0, =S, = H, =N(Ci - C₄ alkyl), =NOH or =NO(Ci - C₄ alkyl); and pharmaceutically acceptable salts, hydrates and solvates thereof.

The present invention also relates to a method for the preparation of a compound according to Formula (1).

The present inventions further relates to pharmaceutical compositions comprising a compound according to Formula (1).

The present invention also relates to the use of a compound according to Formula

(1) and/or a pharmaceutical composition comprising a compound according to Formula (1) for the profylaxis or treatment of a CNS disorder. The present invention also relates to a method for the prophylaxis or treatment of a mammal suffering from a CNS disorder.

Detailed description of the invention

The verb "to comprise" as is used in this description and in the claims and its conjugations is used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. In addition, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one of the element is present, unless the context clearly requires that there is one and only one of the elements. The indefinite article "a" or "an" thus usually means "at least one".

The compounds disclosed in this document may comprise one or more asymmetric centres, and different diastereomers and/or enantiomers may exist of the compounds. The compounds disclosed in this document are meant to include all diastereomers, and mixtures thereof, unless stated otherwise. In addition, the compounds disclosed in this document are meant to include both the individual enantiomers, as well as any mixture, racemic or otherwise, of the enantiomers, unless stated otherwise. When the structure of a compound is depicted as a specific enantiomer, it is to be understood that the invention of the present application is not limited to that specific enantiomer.

The compounds disclosed in this document may occur in different tautomeric forms. The compounds disclosed in this document are meant to include all tautomeric forms, unless stated otherwise.

The compounds disclosed in this document may exist as cis and trans isomers and/or as Z- and i -isomers. Unless stated otherwise, the compounds disclosed in this document are meant to include both the individual cis and the individual trans isomer and/or the individual Z-isomer and i -isomer of a compound, as well as any mixture thereof. Accordingly, when the structure of a compound is depicted as a cis isomer, it is to be understood that the corresponding trans isomer or any mixture of the cis and trans isomer are not excluded from the invention of the present application. Likewise, when the structure of a compound is depicted as a ii-isomer, it is to be understood that the corresponding Z-isomer or any mixture of the E- and Z- isomer are not excluded from the invention of the present application.

The compounds disclosed in this document may exist in an amorphous form or in a crystalline form. Accordingly, the compounds disclosed in this document may exist in different polymorphic forms.

The pharmaceutically acceptable salts of the compounds according to Formula (1) may be acid addition salts or base addition salts. Definitions of substituents

The Ci - C₆ alkyl group may be linear or branched. The alkyl group may further comprise one or more heteroatoms, preferably one, two or three heteroatoms, selected from the group consisting of O, N and S. The alkyl group may further be substituted by one or more substituents, preferably one, two or three substituents. Preferred substituents include halogen, hydroxy, Ci - C₆ alkoxy, Ci - C₆ alkylthio, NH₂, H(Ci - C₄ alkyl) and N(Ci - C₄ alkyl)₂, or two substiutents represent =0, =S, =NH, =N(Ci - C₄ alkyl), =NOH or =NO(Ci - C₄ alkyl). The Ci - C₆ alkenyl group may be linear or branched. The alkenyl group may further comprise one or more heteroatoms, preferably one, two or three heteroatoms, selected from the group consisting of O, N and S. The alkylene group may further be substituted by one or more substituents preferably one, two or three substituents. Preferred substituents include halogen, hydroxy, Ci - C₆ alkoxy, Ci - C₆ alkylthio, NH₂, NH(Ci - C₄ alkyl) and N(Ci - C₄ alkyl)₂, or two substiutents represent =0, =S, =NH,

- C₄ alkyl), =NOH or - C₄ alkyl).

The Ci - C₆ alkynyl group may be linear or branched. The alkynyl group may further comprise one or more heteroatoms, preferably one, two or three heteroatoms, selected from the group consisting of O, N and S. The alkynyl group may further be substituted by one or more substituents, preferably one, two or three substituents. Preferred substituents include halogen, hydroxy, Ci - C₆ alkoxy, Ci - C₆ alkylthio, NH₂, H(Ci - C alkyl) and N(Ci - C alkyl)₂, or two substiutents represent =0, =S, =NH, =N(Ci - C₄ alkyl), =NOH or =NO(C₁ - C₄ alkyl).

The C₆ - C₂₄ aryl group includes monocyclic and bicyclic structures, wherein in the bicyclic structure one ring moiety may be (partly) saturated. The aryl group may be substituted by one or more substituents, preferably one, two, three, four or five substituents. It is preferred that the aryl group is selected from the group consisting of phenyl, indenyl (1-, 2-, 3-, 4-, 5-, 6- or 7-), indanyl (1-, 2-, 3-, 4-, 5-, 6- or 7-), naphtyl (1-, 2-, 3- or 4-), 1,2-dihydronaphtyl (1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-) and 1,2,3,4- tetrahydronaphtyl (1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-). The C₃ - C₂₄ heteroaryl group comprises at least one heteroatom, preferably one, two, three to four heteroatoms, selected from the group consisting of O, N and S and includes monocyclic and bicyclic structures, wherein one or two ring moieties may be (partly) saturated. The heteroaryl group may be substituted by one or more substituents, preferably one, two, three, four or five substituents. It is preferred that the heteroaryl group is selected from the group consisting of 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 1- pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4- imidazolyl, 5-imidazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4- isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, triazolyl (this term includes the radical derived from 1,2,3- triazole and of 1,2,4-triazole, i.e. that "triazolyl" may be 1 -triazolyl, 2-triazolyl, 3- triazolyl, 4-triazolyl or 5-triazolyl), 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, triazinyl, indolyl (1-, 2-, 3-, 4-, 5-, 6- or 7-), 3-H-indolyl (2-, 3-, 4-, 5-, 6-, 7-), isoindolyl (1-, 2-, 4- or 5-), indolizinyl (1-, 2-, 3-, 5-, 6-, 7- or 8-), indazolyl (1-, 3-, 4-, 5-, 6- or 7-), purinyl (2-, 6-, 8-or 9-), benzo[b]furanyl (2-, 3-, 4-, 5-, 6- or 7-), benzo[c]furanyl (1-, 4- , 5- or 6-), benzo[b]-2,3-dihydro-furanyl (2-, 3-, 4-, 5-, 6- or 7-), benzo[c]-l,3-dihydro- furanyl (1-, 3-, 4-, 5-, 6- or 7-), benzo[b]thienyl (2-, 3-, 4-, 5-, 6- or 7-), benzo[c]thienyl (1-, 4-, 5- or 6-), benzo[b]-2,3-dihydro-thienyl (2-, 3-, 4-, 5-, 6- or 7-), benzo[c]-l,3- dihydro-thienyl (1-, 3-, 4-, 5-, 6- or 7-), quinolinyl (2-, 3-, 4-, 5-, 6-, 7- or 8-), isoquinolinyl (1-, 3-, 4-, 5-, 6-, 7- or 8-), phthalazinyl (1-, 5- or 6-), naphthypyridinyl (2-, 3- or 4-), quinoxalinyl (2-, 5- or 6-), quinazolinyl (2-, 5-, 6-, 7- or 8-), cinnolinyl (3- , 4-, 5-, 6-, 7- or 8-) and pteridinyl (2-, 4-, 6- or 7-).

Preferred substituents for the C₆ - C₂₄ aryl group include halogen, hydroxy, Ci - C₆ alkyl, Ci - C₆ alkoxy, Ci - C₆ alkylthio, H₂, H(Ci - C₄ alkyl) and N(Ci - C₄ alkyl)₂.

The group of halogens include fluorine, chlorine, bromine and iodine.

Preferred embodiments

In a preferred group of compounds, R¹ is selected from the group consisting of C₆ - C₁₂ aryl and C3 - C₁₂ heteroaryl.

In another preferred group of compounds, R¹ is a C3 - C₆ heteroaryl.

In another preferred group of compounds, n is 1, 2, 3 or 4. More preferably, n is 1 or 2.

In yet another preferred embodiment, W¹ is O or NR¹⁴.

In yet another preferred group of compounds, U is N. In yet another preferred group of compounds, X is N. In yet another preferred group of compounds, Z is N. In yet another preferred embodiment, Z is C.

In yet another preferred embodiment, V¹ is NR¹⁴. According to this embodiment, it is also preferred that o is 0.

In yet another preferred group of compounds, ^{rr rr}^ represents a single bond and L and M are C(R¹⁴)₂.

In yet another preferred embodiment, E is N.

In yet another preferred embodiment, R⁹ is NH. In yet another preferred embodiment, W² is =0.

In yet another preferred embodiment, Y is C, wherein R⁶ is preferably H.

A particular preferred embodiment of the present invention relates to compounds according to Formula (2):

(2) wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, X, Y, Z, L and M are as defined for the compounds according to Formula (1).

A preferred group of compounds according to this particular preferred embodiment of the present invention are the compounds wherein R¹ is a C₃ - C6 heteroaryl.

In another preferred group of compounds according to this particular preferred embodiment, n is 1, 2, 3 or 4.

Another preferred group of compounds according to this particular preferred embodiment are the compounds wherein X is N. Yet another preferred group of compounds according to this particular preferred embodiment are the compounds wherein Z is N. Yet another preferred group of compounds according to this particular preferred embodiment are the compounds wherein Z is C.

Another preferred group of compounds according to this particular preferred embodiment are the compounds wherein = represents a single bond and L and M are C(R¹⁴)₂.

A more particular preferred embodiment of the present invention relates to compounds according to Formula (3):

(3) wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, X and Z are as defined for the compounds according to Formula (1).

Pharmaceutical compositions

The present invention also relates to pharmaceutical compositions comprising an effective amount of a compound according to Formula (1) and a pharmaceutically acceptable carrier. To prepare the pharmaceutical compositions according to the invention, an effective amount of a compound according to Formula (1), optionally in acid or base addition salt form, is combined in intimate mixture with a pharmaceutically acceptable carrier.

The pharmaceutically acceptable carrier may take a wide variety of forms depending on the form of preparation desired for administration. The pharmaceutical compositions are desirably in unitary dosage form and may be suitable for administration by the oral, nasal, rectal, sublingual, transdermal, percutaneous or parenteral route. Accordingly, the pharmaceutical compositions in oral dosage form may a solid dosage form or a liquid dosage form. Suitable solid oral dosage forms include tablets and capsules and these are very advantageous oral dosage forms because of their ease in administration. Suitable liquid oral dosage forms include suspensions, syrups, elixirs and solutions. Suitable pharmaceutically acceptable carriers for these dosage forms are well known to the skilled formulator.

The pharmaceutical compositions according to the present invention are suitable for preventing and treating CNS disorders, in particular disorders such as depression, major depressive disorder, generalised anxiety disorder, major anxiety disorder and panic disorder.

The present invention also relates to a method for preventing or treating a CNS disorder in a mammal, wherein an effective amount of a compound according to Formula (1) is administered to said mammal. The route of administration may be oral, nasal, rectal, sublingual, transdermal, percutaneous or parenteral.

Examples

Exemplary compounds useful in the invention are described by reference to the illustrative synthetic schemes for their general preparation and specific examples. One skilled in the art will recognize that it may be advantageous to perform the reactions shown in the Schemes in an order different from that depicted. The substituents R¹, R², R³, U, Z, L and M have the meaning as defined above.

Example 1

SCHEME A

OH IV. OH OH

XI ^{^}NBoc

A3 A4 R2 A5 R₂

A6

a Reagents: (/^') R₂R₃ H, paraformaldehyde, ethanol, cone. HC1; (if) DMF-DMA, pyridine; (///^') NaBH₄, water; (iv) Me H₂, EtOH; (v) (Boc)₂0, MeOH, Na₂C0₃; (vi) phthalimide, DMF, KF.

Arylphenones Al were condensed with paraformaldehyde in the presence of FINR₁R₂ to furnish the intermediate amino ketones (Mannich reaction). Subsequent reduction with hydride agents such as NaBH₄ afforded the aminoalcohols A2. Alternatively, the aminoalcohols A2 were prepared by reaction of arylphenones Al with DMF-DMA and subsequent reduction of the enamines formed. Enantiomerically pure aminoalcohols A2 were prepared by resolution with appropriate organic acids. Mono-substituted Boc-protected amino alcohols A5 were synthesized by reaction of the chloride A3 with methylamine and used in subsequent steps as Boc-protected A5. The individual enantiomers of A5 originated from chiral starting material A3. Phthalimide protected aminoalcohols A7 were prepared by reaction of chloride A3 with phthalimide. Also in this case the individual enantiomers of A7 were synthesized starting from (R)- or (S)- A3.

Example 2

SCHEME B l

^a Reagents: (/^') PPh₃, DIAD, 4-nitrophenol; (ii) SnCl₂; (iii) (p-nitro)phenyl chloroformate; (iv) arylamine/indoline, Et₃, THF; (v) 4N HCl dioxane; (vi) N₂H₄, EtOH .

The carboxamides B3-B4 (see Scheme Β 1 ;) were prepared by a Mitsunobu reaction of the required 4-nitrophenol with the secondary alcohol, followed by nitro reduction using either catalytic hydrogenation or metal-promoted reduction (e.g., SnCl₂, Fe) affording aryl amine B2. The majority of the compounds was synthesized using phosgene or, alternatively, (4-nitro)phenylcarbamate with yields ranging from 5- 50%. Aryl amines utilized in the urea formation were substituted indolines, anilines, indoles, 1,2,3,4-tetrahydroquinolines and pyrrolidines. The required indolines were obtained by NaBH₃CN reduction of the corresponding indoles. Secondary and primary amines were prepared by deprotection of the Boc-moiety and phthalimide group according to methods well-known in the art. The individual enantiomers of B3-B4 were obtained by reaction with the appropriate chiral amino alcohols amino A2,A5, A6 or by chiral prep. HPLC of the final product(s).

Example 3

SCHEME B2

U=N, Z=CH; U=Z=N

B5 IV.

R₂ = H, R₃ = e.g., alkyl

R₂ ⁼ R3 ⁼ H ^a Reagents: ( ) NaH, DMF/5-nitro heteroarylhalide; (ii) cat. Pt0₂, methanol, H₂; (iii) (p- nitro)phenyl chloroformate; (iv) arylamine/indoline, NEt₃, THF; (v) 4N HCl dioxane; (vi) N₂H₄, EtOH .

The carboxamides B7-B8 (see Scheme B2; pyridin-3-yl and pyrimidin-5-yl central cores) were prepared by substitution of the required 5-nitro aryl halide with the secondary alcohol, followed by nitro reduction using either catalytic hydrogenation or metal-promoted reduction (e.g., SnCl₂, Fe) yielding aryl amine B6. The majority of the compounds B7 was synthesized by way of the (4-nitro)phenylcarbamate with yields ranging from 5-50%. Also reaction of the amine B6 with the phosgene substitute Ν,Ν'- di(succinimidyl)carbonate, followed by treatment with e.g., indoline resulted in formation of the indole- 1-carboxamides in a good yield. Aryl amines utilized in the urea formation were substituted indolines, anilines, indoles, 1,2,3,4- tetrahydroquinolines and pyrrolidines. The required indolines were obtained by NaBH₃CN reduction of the corresponding indoles. Secondary and primary amines were prepared by deprotection of the Boc-moiety and phthalimide group according to methods well-known in the art.

Example 4

SCHEME B3

¾eagents: (/) PPh₃, DIAD, 6-chloropyridin-3-ol; (//) Pd₂dba₃, (2- diphenyl)(dicyclohexyl)phosphine, LiHMDS; (Hi) LiHMDS, 0°C-rt 7-nitrophenyl aryl/indoline carbamate, THF; (iv) 4 N HCl dioxane; (v) N₂H₄, EtOH; (vi) p- nitrophenylchloroformate, NEt₃.

The carboxamides B 1 1-B 12, containing a pyridin-2-yl central core, were prepared according to Scheme B3. A Mitsunobu reaction of the amino alcohol and a subsequent cross-coupling reaction of the chlorine moiety with LiHMDS afforded, after work-up, amines B IO. Subsequent reaction with the 4-nitrophenyl carbamates of the appropriate aryl/indoline amines furnished B 11. Example 5

SCHEME B4

R₂ = H, R₃ = e.g., alkyl

F¾2 ⁼ 3 ⁼ H ^a Reagents: (/) acetyl chloride, pyridin; ( /) PPh₃, DIAD, DMF; (iii) NaOH, MeOH; (iv) LiHMDS, 0°C-rt p-nitrophenyl aryl/indoline carbamate, THF; (v) 4 N HC1 dioxane; (vi) N₂H₄, EtOH.

The synthesis of carboxamides B 15-B16, containing a pyrimidin-2-yl central core, is depicted in Scheme B4. Acetylation of (derivatives) of 2-amino-pyrimidin-5-ol and a Mitsunobu reaction with an amino alcohol afforded B13. Hydrolysis of the amide moiety and subsequent reaction with the 4-nitrophenyl carbamates of the appropriate aryl/indoline amines yielded B15-B16. Example 6

SCHEME B5

B17

R₂ = H, R₃ = e.g., alkyl

R₂ ⁼ R₃ ⁼ H

" Reagents: (/^') Ac₂0, AcOH; (//) KOtBu, DME, 80°C; (in) NaOH, ethanol, water; (iv) NaH or LiHMDS, indoline -nitrophenylcarbamate; (v) 4 N HC1 dioxane; (vi) N₂H₄, EtOH. Carboxamides with a pyridazinyl and pyrazinyl central core were prepared according to route depicted in Scheme B5. Since acylation of the amine group of 3- chloro-6-aminopyridazine/pyrazine (derivatives) activates the chloride for substitution, B 17 was converted to the corresponding amide B 18. Reaction with the appropriate amino alcohol A2, A5, A6 and subsequent removal of the amide group afforded B20. Finally, treatment with a strong base and reaction of the resulting amide with the p- nitrophenyl carbamate of the appropriate amine (indoline) yielded the desired carboxamide compounds in moderate yield. A similar approach was used for the pyrazine derivatives, although the yield in the substitution step was lower. Example 7

Bioisosteric modifications of the aryl/indoline-l-carboxamide moiety of are depicted in Scheme C1 -C3. A pyridin-3-yl central core is taken as an example.

SCHEME CI

a Reagents: (/^') CSC1₂, NaHC0₃, r.t; (/^'/^') arylamine/indoline (Hi) EDCI, HOBt, DiPEA; ( v) RI, NaH.

Replacement of the urea oxygen by sulphur was easily achieved by reaction of e.g., amine B6 with thiophosgene and quenching of the intermediate isothiocyanate with indole. Secondly, the indane-l -carboxamide C2 in which the indole nitrogen is replaced by methylene, was obtained by coupling of e.g., an indane using EDCI/HOBt (see Scheme CI). N-aryl urea C3 was obtained by alkylation of compound B3. For R₂ = Boc and Ri, R₂ = Phth the corresponding secondary and primairy amines were obtained by e.g., HC1 (R₂ = Boc) and N₂H₄ (Ri, R₂ = Phth). Example 8

HEME C2

H, R₃ = e.g., alkyl

R2 ⁼ R3 ⁼ H ^a Reagents: (/^') NaH, DMF; (//) diethyl malonate, Pd₂dba₃, t-Bu₃P, K₃P0₄, toluene; (/ /) IN NaOH, THF; (iv) IN HCl; (v) indoline, EDCI, HOBt, Et₃N; (vi) 4N HCl dioxane; (vii) N₂H₄, EtOH.

Isomeric amide C7 was prepared from 2-chloro-5-bromopyridine (Scheme C2). Nucleophilic substitution with the appropriate amino alcohol, followed by Pd-catalyzed reaction with diethyl malonate afforded bis-ester C5. Saponification and careful acidification resulted in formation of amino acid C6, which was coupled with several indolines/amines using standard peptide coupling reagents towards C7. Example 9

SCHEME C3

For R₂ = Boc and R₂, R₃ = Phth

R₂ = H, R₃ = e.g., alkyl

R₂ ⁼ R₃ ⁼ H

a Reagents. (?) KOtBu; (ii) KOH; (///^') EDCI, HOBt; (zv) 4N HCl dioxane; (v) N₂H₄, EtOH.

Isomeric amide Cl l was prepared from ethyl 6-chloronicotinate (Scheme C3). Nucleophilic substitution with the appropriate amino alcohol, followed by hydrolysis afforded acid CIO. Coupling with several indolines/amines using standard peptide coupling reagents afforded Cl l .

The synthesis of thio (hetero)aryl carboxamides is depicted in Scheme Dl . Example 10

A pyridin-3-yl central core is taken as an example.

SCHEME Dl

For R₂ = Boc and = Phth

F½ = H, R₃ = e.g., alkyl

R₂ ⁼ R3 ⁼ H

" Reagents: (/) NEt₃, Ms-Cl, CH₂C1₂; (//) Nal, NEt₃, CH₂C1₂; (iii) cat. Pt0₂, methanol, H₂; (iii) p-nitrophenyl chloroformate, CH₂C1₂; (7v) arylamine/indoline, NEt₃, THF; (v) 4N HC1 dioxane; (17) N₂H4, EtOH.

Reaction of an amino alcohol A2, A5, A6 with mesityl chloride afforded the corresponding chloride. Subsequent reaction with 2-mercapto-5-nitropyridine yielded D2. After hydrogenation of the nitro-moiety and urea formation via the 4- nitrophenylcarbamate of the arylamine (indoline) D4 was formed.

The following compounds according to Formula (1) were prepared according to the methods of Examples 1 - 10. The individual enantiomers of the compounds aimed for were obtained by utilization of the appropriate chiral amino alcohols amino in the preparation or by chiral prep. HPLC of the final product(s).

Chemistry:

In obtaining the characterization data described in the examples below, the following analytical and experimental protocols were followed as indicated.

Where solution or mixture were 'concentrated', they were typically concentrated under reduced pressure using a rotary evaporator. Where solutions were dried, they were generally dried over anhydrous Na₂S0₄. Reaction mixtures were magnetically stirred at room temperature (rt) unless otherwise specified.

Mass spectra were recorded by API-ES (electron spray ionization).

NMR spectra were recorded on a Varian Mercury 300MHz machine. Chemical shifts are denoted in δ (ppm) and are referenced to the residual protic solvent. Examples to Scheme A

Step (i): 3 -(Dimethylamino)- 1 -phenylpropan- 1 -ol. The title compound and phenyl substituted analogues were synthesized as described by Kellogg et al. in Synthesis 2003, JO, 1626-1638.

Step (ii): 3 -(Dimethylamino)- l-(pyridin-2-yl)prop-2-en-l -one. To a solution of 2- acetylpyridine (20.0 g, 165 mmol, 1 eq) in toluene (100 mL) was added DMF-DMA (23.6 g, 119 mmol, 1.2 eq). The solution turned yellow after refluxing for 16 hours. The solvent was removed under reduced pressure and the title compound was crystallized from TBME and heptanes (1 : 1) to provide a yellow solid (14.8 g, 83.4 mmol. 51 % ).

Step (iiiV. 3 -(Dimethylamino)- l-(pyridin-2-yl)propan-l-ol. To a cooled (-10°C) solution of 3 -(dimethylamino)- l-(pyridin-2-yl)prop-2-en-l -one (10.0 g, 56.8 mmol, 1 eq) in methanol (100 mL) was carefully added NaBH₄ (8.60 g, 227 mmol, 4 eq). The resulting mixture was stirred at rt overnight. Concentrated HC1 (12 M) was added drop- wise with stirring to the solution until pH<l . Methanol was removed from the solution under reduced pressure. The acidic aqueous layer was washed with ethyl acetate once. The aqueous layer was made alkaline with aqueous NaOH (12 M) up to pH=9 and extracted with ethyl acetate (4x). The combined organic layers were washed with water and brine, dried, filtered and concentrated. The title compound was obtained as a colourless oil (7.30 g, 40.5 mmol, 71 %).

Step (iv): 3-(Methylamino)-l-phenylpropan-l-ol. The title compound and analogues were synthesized as described by Hadrich et al. in J. Med. Chem. 1999, 42, 3103-3108.

Step (v): N-Boc-3-(methylamino)-l-phenylpropan-l-ol. The title compound and analogues were synthesized as described by Hadrich et al. in J. Med. Chem. 1999, 42, 3103-3108.

Step (vi): 3-Phthalimido-l-phenylpropan-l-ol. The title compound and analogues were synthesized as described by Guarna et al. in Bioorg. Med. Chem. 2001, 9, 3197-3206.

Examples to Scheme B 1

Step (i): N,7V-Dimethyl-3-(4-nitrophenoxy)-3-phenylpropan-l -amine . To a solution of 4-nitrophenol (85 mg, 0.61 mmol), 3-(dimethylamino)-l- phenylpropylpropan-l-ol (100 mg, 0.56 mmol), PPh₃ (190 mg, 0.73 mmol) in THF (4 mL) was added drop-wise DIAD (135 mg, 0.67 mmol). The mixture was stirred at room temperature for 16h. The solution was concentrated and further purified using flash chromatography (gradient 2% to 10% MeOH (7 M NH₃) in CH₂C1₂) affording a yellowish oil (133 mg, 0.44 mmol, 80%).

Step (ii): 4-(3-(Dimethylamino)-l-phenylpropoxy)aniline. To a solution of the product from the previous step (104 mg, 0.35 mmol) in EtOH (2 mL) was added anhydrous SnCl₂ (440 mg, 2.32 mmol). The mixture was heated to 70 °C for 30 min. After TLC showed full conversion, the mixture was poured on ice, basified using aqueous NaOH and extracted thrice with EtOAc. The combined organic layers were washed with brine, dried over Na₂S0₄ and concentrated. The crude material (88 mg) was used as such in the next step.

Step (iii): N-(4-(3-(Dimethylamino -l-phenylpropoxy)phenyl)-5-methoxy-6- trifluoromethyl)indoline-l-carboxamide (AG-0041).

To a solution of the product isolated in the previous step (88 mg, 0.32 mmol) in CH₂CI2 (5 ml) at 0 °C was added drop-wise a 20% solution of phosghene in toluene (2.5 mL, 5.0 mmol). The mixture was stirred 5 min at 0 °C and 45 min at room temperature. The mixture was concentrated in vacuo and resuspended in CH2CI2 (5 mL) and cooled to 0 °C. A solution of 5-methoxy-6-(trifluoromethyl)indoline (synthesized as described by Bromidge et al. in J. Med. Che ., 1998, 41, 1598; 71 mg, 0.32 mmol) and Et₃N (182 iL, 1.30 mmol) in CH₂CI₂ (5 mL) was added drop-wise and the suspension was stirred overnight at room temperature. Brine was added and the mixture was extracted twice with CH₂CI₂. The combined organic layers were dried over Na₂S0₄ and concentrated. Purification using prep. HPLC provided AG-0041 as a white solid (33 mg, 0.06 mmol, 19%).

Examples to Scheme B2

Step (i): 2-(3-(Dimethylamino)-l-(4-fluorophenynpropoxy)pyrimidin-5-amine. 3-(Dimethylamino)-l-(4-fluorophenyl)propan-l-ol (1.0 g, 5.1 mmol, 1 eq.) was dissolved in THF (20 mL) and cooled to 0°C under N₂ atmosphere. NaH (60% in oil, 494 mg, 12.4 mmol, 2.44 eq.) was added portion-wise and the mixture was stirred for 1.5 hours. A solution of 2-chloro-5-nitropyrimidine (890 mg, 5.6 mmol, 1.1 eq.) in THF was added drop-wise and the mixture was allowed to warm to rt after addition and stirred for 4h30. The mixture was poured in water and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried, filtered and concentrated. The obtained yellow solid was purified with automated chromatography (0-100% ethyl acetate in heptanes) to afford a yellow oil (695 mg, 2.16 mmol, 42%).

Step (ii): 3-(4-Fluorophenyl)-N,N-dimethyl-3-((5-nitropyrimidin-2-yl)oxy)- propan-1 -amine. The product of the previous step (695 mg, 2.16 mmol) was dissolved in methanol (150 mL) and PtC"₂ (catalytic amount) was added. The reaction vessel was evacuated and charged with hydrogen gas using a balloon (3x). The mixture was stirred at rt for 40 minutes, filtered over Celite and concentrated to afford of a pale oil (650 mg, 2.16 mmol, 100%).

Step (iii): Phenyl (2-(3-(dimethylamino)-l-(4-fluorophenyl)propoxy)pyrimidin- 5-yl carbamate. To a solution of phenyl chloroformate (181 mg, 1.15 mmol, 1.34 eq.) in dichlorom ethane (15 mL), cooled to -14 °C (ice aCl) was added the product of the previous step (250 mg, 0.86 mmol, 1 eq.) and Et₃N (0.12 mL, 0.86 mmol, 1 eq.) in CH₂CI₂ drop-wise. The mixture was stirred for 1 hour at -14°C and 1 hour at rt, poured in saturated aq. NaHC0₃ solution and extracted with dichloromethane (3x). The combined organic layers were dried, filtered, concentrated and the concentrate was used as such.

Step (iv); N-(2-(3-(Dimethylamino)-l -(4-fluorophenyl)propoxy)pyrimidin-5- yn-5-methoxy-6-(trifluoromethyl)indoline-l-carboxamide (AG-0133).

To a solution of the product of the previous step in DMF was added 5-methoxy- 6-(trifluoromethyl)indoline (180 mg, 0.83 mmol, 0.96 eq.) and Et₃N (0. 12 mL, 0.86 mmol, 1 eq.) in DMF drop-wise. The solution was heated to 100°C for 1 hour, allowed to cool to rt and brine was added. The suspension was extracted with ethyl acetate (3x) and the organic layers were washed with brine (2x). The combined organic layers were dried, filtered and concentrated. The obtained oil was purified with automated column chromatography to afford of a pale yellow foam (85 mg, 1.16 mmol, 19%).

Step (v): ^-5-methoxy-N-(6-(3-(methylamino)-l-phenylpropoxy)pyridin-3- yl)-6-(trifluoromethyl)indoline-l -carboxamide (AG-0095).

( ?)-tert-Butyl(3-((5-(5-methoxy-6-(trifluoromethyl)indoline-l-carboxamido)- pyridin-2-yl)oxy)-3-phenylpropyl)(methyl)carbamate (128 mg, 0.21 mmol) was dissolved in 1,4-dioxane. HC1 in dioxane (4N, 1 mL, 20 eq.) was added to the mixture and the solution was stirred at room temperature overnight under N₂ atmosphere. The mixture was concentrated and purified with preparative HPLC to afford AG-0095 as a white solid (6 mg, 0.012 mmol, 6% yield).

Step (vi) : (R)-N-( 6-(3 -amino- 1 -phenylpropoxy)pyridin-3 -y0-5 -methoxy-6- (trifluoromethyl indoline-l-carboxamide (AG-0096).

(R)-N-(6-(3-(l ,3-Dioxoisoindolin-2-yl)-l -phenylpropoxy)pyridin-3-yl)-5- methoxy-6-(trifluoromethyl)indoline-l-carboxamide (100 mg, 0.16 mmol) was suspended in EtOH (5 mL) under N₂ atmosphere. Hydrazine hydrate (64% hydrazine, 0.2 mL) was added followed by water (0.3 mL). The suspension gradually evolved in a solution and it was stirred for 64 hours, concentrated and partitioned between ethyl acetate and sat. aq. NaHC0₃. The organic layer was dried, filtered and concentrated to afford 76 mg of a yellow oil. The product was purified with preparative HPLC to afford AG-0096 as a white solid (22 mg, 0.045 mmol, 28% yield). Examples to Scheme B3

Step (i): 3-((6-Chloropyridin-3-yl)oxy)-N,N-dimethyl-3-phenylpropan-l - amine). To a solution of triphenylphosphine (8.81 g, 33.6 mmol, 6.0 eq) in THF (1 10 mL) at 0°C under nitrogen was added drop-wise DIAL⁾ (6.62 mL, 33.6 mmol, 6.0 eq). The suspension was stirred at 0°C for 15 min. A solution of 3 -(dimethyl amino)- 1- phenyl- l-propanol ( 1.00 g, 5.6 mmol, 1.0 eq) in THF (30 mL) was added drop-wise, followed by 6-chloropyridin-3-ol 1 (3.61 g, 28 mmol, 4.0 eq) as a solid. The ice-bath was removed and the mixture stirred at rt overnight. IN NaOH (50 mL) and water (100 mL) were added and the mixture was extracted with ethyl acetate (100 mL). The aqueous layer was extracted once more (ethyl acetate, 50 mL). The combined organics were washed with brine, dried, filtered and concentrated to a red oil (18.7 g). It was dissolved in toluene (40 mL) and cyclohexane (80 mL) was added with stirring. Stirring was continued in ice for 30 min. The solid was filtered off and washed with cyclohexane:toluene = 3 : 1. The filtrate was concentrated to yield 5.7 g of a red oil. Chromatography (Si0₂, 170 g, 0-10% methanol in dichloromethane) afforded of the product as a light-yellow oil (974 mg, 3.36 mmol, 60%).

Step (ii): 5-(3-(Dimethylamino)-l-phenylpropoxy)pyridin-2-amine. A solution of the product of the previous step (200 mg, 0.69 mmol, 1.0 eq) in THF (2.0 mL) in a flame-dried three-neck was flushed with nitrogen for 10 min. Pd₂dba₃ (19 mg, 0.021 mmol, 3mol%) and (2-diphenyl)(dicyclohexyl)phosphine (19 mg, 0.055 mmol, 8mol%) were added. The system was flushed with nitrogen (5 min) and LiHMDS was added drop-wise at rt. The dark-brown solution was heated at 80°C for 4h. It was allowed to cool, 2N HC1 (2.3 mL, 3.3 eq) was added and the mixture was stirred at rt for 15 min. Sat. aq. NaHC0₃ (40 mL) and ethyl acetate (15 mL) were added. The aqueous layer was extracted (ethyl acetate, 2x15 mL). The combined organics were washed with brine, dried (Na₂SC"4) and concentrated to an orange oil, 254 mg. The oil was purified by automated column chromatography, 0-20% methanol in dichloromethane to afford a yellow oil (106 mg, 0.39 mmol, 57%).

Step (iii): N-(5-(3-(Dimethylamino)-l-phenylpropoxy)pyridin-2-yn-5-methoxy- 6-(trifluoromethyl)indoline- -carboxamide (AG-0390).

The product of step (ii) (106 mg, 0.39 mmol, 1.0 eq) was suspended in THF (2.8 mL) and cooled to 0°C. LiHMDS (1M in ethylbenzene/THF, 1.0 mL, 1.0 mmol, 2.5 eq) was added drop-wise and the resulting dark-yellow solution was stirred at 0°C for 20 min. 4-Nitrophenyl 5-methoxy-6-(trifluoromethyl)-indoline-l-carboxylate (149 mg, 0.39 mmol, 1.0 eq) was added as a solid and the mixture was stirred at rt overnight. Water (10 mL) and ethyl acetate (10 mL) were added. The aqueous layer was extracted (2x10 mL ethyl acetate) and the combined organics were washed with water (3x5 mL), brine, dried, filtered and concentrated to provide 230 mg of a red oil. Automated column chromatography (Si0₂, 0-10% methanol in dichloromethane) afforded a yellow foam (135 mg, 0.26 mmol, 67%).

Step (vi): 4-Nitrophenyl 5-methoxy-6-(trifluoromethyl)indoline-l-carboxylate. To a solution of 5-methoxy-6-(trifluoromethyl) indoline (1.50 g, 6.9 mmol, 1.0 eq) in THF (75 mL) at 0°C was added 7-nitrophenylchloroformate (1.391 g, 1.0 eq), followed by triethylamine (1.1 mL, 7.6 mmol, 1.1 eq). The resulting suspension was stirred at 0°C for 30 min and at rt overnight. The solvent was removed in vacuo. The residue was partitioned between TBME (25 mL) and sat. aq. NaHC0₃ (20 mL). The remaining solid was filtered off, washed with sat. NaHC0₃ (5 mL), TBME (2x5 mL), dried and stripped with toluene (3x) to afford a light-yellow solid (2.26 g, 2.55 mmol, 86%).

Examples to Scheme B4

Step (i): N-(5-Hydroxypyrimidin-2-yl)acetamide. To a suspension of 2-amino- 5-hydroxypyrimidine (100 mg, 0.90 mmol, 1.0 eq) in pyridine (0.50 mL) at rt was added acetyl chloride (0.16 mL, 2.25 mmol, 2.5 eq) drop-wise. A solid was obtained. Pyridine (1.0 mL) was added to allow stirring of the thick mixture for 30 min. at it. Methanol (1 mL) was added and the mixture was concentrated in vacuo. The bis-acyl compound was suspended in methanol (1.5 mL) and 7M NH₃ in methanol (1.0 mL) was added under ice-cooling with stirring. The mixture was stirred overnight at rt and a solution with a precipitate was obtained. It was concentrated and purified by automated column chromatography (Si0₂, 0-100% methanol in dichloromethane) and a white solid was obtained (65 mg, 0.42 mmol, 50%).

Step (ii): N-(5-(3-(Dimethylamino)-l-phenylpropoxy)pyrimidin-2-yl)acetamide. N-(5-Hydroxypyrimidin-2-yl)acetamide (75 mg, 0.49 mmol, 1.0 eq) and triphenyl phosphine (257 mg, 0.98 mmol, 2.0 eq) were mixed in DMF (1.0 mL) and heated until full dissolution. The flask was flushed with nitrogen for 10 min and the solution was allowed to cool to rt. 3 -(Dimethyl amino)- 1-phenylpropan-l-ol (132 mg, 0.74 mmol, 1.5 eq) was added, the mixture was cooled in ice and DIAL) (0.15 mL, 0.74 mmol, 1.5 eq) was added drop-wise. The mixture was stirred for 2h at rt. Water (8 mL) was added and the mixture was stirred for 2 min. It was extracted with dichloromethane (3x10 mL). The organics were washed with water, dried and concentrated. The residue was dissolved in toluene (1.2 mL) and cyclohexane (2.4 mL) was added. The suspension was stirred at 0°C for 30 min. and filtered. The red filtrate was concentrated and purified by automated column chromatography (Si0₂, 0-30% methanol in dichloromethane) affording a light-orange oil (65 mg, contaminated with 3- (dimethylamino)- 1 -phenylpropan- 1 -ol). Step (iii): 5-(3-(Dimethylamino)-l-phenylpropoxy)pyrimidin-2-amine. The product of step (i) (100 mg, max. 0.3 mmol, 1.0 eq) was mixed with IN NaOH (0.5 mL) and methanol (0.8 mL) and heated at reflux for 3h. It was cooled, diluted with water (10 mL) and extracted with dichloromethane (3x10 mL) and 3% methanol in ethyl acetate (10 mL). The combined organics were dried (Na₂S0₄) and concentrated. Automated reversed phase column chromatography afforded the target amine (45 mg, still contaminated with the alcohol impurity).

Step (iv): N-(5-(3-(Dimethylamino)-l-phenylpropoxy)pyrimidin-2-yn-5- methoxy-6-(trifluoromethyl)indoline-l-carboxamide (AG-0055).

The product of step (iii) (45 mg, max. 0.17 mmol, 1.0 eq) was dissolved in THF (1.5 mL) and cooled to 0°C under nitrogen. LiHMDS (1M in ethyl benzene/THF, 0.43 mL, 0.43 mmol, 2.5 eq) was added drop-wise causing a yellow color. After 15 min at 0°C 4-nitrophenyl 5-methoxy-6-(trifluoromethyl)indoline-l-carboxylate (78 mg, 0.2 mmol, 1.2 eq) was added as a solid (exothermic) and the brown solution was stirred at r.t. for 2h. It was poured in water (5 mL) and extracted with ethyl acetate (3x5 mL). The combined organics were washed with water (2x5 mL), brine (5 mL), dried and concentrated to an orange oil, >100 mg. Chromatographic purification (Si0₂, 10 g, 0- 20% methanol in DCM) afforded a brown-orange solid (68 mg, 0.13 mmol, 75%).

Examples to Scheme B5

Step (i): N-(6-Chloropyridazin-3-yl)acetamide. 6-Chloropyridazin-3 -amine (9 g, 69.5 mmol) was dissolved in AcOH/Ac₂0 (50 mL/ 50 mL). The mixture was stirred at an external temperature of 100°C for 3h. The precipitate was filtered and washed with Et₂0. The resulting white solid was air-dried (1 1.3 g, 65.9 mmol, 95%).

Step (ii): N-(6-(3-(dimethylamino)-l-phenylpropoxy)pyridazin-3-yl)acetamide: To a solution of N-(6-chloropyridazin-3-yl)acetamide (1.97 g, 1 1.5 mmol, 1.0 eq) and 3-(dimethylamino)-l-phenylpropan-l-ol (2.26 g, 12.6 mmol, 1.1 eq) in ethylene glycol dimethyl ether (55 mL) at rt was added KOtBu (5.81 g, 51.8 mmol, 4.5 eq). The mixture was heated at reflux for 4h to result in a brown suspension which was allowed to cool down overnight. It was poured in water (150 mL) and extracted with ethyl acetate (3x100 mL). The combined organics were washed with brine, dried and concentrated to a brown oil (3.5 g).

Step (iii): 6-(3-(Dimethylamino)-l-phenylpropoxy)pyridazin-3-amine. The procedure of example B4, step (iii) was followed with the product of the previous step. Part of the reaction product was purified by crystallization from TBME. Automated column chromatography (Si0₂, 3-10% methanol in dichloromethane) of the mother liquor provided an additional amount of product. Light-yellow solid (1.1 g, 4.06 mmol, 50% (two steps)).

Step (iv): N-(6-(3-(Dimethylamino)-l-phenylpropoxy)pyridazin-3-yl)-5- methoxy-6-(trifluoromethyl)indoline-l-carboxamide (AG-0079).

A three-neck was charged with NaH (57 mg, 60% in mineral oil, 1.43 mmol, 2.0 eq), washed with heptanes and mixed with DMF (0.7 mL). A solution of 6-(3- (dimethylamino)-l-phenylpropoxy)pyridazin-3 -amine (214 mg, 0.79 mmol, 1.1 eq) was added drop-wise at 0°C. Stirring was continued for 3 min at 0°C. A suspension of 4- nitrophenyl 5-methoxy-6-(trifluoromethyl)indoline-l-carboxylate (271 mg, 0.71 mmol, 1.0 eq) in DMF (1.0 mL) was added drop-wise. The mixture was stirred at 5°C for 5 min. and 2h30 at rt. All was poured on sat. Aq. NaHC0₃ and extracted with ethyl acetate (4x15 mL). The organics were washed with brine (15 mL), dried and concentrated. Column chromatography (Alox, 0-3% methanol in dichloromethane) afforded a yellow foam (113 mg, 0.22 mmol, 31% ). Step (v): (R)-5-methoxy-N-(6-(3-(methylamino)-l-phenylpropoxy)-pyridazin-3- yl)-6-(trifluoromethyl)indoline-l-carboxamide (AG-0401).

To a solution of (R)- tert-butyl (3-((6-(5-methoxy-6-(trifluoromethyl)indoline-l- carboxamido)pyridazin-3-yl)oxy)-3-phenyl-propyl)(methyl)carbamate (120 mg, 0.20 mmol, 1.0 eq) in dichloromethane (4 mL) at 0°C was added trifluoroacetic acid (0.5 niL) drop-wise. The mixture was stirred at 0°C for 10 min and stirred at rt overnight. It was cooled to 0°C and IN NaOH (10 mL) was added drop-wise. The mixture was separated and the aqueous layer was extracted with dichloromethane (3x10 mL). The combined organics were washed with brine, dried (Na₂S04) and concentrated to a yellow wax (76 mg). ISCO (Alox, 0-5% methanol in dichloromethane) afforded a yellow foam (46 mg, 0.09 mmol, 46%).

Examples to Scheme C 1

Step (Ϊ): 3-((5-Isothiocyanatopyridin-2-yl)oxy)-NN-dimethyl-3-phenylpropan- 1 -amine. A mixture of 6-(3-(dimethylamino)-l-phenylpropoxy)pyridin-3 -amine (250 mg, 0.92 mmol, 1.0 eq) and sodium bicarbonate (510 mg, 6.1 mmol, 6.6 eq) in ethyl acetate (6 mL) and water (6 mL) was cooled in ice. Thiophosgene (76 DL, 1.0 mmol, 1.1 eq) was added drop-wise. The ice-bath was removed and the mixture stirred at rt. The progress of the reaction was followed with TLC (5% 7M NH₃ in methanol / dichloromethane). After lh45 additional thiophosgene (1.1 eq) was added and the mixture was stirred overnight at rt. TLC showed one major spot. The aqueous layer was extracted with ethyl acetate (lx). The combined organics were washed with brine, dried and concentrated to a red oil (325 mg, >quant. yield). The NMR spectrum is consistent with fairly pure target compound and it was used as such. Step (ii): N-(6-(3-(Dimethylamino)-l-phenylpropoxy)pyridin-3-yl)-5-methoxy- 6-(trifluoromethyOindoline-l-carbothioamide (AG-0175).

A mixture of the product of the previous step (65 mg, max. 0.18 mmol) and 5- methoxy-6-(trifluoromethyl)indoline (41 mg, 0.19 mmol) was stirred in dichloromethane (2 mL) overnight. A precipitate formed, which was isolated and purified by automated column chromatography (S1O₂, 0-20% methanol in dichloromethane) to afford a light-yellow foam (46.0 mg, 0.087 mmol, 47% yield).

Step (iii): N-(6-(3-(Dimethylamino)-l-phenylpropoxy)pyridin-3-yn-2,3-dihydro - lH-indene- 1 -carboxamide (AG-0173) .

3-Oxo-2,3-dihydro-lH-indene-l-carboxylic acid (100 mg, 0.57 mmol, 1.0 eq) was dissolved in methanol. A spatula tip of Pd/C (10%) was added and the mixture was stirred under 5 bar hydrogen overnight at rt. The mixture was filtered over Celite and the pad washed with methanol. The filtrate was concentrated to yield 2,3-dihydro-lH- indene-l-carboxylic acid as a colorless oil (81 mg, 0,46 mmol, 88%). It was mixed in dichloromethane (3 mL) with 6-(3-(dimethylamino)-l-phenylpropoxy)pyridin-3-amine (139 mg, 0.51 mmol, 1.0 eq), HOBt (69 mg, 0.51 mmol, 1.0 eq), EDCI (99 mg, 0.52 mmol, 1.01 eq) and Et₃N (0.06 mL, 0.8 eq) and stirred at rt overnight. The mixture was poured in water (10 mL) and ethyl acetate (20 mL). The organic layer was washed with sat. NaHC0₃ (10 mL), brine (10 mL) and the combined aqueous layers were back- extracted with ethyl acetate (5 mL). The combined organic layers were dried (Na₂S0₄) and concentrated to a red oil (192 mg). Automated column chromatography (Si0₂, 0- 10% methanol in dichloromethane) afforded a light-orange solid/foam (108 mg, 0.26 mmol, 51% yield (two steps)).

Step (iv): iV-(6-(3-(dimethylamino)-l-phenylpropoxy)pyridin-3-yl)-5-methoxy-N- methyl-6-(trifluoromethyl indoline-l-carboxamide (AG-0179).

NaH (60%) in mineral oil, 39 mg, 0.097 mmol, 1.0 eq) was weighed into a flame-dried flask. The flask was evacuated and filled with nitrogen (3x). DMF (0.5 mL) was added, followed, at 0°C, by 7Y-(6-(3-(dimethylamino)-l- phenylpropoxy)pyridin-3-yl)-5-methoxy-6-(trifluoromethyl) indoline-l-carboxamide (50 mg, 1.0 eq) and iodomethane (6 \L, 1.0 eq). The mixture was allowed to stir at rt overnight. It was poured in water and extracted with ethyl acetate (3x). The combined organics were dried (Na₂S0₄) and concentrated to a red oil, 47 mg. Preparative HPLC afforded a yellow solid (4.7 mg, 0.009 mmol, 9%) .

Examples to Scheme C2

Step (i): 3-((5-Bromopyridin-2-yl)oxy)-N,/Y-dimethyl-3-phenylpropan-l-amine. To a solution of 3 -(dimethylamino)-l -phenyl- 1-propanol (2.00 g, 1 1.2 mmol, 1.0 eq) in DMF (15 mL) at 0°C was added NaH (60% in mineral oil, 672 mg, 16.8 mmol, 1.5 eq) in one portion. The mixture was stirred at rt for lh with evolution of bubbles, finally to yield a white suspension. 5-Bromo-2-chloropyridine (2.59 g, 13.4 mmol, 1.2 eq) was added and the mixture was heated at 75°C for 12h and allowed to reach rt. The reaction mixture was poured in water (50 mL) and ethyl acetate (100 mL). The organic layer was washed with water (2x50 mL), brine, dried (Na₂S0₄) and concentrated (4.2 g). Automated column chromatography (0-10% methanol in dichloromethane, Si0₂) afforded the title compound as a yellow oil (3.40 g, 10.2 mmol, 91%).

Step (ii): Diethyl 2-(6-(3-(dimethylamino)-l-phenylpropoxy)pyridin-3- yOmalonate. To a mixture of Pd₂dba₃ (7 mg, 0.0075 mmol, 0.01 eq) and K₃P0₄ (478 mg, 2.25 mmol, 3.0 eq) in toluene (1.75 mL) was added the product of the previous step (250 mg, 0.75 mmol, 1.0 eq). The system was carefully evacuated and back-filled with nitrogen (3x). Diethyl malonate (0.1 1 mL, 1.0 eq) was added, followed by tBu₃P (10% in hexane, 0.047 mL, 0.015 mmol, 0.02 eq). The system was flushed with nitrogen for lOmin and the dark-red mixture turned brownish. It was heated at reflux overnight. Toluene (1 mL), diethyl malonate (0.05 mL), Pd₂dba₃ (70 mg) and tBu₃P (0.47 mL) were added and the mixture was heated at reflux overnight. Full conversion was observed and the mixture was filtered over Celite and the filtrate was concentrated to a brown oil (500 mg). Automated column chromatography (0-5% methanol in dichlorom ethane, Si0₂) afforded a colorless oil, (150 mg, 0.36 mmol, 48%).

Step (iii)-(iv): 2-(6-(3-(Dimethylamino)-l-phenylpropoxy)pyridin-3-ynacetic acid. A mixture of the product of the previous step (150 mg, 0.36 mmol, 1.0 eq), IN NaOH (0.4 mL) and THF (2 mL) was heated at reflux for 3h. It was allowed to cool and the pH was carefully adjusted to just 1 with IN HCl. The mixture was stirred at r.t. for lh. HPLC showed incomplete conversion. It was mixed with ethanol (4 mL), water (1 mL) and 180 mg NaOH and refluxed for 3h. After cooling and acidification to pH=l (4-4.5 mL IN HCl), it was allowed to stir for lh at rt. The mixture was concentrated and used as such.

Step (v): 2-(6-(3 -(Dimethylamino)- 1 -phenylpropoxy)pyridin-3 -y0- 1 -(5- methoxy-6-(trifluoromethyl)indolin-l-yl)ethanone (AG-0176).

The crude product of the previous step (max. 0.36 mmol) was suspended in DMF (5 mL) and stirred at rt while adding 5-methoxy-6-(trifluoromethyl)indoline (78 mg, 0.36 mmol, 1.0 eq), HOBt (54 mg, 0.40 mmol, 1.1 eq), EDCI (76 mg, 0.40 mmol, 1.1 eq), Et₃N (0.05 mL). Stirring was continued at rt overnight, concentrated and purified by automated column chromatography (0-10% methanol in dichloromethane, Si0₂) and preparative HPLC afforded a light-orange sticky oil (17 mg, 0.033 mmol, 9% (two steps)). Examples to Scheme C3

Step (T): 3. Ethyl 6-(3-(Dimethylamino)-l-phenylpropoxy)nicotinate). KOtBu (3.023 g, 27 mmol, 1.0 eq) was dissolved in THF (50 mL) and cooled (0°C). A dried (Na2S0₄) and filtered solution of 3-(dimethylamino)-l-phenyl-propan-l-ol (4.83 g, 27 mmol, 1.0 eq) in THF (52 mL) was added drop-wise. After 5 min a solution of ethyl-6- chloronicotinate (5.00 g, 27 mmol, 1.0 eq) was added and the reaction mixture was allowed to reach rt overnight. The yellow suspension was poured in ethyl acetate (150 mL) and washed with brine (70 mL). The aqueous layer was extracted with ethyl acetate (lx). The combined organics were washed with brine, dried and concentrated to a red oil (8.5 g) which was used in the next step without any further purification.

Step (ii): 6-(3-(Dimethylamino)-l-phenylpropoxy)nicotinic acid. The compound from the previous step was dissolved in ethanol (35 mL) and water (5 mL) and KOH (2.5 g) was added. Subsequently, the mixture was heated at reflux for lh. The organic solvent was removed in vacuo and the residue diluted with water (50 mL). TBME (3x25 mL) was used for washing. The aqueous layer was acidified to a pH of 4-5 (litmus paper) and the solid formed was filtered off and discarded. The filtrate was washed with ethyl acetate. The aqueous layer was concentrated in vacuo to afford ca. 9 g of a white solid. Trituration with TBME and acetone resulted in a white solid (7.2 g). It was used as such in the next step.

Step (iii): (6-(3 -(dimethyl amino)- l-phenylpropoxy)pyridin-3-yl)(5-methoxy-6-

(trifluoromethyl)indolin-l-yl)methanone (AG-0196).

A mixture of 5-methoxy-6-(trifluoromethyl)indoline (75 mg, 0.35 mmol, 1.0 eq), the crude acid from the previous step (315 mg), EDCI (74 mg, 0.39 mmol, 1.1 eq), HOBt (52 mg, 1.1 eq) and Et₃N (0.05 mL, 1.0 eq) in DMF (5 mL) was stirred at rt overnight. The mixture was poured on sat. NaHC0₃ (10 mL) and extracted with dichloromethane (20 mL). The organic layer was washed with water (3x5 mL). The combined aqueous layers were back-extracted with dichloromethane (10 mL). The combined organics were washed with brine, dried (Na₂SC"4) and concentrated to 127 mg of an orange oil. Automated column chromatography (Si0₂, 0-5% methanol in dichloromethane) afforded a white solid (37 mg, 0.074 mmol, 32%).

Examples to Scheme Dl

Step (Ϊ): 3-Chloro-N.N-dimethyl-3-phenylpropan-l-amine. To a cooled (0°C) solution of 3 -(dimethylamino)-l -phenyl propan-l-ol (0.5 g, 2.8 mmol, 1 eq.) and Et₃N (0.8 ml, 5.6 mmol, 2 eq.) in dichloromethane was added methanesulfonyl chloride (0.33 ml, 4.2 mmol, 1.5 eq.). The reaction mixture was stirred at rt overnight, washed with water, dried, filtered and concentrated to provide the title compound (460 mg, 1.79 mmol, 64%).

Step (ii): N,N-Dimethyl-3-((5-nitropyridin-2-yl)thio)-3-phenylpropan-l-amine. To a cooled (0°C) solution of the product of the previous step (460 mg, 1.79 mmol, 1 eq.) in dichloromethane was added Et₃N (0.4 ml, 2.68 mmol, 1.5 eq.), followed by Nal (135 mg, 0.9 mmol, 0.5 eq.) and 2-mercapto-5-nitropyridine (550 mg, 3,57 mmol, 2 eq.). The reaction mixture was stirred at rt overnight, washed with water, dried, filtered and concentrated. The crude compound (700 mg) was purified by reversed phase automated column chromatography (260 mg, 0.82 mmol, 46%).

Step (iii): 6-((3-(Dimethylamino)-l-phenylpropynthio)pyridin-3 -amine. The product of the previous step (260 mg, 0.82 mmol, 1 eq.) was dissolved in MeOH. Pt0₂ (ca. 250 mg, 1.1 mmol, 1.3 eq.) was added and the resulting mixture was hydrogenated at rt overnight (with a H₂ balloon). Incomplete conversion was observed, additional Pt0₂ was added and the mixture was stirred another night, resulting in full conversion. The reaction mixture was filtered over Celite and concentrated (160 mg, 0.50 mmol, 62%).

Step (iv): Phenyl (6-((3-(dimethylamino)-l-phenylpropynthio)pyridin-3- yPcarbamate. Phenyl chloroformate (0.1 1 ml, 0.84 mmol, 1.5 eq.) was dissolved in dichloromethane and cooled to 0°C. A solution of the product of the previous step (160 mg, 0.56 mmol, 1 eq.) and Et₃N (0.15 ml, 1.12 mmol, 2 eq.) in DCM was added drop- wise. The reaction mixture was stirred at rt overnight, poured into sat. NaHC0₃. The aqueous layer was extracted with dichloromethane (3x) and the combined organic layers were dried, filtered and concentrated to a crude oil (340 mg, > 100%).

Step (V) : N-(6-(Y3 -(dimethyl amino)- 1 -phenylpropyPthi o)pyridine-3 -yl)-5 - methoxy-6-(trifluoromethyl)indoline- 1 -carboxamide (AG-0378).

The crude of the previous step (340 mg, max. 0.56 mmol, 1 eq.) was dissolved in THF and a solution of 5-methoxy-6-(trifluoromethyl)-indoline (156 mg, 0.72 mmol, 1.2 eq.) and Et₃N (0.25 ml, 1.8 mmol, 3 eq.) in THF was added. The resulting reaction mixture was refluxed for lh, cooled to rt and poured in water. Extraction with ethyl acetate (5x), drying of the combined organic layers, filtration and concentration resulted in 300 mg crude product. Purification with preparative HPLC afforded AG- 0378 as a light-brown foam ((47 mg, 0.089 mmol, 34% (two steps)).

Biological methods

In vitro assays

(Radio)ligand binding assays were performed for the serotonin receptor 5HT2C, the serotonin transporter (5HTT), the norepinephrine transporter (NAT) and the dopamine transporter (DAT). For each assay, commercially available frozen membranes from cells expressing the recombinant or endogenous receptors were used.

A functional assay (measurement of intracellular calcium by the aequorin calcium assay) was performed for the serotonin receptors 5HT2C and 5HT2A. For each assay, commercially available frozen irradiated cells expressing the human recombinant or endogenous receptor were used.

5HTT binding assay

The binding assay for the serotonin transporter (5HTT) was guided by an article of de Jong et al. {Rapid Commun. Mass Spectrom., 2007; 21 : 567-572). In short, commercially available HEK293 cells expressing the human 5HT transporter were used and MADAM was utilized as ligand in the binding assay. All compounds were analysed in triplicate using LC-MS/MS at concentrations ranging from 1 - 1000 nM. The results were expressed as % of the specific MADAM binding and IC50 values were calculated. The Ki was calculated using the ligand concentration and ¾ value of MADAM. Citalopram was used as reference compound (concentration response curve 1 nM - 3000 nM) in each experiment.

5HT2C binding assay The binding assay for the serotonin 5HT2C receptor was guided by an article of

Jerman et al. (Eur. J. Pharmacol., 2001; 414: 23-30). In short, commercially available HEK293 cells expressing the human 5HT2C receptor were used and [³H]-mesulergine was utilized as radioligand in the binding assay. All compounds were analysed in triplicate by liquid scintillation spectrometry at concentrations ranging from 1 - 1000 nM. The results were expressed as % of the specific [^JH]-mesulergine binding and IC₅₀ values were calculated. The Ki was calculated using the ligand concentration and K_<j value of [³H]-mesulergine. Mianserin was used as reference compound (concentration response curve 0.01 nM - 3000 nM) in each experiment. NAT binding assay

The binding assay for the norepinephrine transporter (NAT) was performed using commercially available MDCK cells expressing the human NA transporter. [¾]- Nisoxetine was used as radioligand in the binding assay. All compounds were analysed in triplicate by liquid scintillation spectrometry at concentrations ranging from 10- 10000 nM. The results were expressed as % of the specific [³H]-nisoxetine binding and IC₅₀ values were calculated. The Ki was calculated using the ligand concentration and K_d value of [³H]-nisoxetine. Desipramine was used as reference compound (concentration response curve 0.3 nM - 1000 nM) in each experiment. DAT binding assay

The binding assay for the dopamine transporter (DAT) was performed using commercially available CHO-Kl cells expressing the human DA transporter. [³H]-WIN 35,428 was used as radioligand in the binding assay. All compounds were analysed in triplicate by liquid scintillation spectrometry at concentrations ranging from 10 - 10000 nM. The results were expressed as % of the specific [³H]-WIN 35428 binding and IC_¾o values were calculated. The Ki was calculated using the ligand concentration and ¾ value of [^JH]-WIN 35,428. GBR12909 was used as reference compound (concentration response curve 1 nM - 3000 nM) in each experiment.

5HT r and 5HT?A functional assay

The development of an AequoScreen® calcium assay for the serotonin 5HT₂c and 5HT_2A receptors was guided by an article of Brini et al (J. Biol. Chem. 1995; 270: 9896-9903).

The AequoScreen® assay is a cellular aequorin-based assay in which cells are loaded with the apoaequorin cofactor coelenterazine. Aequorin is a photoprotein originating from the jellyfish Aequorea Victoria. The apo-enzyme (apoaequorin) is a 21 kD protein that needs a hydrophobic prosthetic group, coelenterazine, to be converted to aequorin, the active form of the enzyme. This enzyme possesses three calcium binding sites which control its activity. Upon calcium binding, aequorin oxidizes coelenterazine into coelenteramide with production of C0₂ and emission of light. The consumption of aequorin is proportional to the calcium concentration and the measurement of the light (luminescence) emitted upon oxidation of coelenterazine is therefore a reliable tool for measurement of intracellular calcium flux resulting from the activation of the 5HT₂c or 5HT₂A receptor by a compound.

5ΗΤ Γ aequorin calcium assay

Commercially available frozen irradiated CHO-Kl cells expressing the human recombinant serotonin 5HT₂c receptor were used. Agonist and antagonist dose- response experiments were performed. In the agonist assay, the compounds were analysed in duplicate at 6 concentrations (ranging from 0.1 - 10000 nM). The agonistic response of a compound was expressed as % of the control (i.e. the maximal response of the agonist a-methyl- 5HT was defined as 100%). The E_max values were determined and EC₅₀ values were fitted.

In the antagonist assay, the compounds were screened in duplicate at 6 concentrations (ranging from 0.1 - 10000 nM) allowing an estimation of their IC₅₀ values. The results were expressed as % of the control response (i.e. the response of a- methyl-5HT at its EC₈o value was set as 100%) and the IC50 values were calculated. Methysergide was used as reference inhibitor in each experiment (full concentration response curve 0.003 nM - 1000 nM) for the determination of its IC₅₀ value.

5HT₇A aequorin calcium assay Commercially available frozen irradiated CHO-K1 cells expressing the human recombinant serotonin 5HT₂A receptor were used and antagonist dose-response experiments were performed.

In the antagonist assay, the compounds were screened in duplicate at 6 concentrations (ranging from 0.1 - 10000 nM) allowing an estimation of their IC₅₀ values. The results were expressed as % of the control response (i.e. the response of agonist TCB2 at its EC₈₀ value was set as 100%) and the IC50 values were calculated. Altanserin was used as reference inhibitor in each experiment (full concentration response curve 0.01 nM - 1000 nM) for the determination of its IC₅₀ value.

The compounds in Tables 1-16 were prepared according to procedures described in the examples 1-10. The binding towards the receptors screened is depicted in nM. Table 1

R₂ R₃ R₄ 5-HTT 5-HT_2c NAT DAT 5- Synth.

An.(IC50) HT_2a Example

AG-0001 Me Me CH₂CH₂ 378 7 2160 305 - 3

AG-0002 (el) Me Me CH₂CH₂ 290 45 1630 - - 3

AG-0003 (e2) Me Me CH₂CH₂ 450 5 1920 - - 3

AG-0095 (el) Me H CH₂CH₂ 429 7 - 1930 - 3

AG-0105 (e2) Me H CH₂CH₂ 505 7 - 1070 - 3

AG-0096 (el) H H CH₂CH₂ 443 6 356 - 3

AG-0106 (e2) H H CH₂CH₂ > 552 6 461 1410 - 3

AG-0135 (el) Me Et CH₂CH₂ > 552 10 1830 575 - 3

AG-0136 (e2) Me Et CH₂CH₂ > 552 7 2560 515 - 3

AG-0137 (el) (CH₂)₅ CH₂CH₂ CH₂CH₂ 63 - 3600 - 3

AG-0138 (e2) (CH₂)₅ CH₂CH₂ CH₂CH₂ 8 - - - 3

AG-0211 Me Me CHMeCH₂ > 552 35 163 3 ( , )

Table la

¹H-NMR (CDCI3, in ppm) MS (ESI)

AG -0001 8.20 (s, IH), 7,97 (s, IH), 7.80 (d, IH), 7,20-7.40 (m, 5H), mass calcd. for

6.82 (s, IH), 6.75 (d, IH), 6.37 (s, IH), 6.00 (t, IH), 4.00 (t, C₂₇H₂₉F₃N₄0₃

2H), 3.83 (s, 3H), 3.20 (t, 2H), 2.40 (t, 2H), 2.20 (s, 6H), 514,22; m/z found,

2.05 (m, 2H) 515.2 (M+H)⁺

AG -0002 (el) 8.20 (s, IH), 7,97 (s, IH), 7.80 (d, IH), 7,20-7.40 (m, 5H), mass calcd. for

6.82 (s, IH), 6.75 (d, IH), 6.37 (s, IH), 6.00 (t, IH), 4.00 (t, C₂₇H₂₉F₃N₄03

2H), 3.83 (s, 3H), 3.20 (t, 2H), 2.40 (t, 2H), 2.20 (s, 6H), 514,22; m/z found,

2.05 (m, 2H) 515.2 (M+H)⁺

AG-0003 (e2) 8.20 (s, IH), 7,97 (s, IH), 7.80 (d, IH), 7,20-7.40 (m, 5H), mass calcd. for

2H), 3.83 (s, 3H), 3.20 (t, 2H), 2.40 (t, 2H), 2.20 (s, 6H), 514.22; m/z found,

2.05 (m, 2H) 515.2 (M+H)⁺

AG-0095 (el) 8.18 (s, IH), 7.97 (s, IH), 7.79 (d, IH), 7.20-7.40 (m, 5H), mass calcd. for

6.84 (s, IH), 6.72 (d, IH), 6.48 (s, IH), 6.05 (m, IH), 4.08 C₂₆H₂₇F₃N₄03

(t, 2H), 3.85 (s, 3H), 3.25 (t, 2H), 2.75 (t, 2H), 2.44 (s, 3H), 500.20; m/z found,

2.20 (m, 2H) 501.1 (M+H)⁺

AG-0105 (e2) 8.18 (s, IH), 7.97 (s, IH), 7.79 (d, IH), 7.20-7.40 (m, 5H), mass calcd. for

6.84 (s, IH), 6.72 (d, IH), 6.48 (s, IH), 6.05 (m, IH), 4.08 C₂₆H₂₇F₃N₄0₃

2.20 (m, 2H) 501.1 (M+H)⁺

AG-0096 (el) 8.20 (s, IH), 7.96 (s, IH), 7.80 (d, IH), 7.20-7.40 (m, 5H), mass calcd. for

6.86 (s, IH), 6.77 (d, IH), 6.36 (s, IH), 6.15 (m, IH), 4.09 C₂₅H₂₅F3N₄0₃

(t, 2H), 3.87 (s, 3H), 3.27 (t, 2H), 2.85 (t, 2H), 2.10 (m, 2H) 486.19; m/z found,

487.1 (M+H)⁺

AG-0106 (e2) 8.20 (s, IH), 7.96 (s, IH), 7.80 (d, IH), 7.20-7.40 (m, 5H), mass calcd. for

6.86 (s, IH), 6.77 (d, IH), 6.36 (s, IH), 6.15 (m, IH), 4.09 C₂₅H₂5F₃N₄03

487.1 (M+H)⁺

AG-0135 (el) 8.19 (s, IH), 7.93 (s, IH), 7.80 (d, IH), 7.20-7.40 (m, 5H), mass calcd. for

6.86 (s, IH), 6.77 (d, IH), 6.15 (s, IH), 6.04 (m, IH), 4.08 C₂₈H31F₃N₄0₃

(t, 2H), 3.86 (s, 3H), 3.28 (t, 2H), 2.45 (t, 2H), 2.22 (s, 3H), 528.23; m/z found,

2.10 (m, 2H), 1.01 (t, 3H) 529.2 (M+H)⁺

AG-0136 (e2) 8.19 (s, IH), 7.93 (s, IH), 7.80 (d, IH), 7.20-7.40 (m, 5H), mass calcd. for

2.10 (m, 2H), 1.01 (t, 3H) 529.2 (M+H)⁺

AG-0137 (el) 8.17 (s, IH), 7.91 (s, IH), 7.75 (d, IH), 7.20-7.40 (m, 5H), mass calcd. for

6.82 (s, IH), 6.73 (d, IH), 6.35 (s, IH), 6.00 (m, IH), 4.01 C3oH33F₃N₄0₃

(t, 2H), 3.83 (s, 3H), 3.22 (t, 2H), 2.00-2.40 (m, 8H), 1.57 554.25; m/z found,

(m, 4H), 1.42. (m, 2H) 555.1 (M+H)⁺

AG-0138 (e2) 8.17 (s, IH), 7.91 (s, IH), 7.75 (d, IH), 7.20-7.40 (m, 5H), mass calcd. for

6.82 (s, IH), 6.73 (d, IH), 6.35 (s, IH), 6.00 (m, IH), 4.01 C3oH33F₃N₄03

(t, 2H), 3.83 (s, 3H), 3.22 (t, 2H), 2.00-2.40 (m, 8H), 1.57 554.25; m/z found,

(m, 4H), 1.42 (m, 2H) 555.1 (M+H)⁺

AG-0211 (R,R) 8.18 (s, IH), 7.90 (s, IH), 7.83 (d, IH), 7.20-7.40 (m, 5H), mass calcd. for

6.85 (s, IH), 6.78 (d, IH), 6.25 (s, IH), 6.09 (d, IH), 4.07 C₂₈H3iF₃N₄0₃

(t, 2H), 3.86 (s, 3H), 3.26 (t, 2H), 2.10-2.40 (m, 7H), 528.23; m/z found,

0.98.(d, 3H) 529.2 (M+H)⁺ Table 2

Ri 5-HTT 5-HT_2c NAT DAT 5-HT_2a Synth.

An.(IC50) Example

AG-0001 phenyl 378 7 2160 - - 3

AG-0047 4-Me-phenyl 61% 50 - - - 3

AG-0048 4-CF₃-phenyl 58% 380 - - - 3

AG-0049 4-F-phenyl 287 33 - - - 3

AG-0050 4-OMe-phenyl 387 6 - - - 3

AG-0051 4-CN-phenyl 48% 49 - - - 3

AG-0180 thiophen-2-yl 472 1 - - 2643 3

AG-0181 thiophen-3-yl 314 1 - - 5337 3

AG-0182 pyridine-2-yl 285 2 - - 6616 3

AG-0183 pyridine-3-yl > 552 1 - - 4612 3

Table 2a

¹H-NM R (CDCI₃, in ppm) MS (ESI)

AG-0047 8.18 (s, 1H), 7.94 (s, 1H), 7.78 (d, 1H), 7.28 (d, 2H), mass calcd. for

7.11 (d, 2H), 6.86 (s, 1H), 6.74 (d, 1H), 6.23 (s, 1H), C₂8H₃₁F₃N₄0₃ 6.01 (m, 1H), 4.07 (t, 2H), 3.86 (s, 3H), 3.27 (t, 2H), 528.23; m/z found, 2.00-2.40 (t, 2 x s + m, 13H) 529.2 (M+H)⁺

AG-0048 8.20 (s, 1H), 8.02 (s, 1H), 7.90 (d, 1H), 7.40 (m, 4H), mass calcd. for

6.85 (s, 1H), 6.80 (d, 1H), 6.75 (s, 1H), 6.18 (m, 1H), C₂8H₂₈F₆N₄0₃ 4.15 (t, 2H), 3.80 (s, 3H), 3.24 (t, 2H), 2.75 (t, 2H), 2.41 528.21; m/z found, (s, 6H), 2.20 (m, 2H) 529.1 (M+H)⁺

AG-0049 8.20 (s, 1H), 8.04 (s, 1H), 7.82 (d, 1H), 7.36 (m, 2H), mass calcd. for

6.90 (m, 3H), 6.82 (s, 1H), 6.72 (d, 1H), 6.05 (m, 1H), C₂₇H₂₈F₄N₄0₃ 4.15 (t, 2H), 3.81 (s, 3H), 3.21 (t, 2H), 2.75 (t, 2H), 2.42 532.21; m/z found, (s, 6H), 2.25 (m, 2H) 533.1 (M+H)⁺

AG-0050 8.07 (s, 1H), 8.04 (s, 1H), 7.82 (dd, 1H), 7.30 (m, 2H), mass calcd. for

6.60-6.90 (m, 5H), 5.95 (m, 1H), 4.10 (t, 2H), 3.83 (s, C₂gH3iF3N₄0₃ 3H), 3, 77 (s, 3H), 3.05 (t, 2H), 2.50 (m, 2H), 2.35 (s, 544.23; m/z found, 6H), 2.20 (m, 2H) 545.0 (M+H)⁺

AG-0051 8.19 (s, 1H), 7.90 (s, 1H), 7.82 (d, 1H), 7.40 (dd, 4H), mass calcd. for

6.90 (m, 3H), 6.05 (m, 1H), 4.08 (t, 2H), 3.75 (s, 3H), C₂₈H₂₈F₃Ns0₃ 3.27 (t, 2H), 2.40 (t, 2H), 2.22 (s, 6H), 2.10 (m, 2H) 539.21; m/z found,

540.1 (M+H)⁺

AG-0180 8.21 (s, 1H), 8.01 (s, 1H), 7.77 (d, 1H), 7.24 (d, 1H), mass calcd. for

7.08 (d, 1H), 6.96 (m, 1H), 6.84 (s, 1H), 6.77 (d, 1H), C₂₅H₂₇F₃N₄0₃S 6.42 (m, 1H), 6.35 (s, 1H), 4.06 (t, 2H), 3.86 (s, 3H), 520.18; m/z found, 3.26 (t, 2H), 2.41 (m, 2H), 2.24 (s, 6H), 2.10 (m, 2H) 521.1 (M+H)⁺

AG-0181 8.21 (s, 1H), 7.99 (s, 1H), 7.77 (d, 1H), 7.24 (d, 1H), mass calcd. for

7.14 (d, 1H), 6.86 (s, 1H), 6.74 (d, 1H), 6.32 (s, 1H), C₂₅H₂₇F₃N₄0₃S

6.22 (m, 1H), 4.06 (t, 2H), 3.86 (s, 3H), 3.26 (t, 2H), 520.18; m/z found, 2.37 (m, 2H), 2.24 (s, 6H), 2.09 (m, 2H) 521.1 (M+H)⁺

AG-0182 8.59 (s, 1H), 8.38 (d, 1H), 8.10 (s, 2H), 7.91 (s, 1H), mass calcd. for

7.80-7.90 (m, 2H), 7.23 (m, 1H), 6.83 (s, 1H), 6.72 (d, C₂₆H₂₈F₃N₅0₃ 1H), 6.02 (m, 1H), 4.09 (t, 2H), 3.83 (s, 3H), 3.21 (t, 2H), 515.21; m/z found, 2.45 (m, 2H, CH₂), 2.24 (s, 6H), 2.10 (m, 2H) 516.1 (M+H)⁺

AG-0183 8.59 (s, 1H), 8.22 (d, 1H), 8.10 (s, 1H), 7.93 (s, 1H), 7.85 mass calcd. for

(d, 1H), 7.62 (t, 1H), 7.20-7.40 (m, 2H), 6.84 (s, 1H), C₂₆H₂₈F₃N₅0₃ 6.72 (d, 1H), 6.08 (m, 1H), 4.09 (t, 2H), 3.87 (s, 3H), 515.21; m/z found, 3.32 (t, 2H), 2.15-2.45 (m, 4H), 2.24 (s, 6H) 516.1 (M+H)⁺

AG-0184 8.54 (s, 2H), 8.21 (s, 1H), 7.85 (s, 1H), 7.80 (d, 1H), 7.28 mass calcd. for

(d, 1H), 6.79 (m, 2H), 6.58 (s, 1H), 6.05 (m, 1H), 4.06 (t, C₂₆H₂₈F₃N₅0₃ 2H), 3.83 (s, 3H), 3.24 (t, 2H), 2.05-2.41 (m, 4H), 2.24 515.21; m/z found, (s, 6H) 516.1 (M+H)⁺ Table 3

= Synthetic example Table 3a

¹H-NM R (CDCI₃, in ppm) MS (ESI)

AG -0041 8.20 (s, IH), 7.40-7.21 (m, 5H), 7.18 (d, 2H), 6.85-6.78 (m, mass calcd. for

3H), 6.18 (m, IH), 5.22-5.17 (m, IH), 4.02 (t, 2H), 3.82 (s, C28H30F3 N3O3,

3H), 3.22 (t, 2H), 2.44 (t, 2H), 2.25 (s, 6H), 2.30-2.10 (m, IH), 513.22; m/z found,

2.04-1.90 (m, IH) 514.2 [M+H]⁺

AG-0061 8.20 (s, IH), 8.01 (s, IH), 7.40-7.21 (m, 5H), 6.90 (s, IH), mass calcd. for

6.63 (s, IH), 6.05 (m, IH), 4.04 (t, 2H), 3.82 (s, 3H), 3.28 (t, C₂8H3i F₃N₄03,

2H), 2.44 (t, 2H), 2.25 (s, 6H), 2.20 (s, 3H) , 2.15 (m, 2H) 528.23; m/z found,

529.2 [M+H]⁺

AG-0062 8.21 (s, IH), 7.90 (s, IH), 7.71 (s, IH), 7.40-7.21 (m, 5H), mass calcd. for

6.87 (s, IH), 6.33 (s, IH), 6.19 (m, IH), 4.08 (t, 2H), 3.88 (s, C28H31 F3 N4O3,

3H), 3.31 (t, 2H), 2.51 (t, 2H), 2.33 (s, 6H), 2.29 (s, 3H) , 2.15 528.23; m/z found,

(m, 2H) 529.2 [M+H]⁺

AG-0063 8.20 (s, IH), 8.05 (s, IH), 7.90 (s, IH), 7.40-7.21 (m, 5H), mass calcd. for

6.88 (s, IH), 6.53 (m, IH), 6.20 (m, IH), 4.12 (t, 2H), 3.88 (s, C₂₇H₂₈F₃N₄0₃,

3H), 2.60 (t, 2H), 2.40 (s, 6H), 2.20 (m, 2H) 548.18; m/z found,

549.1 [M+H]⁺

AG -0044 8.54 (s, 2H), 8.18 (s, 2H), 7.45-7.17 (m, 5H), 6.98 (br s, IH), mass calcd. for

6.84 (s, IH), 6.10-6.05 (m, IH), 4.04 (t, 2H), 3.86 (m, 3H), C₂₆H₂8F₃N₅0₃,

3.25 (t, 2H), 2.60-2.20 (m, IH), 2.21 (s, 6H), 2.18-1.95 (m, 515.21; m/z found,

IH) 516.2 [M+H]⁺.

AG-0079 8.37-8.15 (br m, 1.5H), 7.8 (br s, 0.5H), 7.42-7.40 (m, 2H), mass calcd. for

7.33-7.21 (m, 4H), 7.03 (d, IH), 6.86 (s, IH), 6.22-6.17 (m, C₂₆H₂₈F₃N₅03,

IH), 4.14-4.03 (m, 2H), 3.86 (s, 3H), 3.21 (pseudo-t, 2H), 515.21; m/z found,

2.43-2.24 (m, 3H), 2.21 (s, 6H), 2.09-1.97 (m, IH) 516.3 [M+H]⁺

AG-0119 (el) 8.54 (s, 2H), 8.18 (s, 2H), 7.45-7.17 (m, 5H), 6.84 (s, IH), mass calcd. for

6.25 (br s, IH), 6.10-6.05 (m, IH), 4.04 (t, 2H), 3.86 (m, 3H), C₂₅H₂8F₃N₅0₃,

3.25 (t, 2H), 2.60-2.20 (m, IH), 2.21 (s, 6H), 2.18-1.95 (m, 515.21; m/z found,

IH) 516.2 [M+H]⁺

AG-0120 (e2) 8.54 (s, 2H), 8.18 (s, 2H), 7.45-7.17 (m, 5H), 6.84 (s, IH), mass calcd. for

6.47 (br s, IH), 6.10-6.05 (m, IH), 4.04 (t, 2H), 3.86 (m, 3H), C₂₆H₂8F_{3 5}03,

3.25 (t, 2H), 2.60-2.20 (m, IH), 2.21 (s, 6H), 2.18-1.95 (m, 515.21; m/z found,

IH) 515.9 [M+H]⁺.

AG-0204 (el) 8.37-8.15 (br m, 1.5H), 8.0 (br s, 0.5H), 7.42-7.40 (m, 2H), mass calcd. for

7.33-7.21 (m, 4H), 7.03 (d, IH), 6.86 (s, IH), 6.22-6.17 (m, C₂₅H₂8F₃N₅0₃,

IH), 4.14-4.03 (m, 2H), 3.86 (s, 3H), 3.25-3.10 (m, 2H), 2.43- 515.21; m/z found,

2.24 (m, 3H), 2.21 (s, 6H), 2.09-1.97 (m, IH) 516.1 [M+H]⁺

AG-0205 (e2) 8.30-7.90 (br m, 2H), 7.41-7.38 (m, 2H), 7.34-7.22 (m, 3H), mass calcd. for

7.02 (d, IH), 6.86 (s, IH), 6.22-6.17 (m, IH), 4.15-4.08 (m, C₂₆H₂₈F₃N₅03,

2H), 3.87 (s, 3H), 3.25-3.13 (m, 2H), 2.65-2.58 (m, 3H), 2.40 515.21; m/z found,

(s, 6H), 2.40-2.28 (m, IH), 2.22-2.18 (m, IH) 516.1 [M+H]⁺

AG-0291 8.81 (d, IH), 8.20 (s, IH), 7.82 (d, IH), 7.43-7.39 (m, 2H), mass calcd. for

7.35-7.22 (m, 3H), 6.91 (br s, IH), 6.83 (s, IH), 6.07-6.02 (m, ₂₆H₂8F_{3 5}03,

IH), 4.07 (t, 2H), 3.84 (s, 3H), 3.28-3.22 (m, 2H), 2.49-2.20 515,21; m/z found:

(m, 3H), 2.29 (s, 6H), 2.12-2.03 (m, IH) 516.10 [M+H]⁺

AG-0055 8.29 (s, IH), 8.17 (s, 2H), 7.35-7.25 (m, 5H), 6.79 (s, IH), mass calcd. for

5.27-5.23 (m, IH), 4.06 (t, 2H), 3.82 (s, 3H), 3.21 (t, 2H), C₂₆H₂₈F₃N₅03,

2.70-2.55 (m, 2H), 2.39 (s, 6H), 2.36-2.20 (m, IH), 2.16-2.09 515.21; m/z found,

(m, IH) 516.0 [M+H]⁺

AG-0390 8.24 (s, IH), 7.91 (d, IH), 7.85 (d, IH), 7.35-7.20 (m, 5H), mass calcd. for

7.06 (s, IH), 6.86 (s, IH), 5.27-5.23 (m, IH), 4.05 (t, 2H), C₂₇H_2gF₃N₄0₃,

3.87 (s, 3H), 3.26 (t, 2H), 2.70-2.55 (m, 2H), 2.39 (s, 6H), 514.22; m/z found,

2.36-2.20 (m, IH), 2.16-2.04 (m, IH) 515.2 [M+H]⁺ Table 4

R₉ W₂ E 5-HTT 5-HT_2c NAT DAT 5-HT_2a Synth.

An.(IC50) Example

AG-0001 NH 0 N 378 6.6 2160 - - 3

AG-0169 - 0 N 313 1126 628 - 574 9

AG-0173 NH 0 CH 324 6231 - - - 7

AG-0175 NH S N 337 56.2 1810 - 1869 7

AG-0176 CH₂ 0 N 394 4.3 - - 5368 7

AG-0179 NMe 0 N >562 581 - - - 7

Table 4a

¹H-N M (CDCI₃, in ppm) MS (ESI)

AG-0169 8.33 (s, IH), 7,78 (s, IH), 7.20-7.42 (m, 6H), 6.88 (s, IH), mass calcd. for

6.83 (d, IH), 6.21 (t, IH), 4.11 (t, 2H), 3.87 (s, 3H), 3.14 (t, C₂₇H₂₈F₃N₃0₃, 499.21; 2H), 2.45 (m, 2H), 2.28 (s, 6H), 2.05 (m, 2H) m/z found, 500.1

[M+H]⁺

AG-0173 7.96 (s, IH), 7,83 (d, IH), 7,20-7.40 (m, 9H), 6.70 (d, IH), mass calcd. for

6.02 (t, IH), 4.04 (t, IH), 3.00 (m, 2H), 2.40 (m, 4H), 2.24 (s, C₂₆H₂₉N₃0₂, 415.23; 6H), 2.00 (m, 2H) m/z found, 416.1

[M+H]⁺

AG-0175 8.94 (s, IH), 7,97 (s, IH), 7.68 (d, IH), 7,20-7.45 (m, 5H), mass calcd. for

7.11 (s, IH), 6.83 (d, IH), 6.37 (s, IH), 6.08 (m, IH), 4.33 (t, C₂₇H₂₉F₃N₄0₂S, 2H), 3.87 (s, 3H), 3.22 (t, 2H), 2.92 (m, 2H), 2.60 (s, 6H), 2.30 530.20; m/z found, (m, 2H) 431.1 [M+H]⁺

AG-0176 8.46 (s, IH), 7,93 (s, IH), 7.55 (d, IH), 7.40 (d, 2H), 7.20-7.35 mass calcd. for

(m, 3H), 6.83 (s, IH), 6.77 (d, IH), 6.07 (t, IH), 4.11 (t, 2H), C₂₈H₃₀F₃N₃O₃, 513.22; 3.85 (s, 3H), 3.61 (s, 2H), 3.20 (t, 2H), 2.40 (m, 2H), 2.22 (s, m/z found, 514.1 6H), 2.05 (m, 2H) [M+H]⁺

AG-0179 7.95 (s, IH), 7,65 (s, IH), 7.58 (d, IH), 7,20-7.40 (m, 5H), mass calcd. for

6.99 (s, IH), 6.86 (d, IH), 6.02 (m, IH), 3.84 (s, 3H), 3.41 (t, C₂₈H₃₁F₃N₄0₃, 528.23; 2H), 3.23 (s, 3H), 2.96 (t, 2H), 2.41 (t, 2H), 2.23 (s, 6H), 2.05 m/z found, 529.1 (m, 2H) [M+H]⁺

Table 5

Rio Rll R₁₂ Rl3 5-HTT 5-HT_2c NAT DAT 5-HT_2a Synth.

An.(IC50) Ex.

AG -0066 H H H H 56 68 - - 6105 2

AG-0147 H H H CI 44 59 434 566 3659 2

AG-0159 H H H F 49 93 504 - 7955 2

AG-0163 H H H Me 34 50 1280 1482 6053 2

AG-0307 (el) H H H Me 35 10 1587 - - 2

AG-0308 (e2) H H H Me 30 99 - - - 2

AG-0148 H H CI H 26 24 442 272 935 2

AG-0309 (el) H H CI H 42 6 457 25.3 2846 2

AG-0310 (e2) H H CI H 50 383 418 - 4755 2

AG-0160 H H F H 37 84 1570 387 5107 2

AG-0164 H H Me H 38 5 2065 34 6979 2

AG-0387 (el) H H Me H 95 5 - - - 2

AG-0388 (e2) H H Me H 25 45 - - - 2

AG-0167 H H N0₂ H 164 6 - - 9640 2

AG-0149 H CI H H 201 6 340 456 595 2

AG-0161 H F H H 136 68 1460 410 4530 2

AG-0165 H Me H H 121 6 - - 4036 2

AG-0150 H CF₃ H H 314 6 1170 557 - 2

AG-0158 CI H H H 284 3015 - - > 10000 2

AG-0162 F H H H 47 2388 2840 557 > 10000 2

AG-0166 Me H H H 296 5042 > 4080 - - 2

AG -0075 H CI Me H 317 7 - - - 2

AG-0168 H F Me H 115 4 - - 2293 2

AG-0151 H CI CI H 255 7 - - 198 2

AG-0001 H CF₃ OMe H 378 7 2160 - - 2 Table 5a

¹H-NM R (CDCI₃, in ppm) MS (ESI)

AG-0066 7.99 (s, 1H), 7,89 (t, 2H), 7,20-7.45 (m, 7H), 6.98 (t, 1H), mass calcd. for

6.78 (d, 1H), 6.37 (s, 1H), 6.00 (t, 1H), 4.08 (t, 2H), 3.25 (t, C₂₅H₂₈N₄0₂, 416.22;

2H), 2.40 (m, 2H), 2.31 (s, 6H), 2.05 (m, 2H) m/z found, 417.1

[M+H]⁺

AG-0147 7.95 (s, 1H), 7,80 (m, 2H), 7,20-7.45 (m, 5H), 7.12 (t, 1H), mass calcd. for

6.92 (d, 1H), 6.75 (d, 1H), 6.37 (s, 1H), 6.05 (t, 1H), 4.08 (t, C₂₅H₂₇CIN₄0₂, 450.18;

2H), 3.24 (t, 2H), 2.40 (m, 2H), 2.25 (s, 6H), 2.05 (m, 2H) m/z found, 451.0

[M+H]⁺

AG-0159 Not determined mass calcd. for

C₂₅H₂₇FN₄0₂, 434.21; m/z found, 435.2 [M+H]⁺

AG-0163 7.94 (s, 1H), 7.80 (d, 1H), 7.77 (d, 1H), 7.20-7.45 (m, 5H), mass calcd. for

7.11 (t, 1H), 6.75 (m, 2H), 6.46 (s, 1H), 6.04 (t, 1H), 4.01 (t, C₂₆H₃₀N₄O₂, 430.24;

2H), 3.07 (t, 2H), 2.40 (m, 2H), 2.25 (s, 6H), 2.21 (s, 3H), 2.05 m/z found, 431.1

(m, 2H) [M+H]⁺

AG-0307 (el) 7.94 (s, 1H), 7.80 (d, 1H), 7.77 (d, 1H), 7.20-7.45 (m, 5H), mass calcd. for

(m, 2H) [M+H]⁺

AG-0308 (e2) 7.94 (s, 1H), 7.80 (d, 1H), 7.77 (d, 1H), 7.20-7.45 (m, 5H), mass calcd. for

(m, 2H) [M+H]⁺

AG-0148 7.94 (s, 1H), 7.80 (d, 1H), 7.77 (d, 1H), 7.20-7.45 (m, 5H), mass calcd. for

7.11 (t, 1H), 6.75 (m, 2H), 6.46 (s, 1H), 6.04 (t, 1H), 4.01 (t, C₂₅H₂₇CIN₄0₂, 450.18;

2H), 3.07 (t, 2H), 2.40 (m, 2H), 2.25 (s, 6H), 2.21 (s, 3H), 2.05 m/z found, 451.0

(m, 2H) [M+H]⁺

AG-0309 (el) 7.94 (s, 1H), 7.80 (d, 1H), 7.77 (d, 1H), 7.20-7.45 (m, 5H), mass calcd. for

(m, 2H) [M+H]⁺

AG-0310 (e2) 7.93 (s, 1H), 7.82 (d, 1H), 7.75 (d, 1H), 7.10-7.45 (m, 6H), mass calcd. for

6.75 (d, 1H), 6.27 (s, 1H), 6.03 (t, 1H), 4.00 (t, 2H), 3.18 (t, C₂₅H₂₇CIN₄0₂, 450.18;

2H), 2.40 (m, 2H), 2.22 (s, 6H), 1.99 (m, 2H) m/z found, 451.0

[M+H]⁺

AG-0160 7.94 (s, 1H), 7.81 (m, 1H), 7.72 (d, 1H), 7.10-7.45 (m, 5H), mass calcd. for

6.83 (d, 1H), 6.75 (d, 1H), 6.59 (s, 1H), 6.00 (t, 1H), 3.98 (t, C₂₅H₂₇FN₄0₂, 434.21;

2H), 3.18 (t, 2H), 2.40 (m, 2H), 2.23 (s, 6H), 2.00 (m, 2H) m/z found, 435.1

[M+H]⁺

AG-0164 7.98 (s, 1H), 7.84 (d, 1H), 7.73 (d, 1H), 7.10-7.45 (m, 5H), mass calcd. for

7.01 (s, 1H), 6.77 (d, 1H), 6.44 (s, 1H), 6.08 (m, 1H), 4.06 (t, C₂₆H₃₀N₄O₂, 430.24;

2H), 3.19 (t, 2H), 2.46 (m, 2H), 2.22 (s, 9H), 2.08 (m, 2H) m/z found, 430.1

[M+H]⁺

AG-0387 (el) 7.98 (s, 1H), 7.84 (d, 1H), 7.73 (d, 1H), 7.10-7.45 (m, 5H), mass calcd. for

2H), 3.19 (t, 2H), 2.46 (m, 2H), 2.22 (s, 9H), 2.08 (m, 2H) m/z found, 430.1

[M+H]⁺

AG-0388 (e2) 7.98 (s, 1H), 7.84 (d, 1H), 7.73 (d, 1H), 7.10-7.45 (m, 5H), mass calcd. for

2H), 3.19 (t, 2H), 2.46 (m, 2H), 2.22 (s, 9H), 2.08 (m, 2H) m/z found, 430.1

[M+H]⁺

AG-0167 7.99-8.08 (m, 3H), 7.77 (d, 1H), 7.20-7.45 (m, 4H), 7.69 (d, mass calcd. for IH), 6.37 (s, IH), 6.06 (t, IH), 4.18 (t, 2H), 3.33 (t, 2H), 2.38 C₂5 H₂₇N₅04, 461.21; (m, 2H), 2.22 (s, 6H), 2.00 (m, 2H) m/z found, 462.0

[M+H]⁺

AG-0149 7.99 (s, 2H), 7.80 (d, IH), 7.20-7.45 (m, 5H), 7.03 (d, IH), mass calcd. for

6.91 (d, IH), 6.25 (s, IH), 6.02 (t, IH), 4.03 (t, 2H), 3.21 (t, C₂₅H₂₇CIN₄0₂, 450.18; 2H), 2.38 (m, 2H), 2.19 (s, 6H), 2.00 (m, 2H) m/z found, 451.0

[M+H]⁺

AG-0161 7.99 (s, IH), 7.81 (d, IH), 7.70 (d, IH), 7.20-7.45 (m, 4H), mass calcd. for

7.05 (t, IH), 6.75 (d, IH), 6.62 (t, IH), 6.52 (s, IH), 6.06 (t, C₂₅H₂₇FN₄0₂, 434.21; IH), 4.11 (t, 2H), 3.18 (t, 2H), 2.56 (t, 2H), 2.34 (s, 6H), 2.10 m/z found, 435.1 (m, 2H) [M+H]⁺

AG-0165 7.98 (s, IH), 7.83 (d, IH), 7.72 (d, IH), 7.20-7.45 (m, 5H), mass calcd. for

7.03 (d, IH, 6.78 (d, IH), 6.52 (s, IH), 6.03 (m, IH), 4.05 (t, C₂₆H₃₀N₄O₂, 430.24; 2H), 3.19 (t, 2H), 2.50 (m, 2H), 2.34 (s, 3H), 2.31 (s, 6H), 2.10 m/z found, 431.1 (m, 2H) [M+H]⁺

AG-0150 8.24 (s, IH), 7.95 (s, IH), 7.81 (d, IH), 7.20-7.45 (m, 6H), mass calcd. for

6.75 (d, IH), 6.44 (s, IH), 6.04 (m, IH), 4.08 (t, 2H), 3.26 (t, C₂₆H₂₇F₃N₄0₂, 484.21; 2H), 2.45 (m, 2H), 2.26 (s, 6H), 2.05 (m, 2H) m/z found, 485.1

[M+H]⁺

AG-0158 8.05 (s, IH), 7.92 (d, IH), 7.15-7.45 (m, 6H), 7.01 (t, IH), mass calcd. for

6.82 (s, IH), 6.78 (t, IH), 6.04 (m, IH), 4.20 (t, 2H), 3.05 (m, C₂₅H₂₇CIN₄0₂, 450.18; 4H), 2.70 (s, 6H), 2.50 (m, 2H) m/z found, 451.0

[M+H]⁺

AG-0162 8.00 (s, IH), 7.82 (d, IH), 7.15-7.45 (m, 6H), 7.01 (m, 2H), mass calcd. for

6.74 (d, IH), 6.04 (m, IH), 4.25 (t, 2H), 3.05 (t, 2H), 2.36 (m, C₂₅H₂₇FN₄0₂, 434.21; 2H), 2.20 (s, 6H), 2.00 (m, 2H) m/z found, 435.1

[M+H]⁺

AG-0166 7.95 (s, IH), 7.80 (d, IH), 7.15-7.45 (m, 4H), 7.00 (m, 3H), mass calcd. for

6.70 (m, 2H), 6.02 (m, IH), 4.11 (t, 2H), 3.00 (t, 2H), 2.50 (m, C₂₆H₃₀N₄O₂, 430.24; 2H), 2.31 (s, 6H), 2.24 (s, 3H), 2.05 (m, 2H) m/z found, 431.1

[M+H]⁺

AG-0075 7.95 (d, IH), 7.93 (s, IH), 7.15-7.45 (m, 4H), 6.99 (s, IH), mass calcd. for

6.75 (d, IH), 6.40 (s, IH), 6.04 (m, IH), 4.00 (t, 2H), 3.13 (t, C₂₆H₂₉CIN₄0₂, 464.20; 2H), 2.40 (m, 2H), 2.30 (s, 3H), 2.27 (s, 6H), 2.24 (s, 3H), 2.05 m/z found, 465.1 (m, 2H) [M+H]⁺

AG-0168 8.07 (s, IH), 7.96 (dd, IH), 7.60 (d, IH), 7.15-7.45 (m, 4H), mass calcd. for

6.90 (d, IH), 6.74 (d, IH), 6.04 (m, IH), 4.11 (t, 2H), 3.08 (t, C₂₆H₂₉FN₄0₂, 448.23; 2H), 2.95 (t, 2H), 2.58 (s, 6H), 2.35 (m, 2H), 2.20 (s, 3H) m/z found, 449.1

[M+H]⁺

AG-0151 8.06 (s, IH), 8.00 (s, IH), 7.80 (d, IH), 7.15-7.45 (m, 4H), mass calcd. for

6.85 (m, 2H), 6.06 (m, IH), 4.10 (t, 2H), 3.18 (t, 2H), 2.60 (m, C₂₅H₂₆CI₂N₄0₂, 484.14; 2H), 2.38 (s, 6H), 2.20 (m, 2H) m/z found, 485.0

[M+H]⁺ Table 6

Rio Rl2 Rl3 M 5-HTT 5-HT_2c NAT DAT 5-HT_2a S.

An.(IC50) Ex.

AG-0070 H CF₃ OMe H H 62% - - - - 2

AG-0071 H CF₃ Me H H 450 2.8 485 - - 2

AG-0072 H CI Me H H 241 4.2 >537 - 835 2

AG-0145 (el) H CI Me H H 50 219 57% - 2701 2

AG-0146 (e2) H CI Me H H 52 2.3 76% - 99 2

AG-0073 H H H H H 141 - - - 9271 2

AG-0074 Me H H H H 42% - - - - 2

Table 6a

^-NM (CDCI₃, in ppm) MS (ESI)

AG-0070 7.93 (s, IH), 7.62 (dd, IH), 7.15-7.45 (m, 7H), 6.82 (d, mass calcd. for

IH), 6.64 (d, IH), 5.95 (m, IH), 3.80 (s, H), 2.40 (m, C25H27F3N4O3, 2H), 2.20 (s, 6H), 2.10 (m, 2H) 488.20; m/z found,

489.3 [M+H]⁺

AG-0071 7.92 (s, IH), 7.68 (s, IH), 7.60 (dd, IH), 7.52 (m, 2H), mass calcd. for

7.15-7.45 (m, 4H), 7.05 (d, IH), 6.61 (d, IH), 5.95 (m, C₂₅H₂₇F3N₄0₂, IH), 2.40 (m, 5H), 2.20 (s, 6H), 2.10 (m, 2H) 472.21; m/z found,

473.3 [M+H]⁺

AG-0072 7.96 (s, IH), 7.82 (d, IH), 7.60 (dd, IH), 7.40 (s, IH), mass calcd. for

7.15-7.35 (m, 5H), 7.02 (m, IH), 6.61 (d, IH), 5.94 (m, C24H27CI N4O2, IH), 2.40 (m, H), 2.22 (s, 6H), 2.20 (s, 3H), 2.10 (m, 2H) 438.18; m/z found,

439.1 [M+H]⁺

AG-0145 (el) 7.96 (s, IH), 7.82 (d, IH), 7.60 (dd, IH), 7.40 (s, IH), mass calcd. for

439.1 [M+H]⁺

AG-0146 (e2) 7.96 (s, IH), 7.82 (d, IH), 7.60 (dd, IH), 7.40 (s, IH), mass calcd. for

439.1 [M+H]⁺

AG-0073 7.94 (s, IH), 7.60 (dd, IH), 7.15-7.45 (m, 9H), 7.00 (m, mass calcd. for

IH), 6.63 (d, IH), 5.97 (m, IH), 2.40 (m, H), 2.22 (s, C23H26N4O2, 390.21; 6H), 2.10 (m, 2H) m/z found,

391.1 [M+H]⁺

AG-0074 7.78 (s, IH), 7.15-7.55 (m, 9H), 7.00 (m, IH), 6.66 (d, mass calcd. for

IH), 5.97 (m,2H), 3.30 (s, 3H), 2.40 (m, H), 2.21 (s, 6H), C24H28N4O2, 404.22; 2.10 (m, 2H) m/z found,

405.2 [M+H]⁺

Table 7

L M Rii Rl2 5-HTT 5-HT_2c NAT DAT 5-HT_2a S.

An.(IC50) Ex.

AG-0066 CH₂ CH₂ H H 56 68 - - 6105 2

AG-0067 CHMe CH₂ H H 52 55 - - 8545 2

AG-0068 CH₂ CHMe H H 58 67 - - 5266 2

AG-0143 (+) CH₂ CHMe H H 31 519 - 504 1514 2

AG-0144 (-) CH₂ CHMe H H 34 44 - 310 5309 2

AG-0186 (+1) CH₂ CHMe H H 41 836 1480 2436 4804 2

AG-0187 (+2) CH₂ CHMe H H 52 5807 1670 2872 3242 2

AG-0188 (-1) CH₂ CHMe H H 48 45 2260 350 4960 2

AG-0189 (-2) CH₂ CHMe H H 105 625 1150 188 >10000 2

AG-0152 CH₂ CHMe CI Me 229 22 - - 2409 2

AG-0153 CH₂ CHC₂H₄OH H H 229 3724 - - >10000 2

Table 7a

¹H-NMR (CDCI3, in ppm) MS (ESI)

AG-0066 8.00 (s, IH), 7.84 (m, 2H), 7.15-7.45 (m, 6H), 6.98 (t, IH), 6.78 mass calcd. for

(d, IH), 6.38 (s, IH), 6.02 (m, IH), 4.07 (t, 2H), 3.21 (t, 2H), C₂₅H₂₈N₄0₂, 416.22; 2.50 (m, 2H), 2.31 (s, 6H), 2.15 (m, 2H) m/z found,

417.1 [M+H]⁺

AG -0067 7.97 (s, IH), 7.80 (d, IH), 7.60 (t, IH), 7.15-7.45 (m, 6H), 6.98 mass calcd. for

(t, IH), 6.78 (d, IH), 6.43 (s, IH), 6.02 (m, IH), 4.55 (m, IH), C₂₆H₃₀N₄O₂, 430.24; 3.40 (m, IH), 2.62 (d, IH), 2.40 (m, 2H), 2.21 (s, 6H), 2.14 (m, m/z found, 2H), 1.38 (d, 3H) 431.1 [M+H]⁺

AG-0068 7.97 (s, IH), 7.80 (m, 2H), 7.15-7.45 (m, 6H), 6.99 (t, IH), 6.78 mass calcd. for

(d, IH), 6.40 (s, IH), 6.05 (m, IH), 4.20 (m, IH), 3.55 (m, 2H), C₂₆H3oN₄0₂, 430.24; 2.52 (m, 2H), 2.24 (s, 6H), 2.14 (m, 2H), 1.38 (d, 3H) m/z found,

431.1 [M+H]⁺

AG-0143 (+) 7.97 (s, IH), 7.80 (m, 2H), 7.15-7.45 (m, 6H), 6.99 (t, IH), 6.78 mass calcd. for

(d, IH), 6.40 (s, IH), 6.05 (m, IH), 4.20 (m, IH), 3.55 (m, 2H), C₂₆H₃oN₄0₂, 430.24; 2.52 (m, 2H), 2.24 (s, 6H), 2.14 (m, 2H), 1.38 (d, 3H) m/z found,

431.1 [M+H]⁺

AG-0144 (-) 7.97 (s, IH), 7.80 (m, 2H), 7.15-7.45 (m, 6H), 6.99 (t, IH), 6.78 mass calcd. for

(d, IH), 6.40 (s, IH), 6.05 (m, IH), 4.20 (m, IH), 3.55 (m, 2H), C₂₆H₃₀N₄O₂, 430.24; 2.52 (m, 2H), 2.24 (s, 6H), 2.14 (m, 2H), 1.38 (d, 3H) m/z found,

431.1 [M+H]⁺

AG-0186 (+1) 7.97 (s, IH), 7.80 (m, 2H), 7.15-7.45 (m, 6H), 6.99 (t, IH), 6.78 mass calcd. for

431.1 [M+H]⁺

AG-0187 (+2) 7.97 (s, IH), 7.80 (m, 2H), 7.15-7.45 (m, 6H), 6.99 (t, IH), 6.78 mass calcd. for

431.1 [M+H]⁺

AG-0188 (-1) 7.97 (s, IH), 7.80 (m, 2H), 7.15-7.45 (m, 6H), 6.99 (t, IH), 6.78 mass calcd. for

431.1 [M+H]⁺

AG-0189 (-2) 7.97 (s, IH), 7.80 (m, 2H), 7.15-7.45 (m, 6H), 6.99 (t, IH), 6.78 mass calcd. for

431.1 [M+H]⁺

AG-0152 7.98 (m, 2H), 7.82 (d,l H), 7.15-7.45 (m, 6H), 6.99 (s, IH), 6.78 mass calcd. for

(d, IH), 6.20 (s, IH), 6.05 (m, IH), 4.20 (t, IH), 3.55 (m, 2H), C₂₇H₃₁CIN₄0₂, 2.40 (m, 2H), 2.21 (s, 6H), 2.14 (m, 2H), 1.38 (d, 3H) 478.21; m/z found,

479.0 [M+H]⁺

AG-0153 7.98 (m, 2H), 7.82 (m,2 H), 7.15-7.45 (m, 6H), 6.98 (t, IH), 6.79 mass calcd. for

(d, IH), 6.32 (s, IH), 6.03 (m, IH), 4.20 (t, IH), 3.80 (m, 2H), C₂₇H₃₂N₄0₃, 460.25; 3.60 (m, IH), 2.40 (d, 2H), 2.20 (s, 6H), 1.80-2.38 (m, 6H) m/z found,

461.1 [M+H]⁺ Table 8

Ri Rl2 l3 5-HTT 5-HT_2c NAT DAT 5-HT_2a S.

An.(IC50) Ex.

AG-0148 Ph CI H 26 24 - 272 935 2

AG-0164 Ph Me H 38 5 - 34 6979 2

AG-0312 4-F phenyl CI H 44 32 - - 2655 2

AG-0313 4-F phenyl Me H 42 7 2011 29 4832 2

AG-0319 pyridine-2-yl CI H >522 6 - - 6893 2

AG-0316 thiophen-3-yl CI H 53 6 518 42 828 2

AG-0328 pyridine-2-yl Me H >522 6 - - - 2

AG-0329 thiophen-3-yl Me H 28 7 1657 45 - 2

AG-0409 (el) thiophen-3-yl Me H 52 4 - - - 2

AG-0410 (e2) thiophen-3-yl Me H 34 436 - - - 2

AG-0334 pyridine-2-yl H CI >522 7 - - - 2

Table 8a

¹H-N M (CDCI₃, in ppm) MS (ESI)

AG-0312 7.98 (s, IH), 7.80 (t, 2H), 7.77 (d, IH), 7.00-7.45 (m, 5H), mass calcd. for

6.87 (d, IH), 6.36 (s, IH), 6.04 (t, IH), 4.03 (t, 2H), 3.20 (t, C₂₅H₂₆CI FN₄0₂,

2H), 2.50 (m, 2H), 2.36 (s, 6H), 2.10 (m, 2H) 468.17; m/z found,

469.0 [M+H]⁺

AG-0313 7.98 (s, IH), 7.80 (d, IH), 7.75 (d, IH), 7.00-7.45 (m, 5H), mass calcd. for

6.88 (d, IH), 6.35 (s, IH), 6.04 (t, IH), 4.02 (t, 2H), 3.20 (t, C₂₆H₂₉FN₄0₂,

2H), 2.40 (m, 2H), 2.30 (s, 3H), 2.21 (s, 6H), 2.10 (m, 2H) 448.23; m/z found,

449.1 [M+H]⁺

AG-0319 8.56 (s, IH), 7.93 (s, IH), 7.81 (m, 2H), 7.60 (t, IH), 7.39 mass calcd. for

(d, IH), 7.16 (m, 2H), 6.90 (d, IH), 6.55 (d, IH), 6.08 (t, C₂₄H₂₆CI N₅0₂,

IH), 4.05 (t, 2H), 3.21 (t, 2H), 2.47 (m, 2H), 2.23 (s, 6H), 451.18; m/z found,

2.15 (m, 2H) 452.1 [M+H]⁺

AG-0316 8.01 (s, IH), 7.81 (m, 2H), 7.00-7.30 (m, 3H), 6.79 (d, IH), mass calcd. for

6.22 (m, 2H), 4.07 (t, 2H), 3.23 (t, 2H), 2.40 (m, 2H), 2.23 C₂₄H₂₆CIN₅0₂,

(s, 6H), 2.15 (m, 2H) 456.14; m/z found,

457.1 [M+H]⁺

AG-0328 8.60 (s, IH), 7.95 (s, IH), 7.90 (d, IH), 7.71 (d, IH), 7.62 mass calcd. for

(t, IH), 7.40 (d, IH), 7.18 (t, IH), 7.00 (m, 2H), 6.83 (d, C₂₅H₂gN₅0₂, 431.23;

IH), 6.38 (d, IH), 6.06 (t, IH), 4.05 (t, 2H), 3.21 (t, 2H), m/z found,

2.47 (m, 2H), 2.23 (s, 6H), 2.15 (m, 2H) 432.1 [M+H]⁺

AG-0329 8.02 (s, IH), 7,82 (d, IH), 7.73 (d, IH), 7.10 (m, IH), 7.01 mass calcd. for

(m, 2H), 6.76 (d, IH), 6.56 (s, IH), 6.22 (m, 2H), 4.04 (t, C₂₄H₂₈N₄0₂S,

2H), 3.21 (t, 2H), 2.65 (m, 2H), 2.40 (s, 6H), 2.15 (m, 5H) 436.19; m/z found,

437.1 [M+H]⁺

AG-0409 (el) 8.02 (s, IH), 7.82 (d, IH), 7.73 (d, IH), 7.10 (m, IH), 7.01 mass calcd. for

2H), 3.21 (t, 2H), 2.65 (m, 2H), 2.40 (s, 6H), 2.15 (m, 5H) 436.19; m/z found,

437.1 [M+H]⁺

AG-0410 (e2) 8.02 (s, IH), 7.82 (d, IH), 7.73 (d, IH), 7.10 (m, IH), 7.01 mass calcd. for

2H), 3.21 (t, 2H), 2.65 (m, 2H), 2.40 (s, 6H), 2.15 (m, 5H) 436.19; m/z found,

437.1 [M+H]⁺

AG-0334 8.60 (s, IH), 7.96 (s, IH), 7.81 (m, 2H), 7.61 (t, IH), 7.38 mass calcd. for

(d, IH), 7.16 (m, 2H), 6.92 (d, IH), 6.88 (d, IH), 6.50 (s, C₂₄H₂₆CI N₅0₂,

IH), 6.04 (t, IH), 4.06 (t, 2H), 3.22 (t, 2H), 2.42 (m, 2H), 451.18; m/z found,

2.23 (s, 6H), 2.15 (m, 2H) 452.1 [M+H]⁺ Table 9

ii R₁₂ 5-HTT 5-HT_2c NAT DAT 5-HT_2a S.

An.(IC50) Ex.

AG-0176 CF₃ OMe 394 4.3 - - 5368 7

AG-0332 H Me 30 75 551 347 - 7

AG-0333 H CI 28 81 - - - 7

AG-0385 (el) H CI 147 51 - - - 7

AG-0386 (e2) H CI 31 578 - - - 7

Table 9a

¹H-N M (CDCI₃, in ppm) MS (ESI)

AG-0176 8.42 (s, IH), 7.91 (s, IH), 7.53 (d, IH), 7.40 (m, 2H), mass calcd. for

7.00-7.30 (m, 3H), 6.82 (s, IH), 6.78 (d, IH), 6.07 (m, C28H30F3N3O3, IH), 4.11 (t, 2H), 3.60 (s, IH), 3.20 (t, 2H), 2.40 (m, 513.22; m/z found, 2H), 2.21 (s, 6H), 2.12 (m, 2H) 514.1 [M+H]⁺

AG-0332 8.10 (d, IH), 7.98 (s, IH), 7.60 (d, IH), 7.40 (m, 2H), mass calcd. for

7.00-7.30 (m, 3H), 7.00 (s, 2H), 6.80 (d, IH), 6.08 (m, C₂₇H₃i ₃0₂, 429.24; IH), 4.05 (t, 2H), 3.62 (s, IH), 3.18 (t, 2H), 2.44 (m, m/z found, 2H), 2.28 (s, 3H), 2.25 (s, 6H), 2.10 (m, 2H) 430.1 [M+H]⁺

AG-0333 8.08 (d, IH), 7.98 (s, IH), 7.59 (d, IH), 7.40 (m, 2H), mass calcd. for

7.00-7.30 (m, 3H), 6.98 (s, 2H), 6.79 (d, IH), 6.12 (m, C₂₆H₂₈CI N₃0₂, IH), 4.08 (t, 2H), 3.62 (s, IH), 3.19 (t, 2H), 2.40 (m, 449.19; m/z found, 2H), 2.25 (s, 6H), 2.10 (m, 2H) 450.0 [M+H]⁺

AG-0385 (el) 8.08 (d, IH), 7.98 (s, IH), 7.59 (d, IH), 7.40 (m, 2H), mass calcd. for

AG-0386 (e2) 8.08 (d, IH), 7.98 (s, IH), 7.59 (d, IH), 7.40 (m, 2H), mass calcd. for

Table 10

Ri R₁₂ Rii 5-HTT 5-HT_2c NAT DAT 5-HT_2a S.

An.(IC50) Ex.

AG-0044 Ph OMe CF₃ 142 5 - - 234 3

AG-0119 (+) Ph OMe CF₃ 25 63 52% 3310 5865 3

AG-0120 (-) Ph OMe CF₃ 93 1 85% 274 32 3

AG-0121 (+) Ph Me CI 13 208 73% 4980 4595 3

AG-0122 (-) Ph Me CI 267 6 29% 1510 - 3

AG-0133 4-F phenyl OMe CF₃ 198 5 23% 2740 95 3

AG-0292 (el) 4-F phenyl OMe CF₃ 437 6 - - 515 3

AG-0293 (e2) 4-F phenyl OMe CF₃ 148 54 - - 1499 3

AG-0139 4-F phenyl Me CI 35 6 51% 3490 7053 3

AG-0140 4-0 Me OMe CF₃ 177 9 11% 2810 5562 3

AG-0141 4-0 Me Me CI 181 18 2270 4524 5952 3

AG-0288 thiophenyl-2-yl OMe CF₃ 214 4 - - 1798 3

AG-0289 pyridin-3-yl OMe CF₃ 81 5 > 5264 - >10000 3

Table 10a

¹H-N M (CDCI₃, in ppm) MS (ESI)

AG-0044 8.54 (s, 2H), 8.18 (s, 2H), 7.45-7.17 (m, 5H), 6.98 (br. s, mass calcd. for

IH), 6.84 (s, IH), 6.08 (m, IH), 4.04 (t, 2H), 3.86 (m, 3H), C26H28F3N₅O3, 3.25 (t, 2H), 2.40 (m, 2H), 2.21 (s, 6H), 2.10 (m, 2H) 515.21; m/z found,

516.2 [M+H]⁺.

AG-0119 (+) 8.54 (s, 2H), 8.18 (s, 2H), 7.45-7.17 (m, 5H), 6.98 (br. s, mass calcd. for

516.2 [M+H]⁺.

AG-0120 (-) 8.54 (s, 2H), 8.18 (s, 2H), 7.45-7.17 (m, 5H), 6.98 (br. s, mass calcd. for

515.9 [M+H]⁺.

AG-0121 (+) 8.52 (s, 2H), 7.90 (s, IH), 7.47-7.40 (m, 2H), 7.38-7.20 mass calcd. for

(m, 3H), 6.98 (s, IH), 6.27 (br. s, IH), 6.04 (m, IH), 4.02 C_2SH28CI N₅02, (t, 2H), 3.18 (t, 2H), 2.30 (m, 2H), 2.29 (s, 3H), 2.21 (s, 465.19; m/z found, 6H), 2.10 (m, 2H) 466.1 [M+H]⁺.

AG-0122 (-) 8.52 (s, 2H), 7.90 (s, IH), 7.47-7.40 (m, 2H), 7.38-7.20 mass calcd. for

(m, 3H), 6.98 (s, IH), 6.27 (br. s, IH), 6.04 (m, IH), 4.02 C_2SH28CI N₅0₂, (t, 2H), 3.18 (t, 2H), 2.30 (m, 2H), 2.29 (s, 3H), 2.21 (s, 465.19; m/z found, 6H), 2.10 (m, 2H) 466.3 [M+H]⁺.

AG-0133 8.51 (s, 2H), 8.15 (s, IH), 7.42-7.37 (m, 2H), 6.99-6.94 (t, mass calcd. for

2H), 6.83 (s, IH), 6.62 (br. s, IH), 6.02 (m, IH), 4.06 (t, C₂₆H₂₇F_{4 5}03, 533.2; 2H), 3.83 (s, 3H), 3.23 (m, 2H), 2.28 (m, 2H), 2.20 (s, 6H), m/z found, 533.9 2.10 (m, 2H) [M+H]⁺.

AG-0292 (el) 8.51 (s, 2H), 8.15 (s, IH), 7.42-7.37 (m, 2H), 6.99-6.94 (t, mass calcd. for

2H), 6.83 (s, IH), 6.62 (br. s, IH), 6.02 (m, IH), 4.06 (t, C₂₆H₂₇F₄N₅03, 533.2; 2H), 3.83 (s, 3H), 3.23 (m, 2H), 2.28 (m, 2H), 2.20 (s, 6H), m/z found, 533.9 2.10 (m, 2H) [M+H]⁺.

AG-0293 (e2) 8.51 (s, 2H), 8.15 (s, IH), 7.42-7.37 (m, 2H), 6.99-6.94 (t, mass calcd. for

AG-0139 8.53 (s, 2H), 7.90 (s, IH), 7.43-7.38 (m, 2H), 7.00-6.97 mass calcd. for

(m, 3H), 6.59 (br. s, IH), 6.03 (m, IH), 4.04 (t, 2H), 3.14 C₂₅H27CI FN₅02, (t, 2H), 2.43-2.30 (m, 2H), 2.27 (s, 3H), 2.24 (s, 6H), 2.12 483.18; m/z found, (m, 2H) 484.2 [M+H]⁺

AG-0140 8.53 (s, 2H), 8.17 (s, IH), 7.39 (dd, 2H), 6.87-6.82 (m, mass calcd. for 3H), 6.16 (br. s, IH), 6.02 (m, IH), 4.03 (t, 2H), 3.86 (s, C27H30F3N5O4, 3H), 3.77 (s, 3H), 3.29 (m, 2H), 2.36 (m, 2H), 2.21 (s, 6H), 545.22; m/z found, 2.12 (m, 2H) 546.2 [M+H]⁺

AG-0141 8.54 (s, 2H), 7.91 (s, IH), 7.39 (dd, 2H), 7.01 (s, IH), mass calcd. for

6.87-6.82 (m, 2H), 6.20 (br. s, IH), 6.03 (m, IH), 4.06 (t, C₂₆H₃oCIN₅0₃, 2H), 3.77 (s, 3H), 3.19 (t, 2H), 2.36 (m, 2H), 2.30 (s, 3H), 495.20; m/z found, 2.23 (s, 6H), 2.15 (m, 2H) 496.1 [M+H]⁺

AG-0288 8.59 (s, 2H), 8.20 (s, IH), 7.21 (d, IH), 7.17 (d, IH), 6.95 mass calcd. for

(m, IH), 6.87 (s, IH), 6.74 (s, IH), 6.40 (m, IH), 4.05 (t, C24H26F₃N₅0₃S, 2H), 3.84 (s, 3H), 3.23 (m, 2H), 2.35 (m, 2H), 2.25 (s, 6H), 521.17; m/z found, 2.10 (m, 2H) 522.1 [M+H]⁺

AG-0289 8.74 (d, IH), 8.57 (s, 2H), 8.53 (d, IH), 8.19 (s, IH), 7.82 mass calcd. for

(d, IH), 7.24 (m, IH), 6.87 (s, IH), 6.41 (s, IH), 6.15 (m, C2₅H2₇l"3N60₃, IH), 4.16 (t, 2H), 3.86 (s, 3H), 3.34 (m, 2H), 2.35 (m, 2H), 516.21; m/z found, 2.24 (s, 6H), 2.13 (m, 2H) 517.0 [M+H]⁺

Table 11

Rio Rii R₁₂ Rl3 5-HTT 5-HT_2c NAT DAT 5-HT_2a s.

An.(IC50) Ex.

AG-0214 H H H CI 48 9 - - 5090 3

AG-0215 (el) H H H CI 349 7 - - 4929 3

AG-0216 (e2) H H H CI 36 45 - - 5893 3

AG-0226 H H H Me 36 7 - - 7345 3

AG-0227 (el) H H H Me 242 5 - - 7119 3

AG-0228 (e2) H H H Me 25 581 - - >10000 3

AG-0217 H H CI H 42 2 1237 845 3226 3

AG-0218 (el) H H CI H 262 1 2559 388 1264 3

AG-0219 (e2) H H CI H 34 88 1142 2707 5393 3

AG-0229 H H Me H 25 1 2098 430 >10000 3

AG-0230 (el) H H Me H 176 3 - - 4780 3

AG-0231(e2) H H Me H 17 83 - - >10000 3

AG-0220 H CI H H 112 1 - - 743 3

AG-0221 (el) H CI H H 524 1 - - 518 3

AG-0222 (e2) H CI H H 42 9 - - 5577 3

AG-0232 H Me H H 46 1 - - 877 3

AG-0233 (el) H Me H H 475 1 - - 996 3

AG-0234 (e2) H Me H H 31 59 - - 9028 3

AG-0223 CI H H H 444 6711 - - - 3

AG-0235 e H H H 416 464 - - >10000 3

AG-0236 (el) Me H H H >552 818 - - >10000 3

AG-0237 (e2) Me H H H 344 6978 - - >10000 3 Table 11a

¹H-NMR (CDCI₃, in ppm) MS (ESI)

AG-0214 Not measured mass calcd. for

C₂₄H₂₆CIN₅0₂, 451.18; m/z found, 452.1 [M+H]⁺

AG-0215 (el) Not measured mass calcd. for

C₂₄H₂₆CIN₅0₂ 451.18; m/z found, 452.1 [M+H]⁺

AG-0216 (e2) Not measured mass calcd. for

C₂₄H₂₆CIN₅0₂, 451.18; m/z found, 452.1 [M+H]⁺

AG-0226 8.56 (s, 2H), 7.69 (d, IH), 7.41 (d, 2H), 7.36-7.20 (m, 3H), mass calcd. for

7.10 (t, IH), 6.85 (s, IH), 6.80 (d, IH), 6.03 (m, IH), 4.02 (t, C₂₅H₂₉N₅0₂, 431.23; 2H), 3.09 (t, 2H), 2.45 (m, 2H), 2.30 (s, 6H), 2.20 (s, 3H), m/z found, 432.1 2.05 (m, 2H) [M+H]⁺

AG-0227 (el) 8.56 (s, 2H), 7.69 (d, IH), 7.41 (d, 2H), 7.36-7.20 (m, 3H), mass calcd. for

AG-0228 (e2) 8.56 (s, 2H), 7.69 (d, IH), 7.41 (d, 2H), 7.36-7.20 (m, 3H), mass calcd. for

AG-0217 8.57 (s, 2H), 7.81 (d, IH), 7.41 (d, 2H), 7.36-7.20 (m, 3H), mass calcd. for

7.15 (m, 2H), 6.50 (d, IH), 6.03 (m, IH), 4.02 (t, 2H), 3.09 C₂₄H₂₆CIN₅0₂, 451.18; (t, 2H), 2.45 (m, 2H), 2.30 (s, 6H), 2.05 (m, 2H) m/z found, 452.1

[M+H]⁺

AG-0218 (el) 8.57 (s, 2H), 7.81 (d, IH), 7.41 (d, 2H), 7.36-7.20 (m, 3H), mass calcd. for

[M+H]⁺

AG-0219 (e2) 8.57 (s, 2H), 7.81 (d, IH), 7.41 (d, 2H), 7.36-7.20 (m, 3H), mass calcd. for

[M+H]⁺

AG-0229 8.55 (s, 2H), 7.65 (d, IH), 7.42 (d, 2H), 7.36-7.20 (m, 3H), mass calcd. for

7.01 (m, 2H), 6.35 (s, IH), 6.03 (m, IH), 4.00 (t, 2H), 3.18 C₂₅H₂₉N₅0₂, 431.23; (t, 2H), 2.40 (m, 2H), 2.30 (s, 3H), 2.20 (s, 6H), 2.05 (m, 2H) m/z found, 432.1

[M+H]⁺

AG-0230 (el) 8.55 (s, 2H), 7.65 (d, IH), 7.42 (d, 2H), 7.36-7.20 (m, 3H), mass calcd. for

[M+H]⁺

AG-0231(e2) 8.55 (s, 2H), 7.65 (d, IH), 7.42 (d, 2H), 7.36-7.20 (m, 3H), mass calcd. for

[M+H]⁺

AG-0220 Not measured mass calcd. for

C₂₄H₂₆CIN₅0₂, 451.18; m/z found, 452.1 [M+H]⁺

AG-0221 (el) Not measured mass calcd. for

Table 12

Ri l2 Rii 5-HTT 5-HT_2c NAT DAT 5-HT_2a S.

An.(IC50)

AG-0304 Pyridine-3-yl Me CI 40 6 3237 >4597 4466 Ex.

AG-0359 (el) Pyridine-3-yl Me CI 230 6 - - - 3

AG-0360 (e2) Pyridine-3-yl Me CI 19 51 4322 >4597 - 3

AG-0305 Pyridine-3-yl H H 38 6113 - - >10000 3

AG-0306 Pyridine-3-yl CI H 26 86 > 5264 >4597 8893 3

AG-0361 Pyridine-3-yl CI H 212 95 4248 2957 - 3

AG-0362 Pyridine-3-yl CI H 18 705 > 5264 >4597 - 3

AG-0320 Pyridine-2-yl CI H >522 6 - - >10000 3

AG-0321 Pyridine-2-yl Me H >522 6 - - >10000 3

AG-0317 Thiophen-3-yl CI H 50 8 - - 3445 3

AG-0318 Thiophen-3-yl Me H 25 7 4823 1997 5029 3

AG-0363 (el) Thiophen-3-yl Me H 18 603 >5264 >4597 - 3

AG-0364 (e2) Thiophen-3-yl Me H 254 5 >5264 1813 - 3

AG-0314 4-F phenyl CI H 67 10 - - 2308 3

AG-0315 4-F phenyl Me H 52 32 - - 5531 3 Table 12a

¹H-NM R (CDCI₃, in ppm) MS (ESI)

AG-0304 8.68 (s, IH), 8.55 (s, 2H), 8.45 (d, IH), 7.90 (s, IH), 7.79 mass calcd. for

(d, IH), 7.22 (m, IH), 6.98 (s, IH), 6.72 (s, IH), 6.03 (m, C₂₄H₂₇CIN₆0₂, 466.19;

IH), 4.01 (t, 2H), 3.13 (t, 2H), 2.40 (t, 2H), 2.30 (s, 3H), m/z found, 467.1

2.20 (s, 6H), 2.05 (m, 2H) [M+H]⁺

AG-0359 (el) 8.68 (s, IH), 8.55 (s, 2H), 8.45 (d, IH), 7.90 (s, IH), 7.79 mass calcd. for

IH), 4.01 (t, 2H), 3.13 (t, 2H), 2.40 (t, 2H), 2.30 (s, 3H), m/z found, 467.1

2.20 (s, 6H), 2.05 (m, 2H) [M+H]⁺

AG-0360 (e2) 8.68 (s, IH), 8.55 (s, 2H), 8.45 (d, IH), 7.90 (s, IH), 7.79 mass calcd. for

IH), 4.01 (t, 2H), 3.13 (t, 2H), 2.40 (t, 2H), 2.30 (s, 3H), m/z found, 467.1

2.20 (s, 6H), 2.05 (m, 2H) [M+H]⁺

AG -0305 8.72 (s, IH), 8.59 (s, 2H), 8.53 (d, IH), 7.80 (m, 2H), mass calcd. for

7.24 (m, IH), 7.20 (d, IH), 6.98 (s, IH), 6.52 (s, IH), C₂₃H₂₆N₆0₂, 418.21;

6.09 (m, IH), 4.06 (t, 2H), 3.21 (t, 2H), 2.40 (t, 2H), 2.22 m/z found, 419.1

(s, 6H), 2.05 (m, 2H) [M+H]⁺

AG-0306 8.68 (s, IH), 8.53 (s, 2H), 8.47 (d, IH), 7.80 (m, 2H), mass calcd. for

7.24 (m, IH), 7.20 (m, 2H), 6.80 (s, IH), 6.03 (m, IH), C₂₃H₂₅CIN₆0₂, 452.17;

4.04 (t, 2H), 3.20 (t, 2H), 2.38 (t, 2H), 2.20 (s, 6H), 2.05 m/z found, 453.1

(m, 2H) [M+H]⁺

AG-0361 (el) 8.68 (s, IH), 8.53 (s, 2H), 8.47 (d, IH), 7.80 (m, 2H), mass calcd. for

4.04 (t, 2H), 3.20 (t, 2H), 2.38 (t, 2H), 2.20 (s, 6H), 2.05 m/z found, 453.1

(m, 2H) [M+H]⁺

AG-0362 (e2) 8.68 (s, IH), 8.53 (s, 2H), 8.47 (d, IH), 7.80 (m, 2H), mass calcd. for

4.04 (t, 2H), 3.20 (t, 2H), 2.38 (t, 2H), 2.20 (s, 6H), 2.05 m/z found, 453.1

(m, 2H) [M+H]⁺

AG -0320 8.60 (s, 2H), 8.48 (d, IH), 7.87 (d, IH), 7.61 (t, IH), 7.41 mass calcd. for

(d, IH), 7.18 (m, 2H), 6.95 (s, IH), 6.03 (m, IH), 4.04 (t, C₂₃H₂₅CIN₆0₂, 452.17;

2H), 3.20 (t, 2H), 2.38 (t, 2H), 2.20 (s, 6H), 2.05 (m, 2H) m/z found, 453.1

[M+H]⁺

AG-0321 8.60 (s, 2H), 7.70 (d, IH), 7.62 (t, IH), 7.45 (d, IH), 7.23 mass calcd. for

(s, IH), 7.18 (m, IH), 7.01 (m, 2H), 6.38 (s, IH), 6.10 (m, C₂₄H₂₈N₆0₂, 432.17;

IH), 4.05 (t, 2H), 3.20 (t, 2H), 2.50 (t, 2H), 2.30 (s, 3H), m/z found, 433.1

2.20 (s, 6H), 2.15 (m, 2H) [M+H]⁺

AG-0317 8.60 (s, 2H), 7.88 (d, IH), 7.20-7.35 (m, 2H), 7.21 (m, mass calcd. for

3H), 6.20 (m, 2H), 4.08 (t, 2H), 3.23 (t, 2H), 2.40 (t, 2H), C₂₂H₂₄CIN₅0₂S,

2.20 (s, 6H), 2.15 (m, 2H) 457.13; m/z found,

458.1 [M+H]⁺

AG-0318 8.60 (s, 2H), 7.78 (d, IH), 7.15-7.35 (m, 3H), 7.01 (m, mass calcd. for

2H), 6.31 (s, IH), 6.21 (t, IH), 4.05 (t, 2H), 3.20 (t, 2H), C₂₃H₂₇N₅0₂S, 437.19;

2.40 (t, 2H), 2.31 (s, 3H), 2.19 (s, 6H), 2.15 (m, 2H) m/z found, 438.1

[M+H]⁺

AG-0363 (el) 8.60 (s, 2H), 7.78 (d, IH), 7.15-7.35 (m, 3H), 7.01 (m, mass calcd. for

2.40 (t, 2H), 2.31 (s, 3H), 2.19 (s, 6H), 2.15 (m, 2H) m/z found, 438.1

[M+H]⁺

AG-0364 (e2) 8.60 (s, 2H), 7.78 (d, IH), 7.15-7.35 (m, 3H), 7.01 (m, mass calcd. for

2.40 (t, 2H), 2.31 (s, 3H), 2.19 (s, 6H), 2.15 (m, 2H) m/z found, 438.1

[M+H]⁺

AG-0314 8.59 (s, 2H), 7.81 (d, IH), 7.40 (m, 2H), 7.18 (m, 2H), mass calcd. for 7.01 (t, 2H), 6.25 (d, 1H), 6.03 (t, 1H), 4.05 (t, 2H), 3.20 C₂₄H₂₅CIFN₅0₂, (t, 2H), 2.40 (t, 2H), 2.19 (s, 6H), 2.15 (m, 2H) 469.17; m/z found,

470.0 [M+H]⁺

AG-0315 8.59 (s, 2H), 7.82 (d, 1H), 7.40 (m, 2H), 7.00 (m, 4H), mass calcd. for

6.25 (s, 1H), 6.01 (t, 1H), 4.02 (t, 2H), 3.19 (t, 2H), 2.40 C₂₄H₂₅CIFN₅0₂, (t, 2H), 2.26 (s, 3H), 2.20 (s, 6H), 2.15 (m, 2H) 449.22; m/z found,

450.1 [M+H]⁺

Table 13

Ri R₁₂ Rii 5-HTT 5-HT_2c NAT DAT 5-HT_2a S.

An.(IC50) Ex.

AG-0079 phenyl OMe CF₃ 43 6 1690 457 757 6

AG-0204 (-) phenyl OMe CF₃ 45 2.5 1282 290 2998 6

AG-0205 (+) phenyl OMe CF₃ 223 39 3074 2263 4415 6

AG-0134 phenyl Me CI 40 6 297 119 - 6

AG-0206 (el) phenyl Me CI 50 5 319 29 - 6

AG-0207 (e2) phenyl Me CI 52 47 1111 189 5383 6

AG-0380 pyridin-2-yl OMe CF₃ - - >5264 - - 6

AG-0381 pyridin-3-yl OMe CF₃ 117 13 - - - 6

AG-0394 pyridin-3-yl Me CI 62 211 - - - 6

AG-0411 (+) 4-F-phenyl OMe CF₃ 141 79 - - - 6

AG-0412 (-) 4-F-phenyl OMe CF₃ 54 5.6 - - - 6

AG-0413 thiophen-3-yl OMe CF3 116 5.6 - - - 6

AG-0414 (+) 4-F-phenyl Me CI 280 449 - - - 6

AG-0415 (-) 4-F-phenyl Me CI 40 6.1 - - - 6

AG-0416 thiophen-3-yl Me CI 49 6.0 - - - 6 Table 13a

¹H-NM R (CDCI₃, in ppm) MS (ESI)

AG-0079 8.29 (m, 2H), 7.42 (m, 2H), 7.20-7.35 (m, 3H), 7.05 (d, mass calcd. for

1H), 6.90 (s, 1H), 6.21 (t, 1H), 4.15 (t, 2H), 3.89 (s, 3H), C₂₆H₂₈F₃N₅0₃, 515,21; 3.22 (t, 2H), 2.40 (m, 2H), 2.20 (s, 6H), 2.12 (m, 2H) m/z found, 516.1

[M+H]⁺

AG-0204 (-) 8.29 (m, 2H), 7.42 (m, 2H), 7.20-7.35 (m, 3H), 7.05 (d, mass calcd. for

1H), 6.90 (s, 1H), 6.21 (t, IH), 4.15 (t, 2H), 3.89 (s, 3H), C₂₆H₂₈F₃N₅0₃, 515,21; 3.22 (t, 2H), 2.40 (m, 2H), 2.20 (s, 6H), 2.12 (m, 2H) m/z found, 516.1

[M+H]⁺

AG-0205 (+) 8.29 (m, 2H), 7.42 (m, 2H), 7.20-7.35 (m, 3H), 7.05 (d, mass calcd. for

[M+H]⁺

AG-0134 8.24 (br. s, 1H), 7.98 (s, 1H), 7.40 (m, 2H), 7.20-7.35 (m, mass calcd. for

3H), 7.01 (m, 2H), 6.20 (t, 1H), 4.15 (m, 2H), 3.18 (t, 2H), C₂₅H₂₈CIN₅0₂, 465,19; 2.40 (m, 2H), 2.35 (s, 6H), 2.30 (s, 3H), 2.12 (m, 2H) m/z found, 466.1

[M+H]⁺

AG-0206 (el) 8.24 (br. s, 1H), 7.98 (s, 1H), 7.40 (m, 2H), 7.20-7.35 (m, mass calcd. for

[M+H]⁺

AG-0207 (e2) 8.24 (br. s, IH), 7.98 (s, 1H), 7.40 (m, 2H), 7.20-7.35 (m, mass calcd. for

3H), 7.01 (m, 2H), 6.20 (t, IH), 4.15 (m, 2H), 3.18 (t, 2H), C₂₅H₂₈CIN₅0₂, 465,19; 2.40 (m, 2H), 2.35 (s, 6H), 2.30 (s, 3H), 2.12 (m, 2H) m/z found, 466.1

[M+H]⁺

AG-0380 8.57 (d, IH), 8.22 (m, 2H), 7.61 (t, IH), 7.40 (d, IH), 7.20 mass calcd. for

(m, IH), 7.10 (d, IH), 6.88 (s, IH), 6.22 (t, IH), 4.20 (m, C₂₅H₂₇F₃N₆0₃, 516,21; 2H), 3.85 (s, 3H), 3.20 (t, 2H), 2.40 (m, 2H), 2.35 (s, 6H), m/z found, 517.1 2.12 (m, 2H) [M+H]⁺

AG-0381 8.70 (s, IH), 8.54 (s, IH), 8.20 (m, 2H), 7.76 (m, IH), mass calcd. for

7.22 (m, IH), 7.05 (d, IH), 6.88 (s, IH), 6.21 (t, IH), 4.15 C₂₅H₂₇F₃N₆0₃, 516,21; (m, 2H), 3.85 (s, 3H), 3.21 (t, 2H), 2.45 (m, 2H), 2.30 (s, m/z found, 517.1 6H), 2.25 (m, 2H) [M+H]⁺

AG-0394 8.70 (s, IH), 8.58 (s, IH), 8.35 (d, IH), 7.99 (s, IH), 7.77 mass calcd. for

(m, 2H), 7.25 (m, IH), 7.05 (m, 2H), 6.39 (t, IH), 4.18 (t, C₂₄H₂₇CIN₅0₂, 466.19; 2H), 3.20 (t, 2H), 2.45 (s, 3H), 2.40 (m, 2H), 2.30 (s, 6H), m/z found, 467.1 2.25 (m, 2H) [M+H]⁺

AG-0411 (+) 8.20 (s, IH), 7.40 (m, 2H), 7.01 (m, 3H), 6.88 (s, 2H), mass calcd. for

6.19 (t, IH), 4.10 (t, 2H), 3.86 (s, 3H), 3.17 (t, 2H), 2.45 C₂₆H₂₇F₄N₅0₃, 533.21; (m, 2H), 2.34 (s, 6H), 2.20 (m, 2H) m/z found, 534.1

[M+H]⁺

AG-0412 (-) 8.20 (s, IH), 7.40 (m, 2H), 7.01 (m, 3H), 6.88 (s, 2H), 6.19 mass calcd. for

(t, IH), 4.10 (t, 2H), 3.86 (s, 3H), 3.17 (t, 2H), 2.45 (m, C₂₆H₂₇F₄N_s0₃, 533.21; 2H), 2.34 (s, 6H), 2.20 (m, 2H) m/z found, 534.1

[M+H]⁺

AG-0413 8.20 (m, 2H), 7.28 (m, 2H), 7.14 (d, IH), 7.01 (d, IH), mass calcd. for

6.85 (s, IH), 6.39 (t, IH), 4.18 (t, 2H), 3.82 (s, 3H), 3.21 C₂4H₂₆F₃N₅0₃S, 521.17; (t, 2H), 2.45 (m, 2H), 2.35 (s, 6H), 2.20 (m, 2H) m/z found, 522.1

[M+H]⁺

AG-0414 (+) 8.25 (br. s, IH), 8.00 (s, IH), 7.40 (m, 2H), 6.95-7.05 (m, mass calcd. for

4H), 6.19 (t, IH), 4.05 (t, 2H), 3.10 (m, 2H), 2.45 (m, 2H), C₂₅H₂₇CIFN₅0₂, 483.18; 2.36 (s, 3H), 2.32 (s, 6H), 2.20 (m, 2H) m/z found, 484.1

[M+H]⁺

AG-0415 (-) 8.25 (br. s, IH), 8.00 (s, IH), 7.40 (m, 2H), 6.95-7.05 (m, mass calcd. for 4H), 6.19 (t, 1H), 4.05 (t, 2H), 3.10 (m, 2H), 2.45 (m, 2H), C₂₅H₂₇CIFN₅0₂, 483.18; 2.36 (s, 3H), 2.32 (s, 6H), 2.20 (m, 2H) m/z found, 484.1

[M+H]⁺

AG-0416 8.20 (br. s, 1H), 8.00 (s, 1H), 7.25 (m, 2H), 7.16 (d, 1H), mass calcd. for

7.01 (m, 2H), 6.40 (t, 1H), 4.17 (m, 2H), 3.17 (t, 2H), 2.45 C₂₃H₂₆CIN₅0₂S, 471.15; (m, 2H), 2.35 (s, 6H), 2.31 (s, 3H), 2.20 (m, 2H) m/z found, 472.1

[M+H]⁺

Table 14

Rio ii Rl2 Rl3 5-HTT 5-HT_2c NAT DAT 5-HT_2a S.

An.(IC50) Ex.

AG-0178 H H H H 233 4229 1560 330 >10000 6

AG-0260 H H H CI 329 732 - - >10000 6

AG-0272 H H H Me - - - - 6

AG-0273 (el) H H H Me 291 570 - - >10000 6

AG-0274 (e2) H H H Me 316 7051 - - >10000 6

AG-0263 H H CI H 172 81 - - 5987 (5274) 6

AG-0264 (el) H H CI H 175 55 - - 4228 6

AG-0265 (e2) H H CI H 142 706 - - 5768 6

AG-0275 H H Me H 215 57 - - >10000 6

AG-0276 (el) H H Me H 195 45 - - 9813 6

AG-0277 (e2) H H Me H 191 835 - - >10000 6

AG-0266 H CI H H 123 60 - - 5399 6

AG-0267 (el) H CI H H 635 47 - - 4207 6

AG-0268 (e2) H CI H H 207 2749 - - 5606 6

AG-0278 H Me H H 324 219 - - 8131 6

AG-0279 (el) H Me H H 198 69 - - 7987 6

AG-0280 (e2) H Me H H 182 2402 - - >10000 6

AG-0079 H CF₃ OMe H 43 6 1690 457 757 6

AG-0204 (el) H CF₃ OMe H 45 2.5 1282 290 2998 6

AG-0205 (e2) H CF₃ OMe H 223 38.5 3074 2263 4415 6

AG-0134 H CI Me H 40 6 297 119 6

AG-0206 (el) H CI Me H 50 5 319 29 624 6

AG-0207 (e2) H CI Me H 52 47 1111 189 5383 6 AG-0391 (-) H F Me H 151 7 - - - 6

AG-0392 (-) H CF₃ Me H 308 34 - - - 6

AG-0396 (-) H CI CI H 50 6 - - - 6

AG-0397 (-) H CI F H 83 44 - - - 6

AG-0398 (-) H CI OMe H 8 5 - - - 6

AG-0399 (-) H CF₃ CI H - - 199 - - 6

AG-0400 (-) H CF₃ CN H 49 21 - - - 6

Tabel 14a

¹H-NM R (CDCI₃, in ppm) MS (ESI)

AG-0178 8.35 (d, 1H), 7.95 (d, 1H), 7.75 (bs, 1H), 6.95- mass calcd. for C24H27N5O2,

7.42 (m, 8H), 6.25 (t, 1H), 4.16 (m, 2H), 3.20 (t, 417.22; m/z found, 418.1 2H), 2.60 (m, 2H), 2.40 (s, 6H), 2.20 (m, 2H) [M+H]⁺

AG-0260 8.35 (bs, 1H), 7.95 (d, 1H), 7.40 (d,2H), 7.20- mass calcd. for C24H26CIN5O2,

7.38 (m, 3H), 7.19 (t, 1H), 7.04 (d, 1H), 6.99 (d, 451.18; m/z found, 452.0 1H), 6.20 (t, 1H), 4.16 (m, 2H), 3.20 (t, 2H), [M+H]⁺

2.60 (m, 2H), 2.40 (s, 6H), 2.20 (m, 2H)

AG-0272 Not measured mass calcd. for C25H29N5O2,

431.23; m/z found, 432.1 [M+H]⁺

AG-0273 (el) Not measured mass calcd. for C24H26N5O2,

431.23; m/z found, 432.1 [M+H]⁺

AG-0274 (e2) Not measured mass calcd. for C24H26N5O2,

431.23; m/z found, 432.1 [M+H]⁺

AG-0263 Not measured mass calcd. for C24H26CIN5O2,

451.18; m/z found, 452.0 [M+H]⁺

AG-0264 (el) Not measured mass calcd. for C24H26CIN5O2,

451.18; m/z found, 452.0 [M+H]⁺

AG-0265 (e2) Not measured mass calcd. for C24H26CIN5O2,

451.18; m/z found, 452.0 [M+H]⁺

AG-0275 8.35 (d, 1H), 7.78 (d, 2H), 7.40 (d,2H), 7.20- mass calcd. for C25H29N5O2,

7.38 (m, 3H), 7.01 (m, 2H), , 6.20 (t, 1H), 4.06 431.23; m/z found, 432.1 (m, 2H), 3.18 (t, 2H), 2.45 (m, 2H), 2.30 (s, 9H), [M+H]⁺

2.20 (m, 2H)

AG-0276 (el) Not measured mass calcd. for C25H29 5O2,

431.23; m/z found, 432.1 [M+H]⁺

AG-0277 (e2) Not measured mass calcd. for C25H29N5O2,

431.23; m/z found, 432.1 [M+H]⁺

AG-0266 Not measured mass calcd. for C24H26CIN5O2,

451.18; m/z found, 452.0 [M+H]⁺

AG-0267 (el) Not measured mass calcd. for C24H26CIN5O2,

451.18; m/z found, 452.0 [M+H]⁺

AG-0268 (e2) Not measured mass calcd. for C24H26CIN5O2,

451.18; m/z found, 452.0 [M+H]⁺

AG-0278 8.35 (d, 1H), 7.90 (bs, 1H), 7.78 (s, 1H), 7.40 mass calcd. for C25H29N5O2,

(d,2H), 7.20-7.38 (m, 3H), 7.01 (m, 2H), 6.80 431.23; m/z found, 432.1 (d, 1H), 6.20 (t, 1H), 4.06 (m, 2H), 3.17 (t, 2H), [M+H]⁺

2.45 (m, 2H), 2.30 (s, 3H), 2.28 (s, 6H), 2.20 (m,

2H)

AG-0279 (el) Not measured mass calcd. for C25H29N5O2,

431.23; m/z found, 432.1 [M+H]⁺

AG-0280 (e2) Not measured mass calcd. for C25H29N5O2, 431.23; m/z found, 432.1

[M+H]⁺

AG-0206 (el) 8.24 (s, IH), 7.99 (bs,2H), 7.40 (d,2H), 7.20- mass calcd. for C25H28CIN5O2,

7.38 (m, 3H), 7.01 (m, 2H), 6.19 (t, IH), 4.02 465.19; m/z found, 466.1 (m, 2H), 3.09 (t, 2H), 2.45 (m, 2H), 2.30 (s, 3H), [M+H]⁺

2.24 (s, 6H), 2.15 (m, 2H)

AG-0207 (e2) 8.24 (s, IH), 7.99 (bs,2H), 7.40 (d,2H), 7.20- mass calcd. for C25H28CIN5O2,

7.38 (m, 3H), 7.01 (m, 2H), 6.19 (t, IH), 4.02 465.19; m/z found, 466.1 (m, 2H), 3.09 (t, 2H), 2.45 (m, 2H), 2.30 (s, 3H), [M+Hf

2.24 (s, 6H), 2.15 (m, 2H)

AG-0391 (-) 8.31 (d, IH), 7.80 (bs,lH), 7.62 (d, IH), 7.20- mass calcd. for C₂5H₂gCIN₅02,

7.34 (m, 5H), 7.01 (d, IH), 6.98 (d, IH), 6.23 449.22; m/z found, 450.1 (t, IH), 4.12 (m, 2H), 3.19 (t, 2H), 2.85 (m, 2H), [M+H]⁺

2.60 (bs, 6H), 2.25 (m, 2H), 2.20 (s, 3H)

AG-0392 (-) 8.35 (bs, IH), 8.22 (s, IH), 7.80 (bs,lH), 7.20- mass calcd. for C26H28F3N5O2,

7.34 (m, 5H), 7.01 (m, 2H), 6.36 (t, IH), 4.20 499.22; m/z found, 500.1 (m, 2H), 3.20 (m, 4H), 2.85 (bs, 6H), 2.60 (m, [M+H]⁺

2H), 2.40 (s, 3H)

AG-0396 (-) 8.20 (bs, IH), 8.03 (d, IH), 7.20-7.39 (m, 5H), mass calcd. for C24H25CI2N5O2,

7.01 (d, IH), 6.97 (d, IH), 6.20 (t, IH), 4.05 (m, 485.14; m/z found, 486.0 2H), 3.05 (m, 2H), 2.59 (m, 2H), 2.40 (s, 6H), [M+H]⁺

2.25 (m, 2H)

AG-0397 (-) 8.20 (bs, IH), 8.19 (s, IH), 7.20-7.39 (m, 6H), mass calcd. for C24H25CIFN5O2,

7.01 (d, IH), 6.36 (t, IH), 4.05 (m, 2H), 3.00 469.17; m/z found, 470.1 (m, 2H), 2.45 (m, 2H), 2.31 (s, 6H), 2.18 (m, [M+H]⁺

2H)

AG-0398 (-) 8.20 (bs, IH), 8.01 (s, IH), 7.20-7.39 (m, 5H), mass calcd. for C24H28CI 5O3,

7.00 (d, IH), 6.80 (s, IH), 6.21 (t, IH), 4.12 (m, 481.18; m/z found, 482.2 2H), 3.85 (s, 3H), 3.20 (m, 2H), 2.80 (m, 2H), [M+H]⁺

2.52 (s, 6H), 2.38 (m, 2H)

AG-0399 (-) 8.50 (bs, IH), 8.40 (s, IH), 8.20 (s, IH), 7.20- mass calcd. for C25H25CIF3N5O2,

7.39 (m, 5H), 7.00 (d, IH), 6.20 (t, IH), 4.18 519.16; m/z found, 520.2 (m, 2H), 3.08 (m, 2H), 2.60 (m, 2H), 2.35 (s, [M+H]⁺

6H), 2.18 (m, 2H)

AG-0400 (-) 8.48 (s, IH), 8.05 (bs, IH), 7.58 (s, IH), 7.20- mass calcd. for C₂6H25F₃N₅02,

7.39 (m, 5H), 7.05 (d, IH), 6.28 (t, IH), 4.20 510.20; m/z found, 511.2 (m, 2H), 3.06 (m, 2H), 2.55 (m, 2H), 2.38 (s, [M+H]⁺

6H), 2.20 (m, 2H)

Table 15

ii Rl2 5-HTT 5-HT_2c NAT DAT 5-HT_2a Synth.

An.(IC50) Example

AG-0291 CF₃ OMe 394 4 1618 383 - 6

AG-0351 H CI 38 57 421 83 - 6

AG-0352 H Me 25 48 2035 43 - 6

AG-0368 CI Me 245 8 >5264 - - 6

Table 15a

¹H-NMR (CDCI₃, in ppm) MS (ESI)

AG-0291 8.80 (s, IH), 8.20 (s, IH), 7.81 (s, IH), 7.20-7.45 (m, 5H), 6.90 mass calcd. for

(s, IH), 6.82 (s, IH), 6.03 (t, IH), 4.05 (t, 2H), 3.20 (m, 2H), C₂₆H_ZBF₃N₅03, 515.21; 2.40 (m, 2H), 2.25 (s, 6H), 2.15 (m, 2H) m/z found, 516.2

[M+H]⁺

AG-0351 8.82 (s, IH), 7.97 (s, IH), 7.95 (s, IH), 7.20-7.45 (m, 7H), 6.96 mass calcd. for

(s, IH), 6.06 (t, IH), 4.10 (t, 2H), 3.24 (m, 2H), 2.50 (m, 2H), C₂₄H₂₆CIN₅0₂, 451.18; 2.35 (s, 6H), 2.15 (m, 2H) m/z found, 452.1

[M+H]⁺

AG-0352 8.83 (s, IH), 7.97 (s, IH), 7.80 (d, IH), 7.20-7.45 (m, 6H), 7.01 mass calcd. for

(m, 2H), 6.04 (t, IH), 4.08 (t, 2H), 3.20 (m, 2H), 2.50 (m, 2H), C₂₅H₂₉N₅0₂, 431.23; 2.38 (s, 9H), 2.20 (m, 2H) m/z found, 432.2

[M+H]⁺

AG-0368 8.83 (s, IH), 8.00 (s, IH), 7.91 (s, IH), 7.20-7.45 (m, 5H), 7.01 mass calcd. for

(s, IH), 6.96 (s, IH), 6.04 (t, IH), 4.04 (t, 2H), 3.20 (m, 2H), C₂₅H₂₈CIN₅0₂, 465.19; 2.46 (m, 2H), 2.36 (s, 6H), 2.20 (m, 2H) m/z found, 466.1

[M+H]⁺

Table 16

Table 16a

'H-NM R (CDCI3, in ppm) MS (ESI)

AG-0378 8.58 (s, IH), 8.20 (s, IH), 7.81 (d, IH), 7.20-7.45 (m, 5H), 7.08 mass calcd. for

(s, IH), 7.02 (d, IH), 6.82 (s, IH), 4.92 (t, IH), 4.20 (t, 2H), C₂₇H₂₉F₃N₄0₂S, 3.83 (s, 3H), 3.26 (m, 2H), 2.55 (m, 2H), 2.38 (s, 6H), 2.20 (m, 530.20; m/z found, 2H) 531.2 [M+H]⁺

Claims

1. A compound according to Formula (1):

(1)

wherein:

R¹ is selected from the group consisting of C₆ - C₂₄ aryl and C₄ - C₂₄ heteroaryl; R² and R³ are independently selected from the group consisting of hydrogen and Ci - C₁₂ alkyl, or R² and R³ are -[C(R¹⁴)₂]_m- and form a heterocyclic ring with the N-atom to which they are attached, wherein m is 2, 3, 4, 5, 6 or 7;

R⁴ is -[C(R¹⁴)₂]_n-, wherein n is 1, 2, 3, 4 or 5;

W¹ is C(R¹⁴)₂, NR¹⁴, O or S;

U, X, Y and Z are independently C or N;

when U is N, R⁸ is absent;

when X is N, R⁷ is absent;

when Y is N, R⁶ is absent;

when Z is N, R⁵ is absent;

R⁹ is -V¹-[C(R¹⁴)₂]_o or -[QR^_o-V¹-, wherein o is 0, 1, 2, 3, 4 or 5 and wherein V¹ is C(R¹⁴)₂, NR¹⁴, O or S;

W² is =0, =S, =N-CN, =C=C-N0₂ or =N-S0₂NH₂;

1 , 10.

E is CR¹⁴, N or NR¹⁴, provided that when E is NR¹4⁴, L is absent and M is R

14

L and M are C(R¹⁴)₂ when represents a single bond, and L and M are CR when = represents a double bond R¹⁰, R¹¹, R¹² and R¹³ are independently selected from the group consisting of H, Ci - C₆ alkyl, C₂ - C₆ alkenyl, C₂ - C₆ alkynyl, OH, Ci - C₆ alkoxy, C₂ - C₆ alkenoxy, C₂ - C₆ alkynoxy, Ci - C₆ alkylthio, C₂ - C₆ alkenylthio, C₂ - C₆ alkynylthio, N(R¹⁴)₂, halogen, CN, S(0)_pR¹⁴, S(0)₂N(R¹⁴)₂, C(0)R¹⁴, C(W²)OR¹⁴, C(W²)N(R¹⁴)₂, N0₂, N-C(0)R¹⁴, P(0)(R¹⁴)OH, P(0)(R¹⁴) H₂; p is 0, 1 or 2;

R¹⁴ is independently selected from the group consisting of H, Ci - C₆ alkyl, halogen, OH, Ci - C₆ alkoxy, Ci - C₆ alkylthio, NH₂, H(Ci - C₄ alkyl), N(Ci - C₄ alkyl)₂, or two groups R¹⁴ represent =0, =S, = H, =N(Ci - C₄ alkyl), =NOH or

- C₄ alkyl); and pharmaceutically acceptable salts, hydrates and solvates thereof.

2. A compound according to Claim 1, wherein n is 1 or 2.

3. A compound according to Claim 1 or Claim 2, wherein W¹ is O or R¹⁴.

4. A compound according to any one of Claims 1 - 3, wherein o is 0.

5. A compound according to Claim 4, wherein R⁹ is H.

6. A compound according to any one of Claims 1 - 5, wherein W² is =0.

7. A compound according to any one of Claims 1 - 6, wherein E is N.

8. A compound according to any one of Claims 1 - 7, wherein L and M are C(R¹⁴)₂ and ^rrrrrr represents a single bond.

9. A compound according to any one of Claims 1 - 8, wherein Y is C.

10. A compound according to any one of Claims 1 - 9, wherein R¹ is selected from the group consisting of phenyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2- thienyl, 3-thienyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1- imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 4-oxazolyl, 5- oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, triazolyl, 2-pyridinyl, 3- pyridinyl, 4-pyridinyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl and triazinyl.

11. A compound according to any one of Claims 1 - 10, wherein X is N and wherein Y and Z are C.

12. A compound according to any one of Claims 1 - 10, wherein X and Z are N.

13. A compound according to any one of Claims 1 - 10, wherein X and Y are N.

14. A compound according to Formula (2):

(2) wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, X, Y, Z, L and M are as defined in claim 1.

15. A compound according to Formula (3):

(3) wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, X and Z are as defined in claim 1.