ANTIPSYCHOTIC DRUGS

Field of the invention

The present invention relates to azinesulfonamide derivatives of cyclic amines or pharmaceutically acceptable salts thereof, which exhibit significant affinity for serotonergic, dopaminergic, and adrenergic receptors. Such compounds are particularly useful for the treatment of mental disorders such as schizophrenia and autism spectrum disorders.

Background and prior art of the invention

Currently used antipsychotic drugs are typically divided into two categories on the basis of their liability to induce specific neurological side effects after chronic treatment. The typical antipsychotic drugs (such as haloperidol) induce so-called extrapyramidal side effects (EPS) including Parkinsonlike symptoms and tardive dyskinesia. In contrast, atypical ("second generation") antipsychotic, such as clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole and sertindole produce lower risk of EPS (Miyamoto et al. 2012).

Both typical and atypical antipsychotics reduce the "positive" symptoms of psychoses, but are less effective in alleviating the "negative" symptoms and (with some exceptions; sertindole, quetiapine) do not reduce, and even aggravate the cognitive deficits associated with schizophrenia. Although the introduction and further development of antipsychotics has revolutionized the pharmacotherapy of schizophrenia-like disorders, their limited efficacy against the "negative" and cognitive symptoms, and a wide spectrum of side effects provide room for further advancement (Meltzer 1989; Leucht et al. 2009).

The prominent feature of typical antipsychotics is the blockade of dopamine D ₂ receptors in the mesolimbic and nigrostriatal brain areas; it is believed that this mechanism is responsible for the reduction of positive symptoms and for the induction of EPS. Second generation antipsychotics demonstrate substantial lack of selectivity in that atypical antipsychotics exhibit significant affinity for other monoaminergic receptors. For instance, antagonism of 5-HT2A receptors likely allows for enhanced dopaminergic function in the nigrostriatal system, resulting in a decrease of EPS. The same 5-HT2A mechanism is also probably responsible for a more effective alleviation of negative symptoms, and may help to avoid hyperprolactinemia. Nonetheless, atypical antipsychotics have not fulfilled the initial expectations of increased efficacy against the negative symptoms, and particularly, cognitive dysfunctions of schizophrenia. Furthermore, there is no clear consensus regarding the precise mechanism of action of an ideal antipsychotic: effective against all three core symptoms and devoid of undesired side-effects of currently used medications. Specifically, several specific prefrontal-cortex dysfunctions including cognitive inflexibility are not normalized by atypical antipsychotic medications like clozapine, olanzapine and risperidone (Rodefer et al. 2008). To date, only sertindole has consistently been shown to reverse cognitive inflexibility (Gallhofer et al. 2007). Clinical data indicate that among the newer atypical drugs, quetiapine may possess a distinctive cognitive-enhancing action (Riedel et al. 2010). The procognitive efficacy of quetiapine has been demonstrated in several cognitive domains known to be affected in schizophrenia, including executive functions (Nikiforuk & Popik 2012).

It is believed that antagonism at 5-HT6 receptors is responsible for such pro-cognitive actions. This is supported by the exclusive central nervous system localization of the 5-HT6 receptors, limited to the limbic and cortical brain areas, and relatively potent affinity and antagonistic activity of several atypical antipsychotics (Nikiforuk 2014). Recent data indicate that blockade of 5-HT6 receptors may be implicated in a pro-cognitive effect due to the increase in cholinergic transmission. In general, the 5-HT6 receptor has emerged recently as a novel molecular target and 5-HT6 antagonists may serve as potential medications in the treatment of disorders characterized by cognitive impairments, such as schizophrenia and Alzheimer's disease (Goff et al. 2011 ).

The "negative" symptoms of schizophrenia and autism spectrum disorders include, among others, emotional flattening and social withdrawal. It is known that antagonistic activity at 5-HT7 receptors may alleviate this spectrum of symptoms (Siegel & Beaulieu 2012). Serotoninergic 5-HT7 receptors play a role in the control of circadian rhythms, sleep, thermoregulation, cognitive processes, pain and migraine, as well as in neuronal excitability. Potent affinity and antagonistic activity of several antipsychotics at 5-HT7 receptors suggest their role in the pathophysiology of schizophrenia. In the mouse, a selective 5-HT7 receptor antagonist SB-269970 produced antipsychotic-like effects, and recent data from this laboratory demonstrate pro-social (i.e., negative symptoms-alleviating actions) of SB-269970. In fact, not only this 5-HT7 antagonist but also amisulpride reversed ketamine-induced social withdrawal, while the selective D2 antagonists like sulpiride and haloperidol were ineffective. The critical evidence for the engagement of 5-HT7 receptors in alleviating "negative" symptoms in an animal model relies in the observation that 5- HT7 receptor agonist, AS 19 abolished the pro-social efficacy of amisulpride. (Holuj et al. 2014).

There is therefore a need for new add-on therapies to available drugs which may display increased effectiveness for the control of negative and cognitive symptoms of schizophrenia and autism related disorders.

In the state of art certain arylpiperazinyl and arylpiperidinyl derivatives of alicyclic amines are known. Arylsulfonamide derivatives of cyclic amines (pyrrolidine, and piperidine) of general formula (Fl) were reported in W097/48681, as potent 5-HT ₇ receptor ligands,

wherein Ar is naphtyl, phenyl or thienyl optionally substituted with by one or more substituents selected from the group consisting of Ci-6alkyl, alkynyl, alkylthio, cyano, nitro, halogen, alkoxy; and NRiR ₂ forms piperidine ring optionally substituted by one or two Ci-6alkyl groups or a piperazine ring optionally substituted on nitrogen with a substituent selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, phenyl, and phenyl(Ci-6)alkyl.

The sulfonamide derivatives disclosed in WO 02/062788 of a general structure (F2) are characterized by presence of ring X being 5 or 6 membered heterocyclic ring containing oxygen, nitrogen and sulfur. The sulfamoyl moiety is connected in β-position of the aromatic ring bridgehead with ring X. The chemical diversity in the tertiary amine fragment comprises differently substituted piperidines. The pharmacological profile thereof, established as 5-HT ₇ receptor ligands, are different from those possessed by the azinesulfonamides of the present invention.

(F2)

WO 2011/111875 discloses N-acyl cyclic amine derivatives of the general formula presented below.

In the above compounds ring Q may be 4—7 membered heterocycle, with one or two hetero atoms, and saturated, or partially unsaturated; wherein An, and Ar ₂ are aryl or hereroaryl group. The above derivatives were described as showing affinity for adrenergic, dopamine, and serotonin receptors, with potential in the treatment of anxiety and schizophrenia. Aim of the invention

The aim of the invention is to provide novel compounds for the treatment of CNS disorders, with higher efficacy than available medicaments, and minimized risk of side effects in comparison to conventional therapeutic agents. Additionally, the compounds display advantages over standard drugs in central disorders associated with cognitive dysfunction.

Summary of the invention

The invention provides a compound of the general formula (I)

wherein:

A ¹ and A ² are selected from the group comprising nitrogen and carbon atoms, said carbon atom being optionally substituted by halogen, whereby one of A ¹ and A ² represents nitrogen atom and the another one of A ¹ and A ² represents carbon atom optionally substituted by halogen, a wave line between sulfonamido moiety and B/C rings represents a single bond linking sulfur atom to a non-bridgehead carbon atom selected from the group comprising non-bridgehead carbon atoms of ring B being non-substituted by halogen and non-bridgehead carbon atoms of ring C located at vicinal position to a bridgehead carbon atom, so a part of ring C being detached by a dashed broken line is unsubstituted,

n represent an integer from 0 to 3 inclusive,

an asterisk indicates a chiral carbon atom in D ring,

a wave line attached to D ring represents a single bond directed downwards or upwards the plane, defining R/S configuration of said chiral carbon atom,

Y is selected from nitrogen and carbon atoms, with a proviso that when Y represents a nitrogen atom a dotted line in ring E is absent whereby a single bond is present, or when Y represent a carbon atom a dotted line in ring E represents a bond whereby a double bond is present,

Z represents a monovalent group derived from a ring system by removal a hydrogen atom from the non-bridgehead carbon atoms of said ring system, said ring system comprising 5-6 membered aromatic/heteroaromatic ring optionally fused with another 5-6 membered heterocycle being aromatic or non-aromatic, said ring system having up to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms, and said ring system being optionally substituted by up to two substituents selected from Ci-6alkyl, halogen, oxo, 5 -membered aromatic heterocyclic group having 1 -3 heteroatoms selected from nitrogen, oxygen and sulfur atoms, and phenyl optionally substituted by at least one halogen, provided that substitution by oxo may occur in the non-aromatic ring only,

or a tautomer, stereoisomer, mixture of stereoisomers in any different ratios, N-oxide, isotopically-labelled analogue, hydrate or solvate or a pharmacologically acceptable salt thereof.

Further, the invention relates to the method for manufacturing the compound of the formula (I), said method comprising subjecting the functionalized amine derivative (of formula II) to a reaction with azinesulfonyl chlorides (of a formula III) in an inert diluent, in a resence of a base.

The compounds of the invention of formula (I), as well as pharmacologically acceptable salts thereof, have multi-receptor dopamine/serotonin profile. Accordingly, the invention relates to the compound of formula (I), the stereoisomer, the tautomer, hydrate, solvate, or salt thereof for use in the therapy in treating the psychotropic diseases, disorders or conditions associated with disturbances of the dopaminergic/serotoninergic systems. Further, the invention relates to the compound of formula (I), the stereoisomer, the tautomer, hydrate, solvate, or salt thereof for use in the combination therapy in treating psychotropic diseases, disorders or conditions associated with disturbances of the dopaminergic/serotoninergic systems, said therapy comprising administration concurrently or sequentially or as a combined preparation of at least one another therapeutic agent for treating one or more of the psychotropic diseases, disorders or conditions associated with disturbances of the dopaminergic/serotoninergic systems, said administration being performed prior to, simultaneously with, of following the administration of the compounds of the invention. Also, the invention relates to use of the compound of formula (I), the stereoisomer, the tautomer, hydrate, solvate, or salt thereof, in manufacture of a medicament for treatment said diseases, disorders or conditions.

Further, the invention relates to a pharmacological composition comprising the compound of formula (I), or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or diluent. Disclosure of the invention

General terms used in the description of compounds herein disclosed bear their usual meanings. The term alkyl as used herein denotes a univalent saturated branched or straight hydrocarbon chain. Unless otherwise stated such chains can contain from 1 to 6 carbon atoms. Representative of such alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl and structural isomers thereof. The given moiety is defined as Ci-6alkyl.

The term 'aryl' embraces monocyclic or fused carbocyclic aromatic group. The term 'heteroaryl' embraces monocyclic or fused bicyclic aromatic group having at least one heteroatom as a ring atom. Said heteroatoms are selected from N, O, S atoms. Examples of heteroaryl group include but not limited to lH-indol-2-yl, lH-indol-3-yl, lH-indol-6-yl, lH-indol-7-yl, lH-indazol- 7-yl, lH-indazol-6-yl, indolizinyl, l-benzofuran-3-yl, l-benzothien-3-yl, l-benzothien-2-yl, 1,2- benzothiazol-3-yl, 1 ,3-benzothiazol-5-yl.

'Halo' or 'Halogen' means chloro, fluoro, bromo or iodo.

The term 'substituted' means that the specified group or moiety bears one or more substituents. Where any group may carry multiple substituents, and a variety of possible substituents is provided, the substituents are independently selected, and need not to be the same. The term 'unsubstituted' or when substitution is not indicated means that the specified group bears no substituents others than H atoms.

Throughout the description and the claim of the specification the word "comprise" and variations of the word, such as "comprising" and "comprises" is not intended to exclude other additives, components, integers or steps.

The invention provides a compound of the general formula (I)

wherein:

- A ¹ and A ² are selected from the group comprising nitrogen and carbon atoms, said carbon atom being optionally substituted by halogen, whereby one of A ¹ and A ² represents nitrogen atom and the another one of A ¹ and A ² represents carbon atom optionally substituted by halogen, a wave line between sulfonamido moiety and B/C rings represents a single bond linking sulfur atom to a non-bridgehead carbon atom selected from the group comprising non-bridgehead carbon atoms of ring B being non-substituted by halogen and non-bridgehead carbon atoms of ring C located at vicinal position to a bridgehead carbon atom, so a part of ring C being detached by a dashed broken line is unsubstituted,

n represent an integer from 0 to 3 inclusive,

an asterisk indicates a chiral carbon atom in D ring,

- a wave line attached to D ring represents a single bond directed downwards or upwards the plane, defining R/S configuration of said chiral carbon atom,

Y is selected from nitrogen and carbon atoms, with a proviso that when Y represents a nitrogen atom a dotted line in ring E is absent whereby a single bond is present, or when Y represent a carbon atom a dotted line in E ring represents a bond whereby a double bond is present, - Z represents a monovalent group derived from a ring system by removal a hydrogen atom from the non-bridgehead carbon atoms of said ring system, said ring system comprising 5-6 membered aromatic/heteroaromatic ring optionally fused with another 5-6 membered heterocycle being aromatic or non-aromatic, said ring system having up to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms, and said ring system being optionally substituted by up to two substituents selected from Ci^alkyl, halogen, oxo, 5 -membered aromatic heterocyclic group having 1-3 heteroatoms selected from nitrogen, oxygen and sulfur atoms, and phenyl optionally substituted by at least one halogen, provided that substitution by oxo may occur in the non-aromatic ring only, or a tautomer, stereoisomer, mixture of stereoisomers in any different ratios, N-oxide, isotopically-labelled analogue, hydrate or solvate or a pharmacologically acceptable salt thereof.

The compounds of the present invention contain at least one asymmetric center and thus occur as racemates and racemic mixtures or single enantiomers. Also, mixture of enantiomers being enriched in one of enantiomers are available by the method of the invention.

N-oxides of the compounds mentioned above belong to the invention. Tertiary amines may or may not give rise to N-oxide metabolites. The extent to what N-oxidation takes place varies from trace amounts to a near quantitative conversion. N-oxides may be more active than their corresponding tertiary amines, or less active. While N-oxides can easily be reduced to their corresponding tertiary amines by chemical means, in human body this happens to varying degrees. Some N-oxides undergo nearly quantitative reductive conversion to the corresponding tertiary amines, in other cases is a mere trace reaction, or even completely absent.

The compound of the invention may exist in various forms, for example polymorphs, solvates and amorphous forms. Some of the crystalline forms of the compounds may exist as polymorphs: as such intended to belong to the invention. In addition, some of the compounds may form solvates with water (i.e. hydrates), or common organic solvents. Such hydrates and solvates are also encompassed by the scope of present invention. Examples thereof include 1/10 hydrates hydrate, 1/4 hydrate, monohydrate, dihydrochloride, dihydrate, dihydrochloride 3/2 hydrate, and the like. Amorphous forms are non-crystalline materials with no long range order, and generally do not give a distinctive powder X-ray diffraction pattern.

A preferred compound according to the invention is that of formula (F)

wherein:

A ¹ and A ² are selected from the group comprising nitrogen and carbon atoms, said carbon atom being optionally substituted by halogen, whereby one of A ¹ and A ² represents nitrogen atom and the another one of A ¹ and A ² represents carbon atom optionally substituted by halogen,

a line between sulfonamido moiety and B ring represents a single bond linking sulfur atom to a non-bridgehead carbon atom of ring B being non-substituted by halogen,

n represent an integer from 0 to 3 inclusive,

an asterisk indicates a chiral carbon atom in D ring,

a wave line attached to D ring represents a single bond directed downwards or upwards the plane, defining R/S configuration of said chiral carbon atom,

Y is selected from nitrogen and carbon atoms, with a proviso that when Y represents a nitrogen atom a dotted line in ring E is absent whereby a single bond is present, or when Y represent a carbon atom a dotted line in E ring represents a bond whereby a double bond is present,

and Z is defined as above.

Optionally, a compound according to the invention is that of formula (I")

wherein:

A ¹ and A ² are selected from the group comprising nitrogen and carbon atoms, said carbon atom being optionally substituted by halogen, whereby one of A ¹ and A ² represents nitrogen atom and the another one of A ¹ and A ² represents carbon atom optionally substituted by halogen, a line between sulfonamido moiety and C ring represents a single bond linking sulfur atom to a non-bridgehead carbon atom of ring C located at vicinal position to a bridgehead carbon atom, so a part of ring C being detached by a dashed broken line is unsubstituted,

n represent an integer from 0 to 3 inclusive,

an asterisk indicates a chiral carbon atom in D ring,

a wave line attached to D ring represents a single bond directed downwards or upwards the plane, defining R/S configuration of said chiral carbon atom,

Y is selected from nitrogen and carbon atoms, with a proviso that when Y represents a nitrogen atom a dotted line in ring E is absent whereby a single bond is present, or when Y represent a carbon atom a dotted line in E ring represents a bond whereby a double bond is present,

Z is as defined above.

More preferably, in formulae (I), (Γ), (I"), a moiety Z is a monovalent group derived from a ring system by removal a hydrogen atom from the non-bridgehead C atom,

said ring system represented by formula (IV)

in which

Q ¹ is selected from nitrogen and carbon atoms,

Q ² is selected from nitrogen and carbon atoms, said carbon atom optionally being substituted by oxo,

Q ³ is selected from nitrogen, carbon, oxygen and sulfur atoms,

a dotted line line represents a bond whereby a double is present with a proviso that when

Q ² is carbon atom substituted by oxo, a dotted line line is absent whereby a single bond is present,

p is 0 or 1,

R ¹ represents halogen atom;

or said ring system is represented by formula (V)

in which

each Q ⁴ and Q ⁷ represents an atom selected from nitrogen and oxygen atoms,

each Q ⁵ and Q ⁶ represents an atom selected from carbon atoms optionally substituted by with a proviso that at most one of Q ⁵ and Q ⁶ may be substituted by

q is 0 or 1,

R ² represents halogen atom;

or said ring system is represented by formula (VI)

in which

Q ⁸ is selected from nitrogen and carbon atoms,

s is 0, 1, 2 or 3,

R ³ represents G-6alkyl, phenyl optionally substituted by halogen, 5-membered aromatic heterocyclic group having sulfur atom as heteroatom.

Even more preferably, in formulae (I), (Γ), (I"), a moiety Z represents a group selected from l-benzothiophen-4-yl, l-benzothiophene-3-yl, lH-benzimidazol-4-yl, 5-chloro-lH-indol-3-yl, 6-fluoro-lH-indol-3-yl, lH-indol-3-yl, l,2-benzoxazol-3-yl, 1 ,2-benzothiazol-3-yl, 2-oxo-2,3- dihydro- 1 ,3 -benzoxazol-4-yl, 1 ,4-benzodioxan-5 -yl, 3 -okso-3 ,4-dihydro-2H- 1 ,4-benzoxazin-8 -yl, 6-butyl-4-(thiophen-3-yl)pyridin-2-yl, 6-butyl-4-(4-fluorophenyl)pyridin-2-yl.

Formulae (I), (Γ), (I") present the structure of the class of compounds without the preferred stereochemistry. The independent synthesis of theses isomers, their chromatographic separation may be achieved as presented in Examples, and according to the methods known in art by appropriate modifications of the methodology presented therein. The absolute stereochemistry may be determined by the X-ray crystallography of crystalline products or crystalline intermediates, which are denvatized, if necessary, with a reagent containing as asymmetric center of known absolute configuration. On the other hand, starting from racemic mixture, the compounds may be separated using chromatographic methods or enzymatic assays.

According to particularly preferred embodiment, the compound of the invention is selected from the following:

(S)-3-(4-(2-(l-(Quinolin-5-ylsulfonyl)azetid n-2-yl)ethyl)piperazm-l-yl)-l,2-benzothiazole, (S)-3-(4-(2-( 1 -(Isoquinolin-4-ylsulfonyl)azetidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzothiazole, (S)-3-(4-(2-(l -(Isoquinolin-5-ylsulfonyl)azetidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzothiazole, (S)-4-((2-(2-(4-(Benzo[6]thiophen-4-yl)piperazin- 1 -yl)ethyl)azetidin- 1 -yl)sulfonyl)isoquinoline, (S)-4-((2-(2-(4-(Benzo[6]tluophen-4-yl)piperazin-l-yl)ethyl) azetidin-l-yl)sulfonyl)qumoline, (S)-3-((2-(2-(4-(5-Chloro- 1 H-indol-3-yl)-5,6-dihydropyridin- 1 (2H)-yl)ethyl)azetidin- 1 - yl)sulfonyl)quinoline, (S)-4-((2-(2-(4-(5-Chloro- 1 H-indol-3-yl)-5,6-dihydropyridin- 1 (2H)-yl)ethyl)azetidin- 1 - yl)sulfonyl)isoquinoline,

(S)-3-((2-(2-(4-( 1 H-Indol-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)isoquinoline, (S)-4-((2-(2-(4-( 1 H-Indol-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)isoquinoline, (S)-5-((2-(2-(4-( 1 H-Indol-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)isoquinoline,

(S)-5-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)quinoline, (S)-3-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)quinoline, (S)-4-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-l-yl)ethyl) pyrrolidin-l-yl)sulfonyl)½^

(S)-5-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)isoquinoline, (S)-3-(4-(2-( 1 -(Quinolin-2-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzoxazole, (S)-3-(4-(2-( 1 -(Quinolin-5-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzoxazole, (S)-3-(4-(2-( 1 -(Isoquinolin-4-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzoxazole, (S)-3-(4-(2-( 1 -(Isoquinolin-5-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzoxazole, (S)-3-(4-(2-( 1 -Quinolin-2-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzothiazole, (S)-3-(4-(2-(l -Quinolin-5-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin-l -yl)- 1 ,2-benzothiazole, (S)-3-(4-(2-( 1 -Isoquinolin-3-ylsiilfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzothiazole, (S)-3-(4-(2-((l -Chloroisoquinolin-4-ylsulfonyl)pyrrolidin-2-yl)ethyl)pipera zin- 1 -yl)- 1 ,2- benzothiazole,

(S)-3-(4-(2-(l-(Isoquinolin-4-ylsulfonyl)pyrroli

(S)-3-(5-(2-( 1 -(Isoquinolin-4-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzothiazole, (S)-7-(4-(2-(l-(Quinolin-5-ylsulfonyl)pyrrolidin-2-yl)ethyl) piperazin-l-yl)benzo[d]oxazol-2(3H)- one,

(S)-7-(4-(2-(l-(Isoquinolin-3-ylsulfonyl)pyrrolidin-2-yl)eth yl)piperazin-l-yl)benzo[

2(3H)-one,

(S)-7-(4-(2-(l-(Isoquinolin-4-ylsulfonyl)pyrrolidin-2-yl) ethyl)piperazin-l-yl)benzo[d]oxazo^ 2(3H)-one,

(S)-8-(4-(2-(l -(Quinolin-5-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)-2H- benzo[b][l ,4]oxazin-3(4H)-one,

(S)-8-(4-(2-(l -(Isoquinolin-3-ylsidfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)-2H- benzo[b][l,4]oxazin-3(4H)-one,

(S)-8-(4-(2-(l-(Isoquinolin-4-ylsulfonyl)pyrrolidin-2-yl)eth yl)piperazin-l-yl)-2H- benzo[b][l ,4]oxazin-3(4H)-one,

(S)-8-(4-(2-( 1 -(Isoquinolin-5-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)-2H- benzo[b][l,4]oxazin-3(4H)-one, (S)-5-((2-(2-(4-(2,3-Dihydrobenzo[b] [ 1 ,4]dioxin-5-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 - yl)snlfonyl)quinoline,

(S)-4-((2-(2-(4-(2,3-Dihydrobenzo[b][l,4]dioxin-5-yl)piperaz in-l-yl)ethyl)pyrrolidm^ yl)sulfonyl)isoquinoline,

(S)-5-((2-(2-(4-(2,3-Dihydrobenzo[b] [ 1 ,4]dioxin-5-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)isoquinoline,

(S)-5-((2^2-(4-(6-Butyl-4-(tWophen-3-yl)pyridin-2-yl)piperaz in- 1 -yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)quinoline,

(S)-4 (2-(2-(4-(6-Butyl-4-(thiophen-3-yl)pyridin-2-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)isoquinoline,

(S)-5-((2-(2-(4-(6-Butyl-4-(thiophen-3-yl)pyridin-2-yl)piper azin- 1 -yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)isoquinoline,

(S)-5-((2-(2-(4-(6-Butyl-4-(4-fluorophenyl)pyridin-2-yl)pipe razin-l -yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)quinoline,

(S)-4-((2-(2-(4-(6-Butyl-4-(4-fluorophenyl)pyridin-2-yl)p iperazin- 1 -yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)isoquinoline,

(S)-5-((2-(2-(4-(6-Butyl-4-(4-fluorophenyl)pyridin-2-yl)pipe razin- 1 -yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)isoquinoline,

(S)-5-((2-(2-(4-( 1 H-Indol-3-yl)-5,6-dihydropyridin- 1 (2H)-yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)quinoline,

(S)-3-((2-(2-(4-(l H-Indol-3-yl)-5,6-dihydropyridin- 1 (2H)-yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)isoquinoline,

(S)-4-((2-(2-(4-(lH-Indol-3-yl)-5,6-dmydropyridin-l-(2H)-yl) ethyl)pyrrolidin-l- yl)sulfonyl)isoquinoline,

(S)-5-((2 2-(4-(6-Fluoro-lH-mdol-3-yl)-5,^

yl)sulfonyl)quinoline,

(S)-3-((2-(2-(4-(6-Fluoro- 1 H-indol-3-yl)-5,6-dihydropyridin- 1 (2H)-yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)isoquinoline,

(S)-4-((2-(2-(4-(6-Fluoro- 1 H-indol-3-yl)-5,6-dihydropyridin- 1 (2H)-yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)isoquinoline,

(S)-2-((2-(2-(4-(5-Chloro- 1 H-indol-3-yl)-5,6-dihydropyridin- 1 (2H)-yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)quinoline,

(S)-4-((2-(2-(4-(5-Chloro- 1 H-indol-3-yl)-5,6-dihydropyridin- 1 (2H)-yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)isoquinoline, (S)-5-((2-(2-(4-(5-CMoro-lH-indol-3-yl)-5,6-dihydropyridin-l (2H)-yl)ethyl)pyirolidin-l- yl)sulfonyl)isoquinoline,

(S)-4-((2-(2-(4-(l H-Benzo[d]imidazol-4-yl)piperazin-l -yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)isoquinoline,

(S)-2-((2-(2-(4-(Benzo[b]thiophen-3-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)quinoline, (S)-4-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)- 1 - chloroisoquinoline,

(R)-3 -((2-(2-(4-(Benzo[b]thiophen-3 -yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)isoquinoline, (R)-2-((2-(2-(4-( 1 H-Benzo[d]imidazol-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)quinoline,

(R)-3-((2-(2-(4-(l H-Indol-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)quinoline,

(R)-4-((2-(2-(4-(l H-Indol-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)isoquinoline, (R)-5-((2-(2-(4-(l H-Indol-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)isoquinoline, (R)-5-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)quinoline, (R)-4-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)quinoline,

(R)-4-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)isoquinoline, (R)-5-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)isoquinoline, (R)-3-(4-(2-( 1 -(Quinolin-2-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzoxazole, (R)-3 -(4-(2-( 1 -(Quinolin-4-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzothiazole, (R)-3-(4-(2-(l -(Quinolin-5-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzothiazole,

(R)-3-(4-(2-(l -(Isoquinolin-3-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzothiazole, (R)-3-(4-(2-(l -(Isoquinolin-4-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzothiazole, (R)-3-(4-(2-( 1 -(Isoquinolin-5-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)— 1 ,2-benzothiazole, (R)-5-((2-(2-(4-(2,3-Dihydrobenzo[b][ 1 ,4]dioxin-5-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)quinoline,

(R)-4-((2-(2-(4-(2,3-Dihydrobenzo[b][l ,4]dioxin-5-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)isoquinoline,

(R)-5-((2-(2-(4-(2,3-Dihydrobenzo[b][l ,4]dioxin-5-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)isoquinoline,

(R)-5-((2-(2-(4-(6-Butyl-4-(4-fluorophenyl)pyridin-2-yl)p iperazin- 1 -yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)quinoline,

(R)-4-((2-(2-(4-(6-Butyl-4-(4-fluorophenyl)pyridin-2-yl)pipe razin- 1 -yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)isoquinoline, (R)-5-((2-(2-(4-(6-Butyl-4-(4-fluorophenyl)pyridin-2-yl)pipe razin- 1 -yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)isoquinoline,

(R)-2-((2-(2-(4-(6-Fluoro- 1 H-indol-3-yl)-5,6-dihydropyridin- 1 (2H)-yl)ethyl)pyrrolidin- 1- yl)sulfonyl)quinoline,

(R)-4-((2-(2-(4-(6-Fluoro- lH-indol-3-yl)-5,6-dihydropyridin- 1 (2H)-yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)isoquinoline,

(R)-5-((2-(2-(4-(5-Chloro- 1 H-indol-3-yl)-5,6-dihydropyridin- 1 -(2H)-yl)ethyl)piperidin- 1 - yl)sulfonyl)quinoline,

(R)-4-((2-(2-(4-(5-Chloro- 1 H-indol-3-yl)-5,6-dihydropyridin- 1 -(2H)-yl)ethyl)piperidin- 1 - yl)sulfonyl)isoquinoline,

(S)-5-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)piperidin- 1 -yl)sulfonyl)quinoline, (S)-4-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)piperidin- 1 -yl)sulfonyl)isoquinoline, (S)-5-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)piperidin- 1 -yl)sulfonyl)isoquinoline, (S)-3-(4-(2-(l -(Qumolin-2-ylsulfonyl)piperidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzothiazole, (S)-3-(4-(2-(l -(Quinolin-5-ylsulfonyl)piperidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzothiazole, (S)-3-(4-(2-( 1 -(Isoquinolin-4-ylsulfonyl)piperidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzothiazole, (S)-3-(4-(2-(l -(Isoquinolin-5-ylsulfonyl)piperidin-2-yl)ethyl)piperazin- 1 -yl)-l ,2-benzothiazole, (S)-5-((2-(2-(4-(5-Chloro- 1 H-indol-3-yl)-5,6-dihydropyridin- 1 -(2H)-yl)ethyl)piperidin- 1 - yl)sulfonyl)quinoline,

(S)-4-((2-(2-(4-(5-Chloro- 1 H-indol-3-yl)-5,6-dihydropyridin- 1 -(2H)-yl)ethyl)piperidin- 1 - yl)sulfonyl)isoquinoline,

(S)-4-((2-(2-(4-(lH-Benzo[d]irnidazol-4-yl)piperazm-l-yl)eth yl)piperidin-l-yl)sulfony

(S)-4-((2-(2-(4-(Benzo[b]thiophen-3-yl)piperazin- 1 -yl)ethyl)piperidin- 1 -yl)sulfonyl)isoquinoline, (S)-2-((2-(2-(4-( 1 H-Benzo[d]imidazol-4-yl)piperazin- 1 -yl)ethyl)piperidin- 1 -yl)sulfonyl)quinoline, (R)-5-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)azepan- 1 -yl)sulfonyl)quinoline,

(R)-4-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)azepan- 1 -yl)sulfonyl)isoquinoline, (R)-3-(4-(2-( 1 -(Quinolin-5-ylsulfonyl)azepan-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzothiazole, (R)-3-(4-(2-(l -(Isoquinolin-4-ylsulfonyl)azepan-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzothiazole.

The compound of the formula (I) is manufactured according to scheme 1 , by subjecting the functionalized amine derivative (of the formula II) to a reaction with azinesulfonyl chloride (of the formula III), to form azinesulfonamide compound (I) Scheme 1

wherein A ¹ , A ² , Y, Z, n have the meanings indicated above, in an inert diluent, in a presence of a base. Preferably the reaction is carried using a base selected from organic tertiary amines, especially using triethylamine, N,N-diisopropylethylamine, N-methylmorpholine. The diluent is selected from organic solvents comprising halogenated hydrocarbons such as dichloromethane, chloroform, and polar aprotic solvents, such as N,N-dimethylformamide.

The starting material, functionalized amine derivative (of the formula II, optionally protected by protecting group P as given by formula A-4) is prepared according to a general synthetic route (scheme 2) involving intermediate compounds from A-l to A-3, in steps i-iii described below. Azinesulfonyl chlorides (of the formula III) are prepared according to the known procedure (Maslankiewicz et al.2007). Following optional deprotection step iv and then sulfonylation of amine derivative step v (as described below), the various compounds according to the invention are obtained.

Scheme 2

A-4 reduction of compounds of general formula A-l with a reducing agent in an inert solvent. As a reducing agent, lithium aluminium hydride or borane complex (e.g. borane-tetrahydrofuran complex) may be used. Inert solvent may be selected from THF, or 1,4-dioxane, or mixture thereof, or unipolar solvent like dichloromethane, or

if) oxidation of compounds of general formula A-2 under Dess-Martin, or Svern method, or using oxidation agents e.g. manganese dioxide/chromic acid, in polar or unipolar solvents, or a mixture thereof. A preferable oxidation reaction is the use of 2-iodoxybenzoic acid (EX) in dimethyl sulfoxide.

Hi) reductive amination of compounds of general formula A-3 using hydride compounds e.g. sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminium hydride, and diborane polar and unipolar solvents, selected from methanol, ethanol, tetrahydrofuran, 1 ,4-dioxane, dichloromethane, or a mixture thereof.

iv) removal of protecting function "P" of the amine group in compounds of general formula A-4.

"P" is a standard protecting group that may be removed according methods known for the skilled specialist. The protecting function may be for example tert-butoxycarbonyl, which is readily removed by the treatment with acidic reagent (i.e. hydrochloric acid, trifluoroacetic acid) in dichloromethane, 1,4-dioxane, methanol, tetrahydrofuran

v) sulfonylation of deprotected amine derivative of general formula A-4 with azinesulfonyl chlorides under basic conditions using an organic base (for example, triethylamine, N,N- diisopropylethylamine, N-methylmorpholine) in inert solvents (selected from dichloromethane, chloroform, N,N-dimethylformamide).

Isolation and purification of the compounds and intermediates described herein can be affected, by any suitable separation or purification procedures such as, for example, filtration, extraction, crystallization, column chromatography, preparative low or high-pressure liquid chromatography, or a combination of these procedures.

Suitable separation and isolation procedures may be taken from preparation and Examples. However, other equivalent separation or isolation procedures could be used, also.

The compounds of the invention of formula (I), as well as pharmacologically acceptable salts thereof, have multireceptor dopamine/serotonin profile. It has now surprisingly been found that the compounds according to the invention display high affinity for dopamine D ₂ , D ₃ , 5-HTIA, 5-HT ₂ A, 5-HT ₆ , and 5-HT ₇ receptors. This receptor combination is useful for the treatment of psychotropic diseases, disorders or conditions associated with disturbances of the dopaminergic/serotoninergic systems. The compounds of invention behave as antagonists and or partial agonists of D ₂ receptors, 5-HTiA antagonists/partial agonists, as well as 5-ΗΤό and 5-HT ₇ antagonists. Such functional profile seems highly favorable in development of new antipsychotics with procognitive and pro-social- like properties.

Accordingly, the invention provides a compound according of the formula (I) or pharmaceutically acceptable salt thereof for use in the therapy in treating psychotropic diseases, disorders or conditions associated with disturbances of the dopaminergic/serotoninergic systems. The term "pharmaceutically acceptable salt" refers to those salts that are, within the scope medical judgment, suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. They can be prepared in situ when finally isolating and purifying the compounds of the invention, or separately by reacting them with pharmaceutically acceptable non-toxic acids, including inorganic or organic acids (Berge, 1977). The "free base" form may be regenerated by contacting the salt with a base, and isolating the parent compound in the conventional matter. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention. The term "treatment" as used herein refers to any treatment a mammalian, for example human condition or disease, and includes: (i) inhibiting the disease or condition, i.e., arresting its development, (ii) relieving the disease or condition, i.e.; causing the condition to regress, or (iii) stopping the symptoms of the disease.

As used herein, the term "medical therapy" intendeds to include prophylactic, diagnostic and therapeutic regimens carries out in vivo or ex vivo on humans or other mammals.

Said psychotropic diseases, disorders or conditions are selected from the group comprising schizophrenia, anxiety, depression, maniac depression, obsessive compulsive disorders, mood disorders, migraine, aggression, sleep disorders, Alzheimer's disease, age related cognitive decline, mild cognitive impairment, eating disorders, anorexia, bulimia, panic attacks, attention deficit hyperactivity disorder, attention deficit disorder, autism, Parkinson's disease, Huntington's disease, withdrawal from abuse of cocaine, ethanol, nicotine or benzodiazepines.

The invention further relates to combination therapies wherein a compound of the invention, of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administrated concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for treating one or more of the conditions listed. Such other therapeutic agent(s) may be administrated prior to, simultaneously with, of following the administration of the compounds of the invention.

The therapeutic agent or agents used in the combination with the compound of invention relates to the compounds used for treating a disorder or conditions chosen from the disorders listed in the invention, with the mechanism of action that synergistically ameliorate the positive outcomes of therapy.

The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent to treat a condition treatable by administrating a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic or ameliorative response in as tissue system, animal or human. It is not useful to specify an exact effective amount in advance.

With the context of this application, the term "combination preparation" comprises both true combinations, meaning a compound of formula (I) and one or more other medicaments physically combined in one preparation such as a tablet or injection fluid, comprising a compound of formula (I) and one or more other medicaments in separate dosage forms, together with instruction for use, optionally with further means for facilitating compliance with the administration of the component compounds, e.g. label or drawings. With true combinations, the pharmacotherapy by definition is simultaneous.

While it may be possible for the compounds of formula (I) to be administered as the raw chemical, it is preferable to present them as a 'pharmaceutical composition'. According to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof or diluent/diluents, and optionally one or more other therapeutic ingredients. The carrier/carriers) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The term "composition" as used herein encompasses a product comprising specified ingredients in predetermined amount or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts. In relation to pharmaceutical compositions, this term encompasses a product comprising one or more active ingredients, and an optimal carrier comprising inert ingredients, as well as any product that results, directly or indirectly from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interaction of one or more of the ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredients into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into desired formulation. The pharmaceutical composition includes enough of the active object compound to produce the desired effect upon the progress or condition of disease. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician. In general, total daily dose administration to a patient a single or individual doses, may be in amounts, for example from 0.001 to 10 mg/kg body weight daily, and more usually 0.01 to 1000 mg per day, of total active ingredients.

The invention also provides the use of a compound or salt according to formula (I) for the manufacture of medicament.

The chemical names of the substances were generated using ChemBioDraw Ultra 12.0.

Abbreviations

AcOEt ethyl acetate; t-BuOK potassium tert-butoxide

AcOH acetic acid; t-BuONa sodium tert-butoxide

BINAP 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl; TEA triethylamine;

DCM dichloromethane; TFA trifluoroacetic acid;

DIEA diisopropylethylamine; THF tetrahydrofurane;

DMF dimethylformamide; MW molecular weight;

DMSO dimethyl sulfoxide; HPLC high performance liquid

Et ₂ 0 diethyl ether; chromatography;

Hex hexane; Ή NMR Proton Nuclear Magnetic

MeCN acetonitrile; Resonance;

MeOH methanol; LC-MS high performance liquid

Pd/C palladium on activated charcoal; chromatography coupled to mass

Pd ₂ (dba); tris(dibenzylideneacetone)-dipalladium(0); spectrometer.

General analytical methods

The synthesis was carried out at ambient temperature, unless indicated otherwise. Organic solvents (from Aldrich and Chempur) were of reagent grade and were used without purification. The reagents were from Aldrich, Fluorochem, Trimen.

Analytical HPLC were run on a Waters Alliance HPLC instrument, equipped with a

ChromolithSpeedROD column (4.6 x 50 mm). Standard conditions were eluent system A (water/0.1% TFA), system B (acetonitrile/0.1% TFA). A flow rate of 5 mL/min and a gradient of (0-100)% B over 3 min were used. Detection was performed on a PDA detector.

Ή-NMR and ¹³ C-NMR spectra were recorded at 300 MHz and 75 MHz (Varian BB 200 spectrometer) using TMS (0.00 ppm) as an internal standard as well as CDC1 ₃ , and DMSO-ck as solvents; J values are in hertz (Hz), and splitting patterns are designated as follows: s (singlet), d (doublet), t (triplet), m (multiplet).

LC/MS were carried out on a system consisted of a Waters Acquity UPLC, coupled to a Waters TQD mass spectrometer. All the analyses were carried out using a Acquity UPLC BEH C 18, 50 2.1 mm column, at 40°C. A flow rate of 0.3 mL/min and a gradient of (5-95)% B over 10 min was used. Eluent A: water/0.1% HC0 ₂ H; eluent B: acetonitrile/0.1% HC0 ₂ H. The UPLC/MS purity of all the test compounds and key intermediates was determined to be >97%.

Working Examples - Preparation of intermediate compounds

Intermediate 1 : tert-Butyl (2S)-2-(2-hydroxyethyl)azetidine-l-carboxylate

To a mixture of 2-[(2S)-l-tert-butoxycarbonylazetidin-2-yl]acetic acid (1.0 g, 4.64 mmol) in anhydrous DCM (15 mL) lithium aluminum hydride 2.0 M in THF (3.17 g, 3.50 mL, 7.0 mmol), was added dropwise (under argon), and the reaction mixture was heated to 55°C. After stirring for 4 hours (at 55°C), the reaction mixture was cooled to room temperature, diluted with AcOEt (20 mL) and treated with saturated NaHC0 ₃ (3 mL). Then the solution was concentrated under reduce pressure. To the residue were added DCM. The organic layer was washed with water and brine, and then dried over anhydrous Na ₂ S0 ₄ , and concentrated under reduced pressure to give title compound (0.63 g, 3.15 mmol, yield 68%).

Light oil CioHi ₉ N0 ₃ , MW 201.26, Monoisotopic Mass 201.13, [M+H] ⁺ 202.2. UPLC R, = 4.32. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.44 (s, 9 H), 1.80-2.00 (m, 2 H), 2.20-2.46 (m, 2 H), 3.60-3.78 (m, 2 H), 3.80-3.93 (m, 2 H), 4.31-4.442 (m, 1 H), 4.61 (br. s., 1 H). ^,3 C NMR (75 MHz, CDC1 ₃ ) δ (ppm) 22.56, 28.35, 28.42, 32.28, 59.66, 60.25, 80.13.

Intermediate 2: tert-Butyl (2S)-2-{2-oxoethyl)azetidine-l-carboxylate

2-Iodoxybenzoic acid (IBX, 2.66 g, 9.50 mmol) was dissolved in DMSO (20 mL), stirred for 10 min. at room temperature and treated with a solution of intermediate 1 (0.63 g, 3.15 mmol) in DMSO (20 mL). After stirring overnight at room temperature the reaction mixture was diluted with Et ₂ 0 (50 mL), cooled to 0°C and quenched by addition of water (50 mL). The inorganic layer was diluted with brine (30 mL) and extracted with AcOEt. The combined organic layers were washed with saturated NaHC0 ₃ , water and brine, and then dried over anhydrous Na ₂ S0 ₄ . After concentration under reduced pressure the crude product was purified by column chromatography on silica gel, AcOEt/Hex = 30/70 (v/v), to give title compound (0.38 g, 1.90 mmol, yield 64%).

Light oil CioHnN03, MW 199.24, Monoisotopic Mass 199.12, [M+H] ⁺ 200.2. UPLC R, = 4.49. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.45 (s, 9 H), 2.47-2.61 (m, 4 H), 3.30-3.36 (m, 2 H), 3.92-4.02 (m, 1 H), 9.52 (d, 1 H, J = 7.82 Hz). Intermediate 3: tert-butyl (2S)-2-(2-hydroxyethyl)pyrrolidine-l-carboxylate To a mixture of 2-[(2S)-l-tert-butoxycarbonylpyrrolidin-2-yl]acetic acid (2.0 g, 8.7 mmol) in anhydrous DCM (20 mL) lithium aluminum hydride 2.0 M in THF (6.55 g, 7.23 mL, 13.05 mmol) was added dropwise (under argon), and the reaction mixture was heated to 55°C. After stirring for 4 hours (at 55°C), the reaction mixture was cooled to room temperature, diluted with AcOEt (20 mL) and treated with saturated NaHC0 ₃ (4 mL). Then the solution was concentrated under reduce pressure. To the residue were added DCM. The organic layer was washed with water and brine, and then dried over anhydrous Na ₂ S04, and concentrated under reduced pressure to give title compound (1.72 g, 8.0 mmol, yield 91.9%).

Light oil CiiH ₂ iN0 ₃ , MW 215.29, Monoisotopic Mass 215.15, [M+H] ⁺ 216.2. UPLC R, = 4.67. 4.85. 'H NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.40-1.46 (m, 9 H), 1.48-1.64 (m, 7 H), 1.75-1.96 (m, 1 H), 2.20-2.49 (m, 1 H), 3.58-3.71 (m, 1 H), 3.77-3.96 (m, 1 H), 4.29-4.44 (m, 1 H).

Intermediate 4: tert-Butyl (2S)-2-(2-oxoethyl)pyrrolidine-l-carboxylate

2-Iodoxybenzoic acid (IBX, 6.72 g, 24 mmol) was dissolved in DMSO (50 mL), stirred for 10 min. at room temperature and treated with a solution of intermediate 3 (1.72 g, 8.0 mmol) in DMSO (50 mL). After stirring overnight at room temperature the reaction mixture was diluted with Et ₂ 0 (100 mL), cooled to 0°C and quenched by addition of water (100 mL). The inorganic layer was diluted with brine (50 mL) and extracted with AcOEt. The combined organic layers were washed with saturated NaHC0 ₃ , water and brine, and then dried over anhydrous Na ₂ S04. After concentration under reduced pressure the crude product was purified by column chromatography on silica gel, AcOEt/Hex = 30/70 (v/v), to give title compound (1.12 g, 5.24 mmol, yield 65.5%).

Light oil CiiHi ₉ N0 ₃ , MW 213.27, Monoisotopic Mass 213.13, [M+H] ⁺ 214.1. UPLC R, = 5.24. Ή NMR (300 MHz, CDCI3) δ (ppm) 1.27-1.45 (m, 9 H), 1.51-1.66 (m, 1 H), 1.68-1.87 (m, 2 H), 1.93- 2.16 (m, 1 H), 2.19-2.50 (m, 1 H), 2.65-2.94 (m, 1 H), 3.13-3.42 (m, 2 H), 4.02-4.26 (m, 1 H), 9.71 (t, 1 H, J = 2.12). ¹³ C NMR (75 MHz, CDC1 ₃ ) δ (ppm) 22.90, 23.61 , 28.39, 31.11, 46.46, 52.29, 53.90, 79.67, 128.78, 130.90.

Intermediate 5: tert-Butyl (2R)-2-(2-hydroxyethyl)pynOlidine-l-carboxylate

To a mixture of [(2R)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl]acetic acid (2.0 g, 8.7 mmol) in anhydrous DCM (20 mL) lithium aluminum hydride 2.0 M in tetrahydrofurane (6.55 g, 7.23 mL, 13.05 mmol) was added dropwise (under argon), and the reaction mixture was heated to 55°C. After stirring for 4 hours (at 55°C), the reaction mixture was cooled to room temperature, diluted with AcOEt (20 mL) and treated with saturated NaHC0 ₃ (4 mL). Then the solution was concentrated under reduce pressure. To the residue were added DCM. The organic layer was washed with water and brine, and then dried over anhydrous Na ₂ S0 ₄ , and concentrated under reduced pressure to give title compound (1.68 g, 7.8 mmol, 90%)

Light oil C CnH ₂ iN0 ₃ , MW 215.29, Monoisotopic Mass 215.15, [M+H] ⁺ 216.2. UPLC Rt = 4.69. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.41-1.45 (m, 9 H), 1.48-1.64 (m, 7 H), 1.75-1.96 (m, 1 H), 2.20-2.49 (m, 1 H), 3.58-3.71 (m, 1 H), 3.77-3.96 (m, 1 H), 4.29-4.44 (m, 1 H).

Intermediate 6: tert-Butyl (2R)-2-(2-oxoethyl)pyrrolidine-l-carboxylate

2-Iodoxybenzoic acid (IBX, 6.72 g, 24 mmol) was dissolved in DMSO (50 mL), stirred for 10 min. at room temperature and treated with a solution of intermediate 5 (1.68 g, 7.8 mmol) in DMSO (50 mL). After stirring overnight at room temperature the reaction mixture was diluted with Et ₂ 0 (100 mL), cooled to 0°C and quenched by addition of water (100 mL). The inorganic layer was diluted with brine (50 mL) and extracted with AcOEt. The combined organic layers were washed with saturated NaHC0 ₃ , water and brine, and then dried over anhydrous Na ₂ S0 ₄ . After concentration under reduced pressure the crude product was purified by column chromatography on silica gel, AcOEt/Hex = 30/70 (v/v), to give title compound (1.13 g, 5.30 mmol, 68%).

Light oil CnHi ₉ N0 ₃ , MW 213.27, Monoisotopic Mass 213.13, [M+H] ⁺ 214.2. UPLC R, = 5.24. *H NMR (300 MHz, CDCl ₃ ) 6 (ppm) 1.25-1.46 (m, 10 H), 1.52-1.68 (m, 1 H), 1.71-1.89 (m, 2 H), 1.96- 2.15 (m, 1 H), 2.21-2.51 (m, 1 H), 2.65-2.95 (m, 1 H), 3.24-3.38 (m, 1 H), 4.02-4.28 (m, 1 H), 9.72 (t, 1 H, J = 2.07 Hz). ^,3 C NMR (75 MHz, CDC1 ₃ ) δ (ppm) 28.41 , 31.14, 32.06, 38.80, 46.48, 48.87, 49.5, 52.30, 53.91 , 76.63, 77.06, 77.48.

Intermediate 7: tert-Butyl (2S)-2-(2-hydroxyethyl)piperidine-l-carboxylate

To a mixture of [(2S)-l-(tert-butoxycarbonyl)piperidin-2-yl]acetic acid (2.0 g, 8.2 mmol) in anhydrous DCM (20 mL) lithium aluminum hydride 2.0 M in tetrahydrofurane (5.57 g, 6.15 mL, 12.3 mmol) was added dropwise (under argon), and the reaction mixture was heated to 55°C. After stirring for 4 hours (at 55°C), the reaction mixture was cooled to room temperature, diluted with AcOEt (20 mL) and treated with saturated NaHC0 ₃ (4 mL). Then the solution was concentrated under reduce pressure. To the residue were added DCM. The organic layer was washed with water and brine, and then dried over anhydrous Na ₂ S0 ₄ , and concentrated under reduced pressure to give title compound (1.75 g, 7.63 mmol, 93%).

Light oil G ₂ H ₂₃ N0 ₃ , MW 229.31, Monoisotopic Mass 229.16, [M+H] ⁺ 230.2. UPLC R, = 5.45. ^! H NMR (300 MHz, CDCl ₃ ) 6 (ppm) 1.31-1.46 (m, 1 1 H), 1.48-1.63 (m, 7 H), 1.69-1.91 (m, 1 H), 2.19- 2.49 (m, 1 H), 3.57-3.70 (m, 1 H), 3.77-3.97 (m, 1 H), 4.29-4.42 (m, 1 H). Intermediate 8: tert-Butyl (2S)-2-(2-oxoethyl)piperidine-l-carboxylate

2-Iodoxybenzoic acid (IBX, 6.41 g, 22.9 mmol) was dissolved in DMSO (50 mL), stirred for 10 min. at room temperature and treated with a solution of intermediate 7 (1.75 g, 7.63 mmol) in DMSO (50 mL). After stirring overnight at room temperature the reaction mixture was diluted with Et ₂ 0 (100 mL), cooled to 0°C and quenched by addition of water (100 mL). The inorganic layer was diluted with brine (50 mL) and extracted with AcOEt. The combined organic layers were washed with saturated NaHC0 ₃ , water and brine, and then dried over anhydrous Na ₂ S0 ₄ . After concentration under reduced pressure the crude product was purified by column chromatography on silica gel, AcOEt/Hex = 30/70 (v/v), to give title compound (1.04 g, 4.58 mmol, 64%).

Light oil Ci ₂ H ₂ iN0 ₃ , MW 227.30, Monoisotopic Mass 228.16, [M+H] ⁺ 228.2. UPLC Rt = 5.87. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.16-1.48 (m, 11 H), 1.69-1.93 (m, 3 H), 1.96-2.18 (m, 1 H), 2.25- 2.52 (m, 1 H), 2.70-3.04 (m, 1 H), 3.22-3.44 (m, 2 H), 4.01-4.29 (m, 1 H), 9.75 (t, 1 H, J = 2.13). ¹³ C NMR (75 MHz, CDC1 ₃ ) 6 (ppm) 22.94, 24.81, 28.43, 31.26, 39.19, 52.31, 53.88, 61.61, 79.86, 128.81, 130.92.

Intermediate 9: tert-Butyl (2S)-2-(2-hydroxyethyl)azepane-l-carboxylate

To a mixture of 2-[(2S)-l-tert-butoxycarbonylazepan-2-yl]acetic acid (2.0 g, 7.8 mmol) in anhydrous DCM (20 mL) lithium aluminum hydride 2.0 M in tetrahydrofurane (5.32 g, 6.02 mL, 11.74 mmol) was added dropwise (under argon), and the reaction mixture was heated to 55°C. After stirring for 4 hours (at 55°C), the reaction mixture was cooled to room temperature, diluted with AcOEt (20 mL) and treated with saturated NaHC0 ₃ (4 mL). Then the solution was concentrated under reduce pressure. To the residue were added DCM. The organic layer was washed with water and brine, and then dried over anhydrous Na ₂ S0 ₄ , and concentrated under reduced pressure to give title compound (1.88 g, 7.73 mmol, 99%).

Light oil C ₁₃ H ₂₅ N0 ₃ , MW 243.34, Monoisotopic Mass 243.18, [M+H] ⁺ 244.3. UPLC R, = 5.64. »H NMR (300 MHz, CDCl ₃ ) 6 (ppm) 1.28-1.46 (m, 13 H), 1.48-1.64 (m, 7 H), 1.68-1.89 (m, 1 H), 2.15- 2.45 (m, 1 H), 3.51-3.68 (m, 1 H), 3.75-3.94 (m, 1 H), 4.20-4.38 (m, 1 H).

Intermediate 10: tert-Butyl (2S)-2-(2-oxoethyl)azepane-l-carboxylate

2-Iodoxybenzoic acid (IBX, 6.49 g, 23.2 mmol) was dissolved in DMSO (50 mL), stirred for 10 min. at room temperature and treated with a solution of intermediate 9 (1.88 g, 7.73 mmol) in DMSO (50 mL). After stirring overnight at room temperature the reaction mixture was diluted with Et ₂ 0 (100 mL), cooled to 0°C and quenched by addition of water (100 mL). The inorganic layer was diluted with brine (50 mL) and extracted with AcOEt. The combined organic layers were washed with saturated NaHC0 ₃ , water and brine, and then dried over anhydrous Na ₂ S0 ₄ . After concentration under reduced pressure the crude product was purified by column chromatography on silica gel, AcOEt/Hex = 30/70 (v/v), to give title compound (1.37 g, 5.68 mmol, 73%).

Light oil Ci3H ₂₃ N0 ₃ , MW 241.33, Monoisotopic Mass 241.17, [M+H] ⁺ 242.3. UPLC R, = 5.91. *H NMR (300 MHz, CDCl ₃ ) 6 (ppm) 1.16-1.52 (m, 13 H), 1.68-1.92 (m, 3 H), 1.96-2.10 (m, 1 H), 2.21- 2.48 (m, 1 H), 2.68-3.01 (m, 1 H), 3.18-3.42 (m, 2 H), 4.01-4.22 (m, 1 H), 9.71 (t, 1 H, J = 2.10).

Intermediate 1 1 : l-[2-[(2S)-Azetidin-2-yl]ethyl]—- (benzothiophen— -yl)piperazine To a solution of intermediate 2 (0.27 g, 2.3 mmol), 1 -(benzothiophen— -yl)piperazine (0.75 g, 3.45 mmol) in THF (15 mL) was added sodium triaceoxyborohydride (0.97 g, 4.6 mmol) and anhydrous AcOH (0.5 mL). After stirring for 4 hours at room temperature, to the mixture saturated NaHC0 ₃ was added, and the aqueous layer was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous Na ₂ S04, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel, DCM/MeOH = 90/7 (v/v), to give the Boc-protected derivative of the title compound (0.70 g, 1.74 mmol, yield 76%).

Boc-protected derivative: light oil C ₂₂ H ₃ iN ₃ 0 ₂ S, MW 401.56, Monoisotopic Mass 401.21, [M+H] ⁺ 402.4. UPLC Rt = 5.39. »H NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.40-1.53 (m, 1 1 H), 1.81 -1.98 (m, 1 H), 2.03-2.09 (m, 2 H), 2.22-2.40 (m, 1 H), 3.18-3.31 (m, 8 H) 3.76-3.92 (m, 2 H), 4.20-4.33 (m, 1 H), 6.91 (dd, 1 H, J = 7.66, 0.71), 7.28 (t, 2 H, J = 7.87 Hz), 7.34-7.43 (m, 1 H), 7.57 (d,l H, J = 8.08). Intermediate 1 1 was obtained upon removal of Boc protection by the treatment with TFA to give title compound as TFA salt.

Intermediate 1 1 as TFA salt: brown oil Ci ₇ H ₂₃ N ₃ S, MW 301.45, Monoisotopic Mass 301.16, [M+H] ⁺ 302.30. UPLC Rt = 2.68.

Intermediate 12: 3-[4-[2-[(2S)-Azetidin-2-yl]ethyl]piperazin-l-yl]-l ,2-benzothiazole The title compound was obtained by the same procedure as intermediate 11 starting from 2. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/7 (v/v), yield 62%, and then treated with TFA to give intermediate 12 as a TFA salt.

Boc-protected derivative: light oil C ₂ iH ₃₀ N ₄ O ₂ S, MW 402.55, Monoisotopic Mass 402.20, [M+H] ⁺ 403.4. UPLC R, = 5.03. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.42-1.52 (m, 1 1 H), 1.80-1.95 (m, 1 H), 2.04-2.09 (m, 2 H), 2.23-2.39 (m, 1 H), 3.18-3.30 (m, 8 H) 3.75-3.90 (m, 2 H), 4.19-4.33 (m, 1 H), 7.31-7.39 (m, 1 H), 7.43-7.46 (m, 1 H), 7.68-7.77 (m, 2 H).

Intermediate 12 as TFA salt: brown oil Ci ₆ H ₂₂ N ₄ S, MW 302.43, Monoisotopic Mass 302.16, [M+H] ⁺ 303.30. UPLC Rt = 2.35. Intermediate 13: 3-[l-[2-[(2S}-Azetidin-2-yl]emyl]-3,6-dm^^

chloro-1 H-indole

The title compound was obtained by the same procedure as intermediate 11 starting from 2. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/10 (v/v), yield 64%, and then treated with TFA to give intermediate 13 as a TFA salt.

Boc-protected derivative: light oil C ₂ 3H3oClN ₃ 0 ₂ , MW415.96, Monoisotopic Mass 415.20, [M+H] ⁺ 416.2. UPLC ¾ = 5.40. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.40-1.52 (m, 11 H), 1.62-1.74 (m, 2 H), 1.78-1.93 (m, 2 H), 1.97-2.04 (m, 2 H), 2.13-2.27 (m, 2 H), 2.49-2.61 (m, 2 H), 2.80-2.92 (m, 2 H), 3.34-3.41 (m, 1 H), 6.01-6.05 (m, 1 H), 7.17 (d, 1 H, J = 8.72), 7.26-7.39 (m, 2 H), 7.63-7.85 (m, 1 H). 10.41 (br. s. 1 H).

Intermediate 13 as TFA salt: brown oil Ci ₈ H ₂₂ ClN ₃ , MW 315.84, Monoisotopic Mass 315.15, [M+Hf 316.26. UPLC R, = 2.94.

Intermediate 14: 4-[4-[2-[(2S)-Pyrrolidin-2-yl]ethyl]piperazin-l-yl]-l H-indole

The title compound was obtained by the same procedure as intermediate 11 starting from 4. The Boc-protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/10 (v/v), yield 76%, and then treated with TFA to give intermediate 14 as a TFA salt.

Boc-protected derivative: yellow solid C ₂ 3H34N ₄ 0 ₂ , MW 398.54, Monoisotopic Mass 398.26, [M+H] ⁺ 399.4. UPLC R» = 4.90. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.48 (s, 9 H), 1.64-2.30 (m, 6 H), 3.63-3.03 (m, 6 H), 3.25-3.57 (m, 6 H), 3.74-3.91 (m, 1 H), 6.35-6.65 (m, 2 H), 7.02-7.23 (m, 3 H), 9.10 (br. s., 1 H).

Intermediate 14 as TFA salt: brown oil Ci8H ₂₆ N ₄ , MW 298.42, Monoisotopic Mass 298.21, [M+H] ⁺

Intermediate 15: l-(Benzotlnophen-4-yl)-4-[2-[(2S)-pyrroli^

The title compound was obtained by the same procedure as intermediate 11 starting from 4. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/7 (v/v), yield 79%, and then treated with TFA to give intermediate 15 as a TFA salt.

Boc-protected derivative: light oil C ₂₃ H ₃₃ N30 ₂ S, MW 415.59, Monoisotopic Mass 415.22, [M+H] ⁺ 416.4. UPLC Rt = 5.70. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.40-1.55 (m., 10 H), 1.64-1.76 (m, 1 H), 1.78-2.06 (m, 8 H), 2.08-2.29 (m, 1 H), 3.20-3.43 (m, 7 H), 3.77-3.88 (m, 1 H), 6.91 (d, 1 H, J = 7.60), 7.22-7.36 (m, 2 H), 7.41 (d, 1 H, J = 5.39), 7.59 (d, 1 H, J = 8.05).

1 ³ C NMR (75 MHz, CDCI3) δ (ppm) 21.50, 28.51, 29.44, 30.39, 46.62, 49.68, 52.55, 55.00, 79.53, 112.93, 118.21, 121.03, 125.02, 125.85, 133.96, 141.23, 162.46. 162.91, 174.97. Intermediate 15 as TFA salt: brown oil C ₁₈ H ₂₅ N ₃ S, MW 315.47, Monoisotopic Mass 315.7, [M+H] ⁺

Intermediate 16: 3-[4-[2-[(2S)-Pyrrolidin-2-yl]ethyl]piperazin-l-yl]-l ,2-benzoxazole The title compound was obtained by the same procedure as intermediate 11 starting from 4. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/5 (v/v), yield 80%, and then treated with TFA to give intermediate 16 as a TFA salt.

Boc-protected derivative: light oil C ₂₂ H ₃₂ N ₄ 0 ₃ 4, MW 400.51 , Monoisotopic Mass 400.25, [M+H] ⁺ 401.4. UPLC R, = 4.77. 'H NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.39-1.56 (m, 1 1 Η), 1.61-1.73 (m, 1 Η), 1.74-2.28 (m, 3 H), 2.36-2.53 (m, 2 H), 2.59-2.82 (m, 4 H), 3.24-3.46 (m, 2 H), 3.51-3.65 (m, 4 H), 3.72-3.91 (m, 1 H), 7.20 (ddd, 1 H, J = 8.02, 6.58, 1.39), 7.40-7.50 (m, 2 H), 7.67 (d, 1 H, J = 8.07 Hz). ¹³ C NMR (75 MHz, CDC1 ₃ ) δ (ppm) 28.50, 28.59, 48.07, 52.43, 54.24, 55.57, 55.72, 1 10.42, 116.15, 122.13, 122.15, 122.25, 129.46, 154.57, 161.18, 163.95, 163.97.

Intermediate 16 as TFA salt: brown oil C ₁₇ H ₂₄ N ₄ 0, MW 300.40, Monoisotopic Mass 300.19, [M+H] ⁺ 301.4. UPLC R, = 1.99.

Intermediate 17: 3-[4-[2-[(2S>-Pyrrolidin-2-yl]ethyl]piperazin-l-yl]-l ,2-benzothiazole

The title compound was obtained by the same procedure as intermediate 11 starting from 4. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/5 (v/v), yield 88%, and then treated with TFA to give intermediate 17 as a TFA salt.

Boc-protected derivative: light oil C ₂₂ H ₃₂ N ₄ 0 ₂ S, MW 416.58, Monoisotopic Mass 416.22, [M+H] ⁺ 417.3. UPLC Rt = 5.27. ^] H NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.40-1.50 (m, 11 H), 1.56-1.75 (m, 2

H), 1.75-2.05 (m, 6 H), 2.06-2.24 (m, 1 H), 2.69-3.03 (m, 3 H), 3.24-3.47 (m, 2 H), 3.60-3.81 (m, 3

H), 7.31-7.40 (m, 1 H), 7.46 (ddd, 1 H, J = 8.09, 7.02, 1.04), 7.77-7.90 (m, 2 H).

^,3 C NMR (75 MHz, CDC1 ₃ ) δ (ppm) 21.60, 28.55, 46.51 , 48.43, 49.04, 51.91, 52.26, 55.39, 120.6,

123.65, 124.06, 127.66, 152.78, 175.10.

Intermediate 17 as TFA salt: brown oil Ci ₇ H ₂₄ N ₄ S, MW 316.46, Monoisotopic Mass 316.12,

[M+H] ⁺ 317.3. UPLC Rt = 2.27.

Intermediate 18: 7-[4-[2-[(2S)-Pyrrolidin-2-yl]ethyl]piperazin-l-yl]-3H-l ,3-benzoxazol- 2-one

The title compound was obtained by the same procedure as intermediate 11 starting from 4. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/10 (v/v), yield 62%, and then treated with TFA to give intermediate 18 as a TFA salt.

Boc-protected derivative: light oil C ₂₂ H ₃₂ N ₄ 0 ₄ , MW 416.51 , Monoisotopic Mass 416.24, [M+H] ⁺ 417.4. UPLC R, = 4.29. »H NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.20-1.53 (m, 10 H), 1.61 -1.75 (m, 1 H), 1.76-2.34 (m, 4 H), 2.67-3.23 (m, 6 H), 3.24-3.37 (m, 2 H), 3.39-3.60 (m, 4 H), 3.69-3.91 (m, 1 H), 6.56 (d, 1 H, J = 8.37), 6.65-6.76 (m, 1 H), 7.01 (t, 1 H, J = 8.09), 9.01 (m, br.s., 1 H). ¹³ C NMR (75 MHz, CDCb) δ (ppm) 21.44, 23.66 , 28.48, 28.53, 46.81 , 52.04, 79.70, 110.50, 124.65, 130.70, 134.17, 155.01, 175.87.

Intermediate 18 as TFA salt: brown oil Ci7H ₂₄ N ₄ 0 ₂ , MW 316.39, Monoisotopic Mass 316.19, [M+H] ⁺ 317.3. UPLC R, = 1.22.

Intermediate 19: 8 4-[24(2S)-Pyrrolidin-2-yl]ethyl]piperazin-l-yl]-4H-l ,4-benzoxazin- 3-one

The title compound was obtained by the same procedure as intermediate 1 1 starting from 4. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/15 (v/v), yield 65%, and then treated with TFA to give intermediate 19 as a TFA salt.

Boc-protected derivative: light oil C ₂ 3H ₃ 4N ₄ 0 ₄ , MW 430.54, Monoisotopic Mass 430.26, [M+H] ⁺

431.4. UPLC R, = 4.01. »H NMR (300 MHz, CDCI3) δ (ppm) 1.22-1.53 (m, 10 H), 1.62-1.75 (m, 1

H), 1.76-2.33 (m, 4 H), 2.65-3.24 (m, 6 H), 3.26-3.37 (m, 2 H), 3.38-3.61 (m, 4 H), 3.69-3.92 (m, 1 H), 4.83 (s, 2 H), 6.55 (d, 1 H, J = 8.30), 6.63-6.74 (m, 1 H), 7.00 (t, 1 H, J = 8.10), 9.03 (br.s., 1 H).

Intermediate 19 as TFA salt: brown oil C ₁₈ H ₂ 6N ₄ 0 ₂ , MW 330.42, Monoisotopic Mass 330.20,

[M+H] ⁺ 331.3. UPLC Rt = 1.03.

Intermediate 20: l-(2,3-Dihydro-l ,4-benzodioxin-5-ylH-[2-[(2S>-pyrrolidin-2-yl]ethyl]- piperazine

The title compound was obtained by the same procedure as intermediate 11 starting from 4. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/7 (v/v), yield 79%, and then treated with TFA to give intermediate 20 as a TFA salt.

Boc-protected derivative: light oil 3H35N3C , MW 417.54, Monoisotopic Mass 417.26, [M+H] ⁺ 418.4. UPLC Rt = 4.81. ^! H NMR (300 MHz, CDCI3) δ (ppm) 1.46 (s, 9 H), 1.55-1.74 (m, 1 H), 1.76- 2.06 (m, 6 H), 2.07-2.31 (m, 1 H), 2.49-3.45 (m, 10 H), 3.70-3.87 (m, 1 H), 4.21-4.27 (m, 2 H), 4.29- 4.34 (m, 2 H), 6.52 (dd, 1 H, J = 8.00, 1.41), 6.60 (dd, 1 H, J = 8.24, 1.50), 6.72-6.81 (m, 1 H).

Intermediate 20 as TFA salt: brown oil Ci ₈ H ₂ 7N ₃ 0 ₂ , MW 317.42, Monoisotopic Mass 317.21, [M+H] ⁺ 318.3. UPLC R, = 1.73.

Intermediate 21 : l-[6-Butyl-4-(2-tWenyl)-2-pyridyl]^[2-[(2S^

piperazine

The title compound was obtained by the same procedure as intermediate 1 1 starting from 4. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/7 (v/v), yield 79%, and then treated with TFA to give intermediate 21 as a TFA salt. ¹ Boc-protected derivative: light oil C ₂₈ H ₄₂ N ₄ 0 ₂ S, MW 498.72, Monoisotopic Mass 498.30, [M+H] ⁺

499.4. UPLC R, = 5.89. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 0.89-0.99 (m, 3 H), 1.34-1.46 (m, 13 H), 1.62-1.75 (m, 6 H), 1.80-1.89 (m, 1 H), 2.04-2.13 (m, 1 H), 2.59-2.70 (m, 4 H), 3.36-3.45 (m, 4 H), 3.51-3.61 (m., 4 H), 4.02-4.08 (m, 1 H), 6.61-6.74 (m, 2 H), 7.54 (t, 1 H, J = 2.13), 7.71-7.77 (m, 1 H), 8.84 (dd, 1 H, J = 8.60, 0.66).

Intermediate 21 as TFA salt: brown oil C ₂₃ H ₃₄ N ₄ S, MW 398.60, Monoisotopic Mass 398.25, [M+H] ⁺ 399.2. UPLC Rt = 2.37.

Intermediate 22: l-[6-Butyl-4-(4-fluorophenyl)-2-pyridyl]-4-[2-[(2S)-pyrrolid in-2-yl]ethyl]- piperazine

The title compound was obtained by the same procedure as intermediate 11 starting from 4. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/5 (v/v), yield 77%, and then treated with TFA to give intermediate 22 as a TFA salt.

Boc-protected derivative: light oil C ₃ oH ₄₃ FN 0 ₂ , MW 510.68, Monoisotopic Mass 510.3, [M+H] ⁺

511.5. UPLC R, = 7.36.

Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 0.92-0.96 (m, 3 H), 1.33-1.46 (m, 13 H), 1.67-2.06 (m, 8 H), 2.66-2.71 (m, 3 H), 2.88-3.13 (m, 5 H), 3.76-4.03 (m, 5 H), 6.57 (d, 1 H, J = 1.03), 6.72 (s, 1 H), 7.05-7.19 (m, 2 H), 7.47-7.61 (m, 2 H).

Intermediate 22 as TFA salt: brown oil C ₂₅ H ₃₅ FN ₄ , MW 410.57, Monoisotopic Mass 410.28, [M+H] ⁺ 411.4. UPLC R, = 4.46.

Intermediate 23: 6-Fluoro-34142 (2S)-pyrrolidin-2-yl]e l]-3,Mhydrcv-2H-pyria^

4-yl]-lH-indole

The title compound was obtained by the same procedure as intermediate 11 starting from 4. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/7 (v/v), yield 73%, and then treated with TFA to give intermediate 23 as a TFA salt.

Boc-protected derivative: yellow solid C ₂₄ H ₃₂ FN ₃ 0 ₂ , MW 413.53, Monoisotopic Mass 413.25 [M+H] ⁺ 414.3. UPLC Rt = 5.40. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.32-1.46 (m, 11 H), 1.63- 1.74 (m, 1 H), 1.75-2.01 (m, 8 H), 2.71-2.80 (m, 2 H), 3.24-3.33 (m, 2 H), 3.68-3.84 (m, 2 H), 5.88- 6.02, (m, 1 H), 6.79 (td, 1 H, J = 9.10, 1.66), 7.02-7.11 (m, 2 H), 7.54 (dd, 1 H, J = 8.30, 5.31), 10.41 (br. s. 1 H).

Intermediate 23 as TFA salt: brown oil Ci9H ₂₄ FN ₃ , MW 313.41, Monoisotopic Mass 313.19, [M+H] ⁺ 314.4. UPLC R, = 2.35. Intermediate 24: 5-Chloro-3-[ 142-[(2S)-pyrrolidin-2-yl]e l]-3,Mhydro-2H-pyridin- 4-yl]-lH-indole

The title compound was obtained by the same procedure as intermediate 11 starting from 4. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/10 (v/v), yield 67%, and then treated with TFA to give intermediate 24 as a TFA salt.

Boc-protected derivative: yellow solid C ₂ 4H3 ₂ C1N ₃ 0 ₂ , MW 429.98, Monoisotopic Mass 429.22, [M+H] ⁺ 430.4. UPLC Rt = 5.71. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.40-1.56 (m, 13 H), 1.62- 1.79 (m, 2 H), 1.81-1.94 (m, 2 H), 1.95-2.09 (m, 2 H), 2.14-2.28 (m, 2 H), 2.50-2.67 (m, 2 H), 2.87- 2.97 (m, 2 H), 3.36 (br. s., 1 H), 6.00-6.05 (m, 1 H), 7.14 (d, 1 H, J = 8.75), 7.26-7.41 (m, 2 H), 7.67- 7.86 (m, 1 H). 10.42 (br. s. 1 H).

Intermediate 24 as TFA salt: brown oil C ₁₉ H ₂ 4C1N ₃ , MW 329.87, Monoisotopic Mass 329.16, [M+H] ⁺ 330.3. UPLC Rt = 2.82.

Intermediate 25: 4-[4-[2-[(2R)-Pyrrolidin-2-yl]ethyl]piperazin-l-yl]-l H-indole

The title compound was obtained by the same procedure as intermediate 11 starting from 6. The Boc-protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/10 (v/v), yield 75%, and then treated with TFA to give intermediate 25 as a TFA salt.

Boc-protected derivative: yellow solid C ₂ 3H34N40 ₂ , MW 398.54, Monoisotopic Mass 398.26, [M+H] ⁺ 399.4. UPLC R, = 4.89. Ή NMR (300 MHz, CDCI3) δ (ppm) 1.48 (s, 9 H), 1.62-2.20 (m, 6 H), 2.62-3.07 (m, 6 H), 3.26-3.51 (m, 6 H) 3.74-3.88 (m, 1 H) 6.35-6.44 (m, 1 H), 6.47-6.56 (m, 1 H), 7.01-7.22 (m, 3 H), 9.12 (br. s., 1 H)

¹³ C NMR (75 MHz, CDCI3) δ (ppm) 21.69, 23.71, 28.55, 29.25, 30.33, 46.65, 48.50, 52.30 , 55.09, 79.68, 100.15, 106.92, 107.35, 121.16, 122.58, 123.33, 137.03, 175.10.

Intermediate 25 as TFA salt: brown oil Ci ₈ H ₂₆ N ₄ , MW 298.42, Monoisotopic Mass 298.21, [M+H] ⁺ 299.4. UPLC R, = 1.39.

Intermediate 26: l-(Benzothiophen— 4—yl)—-[2— [(2R)-pyrrolidin-2-yl]ethyl]piperazine The title compound was obtained by the same procedure as intermediate 11 starting from 6. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/7 (v/v), yield 75%, and then treated with TFA to give intermediate 26 as a TFA salt.

Boc-protected derivative: light oil C ₂ 3H3 ₃ N30 ₂ S, MW 415.59, Monoisotopic Mass 415.22, [M+H] ⁺ 416.4. UPLC Rt = 5.69. Ή NMR (300 MHz, CDCI3) δ (ppm) 1.40-1.51 (m, 10 H), 1.65-1.76 (m, 1 H), 1.77-2.06 (m, 8 H), 2.08-2.29 (m, 1 H), 3.26-3.45 (m, 7 H), 3.79-3.89 (m, 1 H), 6.93 (dd, 1 H, J = 7.65, 0.69), 7.23-7.27 (m, 1 H), 7.29-7.35 (m, 1 H), 7.42 (d, 1 H, J = 5.55), 7.60 (d, 1 H, J = 8.11). Intermediate 26 as TFA salt: brown oil C ₁₈ H ₂ 5N3S, MW 315.47, Monoisotopic Mass 315.17, [M+H] ⁺ 316.3. UPLC R, = 2.77.

Intermediate 27: 3-[4—[2-[(2R)-PynOlidin-2-yl]ethyl]piperazin-l-yl]-l ,2-benzoxazole The title compound was obtained by the same procedure as intermediate 11 starting from 6. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/5 (v/v), yield 85%, and then treated with TFA to give intermediate 27 as a TFA salt.

Boc-protected derivative: light oil C ₂₂ H ₃₂ N ₄ 0 ₃ 4, MW 400.51, Monoisotopic Mass 400.25, [M+H] ⁺ 401.4. UPLC Rt = 4.79. ¾ NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.38-1.54 (m, 11 H), 1.60-1.73 (m, 1 H), 1.74-2.29 (m, 3 H), 2.35-2.55 (m, 2 H), 2.68 (d, 4 H, J = 4.21), 3.24-3.47 (m, 2 H), 3.50-3.63 (m, 4 H), 3.71-3.90 (m, 1 H), 7.21 (ddd, 1 H, J = 8.01, 6.55, 1.37), 7.40-7.49 (m, 2 H), 7.66 (d, 1 H, J = 8.05 Hz).

Intermediate 27 as TFA salt: brown oil Ci ₇ H ₂₄ N ₄ 0, MW 300.40, Monoisotopic Mass 300.19, [M+H] ⁺ 301.3. UPLC R, = 2.00.

Intermediate 28: 3-[4-[2-[(2R)-Pyrrolidin-2-yl]ethyl]piperazin-l-yl]-l ,2-benzothiazole The title compound was obtained by the same procedure as intermediate 11 starting from 6. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/5 (v/v), yield 84%, and then treated with TFA to give intermediate 28 as a TFA salt.

Boc-protected derivative: light oil C ₂₂ H ₃₂ N ₄ 0 ₂ S, MW 416.58, Monoisotopic Mass 416.22, [M+H] ⁺ 417.4. UPLC Rt = 5.23. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.37-1.50 (m, 1 1 H), 1.53-1.74 (m, 2 H), 1.75-2.06 (m, 6 H), 2.69-3.04 (m, 3 H) 3.20-3.48 (m, 2 H), 3.59-3.80 (m, 3 H), 3.90-3.95 (m, 1 H), 7.30-7.38 (m, 1 H), 7.45 (ddd, 1 H, J = 8.04, 7.01, 1.08), 7.77-7.89 (m, 2 H).

Intermediate 28 as TFA salt: brown oil Ci ₇ H ₂₄ N ₄ S, MW 316.46, Monoisotopic Mass 316.12, [M+H] ⁺ 317.3. UPLC Rt = 2.27.

Intermediate 29: l-(2,3-Dihydro-l ,4-benzodioxin-5-yl)-4-[2-[(R-pyrrolidin-2-yl]ethyl]- piperazine

The title compound was obtained by the same procedure as intermediate 11 starting from 6. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/7 (v/v), yield 78%, and then treated with TFA to give intermediate 29 as a TFA salt.

Boc-protected derivative: light oil C ₂₃ H ₃₅ N ₃ 0 ₄ , MW 417.54, Monoisotopic Mass 417.26, [M+H] ⁺ 417.4. UPLC R, = 4.93. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.45 (s, 9 H), 1.54-1.73 (m, 1 H), 1.75- 2.06 (m, 6 H), 2.05-2.30 (m, 1 H), 2.50-3.47 (m, 10 H), 3.70-3.89 (m, 1 H), 4.20-4.27 (m, 2 H), 4.28- 4.34 (m, 2 H), 6.52 (dd, 1 H, J = 8.00, 1.43), 6.61 (dd, 1 H, J = 8.24, 1.51), 6.73-6.80 (m, 1 H). ^l3 C NMR (75 MHz, CDC1 ₃ ) δ (ppm) 21.60, 28.54, 63.94, 64.39, 110.88, 120.78, 136.26, 144.12, 174.95.

Intermediate 29 as TFA salt: brown oil Ci ₈ H ₂₇ N ₃ 02, MW 317.42, Monoisotopic Mass 317.21, [M+H] ⁺ 317.3. UPLC Rt = 1.91.

Intermediate 30: l-[6-Butyl-4-(4-fluorophenyl)-2^yridyl]-4-[2-[(2R)-pyrrolidi n-2-yl]ethyl]- piperazine

The title compound was obtained by the same procedure as intermediate 11 starting from 4. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/5 (v/v), yield 79%, and then treated with TFA to give intermediate 30 as a TFA salt.

Boc-protected derivative: light oil C30H43FN4O;!, MW 510.68, Monoisotopic Mass 510.34, [M+H] ⁺

Ή NMR (300 MHz, CDCI3) δ (ppm) 0.91-0.96 (m, 3 H), 1.33-1.44 (m, 13 H), 1.66-2.07 (m, 8 H), 2.64-2.72 (m, 3 H), 2.86-3.14 (m, 5 H), 3.74-4.04 (m, 5 H), 6.59 (d, 1 H, J = 1.05), 6.73 (s, 1 H), 7.05-7.21 (m, 2 H), 7.48-7.62 (m, 2 H).

1 ³ C NMR (75 MHz, CDCI3) δ (ppm) 14.00, 21.22, 22.50, 23.65, 28.49, 31.59, 38.01, 43.52, 46.61, 51.85, 54.10, 55.06, 79.48, 102.34, 115.64, 115.92, 128.68, 128.79, 135.72, 149.79, 158.70, 161.48, 161.67, 162.58, 164.77, 175.27.

Intermediate 30 as TFA salt: brown oil C ₂₅ H35FN4, MW 410.57, Monoisotopic Mass 410.28, [M+H] ⁺ 411.4. UPLC Rt = 4.43.

Intermediate 31 :6-Fluoro-3-[l-[2-[(2R)-pyrrolia r^2-yl]e ^

4-yl]-lH-indole

The title compound was obtained by the same procedure as intermediate 11 starting from 6. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/7 (v/v), yield 77%, and then treated with TFA to give intermediate 31 as a TFA salt.

Boc-protected derivative: light oil C ₂₄ H ₃₂ FN30 ₂ , MW 413.53, Monoisotopic Mass 413.25 [M+H] ⁺ 414.4. UPLC Rt = 5.41. Ή NMR (300 MHz, CDCI3) δ (ppm) 1.32-1.46 (m, 11 H), 1.64-1.74 (m, 1 H), 1.76-2.01 (m, 8 H), 2.70-2.91 (m, 2 H) 3.24-3.34 (m, 2 H) 3.67-3.84 (m, 2 H), 5.88-5.94 (m, 1 H), 6.78 (td, 1 H, J = 9.11, 1.65), 7.00-7.11 (m, 2 H), 7.54 (dd, 1 H, J = 8.32, 5.37), 10.38 (br. s. 1 H). ¹³ C NMR (75 MHz, CDCI3) δ (ppm) 23.51, 24.70, 28.31, 29.39, 30.53, 48.58, 48.87, 49.44, 49.72, 53.53, 54.76, 80.12, 97.79, 98.13, 108.39, 108.71, 120.49, 120.62, 121.07, 130.43, 136.94, 137.10, 157.98, 161.14.

Intermediate 31 as TFA salt: brown oil Ci9H ₂ 4FN3, MW 313.41, Monoisotopic Mass 313.19, [M+H] ⁺ 314.4. UPLC Rt = 2.31. Intermediate 32: 5-CWoro-3-[l-[2-[(2R)-pyrrolidin-2-yl]em^^

4-yl]-lH-indole

The title compound was obtained by the same procedure as intermediate 11 starting from 6. The Boc- protected derivative was purified by column chromatography on silica gel, DCM MeOH = 90/7 (v/v), yield 77%, and then treated with TFA to give intermediate 32 as a TFA salt.

Boc-protected derivative: yellow solid C24H3 ₂ C1N ₃ 0 ₂ , MW 429.98, Monoisotopic Mass 429.22, [M+H] ⁺ 430.4. UPLC R, = 5.68. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.40-1.54 (m, 13 H), 1.62- 1.78 (m, 2 H), 1.80-1.93 (m, 2 H), 1.95-2.08 (m, 2 H), 2.15-2.27 (m, 2 H), 2.50-2.66 (m, 2 H), 2.85- 2.95 (m, 2 H), 3.36-3.39 (m, 1 H), 6.01-6.06 (m, 1 H), 7.15 (d, 1 H, J = 8.70), 7.27-7.40 (m, 2 H), 7.64-7.85 (m, 1 H). 10.40 (br. s. 1 H).

Intermediate 32 as TFA salt: brown oil Ci ₉ H ₂₄ ClN3, MW 329.87, Monoisotopic Mass 329.16, [M+H] ⁺ 330.4. UPLC Rt = 2.84.

Intermediate 33: l-(Benzothiophen——yl)-4— [2-[(2S)-2-piperidyl]ethyl]piperazine

The title compound was obtained by the same procedure as intermediate 11 starting from 8. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/7 (v/v), yield 80%, and then treated with TFA to give intermediate 33 as a TFA salt.

Boc-protected derivative: light oil C ₂₄ H35N ₃ 0 ₂ S, MW 429.62, Monoisotopic Mass 429.24, [M+H] ⁺ 430.4. UPLC Rt = 5.86. >H NMR (300 MHz, CDCI3) δ (ppm) 1.21-1.49 (m, 13 H), 1.51 -1.84 (m, 7 H), 1.85-2.07 (m, 2 H), 2.10-2.30 (m, 1 H), 2.45-2.87 (m, 2 H), 3.02-3.11 (m, 1 H), 3.26-3.38 (m, 3 H), 4.23-4.34 (m, 1 H), 6.92 (dd, 1 H, J = 7.66, 0.71), 7.23-7.29 (m, 1 H), 7.31-7.37 (m, 1 H), 7.38- 7.44 (m, 1 H), 7.58 (d, 1 H, J = 8.08).

¹³ C NMR (75 MHz, CDCI3) δ (ppm) 19.03, 21.46, 25.44, 25.54, 28.38, 28.40, 28.48, 28.89, 50.41, 52.90, 55.32, 79.61, 112.71, 117.82, 121.27, 125.00, 125.55, 134.00, 141.19, 155.1 1 , 175.31.

Intermediate 33 as TFA salt: brown oil Ci9H ₂₇ N ₃ S, MW 329.50, Monoisotopic Mass 329.19, [M+H] ⁺ 330.4. UPLC R, = 2.83.

Intermediate 34: 3-[4-[2-[(2S)-2-Piperidyl]ethyl]piperazin-l-yl]-l ,2-benzothiazole The title compound was obtained by the same procedure as intermediate 11 starting from 8. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/7 (v/v), yield 89%, and then treated with TFA to give intermediate 34 as a TFA salt.

Boc-protected derivative: light oil C ₂ 3H ₃ 4N ₄ 0 ₂ S, MW 430.60, Monoisotopic Mass 430.24, [M+H] ⁺ 431.4. UPLC Rt = 5.35. Ή NMR (300 MHz, CDCI3) δ (ppm) 1.21-1.49 (m, 13 H), 1.54-1.70 (m, 2 H), 1.73-2.03 (m, 6 H), 2.06-2.21 (m, 1 H), 2.64-2.95 (m, 3 H), 3.20-3.47 (m, 2 H), 3.58-3.78 (m, 3 H), 7.30^7.39 (m, 1 H), 7.42-7.46 (m, 1 H), 7.68-7.78 (m, 2 H). Intermediate 34 as TFA salt: brown oil Ci ₈ H ₂ o 4S, MW 330.49, Monoisotopic Mass 330.18, [M+H] ⁺ 331.3. UPLC Rt = 2.34.

Intermediate 35: 6-Fluoro-3-[l-[2-[(2S)-2-piperidyl]emyl]-^

yl]-lH-indole

The title compound was obtained by the same procedure as intermediate 11 starting from 8. The Boc-protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/10 (v/v), yield 77%, and then treated with TFA to give intermediate 35 as a TFA salt.

Boc-protected derivative: yellow solid C ₂ 5H34FN ₃ 0 ₂ , MW 427.55, Monoisotopic Mass 427.26, [M+H] ⁺ 428.4. UPLC R, = 5.56. ¹ H NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.28-1.50 (m, 1 1 H), 1.52- 1.78 (m, 6 H), 1.95-2.20 (m, 2 H), 2.38-2.62 (m, 4 H), 2.70-2.89 (m, 3 H), 3.18-3.29 (m, 2 H), 4.20- 4.34 (m, 1 H), 6.08-6.16 (m, 1 H), 6.88 (d, 1 H, J = 1.89), 7.03 (dd, 1 H, J = 9.49, 2.31), 7.10 (d, 1 H, J = 2.28), 7.75 (dd, 1 H, J = 8.85, 5.32).

¹³ C NMR (75 MHz, CDCI3) δ (ppm) 19.12, 25.60, 27.42, 28.52, 28.86, 50.55, 53.13, 55.71, 79.28, 97.39, 97.73, 108.39, 108.70, 1 17.80, 121.28, 121.41 , 121.61, 121.83, 129.61 , 136.74, 136.90, 155.13, 158.17, 161.32.

Intermediate 35 as TFA salt: brown oil C ₀ H ₂₆ FN ₃ , MW 327.44, Monoisotopic Mass 327.21, [M+H] ⁺ 328.3. UPLC Rt = 2.55.

Intermediate 36: 5^Woro-3-[1424(2S)-2-piperidyl]e l]-3,6-dihydro-2H-pyridin--4- yl]-lH-indole

The title compound was obtained by the same procedure as intermediate 11 starting from 8. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/7 (v/v), yield 75%, and then treated with TFA to give intermediate 36 as a TFA salt.

Boc-protected derivative: light oil C ₂₅ H ₃ 4C1N ₃ 0 ₂ , MW 444.01 , Monoisotopic Mass 443.23, [M+H] ⁺ 444.4. UPLC Rt = 5.85. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.23-1.48 (m, 13 H), 1.62-1.75 (m, 4 H), 1.79-1.93 (m, 2 H), 1.97-2.07 (m, 2 H), 2.14-2.26 (m, 2 H), 2.48-2.60 (m, 2 H), 2.81-2.92 (m, 2 H), 3.35-3.40 (m, 1 H), 6.01-6.05 (m, 1 H), 7.08-7.13 (m, 1 H), 7.28-7.42 (m, 2 H), 7.63-7.83 (m, 1 H). 10.39 (br. s. 1 H).

Intermediate 36 as TFA salt: brown oil C20H26CIN3, MW 343.89, Monoisotopic Mass 343.18, [M+H] ⁺ 344.3. UPLC Rt = 2.90. Intermediate 37: (2S)-2-[2-[4— (BenzotWophen- -yl)piperazm^

The title compound was obtained by the same procedure as intermediate 11 starting from 10. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/7 (v/v), yield 83%, and then treated with TFA to give intermediate 37 as a TFA salt.

Boc-protected derivative: light oil C ₂ 5H ₃₇ N ₃ 0 ₂ S, MW 443.65, Monoisotopic Mass 443.26, [M+H] ⁺ 444.3. UPLC R, = 5.91. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.19-1.48 (m, 15 H), 1.50-1.82 (m, 7 H), 1.85-2.02 (m, 2 H), 2.10-2.25 (m, 1 H), 2.44-2.83 (m, 2 H), 3.01-3.10 (m, 1 H), 3.22-3.35 (m, 3 H), 4.20-4.31 (m, 1 H), 6.91 (dd, 1 H, J = 7.60, 0.70), 7.22-7.27 (m, 1 H), 7.33-7.37 (m, 1 H), 7.37- 7.45 (m, 1 H), 7.57 (d, 1 H, J = 8.03).

Intermediate 37 as TFA salt: brown oil Ci ₀ H ₂₉ N ₃ S, MW 343.53, Monoisotopic Mass 343.21, [M+H] ⁺ 344.3. UPLC Rt = 2.80.

Intermediate 38: 3-[4—[2-[(2S)-Azepan-2-yl]ethyl]piperazin-l-yl]-l ,2-benzothiazole The title compound was obtained by the same procedure as intermediate 11 starting from 10. The Boc- protected derivative was purified by column chromatography on silica gel, DCM/MeOH = 90/7 (v/v), yield 85%, and then treated with TFA to give intermediate 38 as a TFA salt.

Boc-protected derivative: light oil C ₂ 4H ₃ 6N ₄ 0 ₂ S, MW 444.63, Monoisotopic Mass 444.25, [M+H] ⁺ 445.3. UPLC Rt = 5.42. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.20-1.49 (m, 15 H), 1.53-1.69 (m, 2 H), 1.72-2.01 (m, 6 H), 2.06-2.20 (m, 1 H), 2.63-2.91 (m, 3 H), 3.20-3.45 (m, 2 H), 3.55-3.73 (m, 3 H), 7.30-7.38 (m, 1 H), 7.42-7.45 (m, 1 H), 7.66-7.75 (m, 2 H).

Intermediate 38 as TFA salt: brown oil C19H28N4S, MW 344.52, Monoisotopic Mass 344.20 [M+H] ⁺

General method for synthesis of azine-sulfonyl chlorides.

Azinesulfonyl chlorides were prepared from the corresponding haloquinolines or isoquinoline via their S-methyl analogs obtained in the reaction with an excess of sodium methanethiolate in the boiling DMF. S-Demethylation led to the respective azinethiolates which submitted to oxidative chlorination yielded the desired quinoline- and isoquinoline-sulfonyl chlorides (Maslankiewicz et al. 2007).

Intermediate 39: 2-Quinolinesulfonyl chloride

Solid at rt, unstable at rt. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 7.79-7.83 (ddd, J = 8.8, 7.0, 0.9 Hz, 1H, H-6), 7.92-7.96 (ddd, J = 8.8, 7.0, 1.2 Hz, 1H, H-7), 7.99-8.01 (d, J = 8.4 Hz, 1H, H-3), 8.14- 8.16 (dd, J = 8.8, 0.9 Hz, 1H, H-5), 8.32-8.34 (dd, J = 8.8, 1.2 Hz, 1 H, H-8), 8.52-8.54 (d, J = 8.4 Hz, 1H, H-4). ¹³ C NMR (75 MHz, CDC1 ₃ ) δ (ppm) 1 17.0 (IIP), 128.2 (IIP), 130.1 (C4a), 130.8 (2 x IIP), 132.5 (IIP), 140.2 (IIP), 139.0 (C4), 147.3 (C8a), 158.1 (C2). Described in Maslankiewicz et al. 2007

Intermediate 40: 4-Quinolinesulfonyl chloride

Isolated only in the form of methylene chloride or chloroform solutions, unstable at 10°C, within 1 h. Ή NMR (300 MHz, CDCI3) δ (ppm) 8.00-8.04 (dd, J = 8.8, 7.6 Hz, 1H, H-6), 8.08-8.09 (d, J=6.0 Hz, 1H, H-3), 8.14-8.18 (dd, J = 8.4, 7.6 Hz, 1H, H-7), 8.47-8.49 (d, J = 8.4 Hz, 1H, H-8), 8.91-8.93 (d, J = 8.8 Hz, 1H, H-5), 9.15-9.16 (d, J = 6.0 Hz, 1H, H-2).

¹³ C NMR (75 MHz, CDCI3) δ (ppm) 122.3 (C3), 122.9 (C6), 125.5 (C5), 127.5 (C4a), 131.6 (C7),136.0 (C8), 139.0 (C4), 143.13 (C8a), 153.5 (C2). Described in Maslankiewicz et al. 2007 Examples of the compounds according to the invention

General method for synthesis of azinesulfonamides (compounds of examples 1-93)

A mixture of the appropriate secondary amines (selected from Intermediates 1 1-38; 1.2 mmol) in DCM (6 mL), and TEA (2.4 mmol) was cooled down (ice bath), and azinesulfonyl chloride (1.3 mmol) was added at 0°C in two portions. The reaction mixture was stirred for 2-6 hours under cooling. Then, the solvent was evaporated and the crude azinesulfonamides were purified by column chromatography.

Example 1 : (S)-3-(4-(2-( 1 -(Quinolin-5-ylsulfonyl)azetidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2- benzothiazole

Brown oil C ₂₅ H ₂₇ N ₅ 0 ₂ S, MW 493.64, Monoisotopic Mass 493.16, [M+H] ⁺ 494.4. UPLC Rt = 4.82. Ή NMR (300 MHz, CDCI3) δ (ppm) 1.26-1.40 (m, 2 H), 1.83-1.94 (m, 1 H), 2.00-2.09 (m, 2 H), 2.12-2.21 (m, 1 H), 2.67-2.69 (m, 4 H), 3.56-3.67 (m, 6 H), 3.87 (q, J = 8.75 Hz, 1 H), 7.39 (ddd, J = 8.12, 7.04, 0.98 Hz, 1 H), 7.50 (ddd, J = 8.08, 7.03, 1.03 Hz, 1 H), 7.62 (dd, J = 8.78, 4.18 Hz, 1 H), 7.82-7.87 (m, 2 H), 7.90 (d, J = 8.17 Hz, 1 H), 8.31-8.43 (m, 2 H), 9.05 (dd, J = 4.18, 1.64 Hz, 1 H), 9.17-9.20 (m, 1 H). ^,3 C NMR (75 MHz, CDCI3) δ (ppm) 25.22, 27.43, 27.93, 30.34, 34.37, 40.46, 51.31, 53.26, 53.67, 55.57, 120.61, 122.65, 123.79, 123.99, 127.61, 127.67, 130.73, 133.76, 136.21, 151.28.

Example 2 : (S)-3-(4-(2-( 1 -(Isoquinolin-4-ylsulfonyl)azetidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2- benzothiazole

Brown oil C ₂₅ H ₂ 7N ₅ 0 ₂ S, MW 493.64, Monoisotopic Mass 493.16, [M+H] ⁺ 494.4. UPLC Rt = 4.78.

Example 3: (S)-3-(4-(2-(l-(Isoquinolin-5-ylsulfonyl)azetidin-2-yl)ethyl )piperazin-l-yl)-l,2- benzothiazole

Brown oil C ₂₅ H ₂₇ N ₅ 0 ₂ S, MW 493.64, Monoisotopic Mass 493.16, [M+H] ⁺ 494.4. UPLC R, = 4.32. Example 4: (S)-4-((2-(2-(4-(Benzo[fe]thiophen-4-yl)piperazin-l-yl)ethyl )azetidin-l- yl)sulfonyl)isoquinoline

Yellow oil C ₂₆ H ₂₈ N ₄ 0 ₂ S ₂ , MW 492.66, Monoisotopic Mass 492.17, [M+H] ⁺ 493.4. UPLC Rt = 4.87.

Example 5: (S)-4-((2-(2-(4-(Benzo[6]thiophen-4-yl)piperazin-l -yl)ethyl)azetidin- 1- yl)sulfonyl)quinoline

Yellow oil C ₂₆ H ₂₈ N ₄ 0 ₂ S ₂ , MW 492.66, Monoisotopic Mass 492.17, [M+H] ⁺ 493.4. UPLC R, = 5.04.

Example 6: (S)-3-((2-(2-(4-(5-Chloro- 1 H-indol-3-yl)-5,6-dihydropyridin- 1 (2H)-yl)ethyl)- azetidin- 1 -yl)sulfonyl)quinoline

Brown oil C ₂₇ H ₂₇ C1N ₄ 0 ₂ S, MW 507.05, Monoisotopic Mass 506.15, [M+H] ⁺ 507.4. UPLC

Example 7: (S)-4-((2-(2-(4-(5-Chloro-lH-indol-3-yl)-5,6-dihydropyridin- l (2H)-yl)ethyl)- azetidin- 1 -yl)sulfonyl)isoquinoline

Brown oil C ₂₇ H ₂₇ C1N ₄ 0 ₂ S, MW 507.05, Monoisotopic Mass 506.15, [M+H] ⁺ 507.4. UPLC Rt = 5.13. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.61-1.81 (m, 4 H), 2.1 1-2.23 (m, 2 H), 2.49-2.62 (m, 4 H), 2.64-2.73 (m, 2 H), 3.40-3.48 (m, 2 H), 4.35^1.43 (m, 1 H), 5.97-6.12 (m, 1 H), 7.15 (dd, J=8.66, 1.96 Hz, 1 H), 7.22 (s, 1 H), 7.32 (dd, J=8.68, 0.37 Hz, 1 H), 7.71 (d, J=1.66 Hz, 1 H), 7.75 (ddd, J=8.13, 7.05, 0.95 Hz, 1 H), 7.91 (ddd, J=8.58, 7.07, 1.37 Hz, 1 H), 8.05 (d, J=8.02 Hz, 1 H), 8.54 (d, J = 8.66 Hz, 1 H), 8.66 (br.s, 1 H), 9.07 (s, 1 H), 9.37 (s, 1 H).

Example 8: (S)-3-((2-(2-(4-(lH-Indol-4-yl)piperazm-l-yl)e l)pyrrolidin-l-yl)sulfonyl)iso- quinoline

Brown oil C ₂₇ H ₃ iN ₅ 0 ₂ S, MW 489.63, Monoisotopic Mass 489.22, [M+H] ⁺ 490.4. UPLC R, = 4.25.

Example 9: (S)-4-((2-(2-(4-(lH-Indol-4-yl)piperazm-l-yl)ethyl)pyrrolidi n-l-yl)sulfonyl)iso- quinoline

Yellow oil C ₂₇ H ₃₁ N ₅ 0 ₂ S, MW 489.63, Monoisotopic Mass 489.22, [M+H] ⁺ 490.3. UPLC Rt = 4.38. Ή NMR (300 MHz, CDCb) δ (ppm) 1.63-1.76 (m, 6 H), 1.86-1.93 (m, 1 H), 2.38-2.49 (m, 2 H), 2.58-2.65 (m, 2 H), 2.68-2.75 (m, 2 H), 3.26-3.31 (m, 4 H), 3.41-3.47 (m, 2 H), 4.02-4.11 (m, 1 H), 6.51-6.62 (m, 2 H), 7.04-7.18 (m, 3 H), 7.71-7.94 (m, 2 H), 8.09 (s, 1 H), 8.86 (d, J = 8.62 Hz, 1 H), 9.11 (s, 1H), 9.40 (s, 1 H).

Example 10: (S)-5-((2-(2-(4-(l H-Indol-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)iso- quinoline

Brown oil C ₂₇ H ₃ iN ₅ 0 ₂ S, MW 489.63, Monoisotopic Mass 489.22, [M+H] ⁺ 490.4. UPLC Rt = 3.89. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.57-1.71 (m, 6 H), 1.82-1.87 (m, 1 H), 2.35-2.44 (m, 2 H), 2.53-2.61 (m, 2 H), 2.64-2.70 (m, 2 H), 3.24 (t, J = 4.10 Hz, 4 H), 3.36-3.41 (m, 2 H), 3.94-4.03 (m, 1 H), 6.47 -6.61 (m, 2 H), 7.00-7.18 (m, 3 H), 7.68 (dd, J = 8.08, 7.50 Hz, 1 H), 8.16 (s, 1 H), 8.40 (dd, J = 7.39, 1.20 Hz, 1 H), 8.64-8.73 (m, 2 H), 9.32 (s, 1 H).

Example 1 1 : (S)-5-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)- sulfonyl)quinoline

Brown oil C ₂₇ H3oN ₄ 0 ₂ S, MW 506.68, Monoisotopic Mass 506.18, [M+H] ⁺ 507.4.UPLC Rt = 5.07.

Example 12: (S)-3-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)- sulfonyl)quinoline

Brown oil C ₂₇ H ₃₀ N ₄ O ₂ S ₂ , MW 506.68, Monoisotopic Mass 506.18, [M+H] ⁺ 507.3. UPLC R, = 5.12.

Example 13: (S)-4-((2-(2-(4-(Benzo[b]tWophen-4-yl)piperazm-l-yl)ethyl)py rrolidin-l-yl)- sulfonyl)isoquinoline

Brown oil C27H ₃₀ N ₄ O ₂ S ₂ , MW 506.68, Monoisotopic Mass 506.18, [M+H] ⁺ 507.4. UPLC Rt = 5.26. ¾ NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.61-1.73 (m, 4 H), 1.73-1.80 (m, 1 H), 1.86-1.95 (m, 1 H), 2.39-2.50 (m, 2 H), 2.60-2.75 (m, 4 H), 3.20 (t, J = 4.00 Hz, 4 H), 3.47 (dd, J = 7.16, 5.94 Hz, 2 H), 4.07-1.12 (m, 1H), 6.92 (dd, J = 7.65, 0.71 Hz, 1 H), 7.27-7.32 (m, 1 H), 7.39-7.44 (m, 2 H), 7.57 (d, J = 8.02 Hz, 1 H), 7.76 (ddd, J = 8.09, 7.04, 0.95 Hz, 1 H), 7.91 (ddd, J = 8.60, 7.05, 1.37 Hz, 1 H), 8.10 (d, J = 8.07 Hz, 1 H), 8.88 (dd, J = 8.68, 0.81 Hz, 1 H), 9.14 (s, 1 H), 9.42 (s, 1 H). ^,3 C NMR (75 MHz, CDCI3) δ (ppm) 24.31, 31.05, 33.01, 48.47, 52.1 1, 53.46, 53.58, 55.18, 58.59, 1 12.17, 116.98, 121.92, 124.65, 124.94, 125.02, 128.36, 128.39, 128.57, 128.95, 129.13, 131.78, 132.54, 134.06, 141.12, 145.06, 148.44, 157.59.

Example 14: (S)-5-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)- sulfonyl)isoquinoline

White solid C ₂₇ H ₃ oN ₄ 0 ₂ S ₂ , MW 506.68, Monoisotopic Mass 506.18, [M+H] ⁺ 507.4. UPLC Rt = 4.77. Ή NMR (300 MHz, CDCI3) δ (ppm) 1.63-1.71 (m, 4 H), 1.72-1.79 (m, 1 H), 1.82-1.95 (m, 1 H), 2.45 (q, J = 7.68 Hz, 2 H) 2.58-2.66 (m, 2 H), 2.69-2.77 (m, 2 H), 3.21 (t, J = 4.00 Hz, 4 H), 3.40-3.45 (m, 2 H), 4.05 (dt, J = 8.20, 3.99 Hz, 1 H), 6.93 (dd, J = 7.68, 0.78 Hz, 1 H), 7.31 (t, J = 7.90 Hz, 1 H), 7.42 (s, 2H), 7.58 (d, J = 8.02 Hz, 1 H), 7.74 (dd, J = 8.14, 7.46 Hz, 1 H), 8.21- 8.27 (m, 1 H), 8.45 (dd, J = 7.38, 1.22 Hz, 1 H), 8.67-8.76 (m, 2 H), 9.37 (d, J = 0.73 Hz, 1 H). ^I3 C NMR (75 MHz, CDC1 ₃ ) δ (ppm) 24.27, 31.04, 33.21, 48.39, 52.10, 53.59, 55.17, 58.4, 1 12.16, 1 17.06, 1 17.92, 121.85, 124.87, 125.02, 125.89, 133.54, 133.56, 145.14, 148.62, 153.18. Example 15 : (S)-3-(4-(2-( 1 -((^nolin-2-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2- benzoxazole

Yellow oil C ₂ 6H29 ₅ 0 ₃ S, MW 491.61 , Monoisotopic Mass 491.2, [M+H] ⁺ 492.4. UPLC R, = 4.40. Ή NMR (300 MHz, CDCb) δ (ppm) 1.59-1.74 (m, 4 H), 1.84-1.90 (m, 1 H), 2.06-2.13 (m, 1 H), 2.37-2.43 (m, 2 H), 2.51-2.58 (m, 2 H), 2.62-2.71 (m, 2 H), 3.39-3.45 (m, 2 H), 3.57 (t, J = 5.00 Hz, 4 H), 4.05 (tt, J = 7.96, 3.87 Hz, 1 H), 7.21 (ddd, J = 8.03, 6.27, 1.76 Hz, 1 H), 7.42-7.48 (m, 2 H), 7.66-7.76 (m, 2 H), 7.88 (ddd, J = 8.55, 7.06, 1.31 Hz, 1 H), 8.09 (s, 1 H), 8.84 (d, J = 8.66 Hz,

1 H), 9.09 (s, 1 H), 9.39 (s, 1 H).

Example 16: (S)-3-(4-(2-(l-(Quinolin-5-ylsulfonyl)pyn-olidin-2-yl)ethyl) piperazin-l-yl)-l ,2- benzoxazole

Yellow oil C26H29 5O3S, MW 491.61, Monoisotopic Mass 491.2, [M+H] ⁺ 492.4. UPLC R, = 4.25. ^■ H NMR (300 MHz, CDCb) δ (ppm) 1.58-1.70 (m, 4 H), 1.79-1.89 (m, 1 H), 1.96-2.08 (m, 1 H), 2.33-2.40 (m, 2 H), 2.48-2.56 (m, 2 H), 2.59-2.67 (m, 2 H), 3.38 (d, J = 5.90 Hz, 2 H), 3.56 (t, J = 5.00 Hz, 4 H), 4.00 (tt, J = 7.85, 3.91 Hz, 1 H), 7.22 (ddd, J = 7.89, 6.28, 1.44 Hz, 1 H), 7.43- 7.48 (m, 2 H), 7.54-7.58 (m, 1 H), 7.69 (d, J = 8.53 Hz, 1 H), 7.79 (t, J = 7.92 Hz, 1 H), 8.24-8.36 (m, 2 H), 9.00 (dd, J = 4.15, 1.30 Hz, 1 H), 9.26 (dt, J = 8.78, 0.74 Hz, 1 H).

Example 17: (S)-3 -(4-(2-( 1 -(Isoquinolin-4-ylsidfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1,2-benzoxazole

Brown oil C ₂ 6H ₂ 9N ₅ 0 ₃ S, MW 491.61, Monoisotopic Mass 491.2, [M+H] ⁺ 492.4. UPLC Rt = 4.42. Ή NMR (300 MHz, CDCb) δ (ppm) 1.60-1.73 (m, 4 H), 1.80-1.91 (m, 1 H), 2.03-2.10 (m, 1 H), 2.36-2.42 (m, 2 H), 2.49-2.57 (m, 2 H), 2.61-2.67 (m, 2 H), 3.41-3.45 (m, 2 H), 3.55-3.58 (m, 4 H), 4.01-4.09 (m, 1 H), 7.21 (ddd, J = 8.04, 6.28, 1.75 Hz, 1 H), 7.42 -7.47 (m, 2 H), 7.68-7.75 (m,

2 H), 7.88 (ddd, J = 8.55, 7.06, 1.35 Hz, 1 H), 8.07 (d, J = 7.98 Hz, 1 H), 8.84 (d, J = 8.62 Hz, 1 H), 9.09 (s, 1 H), 9.38 (s, 1 H).

Example 18: (S)-3-(4-(2-(l-(Isoqumolin-5-ylsulfonyl)pyrrolidm-2-yl)ethyl )piperazin-l-yl)-

1,2-benzoxazole

Brown oil C ₂ 6H ₂₉ N ₅ 0 ₃ S, MW 491.61, Monoisotopic Mass 491.2, [M+H] ⁺ 492.4. UPLC Rt = 3.88. 'H NMR (300 MHz, CDCb) δ (ppm) 1.53-1.71 (m, 4 H), 1.78-1.87 (m, 1 H), 1.98 -2.11 (m, 1 H), 2.32-2.43 (m, 2 H), 2.49-2.56 (m, 2 H), 2.59-2.67 (m, 2 H), 3.34-3.42 (m, 2 H), 3.57 (t, J = 4.98 Hz, 4 H), 4.00 (tt, J = 7.85, 3.91 Hz, 1 H), 7.19-7.24 (m, 1 H), 7.43 -7.53 (m, 2 H), 7.67-7.73 (m, 2 H), 8.20 (d, J = 8.21 Hz, 1 H), 8.42 (s, 1 H), 8.62-8.72 (m, 2 H), 9.33 (s, 1 H). Example 19: (S)-3-(4-(2-(l-Quinolin-2-ylsulfonyl)pyrrolidin-2-yl)ethyl)p iperazin-l-yl)-l,2- benzothiazole

Brown oil C ₂ 6H ₂₉ N ₅ 0 ₂ S ₂ , MW 507.67, Monoisotopic Mass 507.18, [M+H] ⁺ 508.3. UPLC Rt = 5.25. Ή NMR (300 MHz, CDC1 ₃ )□ (ppm) 1.66-1.81 (m, 4 H), 1.88-1.98 (m, 2 H), 2.52-2.63 (m, 2 H), 2.66-2.81 (m, 4 H), 3.56 (t, J = 4.82 Hz, 4 H), 3.60-3.69 (m, 2 H), 4.16-4.24 (m, 1 H), 7.30-7.36 (m, 1 H), 7.44 (td, J = 7.53, 0.67 Hz, 1 H), 7.62-7.68 (m, 1 H), 7.77-7.82 (m, 2 H), 7.88 (d, J = 8.14 Hz, 2 H), 8.00 (d, J = 8.53 Hz, 1 H), 8.16 (s, 1 H), 8.34 (d, J = 8.43 Hz, 1 H).

Example 20 : (S)-3-(4-(2-( 1 -Quinolin-5-ylsiilfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2- benzothiazole

Brown oil C ₂₆ H ₂₉ N ₅ 0 ₂ S ₂ , MW 507.67, Monoisotopic Mass 507.18, [M+H] ⁺ 508.4. UPLC Rt = 4.59. Ή NMR (300 MHz, CDCI3) δ (ppm) 1.56-1.75 (m, 4 H), 1.81-1.89 (m, 1 H), 1.95-2.08 (m, 1 H), 2.33-2.42 (m, 2 H), 2.49-2.58 (m, 2 H), 2.60-2.69 (m, 2 H), 3.33-3.39 (m, 2 H), 3.53 (t, J = 4.87 Hz, 4 H), 3.96-4.02 (m, 1 H), 7.30-7.39 (m, 1 H), 7.45 (ddd, J = 8.09, 7.00, 1.09 Hz, 1 H), 7.56 (dd, J = 8.82, 4.20 Hz, 1 H), 7.75 -7.82 (m, 2 H), 7.87-7.91 (m, 1 H), 8.23-8.35 (m, 2 H), 8.99 (dd, J = 4.17, 1.63 Hz, 1 H), 9.24-9.28 (m, 1 H).

Example 21 : (S)-3-(4-(2-(l-Isoqumolin-3-ylsulfonyl)pyixolidm-2-yl)ethyl) piperazin-l-yl)-l ,2- benzothiazole

Yellow solid C ₂₆ H ₂₉ N ₅ 0 ₂ S ₂ , MW 507.67, Monoisotopic Mass 507.18, [M+H] ⁺ 508.4. UPLC R, = 5.17. >H NMR (300 MHz, CDCI3) θ (ppm) 1.58-1.69 (m, 4 H), 2.54-2.64 (m, 2 H), 2.67-2.74 (m, 2 H), 2.75-2.82 (m, 2 H), 3.50-3.60 (m, 8 H), 4.14 -4.22 (m, 1 H), 7.32-7.38 (m, 1 H), 7.46 (ddd, J = 8.06, 7.02, 1.04 Hz, 1 H), 7.74-7.83 (m, 3 H), 7.90 (d, J = 8.11 Hz, 1 H), 7.97-8.09 (m, 2 H), 8.41 (s, 1 H), 9.27 (s, 1 H). M.p.: 101.1-102.1.

Example 22: (S)-3-(4-(2-((l-CUoroisoqiunolin-4-ylsulfonyl)pyrrolidm-2-yl )ethyl)piperazin-l- yl) 1 ,2-benzothiazole

Brown oil C ₂₆ H ₂₈ C1N ₅ 0 ₂ S, MW 542.12, Monoisotopic Mass 541.14, [M+H] ⁺ 542.4. UPLC R, = 5.72. Ή NMR (300 MHz, CDCI3) δ (ppm) 1.68-1.76 (m, 4 H), 1.77-1.83 (m, 2 H), 1.86-1.95 (m, 1 H), 2.08-2.18 (m, 1 H), 2.5-2.54 (m, 2 H), 2.65-2.67 (m, 1 H), 2.75-2.77 (m, 1 H), 3.39-3.51 (m, 2 H), 3.62-3.65 (m, 4 H), 4.05- .11 (m, 1 H), 7.38 (ddd, J = 8.13, 7.03, 0.98 Hz, 1 H), 7.49 (ddd, J = 8.13, 7.01, 1.05 Hz, 1 H), 7.82-7.83 (m, 1 H), 7.83-7.86 (m, 1 H), 7.92 (dt, J = 8.16, 0.89 Hz, 1 H), 7.97 (ddd, J = 8.57, 7.08, 1.32 Hz, 1 H), 8.49-8.52 (m, 1 H), 8.88 (s, 1 H), 8.91 (dt, J = 8.55, 0.86 Hz, 1 H). ¹³ C MR (75 MHz, CDCb) δ (ppm) 24.29, 31.07, 48.52, 48.55, 49.76, 52.84, 52.86, 52.88, 55.13, 58.65, 120.57, 123.87,123.95, 125.27, 127.08, 127.36, 127.57, 127.98, 129.22, 129.58, 133.15, 133.47, 143.64. Example 23 : (S)-3-(4-(2-( 1 -(Isoquinolin-4-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzothiazole

Yellow oil C ₂₆ H2 ₉ N ₅ 0 ₂ S ₂ , MW 507.67, Monoisotopic Mass 507.18, [M+H] ⁺ 508.3. UPLC Rt = 4.85. »H NMR (300 MHz, CDC , CD3OD) δ (ppm) 1.56-1.66 (m, 2 H), 1.69-1.78 (m, 2 H), 1.87-1.99 (m, 2 H), 2.1 1-2.20 (m, 2 H), 2.26-2.37 (m, 2 H) 3.37-3.48 (m, 4 H), 3.52-3.64 (m, 2 H), 3.69-3.79 (m, 2 H), 4.10-4.22 (m, 1H), 7.40-7.48 (m, 1 H), 7.51-7.58 (m, 1 H), 7.90 (d, J = 8.14 Hz, 1 H), 7.98-8.09 (m, 2 H), 8.28 (t, J = 7.81 Hz, 1 H), 8.51 (d, J = 8.14 Hz, 1 H), 8.98 (d, J = 8.56 Hz, 1 H), 9.17 (s, 1 H), 9.81 (s, 1 H). ^{, 3} C NMR (75 MHz, CDCb, CD3OD) δ (ppm) 23.70, 29.42, 30.72, 46.51 , 48.58, 50.99, 51.57, 54.18, 58.04, 120.40, 123.14, 124.35, 124.85, 126.96, 127.92, 128.33, 131.23, 131.70, 132.79, 133.77, 135.60, 138.26, 152.49, 161.57.

Example 24: (S)-3-(5-(2-(l -(Isoqumolin-4-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1,2-benzothiazole

Yellow oil C26H ₂ 9 ₅ 02S ₂ , MW 507.67, Monoisotopic Mass 507.18, [M+H] ⁺ 508.3. UPLC Rt = 4.75. ¾ NMR (300 MHz, CDCI3) δ (ppm) 1.58-1.66 (m, 2 H), 1.69-1.76 (m, 2 H), 1.83-1.94 (m, 2 H), 2.1 1-2.20 (m, 2 H), 2.28-2.37 (m, 2 H) 3.35-3.48 (m, 4 H), 3.52-3.67 (m, 2 H), 3.72-3.81 (m, 2 H), ΑΛ2- 22 (m, 1H), 7.19-7.24 (m, 1 H), 7.51-7.58 (m, 1 H), 7.90 (d, J = 8.14 Hz, 1 H), 7.98- 8.09 (m, 2 H), 8.20 (d, J = 8.21 Hz, 1 H), 8.42 (s, 1 H), 8.62-8.72 (m, 2 H), 9.33 (s, 1 H).

Example 25 : (S)-7-(4-(2-( 1 -(Quinolin-5-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 - yl)benzo[d]oxazol-2(3H)-one

Yellow oil C26H29N5O4S, MW 507.6, Monoisotopic Mass 507.19, [M+H] ⁺ 508.5. UPLC Rt = 3.65.

Example 26: (S)-7-(4-(2-(l-(Isoquinolin-3-ylsiilfonyl)pyrrolidin-2-yl)et hyl)piperazin-l- yl)benzo[d]oxazol-2(3H)-one

Yellow oil C26H29N5O4S, MW 507.6, Monoisotopic Mass 507.19, [M+H] ⁺ 508.5. UPLC R, = 4.29.

Example 27: (S)-7-(4-(2-(l-(Isoqumolin-4-ylsulfonyl)pyrrolidin-2-yl)ethy l)piperazin-l- yl)benzo[d]oxazol-2(3H)-one

Yellow oil C26H29N5O4S, MW 507.6, Monoisotopic Mass 507.19, [M+H] ⁺ 508.5. UPLC R, = 3.94. ^l U NMR (300 MHz, CDCb) δ (ppm) 1.60-1.72 (m, 4 H), 1.73-1.81 (m, 1 H), 1.85-1.94 (m, 1 H), 2.34-2.46 (m, 2 H), 2.51-2.59 (m, 2 H), 2.60-2.69 (m, 2 H), 3.32 (t, J = 4.62 Hz, 4 H) 3.44-3.52 (m, 2 H), 4.07 (tt, J = 8.03, 3.96 Hz, 1 H), 6.59-6.71 (m, 2 H), 7.02-7.10 (m, 1 H), 7.77 (ddd, J = 8.1 1, 7.03, 1.00 Hz, 1 H), 7.92 (ddd, J = 8.58, 7.07, 1.37 Hz, 1 H), 8.05 (br.s., 1 H), 8.1 1 (d, J = 8.02 Hz, 1 H), 8.86 (dd, J = 8.68, 0.81 Hz, 1 H), 9.13 (s, 1 H), 9.43 (d, J = 0.54 Hz, 1 H). ^I3 C NMR (75 MHz, CDCI3) δ (ppm) 24.30, 31.05, 32.82, 48.44, 49.04, 49.09, 53.06, 55.06, 58.56, 110.49, 124.72, 128.47, 129.18, 130.34, 131.78, 132.64, 134.10, 135.91 , 144.90, 155.23, 157.57. Example 28: (S)-8-(4-(2-(l-(Quinolin-5-ylsulfonyl)pyrrolidin-2-yl)ethyl) piperazin-l-yl)-2H- benzo[b][ 1 ,4]oxazin-3(4H)-one

Yellow oil C27H31N5O4S, MW 521.63, Monoisotopic Mass 521.21, [M+H] ⁺ 522.4. UPLC Rt = 3.45. Ή NMR (300 MHz, CDCI3) δ (ppm) 1.52-1.74 (m, 4 H), 1.75-1.90 (m, 1 H), 1.96-2.12 (m, 1 H), 2.28-2.40 (m, 2 H), 2.48-2.55 (m, 2 H), 2.56-2.66 (m, 2 H), 3.08 (t, J = 6.50 Hz, 4 H), 3.37 (t, J = 6.50 Hz, 2 H), 3.92-4.04 (m, 1 H), 4.64 (s, 2 H), 6.51 (dd, J = 7.89, 1.31 Hz, 1 H), 6.64 (dd, J = 8.21, 1.31 Hz, 1 H), 6.84-6.93 (m, 1 H), 7.56 (dd, J = 8.80, 4.18 Hz, 1 H), 7.79 (dd, J = 8.43, 7.44 Hz, 1 H), 8.26 (dd, J = 7.41 , 1.22 Hz, 1 H), 8.33 (dt, J = 8.00, 2.00 Hz, 1 H), 8.67 (s, 1 H), 9.00 (dd, J = 4.18, 1.62 Hz, 1 H), 9.21-9.31 (m, 1 H). ¹³ C NMR (75 MHz, CDCI3) δ (ppm) 24.23, 30.98, 32.85, 48.33, 50.44, 53.23, 55.1, 58.42, 67.07, 110.09, 113.59, 122.53, 124.96, 126.93, 127.68, 127.7, 129.82, 129.85, 133.75, 135.53, 141.65, 148.54, 151.1 1, 165.8.

Example 29: (S)-8-(4-(2-( 1 -(Isoquinolin-3-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 2H-benzo[b] [ 1 ,4]oxazin-3 (4H)-one

White solid C ₂₇ H3iN ₅ 0 ₄ S, MW 521.63, Monoisotopic Mass 521.21 , [M+H] ⁺ 522.4. UPLC Rt = 4.13. Ή NMR (300 MHz, CDCI3) δ (ppm) 1.59-1.71 (m, 4 H), 1.72-1.91 (m, 1 H), 2.08-2.21 (m, 1 H), 2.49-2.58 (m, 2 H), 2.66-2.72 (m, 2 H), 3.11 (t, J = 6.00 Hz, 4 H), 3.52 (t, J = 5.98 Hz, 2 H), 4.15- 4.23 (m, 2 H), 4.64 (s, 2 H), 6.52 (dd, J = 7.82, 1.06 Hz, 1 H), 6.62 (dd, J = 8.10, 1.10 Hz, 1 H), 6.86-6.92 (m, 1 H), 7.52 (dd, J = 5.66, 3.35 Hz, 1 H), 7.75-7.81 (m, 1 H), 7.81-7.87 (m, 1 H), 7.98 (d, J = 7.98 Hz, 1 H), 8.07 (dd, J = 8.40, 7.30 Hz, 1 H), 8.41 (s, 1 H), 8.85 (s, 1 H) ,9.27 (s, 1 H). M.p.: 189.8-190.9.

Example 30: (S)-8-(4-(2-(l-(Isoquinolin-4-ylsulfonyl)pyrrolidin-2-yl)eth yl)piperazin-l-yl)- 2H-benzo[b] [ 1 ,4]oxazin-3 (4H)-one

Yellow oil C27H31N5O4S, MW 521.63, Monoisotopic Mass 521.21, [M+H] ⁺ 522.4. UPLC Rt = 3.69. ¾ NMR (300 MHz, CDCI3) δ (ppm) 1.56-1.77 (m, 4 H), 1.80-1.93 (m, 1 H), 2.01-2.17 (m, 1 H), 2.31-2.44 (m, 2 H), 2.48-2.58 (m, 2 H), 2.58-2.69 (m, 2 H), 3.09 (t, J = 6.00 Hz, 4 H), 3.36-3.52 (m, 2 H), 3.97-4.09 (m, 1 H), 4.63 (s, 2 H), 6.52 (dd, J = 7.87, 1.23 Hz, 1 H), 6.64 (dd, J = 8.19, 1.23 Hz, 1 H), 6.84-6.92 (m, 1 H), 7.73 (ddd, J = 8.06, 7.10, 0.83 Hz, 1 H), 7.88 (ddd, J = 8.58, 7.05, 1.36 Hz, 1 H), 8.08 (d, J = 7.95 Hz, 1 H), 8.84 (dd, J = 8.64, 0.66 Hz, 1 H), 9.06 (s, 1 H), 9.10 (s, 1 H), 9.39 (s, 1 H). ¹³ C NMR (75 MHz, CDCb) δ (ppm) 24.26, 30.99, 32.92, 48.46, 50.43, 53.25, 55.1, 58.51, 67.03, 1 10.13, 1 13.61, 122.83, 124.61, 126.94, 128.39, 128.58, 128.91, 129.10, 131.74, 132.56, 135.95, 141.63, 144.93,157.56, 166.01. Example 31 : (S)-8-(4-(2-(l-(Isoqumolm-5-ylsulfonyl)pyrrolidin-2-yl)ethyl )piperazin-l-yl)- 2H-benzo[b] [ 1 ,4]oxazin-3 (4H)-one

Yellow solid C27H31N5O4S, MW 521.63, Monoisotopic Mass 521.21, [M+H] ⁺ 522.4. UPLC R, = 3.21. ^! H NMR (300 MHz, CDCI3) δ (ppm) 1.49-1.69 (m, 4 H), 1.74-1.86 (m, 1 H), 1.92-2.06 (m, 1 H), 2.24-2.38 (m, 2 H), 2.45-2.65 (m, 2 H), 2.96-3.08 (m, 6 H), 3.27-3.35 (m, 2 H), 3.91- 3.96 (m, 1 H), 4.64 (s, 2 H), 6.49 (dd, J = 7.87, 1.30 Hz, 1 H), 6.55-6.64 (m, 1 H), 6.79-6.90 (m, 1 H), 7.69 (t, J = 7.81 Hz, 1 H), 8.12 (br.s., 1 H), 8.19 (d, J = 8.17 Hz, 1 H), 8.37 (dd, J = 7.40, 0.99 Hz, 1 H), 8.55-8.67 (m, 2 H), 9.26 (s, 1 H). M.p.: 195.7-196.5.

Example 32: (S)-5-((2 2-(4-(2,3-Dihydrobenzo[b][l,4]dioxin-5-yl)piperazin-l-yl)eth yl)- pyrrolidin-l-yl)sulfonyl)quinoline

White solid C ₂₇ H3 ₂ N ₄ 04S, MW 508.63, Monoisotopic Mass 508.21 , [M+H] ⁺ 509.5. UPLC R, = 4.17. Ή NMR (300 MHz, CDCI3) δ (ppm) 1.51-1.72 (m, 4 H), 1.75-1.89 (m, 1 H), 1.92-2.08 (m, 1 H), 2.25-2.44 (m,l H), 2.51-2.68 (m, 4 H), 3.08 (t, J = 6.50 Hz, 4 H), 3.36 (t, J = 6.54 Hz, 2 H), 3.88- 4.04 (m, 2 H), 4.21-4.27 (m, 2 H), 4.29-4.34 (m, 2 H), 6.56 (ddd, J = 18.03, 8.13, 1.47 Hz, 2 H), 6.71-6.84 (m, 1 H), 7.56 (dd, J = 8.80, 4.18 Hz, 1 H), 7.79 (dd, J = 8.43, 7.47 Hz, 1 H), 8.16-8.40 (m, 2 H), 9.00 (dd, J = 4.18, 1.62 Hz, 1 H), 9.17-9.33 (m, 1 H). M.p.: 143.4-144.3.

Example 33 : (S)-4-((2-(2-(4-(2,3-Dihydrobenzo[b][ 1 ,4]dioxin-5-yl)piperazin-l -yl)ethyl pyrrolidin- 1 -yl)sulfonyl)isoquinoline

White solid C ₂₇ H ₃₂ N ₄ 0 ₄ S, MW 508.63, Monoisotopic Mass 508.21 , [M+H] ⁺ 509.4. UPLC R, = 4.42. Ή NMR (300 MHz, CDCI3) δ (ppm) 1.63-1.82 (m, 4 H), 1.89-2.00 (m, 1 H), 2.05-2.18 (m, 1 H), 2.24-2.36 (m, 1 H), 3.34 (td, J = 3.13, 1.31 Hz, 4 H), 3.62-3.81 (m, 4 H), 3.90-4.01 (m, 2 H), 4.29 (t, J = 3.85 Hz, 2 H), 4.42 (t, J = 2.88 Hz, 2 H), 4.49-4.57 (m, 2 H), 6.79-6.94 (m, 2 H), 7.32(dd, J=6.96, 1.57 Hz, 1 H), 7.95-8.08 (m, 1 H), 8.30 (t, J = 7.57 Hz, 1 H), 8.55 (d, J = 8.01 Hz, 1 H), 9.00 (d, J = 8.59 Hz, 1 H), 9.26 (s, 1 H), 9.96 (s, 1 H). ¹³ C NMR (75 MHz, CDCI3) δ (ppm) 24.20, 29.68, 30.51, 30.74, 51.65, 55.10, 58.35, 64.67, 104. 76, 108.91, 122.56, 126.46, 128.47, 128.63, 128.91, 131.71, 132.72, 147.35, 155.7.

Example 34: (S)-5-((2-(2-(4-(2,3-Dihydrobenzo[b][l,4]dioxin-5-yl)piperaz in-l-yl)ethyl)- pyrrolidin- 1 -yl)sulfonyl)isoquinoline

Yellow oil C ₂₇ H3 ₂ N ₄ 0 ₄ S, MW 508.63, Monoisotopic Mass 508.21, [M+H] ⁺ 509.4. UPLC R, = 3.81. Ή NMR (300 MHz, CDCI3) δ (ppm) 1.55-1.70 (m, 4 H), 1.77-1.86 (m, 1 H), 1.99-2.10 (m, 1 H), 2.30-2.42 (m, 2 H), 2.59-2.68 (m, 2 H), 2.71-2.78 (m, 2H), 3.07 (t, J = 6.50 Hz, 4 H), 3.37 (t, J = 6.50 Hz, 2 H), 3.92-4.02 (m, 1 H), 4.20-4.26 (m, 2 H), 4.28^.33 (m, 2 H), 6.55 (ddd, J = 16.32, 8.06, 1.20 Hz, 2 H), 6.67-6.82 (m, 1 H), 7.69 (t, J = 7.77 Hz, 1 H), 8.19 (d, J = 8.14 Hz, 1 H), 8.40 (dd, J = 7.37, 0.96 Hz, 1 H), 8.56-8.83 (m, 2 H), 9.32 (s, 1 H).

Example 35 : (S)-5-((2-(2-(4-(6-Butyl-4-(thiophen-3-yl)pyridin-2-yl)piper azin- 1 -yl)ethyl)- pyrrolidin- 1 -yl)sulfonyl)quinoline

Brown oil C ₃₂ H39N ₅ 0 ₂ S2, MW 589.81, Monoisotopic Mass 589.25, [M+H] ⁺ 590.4. UPLC Rt = 5.93.

Example 36: (S)-4-((2-(2-(4-(6-Butyl-4-(tWophen-3-yl)pyridin-2-yl)pipera zin-l-yl)ethyl)- pyrrolidin- 1 -yl)sulfonyl)isoquinoline

Brown oil C3 ₂ H ₃ 9N ₅ 02S2, MW 589.81 , Monoisotopic Mass 589.25, [M+H] ⁺ 590.4. UPLC R» = 6.04. Ή NMR (300 MHz, CDC1 ₃ ) 6 (ppm) 0.89-0.98 (m, 3 H), 1.35-1.45 (m, 2 H), 1.62-1.77 (m, 8 H), 1.82-1.91 (m, 1 H), 2.06-2.16 (m, 1 H), 2.61-2.71 (m, 4 H), 3.40-3.49 (m, 4 H), 3.55-5.64 (m., 4 H), 4.02^.10 (m, 1 H), 6.61-6.75 (m, 2 H), 7.39 (d, J = 2.18 Hz, 2 H), 7.56 (t, J = 2.13 Hz, 1 H), 7.71-7.79 (m, 1 H), 7.89 (ddd, J = 8.58, 7.05, 1.36 Hz, 1 H), 8.08 (d, J = 8.05 Hz, 1 H), 8.85 (dd, J = 8.64, 0.66 Hz, 1 H), 9.1 1 (s, 1 H), 9.40 (s, 1 H). ^{, 3} C NMR (75 MHz, CDC1 ₃ ) δ (ppm) 14.06, 22.57, 24.26, 31.06, 31.61, 38.12, 45.13, 48.46, 52.95, 55.17, 58.48, 101.36, 122.13, 124.59, 126.15, 126.39, 128.42, 128.59, 128.93, 132.63, 145.10, 157.64.

Example 37 : (S)-5-((2-(2-(4-(6-Butyl-4-(thiophen-3 -yl)pyridin-2-yl)piperazin- 1 -yl)ethyl pyrrolidin- 1 -yl)sulfonyl)isoquinoline

Brown oil C34H40FN5O2S, MW 601.78, Monoisotopic Mass 601.29, [M+H] ⁺ 602.4. UPLC Rt = 6.43. 'H NMR (300 MHz, CDC1 ₃ ) δ (ppm) 0.94(t, J = 7.31 Hz, 3 H), 1.21-1.28 (m, 2 H), 1.34-1.46 (m, 2 H), 1.54-1.77 (m, 6 H), 1.78-1.91 (m, 1 H), 1.96-2.08 (m, 1H), 2.29-2.57 (m, 4 H), 2.67-2.71 (t, J = 7.9 Hz, 2 H), 3.44 (t, J = 5.4 Hz, 2 H), 3.59 (t, J = 4.86 Hz, 4 H), 3.95-4.03 (m, 1 H), 6.55-6.68 (m, 2 H), 7.08-7.15 (m, 2 H), 7.52-7.59 (m, 3 H), 7.76-7.82 (m, 1 H), 8.26-8.34 (m, 2 H), 8.99 (dd, J = 4.17, 1.57 Hz, 1 H), 9.26 (dd, J = 8.77, 0.63 Hz, 1 H).

Example 38 : (S)-5-((2-(2-(4-(6-Buryl-4-(4-fluorophenyl)pyridin-2-yl)pipe razin- 1 -yl)ethyl)- pyrrolidin- 1 -yl)sulfonyl)quinoline

Brown oil C3 H40FN5Q2S. MW 601.78, Monoisotopic Mass 601.29, [M+H] ⁺ 602.4. UPLC R, = 6.43. Ή NMR (300 MHz, CDCb) δ (ppm) 0.94(t, J = 7.31 Hz, 3 H), 1.21-1.28 (m, 2 H), 1.34-1.46 (m, 2 H), 1.54-1.77 (m, 6 H), 1.78-1.91 (m, 1 H), 1.96-2.08 (m, 1H), 2.29-2.57 (m, 4 H), 2.67-2.71 (t, J = 7.9 Hz, 2 H), 3.44 (t, J = 5.4 Hz, 2 H), 3.59 (t, J = 4.86 Hz, 4 H), 3.95-4.03 (m, 1 H), 6.55-6.68 (m, 2 H), 7.08-7.15 (m, 2 H), 7.52-7.59 (m, 3 H), 7.76-7.82 (m, 1 H), 8.26-8.34 (m, 2 H), 8.99 (dd, J = 4.17, 1.57 Hz, 1 H), 9.26 (dd, J = 8.77, 0.63 Hz, 1 H). Example 39: (S)-4-((2-(2-(4-(6-Butyl-4-(4-fluorophenyl)pyridin-2-yl)pipe razin-l-yl)ethyl)- pyrrolidin- 1 -yl)sulfonyl)isoquinoline

Brown oil C ₃ 4H ₄ oFN ₅ 0 ₂ S, MW 601.78, Monoisotopic Mass 601.29, [M+H] ⁺ 602.4. UPLC ¾ = 6.78. »H NMR (300 MHz, CDC1 ₃ ) δ (ppm) 0.95(t, J = 7.1 Hz, 3 H), 1.19-1.30 (m, 2 H), 1.32-1.48 (m, 2 H), 1.60-1.78 (m, 6 H), 1.80-1.93 (m, 1 H), 2.03-2.18 (m, IH), 2.34-2.63 (m, 4 H), 2.65-2.73 (m, 2 H), 3.44 (t, J = 5.4 Hz, 2 H), 3.61 (t, J = 4.9 Hz, 4 H), 4.01-4.11 (m, 1 H), 6.52-6.69 (m, 2 H), 7.08- 7.17 (m, 2 H), 7.51-7.59 (m, 2 H), 7.71-7.77 (m, 1 H), 7.89 (ddd, J = 8.1 1, 7.06, 1.38 Hz, 1 H), 8.08 (d, J = 7.89 Hz, 1 H), 8.85 (dd, J = 8.64, 0.75 Hz, 1 H), 9.11 (s, 1 H), 9.40 (d, J = 0.54 Hz, 1 H).

Example 40: (S)-5-((2-(2-(4-(6-Butyl-4-(4-fluorophenyl)pyridin-2-yl)pipe razin-l -yl)ethyl)- pyrrolidin- 1 -yl)sulfonyl)isoquinoline

Brown oil C ₃₄ H ₄ oFN ₅ 0 ₂ S, MW 601.78, Monoisotopic Mass 601.29, [M+H] ⁺ 602.4. UPLC Rt - 6.78. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 0.95(t, J = 7.1 Hz, 3 H), 1.22-1.45 (m, 4 H), 1.61-1.77 (m, 6 H), 1.78-1.88 (m, 1 H), 1.99-2.12 (m, IH), 2.31-2.40 (m, 2 H), 2.42-2.60 (m, 2 H), 2.66-2.72 (m, 2H), 3.36-3.42 (m, 2 H), 3.60 (t, J = 4.94 Hz, 4 H), 3.97-4.07 (m, 1 H), 6.56 (d, J = 1.06 Hz, 1 H), 6.67 (d, J = 1.03 Hz, 1 H), 7.08-7.16 (m, 2 H), 7.52-7.59 (m, 2 H), 7.71 (dd, J = 8.1 1, 7.47 Hz, 1 H), 8.20 (d, J = 8.11 1 H), 8.42 (dd, J = 7.41 , 1.22 Hz, 1 H), 8.68 (d, J = 2.69 Hz, 2 H), 9.34 (s, 1 H). ^!3 C NMR (75 MHz, CDC1 ₃ ) δ (ppm) 14.05, 22.58, 22.68, 24.25, 29.68, 30.30, 31.01, 31.63, 31.91, 32.88, 38.17, 45.41 , 48.35, 53.09, 55.18, 58.48, 101.92, 1 10.88, 1 15.53, 115.81, 117.89, 125.88, 128.67, 128.78, 129.12, 132.16, 133.54, 133.86, 136.18, 145.11 , 149.33, 153.16, 159.77, 161.45.

Example 41 : (S)-5-((2-(2-(4-(lH-mdol-3-yl)-5,6- hy^

yl)sulfonyl)quinoline

Yellow solid C ₂₈ H ₃ oN ₄ 0 ₂ S, MW 486.63, Monoisotopic Mass 486.21, [M+H] ⁺ 487.2. UPLC Rt = 4.55. M.p.: 153.1-154.8.

Example 42: (S)-3-((2-(2-(4-(lH-Indol-3-yl)-5,6-dihydropyridin-l (2H)-yl)ethyl)pyrrolidin-l - yl)sulfonyl)isoquinoline

Brown oil C ₂ 8H ₃₀ N ₄ O ₂ S, MW 486.63, Monoisotopic Mass 486.21, [M+H] ⁺ 487.2. UPLC Rt = 5.11. Ή NMR (300 MHz, CDCb δ (ppm) 1.55-1.70 (m, 4 H), 1.71-1.87 (m, 2 H), 2.08-2.23 (m, 4 H), 3.10-3.24 (m, 2 H), 3.36-3.52 (m, 2 H), 3.67-3.69 (m., 2 H), 4.25-4.39 (m, 1 H), 5.94-5.97 (m, 1 H), 6.93-7.23 (m, 3 H), 7.47 (d, J = 8.01 Hz, 1 H), 7.62-7.89 (m, 3 H), 8.00 (dd, J = 14.62, 7.82 Hz, 2 H), 8.43 (s, 1 H), 9.23 (s, 1 H), 9.84 (br. s, 1 H).

Example 43 : (S)-4-((2-(2-(4-(l H-Indol-3-yl)-5,6-dihydropyridin- 1 -(2H)-yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)isoquinoline

Brown oil C ₂₈ H ₃₈ FN ₄ 0 ₂ S, MW 486.63, Monoisotopic Mass 486.21 , [M+H] ⁺ 487.5. UPLC Rt = 5.29. Example 44: (S)-5-((2-(2-(4-(6-Fluoro-lH-indol-3-yl)-5,6-dihydropyridin- l(2H)-yl)ethyl)- pyrrolidin- 1 -yl)sulfonyl)quinoline

Brown oil C28H29FN4O2S, MW 504.62, Monoisotopic Mass 504.2, [M+H] ⁺ 505.3. UPLC Rt = 4.67.

Example 45: (S)-3-((2-(2-(4-(6-Fluoro-lH-mdol-3-yl)-5,6-dihydropyridin-l (2H)-yl)ethyl)- pyrrolidin- 1 -yl)sulfonyl)isoquinoline

Brown oil C ₂₈ H ₂₉ FN40 ₂ S, MW 504.62, Monoisotopic Mass 504.2, [M+H] ⁺ 505.3. UPLC R, = 5.22.

Example 46: (S)-4^(2-(2-(4-(6-Fluoro-lH-mdol-3-yl)-5,6-dihydropyridin-l( 2H)-yl)ethyl)- pyrrolidin- 1 -yl)sulfonyl)isoquinoline

Yellow oil C ₂ 8H29FN ₄ 0 ₂ S, MW 504.62, Monoisotopic Mass 504.2, [M+H] ⁺ 505.3. UPLC R, = 4.86. ¾ NMR (300 MHz, CDCb) δ (ppm) 1.61-1.81 (m, 4 H), 1.84-1.93 (m, 1 Η), 2.11-2.23 (m, 1 Η), 2.49-2.62 (m, 4 H), 2.64-2.73 (m, 1 H), 2.74-2.85 (m, 1 H), 3.21 (dd, J = 8.29, 1.75 Hz, 2 H), 3.40- 3.48 (m, 2 H), 4.05-4.13 (m, 1 H), 6.12-6.15 (m, 1 H), 6.88 (td, J = 9.16, 2.36 Hz, 1 H), 7.05 (dd, J = 9.49, 2.31 Hz, 1 H), 7.12 (d, J = 2.34 Hz, 1 H), 7.66-7.80 (m, 2 H), 7.86 (ddd, J = 8.58, 7.08, 1.33 Hz, 1 H), 8.06 (d, J = 8.14 Hz, 1 H), 8.50 (br. s., 1 H), 8.86 (d, J = 8.66 Hz, 1 H), 9.12 (s, 1 H), 9.39 (s, 1 H). ¹³ C NMR (75 MHz, CDC1 ₃ ) 6 (ppm) 24.26, 31.11, 48.48, 50.13, 52.99, 54.82, 58.49, 97.3, 108.4, 120.5, 121.3, 124.61, 128.42, 128.53, 128.91, 132.64, 137.1 , 138.1 , 145.04, 152.5, 157.62, 160.3.

Example 47: (S)-2-((2-(2-(4-(5-Chloro- 1 H-indol-3-yl)-5,6-dihydropyridin- 1 (2H)-yl)ethyl)- pyrrolidin- 1 -yl)sulfonyl)quinoline

Brown oil C ₂₈ H ₂ 9C1N ₄ 0 ₂ S, MW 521.07, Monoisotopic Mass 520.17, [M+H] ⁺ 521.4. UPLC Rt 5.81.

Example 48: (S)-4-((2-(2-(4-(5-ClJoro-lH-indol-3-yl)-5,6-dihydropyridin- l(2H)-yl)ethyl)- pyrrolidin- 1 -yl)sulfonyl)isoquinoline

Brown oil C ₂ 8H2 ₉ C1 ₄ 0 ₂ S, MW 521.07, Monoisotopic Mass 520.17, [M+H] ⁺ 521.5. UPLC Example 49: (S)-5-((2-(2-(4-(5-CMoro-lH-indol-3-yl)-5,6-dihydropyridin-l (2H)-yl)ethyl)- pyrrolidin- 1 -yl)sulfonyl)isoquinoline

Yellow solid C ₂₈ H2 ₉ C1N ₄ 02S, MW 521.07, Monoisotopic Mass 520.17, [M+H] ⁺ 521.4. UPLC Rt = 5.43. M.p.: 145.7-146.7.

Example 50: (S)-4-((2-(2-(4-(l H-Benzo[d]imidazol-4-yl)piperazin-l -yl)ethyl)pyrrolidin-l - yl)sulfonyl)isoquinoline

Yellow oil C26H30N6O2S, MW 490.62, Monoisotopic Mass 490.22, [M+H] ⁺ 491.3. UPLC Rt = 4.24. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.63-1.76 (m, 6 H), 1.86-1.93 (m, 1 H), 2.38-2.49 (m, 2 H), 2.58-2.65 (m, 2 H), 2.68-2.75 (m, 2 H), 3.26-3.31 (m, 4 H), 3.41-3.47 (m, 2 H), 4.02^.11 (m, 1 H), 6.51-6.62 (m, 1 H), 7.04-7.18 (m, 3 H), 7.71-7.94 (m, 2 H), 8.09 (s, 1 H), 8.86 (d, J = 8.62 Hz, 1 H), 9.11 (s, 1H), 9.40 (s, 1 H).

Example 51 : (S)-2-((2-(2-(4-(Benzo[b]thiophen-3-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)quinoline

Yellow oil C ₂₇ H ₃ oN ₄ 0 ₂ S ₂ , MW 506.68, Monoisotopic Mass 506.18, [M+H] ⁺ 507.4. UPLC Rt = 4.62.

Example 52: (S)-4-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-l -yl)ethyl)pyrrolidin-l - yl)sulfonyl) 1 -chloroisoquinoline

Brown oil C ₂₇ H ₂₉ C1N40 ₂ S ₂ , MW 541.13, Monoisotopic Mass 540.14, [M+H] ⁺ 541.3. UPLC R« = 5.12. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.63-1.71 (m, 4 H), 1.72-1.79 (m, 1 H), 1.82-1.95 (m, 1 H), 2.45 (q, J = 7.68 Hz, 2 H) 2.58-2.66 (m, 2 H), 2.69-2.77 (m, 2 H), 3.21 (t, J = 4.00 Hz, 4 H), 3.40- 3.45 (m, 2 H), 4.05 (dt, J = 8.20, 3.99 Hz, 1 H), 6.93 (dd, J = 7.68, 0.78 Hz, 1 H), 7.49 (ddd, J = 8.13, 7.01, 1.05 Hz, 1 H), 7.58 (d, J = 8.02 Hz, 2 H), 7.74 (dd, J = 8.14, 7.46 Hz, 1 H), 8.21-8.27 (m, 1 H), 7.82-7.83 (m, 1 H), 7.83-7.86 (m, 1 H), 8.49-8.52 (m, 1 H), 8.91 (dt, J = 8.55, 0.86 Hz, 1 H).

Example 53: (R)-3-((2-(2-(4-(Benzo[b]tmophen-3-yl)piperazin-l-yl)ethyl)p yrrolidin-l-yl)- sulfonyl)isoquinoline

Yellow oil C ₂₇ H3oN ₄ 0 ₂ S ₂ , MW 506.68, Monoisotopic Mass 506.18, [M+H] ⁺ 507.4. UPLC R, = 4.62. Ή NMR (300 MHz, CDCI ₃ ) δ (ppm) 1.63-1.71 (m, 4 H), 1.72-1.79 (m, 1 H), 1.82-1.95 (m, 1 H), 2.45 (q, J = 7.68 Hz, 2 H) 2.58-2.66 (m, 2 H), 2.69-2.77 (m, 2 H), 3.21 (t, J = 4.00 Hz, 4 H), 3.40- 3.45 (m, 2 H), 4.05 (dt, J = 8.20, 3.99 Hz, 1 H), 6.93 (dd, J = 7.68, 0.78 Hz, 1 H), 7.52 (dd, J = 5.66, 3.35 Hz, 1 H), 7.58 (d, J = 8.02 Hz, 2 H), 7.75-7.81 (m, 2 H), 7.88 (ddd, J = 8.55, 7.06, 1.31 Hz, 1 H), 7.98 (d, J = 7.98 Hz, 1 H), 8.07 (dd, J = 8.40, 7.30 Hz, 1 H), 8.21-8.27 (m, 1 H), 9.27 (s, 1 H).

Example 54: (R)-2-((2-(2-(4-(l H-Benzo[d]imidazol-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)quinoline

Yellow oil C ₂₆ H ₃ oN ₆ 0 ₂ S, MW 490.62, Monoisotopic Mass 490.22, [M+H] ⁺ 491.3. UPLC Rt = 4.27.

Example 55 : (R)-3 -((2-(2-(4-( 1 H-Indol-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)- quinoline

Yellow solid C ₂₇ H3iN ₅ 0 ₂ S, MW 489.63, Monoisotopic Mass 489.22, [M+H] ⁺ 490.3. UPLC Rt = 4.22. M.p.: 167.7-168.8.

Example 56: (R)-4-((2-(2-(4-(lH-mdol-4-yl)piperazm-l-yl)e l)pyrrolidm-l-yl)sulfonyl)- isoquinoline

Brown oil C ₂₇ H3iN ₅ 0 ₂ S, MW 489.63, Monoisotopic Mass 489.22, [M+H] ⁺ 490.4. UPLC Rt = 4.38. Example 57: (R)-5-((2-(2-(4-(l H-Indol-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)- isoquinoline

Yellow oil C ₂₇ H3iN ₅ 0 ₂ S, MW 489.63, Monoisotopic Mass 489.22, [M+H] ⁺ 490.4. UPLC Rt = 3.85. »H NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.61-1.75 (m, 6 H), 1.81-1.90 (m, 1 H), 2.00-2.13 (m, 1 H), 2.36-2.47 (m, 2 H), 2.57-2.63 (m, 2 H), 2.65-2.73 (m, 2 H), 3.27 (t, J = 4.54 Hz, 4 H), 3.42 (d, J = 5.99 Hz, 2 H), 3.96-^.05 (m, 1 H), 6.52-6.63 (m, 2 H), 7.05-7.11 (m,l H), 7.16 (dd, J = 3.05, 2.53 Hz, 1 H), 7.69-7.76 (m, 1 H), 8.19-8.28 (m, 1 H), 8.43 (dd, J = 7.40, 1.22 Hz, 1 H), 8.66-8.72 (m, 2 H), 9.34 (s, 1 H). ^,3 C NMR (75 MHz, CDCI3) δ (ppm) 24.24, 31.01 , 32.86, 48.37, 51.22, 53.57, 55.2, 58.49, 101.19, 105.83, 106.62 ,1 17.92, 121.18, 122.66, 125.9, 129.13, 132.17, 133.56, 133.84, 136.94, 145.12, 145.62, 153.16.

Example 58 : (R)-5-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)pyrrolidin- 1 - yl)sulfonyl)quinoline

Brown oil C ₂₇ H ₃ oN ₄ 0 ₂ S ₂ , MW 506.68, Monoisotopic Mass 506.18, [M+H] ⁺ 507.3. UPLC Rt = 4.95. ^l H NMR (300 MHz, CDCI3) 8 (ppm) 1.60-1.73 (m, 4 H), 1.73-1.81 (m, 1 H), 1.84-1.93 (m, 1 H), 2.39-2.47 (m, 2 H), 2.59-2.73 (m, 4 H), 3.20 (t, J = 4.00 Hz, 4 H), 3.38-3.44 (m, 2 H), 4.03 (tt, J = 8.13, 3.95 Hz, 1 H), 6.92 (dd, J = 7.65, 0.76 Hz, 1 H), 7.27-7.33 (m, 2 H), 7.42 (s, 2 H), 7.56- 7.62 (m, 1 H), 7.82 (dd, J = 8.44, 7.41 Hz, 1 H), 8.31 (dd, J = 7.41, 1.25 Hz, 1 H), 8.37 (dt, J = 8.46, 0.98 Hz, 1 H), 9.04 (dd, J = 4.18, 1.64 Hz, 1 H), 9.28-9.31 (m, 1 H). ^,3 C NMR (101 MHz, CDCb) δ (ppm) 24.29, 31.03, 48.37, 52.10, 53.58, 55.18, 58.47, 121.87, 122.56, 125.00, 127.69, 129.87, 133.77, 135.57, 151.15.

Example 59: (R)-4-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-l-yl)ethyl) pyrrolidin-l - yl)sulfonyl)quinoline

White solid C ₂ 7H3o 40 ₂ S ₂ , MW 506.68, Monoisotopic Mass 506.18, [M+H] ⁺ 507.3. UPLC Rt = 5.05. M.p.: 102.2-103.5.

Example 60: (R)-4-((2-(2-(4-(Berizo[b]tWophen-4-yl)piperazm-l-yl)ethyl)p yrrolidin-l- yl)sulfonyl)isoquinoline

Brown oil C ₂ 7H3oN ₄ 0 ₂ S ₂ , MW 506.68, Monoisotopic Mass 506.18, [M+H] ⁺ 507.3. UPLC Rt = 5.07. Ή NMR (300 MHz, CDCb) δ (ppm) 1.60-1.74 (m, 4 H), 1.85-1.96 (m, 2 H), 2.08-2.18 (m, 2 H), 2.39-2.53 (m, 2 H), 2.58-2.77 (m, 2 H), 3.21 (t, J = 6.00 Hz, 4 H). 3.47 (dd, J = 7.16, 5.94 Hz, 2 H), 4.09 (tt, J = 8.11, 3.89 Hz, 1 H). 6.92 (dd, J = 7.61 , 0.56 Hz, 1 H), 7.25-7.34 (m, 1 H), 7.38-7.46 (m, 2 H), 7.57 (d, J = 8.07 Hz, 1 H), 7.76 (ddd, J = 8.08, 7.08, 0.93 Hz, 1 H), 7.92 (ddd, J = 8.58, 7.07, 1.32 Hz, 1 H), 8.10 (d, J = 8.12 Hz, 1 H), 8.88 (dd, J = 8.68, 0.71 Hz, 1 H), 9.14 (s, 1 H), 9.42 (s, 1 H). Example 61 : (R)-5-((2-(2-(4-(Benzo[b]lhiophen-4-yl)piperazin-l-yl)ethyl) pyrrolidin-l - yl)sulfonyl)isoquinoline

Brown solid C27H ₃ oN ₄ 0 ₂ S ₂ , MW 506.68, Monoisotopic Mass 506.18, [M+H] ⁺ 507.3. UPLC R, = 4.75.

Example 62: (R)-3-(4-(2-(l-(Cndnolin-2-ylsulfony ^

benzoxazole

Brown oil C ₂ 6H2 ₉ N ₅ 0 ₃ S, MW 491.61, Monoisotopic Mass 491.2, [M+H] ⁺ 492.4. UPLC R, = 5.06. »H NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.67-1.79 (m, 4 H), 1.86-1.99 (m, 2 H), 2.52-2.61 (m, 2 H), 2.64-2.70 (m, 2 H), 2.72-2.79 (m, 2 H), 3.54-3.65 (m, 6 H), 4.17-4.27 (m, 1 H), 7.20 (ddd, J = 8.05, 6.33, 1.68 Hz, 1 H), 7.41-7.50 (m, 2 H), 7.64-7.70 (m, 2 H), 7.78-7.84 (m, 1 H), 7.88-7.92 (m, 1 H), 8.00 (d, J = 8.53 Hz, 1 H), 8.15 (dd, J = 8.51, 0.53 Hz, 1 H), 8.36 (d, J = 8.24 Hz, 1 H).

Example 63 : (R)-3-(4-(2-( 1 -(Quinolin-4-ylsiilfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2- benzothiazole

Brown oil C26H ₂₉ N ₅ 02S, MW 507.67, Monoisotopic Mass 507.18, [M+H] ⁺ 508.3. UPLC R, = 4.83.

Example 64: (R)-3-(4-(2-(l-(Quinolin-5-ylsulfonyl)pyrrolidin-2-yl)ethyl) piperazin-l-yl)-l,2- benzothiazole

Yellow oil C26H29N5O2S2, MW 507.67, Monoisotopic Mass 507.18, [M+H] ⁺ 508.3. UPLC Rt = 4.54. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.52-1.76 (m, 4 H), 1.81-1.89 (m, 1 H), 2.00 (td, J = 7.92, 4.84 Hz, 1 H), 2.33-2.41 (m, 2 H), 2.50-2.57 (m, 2 H), 2.60-2.68 (m, 2 H), 3.34-3.40 (m, 2 H), 3.53 (t, J = 4.82 Hz, 4 H), 3.95-4.04 (m, 1 H), 7.30-7.39 (m, 1 H), 7.46 (td, J = 7.54, 1.01 Hz, 1 H), 7.57 (dd, J = 8.82, 4.17 Hz, 1 H), 7.76-7.81 (m, 2 H), 7.89 (d, J = 8.1 1 Hz, 1 H), 8.24-8.35 (m, 2 H), 9.00 (dd, J = 4.17, 1.60 Hz, 1 H), 9.26 (d, J = 8.33 Hz, 1 H).

Example 65: (R)-3-(4-(2-(l-(Isoqumolin-3-ylsulfonyl)pyn-olidin-2-yl)ethy l)piperazin-l-yl)- 1 ,2-benzothiazole

Yellow oil C26H ₂₉ N ₅ 0 ₂ S ₂ , MW 507.67, Monoisotopic Mass 507.18, [M+H] ⁺ 508.3. UPLC Rt = 5.09. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.60-1.70 (m, 2 H), 1.71-1.91 (m, 2 H) ,2.11-2.23 (m, 2 H), 2.50-2.59 (m, 2 H), 2.63-2.71 (m, 2 H), 2.72 -2.80 (m, 2 H), 3.55 (t, J = 4.87 Hz, 6 H), 4.13^1.23 (m, 1 H), 7.32-7.38 (m, 1 H), 7.46 (ddd, J = 8.08, 7.00, 1.1 1 Hz, 1 H), 7.74-7.86 (m, 3 H), 7.90 (d, J = 8.11 Hz, 1 H), 7.97-8.10 (m, 2 H), 8.40 (s, 1 H), 9.27 (s, 1 H).

Example 66: (R)-3-(4-(2-(l-(Isoqmnolin-4-ylsulfonyl)pyirolidin-2-yl)ethy l)piperazin-l-yl)-

1,2-benzothiazole

Yellow oil C ₂ 6H ₂ 9N ₅ 0 ₂ S ₂ , MW 507.67, Monoisotopic Mass 507.18, [M+H] ⁺ 508.3. UPLC R, = 4.61. Ή NMR (300 MHz, CDCI ₃ ) δ (ppm) 1.59-1.75 (m, 4 H), 1.81-1.91 (m, 1 H), 2.03-2.16 (m, 1 H), 2.38-2.47 (m, 2 H), 2.55-2.61 (m, 2 H), 2.63-2.73 (m, 2 H), 3.40-3.46 (m, 2 H), 3.55 (t, J = 4.68 Hz, 4 H), 4.05 (dt, J = 8.05, 3.84 Hz, 1 H), 7.31-7.38 (m, 1 H), 7.45 (t, J = 7.52 Hz, 1 H), 7.70-7.83 (m, 2 H), 7.85-7.94 (m, 2 H), 8.07 (d, J = 8.08 Hz, 1 H), 8.84 (d, J = 8.66 Hz, 1 H), 9.10 (s, 1 H), 9.39 (s, 1 H). ¹³ C NMR (75 MHz, CDCb) δ (ppm) 24.27, 31.03, 32.89, 48.46, 50.02, 52.99, 55.17, 58.51, 120.53, 123.9, 124.59, 127.54, 128.48, 128.56, 128.77, 128.95, 131.73, 132.57, 145.04, 152.7, 157.59, 163.88.

Example 67: (R)-3-(4-(2-(l -(Isoqumolin-5-ylsulfonyl)pyrrolidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2-benzothiazole

Yellow oil C ₂ 6H ₂₉ N ₅ 0 ₂ S ₂ , MW 507.67, Monoisotopic Mass 507.18, [M+H] ⁺ 508.3. tJPLC Rt = 4.31. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.56-1.73 (m, 4 H), 1.80-1.89 (m, 1 H), 2.00-2.12 (m, 1 H), 2.36-2.44 (m, 2 H), 2.51-2.60 (m, 2 H), 2.63-2.70 (m, 2 H), 3.37-3.43 (m, 2 H), 3.54 (t, J = 4.87 Hz, 4 H), 3.96-4.04 (m, 1 H), 7.32-7.38 (m, 1 H), 7.46 (td, J = 7.55, 0.99 Hz, 1 H), 7.68-7.75 (m, 1 H), 7.79-7.93 (m, 2 H), 8.20 (d, J = 8.17 Hz, 1 H), 8.41 (dd, J = 7.41, 1.19 Hz, 1 H), 8.64-8.70 (m, 2 H), 9.34 (s, 1 H). ¹³ C NMR (75 MHz, CDCb) δ (ppm) 24.23, 31.00, 32.81 , 48.37, 50.06, 53.00, 55.14, 58.46, 120.55, 123.89, 125.90, 127.54, 128.00, 129.1 1, 132.14, 133.54, 133.80, 145.10, 152.72, 153.16, 163.89.

Example 68: (R)-5-((2-(2-(4-(2,3-Dihydrobenzo[b][ 1 ,4]dioxin-5-yl)piperazin-l - yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)quinoline

Yellow oil C ₂₇ H ₃₂ N ₄ 0 ₄ S, MW 508.63, Monoisotopic Mass 508.21 , [M+H] ⁺ 509.4. UPLC R, = 4.27.

Example 69: (R)-4-((2-(2-(4-(2,3-Dihydrobenzo[b][l ,4]dioxin-5-yl)piperazin-l- yl)ethyl)pyrrolidin- 1 -yl)sulfonyl)isoquinoline

Brown oil C ₂₇ H ₃₂ N ₄ 0 S, MW 508.63, Monoisotopic Mass 508.21, [M+H] ⁺ 509.4. UPLC Rt = 4.45.

Example 70: (R)-5-((2-(2-(4-(2,3-Dihydrobenzo[b][ 1 ,4]dioxin-5-yl)piperazin- 1 -yl)ethyl)- pyrrolidin- 1 -yl)sulfonyl)isoquinoline

Brown oil C ₂₇ H ₃₂ N ₄ 0 ₄ S, MW 508.63, Monoisotopic Mass 508.21, [M+H] ⁺ 509.4. UPLC Rt = 4.42. *H NMR (300 MHz, CDCb) δ (ppm) 1.58-1.78 (m, 4 H), 1.82-1.93 (m, 2 H), 2.37-2.45 (m, 2 H), 2.52-2.60 (m, 2 H), 2.64-2.71 (m, 2 H), 3.11 (t, J = 6.50 Hz, 4 H), 3.37-3.45 (m, 2 H), 3.95^.07 (m, 1 H), 4.24-4.29 (m, 2 H), 4.32-4.39 (m, 2 H), 6.54-6.66 (m, 2 H), 6.76-6.84 (m, 1 H), 7.73 (dd, J = 8.05, 7.51 Hz, 1 H), 8.23 (d, J=8.17 Hz, 1 H), 8.44 (dd, J = 7.39, 1.22 Hz, 1 H), 8.66-8.75 (m, 2 H), 9.37 (d, J = 0.64 Hz, 1 H). Example 71 : (R)-5-((2-(2-(4-(6-Butyl-4-(4-fluorophenyl)pyridin-2-yl)pipe razin-l-yl)ethyl)- pyrrolidin- 1 -yl)sulfonyl)quinoline

Brown oil C34H ₄ oFN ₅ 0 ₂ S, MW 601.78, Monoisotopic Mass 601.29, [M+H] ⁺ 602.4. UPLC Rt = 6.43. Ή NMR (300 MHz, CDCh) δ (ppm) 0.94(t, J = 7.31 Hz, 3 H), 1.21-1.28 (m, 2 H), 1.34-1.46 (m, 2 H), 1.54-1.77 (m, 6 H), 1.78-1.91 (m, 1 H), 1.96-2.08 (m, 1H), 2.29-2.57 (m, 4 H), 2.67-2.71 (t, J = 7.9 Hz, 2 H), 3.44 (t, J = 5.4 Hz, 2 H), 3.59 (t, J = 4.86 Hz, 4 H), 3.95-4.03 (m, 1 H), 6.55-6.68 (m, 2 H), 7.08-7.15 (m, 2 H), 7.52-7.59 (m, 3 H), 7.76-7.82 (m, 1 H), 8.26-8.34 (m, 2 H), 8.99 (dd, J = 4.17, 1.57 Hz, 1 H), 9.26 (dd, J = 8.77, 0.63 Hz, 1 H).

Example 72: (R)-4-((2-(2-(4-(6-Butyl-4-(4-fluorophenyl)pyridin-2-yl)pipe razin-l -yl)ethyl)- pyrrolidin- 1 -yl)sulfonyl)isoquinoline

Brown oil C ₃₄ H ₄₀ FN ₅ O ₂ S, MW 601.78, Monoisotopic Mass 601.29, [M+H] ⁺ 602.4. UPLC R, = 6.78. »H NMR (300 MHz, CDCh) δ (ppm) 0.95(t, J = 7.1 Hz, 3 H), 1.19-1.30 (m, 2 H), 1.32-1.48 (m, 2 H), 1.60-1.78 (m, 6 H), 1.80-1.93 (m, 1 H), 2.03-2.18 (m, 1H), 2.34-2.63 (m, 4 H), 2.65-2.73 (m, 2 H), 3.44 (t, J = 5.4 Hz, 2 H), 3.61 (t, J = 4.9 Hz, 4 H), 4.01-^.1 1 (m, 1 H), 6.52-6.69 (m, 2 H), 7.08- 7.17 (m, 2 H), 7.51-7.59 (m, 2 H), 7.71-7.77 (m, 1 H), 7.89 (ddd, J = 8.11, 7.06, 1.38 Hz, 1 H), 8.08 (d, J = 7.89 Hz, 1 H), 8.85 (dd, J = 8.64, 0.75 Hz, 1 H), 9.11 (s, 1 H), 9.40 (d, J = 0.54 Hz, 1 H).

Example 73 : (R)-5-((2-(2-(4-(6-Butyl-4-(4-fluorophenyl)pyridin-2-yl)pipe razin-l -yl)ethyl> pyrrolidin- 1 -yl)sulfonyl)isoquinoline

Brown oil C ₃ H ₄₀ FN ₅ O ₂ S, MW 601.78, Monoisotopic Mass 601.29, [M+H] ⁺ 602.4. UPLC R, = 6.78. »H NMR (300 MHz, CDC1 ₃ ) 6 (ppm) 0.95(t, J = 7.1 Hz, 3 H), 1.22-1.45 (m, 4 H), 1.61-1.77 (m, 6 H), 1.78-1.88 (m, 1 H), 1.99-2.12 (m, 1H), 2.31-2.40 (m, 2 H), 2.42-2.60 (m, 2 H), 2.66-2.72 (m, 2H), 3.36-3.42 (m, 2 H), 3.60 (t, J = 4.94 Hz, 4 H), 3.97-4.07 (m, 1 H), 6.56 (d, J = 1.06 Hz, 1 H), 6.67 (d, J = 1.03 Hz, 1 H), 7.08-7.16 (m, 2 H), 7.52-7.59 (m, 2 H), 7.71 (dd, J = 8.11, 7.47 Hz, 1 H), 8.20 (d, J = 8.1 1 1 H), 8.42 (dd, J = 7.41, 1.22 Hz, 1 H), 8.68 (d, J = 2.69 Hz, 2 H), 9.34 (s, 1 H). ¹³ C NMR (75 MHz, CDCh) δ (ppm) 14.05, 22.58, 22.68, 24.25, 29.68, 30.30, 31.01, 31.63, 31.91, 32.88, 38.17, 45.41, 48.35, 53.09, 55.18, 58.48, 101.92, 110.88, 1 15.53, 115.81, 117.89, 125.88, 128.67, 128.78, 129.12, 132.16, 133.54, 133.86, 136.18, 145.11, 149.33, 153.16, 159.77, 161.45.

Example 74: (R)-2-((2-(2-(4-(6-Fluoro-lH-mdol-3-yl)-5,6-dihydropyridin-l (2H)-yl)ethyl)- pyrrolidin- 1 -yl)sulfonyl)quinoline

Brown solid C ₂₈ H ₂₉ FN ₄ 0 ₂ S, MW 504.62, Monoisotopic Mass 504.2, [M+H] ⁺ 505.5. UPLC R, = 6.1 1. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.64-1.81 (m, 4 H), 1.84-1.22 (m, 2 H), 2.55-2.62 (m, 4 H), 2.64-2.73 (m, 1 H), 2.74-2.83 (m, 1 H), 3.21 (dd, J = 8.29, 1.75 Hz, 2 H), 3.42-3.48 (m, 2 H), 4.05-4.12 (m, 1 H), 6.1 1-6.15 (m, 1 H), 6.88 (td, J = 9.16, 2.36 Hz, 2 H), 7.05 (dd, J = 9.49, 2.31 Hz, 1 H), 7.12 (d, J = 2.34 Hz, 1 H), 7.66-7.80 (m, 2 H), 7.86 (ddd, J = 8.58, 7.08, 1.33 Hz, 2 H), 8.12 (d, J = 8.14 Hz, 1 H), 8.50 (br. s., 1 H), 8.86 (d, J = 8.66 Hz, 1 H). M.p.: 191.9-193.

Example 75 : (R)-4-((2-(2-(4-(6-Fluoro- 1 H-indol-3-yl)-5,6-dihydropyridin- 1 (2H)-yl)ethyl)- pyrrolidin- 1 -yl)sulfonyl)isoquinoline

Yellow oil C ₂₈ H29FN ₄ 0 ₂ S, MW 504.62, Monoisotopic Mass 504.2, [M+H] ⁺ 505.5. UPLC R, = 5.41. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.61-1.81 (m, 4 H), 1.84-1.93 (m, 1 H), 2.11-2.23 (m, 1 H), 2.49-2.62 (m, 4 H), 2.64-2.73 (m, 1 H), 2.74-2.85 (m, 1 H), 3.21 (dd, J = 8.29, 1.75 Hz, 2 H), 3.40- 3.48 (m, 2 H), 4.05^.13 (m, 1 H), 6.12-6.15 (m, 1 H), 6.88 (td, J = 9.16, 2.36 Hz, 1 H), 7.05 (dd, J = 9.49, 2.31 Hz, 1 H), 7.12 (d, J = 2.34 Hz, 1 H), 7.66-7.80 (m, 2 H), 7.86 (ddd, J = 8.58, 7.08, 1.33 Hz, 1 H), 8.06 (d, J = 8.14 Hz, 1 H), 8.50 (br. s., 1 H), 8.86 (d, J = 8.66 Hz, 1 H), 9.12 (s, 1 H), 9.39 (s, 1 H).

Example 76: (R)-5-((2-(2-(4-(5-Chloro- 1 H-indol-3-yl)-5,6-dihydropyridin- 1 -(2H)-yl)ethyl)- piperidin- 1 -yl)sulfonyl)quinoline

Yellow solid C28H29CIN4O2S, MW 521.07, Monoisotopic Mass 520.17, [M+H] ⁺ 521.4. UPLC Rt = 5.05. M.p.: 113.1-114.1.

Example 77: (R)-4-((2-(2-(4-(5-Chloro- 1 H-indol-3-yl)-5,6-dihydropyridin- 1 -(2H)-yl)ethyl)- piperidin- 1 -yl)sulfonyl)isoquinoline

Yellow solid C ₂₈ H ₂ 9C1N ₄ 0 ₂ S, MW 521.07, Monoisotopic Mass 520.17, [M+H] ⁺ 521.4. UPLC R, = 5.32. M.p.: 157.2-159.

Example 78: (S)-5-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-l-yl)ethyl) piperidin-l-yl)- sulfonyl)quinoline

Brown oil C ₂ 8H3 ₂ N ₄ 0 ₂ S ₂ , MW 520.71, Monoisotopic Mass 520.2, [M+H] ⁺ 521.4. UPLC R _t = 5.14. Ή NMR (300 MHz, CDCI3) δ (ppm) 1.57-1.62 (m, 6 H), 1.69-1.81 (m, 2 H), 1.87-1.99 (m, 2 H), 2.22-2.32 (m, 2 H), 2.47-2.56 (m, 4 H), 3.07-3.18 (m, 4 H), 3.85-3.93 (m, 1 H), 6.89 (dd, J = 7.68, 0.73 Hz, 1 H), 7.29 (t, J = 7.83 Hz, 1 H), 7.37-7.44 (m, 2 H), 7.54-7.63 (m, 2 H), 7.81 (dd, J = 8.51, 7.38 Hz, 1 H), 8.31-8.40 (m, 2 H), 8.96-9.02 (m, 1 H), 9.04 (dd, J = 4.18, 1.64 Hz, 1 H).

Example 79: (S)-4-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)piperidin- 1 -yl)- sulfonyl)isoquinoline

Brown oil C ₂₈ H32 40 ₂ S ₂ , MW 520.71, Monoisotopic Mass 520.2, [M+H] ⁺ 521.4. UPLC Rt = 5.41.

Example 80: (S)-5-((2-(2-(4-(Benzo[b]tldophen-4-yl)piperazm-l-yl)ethyl)p iperidin-l-yl)- sulfonyl)isoquinoline

Yellow oil C ₂ 8H ₃₂ N40 ₂ S ₂ , MW 520.71 , Monoisotopic Mass 520.2, [M+H] ⁺ 521.3. UPLC R, = 4.91. Example 81 : (S)-3-(4-(2-( 1 -(Quinolin-2-ylsulfonyl)piperidin-2-yl)ethyl)piperazin- 1 -yl)- 1 ,2- benzothiazole

Brown oil C ₂₇ H ₃ iFN ₅ 0 ₂ S ₂ , MW 521.7, Monoisotopic Mass 521.19, [M+H] ⁺ 522.3. UPLC Rt = 4.76.

Example 82: (S)-3-(4-(2-(l-(Quinolin-5-ylsulfonyl)piperidin-2-yl)ethyl)p iperazin-l-yl)-l,2- benzothiazole

Yellow oil C ₂₇ H ₃ iN ₅ 0 ₂ S ₂ , MW 521.70, Monoisotopic Mass 521.19, [M+H] ⁺ 522.4. UPLC R, = 4.81. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.48-1.52 (m., 6 H), 1.65-1.77 (m, 1 H), 1.80-1.95 (m, 1 H), 2.38-2.52 (m, 6 H), 3.09 (td, J = 13.55, 2.13 Hz, 2 H), 3.48 (t, J = 4.82 Hz, 4 H), 3.82-3.90 (m, 1 H), 7.30-7.38 (m, 1 H), 7.41-7.48 (m, 1 H), 7.56 (dd, J = 8.74, 4.18 Hz, 1 H), 7.74-7.81 (m, 2 H), 7.86 (d, J = 8.17 Hz, 1 H), 8.32 (dd, J = 7.85, 3.91 Hz, 2 H), 8.92-8.97 (m, 1 H), 9.00 (dd, J = 4.12, 1.30 Hz, 1 H).

Example 83: (S)-3-(4-(2-(l-(Isoquinolin-4-ylsulfonyl)piperidin-2-yl)ethy l)piperazin-l-yl)-l ,2- benzothiazole

Brown oil C ₂₇ H ₃ iN ₅ 0 ₂ S ₂ , MW 521.70, Monoisotopic Mass 521.19, [M+H] ⁺ 522.4. UPLC R, = 4.95. ^! H NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.48-1.55 (m, 6 H), 1.66-1.78 (m, 1 H), 1.83-1.98 (m, 1 H), 2.41-2.56 (m, 6 H), 3.06-3.18 (m, 2 H), 3.49 (t, J = 4.17 Hz, 4 H), 3.91 (dd, J = 13.94, 3.56 Hz, 1 H), 7.31-7.37 (m, 1 H), 7.42-7.48 (m, 1 H), 7.71-7.80 (m, 2 H), 7.85-7.94 (m, 2 H), 8.08 (d, J = 8.01 Hz, 1 H), 8.57 (d, J = 0.77 Hz, 1 H), 9.16 (s, 1 H), 9.39 (s, 1 H).

Example 84: (S)-3-(4-(2-(l-(Isoqumolin-5-ylsulfonyl)piperidin-2-yl)ethyl )piperazin-l-yl)-l,2- benzothiazole

Brown oil C ₂₇ H ₃₁ N ₅ 0 ₂ S ₂ , MW 521.70, Monoisotopic Mass 521.19, [M+H] ⁺ 522.4. UPLC R, = 4.58. >H NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.48-1.52 (m., 6 H) 1.65-1.78 (m, 1 H), 1.83-1.96 (m, 2 H), 2.05-2.14 (m, 1 H), 2.18 -2.29 (m, 1 H), 2.40-2.55 (m, 4 H), 3.1 1 (td, J = 13.58, 2.37 Hz, 1 H), 3.48 (t, J = 4.81 Hz, 4 H), 3.88 (dd, J = 13.90, 3.51 Hz, 1 H), 7.33-7.38 (m, 1 H), 7.44-7.49 (m, 1 H), 7.70 (dd, J = 8.14, 7.47 Hz, 1 H), 7.76-7.91 (m, 2 H), 8.19 (d, J = 8.21 Hz, 1 H), 8.36 (d, J = 6.12 Hz, 1 H), 8.44-8.53 (m, 1 H), 8.70 (d, J = 6.12 Hz, 1 H), 9.35 (s, 1 H).

Example 85: (S)-5-((2-(2-(4-(5-CMoro-lH-mdol-3-yl)-5,6-dihydropyridin-l- (2H)-yl)ethyl)- piperidin- 1 -yl)sulfonyl)quinoline

Yellow solid C ₂₉ H ₃ iClN ₄ 0 ₂ S, MW 535.1 , Monoisotopic Mass 534.19, [M+H] ⁺ 535.4. UPLC R, = 5.32. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.49-1.61 (m, 6 H), 1.72-1.84 (m, 1 H), 1.95-2.07 (m, 1 H), 2.16-2.26 (m, 1 H), 2.27-2.38 (m, 1 H), 2.46-2.56 (m, 3 H), 2.58-2.66 (m, 1 H), 3.02- 3.18 (m, 3 H), 3.88 (dd, J = 13.96, 3.30 Hz, 1 H), 4.09-4.16 (m, 1 H), 6.01-6.06 (m, 1 H), 7.12-7.17 (m, 2 H), 7.30 (dd, J = 8.71, 0.34 Hz, 1 H), 7.58 (dd, J = 8.75, 4.21 Hz, 1 H), 7.76-7.83 (m, 2 H), 8.32-8.38 (m, 2 H), 8.75 (br. s., 1 H), 8.99-9.01 (m, 1 H), 9.03 (dd, J = 4.21, 1.61 Hz, 1 H). ¹³ C NMR (75 MHz, CDC1 ₃ ) δ ppm 18.51, 25.04, 28.04, 51.30, 55.13, 120.08, 122.47, 122.76, 124.61, 127.71, 128.53, 130.38, 133.39, 135.37, 145.14, 151.07, 157.78, 161.32. M.p.: 120.3-121.6.

Example 86: (S)-4-((2-(2-(4-(5-Chloro- 1 H-indol-3-yl)-5,6-dihydropyridin- 1 -(2H)-yl)ethyl)- piperidin- 1 -yl)sulfonyl)isoquinoline

Yellow solid C ₂₉ H ₃ iClN ₄ 0 ₂ S, MW 535.1, Monoisotopic Mass 534.19, [M+H] ⁺ 535.4. UPLC Rt = 5.46. M.p. 140.2-140.8.

Example 87: (S)-4-((2-(2-(4-(l H-Benzo[d]imidazol-4-yl)piperazin- 1 -yl)ethyl)piperidin- 1 -yl)- sulfonyl)quinoline

Yellow oil C ₂₇ H ₃₂ N ₆ 0 ₂ S, MW 504.65, Monoisotopic Mass 504.23, [M+H] ⁺ 505.3. UPLC Rt = 4.29. Ή NMR (300 MHz, CDCI3) 6 (ppm) 1.57-1.62 (m, 6 H), 1.69-1.81 (m, 2 H), 1.87-1.99 (m, 2 H), 2.22-2.32 (m, 2 H), 2.47-2.56 (m, 4 H), 3.07-3.18 (m, 4 H), 3.85-3.93 (m, 1 H), 6.51-6.62 (m, 1 H), 7.04-7.18 (m, 3 H), 7.71-7.94 (m, 2 H), 8.07 (dd, J = 8.40, 7.30 Hz, 1 H), 8.09 (s, 1 H), 8.86 (d, J = 8.62 Hz, 1 H), 9.11 (s, 1H), 9.40 (s, 1 H).

Example 88: (S)-4-((2-(2-(4-(Benzo[b]thiophen-3-yl)piperazin-l-yl)ethyl) piperidin-l-yl)- sulfonyl)isoquinoline

Yellow oil C ₂₈ H ₃ 2N ₄ 0 ₂ S ₂ , MW 520.71, Monoisotopic Mass 520.21, [M+H] ⁺ 521.3. UPLC Rt = 4.67

Example 89: (S)-2-((2-(2-(4-(lH-Benzo[d]imidazol-4-yl)piperazm -yl)ethyl)piperidin-l-yl)- sulfonyl)quinoline

Yellow oil C ₂ 7H ₃₂ N ₆ 0 ₂ S, MW 504.65, Monoisotopic Mass 504.23, [M+H] ⁺ 505.3. UPLC R, = 4.29. Ή NMR (300 MHz, CDCI3) 6 (ppm) 1.57-1.62 (m, 6 H), 1.69-1.81 (m, 2 H), 1.87-1.99 (m, 2 H), 2.22-2.32 (m, 2 H), 2.47-2.56 (m, 4 H), 3.07-3.18 (m, 4 H), 3.85-3.93 (m, 1 H), 6.51-6.62 (m, 1 H), 7.04-7.18 (m, 3 H), 7.21 (ddd, J = 8.03, 6.27, 1.76 Hz, 1 H), 7.88 (ddd, J = 8.55, 7.06, 1.31 Hz, 1 H), 8.09 (s, 1 H), 8.84 (d, J = 8.66 Hz, 1 H), 9.09 (s, 1 H), 9.39 (s, 1 H).

Example 90: (R)-5-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-l-yl)ethyl) azepan-l-yl)- sulfonyl)quinoline

Brown oil C ₂ 9H ₃ 4N ₄ 0 ₂ S, MW 534.74, Monoisotopic Mass 534.21, [M+H] ⁺ 535.3. UPLC Rt = 5.33. 'HNMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.19-1.48 (m, 6 H), 1.50-1.82 (m, 7 H), 1.85-2.02 (m, 2 H), 2.10- 2.25 (m, 1 H), 2.44-2.83 (m, 2 H), 3.01-3.10 (m, 1 H), 3.22-3.35 (m, 3 H), 4.20-4.31 (m, 1 H), 6.91 (dd, 1 H, J=7.60, 0.70), 7.18 (dd, J = 8.51, 1.94 Hz, 1 H), 7.22-7.27 (m, 1 H), 7.33-7.37 (m, 1 H), 7.39- 7.48 (m, 1 H), 7.53 (dd, J = 8.75, 4.20 Hz, 1 H), 7.57 (d, 1 H, J=8.03), 7.66 (dd, J = 8.74, 5.08 Hz, 1 H), 7.81 (dd, J = 8.48, 7.39 Hz, 1 H), 8.92-8.98 (m, 1 H), 8.99-9.04 (m, 1 H). Example 91 : (R)-4-((2-(2-(4-(Benzo[b]thiophen-4-yl)piperazin- 1 -yl)ethyl)azepan- 1 -yl)- sulfonyl)isoquinoline

Brown oil C ₂₉ H ₃ 4N ₄ 0 ₂ S ₂ , MW 534.74, Monoisotopic Mass 534.21, [M+H] ⁺ 535.3. UPLC R» = 5.21. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.19-1.48 (m, 6 H), 1.50-1.82 (m, 7 H), 1.85-2.02 (m, 2 H), 2.10-2.25 (m, 1 H), 2.44-2.83 (m, 2 H), 3.01-3.10 (m, 1 H), 3.22-3.35 (m, 3 H), 4.20-4.31 (m, 1 H), 6.91 (dd, 1 H, J=7.60, 0.70), 7.21 (dd, J = 8.51, 2.13 Hz, 1 H), 7.25-7.28 (m, 1 H), 7.33-7.37 (m, 1 H), 7.38-7.45 (m, 1 H), 7.57 (d, 1 H, J=8.03), 7.88 (ddd, J = 8.54, 7.05, 1.36 Hz, 1 H), 8.08 (d, J = 7.95 Hz, 1 H), 8.55 (d, J = 8.59 Hz, 1 H), 9.16 (s, 1 H), 9.38 (s, 1 H).

Example 92: (R)-3-(4-(2-(l -(Quinolin-5-ylsulfonyl)azepan-2-yl)ethyl)piperazin-l -yl)-l ,2- benzothiazole

Brown oil C ₂₈ H ₃₃ N ₅ 0 ₂ S ₂ , MW 535.72, Monoisotopic Mass 535.21, [M+H] ⁺ 536.3. UPLC Rt = 5.27. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.20-1.49 (m, 6 H), 1.53-1.69 (m, 2 H), 1.72-2.01 (m, 6 H), 2.06-2.20 (m, 1 H), 2.63-2.91 (m, 3 H), 3.20-3.45 (m, 2 H), 3.55-3.73 (m, 3 H), 7.18 (dd, J = 8.51, 1.94 Hz, 1 H), 7.30-7.38 (m, 1 H), 7.42-7.45 (m, 1 H), 7.53 (dd, J = 8.75, 4.20 Hz, 1 H), 7.62 (dd, J = 8.74, 5.08 Hz, 1 H), 7.66-7.75 (m, 2 H), 7.81 (dd, J = 8.48, 7.39 Hz, 1 H), 8.92-8.98 (m, 1 H), 8.99-9.04 (m, 1 H).

Example 93: (R)-3-(4-(2-(l -(Isoquinolin-4-ylsulfonyl)azepan-2-yl)ethyl)piperazin-l -yl)-l ,2- benzothiazole

Brown oil C ₂₈ H ₃₃ N ₅ 0 ₂ S ₂ , MW 535.72, Monoisotopic Mass 535.21, [M+H] ⁺ 536.3. UPLC R, = 5.27. Ή NMR (300 MHz, CDC1 ₃ ) δ (ppm) 1.20-1.49 (m, 6 H), 1.53-1.69 (m, 2 H), 1.72-2.01 (m, 6 H), 2.06-2.20 (m, 1 H), 2.63-2.91 (m, 3 H), 3.20-3.45 (m, 2 H), 3.55-3.73 (m, 3 H), 7.30-7.38 (m, 1 H), 7.42-7.45 (m, 1 H), 7.57 (d, 1 H, J=8.03), 7.66-7.75 (m, 2 H), 7.88 (ddd, J = 8.54, 7.05, 1.36 Hz, 1 H), 8.08 (d, J = 7.95 Hz, 1 H), 8.55 (d, J = 8.59 Hz, 1 H), 9.16 (s, 1 H), 9.38 (s, 1 H).

Test Examples

Test Example 1A - in vitro evaluation

Radioligand binding assays were employed for determining the affinity and the selectivity profile of the synthesized compounds for cloned serotonin: 5-HT1A, 5-HT2A, 5-HT6, 5-HT7 and dopamine D2L receptors, all stably expressed in HEK293 cells except 5-HT2A which was stably expressed in CHO-K1 cells. This was accomplished by displacement of respective radioligands from cloned human receptors,: [3H]-8-OH-DPAT for 5-HTlAR, [ ³ H]-ketanserin for 5-HT _2A R, [ ³ H]-LSD for 5-HT ₆ R, [ ³ H]-5-CT for 5-HT ₇ R and [ ³ H]-raclopride for D ₂ R Cell culture and preparation of cell membranes

HEK293 cells with stable expression of human serotonin 5-HTIAR, 5-HT ₆ , 5-HT ₇ bR or dopamine D _2L R (all prepared with the use of Lipofectamine 2000) were maintained at 37°C in a humidified atmosphere with 5% C0 ₂ and were grown in Dulbeco's Modifier Eagle Medium containing 10% dialysed foetal bovine serum and 500 mg/ml G418 sulphate. For membranes preparations, cells were subcultured in 10 cm diameter dishes, grown to 90% confluence, washed twice with prewarmed to 37°C phosphate buffered saline (PBS) and were pelleted by centrifugation (200 g) in PBS containing 0.1 mM EDTA and 1 mM dithiothreitol. Prior to membrane preparations pellets were stored at -80°C.

CHO-K1 cells with stable expression of human serotonin 5-HT _2A R were purchased from

PerkinElmer BioSignal Inc and were maintained according to manufacturer's protocol.

Radioligand binding assays

Cell pellets were thawed and homogenized in 20 volumes of assay buffer using an Ultra Turrax tissue homogenizer and centrifuged twice at 35 000 g for 20 min at 4°C, with incubation for 15 min at 37°C in between. The composition of the assay buffers was as follows: for 5-HTi AR: 50 mM Tris- HC1, 0.1 mM EDTA, 4 mM MgCl ₂ , 10 mM pargyline and 0.1% ascorbate; for 5-HT _2A R: 50 mM Tris-HCl, 4 mM MgCl ₂ and 0.1% ascorbate; for 5-HT ₆ R: 50 mM Tris-HCl, 0.5 mM EDTA and 4 mM MgCl ₂ , for 5-HT _7b R: 50 mM Tris-HCl, 4 mM MgCl ₂ , 10 mM pargyline and 0.1% ascorbate; for dopamine D _2L R: 50 mM Tris-HCl, 1 mM EDTA, 4 mM MgCl ₂ , 120 mM aCl, 5 mM KC1, 1.5 mM CaCl ₂ and 0.1 % ascorbate.

All assays were incubated in a total volume of 200 ml in 96-well microtitre plates for 1 h at 37°C, except for 5-HTIAR and 5-HT ₂ AR which were incubated for 1 h at room temperature and at 27°C respectively. The process of equilibration is terminated by rapid filtration through Unifilter plates with a 96-well cell harvester and radioactivity retained on the filters was quantified on a Microbeta plate reader.

For displacement studies the assay samples contained as radioligands: 1.5 nM [ ³ H]- 8-OH-DPAT (135.2 Ci/mmol) for 5-HTIAR; 2nM [ ³ H]-Ketanserin (53.4 Ci mmol) for 5-HT _2A R; 2 nM [ ³ H]-LSD (83.6 Ci mmol) for 5-HT ₆ R; 0.6 nM [ ³ H]-5-CT (39.2 Ci/mmol) for 5-HT ₇ R or 2.5 nM [ ³ H]-Raclopride (76.0 Ci mmol).

Non-specific binding is defined withlO μΜ of 5-HT in 5-HTI _A R and 5-HT ₇ R binding experiments, whereas 20 μΜ of mianserin, 10 μΜ of methiothepine or 1 μΜ of (+)butaclamol were used in 5-HT ₂ AR, 5-HT ₆ R and D ₂ L assays, respectively.

Each compound was tested in triplicate at 7-8 concentrations (lO^'-lO ^-4 M). The inhibition constants (Ki) were calculated from the Cheng-Prusoff equation: (Cheng et al., 1973).

esults were expressed as means of at least three separate experiments.

Membrane preparation and general assay procedures for cloned receptors were adjusted to 96- microwell format based on described protocols (Perkin Elmer).

Membrane preparation and general assay procedures for cloned receptors were adjusted to 96- microwell format based on described protocols (Bojarski et al., 1993; Paluchowska et al., 2007; Zajdel et al., 2012a; Zajdel et al., 2012b).

Table 1A. The binding data of the library members for 5-HTiA, 5-HT ₆ , 5-HT ₇ and D ₂ receptors

Compound Ki [nM]

of Example No 5-HT,A 5-HT2A 5-HT ₆ 5-HT ₇ D ₂

1 54 NT 344 57 1 1

2 56 24 248 15 10

3 50 15 474 46 9

4 16 NT 104 31 29

5 9 7 75 48 24

7 228 2020 209 341 20

9 8 NT 2057 75 37

10 14 NT 2310 165 42

11 13 NT 82 19 16

13 18 9 116 19 11

14 10 NT 72 23 5

15 34 NT 63 1 2

16 179 NT 291 7 <4

17 62 33 497 6 <3

18 268 37 664 9 <1

19 15 15 224 10 5

20 25 NT 31 1 7 1

21 12 NT 306 14 4

22 58 NT 189 27 14

23 37 13 181 10 <1

24 37 5 400 12 <1

25 23 2453 3912 1 1 19 9

26 18 NT 2499 433 15

27 27 NT 2986 672 5

28 9 2387 4691 1223 19

29 22 1737 4920 641 30

30 19 1527 4125 945 7

31 16 NT 5126 1677 29

32 6 NT 2533 349 13

33 6 91 1483 142 19

34 1 NT 3264 279 38

35 103 20 20 122 3

36 176 20 15 90 3 Compound Kj [nM]

of Example No 5-HT _1A 5-HTZA 5-HT ₆ 5-HT ₇ D ₂

37 142 NT 26 101 3

38 66 NT 10 201 8

39 1 13 33 1 1 97 7

40 67 30 12 262 7

41 314 NT 541 26 31

42 254 NT 587 22 35

43 467 NT 637 17 38

44 271 NT 379 25 6

45 80 NT 243 29 1 1

46 284 NT 1 13 8 3

47 87 NT 125 132 14

48 66 NT 60 97 13

49 146 NT 77 65 1 1

56 6 NT 766 4 3

57 5 NT 641 14 8

58 15 NT 13 1 4

59 1 1 NT 10 4 4

60 24 NT 1 1 4 6

61 13 19 9 3 5

62 42 36 72 1 <1

63 29 NT 40 2 1

64 24 NT 38 1 <1

65 24 NT 78 2 <1

66 14 10 40 3 <1

67 16 15 40 1 <1

68 5 NT 996 66 12

69 7 390 1263 35 7

70 7 NT 902 24 8

71 109 NT 12 127 5

72 205 57 12 73 2

73 90 NT 10 55 4

74 5414 NT 2500 318 176

75 2762 2574 1808 373 521

76 91 NT 18 12 15

77 147 NT 23 8 12

78 15 35 337 22 21

79 12 64 221 32 23

80 12 65 361 25 33

81 6 31 297 13 3

82 28 29 949 52 7

83 24 NT 1259 69 5

84 33 NT 1496 39 5

85 153 NT 200 576 108

86 462 1 140 196 567 68

90 12 51 176 19 10

91 8 29 190 24 6 Compound Ki [nM]

of Example No 5-HT,A 5-HT _2A 5-HT ₆ 5-HTv D ₂

92 48 NT 457 17 4

93 50 26 623 19 3

Test Example IB - in vitro evaluation

Radioligand binding assays were employed for determining the affinity of the selected compounds for ai receptors (Greengrass et al., 1979) in rat cerebral cortex, Hi receptors (Smit et al., 1996) and 5-HT ₂ c receptors (Stam et al. ) expressed in HEK-293 cells, and Mi receptors (Dorje et al., 1991) and D3 receptors (Mackenzie et al., 1994) expressed in CHO cells., 1994). This was accomplished by displacement of respective radioligands: [ ³ H]prazosin for aiR, [ ³ H]pyrilamine for HiR, [ ³ H]pirenzepine for MiR, [ ³ H]mesulergine for 5-HT ₂ cR and [ ³ H]methyl-spiperone for D ₃ R.

Non specific binding was defined with 0.5 μΜ prazosine in aiR binding experiments and 1 μΜ pyrilamine in HiR assays. Solutions containing 1 μΜ of atropine, 10 μΜ of RS 102221 and 10 μΜ of (+)butaclamol were used in MiR, 5-HT ₂ cR and D3R experiments, respectively. Each compound was tested in duplicate at 10 ^"6 M concentration. Results were expressed as a mean of two separate experiments (Table IB).

Table IB. The binding data of the library members for ai, Hi, Mi, 5-HT ₂ c and D3 receptors

Compound % inhibition of control binding at lO^M

of Example No (Xl H, Mi 5-HT2C D ₃

13 94 96 6 96 NT"

23 97 81 -12 84 98

24 91 57 3 79 98

28 31 26 -10 NT ^a 98

30 39 37 -18 NT" 99

33 85 32 -8 47 76

66 98 95 -6 NT ³ 98

67 95 94 -25 NT ^a 100

"NT - not tested Test Example 2 - in vitro functional activity ago-/antago-nism) on human D2/5-HT2A receptors

Compound ability to affect the Dopamine Receptor 2 (D2R) function

The drug ability to influence the dopamine-activated D2R was measured in GeneBLAzer® D2-Gqo5-NFAT-bla CHO-K1 cells with LiveBLAzer™-FRET B/G Loading Kit (Life Technologies).

Twenty four hrs before the experiment the cells at a density of 10 000 cells/well in 384-well plates were seeded. Assay medium (4μ1) was supplemented with appropriate concentrations of test agents (at least 7 concentrations plus blank) and were added to the cells. The cells were incubated for 30 min at 37°C. Dopamine (360 nm final concentration) in 4 μΐ assay medium was added and the incubation proceeded for 5 hours 37°C. Then, the tested agent-induced inhibition of activated D2R complex was assayed according to manufacturer's protocol.

Data analysis

Assays were performed in duplicate, and replicated at least two times. Experimental results, the antagonistic properties or antagonist/partial agonist properties were determined from the dose- response curve and IC50 analyzed using Prism 5.0 (GraphPad Software, San Diego, CA).

Compound ability to affect the Serotonin 2 A receptor (5-HT2R) function

For the assessment of 5-HT2AR function, the accumulation of GPCR- Gq-linked second messenger, inositol phosphate (IP), was measured with use of IP-One HTRF® assay kit (Cisbio) in the inducible expression system with human 5-HT2AR expressed in HEK293 T-REx cells. This construct has been created in the laboratory of the Institute of Pharmacology of Polish Academy of Sciences.

The cells were seeded at a density of 7000 cells/well in 384-well plates. Assay medium (3.5 μΐ) was supplemented with appropriate concentrations of test agents (at least 7 concentrations plus blank) and were added to the cells. The cells were incubated for 5 min at room temperature. Serotonin (100 nm final concentration) in 3.5 μΐ of assay medium was added and the incubation proceeded for 75 min 37°C. IP was assayed according to manufacturer's protocol (i.e., IP-One HTRF® assay kit, Cisbio) (Table 2).

Table 2. Antagonist effect of the selected library members for D ₂ and 5-HT _2A .

Compound Log IC ₅ o Compound Log IC50

of Example No D ₂ 5-ΗΤ2Α of Example No D ₂ 5-HT2A

2 -7.83 -6.46 36 -7.3 NS

4 -7.13 -6.89 48 -6.8 NT

9 NT -6.23 60 -8.27 -6.67

13 -7.67 -6.95 71 -8.04 -6.62

23 -8.2 NT 93 -8.28 -6.6

24 -7.51 -6.47 Raclopride -8.9 NT

28 -8.1 NT Serotonin NT -6.87

33 -7.2 NT - - -

NT - not tested

NS - non specific inhibition Test Example 3 - in vitro functional activity ago-/antago-nism) on human 5-HT1A/5-HT7 receptors

The functional activity of the selected compounds 13 and 23 on 5-HTiA and 5-HT ₇ Rs, was determined at Cerep (Le Bois l'Eveque, 86600 Celle L'Evescault, France), according to methods reported on www.cerep.fr. Assays were carried out in HEK-293 and CHO cells, which stably expressed the human 5-HT ₇ and 5-HTIA receptors, respectively.

Table 3. The agonist and antagonist effect of the selected library members.

Compound 5-HT,A 5-HT ₇

of Example No ago ³ antag ^b ago an tag

13 33 94° NT 94

23 5.3 87 NT" 100

a% of control agonist response at lO^M

b% inhibition of control agonist response at lO^M

°The tested compound induced at least 25% agonist or agonist-like effect

"NT - not tested

Test Example 4. Behavioral studies

Animals

Male Sprague— Dawley rats (Charles River, Germany) weighing -250 g at the arrival were housed in the standard laboratory cages, under standard colony A/C controlled conditions: room temperature 21 ± 2°C, humidity (40-50 %), 12-hr light/dark cycle (lights on: 06:00) with ad libitum access to food and water. Rats were allowed to acclimatize for at least 7 days before the start of the experimental procedure. During this week animals were handled for at least 3 times. Behavioral testing was carried out during the light phase of the light/dark cycle. At least 1 h before the start of the experiment, rats were transferred to the experimental room for acclimation.

Drugs. Phencyclidine hydrochloride, ketamine hydrochloride and dizocilpine (MK-801) (Sigma-Aldrich) were dissolved in the distilled water while the experimental compounds were suspended in methylcellulose. All compounds were administrated in the volume of 1 ml/kg.

a) Screening test: Spontaneous and phencyclidine (PCP)-induced locomotor activity

Both spontaneous and PCP-induced locomotor activity were measured automatically in Opto-

Varimex-4 Auto-Tracks (Columbus Instruments, Ohio, USA) located in sound-attenuated and ventilated boxes. The Auto-Track System sensed the motion with a grid of infrared photocells (16 beams per axis) surrounding the arena.

Locomotor activity procedure: The compounds were administered immediately before placing the animals individually in auto-tracks for 30 min of spontaneous locomotor activity measurement. Thereafter, the rats were removed from the boxes, injected with PCP at a dose of 5 mg/kg (SC) and then, the PCP-induced locomotor activity was measured for the following 150 min. The data (number of counts) collected every 5 min are presented as the total distance traveled.

b) Screening test: Novel object recognition (NOR) test: a tool assessing the pro-cognitive drug action in phencyclidine (PCP)-disturbed conditions

Rats were tested in a dimly lit (25 lx) "open field" apparatus made of a dull gray plastic

(66 x 56 x 30 cm). After each measurement, the floor was cleaned and dried. The procedure lasting for 2 days consisted of the habituation to the test arena (without any objects) for 5 min. The test session comprising of two trials separated by an inter-trial interval (ITI) of 1 h was carried out on the next day. During the first trial (familiarization, Tl) two identical objects (Al and A2) were presented in the opposite corners of the open field, approximately 10 cm from the walls. During the second trial (recognition, T2) one of the A objects was replaced by a novel object B, so that the animals were presented with the A=familiar and B=novel objects. Both trials lasted for 3 min and the animals were returned to their home cages after Tl. The objects used were the glass beakers filled with the gravel and the plastic bottles filled with the sand. The heights of the objects were comparable (~12 cm) and the objects were heavy enough not to be displaced by the animals. The sequence of presentations and the location of the objects was randomly assigned to each rat.

The animals explored the objects by looking, licking, sniffing or touching the object while sniffing, but not when leaning against, standing or sitting on the object. Any rat exploring the two objects for less than 5 s within 3 min of Tl or T2 was eliminated from the study. Exploration time of the objects and the distance traveled were measured using the Any-maze® video tracking system. Based on exploration time (E) of two objects during T2, discrimination index (DI) was calculated according to the formula: DI = (EB-EA)/(EA+AB).

Phencyclidine (PCP), used to attenuate learning, was administered at the dose of 5 mg/kg (IP) 45 min before familiarization phase (Tl). The compounds were administrated IP or PO, 1 hour and 15 min before Tl .

Table 4. The results of selected compounds in PCP-induced hyperactivity

and PCP-induced novel object recognition in rats

Data given as MED (mg/kg) c) Prepulse inhibition in dizocilpine-disturbed conditions (Antipsychotic drug action)

Rats were tested in the startle apparatus (Med Associates, USA) consisting of acrylic animal holders with a grid floor made of stainless bars, mounted onto a startle platform placed in a ventilated, sound-attenuating chambers. Acoustic stimuli were generated by two speakers: background noise speaker and stimulus speaker, placed at the back of a chamber, 7 cm from an animal holder. Startle responses were detected and transduced by the load cell, digitized and stored by Startle Reflex software (Med Associates, version 5).

Procedure: Rats were subjected to two pretest sessions: the afternoon session on the day before testing and the morning session on the test day. The pretest on the test day was performed about 2 hours before the pharmacological challenge. The testing/experimental protocols used during the pretest and test sessions were identical. Sessions started with a 5 min acclimatization period. A 62 dB background white noise was continuously presented once animals were placed in the test chambers and was maintained throughout the whole session. The following types of acoustic stimuli were used in the test protocol: pulse alone [intensity: 120 dB, duration: 40 ms, (P)], pulse preceded by an acoustic prepulse of intensities: 70, 73, and 76 dB [duration: 20 ms; (PP)] applied 100 ms before pulse (P)], prepulse alone [intensity 70, 73 and 76 dB, duration 20 ms] and null period. The session consisted of 3 blocks. During the first block animals were exposed to 10 pulse alone trials. During the second block the following trials were presented in the random order: 4 trials of pulse alone, 4 trials of pulse preceded with each prepulse, along with 1 repetitions of each prepulse alone and 4 null trials. The interstimulus interval was 20 seconds. The third block consisted of 10 pulse alone trials. For calculations, the measures obtained in a second block were used. The mean response amplitude for pulse alone [P] and prepulse-pulse [PP] trials was computed for each rat and PPI was determined according to the formula: PPI (%) = [(P-PP)/P] * 100

Rats were pretreated either with either vehicle or the experimental compounds at various times before MK-801 administration (0.1 mg kg, SC), which was given 15 min before the testing session. d) Attentional set shifting in ketamine-disturbed condition (measure of cognitive functions dependent on prefrontal cortex)

The procedure entailed three days for each rat.

Day 1, habituation: rats were habituated to the testing area and trained to dig in the pots filled with sawdust to retrieve the food reward. Rats were transported from the housing facility to the testing room where they were presented with one unscented pot (filled with several pieces of Cheerios) in their home cages. After the rats had eaten the Cheerio from the home cage pot, they were placed in the apparatus and given three trials to retrieve the reward from both of the sawdust- filled baited pots. With each exposure, the bait was covered with an increasing amount of sawdust. Day 2, training: rats were trained on a series of simple discriminations (SD) to a criterion of six consecutive correct trials. For these trials, rats had to learn to associate the food reward with an odor cue (e.g., arrack vs. orange, both pots filled with sawdust) and/or a digging medium (e.g., e.g., red beads vs. crumpled aluminum, no odor). All rats were trained using the same pairs of stimuli. The positive and negative cues for each rat were presented randomly and equally. These training stimuli were not used again in later testing trials.

Day 3, testing: rats performed a series of discriminations in a single test session. The first four trials at the beginning of each discrimination phase were a discovery period (not included in the six criterion trials). In subsequent trials, an incorrect choice was recorded as an error. Digging was defined as any distinct displacement of the digging media with either the paw or the nose; the rat could investigate a digging pot by sniffing or touching without displacing material. Testing was continued at each phase until the rat reached the criterion of six consecutive correct trials, after which testing proceeded to the next phase.

In the simple discrimination (SD) involving only one stimulus dimension, the pots differed along one of two dimensions (i.e., a digging medium). For the compound discrimination (CD), the second (irrelevant) dimension (i.e., an odor) was introduced but the correct and incorrect exemplars of the relevant dimension remained constant. For the reversal of this discrimination (Rev 1), the exemplars and relevant dimension were unchanged but the previously correct exemplar was now incorrect and vice versa. The intra-dimensional (ID) shift was then presented, comprising new exemplars of both the relevant and irrelevant dimensions with the relevant dimension remaining the same as previously. The ID discrimination was then reversed (Rev 2) so that the formerly positive exemplar became the negative one. For the extra-dimensional (ED) shift a new pair of exemplars was again introduced, but this time a relevant dimension was also changed. Finally, the last phase was the reversal (Rev 3) of the ED discrimination problem. The exemplars were always presented in pairs and varied so that only one animal within each treatment group received the same combination. The following pairs of exemplars were used: Pair 1 : odor: spicy vs. vanilla, medium: cotton wool vs. crumpled; Pair 2: odor: lemon vs. almond, medium: shredded pipette tips vs. wooden sticks; Pair 3: odor: rum vs. cream, medium: shredded papers vs. silk. The assignment of each exemplar in a pair as being positive or negative at a given phase and the left-right positioning of the pots in the test apparatus on each trial were randomized.

The ASST was disturbed by the administration of 10 mg/kg of ketamine (SC) 75 min before testing. The experimental compounds were administered at various times before ketamine injection. e) Social interaction in ketamine-disturbed conditions (a measure of negative symptoms of scHizophrenia)

The experiments were conducted in the open field arena (length x width x height: 57 x 67 x 30 cm) made of black Plexiglas. The arena was dimly illuminated with an indirect light of 18 Lux. The behavior of the rats was recorded by two cameras placed above the arena and connected to the Noldus MPEG recorder 2.1. Videos were analyzed off-line by the Noldus Observer XT, version 10.5.

Procedure. Rats were individually housed for 5 days prior to the start of the procedure. On the fifth day of social isolation, all rats were transferred to the experimental room and individually adapted to the open field arena for 7 min. Afterward, the rats were handled, weighed and half were dyed with a gentian violet (2% Methylrosanilinium chloride) on the rear part of the body. On the test day (the sixth day of social isolation), two unfamiliar rats of matched body weight (+/-5 g), one white and one dyed, were placed in the open field arena and their behavior was recorded for 10 min. Both rats in a given pair received the same treatment. Social interaction time was measured for each rat separately and expressed as a summed score per each pair of rats. The following active social behaviors were scored: sniffing (rat sniffs the conspecific's parts of the body, including the anogenital region), social grooming (rat licks and chews the fur of the conspecific), following (rat moves towards and follows the other rat), mounting (rat stands on the conspecific's back) and climbing (rat climbs over the conspecific's back).

Ketamine at a dose of 20 mg/kg (IP) was given 30 min before the test. The test compounds were given 30 min before the ketamine injections.

f) Conditioned Avoidance response (CAR)

The training and the testing were performed in four shuttle boxes (Med Associates, Inc, USA). Each box (44 x 21 x 18 cm) was housed in the ventilated, sound-isolated cubicles and was divided in two equal-sized compartments by the guillotine doors. The rats were allowed to move freely from one compartment to another at any time. The position of animal was tracked by 8 photocells in each of the boxes. A cue light was situated on the wall opposing the compartment entry.

The training and testing sessions were started by presenting the conditioned stimulus (CS, the light) for 10 s, followed by unconditioned stimulus (UCS, continuous foot shock of 0.25 mA at the start of training, and 0.37 mA at the end of training and during the tests) for the maximum of 10 s. The procedure was repeated with 20 trials daily with an intra-trial interval of 20-40s. If a rat moved from one compartment into the other within 10 s of CS presentation, it avoided the foots hock and this shuttle response was recorded as avoidance. If the rat remained in the same compartment for more than 10 s and made a crossing upon receiving the foot shock, this response was recorded as an escape. If the rats did not respond neither during the 10 s of CS nor by 10 s of UCS, the trial was terminated and the failure was recorded. About 12-15 training sessions (during 2-3 weeks) was needed to start the tests. Approximately 40% of the rats has dropped off during the training. The test was started if the rats reached the stable avoidance level of above 80% on two subsequent days. The rats were used several times with 4-7 days a drug-free period between tests.

Table 6. The results of selected compounds in rats

NT - not tested

NA - not active

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