SK11892000A3 - Novel compounds and their use as positive ampa receptor modulators - Google Patents

Abstract

The invention provides novel compounds represented by general formula (I) wherein the bond represented by the broken line may be a single, double bond or absent; and if the bond is absent, then the nitrogen is substituted with a hydrogen and R<2>; X represents SO2 or C=O of CH2; Y represents -CH(R<4>)-, -N(R<4>)- or -N(R<4>)-CH2-, O; and the meaning of R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, and R<8> are as defined in the application. The compounds are useful as positive modulators of the AMPA-receptor.

Description

Technical field

The present invention relates to novel compounds useful as modulators of AMPA sensitive glutamate receptors, pharmaceutical compositions containing such compounds, and their use in therapies.

BACKGROUND OF THE INVENTION

L-Glutamate is a major excitatory nerve mediator in the mammalian central nervous system that activates several subtypes of ionotropic and metabotropic receptors. Ionotropic receptors can be divided into three subtypes, NMDA, AMPA and kainate receptors, based on structural and pharmacological differences.

Impaired glutamatergic neurotransmission has been demonstrated in the learning and memory loss observed in many neurological diseases, such as e.g. Alzheimer's disease, senile dementia, stroke (McEntee and Crook, Psychopharmacology 111: 391-401 (1993)). It is widely accepted that learning and memory are related to induction of long-term potentiation (LTP), which represents a steady increase in synaptic strength, following repetitive high-frequency stimulation. Experimental studies have shown that an increase in the synaptic response mediated by AMPA receptors increases LTP induction (Arai and Lynch, Brain Research, 598: 173 184 (1992)). For the above reasons, compounds that stimulate AMPA receptor responses in the brain may induce an improvement in intellectual behavior and performance.

Activation of AMPA receptors by L-glutamate or a selective AMPA agonist leads to a severe desensitization of the receptor; ie. the receptor channel does not resist the continued presence of the agonist. Thus, it is possible to obtain an increase in synaptic strength by alleviating desensitization of the AMPA receptor normally induced by an endogenous neural mediator

L-glutamate.

In 1990, Ito et al. reported (J. physiol., 424: 533-543) that the nootropic drug aniracetam (N-anisoyl-2-pyrrolidine) increases AMPA-induced oocyte fluxes injected with rat brain mRNA. In another study, it was reported that 1- (1,3-benzodioxol-5-ylcarbonyl) -1,2,3,6-tetrahydropyridine, a compound that enhances AMPA receptor-mediated synaptic transmission, is effective in improving memory in experimental animals at very high doses of 120 mg / kg (Staubli et al., Proc. Natl. Acad. Sci. USA, 91: 11158-11162 (1994)).

Cyclotiazide benzothiadiazide is a more potent and efficient in vitro AMPA receptor flow modulator than aniracetam (Johansen et al., Mol. Pharmacol. 48: 946-955 (1995)). The effect of cyclotiazide on the kinetic properties of AMPA receptor fluxes has a different mechanism than aniracetam (Partin et al., J. Neuroscience 16: 6634-6647 (1996)). However, cyclothiazide does not have therapeutic efficacy for AMPA receptor modulation since it cannot cross the blood-brain barrier after peripheral administration. The known compounds have lower efficacy and therefore require high solubility requirements at higher doses

U.S. Patent No. 5,488,049 discloses the use of benzothiadiazide derivatives for the treatment of memory and learning disorders. The compounds are structurally very similar to the compounds of the present invention. However, the compounds of the present invention show greater potency at lower concentrations. (Fig. 3 of US Patent No. 5,488,049)

U.S. Patent No. 4,184,039 discloses benzothiadiazides for use in promoting hair growth.

DE 1470316 discloses a process for the production of certain benzothiadiazides for use as additives in a plating bath.

In Synthesis (10), 183, p. 851 describes a process for preparing benzothiadiazine-1,1-dioxide. The compounds are described as active antihypertensive and antimicrobial agents.

J. Med. Chem. (15, No. 4), 1972, p. 400-403, benzothiadiazine-1,1-dioxides are studied in terms of their π-substituent constants as a study of structure-activity relationship for antihypertensive activity

WO 9812185 describes benzothiadiazines of structures other than the compounds of the present invention.

It is an object of the present invention to provide positive AMPA modulators that are effective in the treatment of diseases or disorders in mammals, including humans, and in particular in the treatment of diseases and disorders that are responsive, i. j. are responsive to the modulation of AMPA receptors in the brain.

It is another object of the present invention to provide a method of treating a disorder or disease in a mammal, including a human, that is susceptible to AMPA receptor modulators, which comprises administering to the mammal in need of such treatment a compound of the present invention.

A third object of the present invention is to provide novel pharmaceutical compositions for the treatment of those diseases or disorders in mammals, including humans, that are susceptible to AMPA modulators.

in

Other objects of the present invention will be apparent to those skilled in the art from the following description.

SUMMARY OF THE INVENTION

The invention includes, inter alia, alone or in combination:

Compound represented by the general formula:

where

the bond represented by the dotted line may be single, double bond or absent; and when the bond is absent, then nitrogen is substituted with hydrogen and R ² ;

X is SO ₂ or C = O or CH ₂ ;

Y is -CH (R ⁴ ) -, -N (R ⁴ ) - or -N (R ⁴ ) -CH ₂ -, O;

R ² represents a hydrogen atom, alkyl, cycloalkyl, aryl, benzyl;

CO-R ⁹ wherein R ⁹ represents alkyl, cycloalkyl, benzyl, aryl; or

R together with the substituent R and together with the atoms to which they are attached form

A 4-membered to 7-membered ring optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups;

R ³ represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR ¹³ R ¹⁴ , alkyl-SR ¹³ wherein R ¹³ and R ¹⁴ independently represent hydrogen alkyl, cycloalkyl; or R ¹³ and R ¹⁴ together with the nitrogen to which they are attached form a 3 to 8 membered heterocyclic ring structure;

A carbocyclic 7-membered to 12-membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; or

Heterocyclic 3-membered to 8-membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; and optionally the heterocyclic ring is fused to aryl;

Benzyl which is optionally substituted with one or more substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino;

Aryl which is optionally substituted by one or more substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; or

R ³ together with the substituent R ² or R ⁴ and together with the atoms to which they are attached form a 4-membered to 7-membered ring optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy , amino groups or thio groups and optionally containing one or more heteroatoms and optionally containing carbonyl groups.

R ⁴ represents a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R ¹⁰ or CO ₂ R ¹⁰ , wherein R ¹⁰ represents a hydrogen atom, cycloalkyl, alkyl, aryl or benzyl; or

R ⁴ together with the substituent R ³ and the atoms to which they are attached form a 4-membered or 7-membered ring optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino groups or thio groups and optionally containing one or more heteroatoms and optionally containing carbonyl groups.

R ⁵ represents a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, aryl,

-SO ₂ NR "R ^12, wherein R ¹¹ and R ¹² independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R R ^N, and R ¹² together with the nitrogen to which they are attached forms a heterocyclic 3 an up to 8-membered ring structure optionally substituted with halogen, alkyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

R ⁶ represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohalogenoalkyl,

-NR ¹⁵ R ¹⁶ , NHSO 2 -R ¹⁵ , NHS Ch 2 -aryl, wherein the aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF ₃ , OCF ₃ , NO2, aryl;

Aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl or amino;

HET optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy;

- (alkyl) _m -SR ¹⁵ ; - (alkyl) m-SO-R ¹⁵ ; - (alkyl) m-SO ₂ -R ¹⁵ ; - (alkyl) m-SO ² OR ¹⁵ ; - (alkyl) m-SO ² NR ¹⁵ R ¹⁶ ; - (alkyl) m-NHCOR ¹⁵ ; - (alkyl) m-CONR ¹⁵ R ¹⁶ ; - (alkyl) m -CR '= NOR; - (alkyl) m CO-R ^15; - (alkyl) m-CO ₂ -R ¹⁵ , wherein the index m is 0 or 1; and R 'and R' independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R ¹⁵ and R ¹⁶ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SCh-alkyl, SO ₂ aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

R is hydrogen, halogen, alkyl, cyano, nitro, nitroalkyl; alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohalogenoalkyl.

-NR ¹⁷ R ¹⁸ , NHSO 2 -R ¹⁷ , NHSCl 2 -alkyl, wherein the aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF ₃ , OCF ₃ , NO2, aryl;

- (alkyl) _m -SR ¹⁷ ; - (alkyl) ^m-SO-R17 ;-( alkyl) m-SO ₂ -R ^17; - (alkyl) m-SO 2 OR ¹⁷ ; - (alkyl) m-SO ₂ NR ⁷ R ¹⁸ ; - (alkyl) m-NHCOR ¹⁷ ; - (alkyl) ^{m-CONR 7} R ^18; - (alkyl) m -CR '= NOR; - (alkyl) m CO-R ^17; - (alkyl) m-CO ₂ -R ¹⁷ , wherein the index m is 0 or 1; and R and R 'are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ -alkyl, SO ₂ aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

HET optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SO _2- alkyl, SO ₂ -aryl, SO ₂ NR ^, R ⁷ ;

Aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF ₃ , SO ₂ -NR ¹⁷ R ¹⁸ wherein R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

or

R ⁷ together with R ⁶ or R ⁸ together form a 5- to 7-membered ring having one of the following structures -O- (CH 2) _n -O-; wherein n is 1, 2 or 3; -SO 2 -NR- (CH 2) _n - wherein the index n is 1 or 2; -SO-NR- (CH ₂ ) _n - wherein the index n is 1 or 2; -SO 2 - (CH 2) _n - wherein the index n is 2 or 3; -SO- (CH ₂ ) _n - wherein the index n is 2 or 3; -CO-CH = CH-NH; -CO-CH = CH-O-; -CO- (CH ₂ ) n -N-, wherein the index n is 1 or 2; -CONH- (CH ₂ ) n -, wherein the index n is 1 or 2; -CO- (CH ₂ ) ₂ -O-; -O- (CH ₂ ) _n -O-; wherein n is 1, 2 or 3;

Λ _t

R is hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, nitroalkyl;

Aryl optionally substituted with one or more substituents selected from the group consisting of halogen, CF ₃ , OCF ₃ , NO ₂ , alkyl, cycloalkyl, alkoxy;

HET optionally substituted with one or more substituents selected from the group consisting of halogen, CF 3, OCF 3, NO ₂ , alkyl, cycloalkyl, alkoxy;

- (alkyl) _m -SR ¹⁹ ; - (alkyl) ^{m-SO-R 9} ;-( alkyl) m-SO ₂ -R ^19; - (alkyl) m -SO 2 O-R ¹⁹ ; - (alkyl) m-SO ₂ NR ¹⁹ R ²⁰ ; - (alkyl) m-NHCOR ¹⁹ ; - (alkyl) m-CONR ¹⁹ R ²⁰ ; - (alkyl) m-CR '= NOR; - (alkyl) _m CO-R ¹⁹ ; - (alkyl) _m -CO ₂ -R ¹⁹ , wherein the index m is 0 or 1; and R 'and R''independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R ¹⁹ and R ²⁰ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁹ and R ²⁰ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ -alkyl, SO ₂ aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl; provided that when the dotted line in formula I represents a double bond and X represents SO ₂ and Y represents NH and the compound is monosubstituted, then the compound is not monosubstituted with R ³ representing OCH 3, methyl, pentyl, tert-butyl, aminophenyl, 2- phenylethylene, phenethyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, nomorbornylene, benzyl, thienyl, furyl, aryl, aryl substituted with 4-methyl, 4-methoxy, 4-chloro, 4-nitro or 3-nitro;

and when the compound is disubstituted with R ³ which is methyl, then R ⁵ is not Cl, CH 3; or then R ⁷ is not F, Cl, Br, I, CH 3, CF 3, nitro, SO ₂ N (CH 3) ₂ ; or then R ⁶ is not Cl, Br, CH 3, CF 3, ethyl, methoxy;

or when R ⁷ is chloro then R ³ is not ethyl, butyl, 5'-butyl, tert-butyl, cyclobutyl, 2,2-dimethylpropyl, phenyl;

and when the compound is disubstituted then it is not disubstituted by R ⁶ = OMe, R ³ = ethyl; R ⁶ = methyl, R ³ = propyl; R ⁷ = SO 2 NH 2, R ⁶ = Cl; R ⁷ = SO ₂ NH ₂ , R ³ = phenyl; R ⁷ = Br, R ³ = phenyl;

provided that when the compound is trisubstituted, then R ³ = CH 3, R ⁵ = NO 2, R ⁷ = Cl; R ³ = CH 3, R ⁶ = NO 2, R ⁷ = Cl; R ³ = CH 3, R ⁵ = NH ₂ , R ⁷ = Cl;

and provided that when the dotted line in formula I represents a single bond and X represents SO ₂ and Y represents NH, then the compound is not a disubstituted compound having substituents R ⁷ or R ⁶ which are chlorine and R ⁷ is alkyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclohexene, norbornylene, norbornanyl, ethylthiomethyl, ethyloxymethyl, ethyloxyethyl, methyloxymethyl, methylamino, 2-chloroethyl, chloromethyl, dichloromethyl, trifluoromethyl, amino;

and the compound is not a trisubstituted compound having the substituents R ³ , which is CH 3 and R ⁵ = isopropyl, R ⁷ = F; R ⁵ = ethyl, R ⁷ = Cl; R ⁵ = propyl, R ⁷ = Cl; R ⁵ = ethyl, R ⁷ = F; R ⁵ = methyl, R ⁷ = Cl; R ⁵ = ethyl, R ⁷ = methyl; R ⁵ = Cl, R ⁷ = methyl; R ⁵ = methyl, R ⁷ = Cl; R ⁴ = methyl, R ⁵ = ethyl; or trisubstituted with R ⁴ = methyl, R ⁵ = methyl, R ⁷ = F;

The present invention further includes a pharmaceutical composition comprising a therapeutically effective amount of the above compound together with pharmaceutically acceptable carriers or excipients;

The present invention further encompasses the use of a compound represented by the general formula

Although the bond represented by the dotted line may be single, double bond or absent; and when there is no bond, then nitrogen is substituted with hydrogen and R ² ;

X is SO ₂ or C = O or CH ₂ ;

Y is -CH (R ⁴ ) -, -N (R ⁴ ) - or -N (R ⁴ ) -CH ₂ -, O;

R ² represents a hydrogen atom, alkyl, cycloalkyl, aryl, benzyl;

CO-R ⁹ wherein R ⁹ represents alkyl, cycloalkyl, benzyl, aryl; or

R ² together with the substituent R ³ and together with the atoms to which they are attached form

A 4-membered to 7-membered ring optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups;

R ³ represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR ¹³ R ¹⁴ , alkyl-SR ¹³ wherein R ¹³ and R ¹⁴ independently represent hydrogen alkyl, cycloalkyl; or R ¹³ and R ¹⁴ together with the nitrogen to which they are attached form a 3 to 8 membered heterocyclic ring structure;

A carbocyclic 7-membered to 12-membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; or

Heterocyclic 3-membered to 8-membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; and optionally the heterocyclic ring is fused to aryl;

Benzyl which is optionally substituted with one or more substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino;

Aryl which is optionally substituted by one or more substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; or

R ³ together with the substituent R ² or R ⁴ and the atoms to which they are attached form a 4-membered to 7-membered ring optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy , amino groups or thio groups and optionally containing one or more heteroatoms and optionally containing carbonyl groups.

R ⁴ represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R ¹⁰ or CO 2 R ¹⁰ , wherein R ¹⁰ represents hydrogen, cycloalkyl, alkyl, aryl or benzyl; or

R ⁴ together with R ³ and the atoms to which they are attached form a 4-membered or 7-membered ring optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino groups or thio groups and optionally containing one or more heteroatoms and optionally containing carbonyl groups.

R ⁵ represents a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, aryl,

-SO ₂ NR ⁿ R ^12, wherein R ¹¹ and R ¹² independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, and the substituents R ¹¹ and R ¹² together with the nitrogen to which they are attached forms a heterocyclic 3 up to 8-membered ring structure optionally substituted by halogen, alkyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SCh-alkyl, SCh-aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to aryl;

R ⁶ represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohalogenoalkyl,

-NR ¹⁵ R ¹⁶ , NHSO 2 -R ¹⁵ , NHSO 2 -aryl, wherein the aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF 3, OCF ₃ , NO ₂ , aryl;

Aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl or amino;

HET optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy;

- (alkyl) _m -SR ¹⁵ ; - (alkyl) m-SO-R ¹⁵ ; - (alkyl) m -SO 2 -R ¹⁵ ; - (alkyl) m -SO 2 O-R ¹⁵ ; - (alkyl) mSO ₂ -NR ¹⁵ R ¹⁶ ; - (alkyl) m-NHCO-R ¹⁵ ; - (alkyl) m-CONR ¹⁵ R ¹⁶ ; - (alkyl) m-CR '= NOR; - (alkyl) m-CO-R ¹⁵ ; - (alkyl) m-CO ₂ -R ¹⁵ , wherein the index m is 0 or I; and R 'and R' are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R ¹⁵ and R ¹⁶ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ -alkyl, SO ₂ aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

R ⁷ represents a hydrogen atom, halogen, alkyl, cyano, nitro, nitroalkyl; alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohalogenoalkyl,

-NR ¹⁷ R ¹⁸ , NHSO 2 -R ¹⁷ , NHSO 2 -aryl, wherein the aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF 3, OCF 3, NO 2, aryl;

- (alkyl) _m -SR ¹⁷ ; - (alkyl) ^m-SO-R17 ;-( alkyl) m-SO ₂ -R ^17; - (alkyl) m -SO 2 O-R ¹⁷ ; - (alkyl) m-SO ₂ NR ⁷ R ¹⁸ ; - (alkyl) m-NHCOR ¹⁷ ; - (alkyl) m-CONR ¹⁷ R ¹⁸ ; - (alkyl) m-CR '= NOR; - (alkyl) m CO-R ^17; - (alkyl) m-CO ₂ -R ¹⁷ , wherein the index m is 0 or 1; and R 'and R' independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted by halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ -alkyl, SO ₂ aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

HET optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SO _2- alkyl, SO ₂ -aryl, SO ₂ NR ¹⁷ R ¹⁸ ;

Aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF ₃ , SO 2 -NR ¹⁷ R ¹⁸ , wherein R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SCh-alkyl, SCh-aryl, SCh-benzyl; and optionally the heterocyclic ring is fused to aryl;

or

R ⁷ together with R ⁶ or R ⁸ together form a 5- to 7-membered ring having one of the following structures -O- (CH 2) _n -O-; wherein n is 1, 2 or 3; -SO ₂ -NR- (CH 2) _n - wherein the index n is 1 or 2; -SO-NR- (CH 2) _n wherein the index n is 1 or 2; -SO 2 - (CH 2) _n - wherein the index n is 2 or 3; -SO- (CH 2) _n - wherein the index n is 2 or 3; -CO-CH = CH-NH-; -CO-CH = CH-O-; -CO- (CH ₂ ) n -NH- wherein the index n is 1 or 2; CONH _{(CH2) n,} wherein n is 1 or 2; -CO- (CH 2) 2 -O-; -O- (CH ₂ ) _n -O-; wherein n is 1, 2 or 3;

R ⁸ represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, nitroalkyl;

Aryl optionally substituted with one or more substituents selected from the group consisting of halogen, CF ₃ , OCF ₃ , NO 2, alkyl, cycloalkyl, alkoxy;

HET optionally substituted with one or more substituents selected from the group consisting of halogen, CF ₃ , OCF ₃ , NO ₂ , alkyl, cycloalkyl, alkoxy;

- (alkyl) _m -SR ¹⁹ ; - (alkyl) ^m-SO-R19 ;-( alkyl) m-SO ₂ -R ^19; - (alkyl) n -SO 2 O-R ¹⁹ ; - (alkyl) m-SO ₂ NR ¹⁹ R ²⁰ ; - (alkyl) m-NHCOR ¹⁹ ; - (alkyl) m-CONR ¹⁹ R ²⁰ ; - (alkyl) m -CR '= NOR; - (alkyl) n CO-R ¹⁹ ; - (alkyl) m-CO ₂ -R ¹⁹ , wherein the index m is 0 or 1; and R 'and R' are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R ¹⁹ and R ²⁰ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁹ and R ²⁰ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SCh-alkyl, SO ₂ aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to aryl;

for the manufacture of a medicament for the treatment of disorders and diseases susceptible to modulation of the AMPA receptor complex.

The present invention also provides a method for the treatment of disorders and diseases susceptible to modulation of the AMPA receptor complex by administering a therapeutically effective amount of a compound represented by the general formula

wherein the bond represented by the dotted line may be single, double bond or absent; and when the bond is absent, then nitrogen is substituted with hydrogen and R ² ;

X represents SO 2 or C = O or CH 2;

represents -CH (R ⁴ ) -, -N (R ⁴ ) - or -N (R ⁴ ) -CH ₂ -, O;

R ² represents a hydrogen atom, alkyl, cycloalkyl, aryl, benzyl;

CO-R ⁹ wherein R ⁹ represents alkyl, cycloalkyl, benzyl, aryl; or

R ² together with the substituent R ³ and together with the atoms to which they are attached form

A 4-membered to 7-membered ring optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups;

R ³ represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR ¹³ R ¹⁴ , alkyl-SR ¹³ wherein R ¹³ and R ¹⁴ independently represent hydrogen alkyl, cycloalkyl; or R ¹³ and R ¹⁴ together with the nitrogen to which they are attached form a 3 to 8 membered heterocyclic ring structure;

A carbocyclic 7-membered to 12-membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; or

Heterocyclic 3-membered to 8-membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; and optionally the heterocyclic ring is fused to aryl;

Benzyl which is optionally substituted with one or more substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino;

Aryl which is optionally substituted by one or more substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; or

R ³ together with the substituent R ² or R ⁴ and together with the atoms to which they are attached form a 4-membered to 7-membered ring optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy , amino groups or thio groups and optionally containing one or more heteroatoms and optionally containing carbonyl groups.

R ⁴ represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R ¹⁰ or CO 2 R ¹⁰ , wherein R ¹⁰ represents hydrogen, cycloalkyl, alkyl, aryl or benzyl; or

R ⁴ together with the substituent R ³ and together with the atoms to which they are attached form

A 4-membered or 7-membered ring optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups.

R ⁵ represents a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, aryl,

-SO ₂ -NR ¹¹ R ¹² where R ¹¹ and R ¹² independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹¹ and R ¹² together with the nitrogen to which they are attached form a heterocyclic 3- a membered to 8-membered ring structure optionally substituted by halogen, alkyl, hydroxy, alkoxy, amino, or thio, aryl, benzyl, SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

R ⁶ represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohalogenoalkyl,

-NR ^IS R ¹⁶ , NHSO 2 -R ¹⁵ , NHSO 2 -aryl, wherein the aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF 3, OCF ₃ , NO ₂ , aryl;

Aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl or amino;

HET optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy;

- (alkyl) _m -SR ¹⁵ ; - (alkyl) m-SO-R ¹⁵ ; - (alkyl) in-SO ₂ -R ¹⁵ ; - (alkyl) m -SO 2 O-R ¹⁵ ; - (alkyl) mSO ₂ -NR ¹⁵ R ¹⁶ ; - (alkyl) m-NHCO-R ¹⁵ ; - (alkyl) m-CONR ¹⁵ R ¹⁶ ; - (alkyl) m-CR '= NOR'; - (alkyl) m-CO-R ¹⁵ ; - (alkyl) m-CO ₂ -R ¹⁵ , wherein the index m is 0 or 1; and R 'and R' independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R ¹⁵ and R ¹⁶ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ -alkyl, SO ₂ aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

R ⁷ represents a hydrogen atom, halogen, alkyl, cyano, nitro, nitroalkyl; alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohalogenoalkyl,

-NR ¹⁷ R ¹⁸ , NHSO 2 -R ¹⁷ , NHSO 2 -aryl, wherein the aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF ₃ , OCF ₃ , NO ₂ , aryl;

- (alkyl) _m -SR ¹⁷ ; - (alkyl) ^m-SO-R17 ;-( alkyl) m-SO ₂ -R ^17; - (alkyl) m -SO 2 O-R ¹⁷ ; - (alkyl) m-SO ₂ NR ¹⁷ R ¹⁸ ; - (alkyl) m-NHCOR ¹⁷ ; - (alkyl) m-CONR ¹⁷ R ¹⁸ ; - (alkyl) m-CR = NOR; - (alkyl) m CO-R ^17; - (alkyl) m-CO ₂ -R ¹⁷ wherein m is 0 or 1; and R 'and R' are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ -alkyl, SO ₂ aryl, SCh-benzyl; and optionally the heterocyclic ring is fused to aryl;

HET optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SO _2- alkyl, SCh-aryl, SO 2 NR ¹⁷ R ¹⁸ ;

Aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF ₃ , SO ₂ -NR ¹⁷ R ¹⁸ wherein R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

or

R ⁷ together with R ⁶ or R ⁸ together form a 5-membered to 7-membered ring having one of the following structures -O- (CH ₂ ) n O-; wherein n is 1, 2 or 3; -SO ₂ -NR- (CH ₂ ) _n - wherein the index n is 1 or 2; -SO-NR- (CH ₂ ) _n wherein the index n is 1 or 2; -SO ₂ - (CH ₂ ) n - wherein the index n is 2 or 3; -SO- (CH ₂ ) _n - wherein the index n is 2 or 3; -CO-CH = CH-NH-; -CO-CH = CH-O-; -CO- (CH ₂ ) _n -NH-, wherein the index n is 1 or 2; -CO20

-NH- _{(CH2) n,} wherein n is 1 or 2; -CO- (CH ₂ ) ₂ -O-; -O- (CH ₂ ) _n -O-; wherein n is 1, 2 or 3;

R ⁸ represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, nitroalkyl;

Aryl optionally substituted with one or more substituents selected from the group consisting of halogen, CF ₃ , OCF ₃ , NO ₂ , alkyl, cycloalkyl, alkoxy;

HET optionally substituted with one or more substituents selected from the group consisting of halogen, CF ₃ , OCF ₃ , NO ₂ , alkyl, cycloalkyl, alkoxy;

- (alkyl) _m -SR ¹⁹ ; - (alkyl) ^{m-SO-R 9} ;-( alkyl) m-SO ₂ -R ^19; - (alkyl) m -SO 2 O-R ¹⁹ ; - (alkyl) m-SO ₂ NR ¹⁹ R ²⁰ ; - (alkyl) m-NHCOR ¹⁹ ; - (alkyl) m-CONR ¹⁹ R ²⁰ ; - (alkyl) m-CR = NOR; - (alkyl) mCO-R ¹⁹ ; - (alkyl) m-CO ₂ -R ¹⁹ , wherein the index m is 0 or 1; and R 'and R' independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R ¹⁹ and R ²⁰ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁹ and R ²⁰ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ -alkyl, SO ₂ aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

DETAILED DESCRIPTION OF THE INVENTION

The invention provides novel compounds of the above formula I

Preferred embodiments of the invention are compounds of the above formula I wherein

R ² represents a hydrogen atom, alkyl, cycloalkyl, aryl, benzyl;

or

R ² together with the substituent R ³ and together with the atoms to which they are attached form

A 5-membered to 6-membered ring optionally substituted with one or more substituents selected from halogen, alkyl, hydroxy, alkoxy, amino, or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups;

R ³ represents a hydrogen atom, a cycloalkyl, a cycloalkylalkyl, an alkyl, a haloalkyl, an alkoxy group, and a carbocyclic 7-membered to 10-membered ring; a heterocyclic 5-membered to 6-membered ring; benzyl; aryl;

or R ³ together with R ² or R ⁴ forms a 5-membered to 3-membered compound

6-membered ring;

R ⁴ represents a hydrogen atom, alkyl, or R ⁴ together with R ³ and together with the atoms to which they are attached form a 5-membered to 6-membered ring; optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups.

R ⁵ represents hydrogen, halogen, alkyl, alkenyl, alkynyl, phenyl,

-SO ₂ -NR 11 R ¹² where R ¹¹ and R ¹² independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹¹ and R ¹² together with the nitrogen to which they are attached form a heterocyclic 5-membered a 6-membered ring structure;

R ⁶ represents a hydrogen atom. Br, F, 1, cycloalkyl, alkyl, alkoxy, alkoxyalkyl.

phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy;

HET;

-SR ¹⁵ ; -SO-R ^15; -SO 2 -R ¹⁵ ; -SO 2 O-R ¹⁵ ; -SO 2 -NR ¹⁵ R ¹⁶ ; -NHCO-R ^15; CONR ¹⁵ R ¹⁶ ; -CR '= NOR "; -CO-R ^15; -CO ₂ -R ¹⁵ , wherein R 'and R' independently represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl; and R ¹⁵ and R ¹⁶ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, SO ₂ -alkyl, SO ₂ aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

R ⁷ represents a hydrogen atom, Br, F, I, alkyl, cyano group, cyanoalkyl, nitro group, nitroalkyl; alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohalogenoalkyl, - (alkyl) ₁ -NR ¹⁷ R ¹⁸ , NHSO 2 -R ¹⁷ , -SR ¹⁷ ; -SO-R ^17; -SO 2 -R ¹⁷ ; -SO 2 O-R ¹⁷ ; -SO 2 NR ¹⁷ R ¹⁸ ; -NHCOR ¹⁷ ; -CONR ¹⁷ R ¹⁸ ; -CR '= NOR; -CO-R ^17; -CO ₂ -R ¹⁷ , wherein R 'and R' are independently hydrogen, alkyl, cycloalkyl, phenyl, benzyl; and R and R independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with alkyl, SO _2- alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

HET optionally substituted with one or more substituents selected from halogen, alkyl, phenyl, SO 2 NR ¹⁷ R ¹⁸ ;

Phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF ₃ , -SO 2 -NR ¹⁷ R ¹⁸ , wherein R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, SCh- alkyl, SO2-aryl, SCh-benzyl; and optionally the heterocyclic ring is fused to aryl;

or

And o

R together with R, or together with R, form a 5-membered to 2-membered compound

A 7-membered ring having one of the following structures -O- (CH ₂ ) _n -O-; wherein n is 1, 2 or 3; -SO ₂ -NR- (CH ₂ ) _n - wherein the index n is 1 or 2; -SO-NR- (CH 2) _n wherein the index n is 1 or 2; -SO 2 - (CH 2) _n - wherein the index n is 2 or 3; -SO- (CH 2) _n - wherein the index n is 2 or 3; -CO-CH = CH-NH-; -CO-CH = CH-O-; -CO- (CH ₂ ) _n -NH-, wherein the index n is 1 or 2; CONH _{(CH2) n,} wherein n is 1 or 2; -CO- (CH 2) 2 -O-; -O- (CH 2) _n -O-; wherein n is 1, 2 or 3;

R ⁸ represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, nitroalkyl;

Phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy;

HET;

-SR ¹⁹ ; -SO 2 -R ¹⁹ ; -SO 2 -R ¹⁹ ; -SO 2 O-R ¹⁹ ; -SO ₂ -NR ¹⁹ R ^m ; -NHCOR ¹⁹ ; ^{-CONR 9} R ^20;

-CR = NOR; -CO-R ¹⁹ ; -CO ₂ -R ¹⁹ , wherein R 'and R' are independently hydrogen, alkyl, cycloalkyl, phenyl, benzyl; and R ¹⁹ and R ²⁰ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁹ and R ²⁰ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, SO ₂ -alkyl, SO ₂ aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

provided that when X represents SO ₂ and Y represents N and the dotted line represents a single bond, then neither R ⁷ or R ⁶ is chlorine when R ² , R ⁴ , R ⁵ , R ⁸ and the remaining R ⁶ substituents and ^R7 are all H; and provided that R ³ can represent CH 3 only when R is hydrogen or R is not sulfamoyl;

and provided that when X is SO ₂ and Y is N and the dotted line represents a double bond, then neither R ⁷ or R ⁶ is chlorine when R ² , R ⁴ , R ⁵ , R ⁸ and the remaining R substituents ⁶ and R ⁷ are all hydrogen; and provided that R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are not all hydrogen; and provided that the compound is not disubstituted by R ³ which is CH 3 when R ⁷ is fluoro, bromo, iodo, CF 3, CH 3, NO ₂ , SO ₂ N (CH ₃ ) _2, or R ⁶ is bromo, CF 3, CH 3, ethyl, methoxy; or R ⁵ is chloro, CH 3; or R ⁸ is chloro; and provided the compound is not

3-ethyl-6-methoxy-1,2,4-benzothiadiazine-1,1-dioxide;

3-propyl-6-methyl-1,2,4-benzothiadiazine-1,1-dioxide;

3-ethyl-6-methoxy-1,2,4-benzothiadiazine-1,1-dioxide;

3-phenyl-7-bromo-1,2,4-benzothiadiazine-1,1-dioxide;

3-phenyl-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide;

5-bromo-7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide; 5-iodo-7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide;

5-nitro-7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide;

6-nitro-7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide; or 6-amino-7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide;

A more preferred embodiment of the invention is a compound of the above formula I wherein

R ² represents a hydrogen atom, alkyl, cycloalkyl;

or

R ² together with R ³ forms

A 5- to 6-membered ring; optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups;

A preferred embodiment is where

R ³ represents a hydrogen atom, a cycloalkyl, an alkyl, a haloalkyl, an alkoxy group, and a carbocyclic 7 to 10 membered ring; a heterocyclic 5-membered to 6-membered ring; benzyl; aryl; or

R ³ together with R ² or R ⁴ forms a 5-membered to 6-membered ring; optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups.

And another preferred embodiment is where

R ⁴ represents a hydrogen atom, alkyl, or o

together with R and together with the atoms to which they are attached form a 5-membered to 6-membered ring; optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups.

And another preferred embodiment is where

R ⁵ represents hydrogen, halogen, alkyl, alkenyl, alkynyl, phenyl,

-SO ₂ -NRR ' ² wherein R ¹¹ and R ¹² independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹¹ and R ¹² together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure;

And another preferred embodiment is where

R ⁶ represents a hydrogen atom, halogen, cycloalkyl, alkyl, alkoxy, alkoxyalkyl,

Aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy;

HET;

-SR ¹⁵ ; -SO-R ^15; -SO 2 -R ¹⁵ ; -SO 2 O-R ¹⁵ ; -SO 2 -NR ¹⁵ R ¹⁶ ; -NHCO-R ^15; CONR ¹⁵ R ¹⁶ ; -CR '= NOR; -CO-R ^15; -CO ₂ -R ¹⁵ , wherein R 'and R' independently represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl; and R ¹⁵ and R ¹⁶ independently represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl, aryl, or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, SO ₂ -alkyl, SO ₂ aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

And another preferred embodiment is where

R ⁷ represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, - (alkyl) _m -NR ¹⁷ R ¹⁸ , NHSO 2 -R ¹⁷ , -SR ¹⁷ ; -SO-R ^17; -SO 2 -R ¹⁷ ; -SO 2 O-R ¹⁷ ; -SO 2 -NR ¹⁷ R ¹⁸ ; -NHCOR ¹⁷ ; ^{-CONR 7} R ^18; -CR '= NOR; -CO-R ^17; -CO ₂ -R ¹⁷ , wherein R 'and R' are independently hydrogen, alkyl, cycloalkyl, phenyl, benzyl; and R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with alkyl SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

HET optionally substituted with one or more substituents selected from halogen, alkyl, phenyl, SO ₂ NR ¹⁷ R ¹⁸ ;

Phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF ₃ , -SO ₂ -NR ¹⁷ R ¹⁸ , wherein R ¹⁷ substituents and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

or

R ⁷ together with R ⁶ or R ⁸ together form a 5-membered to 6-membered compound

A 7-membered ring having one of the following structures -O- (CH 2) _n -O-; wherein n is 1, 2 or 3; -SO ₂ -NR- (CH ₂ ) _n - wherein the index n is 1 or 2; -SO-NR- (CH ₂ ) _n wherein the index n is 1 or 2; -SO ₂ - (CH ₂ ) _n - wherein the index n is 2 or 3; -SO- (CH ₂ ) _n - wherein the index n is 2 or 3; -CO-CH = CH-NH-; -CO-CH = CH-O-; -CO- (CH ₂ ) _n -NH-, wherein the index n is 1 or 2; CONH _{(CH2) n,} wherein n is 1 or 2; -CO- (CH ₂ ) 2 -O-; -O- (CH ₂ ) _n -O-; wherein n is 1, 2 or 3;

And another preferred embodiment is where

R ⁸ represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, nitroalkyl;

Phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy;

HET;

-SR ¹⁹ ; -SO 2 -R ¹⁹ ; -SO 2 -R ¹⁹ ; -SO 2 O-R ¹⁹ ; -SO 2 -NR ⁹ R ²⁰ ; -NHCOR ¹⁹ ; -CONR ¹⁹ R ²⁰ ; -CR '= NOR; -CO-R ¹⁹ ; -CO 2 -R ¹⁹ , wherein R 'and R' independently represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl; and R ¹⁹ and R ²⁰ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁹ and R ²⁰ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, SO ₂ -alkyl, SO ₂ aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

Particularly preferred embodiments are compounds of the above formula I wherein

X represents SO ₂ ; Y is N and the dotted line represents a single bond; R ² is H;

R ³ represents a cycloalkyl, carbocyclic 7-membered to 10-membered ring; a heterocyclic 5- to 6-membered ring;

R ⁴ represents H;

R ⁵ represents H;

R ⁶ represents a hydrogen atom, an alkyl or a halogen;

R ⁷ represents cyanoalkyl, nitroalkyl, haloalkyl, - (alkyl) _m -SO-R ¹⁷ ; - (alkyl) m -SO 2 -R ¹⁷ ; - (alkyl) mSO ₂ -NR ¹⁷ R ¹⁸ ; - (alkyl) m-CONR ¹⁷ R ¹⁸ ; - (alkyl) ni-CR '= NOR; - (alkyl) _m -CO-R ¹⁷ ; - (alkyl) _m -CO ₂ -R ¹⁷ , wherein m is 0 or 1, R 'and R' independently represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl; and R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with alkyl SO 2 -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

HET;

or

R ⁷ together with R ⁶ or R ⁸ together form a 5- to 7-membered ring having one of the following structures

-O- (CH 2) _n -O-; wherein n is 1, 2 or 3; -SO 2 -NR- (CH 2) _n - wherein the index n is 1 or 2; -SO-NR- (CH 2) _n wherein the index n is 1 or 2; -SO 2 - (CH 2) _n - wherein the index n is 2 or 3; -SO (CH ₂ ) _n - wherein the index n is 2 or 3; -CO-CH = CH-NH-; -CO-CH = CH-O-; -CO- (CH ₂ ) _n NH-, wherein the index n is 1 or 2; -CO-NH- (CH 2) _n wherein n is 1 or 2; -CO- (CH 2) 2 O-; -O- (CH 2) _n -O-; wherein n is 1, 2 or 3;

R ⁸ represents alkyl, halogen, cyanoalkyl, nitroalkyl, haloalkyl,

- (alkyl) _m -SO 2 -R ^17; - (alkyl) m-SO 2 -R ¹⁷ ; - (alkyl) n 1 -SO 2 -NR ¹⁷ R ¹⁸ ; - (alkyl) m-CONR ¹⁷ R ¹⁸ ; - (alkyl) m-CR '= NOR; - (alkyl) _m -CO-R ¹⁷ ; - (alkyl) _m -CO ₂ -R ¹⁷ , wherein the index m is 0 or 1;

R 'and R' independently represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl; and

R @ 1 and R @ 2 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R @ 1 and R @ 2, together with the nitrogen to which they are attached, form a heterocyclic 3- to 8-membered ring structure optionally substituted by alkyl, C1-4 alkyl SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to aryl; or

HET;

Specific embodiments of the present invention are as follows, all of which relate to formula 1 above.

An embodiment of the invention is where

R &lt; ¹ &gt; represents a hydrogen atom, cyclopropyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, CF3, ethoxy, norbomylene, norbornane, adamantane, benzyl; phenyl;

or

R ³ together with R ² or R ⁴ and together with the atoms to which they are attached form a 5-membered ring;

Another embodiment of the invention is where

R ⁴ represents a hydrogen atom, methyl, ethyl; or R ⁴ together with R ³ and together with the atoms to which they are attached form a 5-membered ring;

Another embodiment of the invention is where

R ⁵ represents a hydrogen atom, chlorine, bromine, methyl, phenyl, -SO 2 NH 2;

Another embodiment of the invention is where

R ⁶ represents a hydrogen atom, 2-methoxyphenyl, 2-pyridyl, 3-pyridyl, methyl, methoxy, chloro or bromo;

Another embodiment of the invention is where

R ⁷ represents a hydrogen atom, chlorine, bromine, methyl, 1-hydroxyethyl, acetyl, - (CH 3) C = N-OH, CONH 2, CO ₂ ethyl, cyano, phenyl, 2- N -acetylaminophenyl, 2-nitrophenyl, 2-methoxyphenyl, 4trifluórmetyi-2-methoxyphenyl, 2,4-dimethoxyphenyl, 2-A ^/,? / - dimetylsulfamoylfenyí, 2-chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2- furyl, 3-furyl, 2-thienyl, 2- ^(f-methyl) imidazolyl, 5-triazolyl, 4-phenyl-triazol-5-yl, 5-methyl-1,2,4-oxadiazol-3-yl, CH3CONH-, CH ₃ SO ₂ NH-, NO ₂ , SO ₂ OH, phenyl-SO ₂ -, sulfamoyl, N, N-dimethylsulfamoyl, Ύ, Ν-diethylsulfamoyl, N -phenyl-N-methylsulfamoyl, Ύ -cyclohexylsulfamoyl, -SO 2 -heterocyclic ring, heterocyclic the rings are selected from piperidine, pyrrolidine, 1,2,5,6-tetrahydropyridine, tetrahydroquinoline, N-methylpiperazine, az-sulfonylmethylpiperazine, morpholine;

A further embodiment of the invention is where

R ⁸ represents a hydrogen atom, methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl, methoxy;

Particularly preferred embodiments are compounds represented by the above formula I wherein X is SO ₂ and Y is N and the dotted line represents a single bond and R ² represents a hydrogen atom or CH ₃ ;

and R ³ represents cyclohexyl, cyclopentyl, norbornylene, norborane, adamantane, phenyl, ethoxy;

and R ⁴ represents a hydrogen atom or CH ₃ ;

and R ⁵ represents hydrogen, CH ₃ , phenyl, sulfamoyl, chloro, bromo, and R ⁶ represents hydrogen, CH ₃ , 2-methoxyphenyl, methoxy, chloro, bromo, 2-pyridyl, 3-pyridyl;

and R ⁷ represents hydrogen, chloro, bromo, methyl, 1-hydroxyethyl, acetyl, - (CH ₃ ) C = N-OH, CONH ₂ , CO ₂ ethyl, cyano, phenyl, 2-N-acetylaminophenyl, 2 -nitrophenyl, 2-methoxyphenyl, 4-trifluoromethyl-2-methoxyphenyl, 2,4-dimethoxyphenyl, 2-7 N, N-dimethylsulfamoylphenyl, 2-chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2 -furyl, 3furyl, 2-thienyl, 2- (N-methyl) -imidazolyl, 5-triazolyl, 4-phenyl-triazol-5-yl, 5-methyl-1,2,4-oxadiazol-3-yl, CH ₃ CONH -, CH ₃ SO ₂ NH-, NO ₂ , SO ₂ OH, phenyl-SO ₂ -, sulfamoyl, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N-phenyl-N-methylsulfamoyl, N-cyclohexylsulfamoyl, -SO _{A 2-} heterocyclic ring wherein the heterocyclic rings are selected from piperidine, pyrrolidine, 1,2,5,6-tetrahydropyridine, tetrahydroquinoline, N-methylpiperazine, N -sulfonylmethylpiperazine, morpholine;

R ⁸ represents methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl, methoxy,

Other particularly preferred embodiments of the invention are compounds of the above formula I wherein X is SO ₂ and Y is N and the dotted line represents a double bond and R ³ represents CH ₃ or CF ₃ or R ³ together with R ⁴ and atoms to which they are attached, form and R ⁴ , R ⁶ and R ⁸ are all hydrogen;

and R ⁵ is hydrogen or halogen;

and R ⁷ is N-methylsulfamoyl, NN-dimethylsulfamoyl, N -cyclohexylsulfamoyl, tetrahydropyridylsulfonyl; SO ₂ OH, sulfamoyl;

Other particularly preferred embodiments of the invention are compounds of the above formula I wherein X is C = O and Y is N, O or CH; and

R ² is H; and

R ³ represents a hydrogen atom, CH 3, CF ₃ , cyclohexyl, norbomylene, phenyl, ethyl; and

R ⁷ represents a hydrogen atom, ΛζΎ-dimethylsulfamoyl, N-cyclohexylsulfamoyl, tetrahydropyridylsulfonyl, morpholinosulfonyl, sulfamoyl, bromine; and

R ⁵ represents a hydrogen atom or a bromine atom; and

R ⁴ , R ⁶ and R ⁸ are hydrogen;

Other particularly preferred embodiments of the invention are compounds of the above formula I wherein X is CH ₂ and Y is N; and

R ³ represents cyclohexyl or norbomylene; and

R ⁵ represents a hydrogen atom or a bromine atom; and

R ⁷ is bromo or sulfamoyl; and

R ² , R ⁴ , R ⁶ and R ⁸ are all hydrogen;

Other particularly preferred embodiments of the invention are compounds of the above formula I wherein X is SO ₂ and Y is NH; and the dashed line is absent and R, R, R and R are hydrogen;

R ³ represents cyclohexyl, methyl or hydrogen; and

R ⁷ represents N, N-dimethylsulfamoyl, tetrahydropyridylsulfonyl, bromo; and

R ⁶ represents bromo or hydrogen;

Other particularly preferred embodiments of the invention are compounds of the above formula I wherein X is SO ₂ and N is -NHCH ₂ -; and R ³ represents 3-methylbut-2-yl, phenyl or cyclohexyl; and R ⁷ represents 1-piperidinesulfonyl.

Most preferred embodiments of the invention are compounds of the above formula I, wherein the compounds are selected from the group consisting of:

2-Cyclohexyl-4-oxo-l, 2,3,4-tetrahydroquinazoline;

2-phenyl-4-oxo-1,2,3,4-tetrahydroquinazoline;

2-Methyl-3,4-dihydro-1,3-benzoxazin-4-one;

2-Phenyl-3,4-dihydro-1,3-benzoxazin-4-one;

3-Bicyclo [2.2.1] hept-5'-en-2'-yl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

1,2,3,5,10,1 Oa-Hexahydrobenzo [e] pyrrolo [1,2-a] -1,2,4-thiadiazine-5,5-dioxide;

2-Ethyl-2-methyl-3,4-dihydro-1,3-benzoxazin-4-one;

3-Cyclohexyl-6- (2-methoxyphenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-6- (2-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-6- (3-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (1-hydroxyethyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-acetyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7- (1-hydroxyiminoethyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-carbamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7-ethoxycarbonyl-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide;

3-Cyclohexyl-7-cyano-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Bicyclo [2.2.1] hept-5'-en-2'-yl-7-phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (2'-acetamidophenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (2'-nitrophenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (2'-methoxyphenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- ^{(2'-methoxy-4,} -trifluórmetyIfenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-l, 1dioxidu;

3-Cyclohexyl-7- (2 ', ^{4-dimethoxyphenyl)} -l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide; 3-Cyclohexyl-7- (2 '- (N, N-dimethylsulfamoyl) phenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7- (2'-chlorophenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (2'-fluorophenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (3'-hydroxyphenyl) -l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide;

3-Cyclohexyl-7- (2'-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7- (3'-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (2'-pyrimidinyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7- (2'-furyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7- (3'-phenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (2'-thienyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7- (1-methyl-1H-2-imidazolyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7- (1 ', 2', 3'-triazol-4'-yl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (5'-phenyl-1 ', 2', 3'-triazol-4'-yl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7- (5'-methyl-1 ', 2', 4'-oxadiazol-3-yl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide ;

3-Cyclohexyl-7-acetamido-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7-methylsulfonylamino-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-nitro-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide;

3-Cyclohexyl-7-phenylsulfonyl-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-1,1-dioxide;

2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline sulfonamide;

3-Cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Methyl-7-dimethylsulfamoyl-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide;

2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline-7 H, N-dimethylsulfonamide;

3-Cyclohexyl-7-dimethylaminosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-N-1,1-dioxide;

3-Cyclohexyl-7- (N, j ¥ diethylamino) sulfonyl-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l-dioxide;

3-Cyclohexyl-7-pyrrolidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Methyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclopropyl-7-piperidinosulfonyl-2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide;

3-Isopropyl-7-piperidinosulfonyl-2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide; 3-propyl-7-piperidinosulfonyl-2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide;

3-Benzyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclopentyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-piperidinosulfonyl-2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide;

3-Bicyclo [2.2.1] hept-5'-en-2'-yl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

5-Cyclohexyl-1'-G ', 4', 6'-tetrahydropiperidinoJsulfonyl-1,1'S, 4'-tetrahydro-1,1'-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7- (N-methyl-N-phenylamino) sulfonyl-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l-dioxide;

S-Cyclohexyl-N-β-β-β, β-β-tetrahydroquinolinyl-4-sulfonyl-1,1'-tetrahydro-1'-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7- (4'-methylpiperazino) sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine 1,1-dioxide;

3-Cyclohexyl-7- (4'-metylsulfonypiperazino) sulfonyl-l, 2,3,4-tetrahydro-2,4-dioxide-benzotiadiazín1,1;

3-Cyclohexyl-7-morpholinosulfonyl-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-1,1-dioxide;

3-bicyclo [2,2, l] ^{hept-5'-en-2-yl-7-bromo-1,2,3,4-tetrahydro-l,} 2,4-benzothiadiazine-1,1-dioxide;

2-methyl-4-oxo-3,4-dihydro-6-quinazoline-N, N-dimethyl sulfonamide;

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-chinazolínsulfónamidu;

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline-N, N-dimethyl sulfonamide;

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline-I ', ^2', 3 ^{', 5,} -tetrahydropiperidinosulfónamidu;

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline-N-cyklohexylsuifónamidu;

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline-morfolinosulfónamidu;

2-Cyclohexyl-4-oxo-3,4-dihydro-6-quinazoline-N, N-dimethylsulfonamide;

3-Methyl-7-sulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Methyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Methyl-7- (1 ^, 2 ^, 3 ^, 6'-tetrahydropiperidino) sulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Methyl-7-cyclohexylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;

Trifluoromethyl-7-dimethylsulphamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline sulfonic acid;

-Cyclohexyl-8-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-8-hydroxymethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-8- (2-methoxyphenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-8- (3-methoxyphenyl) -l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide;

3-Cyclohexyl-8- (2-pyridyl) -l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide;

3-Cyclohexyl-8-methoxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

5,7-Dibromo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-2-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine 1,1-dioxide;

3-Cyclohexyl-4-methyl-7-morpholinosulfonyl-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l-dioxide;

7-methylsulfonylamino-l, 2,3,3a, 4,5-hexahydro-benzo [e] pyrrolo [2, l-c] -l, 2,4-thiadiazine-5,5dioxidu;

7-sulfamoyl-l, 2,3,3a, 4,5-hexahydro-benzo [e] pyrrolo [2, l-c] -l, 2,4-thiadiazine-5,5-dioxide;

7-Metylsulfamoyi-l, 2,3,3a, 4,5-hexahydro-benzo [e] pyrrolo [2, l-c] -l, 2,4-thiadiazine-5,5-dioxide;

7-cyclohexylsulfamoyl-l, 2,3,3a, 4,5-hexahydro-benzo [e] pyrrolo [2, l-c] -l, 2,4-thiadiazine-5,5dioxidu;

7-Dimethylsulfamoyl-1,2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide;

7-Methylsulfamoyl-l, 2,3,5-tetrahydro-benzo [e] pyrrolo [2, l-c] -l, 2,4-thiadiazine-5,5-dioxide;

7-dimethylsulfamoyl-l, 2,3,5-tetrahydro-benzo [e] pyrrolo [2, l-c] -l, 2,4-thiadiazine-5,5-dioxide;

7-cyclohexylsulfamoyl-l, 2,3,5-tetrahydro-benzo [e] pyrrolo [2, l-c] -l, 2,4-thiadiazine-5,5-dioxide;

7 (I ', ^2', 3 ', ^6, -Tetrahydropiperidino) sulfonyl-l, 2,3,5-tetrahydro-benzo [e] pyrrolo [2-c] -l, 2,4tiadiazín-5,5-dioxide;

3-Bicyclo [2.2.1] hept-5'-en-2'-yl-5,7-dimethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7- (7V, V-diethylsulphamoyl) -5-methyl-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l-dioxide;

3-bicyclo [2,2, l] hept-5'-en-2'-yl | -5,7-diphenyl-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l-dioxide ;

3-Bicyclo [2.2.1] hept-5'-en-2'-yl-5,7-disulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Bicyclo [2.2.1] hept-5'-en-2'-yl-5,7-dichloro-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

5-bromo-3-cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-l, 2,4-benzothiadiazine-1,1-dioxide;

2-bicyclo [2,2, l] hept-5 ' ^{l-2-yl-6,8-dibromo-l,} 2,3,4-tetrahydroquinazoline;

2-Bicyclo [2.2.1] hept-5'-en-2'-yl] -6,8-dibromo-4-oxo-1,2,3,4-tetrahydroquinazoline;

3-Bicyclo [2.2.1] hept-5'-en-2'-yl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

5,7-Dibromo-3-bicyclo [2.2] heptane-2-yl-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide;

3-Cyclohexyl-5,7-dibromo-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide;

3-Adamantyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Phenyl-5,7-dibromo-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide;

3-Ethoxy-5,7-dibromo-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide;

3-methyl-5,7-dibromo-l, 2-dihydro-l, 2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-6-methyl-7- (2'-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-6-methyl-7- (4'-triazolyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-cyclohexyl-6-methyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclopentyl-6-methyl-7-piperidinosulfonyl-2,3,4-tetrahydro-2,4-benzothiazepine-diazine-l-dioxide;

3-Cyclohexyl-6-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine 1,1-dioxide;

3-Cyclohexyl-6- (2-methoxyphenyl) -7-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-6-methoxy-7-piperidinosulfonyi-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine 1,1-dioxide;

3-Cyclohexyl-7,8-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-cyclohexyl-6,7-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-6-chloro-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Phenyl-6-chloro-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-6-bromo-7-piperidinosulfonyl-2,3,4-tetrahydro-2,4-benzothiazepine-diazine-l-dioxide;

2-Cyclohexyl-5-N, N-Dimethylsulfamoyl-benzenesulfonamide;

2-ethylamino-7- ^(l, 2 ', ^3', 6'-tetrahydropiperidino) sulfonylbenzénsulfónamidu;

3-isobutyl-8- (piperidinosulfonyl) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide; 3-Cyclohexyl-7-cyclopentylsulfinyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-cyclopentyisulfinyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-cyclopentylsulfinyl-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide; or 3-Cyclohexyl-7-cyclopentylsulfinyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide or a pharmaceutically acceptable salt thereof.

Pharmaceutically acceptable salts

The chemical compound of the invention may be prepared in any form suitable for the intended application. Suitable forms include pharmaceutical (i.e., physiologically) acceptable salts and prodrugs of the chemical compound of the invention.

Examples of pharmaceutically acceptable addition salts include, but are not limited to, non-toxic inorganic and organic acid addition salts such as e.g. acetate derived from acetic acid, aconitate derived from aconitic acid, ascorbate derived from ascorbic acid, benzenesulfonate derived from benzenesulfonic acid, benzoate derived from benzoic acid, cinnamate derived from citric acid, citrate derived from citric acid, embonate derived from embonic acid, enanthate from enantic acid, formate derived from formic acid, fumarate derived from filmaric acid, glutamate derived from glutamic acid, glycolate derived from glycolic acid, hydrochloride derived from hydrochloric acid, hydrobromide derived from hydrobromic acid, lactate derived from lactic acid, maleate derived from acid maleic acid, malonic acid malonate, mandelic acid mandelate, methanesulphonic acid methanesulphonate, naphthalene-2-sulphonate-derived naphthalene-2-sulphonate, acid-derived nitrate nitric selines, perchlorate derived from perchloric acid, phosphate derived from orthophosphoric acid, phthalate derived from violet acid, salicylate derived from salicylic acid, sorbate derived from sorbic acid, stearate derived from stearic acid, succinate derived from succinic acid, sulphate derived from sulfuric acid , tartaric acid-derived tartrate, p-toluenesulfonic acid-derived toluene-p-sulfonate, etc. Such salts may be prepared by methods known and described in the art.

in

Other acids such as e.g. Oxalic acid, which cannot be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and a pharmaceutically acceptable acid addition salt thereof.

Metal salts of the chemical compound of the invention include alkali metal salts such as e.g. the sodium salt of a carboxy group-containing chemical compound of the invention.

The chemical compound of the invention may be prepared in soluble or insoluble forms together with pharmaceutically acceptable solvents such as e.g. water, ethanol, and the like. Soluble forms may also include hydrated forms such as e.g. monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like. In general, for the purposes of the present invention, the soluble forms are considered equivalent to the insoluble forms.

Definitions of substituents

Halogen is fluorine, chlorine, bromine or iodine.

Alkyl means a straight or branched chain having 1 to 6 carbon atoms or a cyclic alkyl having 1 to 7 carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl; methyl, ethyl, propyl and isopropyl are preferred groups.

Haloalkyl means the above-mentioned alkyl substituted one or more times with halogen as defined above. Preferred embodiments are CF 3, C 2 F 5, CH ₂ Cl, CHCl ₂ , -CHFCH ₂ F, -CHCl ₂ Cl ₂ ;

Cycloalkyl means cyclic alkyl having 3 to 7 carbon atoms such as e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

Cycloalkylalkyl means the above-mentioned cyclic alkyl and the above-mentioned alkyl, wherein alkyl may be considered as a substituent on the cycloalkyl and vice versa. Preferred groups are C ₃ cycloalkyl and alkyl-wire such. - (CH ₂ ) -cyclopropyl, -cyclopropyl- (C 1-4 -alkyl), - (CH ₂ ) _n cyclohexyl, -cyclohexyl- (C 1-4 -alkyl), (C 1-4 -alkyl) -cyclobutyl, -cyclobutyl (CM alkyl) - (ϋμalkyl) cyclopentyl, -cyclopentyl (C-alkyl), - (Ci-4-alkyl) cyclohexyl, cyclohexyl (Ci. ₄ alkyl);

Halocycloalkyl means the above-mentioned cyclic alkyl which is substituted with one or more of the above-mentioned halogen including, but not limited to, chlorocyclopropyl, fluorocyclopropyl, iodocyclopropyl, dichlorocyclopropyl, difluorocyclopropyl, chlorocyclobutyl, fluorocyclobutyl, hexocyclocyclopentyl, chlorocyclopentyl, chlorocyclopentyl, , difluorocyclohexyl, iodocyclohexyl. A preferred embodiment is a monosubstituted and disubstituted cycloalkyl having 3 to 6 carbon atoms such as e.g. dichlorocyclopropyl, difluorocyclopropyl, chlorocyclohexyl, fluorocyclohexyl, iodocyclohexyl, chlorocyclopentyl, fluorocyclopentyl.

Alkenyl means an unbranched or branched chain having 2 to 6 carbon atoms containing one triple bond including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl and 3-butenyl.

Alkynyl means an unbranched or branched chain having 2 to 6 carbon atoms containing one triple bond and including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl.

The alkoxy group is O-alkyl, wherein alkyl is as defined above.

Alkoxylakyl is -alkyl-O-alkyl, wherein alkyl is as defined above.

Hydroxyalkyl is alkyl as defined above substituted by OH;

The amino group is NH 2 or NH-alkyl or N- (alkyl) 2, wherein alkyl is as defined above.

An alkylamino group is an alkyl group as defined above which is substituted with an amino group as defined above. Preferred embodiments are -CH 2 -N (alkyl) 2, -CH-N (alkyl) 2 CH ₃ , -CH ₂ CH ₂ N (alkyl) ₂ , -CH ₂ -NH ₂ , -CH- (NH ₂ ) -CH ₃ , -CH ₂ CH ₂ NH _2;

The cyano group is CN;

Cyanoalkyl is alkyl as defined above substituted with CN;

The nitro group is -NO2;

Nitroalkyl is an alkyl as defined above substituted by a nitro group as defined above.

The thio group is SH or S-alkyl, wherein alkyl is as defined above;

An alkylthio group is an alkyl as defined above substituted by a thio group as defined above.

Acyl is (C = O) -R 0 or (C = S) -R 0, wherein R 0 is alkyl; phenyl which may be substituted by one or more substituents selected from the group consisting of halogen, CF ₃ , NO 2, amino, alkyl, alkoxy, phenyl and SO ₂ NR'R, wherein R 'and R' are each independently hydrogen or alkyl or wherein R 'and R' together with (CH 2) _m wherein m is 2, 3, 4, 5, or 6; or R c is benzyl; or NR ^m R ^IV each independently are hydrogen or alkyl or wherein R ¹¹¹ and R ^IV together are (CH 2) _p , wherein the index p is 2, 3, 4, 5 or 6.

The acylamino group is acyl-ΝΗ-, wherein acyl is as defined above.

Aryl is an aromatic carbocyclic ring such as e.g. phenyl or biphenyl and a fused carbocyclic ring such as e.g. naphthyl;

HET is a 5- to 6-membered cyclic heteroaryl and includes e.g. oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5- yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazole- 3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl and 4-pyrazolyl, furanyl, tetrahydrofuranyl, pyrrolyl, pyrrolidyl, imidazolyl, oxadiazolyl, pyridyl, thienyl, isoxazolyl, pyrimidyl, pyrazole, triazolyl. Particularly preferred heteroaryls of the invention are pyridyl, pyrimidyl, triazole, furyl, thienyl, oxadiazolyl, imidazolyl;

The carbocyclic 7-membered to 12-membered ring structure includes monocyclic, bicyclic and tricyclic structures. Preferred embodiments are 7-membered to 10-membered ring structures such as e.g.

a heterocyclic 3- to 8-membered ring structure includes a partially or fully saturated heterocyclic ring structure such as e.g. aziridine, pyrrolidine, piperidine, piperazine, homopiperidine, homopiperazine, azacyclooctane, 1,3-diazacyclooctane, 1,4-diazacyclooctane, tetrahydrofuran, tetrahydrothiophene, morpholine, tetrahydropyridine and compounds such as e.g.

A Λ Λ A

Preferred embodiments are 5-membered to 6-membered rings containing at least one nitrogen such as e.g. pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyridine.

The described 4-membered to 7-membered rings fused to a ring structure of formula I formed between R ² and R ³ or R ³ and R ⁴ or R ⁵ and R ⁶ or R ⁶ and R ⁷ or R ⁷ and R ⁸ are carbocyclic rings optionally containing a heteroatom and optionally containing a carbonyl group. Preferred rings are 5-membered and 6-membered carbocyclic rings;

The rings formed between the substituents R ⁷ and R ⁶ or R ⁸ are 5-membered or 6-membered and contain O, C = O, S = O or SO ₂ groups and optionally contain nitrogen.

Preferred rings are -O- (CH ₂ ) _n -O-; wherein n is 1, 2 or 3; -SO ₂ -NR- (CH ₂ ) _n - wherein the index n is 1 or 2; -SO-NR- (CH ₂ ) _n wherein the index n is 1 or 2; -SO ₂ - (CH ₂ ) _n - wherein the index n is 2 or 3; -SO- (CH ₂ ) _n - wherein the index n is 2 or 3; -CO-CH = CH-NH-; -CO- (CH ₂ ) _n -NH-, wherein the index n is 1 or 2; -CO-NH- (CH ₂ ) _n wherein the index n is 1 or 2; -CO- (CH ₂ ) ₂ -O-;

The compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as e.g. water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.

Steric isomers

The chemical compounds of the present invention can exist in (+) and (-) forms as well as in racemic forms. The racemates of these isomers and the individual isomers are within the scope of the present invention.

Racemic forms can be resolved into optical antipodes by known methods and techniques. One method of separating diastereomeric salts is by using an optically active acid and liberating the optically active amine compound by reaction with a base. Another method for resolving racemates into optical antipodes is based on chromatography on an optically active matrix. The racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g. by fractional crystallization of d- or 1- (tartrates, mandelates or camphorsulfonate) salts.

The chemical compounds of the present invention may also be resolved by forming diastereomeric amides by reacting the chemical compounds of the present invention with an optically active activated carboxylic acid such as e.g. derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphoric acid, or by formation of diastereomeric carbamates by reaction of the chemical compounds of the present invention with optically active chloroformate, and the like.

Other methods for distinguishing optically active isomers are known in the art. Such methods are described in Jaques, Collet A, & Wilen S in: Enantiomers, Racemates, and Resolutions, John Wiley &amp; Sons, New York (1981).

In addition, some of the chemical compounds of the invention that are oximes can exist in two forms, the syn- and anti-forms (Z-form and E-form), depending on the arrangement of the substituents on the -ON- double bond. Thus, the chemical compound of the present invention may be a syn-form or an anti-form (Z-form and E-form) or a mixture thereof.

The compound of the invention includes, where possible, endo-forms and exo-forms and tautomers.

An aspect of the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of a chemical compound of the invention and the use of the compounds of the invention for the manufacture of a medicament for the treatment of specific diseases and disorders.

While the chemical compound of the invention for use in therapy may be administered in the form of an unmodified chemical compound, it is preferred to incorporate the active ingredient, optionally in the form of a physiologically acceptable salt, into the pharmaceutical composition together with one or more excipients, excipients, carriers, buffers, diluents and diluents. and / or other conventional pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceutical compositions comprising a chemical compound of the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers and optionally other therapeutic and / or prophylactic ingredients. The carrier (s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical compositions of the invention may be those suitable for oral, rectal. bronchial, nasal, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular and intravenous injection) administration, or such that are in a suitable form for administration by inhalation or insufflation.

The chemical compound of the invention together with a conventional adjuvant, carrier or diluent may thus be incorporated into the pharmaceutical compositions and unit doses thereof. Such forms include solids and in particular tablets, filled capsules, powder and pellet forms, and liquids, especially aqueous or non-aqueous solutions, suspensions, emulsions, medical drinks, and capsules filled in the same, all for oral use, rectal suppositories for rectal administration, and sterile injectable solutions for parenteral use. Such pharmaceutical compositions and unit dosage forms thereof may contain conventional components in conventional dosages with or without other active compounds or ingredients, and such unit dosage forms may contain any effective amount of active ingredient proportional to the intended use of the daily dosage range.

The chemical compound of the present invention can be administered in a wide range of oral and parenteral dosage forms. It will be appreciated by those skilled in the art that the following dosage forms may contain as an active ingredient either a chemical compound of the invention or a pharmaceutically acceptable salt of the chemical compound of the invention.

In preparing pharmaceutical compositions from a chemical compound of the present invention, pharmaceutically acceptable carriers can be either liquid or solid. Solid form preparations include powders, tablets, pills, capsules, capsules, rectal suppositories, and dispersible granules. The solid carrier may be one or more substances which may also function as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents after ingestion or a substance used for microencapsulation.

In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.

In tablets, the active ingredient is mixed with a carrier having the necessary binding capacity in suitable doses and compressed to the desired form and size.

The powders and tablets preferably contain from 5% or 10% up to about 70% of the active ingredient. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethyl cellulose, low melting waxes, cocoa fat, and the like. The term formulation refers to the association of the active ingredient with the microencapsulated substance as the carrier providing the capsule in which the active ingredient, with or without carriers, is surrounded by a carrier which is thus bound to it. Similarly, capsules and lozenges are included. Tablets, powders, capsules, pills, capsules, and lozenges can be used as solid forms suitable for oral administration.

To prepare rectal suppositories, low melting point waxes such as e.g. the fatty acid glyceride or cocoa fat is dissolved and the active ingredient is dispersed homogeneously by stirring. The liquid homogeneous mixture is then poured into a suitable sized mold, allowed to cool and thereby solidify.

Formulations suitable for vaginal administration may be pessaries, tampons, creams, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Liquid formulations include solutions, suspensions and emulsions, e.g. water or water-propylene glycol solutions. For example, parenterally injected liquid preparations may be prepared as solutions in aqueous polyethylene glycol solution.

Thus, the chemical compound of the present invention may be formulated for parenteral administration (e.g., injection, e.g., bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules, pre-filled syringes, mild infusion or multi-dose containers with preservative added. . The formulations may be such forms as e.g. suspensions, solutions or emulsions in an oily or aqueous carrier, and may contain agents to form a preparation such as e.g. suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for use with a suitable carrier, e.g. sterile pyrogen-free water, obtained by aseptic isolation of a sterile solid or by lyophilization from solution.

Aqueous solutions suitable for oral use may be prepared by dissolving the active ingredient in water and adding, if desired, a suitable coloring agent, flavoring, stabilizing agent and thickening agent.

Aqueous suspensions suitable for oral use may be formed by dispersing the finely divided active ingredient in water with a viscous substance, such as e.g. natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose or other well known suspending agents.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, coloring agents, flavoring agents, stabilizing agents, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

For topical application to the epidermis, the chemical compound of the invention may be formulated as an ointment, cream or lotion or as a transdermal patch. Ointments and creams may be prepared e.g. with an aqueous or oily base with the addition of a suitable thickening agent and / or gelling additives. The lotion may be formulated with an aqueous or oily base and will generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or coloring agents.

Formulations suitable for topical administration in the mouth include tablets containing the active ingredient in an aromatized base, usually sucrose and a resin or tragacanth; pastilles comprising the active ingredient in an inert base such as e.g. gelatin and glycerol or sucrose and resin; and mouthwashes containing the active ingredient in a suitable liquid carrier.

Solutions or suspensions are applied directly to the nasal cavity by conventional means, e.g. with a dropper, pipette or spray. The formulations may be provided in single or multidose forms. These in the case of drops or pipettes may be administered by the application of a suitable, predetermined volume of solution or suspension. In the case of a spray, the dosing can be administered by means of a spray pump with dosing spray

Administration to the respiratory tract may also be achieved by aerosol delivery means, wherein the active ingredient is in a pressurized pack together with a suitable propellant such as CFC, e.g. dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gases. The aerosol may suitably also contain a surfactant such as e.g. lecithin. The dose of the drug may be controlled by providing a dispensing closure.

In another method, the active ingredients may be provided in the form of a dry powder, e.g. a powder mixture of the compound in a suitable powder base such as e.g. lactose, starch, starch derivatives such as e.g. hydroxypropylmethylcellulose; and polyvinylpyrrolidone (PVP). A suitable powder carrier forms a gel in the nasal cavity. The powder formulation may be presented in unit dosage form e.g. in capsules or cartridges, such as e.g. gelatin, or soft, transparent packages from which the powder may be administered by means of an inhalation device.

In formulations intended for administration to the respiratory tract, including intranasal formulations, the compounds will generally have a small particle size e.g. on the order of 5 microns or less. Such a particle size can be obtained by means known in the art, e.g. grinding into fine particles.

When desired, the formulations used may be adapted to provide sustained release of the active ingredient.

The pharmaceutical preparations are preferably in unit dosage forms. In such forms, the preparation is subdivided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form may be a packaged preparation, a package containing a small amount of the preparation, e.g. tablets, capsules and powders in tubes or ampoules. The unit dosage form may also be a capsule, tablet, capsule or lozenge itself, or the appropriate number of any of these may be in packaged form.

Preferred formulations are tablets or capsules for oral administration and fluids for intravenous administration and sustained infusion.

Of course, the dose administered must be carefully adjusted according to the age, weight and condition of the patient being treated, as well as the route of administration, dosage form and regimen, and the desired outcome.

The active ingredient may be administered at once or in multiple doses per day. A satisfactory result may in certain cases be obtained at a dose as low as 0.1 Hg / kg i.v. and 1 pg / kg p.o. The upper limit of the dose range is considered to be about 10 mg / kg i.v. and 100 mg / kg p.o. Preferred ranges are from about 0.1 µg / kg to about 10 mg / kg / day i.v. and from about 1pg / kg to about 100 mg / kg / day p.o.

Method of treatment

The compounds of the present invention are AMPA receptor stimulators and are therefore useful in the treatment of an area of disorders and diseases that are susceptible to AMPA receptor modulators. As an embodiment of the invention, the diseases are susceptible to positive modulation of the AMPA receptor. The compounds may be used in the treatment, prevention, prophylaxis or amelioration of diseases, disorders or conditions of the central nervous system such as: neurodegenerative disorders, cognitive or memory dysfunctions, memory and learning disorders, attention deficit, memory disorders or learning disabilities, trauma, stroke, epilepsy; Alzheimer's disease, depression, schizophrenia, memory loss, dementia due to AIDS, senile dementia, learning deficit, cognitive deficit, sexual dysfunction, psychotic disorders, intellectual disorders, schizophrenia, depression or autism, lack of attention, or illness or disorder due to neurotoxic agents, alcohol intoxication, substance abuse, cardiac bypass surgery or brain ischemia. A suitable dose range is 0.1-500 milligrams per day, and particularly 10-70 milligrams per day, administered once or twice a day, depending as usual on the correct route of administration, form of administration, indication of the route of administration chosen, the subject and body weight of the subject. from other priorities and practices of a doctor or veterinarian.

Ip means intraperitoneal, which is a well known route of administration.

After. means orally, which is also a well-known route of administration.

The invention then includes the following, alone or in combination:

Use of the above compound for the manufacture of a medicament for the treatment of diseases which are susceptible to AMPA receptor modulation.

The above uses wherein the disorders are memory or learning disorders, psychotic disorders, sexual dysfunction, intellectual disorders, schizophrenia, depression, autism, Alzheimer's disease, learning deficit, attention deficit, memory loss or senile dementia; or disorders or diseases resulting from trauma, stroke, epilepsy, Alzheimer's disease, neurotoxic agents, aging, neurodegenerative disorders, alcohol intoxication, substance abuse, cardiac bypass surgery or brain ischemia.

biology

Determination of in vitro inhibition of H-AMPA binding

L-glutamate (GLU) is a major excitatory nerve mediator in the mammalian central nervous system. Electrophysiological and binding studies have shown that there are at least three GLU receptor subtypes, pre-labeled with N-methyl-D-aspartate (NMDA), chischalate, and kainate receptors. GLU receptor subtypes that respond to chischalate and kainate are often referred to as non-NMDA receptors as a group. Receptor binding studies using labeled ³ H-AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) agonists (for chischalate receptors) and ³ Hcainate (for kainate receptors) showed different antagonist selectivity and local incidence. For several years, it has been known that AMPA is a potent and selective agonist at the traditionally labeled chischalate receptors. Activation of the chissalate receptors by AMPA is associated with Na ⁺ input and K ⁺ output, resulting in depolarization.

Non-NMDA receptors have recently been reclassified to include an activated metabotropic type of chischalate receptor associated with the metabolism of inositol triphosphate and diacyl glycerate. AMPA does not interact with the metabotropic chischalate receptor, but only with the ionotropic chischalate receptor. Selective activation of the metabotropic type has been claimed for trans-ACPD. Recently, potent and competitive antagonists of the CNQX and NBQX non-NMDA receptor have been described and CNQX has been reported not to block the effect of chischalate on the metabotropic receptor subtype. ³ H-AMPA is a selective radioligand for the labeling of ionotropic chissalate (AMPA) receptors.

Tissue preparation

Preparations are performed at 0-4 ° C unless otherwise noted. The cerebral cortex of male Wistar rats (150-200 g) is homogenized for 5-10 seconds in 20 ml Tris-HCl (30 mM, pH 7.4) using an Ultra-Turrax homogenizer. The suspension is centrifuged at 27,000 x g for 15 minutes and the pellets are washed three times with buffer (centrifuged at 27,000 x g for 10 minutes). The washed pellets are homogenized in 20 ml buffer and incubated in a water bath (37 ° C) for 30 minutes to remove endogenous glutamate, and then centrifuged for 10 minutes at 27,000 x g. The pellets are then resuspended in 30 ml of buffer and the preparation is frozen and stored at -20 ° C.

determination

The membrane preparation is thawed and centrifuged at 2 ° C for 10 minutes at 27,000 xg for 10 minutes. The pellets were washed twice with 20 ml of 30 mM Tris-HCl containing 2.5 mM CaCl 2, pH 7.4 using an Ultra-Turrax homogenizer and centrifuged for 10 minutes at 27,000 x g. The final pellets are resuspended in 30 mM Tris-HCl containing 2.5 mM CaCl 2 and 100 mM KSCN, pH 7.4 (100 ml per g of original tissue) and used to determine binding. Aliquots of 0.5 (0.2) ml are added to 25 (20) μΐ test solution and 25 (20) μΐ ³ HAMPA (5 nM, final concentration), mixed and incubated for 30 minutes at 2 ° C. Non-specific binding was determined using L-glutamate (0.6 mM, final concentration). After incubation, 5 ml of ice-cold buffer is added to 550 μΐ samples and poured directly into Whatman GF / C glass fiber filters with suction turned on and immediately washed with 5 ml of ice-cold buffer. The filters were washed with 3 ml ice-cold buffer. The amount of radioactivity on the filters is determined by standard liquid scintillation counting. Specific binding is total binding minus non-specific binding.

The results

The test results shall be reported as IC50 (concentration (μΜ) of the test substance at

50% inhibits specific binding of ³ H-AMPA)

Test results

Compound numbers correspond to those in the table below.

compound IC (pM) 13 22.0 14 45.0 15 39.0 44 3.5 47 5.3 48 4.4 49 17.0 57 26.0 58 3.4 61 8.5 62 6.0 63 6.0 113 13.0 114 33.0 115 7.0

Potentiation of AMPA induced [ ³ H] GABA release from cultured cortical neurons

Neurons that express receptors for excitatory amino acids can be depolarized by such compounds, and this depolarization actually results in the release of the mediator from the neurons. Cultured neurons derived from the cortex of 16 day old mouse embryos are mainly GABAergic and express all types of excitatory amino acid receptors. That is, they can be stimulated with potassium (55 mM) or excitation amino acids NMDA (μΜ), AMPA (5 μΜ) and kainate (5 μΜ) to release their neural mediators GABA.

³ H-GABA can be used to label the GABA mediator pool in neurons, and release of ³ H-GABA from neurons can be used as a simple functional model for studies of the effects of agonists, antagonists and modulators of excitatory amino acid receptors.

ways

Cell culture

The cerebral cortex of 15-16 day old NMRI mouse embryos is trimmed to 0.4 x 0.4 mm cubes and the tissue dissociated by weak trypsinization (0.1% (w / v) trypsin, 37 ° C, 10 min ). Another cell suspension (3 mill / ml) is inoculated into Petri dishes (3 ml / dish) coated with 30 mm poly-L-lysine containing lightly modified DMEM (24.5 mM KCl) supplemented with p-aminobenzoate (7 μΜ, insulin (100 ml). mU / L) and 10% (v / v) horse serum Cells are maintained in culture medium for 5-7 days in vitro by adding the antimitotic agent cytosine arbinoside (5μΜ) from day 2 to prevent glial proliferation. Drejer et al. (Exp. Brain Res. 47: 259 (1982)).

Experiments to determine release

Release experiments are performed using the model described by Drejer et al. (Life Sci. 38: 2077 (1986)). 10 mM γ-vinyl-GABA is added to brain cortex neurons cultured in Petri dishes (30 mm) one hour prior to the experiment to inhibit GABA degradation in neurons. Thirty minutes before the experiment, 5 µCi of ³ H-GABA is added to each culture. After this precoating, the cell monolayer at the bottom of the container is covered with pieces of nylon mesh against mechanical damage and to facilitate dispersion of the medium across the cell layer. The precoating medium is removed and Petri dishes are placed in a superfusion system containing a peristaltic pump continuously delivering a thermostated 37 ° C superfusion medium (HEPES buffer (HBS): 10 mM HEPES, 135 mM NaCl, 5 mM KCl, 0.6 mM MgSO 4. , 1.0 mM CaCl ₂ and 6 mM D-glucose; pH 7.4) from the stock solution to the top of the slightly inclined Petri dishes. The medium is continuously concentrated from the lower part of the dish and fed to the fraction collector. Initially, cells are super-fused with HBS for 30 minutes (flow rate 2 ml / min), then stimulated for 30 seconds every 4 minutes by changing the superfusion medium from HBS to the corresponding medium containing 5 μΜ AMPA in the presence or absence of modulators.

Test substances are dissolved in 50% DMSO, 48% ethanol. The final concentration of DMSO and ethanol in the assay shall not exceed 0,1%.

The results

Induced ³ H-GABA release (cpm) is corrected for mean basal release (cpm) before and after stimulation and is used to calculate the assay value.

The potency of the AMPA response by the test substance is expressed as a ratio to the potency of the AMPA response induced by cyclothiazide (30 μΜ).

The results

The test results are shown in Figures 1 and 2. The results show a significant increase, Figure 1 shows potentiation of AMPA-induced [H ³ ] GABA release from cultured cortical neurons by compound 115. Potentiation is expressed as a ratio to potency induced by 30 μΜ cyclotiazide.

Figure 2 shows potentiation of AMPA-induced [ ³ H] GABA release from cultured cortical neurons by compound 11. Potentiation is expressed as a ratio to potencies induced by 30 μΜ of cyclotiazide.

Artificial keeping the membrane potential at a certain level

ways

The experiments are carried out in an apparatus for artificially maintaining the membrane potential at a certain level using standard methods for these experiments (Hamill et al., 1981) essentially as described above (Mathiesen et al., 1998). The following salt solutions are used: NaCl (140), KCl (4), CaCl ₂ (2), MgCl ₂ (1), sucrose (30), tetrodotoxin (0.0003), bicucine iodomethylate (0.005) and HEPES (10, pH) 7.4). intracellular solution (mM): CsCl (120), CsF (20), MgCl ₂ (2), EGTA (10), HEPES (10, pH = 7.2).

Cell culture

Mouse neocortical neurons are cultured essentially as described above by Drejer et al. (1987). Briefly, the forebrain from embryonic (E 17) NMRI mice are removed under sterile conditions. The tissue is cut into 0.4 mm cubes and triturated with trypsin (12.5 gg / ml) and DNAse (2.5 µg / ml), 15 minutes, 37 ° C. Cells are suspended at a concentration of 1 x 10 ⁶ cells / ml in lightly modified DMEM containing horse serum (10% (v / v)), penicillin (333 U / ml), paraaminbenzoic acid (1 mg / ml), L- glutamine (0.5 mM), insulin (0.08 U / ml) and KCl (23.8 mM). The cell suspension is then inoculated into poly-L-lysine-coated petri dishes (2 ml / dish). Glass coverslips (3.5 mm) were placed in the dishes before coating. After cultivation for 24 hours, the medium is replaced with freshly prepared medium containing 1% N ₂ as a supplement instead of serum.

Before the experiment, the cells are maintained in culture for 7-14 days at 37 ° C (5% CO ₂ /95% O ₂ ).

Electronics, programs and data acquisition:

An EPC-9 amplifier (HEKA-electronics, Lambrect, Germany) was used on the Power Macintosh G3 via the ITC-16 interface. The experimental conditions were set by the Pulse software connected to the amplifier. The data was slowly discharged and taken directly to the hard drive at 3 times the cutoff frequency.

Pipettes and electrodes:

Pipettes were made of borosilicate glass (Modulohm, Copenhagen, Denmark) using a horizontal electrode extractor (Zeitz-Instrumente, Augsburg, Germany). In salt solutions in these experiments the pipette resistance was 1.7-2.4 MW. The pipette electrode was a chlorinated silver wire and the reference electrode was a silver chloride chloride pellet electrode (In Vivo Metric, Healdsburg, USA) mounted at the site of the experiments. Just prior to sealing, the electrodes were zeroed with an open pipette in the bath.

Experimental:

The coverslips were transferred to a 15 ml experimental chamber mounted on an inverted microscope (IMT-2, Olympus) design supplied by Nomarski. Neurons were continuously superfused with extracellular saline at a rate of 2.5 ml / min. After generation of the giga sealed (1-5GW, success rate &gt; 90%), the whole cell pool was obtained by suction.

Cells were maintained at a maintenance voltage of -60 mV and at the start of each experiment, current was continuously measured for at least 30 seconds to ensure stable current leakage. Solutions containing AMPA were fed into the chamber through a weight-driven custom-made feed line, the tip of which was placed approximately 50 µm from the cell. The application started when the pipe connected to the inlet pipe was pressed by a valve controlled by Pulse software. AMPA (30 μΜ) was applied for 1 second every 45 seconds. Upon receiving repeatable amplitude responses, the compound to be tested was included in both the chamber and the solution containing AMPA. The compound was present until responses from new repeat amplitudes were received.

The sampling interval in all experiments was 310 seconds. All experiments were performed at room temperature (20-25 ° C).

Substances

Pregnant (9 days) NMRO mice were obtained from the Bomhlotgaard Breeding and Research Center, Ry, Denmark.

Horse serum, N2 supplement and culture medium were purchased from Life Technologies (GIBCO), Roskilde, Denmark.

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) was synthesized in NeuroSearch A / S. The tetrodotoxin was purchased from Alomone Labs, Jerusalem, Israel, and bikuculinine iodomethylate from RBI, MA, USA. Sucrose was from Fluka Chemie, Buchs, Switzerland. All other reagents were from SIGMA, USA.

The results

The results are shown in FIG. 3-7.

Compounds 56 (Figure 3), 63 (Figure 4), 111 (Figure 6), 114 (Figure 7), and 115 (Figure 5) potentiated the flux induced by the addition of 30 μΜ AMPA. An example for each compound is given below. Potentiation in any case is seen to be reversible, even if the effect of Compounds 56 and 63 persists for several minutes after compound wash. The time between AMPA stimulations was 45 seconds.

Bars in the graph: 63: 200 pA / 2 sec; 56: 500 pA / 5 sec; 115: 50 pA / 2 sec; 111: 400 pA / 3 sec; 114:

pA / sec. In the above experiments the compound concentration was 3 μΜ (56, 63 and 114) or 10 μΜ (111 and 115). The effect of the compounds was concentration-dependent as shown in the example of compound 114 below (bar graph 200 pA / 5 sec) (Fig. 8).

references

Drejer J., Honore T. and Schousboe A. (1987) Excitatory amino acid-induced release of ³ H-GABA from cultured mouse cerebral cortex interneurons. J. Neurosci. 7: 2910-2916.

Hamill O.P., Marty A., Neher E., Sakmann B. and Sigworth F.J. (1981) Improved patch-clamp techniques for high-resolution current recording from cell and cell-free membrane patches. PlugersArch. 39: 85-100.

Mathiesen C., Varming T. and Jensen L.H. (1998) In vivo and in vitro evaluation of AMPA receptor antagonists in rat hippocampal neurones and cultured mouse cortical neurones. Eur. J. Pharmacol. 353: 159-157.

Ionophoretic application

Purpose

Evaluation of the in vivo effects of AMPA positive modulators (PAM) on the activity of AMPA-induced pulses in the rat hippocampus.

principle

Simple hippocampal neuron pulse activity is strongly influenced by excitatory input, and ionophoretic application of AMPA induces pulse activity in vivo in a dose-dependent manner (Mathiesen et al. 1998). AMPA-induced pulse activity is inhibited by intravenous (i.v.) administration of a wide variety of AMPA receptor antagonists (Mathiesen et al. 1998), indicating that excitation is primarily mediated through AMPA receptors. PAM potentiates activation of the AMPA receptor in vitro, and when this mechanism also works in vivo, it should i.v. injection of PAM to increase the activity of AMPA-induced pulses. Thus, the aim of this study was to test the in vivo effect of a group of in vitro active PAMs. This was done by studying their ability to increase the activity of AMPA-induced pulses after i.v. application.

preparation

Experiments were performed on male Wistar rats (M & B, Denmark) weighing 280-380 g, confined in two cages with free access to food and drink. Rats were anesthetized with mebumal (50 mg kg -1) ip and the femoral artery was catheterized to monitor blood pressure and vein for intravenous drug injection and regular injections of 0.9% NaCl (0.5-1.0 mL h ^-1 ) and mebumal (5-10 mg h ^-1 ). When the rat responded to compression of the hindpaw, another anesthetic was administered. Trachea was cannulated and the rats were placed in a stereotaxic skeleton and ventilated by a rodent fan (Ugo Basile, Comerio-Varese, Italy). The internal body temperature was maintained at 37.5 ° C using an electric pad. The left and dorsal parts of the parietal bone were removed by craniotomy, and the hard diapers were pulled together by exposing the vascular diaper and the lower lying brain, covered with 0.9% NaCl.

The compounds / reagents

AMPA (Sigma, USA) was dissolved to 10 mM in 0.2 M NaCl. NMDA (Sigma, USA) was dissolved to 100 mM in 100 mM NaCl. Both solutions were adjusted to pH 7.5 - 8.0 with NaOH. COMPOUND 61 was dissolved in 200 mM CH 3 SO 3 * Na ⁺ to a concentration of 10 mM for iontophoretic applications (pH 5.7) and in isotonic glucose (278 mM) for iv administration. Cyclotiazide, COMPOUND 63, COMPOUND 56, COMPOUND 56, COMPOUND 115 and COMPOUND 114 were dissolved in 5% chremophor solution to a concentration of 5 mg ml ^-1 .

parameters

The induced neuronal activity of the pulses was analyzed online by a computer, storing individual pulse values and event time. Neuronal pulse activity (number of action potentials with ‘) was monitored in the pulse rate histogram along with indicators for AMPA, COMPOUND 61, and transmitter application.

Approach

Extracellular recordings of individual hippocampal neuron pulses were obtained using five-cylinder glass electrodes (5B120F-6, World Precision Instruments Inc., Sarasota, Florida, USA) with a 10-12 µm diameter tip. The individual cylinders were filled with 5 M NaCl (recorders) 400 mM NaCl (equalizing choke), 10 mM COMPOUND 61 in 200 mM CH 3 SO 3 * Na ⁺ (pH 4.7), 200 mM CH 3 SO 3 Na ⁺ (pH 4.7, transporter), and the last cylinder was filled with AMPA.

Experiments were performed on hippocampal neurons (A = 5.5 - 6.5 mm, L = 1.5 - 2.0 mm, H = 2.0 - 3.0 mm, according to Paxinos and Watson, 1986). Neuronal pulse activity was induced by ionophoretic application of AMPA for periods of 10 to 15 seconds at 1.5 minute intervals. Individual neuron pulse activity was amplified 500 times with the 0.3 and 3 kHz wavelength bands (CyberAmp 320 with Al 402 x 50 with smart probe, Axon Instruments, California, USA). On-line and off-line analyzes were performed using the Spike2 program using a 140 \ plus interface (Cambridge Electronic Design Limited, England). The calculation program also recorded mean arterial blood pressure and monitored and controlled iontophoretic application.

AMPA was expelled into the hippocampus in standard cycles of 100-105 seconds. If the neuronal responses are still (when the AMPA responses do not deviate by more than 10%, measured at 10 second intervals) for at least 30 minutes, then a single dose of either cyclotiazide, COMPOUNDS 63, COMPOUNDS 56, COMPOUNDS 115, COMPOUNDS 61 or COMPOUNDS 114 (10 mg kg ^-1 ) injected into the femoral vein. Recording of neuronal pulse activity was continued for at least 45 minutes after intravenous injection. PAM reactivity was tested by microionophoretic application of COMPOUND 61 (20 nA, Fig.).

The results

Fig. 8 shows that the iontophoretic application of COMPOUND 61 increases the activity of pulses induced by AMPA, since the transmitter does not affect the pulse activity induced. Intravenous application of cyclotiazide (10 mg kg ^-1 ) does not increase the activity of AMPA-induced pulses.

Fig. 9. Ionophoretic application of COMPOUND 61 increases pulse activity of individual neurons induced by the combined AMPA.

Fig. 10. Cyclotiazide (10 mg kg ^-1 iv) does not affect the activity of AMPA-induced hippocampus impulses. The shaded box above the AMPA1 write line indicates the application time (1500 s after the start of recording).

The in vivo effects of PAM on the activity of AMPA-induced pulses were dependent on the level of pulse control activity. COMPOUND 63 increases small AMPA responses due to low AMPA stimulation intensity but has only a marginal effect on large AMPA responses due to high AMPA stimulation intensity (Fig. 11) Initial inhibition of AMPA responses and onset of increase occurs from 15 to 30 minutes after iv administration (Fig. 11). 11). The figure shows an increase in AMPA responses by COMPOUND 56 (10 mg kg ^-1 ). The onset appears approximately 10 minutes after application (Fig. 12).

Fig. 11. COMPOUND 63 (10 mg kg ^-1 iv) increases low AMPA response intensity (12 nA) but has only a marginal effect on high AMPA response intensity (17 nA). 1500 mg from the beginning of the recording 10 mg kg -1 COMPOUND 63 was applied. The injection time is indicated by a shaded box above the AMPA2 writing line.

Fig. 12. COMPOUND 56 (10 mg kg ^-1 iv) increases the activity of AMPA-induced pulses. The compound is injected 1250 s after the start of the recording. The injection time is indicated by a shaded box above the AMPA entry line.

Fig. 13. Shows an example of an increase in AMPA pulse activity following iv administration of COMPOUND 115 (10 mg kg ^-1 ). Effect started 2 min. after iv administration and lasted more than 2 hours. COMPOUND 61 (10 mg kg ^-1 ) also increases AMPA responses in the hippocampus. A 3-fold increase in the activity of the Compound 61-induced AMPA pulses begins 20 minutes after administration and lasts longer than 2 hours (Fig. 14). COMPOUND 114 (10 mg kg ^-1 ) induces a 10-fold increase in AMPA responses, the control level of AMPA responses is low (from 21 to 209 pulses- ¹ responses, moderate response, Fig. 15), while only a minor increase with a higher increase is observed. control response (from 124 to 204 pulses ¹ , Fig. 16).

Fig. 13. COMPOUND 115 (10 mg kg ^-1 iv) increases the activity of AMPA-induced impulses in the hippocampus. The shaded box indicates the time at iv injection, 1990 s after the start of the recording. The effect of COMPOUND 115 lasted longer than 2 hours.

Fig. Compound 61 increases the AMPA responses in the hippocampus. The compound (10 mg kg ^-1 ) is administered 1000 s after the start of the recording (application time is indicated by a shaded box above the writing line). The effect of COMPOUND 61 lasted longer than 2.5 hours.

Fig. 15. COMPOUND 114 (10 mg kg ^-1 iv) increases the activity of AMPA-induced pulses. The compound (10 mg kg ^-1 ) is administered 1730 s after the start of the recording, indicated by a shaded box above the AMPA entry line.

Fig. 16. COMPOUND 114 (10 mg kg ´) approximately doubles the AMPA responses. The compound is administered 3900 s after the start of the recording, which is indicated by a shaded box above the AMPA entry line.

The results show that cyclotiazide shows no in vivo effects after i.v. application. However, COMPOUND 63, COMPOUND 56, COMPOUND 115, COMPOUND 61, and COMPOUND 114 increase the activity of the AMPA-induced pulses in an activity-dependent manner.

references

Mathiesen, C., Varming, T. & Jensen, L.H. (1998). In vivo and in vitro evaluation of AMPA receptor antagonists in rat hippocampal neurones and cultured mouse cortical neurones. European Journal of Pharmacology 353, 159-167.

Paxinos, G. & Watson, C. (1986). The rat brain in sierotaxic coordinates. Second Edition.

Passive deprivation

Purpose: To test the pharmacological effect of compounds on associative memory.

Principle: Mice are placed in a light chamber with access to a dark chamber. When they enter the dark chamber they receive an electric shock to the foot (0.4 mA). After 24 hours, the association is tested to risk an unpleasant electric shock to the foot by re-entering the dark chamber.

Animals: Female NMRI mice (Bomholdgaard, DK) weighing 22-25g were used. Mice were stored in Macrolon plastic cages with free access to food (Altromin, DK) and tap water. Mice were allowed to adjust to room temperature for at least 3 days prior to testing (light 7: 00 / dark 19:00).

Apparatus: Passive deprivation devices consisted of modular test chambers (ENV-307, MED-Associates, US). Light and dark chambers consisted of plexiglass boxes of uniform size (15x17x13 cm; width x length x depth) with metal grid floors. The movable guillotine door was placed in an opening connecting the two chambers. A manual scrambler network (ENV-412, MED-Associates, US) was used to receive a non-0.4 mA foot electric shock.

Parameters: Input latency (sec) to re-enter the dark chamber was measured.

Procedure: Mice were pre-conditioned (typically 30 minutes) prior to preparation with the test compound.

Preparation: One mouse is placed in the light chamber and the guillotine door in the dark chamber is open. When the mouse enters the dark chamber with all four paws, it receives one elect. paw shock (0.4 mA) and removed to its home cage. Test. After 24 hours, the mice re-enter the light chamber and the waiting time to enter the dark chamber is measured with a time limit of 2 minutes. If the mouse does not enter the dark chamber for a limited time (2 minutes), the mouse is assigned a waiting time of 2 minutes.

Carrier: 10% Tween 80.

Dose volume: 10 ml / kg

N = 10;

The results; The mean (± SEM) entry latency for each group is shown.

The results in FIG. 17 show the effect of various concentrations of Compound 61 on memory improvement;

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 and FIG. 2 show the potentiation of AMPA induced [ ³ H] GABA release from cultured cortical neurons of the compounds of the invention.

Fig. 3-8 show experiments to artificially maintain the membrane potential at a certain level on the compounds of the invention. Compounds 56 (Fig. 3), 63 (Fig. 4), 111 (Fig. 6), 114 (Fig. 7) and 115 (Fig. 5) potentiate the flux induced by the application of 30 μΜ of AMPA.

Fig. 8 shows the concentration-dependent effect of the compounds of the invention (114).

Fig. 9-16 are ionophoresis experiments.

Fig. 9. Ionophoretic application of COMPOUND 61 and ionophoretic application of transporter;

Fig. 10. Cyclotiazide is administered in the hippocampus.

Fig. 11 Application of COMPOUND 63;

Fig. 12. Application of COMPOUND 56.

Fig. 13. Application of COMPOUND 115;

Fig. 13. COMPOUND 115 in the hippocampus.

Fig. 14. COMPOUND 61 in the hippocampus.

Fig. 15. COMPOUND 114;

Fig. 16. COMPOUND 114;

Fig. 17. Passive deprivation assay for Compound 61.

DETAILED DESCRIPTION OF THE INVENTION

General synthesis methods

Method A

General sulfamoylation

i. ClSO3H-H. HMR'j

The compound (32.5 mmol) to be chlorosulfonated was dissolved in chlorosulfonic acid (75 mL) and heated in an oil bath at 110 ° C until TLC indicated completion of the reaction *. The reaction mixture was poured onto ice and the precipitate formed was collected by filtration. The isolated solid was washed with a small amount of water and dried on a filter. The solid was dissolved in dry THF (200 mL) and excess amine (230 mmol) was added and the reaction was allowed to stir at room temperature overnight. The reaction mixture was evaporated to dryness, then stirred with water to give a solid which was isolated by filtration and washed with EtOAc on the filter. Further purification is possible either by column chromatography or by recrystallization from EtOAc / hexanes. The yields are mostly: 60-90%.

* [A small aliquot was removed, added to ice in a tube, neutralized with NA2CO3 and then extracted with EtOAc. The aqueous phase is removed and piperidine (xs) is added to the organic phase and allowed to stand for some time. This small reaction mixture was scaled to TLC].

Method B o -Sulfamoylation of anilines *

NHR

I. CISQjNCO

H. AIC ^ δ

R

To a stirred solution of the aminobenzene derivative (250 mmol) in nitroethane or nitromethane (100 mL) at -50 ° C was added a solution of CISO 2 NCO (275 mmol) in nitroethane or nitromethane (75 mL) such that the reaction temperature did not exceed -30 ° C. The cooling bath was removed and the thick reaction mixture was warmed to 0 ° C. Solid AlCl 3 (300 mmol) was added in one portion. The clear brown reaction mixture was heated in an oil bath at 120 ° C for 20 minutes, then cooled to room temperature and poured into a beaker with stirred ice water (1 L). The precipitate formed is isolated by filtration *. The urea intermediate (98 mmol) was suspended in a mixture of dioxane (250 mL) and 6 M H 2 SO 4 (or concentrated HCl only) (500 mL) and heated to reflux overnight. The reaction mixture was cooled to room temperature, filtered and the dioxane was removed from the filtrate by evaporation. The aqueous residue was neutralized to pH = 7-8 using 4 M NaOH. The precipitate formed is isolated by filtration and washed with water and EtOAc. * Yields range from 10% to 75%. * See also Girard Y., Atkinson J.G. and Rokach J., J. Chem. Soc., Perkin I, (1979) 1043.

* [Meta-substituted anilines give a mixture of two possible isomers that at the intermediate urea stage can be separated by crystallization from MeOH or at the final product by crystallization from EtOAc / hexanes or by chromatography.]

Method C

Application of a trifluoroacetyl protecting group

NH 1 R

PPA

N CF.

I

R

To a stirred solution of the 2-aminobenzenesulfonamide derivative (27 mmol) in dry THF (75 mL) at 0 ° C was added trifluoroacetic anhydride such that the reaction mixture did not exceed +10 ° C. The reaction mixture was stirred at room temperature until all of the starting material had reacted. The reaction mixture was evaporated to dryness, stirred with water, filtered and washed with hexanes. PPA (250 g) was added to the isolated solid and heated in an oil bath at 140 ° C for 2.5 hours. The reaction mixture was cooled to 60-70 ° C and poured into a mechanically stirred ice water solution. The precipitate formed is isolated by filtration and air dried. The overall yields are mostly between 85-90%.

Method D

Removal of the trifluoroacetyl protecting group

A stirred solution of the trifluoroacetyl protected compound (3.6 mmol) dissolved in 1 M KOH (30 mL) was heated at 80 ° C for 1 hour. The reaction mixture was cooled to room temperature and the pH was adjusted to 7 using concentrated HCl (aq). The reaction mixture was cooled to 0 ° C and filtered. The isolated solid was washed with water and air dried. The yields are generally in the range of 85-95%.

Method E

Formation of dihydrobenzothiadiazine-1,1-dioxide from 2-aminobenzenesulfonamides

To a stirred solution of the 2-aminobenzenesulfonamide derivative (148 mmol), triethylamine (150 mmol), 4- (N, N-dimethylamino) pyridine (7.5 mmol in 600 mL THF at 5 ° C) was added carboxylic acid chloride. The crude was stirred with water and filtered, and the isolated solid was dissolved in 1 M NaOH (250 mL) and heated at 80 ° C for 3 hours. room temperature and pH are adjusted to 7 using concentrated HCl The precipitate formed is isolated and recrystallized from i -PrOH, with total yields ranging from 80-90%.

Method F

Reduction of dihydrobenzothiadiazines-1,1-dioxide to tetrahydrobenzo-thiadiazines-1,1-dioxides

(H)

DIBALH

To a stirred solution of dihydrobenzothiadiazine-1,1-dioxide (19.4 mmol) in dry THF (200 mL) at -70 ° C was added a solution of DIBALH 1.5 M in toluene (33 mL; 50 mmol). The reaction mixture was allowed to stir overnight while the temperature was slowly raised from -70 ° C to -15 ° C *. To the reaction mixture was added water (10 mL), 1 M NaOH (5 mL). The reaction mixture was then warmed to room temperature and extracted with EtOAc. The combined organic fractions were dried over MgSO ₄ and evaporated to dryness. In some cases, the product is further purified by column chromatography. The yields range from 45 to 85%.

* [When the temperature is not carefully controlled, the aminal product is further reduced to the ring-opened alkylamine].

Method G

Formation of tetrahydrobenzothiadiazines-1,1-dioxides from 2-aminobenzenesulfonamides

R

R'-CHO. MgSO ₄ , Δ

O O

The NH _ ^ R · N · ^R V

A stirred solution of the 2-aminobenzenesulfonamide derivative (7 mmol), aldehyde (10 mmol) and MgSO ₄ (20 mmol) in dry THF or dry dioxane (40 mL) was refluxed under N ₂ until TLC indicated complete reaction of the 2-aminobenzenesulfonamide derivative (mostly 12-36 hours). The reaction mixture is filtered, and the precipitate is washed with THF or dioxane. The filtrate was evaporated to dryness, water was added and extracted with EtOAc. The combined organic fractions were dried over MgSO ₄ and evaporated to dryness. Column chromatography (EtOAc / hexanes) gave pure product. The yields range from 25-75%.

Method H

Formation of substituted aryl or hetaryl using catalyzed cross coupling

Pd k’la ^ -Pd additives

4. Metalova arý / hetaren ----------------- «'X b Br. I

Suzuki Couplings ·. A mixed mixture of aryl halide (2 mmol), aryl or hetaryl boronic acid, boronic ester or dialkyl borate (6 mmol), K 2 CO 3 (10 mmol), Pd (PPh 3) 4 (30 mg), 1,3-propanediol (10 mmol), dimethoxyethane (50 mL) and H ₂ O (25 mL) under N ₂ was heated at 70 ° C for 3 h. The reaction mixture was cooled to room temperature. Additional water was added and the reaction mixture was extracted with EtOAc. The combined organic fractions were dried over MgSO 4 and evaporated to dryness. Column chromatography gives pure product. The yields range from 40-100%.

Method I

Formation of compounds having triazolyl substitution

Sonogashira coupling: a mixture of aryl iodide or aryl bromide (2 mmol); acetylene (10 mmol); Pd (PPIi3) 2 Cl2 (140 mg; 0.2 mmol); Cul (40 mg; 0.1 mmol) and triethylamine (10 mL) under N 2 are stirred at room temperature overnight (for aryl bromides prolonged heating at 60 ° C is necessary). THF was added and the reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. Column chromatography yields an ethynylated arene. The yields range from 40-53% for aryl bromides to 97% for aryl iodides.

Detrimethylsilylation for R '= TMS: To a solution of the ethynylated arene (1.7 mmol) in MeOH (8 mL) was added 1 M KOH in MeOH (2 mL; 2 mmol) and stirred at room temperature for 2 hours. The reaction mixture was diluted with THF, adsorbed onto silica gel and chromatographed to afford desilylated ethynylarene. The yields range from 61% to 73%.

Formation of triazoles: Ethinylarene (0.7 mmol) and TMS-N ₃ (2 mL; 15 mmol) were heated at 170 ° C in an ampoule for 50 hours. The reaction mixture is cooled to room temperature and evaporated to near dryness (caution! Evaporation to dryness may lead to explosion due to the presence of HN ₃ ) and MeOH is added. The reaction mixture was stirred for 1 hour (to remove the TMS group in the TMS-triazole), then adsorbed onto silica gel and purified by chromatography. The yields range from 20 72%.

Syntheses of individual compounds

Compound 1

2-Cyclohexyl-4-oxo-l, 2,3,4-tetrahydroquinazoline

The anthranilamide is treated by Method G (using cyclohexanecarboxaldehyde). M.p. 172-174 ° C.

Compound 2

2-phenyl-4-oxo-1,2,3,4-tetrahydroquinazolin

The anthranilamide is treated by Method G (using benzaldehyde). Melting point 221-222 ° C.

Compound 3

2-Methyl-3,4-dihydro-1,3-benzoxazin-4-one

2-Hydroxybenzamide is treated by Method G (using paraldehyde). Melting point 124126 ° C.

Compound 4

2-phenyl-3,4-dihydro-1,3-benzoxazin-4-one

2-Hydroxybenzamide is treated by Method G (using benzaldehyde). Melting point 157160 ° C.

Compound 5

3-Bicyclo [2.2.1] hept-5'-en-2'-yl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

The 2-aminobenzenesulfonamide is treated according to Method G (using an endo / exo racemic mixture of 2-borbornylenecarboxaldehyde). Mp 206-209 ° C.

Compound 6

3-Phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

The 2-aminobenzenesulfonamide is treated by Method G (using benzaldehyde). Melting point 125.5-128.5 ° C

Compound 7 1,2,3,5,10,10a-Hexahydrobenzo [e] pyrrolo [1,2-b] -1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide was used as the starting material for the following: work-up procedure: method E (using 4-chlorobutanoyl chloride. The reaction mixture was not subjected to NaOH-catalyzed ring closure, but dissolved in H 2 SO 4 and heated at 100 ° C for 72 hours and precipitated on ice). Mp 149-154 ° C.

Compound 8

2-ethyl-2-methyl-3,4-dihydro-1,3-benzoxazin-4-one

The 2-hydroxybenzamide is treated by Method G (using 2-butanone). Mp 76-78 ° C.

Compound 9

3- Cyclohexyl-6- (2-methoxyphenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Bromoaniline is treated according to Method B (see Compound 121) to give to obtain 4-bromo-2-aminobenzenesulfonamide.

A mixture of 4-bromo-2-aminobenzenesulfonamide (140 mg, 0.56 mmol), 2-methoxyphenylboronic acid (106 mg, 0.70 mmol), Pd (PPh 3) ₂ Cl ₂ (20 mg, 5 mol%) in 1, 2-dimethoxyethane (30 mL) and Na ₂ CO 3 (2M, 3 mL, 6 mmol) were refluxed under N ₂ for 4 hours. The solvents were removed under reduced pressure and the residue was treated with saturated NaHCO 3 (20 mL) and extracted with EtOAc (2 x 40 mL). The organic layer was washed with brine (20 mL), dried (Na ₂ SO 4), and the solvent was removed under reduced pressure. The product was purified by flash column chromatography on silica gel using EtOAc: n-hexane (1: 1, v / v) as eluent to give 155 mg (100%) of 2-amino-4- (2-methoxyphenyl) -benzenesulfonamide as colorless powder. The product is further processed by Method G (using cyclohexanecarboxaldehyde). Melting point 219-221 ° C.

Compound 10

3-Cyclohexyl-6- (2-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Aminophenylboronic acid hemisulfate (5.58 g, 30 mmol), 2-bromopyridine (2.7 mL, 28 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (100 mg, 0.5 mol%), 2M K ₂ CO 3 (50 mL) is refluxed in 1,2-dimethoxyethane (50 mL) for 24 hours under N ₂ . The mixture was diluted with CH ₂ Cl ₂ (100 mL) and washed with saturated NaHCO ₃ (50 mL). The organic layer was dried (Na ₂ SO ₄ ) and the solvent was removed under reduced pressure. Flash chromatography with CH ₂ Cl ₂ as eluent gave 3- (2-pyridyl) aniline as a yellow oil, 1.0 g (21%). The 3- (2-pyridyl) aniline is treated by Method B and Method G (using cyclohexanecarboxaldehyde). Mp 213-216 ° C.

Compound 11

3-Cyclohexyl-6- (3-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

3-Bromo-aniline is treated by Method B (see Compound 121) to give 4-bromo-2-aminobenzenesulfonamide.

A mixture of 4-bromo-2-aminobenzenesulfonamide (250 mg, 1.0 mmol), diethyl 3-pyridylborane (225 mg, 1.5 mmol), Pd (PPh 3) ₂ Cl ₂ (35 mg, 5 mol%) in 1 , 2-dimethoxyethane (30 mL) and Na ₂ CO ₃ (2M, 3 mL, 6 mmol) were refluxed under N ₂ for 4 hours. The solvents were removed under reduced pressure and the residue was treated with saturated NaHCO 3 (20 mL) and extracted with EtOAc (2 x 40 mL). The organic layer was washed with brine (20 mL), dried (Na ₂ SO ₄ ), and the solvent was removed under reduced pressure. The product was purified by flash column chromatography on silica gel using EtOAc: n-hexane (1: 1, v / v) as eluent to give 240 mg (96%).

2-amino-4- (3-pyridyl) -benzenesulfonamide as a colorless powder. The product is further processed by Method G (using cyclohexanecarboxaldehyde). Mp 240-243 ° C.

Compound 12

3-Cyclohexyl-7- (1-hydroxyethyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-5- (1-hydroxyethyl) benzenesulfonamide: 5- Acetyl-2-aminobenzenesulfonamide (see Compound 13) (0.95 g, 4.4 mmol) was suspended in 96% EtOH (50 mL) and NaBH ₄ (0.46 g, 1.2 mmol) was added in one portion. The mixture was stirred at 25 ° C for 4 hours and filtered through Celite, and the solvent was removed under reduced pressure. The residue was treated with saturated NaHCO ₃ (50 mL) and the ex70 was triturated with EtOAc (2 x 50 mL), dried (Na ₂ SO 4) and evaporated to dryness. Flash chromatography EtOAc: n-hexane: Et ₃ N (200: 100: 4, v / vv) as eluent gave 0.35 g (37%) of 2-amino-5- (1-hydroxyethyl) benzenesulfonamide as a light brown powder. Melting point 160-162 ° C.

Compound 13

3-Cyclohexyl-7-acetyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

To a solution of ethyl vinyl ether (5.8 mL, 60 mmol) in dry THF (50 mL) at -78 ° C was added tert-BuLi (1.7 M in pentane, 25 mL, 40 mmol) and the yellow mixture was stirred for 1 hour at -78 ° C. The cooling bath was removed and the mixture was slowly warmed to 0 ° C and stirred for an additional 30 min. The mixture was recooled to -78 ° C and a solution of ZnCl ₂ (2 M in THF, 20 mL, 40 mmol) was slowly added and the cooling bath was removed and heated to 20 ° C. Add 5-iodo-2-aminobenzenesulfonamide (see compound 37) (1.8 g, 6 mmol) and Pd (PPh ₃ ) ₄ (0.2 g, 3 mol%) and reflux for 6 h. THF was evaporated and the residue was boiled in 1 M hydrochloric acid (30 mL) and MeOH (30 mL) for 30 min. Add EDTA (14.6 g, 50 mmol) and basify easily (pH = 8-9) with 1 M NaOH followed by extraction with EtOAc (3 x 150 mL), drying (Na ₂ SO ₄ ) and evaporation of the solvent to give a brown solid . Trituration with n-hexanes afforded 0.95 g (74%) of 5-acetyl-2-aminobenzenesulfonamide as an off-white powder. The product is further processed by Method G (using cyclohexanecarboxaidehyde). Mp 224-226 ° C (dec.).

Compound 14

3-Cyclohexyl-7- (1-hydroxyiminoethyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

To a suspension of 5-acetyl-2-aminobenzenesulfonamide (see compound 13) (0.45 g, 2.1 mmol) in 96% EtOH (40 mL) was added H ₂ NOH * HCl (0.28 g, 4 mmol) and 2 M NaOH (2 mL). The mixture was boiled for 2 hours and the solvent was evaporated. The residue was triturated with water (25 mL) and the product was filtered off and dried to give 0.39 g (81%) of 2-amino-5- (1-hydroxyiminoethyl) benzenesulfonamide as a yellow powder. The product is further processed by Method G (using cyclohexanecarboxaldehyde). Mp 230-233 ° C.

Compound 15

3-Cyclohexyl-7-carbamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

A mixture of 5-cyano-2-aminobenzenesulfonamide (see compound 37) (2 g, 10 mmol), concentrated

H ₂ SO 4 (4 mL) and absolute EtOH (4 mL) were heated at 80 ° C for 5 hours and overnight at 50 ° C. The reaction mixture was poured onto ice and extracted with EtOAc (1x) *. The organic phase was removed and the aqueous phase was neutralized with Na ₂ CO ₃ and extracted with EtOAc (3x). The organic phase is evaporated to dryness and subjected to column chromatography (EtOAc / hexane = 2/1) to give 200 mg (9%) of the carboxamide. The carboxamide is further processed by Method G (using cyclohexanecarboxaldehyde). Mp 235-237 ° C.

* [First extraction contains nitrile (starting material) and others contain by-product]

Compound 16

3-Cyclohexyl-7-ethoxycarbonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

A mixture of 5-cyano-2-aminobenzenesulfonamide (see compound 37) (3 g, 15 mmol), concentrated H 2 SO 4 (5 mL) and absolute EtOH (15 mL) was heated at 80 ° C overnight. The reaction mixture was poured onto ice. The precipitate formed is isolated by filtration. The precipitate was washed with EtOAc to give 2.01 g (55%) of pure ethyl ester. The ester is further processed by Method G (using cyclohexanecarboxaldehyde). Mp 234-236 ° C.

Compound 17

3-Cyclohexyl-7-cyano-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Cyano-2-aminobenzenesulfonamide (see compound 37) is treated by Method G (using cyclohexanecarboxaldehyde ). Mp 234-237 ° C.

Compound 18

3-Bicyclo [2.2.1] hept-5'-en-2'-yl-7-phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5 -Bromo-2-aminobenzenesulfonamide: To a stirred solution of 2-aminobenzenesulfonamide (1.72 g;

mmol) in AcOH (15 mL) was added a solution of Br ₂ (0.55 mL; 10.5 mmol) in AcOH (5 mL). The reaction mixture was poured into H 2 O (100 mL) and filtered. The isolated solid was adsorbed onto silica gel and flash chromatographed to give 1.428 g (57%) of the product (and 650 mg (20%) of the 3,5-dibromo derivative).

3-Bicyclo [2.2.1] hept-5'-en-2'-yl-7-phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide ( 18): 5-Bromo-2-aminobenzenesulfonamide is treated by Method H (using phenylboronic acid) and Method G (using endo / exo racemic bicyclo [2.2.1] hept-5-ene-2-carboxaldehyde). Mp 190.5-195.0 ° C.

Compound 19

3-Cyclohexyl-7- (2'-acetamidophenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Nitrophenylboronic acid: A solution of phenylboronic acid (10 g; 82 mmol) in acetic anhydride (100 mL) at -15 ° C was added fuming HNO3 (5 mL; 120 mmol) over 30 min to maintain the reaction temperature. below -10 ° C. The reaction mixture was warmed to room temperature. Pour the reaction mixture on ice and concentrate to 50 mL. The residue was then re-evaporated 5 times from an additional 100 mL of H ₂ O and finally filtered to give 7.1 g of crude product as a mixture of isomers. Column chromatography (CH 2 Cl 2 / EtOH ³ 10 / 0.5) gave 4.8 g (35%) of the pure product as an oil.

2-Acetamidophenylboronic acid: A mixture of 2-nitrophenylboronic acid (2 g; 12 mmol) and 5% Pd / C (100 mg) in EtOH (100 mL) was hydrogenated at 1 bar until TLC showed complete reaction of the starting material. The reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was washed with hexanes and filtered to give 900 mg (55%) of 2-aminophenylboronic acid. A mixture of 2-aminophenylboronic acid (900 mg; 6.6 mmol), triethylamine (0.57 mL; 7 mmol) and acetyl chloride (0.5 mL; 7 mmol) was stirred at reflux temperature for 1 hour. The reaction mixture was evaporated to dryness, stirred with H 2 O and filtered to give 750 mg (63%) of the product.

3-Cyclohexyl-7- ^(2, -acetamidofenyl) -l, 2,3,4-tetrahydro-7.2.4-benzothiadiazine-l, l-dioxide (19): 5-lodo-2-aminobenzenesulfonamide (see compound 37) was treated by Method H (using 2-acetamidophenylboronic acid) and Method G (using cyclohexanecarboxaldehyde). Mp 245-249 ° C.

Compound 20

3-Cyclohexyl-7- (2'-nitrophenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Iodo-2-aminobenzenesulfonamide (see compound 37) is treated with method H (using 2-nitrophenylboronic acid (see compound 19)) and method G (using cyclohexanecarboxaldehyde) Melting point 204-207 ° C.

Compound 21

3-Cyclohexyl-7- (2'-methoxyphenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

5-Iodo-2-aminobenzenesulfonamide (see compound 37) is treated by Method H (using 2-methoxyphenylboronic acid) and Method G (using cyclohexanecarboxaldehyde). Melting point 219-222 ° C

Compound 22

3-Cyclohexyl-7- (2'-methoxy-4'-trifluoromethylphenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

4- Trifluoromethylanisole: Sodium (12.78 g; 555 mmol) was added to dry MeOH (100 mL). After gas evolution ceased, the reaction mixture was evaporated to dryness and dry NMP (250 mL), Cu (s) (35.3; 555 mmol) and 4-bromo-trifluoromethylbenzene (25 g; 111 mmol) were added. The reaction mixture was heated at 130 ° C for 4 hours, cooled to room temperature and filtered. Water (500 mL) was added to the filtrate and extracted with Et ₂ O (2 x 200 mL). The combined organic fractions were washed with H ₂ O (2 x 100 mL), dried (MgSO 4) and evaporated to dryness. Column chromatography gave 8.05 g (41%) of the product.

2-Methoxy-5-trifluoromethylphenylboronic acid: To a solution of 4-trifluoromethylanisole (8 g; 45 mmol) in dry THF (80 mL) at -30 ° C under N ₂ is added a solution of 2.5 M nBuLi in hexane (20 mL). ml; 50 mmol). The reaction mixture was stirred for 1 hour at -30 ° C, then cooled to -70 ° C and B (O / -Pr) 3 (14.1 mL; 64 mmol) was added. The reaction mixture was allowed to warm slowly to room temperature overnight. 2 M HCl (40 mL) was added to the reaction mixture and the THF was evaporated. The aqueous residue was extracted with Et ₂ O (4x 20 mL) and the combined organic fractions were extracted with 1 M NaOH (5x 17 mL). The combined organic fractions were neutralized with 10 M HCl. The precipitate formed was collected by filtration and washed with 1 M HCl to give 8.1 g (81%) of the product.

3-Cyclohexyl-7- ^{(2'-methoxy-4-trifluoromethylphenyl)} -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (22):

5-Iodo-2-aminobenzenesulfonamide (see compound 37) is treated by Method H (using 2-methoxy-5-trifluoromethylphenylboronic acid) and Method G (using cyclohexanecarboxaldehyde). Mp 255-257 ° C.

Compound 23

3-Cyclohexyl-7- (2 ', 4'-dimethoxyphenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Iodo-2-aminobenzenesulfonamide (see compound 37 ) was treated with Method H (using 2,4-dimethoxyphenylboronic acid) and Method G (using cyclohexanecarboxaldehyde). Mp 208-213 ° C.

Compound 24

3-Cyclohexyl-7- (2 - ((N, N-dimethylsulfamoyl) phenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2- (N, N-Dimethylsulfamoyl) phenyl boronic acid: To a solution of benzenesulfonyl chloride (10 mL; 78 mmol) in THF (100 mL) is added a 40% solution of dimethylamine in H ₂ O (20 mL; 160 mmol) to the reaction temperature was kept below 50 ° C. The reaction mixture was stirred for 1 hour at room temperature. H ₂ O was added to the reaction mixture and THF was removed by evaporation. The precipitate formed was collected by filtration and dried to give 14 g (97%) of ΛζΝ-dimethylbenzenesulfonamide.

A solution of N-dimethylbenzenesulfonamide (9.25 g; 50 mmol) in dry Et ₂ O (150 mL) under N ₂ was cooled to -70 ° C and a solution of 2.5 M n-BuLi in hexane (24 mL) was added. 60 mmol) to maintain the reaction temperature below -60 ° C. Remove the cooling bath and slowly heat the reaction mixture to + 20 ° C. The reaction mixture was recooled to -70 ° C and B (O / -Pr) 3 (16.1 mL; 70 mmol) was added. The reaction mixture was allowed to cool and warm overnight, 1 M HCl (100 mL) was added and stirring was continued at room temperature for 1 h. The reaction mixture was then extracted with Et ₂ O (2 x 50 mL) and the combined organic fractions were extracted with 1 M NaOH (4 x 50 mL). The combined aqueous fractions were neutralized with 1 M HCl and extracted with Et ₂ O (4 x 100 mL). The combined organic fractions were dried (Na ₂ SO 4) and evaporated to dryness, washed with Et ₂ O / hexanes to give 3.4 g (30%) of the product.

3- Cyclohexyl-7- (2 '- (N ^' , N-dimethylsulfamoyl) phenyl) -1,2,3,4-tetrahydro-1,2,4-benzatiadiazine-1,1-dioxide (24): 5-Iodine The 2-aminobenzenesulfonamide (see compound 37) is treated by Method H (using 2- (N, N-dimethylsulfamoyl) phenylboronic acid) and Method G (using cyclohexanecarboxaldehyde). Melting point 290-300 ° C.

Compound 25

3-Cyclohexyl-7- (2'-chlorophenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Iodo-2-aminobenzenesulfonamide (see compound 37) is treated with method H (using 2-chlorophenylboronic acid) and method G (using cyclohexanecarboxaldehyde). Mp 233-236 ° C.

Compound 26

3-Cyclohexyl-7- (2'-fluorophenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

5-Iodo-2-aminobenzenesulfonamide (see compound 37) is treated by Method H (using 2-fluorophenylboronic acid) and Method G (using cyclohexanecarboxaldehyde). Mp 249-250 ° C.

Compound 27

3-Cyclohexyl-7- (3'-hydroxyphenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-hydroxyphenylboronic acid: To a stirred solution of 3-aminophenylboronic acid hemisulphate ( 6.2 g; 33.3 mmol) and 50% H 2 SO 4 (3.7 mL; 33.3 mmol) in H 2 O (100 mL) at -2 ° C are added NaNO 2 solution (2.5 g) over 1 hour 36.3 mmol) in H 2 O (20 mL). The reaction mixture was slowly added to a stirred solution of concentrated H 2 SO 4 (25 mL) in H 2 O (20 mL) at reflux. After the addition was complete, the reaction mixture was refluxed for 30 min, cooled, added charcoal, heated to reflux, cooled and filtered through Celite. The filtrate was saturated with NaCl (s), filtered, and extracted with Et 2 O (5 x 100 mL). The combined organic fractions were dried (Na 2 SO 4) and evaporated to dryness to give 4.3 g (94%) of the product.

3-Cyclohexyl-7- (3'-hydroxyphenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (27): 3-Hydroxyphenylboronic acid is treated according to method H and method G (using cyclohexanecarboxaldehyde). Mp 238-246 ° C.

Compound 28

3-Cyclohexyl-7- (2'-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

4- (2'-Pyridyl) -2-aminobenzenesulfonamide: A mixed mixture of 5-iodo-2-aminobenzenesulfonamide (1 g; 3.3 mmol), 2-tributylstannylpyridine (5.5 g; 15 mmol), Pd (PPh ₃ ) 4 ( 240 mg, 0.34 mmol) and Ag 2 O (780 mg; 3.36 mmol) in DMF (50 mL) under N 2 was heated at 100 ° C for 6 hours at room temperature overnight. The reaction mixture was evaporated to dryness and resuspended and stirred in phyO / EtOAc and finally filtered. The organic phase is isolated and the aqueous phase is extracted with EtOAc (2 x volume of water). The combined organic fractions were dried (Na 2 SO 4), evaporated to dryness and subjected to column chromatography to give 200 mg (24%) of the product.

3-Cyclohexyl-7- (2'-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,7-dioxide (28):

4- (2'-Pyridyl) -2-aminobenzenesulfonamide was treated by Method G (using cyclohexanecarboxaldehyde). Mp 222-224 ° C

Compound 29

3-Cyclohexyl-7- (3'-Pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

5-Iodo-2-aminobenzenesulfonamide (see compound 37) is treated by Method H (using diethyl 3-pyridylborane) and Method G (using cyclohexanecarboxaldehyde). Mp 240-242 ° C.

Compound 30

3-Cyclohexyl-7- (2'-pyrimidinyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

4 - ((2,2-Dimethylpropanoyl) amino) phenylboronic acid: To a solution of 4-bromo-N-pivaloylaniline (1.56 g, 6 mmol) in dry THF (50 mL) at -78 ° C is added tert- BuLi (1.5 M in pentane, 13.3 mL, 20 mmol) and the yellow mixture was stirred for 1 h at -78 ° C under N 2 atmosphere. The reaction was quenched with B (OCH 3) 3 (1.7 mL, 15 mmol) and stirred for an additional 1 hour at -78 ° C. The reaction mixture was then warmed to room temperature, hydrolyzed with 0.5 M hydrochloric acid (50 mL) and extracted with EtOAc (3 x 80 mL), dried (Na ₂ SO 4) and concentrated to about 40 mL. N-Hexane (120 mL) was added slowly and the colorless crystalline product was filtered and dried to give 1.26 g (95%).

N- (4- (2-pyrimidinyl) phenyl) -2,2-dimethylpropanamide:

A mixture of 4 - ((2,2-dimethylpropanoyl) amino) phenylboronic acid (2.0 g, 9 mmol), 2-chloropyrimidine (0.8 g, 7 mmol), Pd (PPh 3) 2 Cl 2 (100 mg, 2 mol%) Of 1,2-dimethoxyethane (40 mL) and Na 2 CO 3 (2 M, 7 mL, 14 mmol) was refluxed under N 2 for 5 h. The mixture was diluted with 10% Na ₂ CO 3 (20 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was dried (Na 2 SO 4) and the solvent was removed in vacuo. The crude product was recrystallized from MeOH / water (1: 1) to give 0.52 g (85%) of N (4- (2-pyrimidinyl) phenyl) -2,2-dimethylpropanamide as colorless crystals.

4- (2-Pyrimidinyl) aniline: N - (4- (2-pyrimidinyl) phenyl) -2,2-dimethylpropanamide (1.41 g, 5.48 mmol) was boiled in 6 M hydrochloric acid (40 mL) for 2 hours. The mixture was cooled and strongly basified with NaOH (s) and extracted with CH ₂ Cl ₂ (2 x 50 mL), dried (Na ₂ SO ₄ ) and the solvent removed in vacuo. Trituration with n-hexanes gave 0.83 g (88%) of 4- (2-pyrimidinyl) aniline as a light yellow powder. The product is further processed by Method B and Method G (using cyclohexanecarboxaldehyde). Mp 236-238 ° C.

Compound 31

3-Cyclohexyl-7- (2'-furyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

5-Iodo-2-aminobenzenesulfonamide (see compound 37) is treated by Method H (using furyl-2-boronic acid) and Method G (using cyclohexanecarboxaldehyde). Melting point 226-228 ° C.

Compound 32

3-Cyclohexyl-7- (3'-furyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

5-Iodo-2-aminobenzenesulfonamide (see compound 37) is treated by Method H (using furyl-3-boronic acid) and Method G (using cyclohexanecarboxaldehyde). Mp 204-205 ° C.

Compound 33

3-Cyclohexyl-7- (2'-thienyl) -l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide

5-Iodo-2-aminobenzenesulfonamide (see compound 37) is treated by Method H (using thienyl-2-boronic acid) and Method G (using cyclohexanecarboxaldehyde). Mp 234-236 ° C.

Compound 34

3-Cyclohexy 1-7- (1-methyl-1H-2-imidazolyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide) To the solution of 1-methylimidazole (4.8 mL, 60 mmol) in dry THF (120 mL) at -78 ° C was added n-BuLi (2.5 M in hexanes, 26 mL, 65 mmol) and the yellow mixture was stirred for 45 min at at -78 ° C. A solution of ZnCl ₂ (2 M in THF, 75 mL, 150 mmol) was slowly added and the cooling bath was removed. The colorless solution was stirred for an additional 10 min at 0 ° C. 5-Iodo-2-aminobenzenesulfonamide (see compound 37) (2.1 g, 7 mmol) and Pd (PPh ₃ ) 4 (0.5 g, 5 mol%) were added and the mixture was refluxed for 6 hours. THF was evaporated and the residue was treated with EDTA (53 g, 0.18 mol) and basified slightly (pH = 8-9) with 1 M NaOH, then extracted with EtOAc (3 x 150 mL), dried (Na ₂ SO 4) and evaporation of the solvent gave a dark oil. Flash chromatography with 5% MeOH in CH ₂ Cl ₂ as eluent gave 1.33 g (75%) of 2-amino-5- (1-methyl-1 H -imidazolyl) -1-benzenesulfonamide as colorless crystals. The product is further processed by Method G (using cyclohexanecarboxaldehyde). Mp> 250 ° C (dec.).

Compound 35

3-Cyclohexyl-7- (1 ', 2', 3'-triazol-4'-yl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

5-Iodo-2-aminobenzenesulfonamide (see compound 37) is treated by Method I (using trimethylsilylacetylene) and Method G (using cyclohexanecarboxaldehyde). Mp 230-234 ° C (dec.).

Compound 36 3-Cyclohexyl-7- ^(5-phenyl ', 2', ^{3-triazol-4-yl)} -l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, -dioxide

5-Iodo-2-aminobenzenesulfonamide (see compound 37) is treated by Method 1 (using phenylacetylene) and Method G (using cyclohexanecarboxaldehyde). Mp 231-232 ° C (dec.).

Compound 37

3-Cyclohexyl-7- ^(5-methyl-l ', 2', 4'-oxadiazol-3-yl) -l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l-dioxide

5-Iodo-2-aminobenzenesulfonamide: To a cold (0 ° C) stirred solution of 2-aminobenzenesulfonamide (17.2 g; 100 mmol) in CHCl 3 (200 mL) was added iodine chloride solution (17.1 g; 105 mmol) in CHCl 3 (50 mL). The reaction mixture was slowly warmed to room temperature and allowed to stir overnight. The reaction mixture was filtered and the isolated solid was washed on the filter with CHCl 3 (3x 20 mL), NaHCO ₃ (saturated aqueous solution, 1 x 20 mL), H ₂ O (4x 50 mL). The isolated solid was dried to give 27.3 g (92%) of the product.

5-Cyano-2-amino-benzenesulfonamide. A mixture of 5-iodo-2-aminobenzenesulfonamide (17.9 g; 60 mmol), Zn (CN) ₂ (4.9 g; 41.9 mmol) and Pd (PPh ₃ ) 4 (2.5 g; 2) , 2 mmol) in DMF (150 mL) under N ₂ was heated at 80 ° C for 2 h. The reaction mixture was poured into NaHCO ₃ (saturated aqueous solution, 600 mL) and extracted with EtOAc (9x 200 mL). The combined organic fractions were washed with NaHCO 3 (saturated aqueous solution) and NaCl (saturated aqueous solution), dried (Na ₂ SO 4), filtered and evaporated to dryness. The residue was washed with water and hexanes and filtered to give 10.9 g (92%) of the product.

5- (N-Hydroxyamidino) -2-aminobenzenesulfonamide: A mixture of hydroxylamine hydrochloride (764 mg;

mmol) and NaOMe (616 mg; 11.4 mmol) in MeOH (10 mL) was stirred at room temperature for 1 h, then 5-cyano-2-aminobenzenesulfonamide (1 g; 5 mmol) was added. The reaction mixture was allowed to stir for 48 hours and poured into water and extracted with EtOAc (2 x 50 mL). The combined organic fractions were dried (Na ₂ SO 4), evaporated to dryness and purified by column chromatography to give 200 mg (17%) of the product.

3-Cyclohexyl-7- (5'-methyl-1 ', 2', 4'-axadiazol-3-yl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine 1,1-dioxide ( 37): A mixture of 5- (N-hydroxyamidino) -2-aminobenzenesulfonamide (200 mg; 0.9 mmol), NaOMe (50 mg; 1 mmol), EtOAc (5 mL), crushed MS3A (2 g) in anhydrous EtOH ( 20 ml) was heated at 70 ° C overnight. The reaction mixture was evaporated to dryness, stirred with water and extracted with EtOAc. The combined organic fractions were dried (Na ₂ SO 4) and evaporated to dryness to give a brown oil which was treated by Method G (using cyclohexanecarboxaldehyde) to yield 8 mg of product after chromatography. Mp 249-251 ° C.

Compound 38

3-Cyclohexyl-7-acetamido-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 7-Amino-3-cyclohexyl-1,2,3,4-tetrahydro-1 2,4-Benzothiadiazine-1,1-dioxide: To a stirred solution of 7-amino-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (0.5 g; 2 mmol) in dry THF (10 mL) at -70 ° C was added a solution of 1.5 M DIBALH in toluene (2.7 mL; 4 mmol) under N ₂ atmosphere. The reaction mixture was stirred for 2 hours at -70 ° C; 2 hours at -40 ° C and then warmed to 0 ° C. The reaction was quenched with H ₂ O and stirred for 30 minutes at 0 ° C and allowed to stand overnight at + 5 ° C without stirring. The mixture was evaporated to dryness, resuspended in MeOH and filtered. The isolated solid was washed with MeOH and filtered. Adsorption of the combined filtrates onto silica gel is performed. Column chromatography (EtOAc) yielded 200 mg of the product.

7-Acetylamino-3-cyclohexyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (38): A mixture of 7 amino-3-cyclohexyl-1,2,3,4- tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (100 mg; 0.26 mmol), acetyl chloride (20 μΙ; 0.29 mol) and triethylamine (42 μΐ; 0.3 mmol) were stirred for 2 hours. h at room temperature. The reaction mixture was re-suspended in H ₂ O and filtered. The isolated solid was purified by column chromatography (EtOAc) to give 22 mg of compound 27a. Melting point 202206 ° C

Compound 39

3-Cyclohexyl-7-methylsulfonylamino-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide

3-Cyclohexyl-1,2-dihydro-1,2,4-benzatiadiazine-1,1-dioxide: 2-Aminobenzenesulfonamide is treated by Method E (using cyclohexanecarbonyl chloride),

3-Cyclohexyl-7-nitro-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: To a stirred solution of KNO3 (1.2 g; 11.5 mmol) and concentrated H2SO4 (8 mL) a solution of 3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide in concentrated H 2 SO 4 (8 mL) was added at 5 ° C. The reaction mixture was allowed to warm to room temperature and allowed to stir overnight. The product precipitated by the slow addition of ice and isolated by filtration. The crude product (4.3 g) was used without further purification

7-Amino-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: A mixed suspension of 3cyclohexyl-7-nitro-1,2-dihydro-1,2,4-benzothiadiazine- 1,1-dioxide (4.2 g; 14 mmol) and 10% Pd / C (400 mg) in absolute EtOH (100 mL) were hydrogenated at 1 bar. After the calculated amount of H _{2 has} reacted, the reaction mixture is filtered through Celite. The celite was washed with DMF (2 x 75 mL) and the combined organic fractions were evaporated to dryness. The residue was resuspended in EtOAc / i-PrOH and the precipitate formed was collected by filtration. The isolated solid was dissolved in 0.5 M NaOH (aq) and reprecipitated with 4 M HCl (aq). Filtration gave 1.6 g of product.

7-Methylsulfonylamino-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: To a stirred solution of 7-amino-3-cyclohexyl-1,2-dihydro-1,2,4 -benzothiadiazine-1,1-dioxide (1 g; 3.6 mmol) and triethylamine (1.2 mL; 8 mmol) in dry THF (25 mL) were added methanesulfonyl chloride (0.6 mL; 8 mmol) and stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness, resuspended in H ₂ O / EtOAc and filtered. The filtrate is adsorbed onto silica gel. Column chromatography (CH ₂ Cl _2: acetone = 9: 1) gave 210 mg of product.

3-Cyclohexyl-7-methylsulfonylamino-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (39): 7-Methylsulfonylamino-3-cyclohexyl-1,2-dihydro-1 The 2,4-benzothiadiazine-1,1-dioxide is treated by Method F. Mp 255-258 ° C.

Compound 40

3-Cyclohexyl-7-nitro-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

3-Trifluoromethyl-1,2,4-benzothiadiazine-1,1-dioxide: The 2-aminobenzenesulfonamide is deprotected with trifluoroacetyl using Method C. To this solution (1 g; 4 mmol) in H 2 SO 4 (16 mL) at 0 ° C solid KNO3 (4.4 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into ice water (150 mL), filtered and dried to give 1.11 g (94%) of pure product as a yellow solid.

3-Cyclohexyl-7-nitro-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (40): 3-Trifluoromethyl-1,2,4-benzothiadiazine-1,1 -dioxide is processed according to the following scheme: method D and method F (using cyclohexanecarboxaldehyde). Mp 209-211 ° C.

Compound 41

3-Cyclohexyl-7-phenylsulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

4-Phenylsulfonylaniline was used as the starting material for the following work-up procedure: Method B and Method G (using cyclohexanecarboxaldehyde). Melting point 243-245 ° C. Compound 42

2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline sulfonamide

To a solution of 2-aminobenzylamine (3 g; 25 mmol) in THF (50 mL) was added trifluoroacetic anhydride (3.8 mL; 27 mmol) and stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness, stirred with H ₂ O and filtered. The crude product was worked up by Method A (using 25% NH 3 (aq) as an amine) and Method G (using cyclohexanecarboxaldehyde). Melting point 178-180 ° C.

Compound 43

3-Cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

4- Sulfamoylantranilamide: To a stirred solution of Cl 2 SO 3 H (20 mL) was added in small portions anthranilamide (7.5 g; 55 mmol). The reaction mixture was heated at 100 ° C for 1 hour and then poured into ice water (300 mL). The precipitate formed is isolated by filtration and dried on the filter. The isolated solid was dissolved in 25% NH 3 (aq) and stirred at room temperature overnight. The aqueous phase was washed with EtOAc and concentrated to 20 mL. The aqueous phase was saturated with NaCl (s) and extracted with THF (3 x 50 mL). The combined organic fractions were evaporated to dryness and column chromatographed to give 13 mg of the product.

3-Cyclohexyl-7-sulfamoyl-7,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (43):

4- Sulfamoylantranilamide was processed via Method G (using cyclohexanecarboxaldehyde), Fab + 310, 1 H NMR (DMSO-d ₆ ): 8.1 (1H, br,), 8.0 (1H, d), 7.58 ( 1 H; dd), 7.3 (1H, br,), 7.05 (2H; br,), 6.79 (1H, d), 4.5 (1H, m), 1.8 -1.5 (6H; m); 1.2-1.0 (5H; m).

Compound 44

3-Cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Amino-5-sulfamoylbenzenesulfonamide (see compound 101) was treated by Method G (using cyclohexanecarboxaldehyde). Mp 252-254 ° C.

Compound 45

3-Methyl-7-dimethylsulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Methyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4 -benzothiadiazine-1,1-dioxide is reduced using Method F. Melting point 210-212 ° C.

Compound 46

2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline N, N-dimethyl sulfonamide

To a solution of 2-aminobenzylamine (3 g; 25 mmol) in THF (50 mL) was added trifluoroacetic anhydride (3.8 mL; 27 mmol) and stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness, stirred with H 2 O and filtered. The crude product is worked up by Method A (using dimethylamine as the amine), Method D and Method G (using cyclohexanecarboxaldehyde). Mp> 300 ° C. MS (electrospray) M + 323, 1 H NMR (DMSO-d 6): 7.2 (1H; dd); 7.1 (1H, d); 6.68 (1H, br); 6.62 (1H, d); 3.85 (1H, s); 3.8 (2H, s); 2.2 (1H, br); 1.8-1.0 (11H, m).

Compound 47 3-Cyclohexyl-7-dimethylaminosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method E (using cyclohexanecarbonyl chloride), Method A (using dimethylamine as amine), Method F. Melting point 243-245 ° C.

Compound 48

3-Cyclohexyl-7- (N, N-diethylamino) sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method E (using cyclohexanecarbonyl chloride), Method A (using diethylamine as amine), Method F. Mp 207-209 ° C.

Compound 49

3-Cyclohexyl-7-pyrrolidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method E (using cyclohexanecarbonyl chloride), Method A (using pyrrolidine as amine), Method F. Mp 244-246 ° C.

Compound 50

3-Methyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method C, Method A (using piperidine as an amine), Method D, Method G [using paraldehyde and a catalytic amount of TsOHJ. Mp 255-256 ° C.

Compound 51

3-Cyclopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method C, Method A (using piperidine as amine), Method D, Method G [using cyclopropanecarboxaldehyde]. Melting point 228-231 ° C.

Compound 52

3-Isopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method G, Method A (using piperidine as amine), Method D, Method G [using isobutyraldehyde]. Mp 237-239 ° C.

Compound 53

3-Propyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method C, Method A (using piperidine as amine), Method D, Method G [using butyraldehyde]. Melting point 147.4-151.2 ° C.

Compound 54

3-Benzyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method C, Method A ( using piperidine as amine), Method D, Method G [using phenylacetaldehyde]. Melting point 242-244 ° C.

Compound 55

3-Cyclopentyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide Cyclopentanecarboxaldehyde: To a stirred solution of cyclopentanecarboxylic acid (2.16 mL; 20 mmol) in dry THF (50 mL) at room temperature under N ₂ atmosphere, add NaBH 4 (2.28 g; 60 mmol) and allow to stir for 20 min. The reaction mixture was cooled to 0 ° C and BF ₃ OEt ₂ (10 mL; 80 mmol) was added over 1 hour while maintaining the reaction temperature below +3 ° C. NaHCO ₃ (sat. Aq.), H ₂ O was added to the reaction mixture and extracted with EtOAc. The combined organic fractions were washed with NaCl (saturated aqueous solution), dried (Na ₂ SO 4) and evaporated to dryness to give 1.4 g of an oil which was used without further purification. The oil (1.4 g) was dissolved in CH 2 Cl 2 (75 mL) and PCC on Al ₂ O ₃ (30 g; 30 mmol) * was added and allowed to stir for 1 hour at room temperature. The reaction mixture was filtered and the evaporated filtrate was loaded onto silica gel. Column chromatography gave pure aldehyde which was used as a solution in CH 2 Cl 2.

* [see Cheng Y.-S., Liu W.-L. and Chen S.-H., Synthesis, (1980) 223.]

3-Cyclopentyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (55):

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method C, Method A (using piperidine as amine), Method D, Method G [using cyclopentanecarboxaldehyde]. Mp 258-260 ° C.

Compound 56

3-Cyclohexyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method E (using cyclohexanecarbonyl chloride), Method A (using piperidine as amine), Method F. Mp 262-264 ° C.

Compound 57

3-bicyclo [2.2] ^{hept-5-en-2-yl-7-piperidinosulfonyl-2,3,4-tetrahydro-2,4-dioxide-benzotiadiazín1,1}

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method C, Method A (using piperidine as amine), Method D, Method G [using endo / exo racemic 2-norbornylene carboxaldehyde]. Two separate diastereomeric mixtures with a melting point (A) of 240-242 ° C and a melting point (B) of 234-238 ° C are isolated.

Compound 58

3-Cyclohexyl-7- (1 ', 2', 3 ', 6'-tetrahydropiperidino) sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method E (using cyclohexanecarbonyl chloride), Method A (using 1,2,3,6-tetrahydropyridine as amine), Method F. Melting point: 237-239 ° C.

Compound 59

Cyclohexyl-7- (N-methyl-N-phenyl] amino) sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine 1,1-dioxide

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method E (using cyclohexanecarbonyl chloride), Method A (using N-methylaniline as an amine), Method F. Melting point 210-212 ° C.

Compound 60

3-Cyclohexyl-7- (Γ- (1 ', 2', 3 ', 4'-tetrahydroquinolinyl)) sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method E (using cyclohexanecarbonyl chloride), Method A (using 1,2,3,4-tetrahydroquinoline as amine), Method F. Melting point 218-220 ° C.

Compound 61

3-Cyclohexyl-7- (4'-methylpiperazino) sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method C, Method A (using N-methylpiperazine as an amine), Method D, Method G (using cyclohexanecarboxaldehyde). Melting point 227-229 ° C.

methanesulfonate salt: 61 (0.6 g; 1.4 mmol) was dissolved in 99% EtOH (30 mL) and a solution of 1 M CH 3 SO 3 H in 99% EtOH was added. The mixture was allowed to stand for 2 hours to precipitate and the salt was isolated by filtration. The salt composition is checked by HPLC for stability compared to the free base. It was found that under these conditions the salt is stable to hydrolysis and has a water solubility of 10 mg / ml

Compound 62

3-Cyclohexyl-7- (4'-methylsulphonylpiperazin) sulfonyl-l, 2,3,4-tetrahydro-2,4-dioxide-benzotiadiazín1,1

N-Mesylpiperazinium chloride: To a stirred solution of piperazine (4.3 g; 50 mmol) in CH 2 Cl 2 (50 mL) at + 5 ° C was added a solution of CH ₃ SO ₂ Cl (4.25 mL; 55 mmol) in CH 2 Cl 2 ( 15 ml). The thick reaction mixture was stirred at room temperature for 12 hours, CH 2 Cl 2 (100 mL) was added and extracted with 1 M HCl (300 mL). The precipitate formed in the aqueous phase was filtered off to give 2.66 g of N-mesylpiperazinium chloride (32%).

3-Cyclohexyl-7- (4'-methylsulfonylpiperazino) sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine 1,1-dioxide (62): 2-Aminobenzenesulfonamide was used as the starting material for the following procedure. Workup: Method E (using cyclohexanecarbonyl chloride), Method A (using NMezylpiperazinium chloride as amine (1.5 equiv.), 3 equiv. K ₂ CO ₃ are used for neutralization), Method F. Melting point 272-274 ° C.

Compound 63

3-Cyclohexyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method E (using cyclohexanecarbonyl chloride), Method A (using morpholine as an amine), Method F. Melting point 262-264 ° C.

Compound 64

3-Bicyclo [2.2.1] hept-5'-en-2'-yl-7-bromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5 The bromo-2-aminobenzenesulfonamide (see compound 18) is treated by Method G (using an endo / exo racemic mixture of bicyclo [2.2.1] hept-5-ene-2-carboxaldehyde). Melting point 200-204 ° C.

Compound 65

2-Methyl-4-oxo-3,4-dihydro-6-quinazoline-N, N-dimethylsulfonamide 2-Methyl-4-oxo-3,4-dihydroquinazoline: A solution of anthranilamide (13.6 g; 100 mmol) in acetic acid acid (100 mL) was refluxed for 60 hours. The reaction mixture is evaporated to dryness, suspended in H ₂ O, filtered and washed with NaHCO ₃ until the filtrate has a pH of 8-8.5.

2-Methyl-4-oxo-3,4-dihydro-6-quinazoline-N, N-dimethylsulfonamide: 2-Methyl-4-oxo-3,4-dihydroquinazoline was treated by Method A (using dimethylamine as the amine). Melting point 264-266 ° C.

Compound 66

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-chinazolínsulfónamid

2-Trifluoroacetamidobenzamide (see Compound 68) was treated by Method A (using 0.5 M NH 3 in THF as the amine). Mp 311 -314 ° C.

Compound 67

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline 2-Trifluoroacetamidobenzamide (see Compound 68) was treated with Method A (using dimethylamine as an amine) Ν, Ν-dimethylsulfonamide. Mp 257-258 ° C.

Compound 68

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline-I ', ^{2', 3, 6,} -tetrahydropiperidinosulfónamid

To a stirred mixture of anthranilamide (13.6 g; 100 mmol) in THF (100 mL) at 0 ° C was added trifluoroacetic anhydride (15.2 mL; 110 mmol), allowed to warm to room temperature and stirred overnight. The reaction mixture is evaporated to dryness, suspended in H ₂ O and filtered. The isolated solid was air dried to give 21.6 g (93%) of 2-trilfluoroacetamidobenzamide. The 2-trifluoroacetamidobenzamide is treated by Method A (using 1,2,3,6-tetrahydropyridine as the amine). Melting point 227-230 ° C.

Compound 69

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline N-cyclohexylsulfonamide 2-Trilfluoroacetamidobenzamide (see compound 68) was treated by Method A (using cyclohexylamine as the amine). Mp 261-263 ° C.

Compound 70

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline-morpholinosulfonamide 2-Trilfluoroacetamidobenzamide (see compound 68) is treated by Method A (using morpholine as the amine). Mp 282-285 ° C.

Compound 71

2-Cyclohexyl-4-oxo-3,4-dihydro-6-quinazoline-N, N-dimethylsulfonamide

The anthranilamide was used as a starting material for the following work-up procedure: Method A (using 25% NH ₃ (aq) as an amine. The reaction mixture contained both 5-monosulfonamide and 5,7-disulfonamide which were separated by chromatography) Method G (using amine autooxidizes to the aromatic hydroxyquinazoline). Mp 306-310 ° C.

Compound 72

3-Methyl-7-sulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide

3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (see compound 73) was treated by Method A (using 0.5M NH ₃ in THF as the amine). Mp 295-297 ° C.

Compound 73

3-Methyl-7-dimethylsulfamoyl-l, 2-dihydro-l, 2,4-benzothiadiazine-l, l-dioxide

2-Aminobenzenesulfonamide (17.2 g; 100 mmol) was refluxed in AcOH for 5 days. The precipitate formed was collected by filtration and washed with water to give 17.8 g (91%) of 3-methyl-1,2-dihydro-

3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide, 1,2,4-benzothiadiazine-1,1-dioxide, was treated by Method A (using dimethylamine as the amine). Mp 260-261 ° C.

Compound 74

3-Methyl-7- (1 ', 2', 3 ', 6 ^, -tetrahydropiperidino) sulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Methyl-1,2-dihydro -1,2,4-Benzothiadiazine-1,1-dioxide (see Compound 73) was treated by Method A (using 1,2,3,6-tetrahydropiperidine as the amine). Melting point 265-268 ° C.

Compound 75

3-Methyl-7-cyclohexylsulfamoyl-1,2-dihydro-l, 2,4-benzothiadiazine-1,1-dioxide

3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (see compound 73) was treated by Method A (using cyclohexylamine as the amine). Mp 239-242 ° C.

Compound 76

3-Trifluoromethyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method C and Method A (using dimethylamine as amine). Mp 240-242 ° C.

Compound 77

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline sulfonic acid

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method C and Method A (using NaOH instead of amine). Mp> 330 ° C.

Compound 78

3-Cyclohexyl-8-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide n-Toluidine was used as the starting material for the following work-up procedure: Method B [2 amino-6 -methylbenzenesulfonamide is separated from 2-amino-4-methylbenzenesulfonamide by recrystallization (EtOAc / hexane)], 2-Amino-6-methylbenzenesulfonamide is further purified by column chromatography and worked up by Method G (using cyclohexanecarboxaldehyde). Melting point 228-230 ° C.

Compound 79

3-Cyclohexyl-8-hydroxymethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

5-Chloro-3-cyclohexyl-7,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide-8-carboxylic acid: To a solution of 5-chloro-3-cyclohexyl-1,2-dihydro-1 2,4-Benzothiadiazine-1,1-dioxide (see Compound 80) (0.30 g, 1.0 mmol) in dry THF (15 mL) at -78 ° C was added s-BuLi in cyclohexane (1 mL). (3 M, 1.6 mL, 2.1 mmol) under N ₂ atmosphere. The yellow mixture was stirred for 15 minutes at -78 ° C and dry, gaseous CO _{2 was} bubbled through the solution for 30 minutes. Remove the cooling bath and warm to 0 ° C. The solvent was removed under reduced pressure and the residue was triturated with hydrochloric acid (0.2 M, 12 mL). The crude product was recrystallized from 50% MeOH to give 300 mg (82%) of 5-chloro-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide-8-carboxylic acid as colorless crystals,

3-Cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide-8-carboxylic acid: 5-chloro-3cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1 1-Dioxide-8-carboxylic acid (160 mg, 0.47 mmol) was dissolved in 99% EtOH (50 mL) and hydrogenated for 24 h using Pd / C (10%, 10 mg) at 1 bar. NaOH (1 M, 12 mL) was added and the mixture was filtered through a pad of Celite ™ and concentrated to 10 mL and concentrated hydrochloric acid was slowly added to the precipitate to give 110 mg (76%) of 3-cyclohexyl-1,2- dihydro-1,2,4-benzothiadiazine-1,1-dioxide-8-carboxylic acid as a colorless powder.

3-Cyclohexyl-8-hydroxymethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (79): NaBH ₄ in triglyme (2 M, 0.75 ml, 1, 5 mmol) was dissolved in dry THF (20 mL) and cooled to -50 ° C under N ₂ , BF ₃ -etherate (0.25 mL, 2.0 mmol) was added and the mixture was stirred for 10 minutes at -50 ° C. Solid 3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide-8-carboxylic acid (170 mg, 0.55 mmol) was added in one portion and the suspension was stirred for 6 hours at -50. ° C and overnight at 20 ° C. The mixture was hydrolyzed with hydrochloric acid (1 M, 2 mL) and the solvent was removed under reduced pressure. The residue was extracted with EtOAc (50 mL) and the organic layer was washed with brine (10 mL), dried (Na ₂ SO ₄ ) and evaporated to dryness. The product was purified by flash column chromatography on silica gel using EtOAc: n-hexane (2: 1, v / v) as eluent to give 100 mg (62%) of 3-cyclohexyl-8-hydroxymethyl-1,2-dihydro-1, 2,4-benzothiadiazine-1,1-dioxide in the form of colorless needles. The product is further processed by Method F. Mp 220-223 ° C.

Compound 80

3-Cyclohexyl-8- (2-methoxyphenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Chloro-3-cyclohexyl-7,2- dihydro-1,2,4-benzothiadiazine-1,1-dioxide: 3-Chloroaniline was used as a starting material for the following work-up procedure: Method B followed by Method E (using cyclohexylcarbonyl chloride).

5-Chloro-3-cyclohexyl-8-iodo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: To a solution of 5-chloro-3-cyclohexyl-1,2-dihydro-1,2, 4-Benzothiadiazine-1,1-dioxide (596 mg, 2 mmol) in dry THF (20 mL) at -78 ° C was added under N ₂ s-BuLi in cyclohexane (1.3 M, 3.8 mL) , 5 mmol). The yellow mixture was stirred for 15 minutes at -78 ° C and a solution of I ₂ (1.27 g, 5 mmol) in dry THF (5 mL) was added. Remove the cooling bath and warm to 0 ° C. NaHSO ₃ (5%, 20 mL) was added and extracted with EtOAc (2 x 30 mL), dried (Na ₂ SO ₄ ) and evaporated to dryness to give 0.76 g (90%) of 5-chloro-3-cyclohexyl- 8-iodo-l, 2-dihydro-l, 2,4-benzothiadiazine 1,1-dioxide.

5-Chloro-3-cyclohexyl-8- (2-methoxyphenyl) -1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: Mixture of 5-chloro-3-cyclohexyl-8-iodo-1,2 -dihydro-1,2,4-benzothiadiazine-1,1-dioxide (290 mg, 0.68 mmol), 2-methoxyphenylboronic acid (122 mg, 0.80 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (10 mg, 2 mol%) in 1,2-dimethoxyethane (50 mL) and Na ₂ CO ₃ (2M, 2 mL, 4 mmol) were refluxed under N ₂ for 2 hours. The solvents were removed under reduced pressure and the residue was extracted with EtOAc (2 x 40 mL) and the organic layer was washed with saturated NaHCO ₃ (20 mL), dried (Na ₂ SO ₄ ) and the solvent was removed under reduced pressure. The product was purified by flash column chromatography on silica gel using EtOAc: n-hexane (1: 2, v / v) as eluent to give 200 mg (73%) of 5-chloro-3-cyclohexyl-8- (2-methoxyphenyl) -1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide in the form of colorless crystals.

3-Cyclohexyl-8- (2-methoxyphenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-7,7-dioxide (80):

5-Chloro-3-cyclohexyl-8- (2-methoxyphenyl) -1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (190 mg, 0.47 mmol) was dissolved in 99% EtOH (30 m4) and hydrogenated using Pd / C (10%, 10 mg) at 1 bar. The mixture was filtered through a pad of Celite ™ and the solvent was removed under reduced pressure to give 174 mg (100%) of 5-chloro-3-cyclohexyl-8- (2-methoxyphenyl) -1,2-dihydro-1,2, 4-benzothiadiazine-1,1-dioxide in the form of colorless crystals. The product is worked up by Method F. Mp 100-105 ° C.

Compound 81

3-Cyclohexyl-8- (3-methoxyphenyl) -l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide

Same synthesis as for compound 80 (using 3-methoxyphenylboronic acid for cross-coupling with Pd catalyst). Melting point 108-115 ° C.

Compound 82

3-Cyclohexyl-8- (2-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

5-Chloro-3-cyclohexyl-8- (dihydroxyboryl) -1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: To a solution of 5-chloro-3-cyclohexyl-1,2-dihydro- 1,2,4-benzothiadiazine-1,1-dioxide (see compound 80) (0.60 g, 2.0 mmol) in dry THF (15 mL) at -78 ° C was added under N ₂ atmosphere at -78 ° C. BuLi in cyclohexane (1.3 M, 3.8 mL, 5 mmol). The yellow mixture was stirred for 15 minutes at -78 ° C and B (OCH 3) 3 (0.57 mL, 5 mmol) was added. The cooling bath was removed and the mixture was warmed to 0 ° C and stirred for an additional 1 hour. The mixture was hydrolyzed with hydrochloric acid (0.5 M, 12 mL) and extracted with EtOAc (2 x 50 mL), dried (Na ₂ SO ₄ ) and evaporated to dryness to afford 0.65 g (95%) of 5-chloro-3. cyclohexyl-8- (dihydroxyboryl) -l, 2-dihydro-l, 2,4-benzothiadiazine-l-dioxide.

5-Chloro-3-cyclohexyl-8- (2-pyridyl) -1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: A mixture of 5-chloro-3-cyclohexyl-8- (dihydroxyboryl) - 1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (440 mg, 1.28 mmol), 2-bromopyridine (0.14 mL, 1.50 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (10 mg, 2 mol%) in 1,2-dimethoxyethane (30 mL) and Na ₂ CO ₃ (2M, 3 mL, 6 mmol) was refluxed under N ₂ for 24 hours. The solvents were removed under reduced pressure and the residue was treated with saturated NH ₄ Cl (10 mL) and extracted with EtOAc (2 x 40 mL). The organic layer was washed with water (20 mL), dried (Na ₂ SO 4), and the solvent was removed under reduced pressure. The product was purified by flash column chromatography on silica gel using EtOAc: n-hexane (2: 1, v / v) as eluent to give 280 mg (58%) of 5-chloro-3-cyclohexyl-8- (2-pyridyl) ) -l, 2-dihydro-

1,2,4-benzothiadiazine-1,1-dioxide in the form of colorless crystals.

3-Cyclohexyl-8- (2-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (82): 5-chloro-3-cyclohexyl-8- (2-pyridyl) -1,2-Dihydro-1,2,4-benzothiadiazine-1,1-dioxide (0.268 g, 0.713 mmol) was dissolved in 99% EtOH (50 mL) and hydrogenated using Pd / C (10%, 10 mg) ) at 4 bar for 24 hours. The mixture was filtered through a pad of Celite and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with phosphate buffer (pH = 7, 10 mL), dried (Na ₂ SO 4) and the solvent was removed under reduced pressure to give 200 mg (82%) of 3-cyclohexyl-8. - (2-pyridyl) -1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide in the form of colorless crystals. The product is further processed by Method F. Mp 200-203 ° C.

Compound 83 3-Cyclohexyl-8-methoxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide n-Anisidine was used as the starting material for the following work-up procedure: Method B [2-amino] The 6-methoxybenzenesulfonamide is separated from the 2-amino-4-methoxybenzenesulfonamide by flash chromatography (EtOAc / hexane)] and then Method G (using cyclohexanecarboxaldehyde). Mp 221-223 ° C.

Compound 84

5,7-Dibromo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was treated by Method G (using ethyl formate and a catalytic amount of triethylamine). Melting point 289-292 ° C.

Compound 85 and Compound 86

3-Cyclohexyl-2-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (85) and 3-Cyclohexyl-4-methyl-7-morpholinosulfonyl -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (86)

3-Cyclohexyl-7-morpholinosulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide:

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method E (using cyclohexanecarbonyl chloride) and Method A (using morpholine as amine) to give 3-cyclohexyl-7-morpholinosulfonyl-1,2-dihydro-1,2,4 -benzotiadiazín-l-dioxide.

3-Cyclohexyl-2-methyl-7-morpholinosulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide; 2,4-benzothiadiazine-l, l-dioxide; A mixture of 3-cyclohexyl-7-morpholinosulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (2 g; 5 mmol), DEAD (2.35 mL; 15 mmol), PPhj (4 g; 15 mmol) in dry THF (30 mL) was cooled to 0 ° C and MeOH (1.25 mL; 30 mmol) was added. The reaction mixture was stirred overnight at room temperature, evaporated to dryness, stirred with EtOAc and filtered. The isolated precipitate was stirred with CH 2 Cl 2 and filtered to give the 2-methyl isomer in the filtrate and the 4-methyl isomer as a precipitate.

4-Methyl is purified by recrystallization from DMSO / H 2 O. The 2-methyl isomer is purified by column chromatography (EtOAc).

3-Cyclohexyl-2-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (85): 3-Cyclohexyl-2-methyl-7-morpholinosulfonyl -1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide was reduced according to Method F. Mp 243-245 ° C.

3-Cyclohexyl-4-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (86): 3-Cyclohexyl-4-methyl-7-morpholinosulfonyl The 1,2,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide is reduced according to Method F. Mp 207-210 ° C.

Compound 87 7-Methylsulfonylamino-1,2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide 1,2,3,5- tetrahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide: 2-Aminobenzenesulfonamide was treated by Method E (using 4-chlorobutanoyl chloride).

7-Nitro-1,2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide: To a stirred solution of 1,2,3,5-tetrahydrobenzo [ e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide (222 mg; 1 mmol) in

H 2 SO 4 (2 mL) at 5 ° C was added a solution of KNO 3 (122 mg; 1.2 mmol) in H 2 SO 4 (2 mL). The Re94 action mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into ice water, filtered and air dried to give 190 mg (71%) of the product.

7-Amino-1,2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -7,2,4-thiadiazine-5,5-dioxide: To a stirred solution of 7-nitro-1,2,3, 3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide (167 mg; 0.6 mmol) in dry THF (2 mL) at -50 ° C was added in one portion L1AIH4 (115 mg; 3 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of H ₂ O and 10 M NaOH, stirred, filtered through celite, and evaporated to dryness to give 150 mg of product.

7-Methylsulfonylamino-1,2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide (87): To a stirred solution of 7-amino -1,2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1c] -1,2,4-thiadiazine-5,5-dioxide (150 mg; 0.5 mmol) and triethylamine (70 μΐ; 0.5 mmol) in THF (1 mL) was added a solution of CH ₃ SO ₂ Cl (40 µΐ; 0.5 mmol) in THF (1 mL) and stirred at room temperature overnight. The reaction mixture was evaporated to dryness, suspended in H ₂ O and extracted with EtOAc. The combined organic fractions were evaporated to dryness. Column chromatography gave 40 mg of the product. Melting point 177-180 ° C.

Compound 88

7-Sulfamoyl-1,2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide is used as the starting material for the following work-up procedure: Method E (using 4-chlorobutanoyl chloride), Method A (using 0.5 M NH 3 in THF as the amine), Method F (using L 1 AlH 4 and at room temperature). Mp 260-262 ° C.

Compound 89 7-Methylsulfamoyl-1,2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide was used as the starting material. for the following work-up procedure: Method E (using 4-chlorobutanoyl chloride), Method A (using methylamine as amine), Method F (using LiAlH 4 and at room temperature). Mp 244-245 ° C.

Compound 90

7-cyclohexylsulfamoyl-t, 2,3,3a, 4,5-hexahydro-benzo [e] pyrrolo [2, l-c] -l, 2,4-thiadiazine-5,5-dioxide

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method E (using 4-chlorobutanoyl chloride), Method A (using cyclohexylamine as the amine), Method F (using LiAlH 4 and at room temperature). Mp 195-197 ° C.

Compound 91 7-Dimethylsulfamoyl-1,2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide was used as the starting material. for the following treatment procedure: Method E (using 4-chlorobutanoyl chloride), Method A (using dimethylamine as an amine), Method F (using L 1 AlH 4 and at room temperature). Mp 240-243 ° C.

Compound 92

7-Methylsulfamoyl-1,2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method E (using 4-chlorobutanoyl chloride), Method A (using methylamine as amine). Mp 244-247 ° C.

Compound 93

7-Dimethylsulfamoyl-1,2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide was treated by Method E (using 4-chlorobutanoyl chloride) and Method A (using dimethylamine). Melting point 251-253 ° C.

Compound 94 7-Cyclohexylsulfamoyl-1,2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure. Method E (using 4-chlorobutanoyl chloride) Method A (using cyclohexylamine as amine). M.p. 151-153 ° C.

Compound 95

7- (1'-X''-Tetrahydropiperidinosulfonyl-1,2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method E (using 4-chlorobutanoyl chloride), Method A (using 1,2,3,6-tetrahydropyridine as the amine). Mp 204-206 ° C.

Compound 96

3-bicyclo [2,2, l] ^{hept-5'-en-2-yl-5,7-dimethyl-l,} 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l- dioxide

2,4-Dimethylaniline was used as the starting material for the following work-up procedure: Method B, Method G [using racemic endo / exo bicyclo [2.2.1] hept-5-ene-2-carboxaldehyde, two diastereomeric fractions were obtained by column chromatography. , each being a mixture of diastereoisomers]. Isomer mixture A, mp 160-165 ° C; isomeric mixture B, m.p. 182-187 ° C.

Compound 97 3-Cyclohexyl-7 - (N, N -diethylsulfamoyl) -5-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

3-Cyclohexyl-7- (N, N-diethylsulfamoyl) -5-formyl-1,2-dihydro-1,2,4-banzothiadiazine-1,1-dioxide:

2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method E (using cyclohexanecarbonyl chloride) and Method A (using diethylamine as an amine). To this product (0.60 g, 1.5 mmol) dissolved in dry THF (15 mL) at -78 ° C was added N ₂ s-BuLi in cyclohexane (1.3 M, 2.5) at -78 ° C. ml, 3.2 mmol). The yellow mixture was stirred for 25 minutes at -78 ° C. The reaction was quenched with dry DMF (0.3 mL, 4 mmol) and stirred for 20 minutes at -78 ° C. Remove the cooling bath and warm to 0 ° C. Hydrochloric acid (0.5 M, 10 mL) was added and the mixture was extracted with EtOAc (40 mL). The organic layer was washed with brine (10 mL), dried (Na ₂ SO 4) and evaporated to dryness. The residue was dissolved in acetone (8 mL), Et ₂ O (30 mL) was added and the product crystallized over a few minutes to give 0.41 g (64%) of 3-cyclohexyl-7- (N, N-diethylsulfamoyl) - 5-formyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide in the form of colorless crystals.

3-Cyclohexyl-7- (N, N-diethylsulfamoyl) -5-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (97): 3-Cyclohexyl-7- ( A (N-diethylsulfamoyl) -5-formyl-1,2-dihydro-1,2,4-benzothiadiazine 1,1-dioxide (0.20 g, 0.46 mmol) was dissolved in 99% EtOH (60 mL). Hydrochloric acid is added in small drops for complete hydrogenation, and the mixture is hydrogenated using Pd / C (10%, 10 mg) at 4 bar for 24 hours, filtered through Celite ™ and evaporated to dryness. 50 mL) and washed with water (10 mL), dried (Na ₂ SO ₄ ) and evaporated to dryness to give 0.18 mg (95%) of 3-cyclohexyl-7- (N, N-diethylsulfamoyl) -5- methyl 1,2-dihydro-1,2,497 benzothiadiazine 1,1-dioxide as a colorless powder The product is further processed by Method F. Mp 206-208 ° C.

Compound 98

3-Bicyclo [2.2.1] hept-5'-en-2'-yl-5,7-diphenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1- dioxide

The 3,5-dibromo-2-aminobenzenesulfonamide (see compound 125) is treated by Method H (using phenylboronic acid) and Method G (using endo / exo racemic bicyclo [2.2.1] hept-5-ene-2-carboxaldehyde) ). Mp 222-225 ° C.

Compound 99

3-Bicyclo [2.2.1] hept-5'-en-2'-yl-5,7-disulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

The 2-aminobenzenesulfonamide is treated by Method A (using 25% NH ₃ (aq) as an amine) and Method G (using endo / exo racemic bicyclo [2.2.1] hept-5-ene-2-carboxaldehyde). Melting point 172-180 ° C.

Compound 100

3-Bicyclo [2.2.1] hept-5'-en-2'-yl-5,7-dichloro-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1, 2,4-Dichloroaniline 1-dioxide is treated by Method B and Method G (using a racemic endo / exo mixture of bicyclo [2.2.1] hept-5-ene-2-carboxaldehyde. The product is isolated as a mixture of diastereoisomers). Mp 149-151 ° C.

Compound 101

5-Bromo-3-cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Amino-5-sulfamoylbenzenesulfonamide: A stirred suspension of 2-amino-4-chloro-5-sulfamoylbenzenesulfonamide (11.4 g; 40 mmol) and 10% Pd / C (750 mg) in EtOH (300 mL) is hydrogenated under pressure I bar until hydrogen is consumed (24 hours). The reaction mixture was evaporated to dryness, resuspended in THF and filtered through celite. The filtrate was evaporated to dryness and the isolated solid was washed with boiling EtOAc (2 x 150 mL) to give 9.58 g (95%) of the product.

2-Amino-3-bromo-5-sulfamoylbenzenesulfonamide: To a stirred solution of 2-amino-5-sulfamoylbenzenesulfonamide (3.77 g; 15 mmol) in AcOH (50 mL) was added a solution of Br ₂ (0.78 mL; 15 mmol). ) in AcOH (10 mL). The reaction mixture was heated at 70 ° C for 6 days, evaporated to dryness, resuspended in MeOH (85 mL) and KOH solid (3.8 g; 68 mmol) was added. The reaction mixture is heated at 60 ° C for 2.5 hours (hydrolysis of the 3-methyl-, 3-bromomethyl-, 3-dibromomethyl and 3-trifluoromethyl-1,2-dihydro-1,2,4-benzothiadiazine isomers formed in situ), filtered, neutralized and evaporated to dryness to give 3.1 g (63%) of the product by column chromatography.

5-Bromo-3-cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-7,2,4-benzothiadiazine-1,1-dioxide (101): 2-Amino-3-bromo-5-sulfamoylbenzenesulfonamide is treated by Method G (using cyclohexanecarboxaldehyde). Melting point 254-258 ° C.

Compound 102

2-bicyclo [2,2, l] hept-5'-en-2'-yl-6,8-dibromo-l, 2,3,4-tetrahydroquinazoline

2-Amino-3,5-dibromobenzylamine: To a mixture of 2-aminobenzylamine (6.1 g; 50 mmol) in CHCl 3 (100 mL) at 0 ° C is added a solution of Br ₂ (5.1 mL; 100 mmol) in CHCl 3 (45 mL) to maintain the temperature below +2 ° C. The cooling bath was then removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, the precipitate was washed with EtOAc and purified by column chromatography.

2-Bicyclo [2.2.1] hept-5'en-2'-yl-6,8-dibromo-1,2,3,4-tetrahydroquinazoline (102) 2-Amino-3,5-dibromobenzylamine is treated with Method G (using an endo / exo racemic mixture of 2-norbornylenecarboxaldehyde). Mp 240 ° C.

Compound 103

2-Bicyclo [2.2.1] hept-5'-en-2'-yl-6,8-dibromo-4-oxo-1,2,3,4-tetrahydroquinazoline

3,5-Dibromantranilamide: To a stirred suspension of anthranilamide (13.6 g; 0.1 mol) in AcOH (350 mL) was added a solution of Br ₂ (10.3 mL; 0.2 mol). The reaction mixture was stirred at 45 ° C to 120 ° C, poured into H ₂ O (1.5 L) and filtered. Recrystallization (including hot filtration) from 96% EtOH (approximately 1 L) gave 23.6 g (80%) of the product.

2-Bicyclo [2.2.1] hept-5'-en-2'-yl-6,8-dibromo-4-oxo-1,2,3,4-tetrahydroquinazoline (103):

3.5-Dibromantranilamide was treated by Method G (using a racemic endo / exo mixture of bicyclo [2.2.1] hept-5-ene-2-carboxaldehyde). The product is separated into two separate mixtures of diastereoisomers. Melting point (A) 213-215 ° C. Melting point (B) 209-210 ° C.

Compound 104

3-Bicyclo [2.2.1] hept-5'-en-2'-yl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1- dioxide

2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) is treated by Method G (using the endo / exo racemic bicyclo [2.2.1] hept-5-ene-2-carboxaldehyde). The mixture of diastereoisomers is purified by column chromatography to obtain three of the theoretically four possible diastereoisomers. Melting point (A) 202-206 ° C. Melting point (B) 196-199 ° C. Melting point (C) 180-184 ° C.

Compound 105

5,7-Dibromo-3-bicyclo [2.2.1] heptan-2'-yl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 1] Heptane-2-carboxaldehyde: To a stirred suspension of 2-norbomenylenethanol (0.5 mL; 5.8 mmol) and PCC on Al 2 O 3 * in CH 2 Cl 2 (25 mL) was stirred at 2-3 ° C for 1 hour, then Allow to warm slowly to room temperature. The reaction mixture was filtered and the solid was washed with CH 2 Cl 2 (2 x 25 mL). The combined organic fractions were adsorbed onto silica gel and chromatographed to give 300 mg (42%) of the product as an oil.

‘[See Gheng Y. -S, Liu W.-L. and Chen S.-H., Synthesis, (1980) 223.]

5.7-Dibromo-3-norbornanyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (105): 2-Amino-

The 3,5-dibromobenzenesulfonamide (see compound 125) was treated by Method G (using bicyclo [2.2.1] heptane-2-carboxaldehyde). M.p. 182-183 ° C.

Compound 106

3-Cyclohexyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) is treated as follows: G (using cyclohexanecarboxaldehyde). Melting point 166-167 ° C.

100

Compound 107

3-Adamantyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

1- Adamantanecarboxaldehyde: 1-Adamantanecarboxaldehyde is oxidized according to the method used for

2-norbornylmethanol (see compound 105), * [see Cheng Y.-S, Liu W.-L, and Chen S.-H., Synthesis, (1980) 223.]

3-Adamantyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (107):

2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was treated by Method G (using 1-adamantylcarboxaldehyde). Mp 270-273 ° C.

Compound 108

3-Phenyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was treated by Method G (using benzaldehyde). Melting point 186-189 ° C.

Compound 109

3-Ethoxy-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

A stirred mixture of 2-amino-3,5-dibromobenzenesulfonamide (see compound 125) (666 mg; 2 mmol), ethyl orthoformate (15 mL; 90 mmol) and H 2 SO 4 (0.05 mL) was refluxed overnight. The reaction mixture is evaporated to dryness and column chromatography is performed. Melting point 96-98 ° C.

Compound 110

3-methyl-5,7-dibromo-l, 2-dihydro-l, 2,4-benzothiadiazine-l, l-dioxide

A stirred solution of 2-amino-3,5-dibromobenzenesulfonamide (see compound 125) (660 mg; 2 mmol) was refluxed in AC 2 O (25 mL; 265 mmol) overnight. The reaction mixture was poured onto ice and filtered. The isolated solid was washed with Et 2 O. Melting point 287-289 ° C.

Compound 111

3-Cyclohexyl-6-methyl-7- (2'-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide To a tert-BuLi solution (1.7 M) in pentane, 25 mL, 42 mmol) in dry THF at -78 ° C was added 2-bromopyridine (1.9 mL, 20 mmol) such that the temperature did not exceed -70 ° C. The mixture was stirred for an additional 30 minutes at -78 ° C. A solution of ZnCl ₂ (2 M in THF, 30 mL) was added slowly

101 mL, 60 mmol), remove the cooling bath and warm to 20 ° C. Add 5-iodo-2-aminobenzenesulfonamide (see compound 37) (1.0 g, 3.2 mmol) and Pd (PPh 3) ₄ (0.3 g, 8 mol%) and reflux for 6 h. THF was evaporated and the residue was treated with EDTA (53 g, 0.18 mol) and basified slightly (pH = 8-9) with 1 M NaOH, then extracted with EtOAc (3 x 100 mL), dried (Na ₂ SO ₄ ). Concentrate the organic layer to ca. 40 ml and slowly add n-hexane. The product was filtered off to give 0.72 g (87%) of 2-amino-4-methyl-5- (2-pyridyl) -1-benzenesulfonamide as pale yellow crystals. The product is further processed by Method G (using cyclohexanecarboxaldehyde). Melting point 229-231 ° C.

Compound 112

3-Cyclohexyl-6-methyl-7- (4'-triazolyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Iodo-4-methyl-2- The aminobenzenesulfonamide: N -toluidine was treated by Method B and the two isomers separated by column chromatography gave 4-methyl-2-aminobenzenesulfonamide.

To a stirred suspension of 4-methyl-2-aminobenzenesulfonamide (620 mg; 3.3 mmol) in CHCl 3 (7 mL) at 0 ° C was added a solution of iodine chloride (1.6 g; 9.9 mmol) in CHCl 3 (7 mL). ml). The reaction mixture was stirred at 0 ° C until 1 H NMR indicated complete reaction of the starting material. The reaction mixture was filtered and the isolated solid was washed with a small volume of CHCl 3, NaHCO 3 (saturated aqueous solution), H ₂ O and air dried to afford 640 mg (62%) of the product.

-Cyclohexyl-6-methyl-7- (4'-triazolyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (112): 5-iodo-4-methyl The 2-aminobenzenesulfonamide was processed according to Method I (using trimethylsilylacetylene) and Method G (using cyclohexanecarboxaldehyde), FAB ⁺ 348, 1 H NMR (DMSO-d ₆ ): 8.0 (1H, br); 7.65 (1H, br); 7.25 (1H, s); 7.22 (1H, s); 6.95 (1H, br); 6.8 (1H, s); 4.45 (1H, dd); 2.35 (3H, s); 1.95-1.8 (2H, m); 1.8-1.6 (3H, m); 1.3-1.0 (6H, m),

Compound 113

-Cyclohexyl-6-methyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide N-Acetyl-3-methylaniline: m-Toluidine (10 mL; 93 mmol) was added to a stirred solution of acetic anhydride (30 mL). The reaction mixture was stirred for 1.5 hours at room temperature, evaporated to dryness, stirred with H 2 O and filtered to give 13 g of product (94%).

3-Cyclohexyl-6-methyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide:

102

N-acetyl-3-methylaniline is treated by Method A (using 25% NH 3 (aq) as an amine, complete deacetylation) and Method G (using cyclohexanecarboxaldehyde). Mp 231233 ° C.

Compound 114 3-Cyclopentyl-6-methyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide Cyclopentanecarbonyl chloride: Cyclopentanecarboxylic acid (0.55 mL; 5 mmol) is refluxed in thionyl chloride (1 mL) for 3 hours. The reaction mixture was cooled to room temperature, evaporated to dryness and used without further purification.

3-Cyclopentyl-6-methyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (114): m-Toluidine was used as the starting material for the following procedure Workup: Method B [2-amino-6-methylbenzenesulfonamide was separated from 2-amino-4-methylbenzenesulfonamide by recrystallization (EtOAc / hexane)], method E (using cyclopentanecarbonyl chloride), method A (using piperidine as amine), method F. mp 229-230 ° C.

Compound 115

-Cyclohexyl-6-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide n-Toluidine was used as a starting material for the following work-up procedure: Method B [ The 2-amino-6-methylbenzenesulfonamide is separated from the 2-amino-4-methylbenzenesulfonamide by recrystallization (EtOAc / hexane)], Method E (using cyclohexanecarbonyl chloride), Method A (using morpholine as amine), Method F. Mp 268-271 ° C.

Compound 116 3-Cyclohexyl-6- (2-methoxyphenyl) -7-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

3-Bromo-4-methylaniline was subjected to Method B (Isomers separated by fractional crystallization from MeOH) to give 2-amino-4-bromo-5-methylbenzenesulfonamide. A mixture of 2-amino-4-bromo-5-methylbenzenesulfonamide (100 mg, 0.38 mmol), 2-methoxyphenylboronic acid (76 mg, 0.50 mmol), Pd (PPh ₃ ) ₂ C12 (13 mg, 5 mol%) in 1,2-dimethoxyethane (20 mL) and Na ₂ CO 3 (2 M, 1 mL, 2 mmol) were refluxed under N ₂ for 4 hours. The solvents were removed under reduced pressure and the residue was treated with saturated NaHCO ₃ (10 mL) and extracted with EtOAc (2 x 25 mL). The organic layer was washed with brine (20 mL), dried (Na ₂ SO 4), and the solvent was removed under reduced pressure. The product was purified by flash column chromatography using silica gel

103 eluting with EtOAc: n-hexane (1: 1, v / v) as eluent to give 100 mg (90%) of 2-amino-4- (2-methoxyphenyl) -5-methylbenzenesulfonamide as a colorless powder. The product is further processed by Method G (using cyclohexanecarboxaldehyde). Melting point 172-175 ° C.

Compound 117

3-Cyclohexyl-6-methoxy-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide m-Anisidine was used as a starting material for the following work-up procedure: Method B [2] -amino-6-methoxybenzenesulfonamide is separated from 2-amino-4-methoxybenzenesulfonamide by flash chromatography (EtOAc / hexane)], Method C, Method A (using piperidine as amine), Method D, Method G (using cyclohexanecarboxaldehyde). Mp 237-240 ° C.

Compound 118 and Compound 122 3-Cyclohexyl-7,8-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (122) and 3-cyclohexyl-6,7- Ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (118) 6-Amino-1,4-benzodioxane is used as the starting material and is processed to a mixture of isomers of ethylenedioxy- 2-aminobenzenesulfonamide using Method B. Two isomers are separated by column chromatography.

3-Cyclohexyl-6,7-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (118):

The 2-amino-5,6-ethylenedioxybenzenesulfonamide is processed according to Method G (using cyclohexanecarboxylaldehyde). Melting point 196-200 ° C.

3-Cyclohexyl-7,8-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (122):

The 2-amino-7,8-ethylenedioxybenzenesulfonamide is processed according to Method G (using cyclohexanecarboxylaldehyde). Mp 268-270 ° C.

Compound 119

3-Cyclohexyl-6-chloro-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-4-chloro-5-sulfamoylbenzenesulfonamide is processed by Method G (using cyclohexanecarboxaldehyde). Mp 274-276 ° C.

104

Compound 120

3-Phenyl-6-chloro-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Amino-4-chloro-5-sulfamoylbenzenesulfonamide was treated by Method G (using benzaldehyde). Mp 235-238 ° C.

Compound 121

3-Cyclohexyl-6-bromo-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide m-Bromoaniline was used as the starting material for the following work-up procedure: Method B The [2-amino-6-bromobenzenesulfonamide is separated from the 2-amino-4-bromobenzenesulfonamide by recrystallization (EtOAc / hexane), Method C, Method A (using piperidine as amine), Method D, Method G (using cyclohexanecarboxaldehyde). Mp 238-241 ° C.

Compound 122

See Compound 118.

Compound 123

2-Cyclohexylmethylamino-5- N, N -dimethylsulfamoylbenzenesulfonamide 2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method E (using cyclohexanecarbonyl chloride), Method A (using dimethylamine as amine), Method F (reaction mixture allowed to stir) overnight (at room temperature). Melting point 123-125 ° C.

Compound 124

2-ethylamino-7- (I ', ^{2, 3, 6,} -tetrahydropiperidino) sulfonylbenzénsulfónamid

3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (see compound 73) is treated by Method A (using 1,2,3,6-tetrahydropyridine as the amine) followed by Method F ( using LiAlFU and at room temperature). Melting point 175-177 ° C.

Compound 125

2-Amino-3,5-dibromobenzenesulfonamide

To a stirred solution of 2-aminobenzenesulfonamide (8.6 g; 50 mmol) in AcOH (100 mL) was slowly added a solution of Br ₂ (5.13 mL; 100 mmol) in AcOH (20 mL). The reaction mixture was heated at 55 ° C for 60 hours, poured into ice water (800 mL), filtered, adsorbed onto silica

105 gel and purified by column chromatography to give 11.1 g (67%) of the product. Mp 165-169 ° C.

Compound 126

2- Acetamidobenzenesulfonamide

To a stirred solution of 2-aminobenzenesulfonamide (1.72 g; 10 mmol) and triethylamine (1.53 mL;

mmol) in THF (25 mL) at 0 ° C was added AcCl (0.85 mL; 12 mmol) and allowed to stir at room temperature overnight. The reaction mixture was filtered and adsorbed onto silica gel. Column chromatography gave 1.7 g (79%) of the product. Mp 153.5-155.5 ° C.

Compound 127

3-Isobutyl-8- (piperidinosulfonyl) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide N- (3'-Methyl-1'-carboxybutyl) -2-nitrobenzenesulfonamide: To a solution of 2-nitrobenzenesulfonyl chloride (11 g; 50 mmol) and NaOH (2.1 g; 53 mmol) in H 2 O (100 mL) was added DL-leucine (6.55 g; 50 mmol) and allowed to stir overnight at room temperature. Add 4 M NaOH (12.5 mL) to the reaction mixture and filter. The filtrate was acidified with 1 M HCl (50 mL) and extracted with EtOAc. The combined organic fractions were dried (Na ₂ SO ₄ ) and evaporated to dryness to give 6.7 g (42%) of the product.

3-Isobutyl-4-oxo-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide: A mixed suspension of N (3'-methyl-1'-carboxybutyl) -2-nitrobenzenesulfonamide ( 6.7 g (21.2 mmol) and 10% Pd / C (200 mg) in absolute EtOH were hydrogenated at 1 bar. The reaction mixture was filtered through celite and evaporated to dryness. To a solution of the crude product in dry THF (50 mL) at 0 ° C was added N-hydroxysuccinimide (2.53 g; 22 mmol) and DCC (4.54 g; 22 mmol). The reaction mixture was slowly warmed to room temperature and allowed to stir overnight. The reaction mixture was filtered and the solid washed with THF. The combined organic fractions were evaporated to dryness and H ₂ O was added to the residue and extracted with EtOAc. The combined organic fractions were dried (Na ₂ SO ₄ ) and evaporated to dryness to give 3 g (53%) of the product.

3-Isobutyl-8-piperidinosulfonyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide: To a solution of 3-isobutyl-4-oxo-2,3,4,5- tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide (500 mg; 1.8 mmol) in dry THF (20 mL) under N ₂ at 0 ° C was added a solution of 2 M BH ₃ * SMe ₂ (9.2 mL; 18 mmol) in THF. After complete reaction, the reaction mixture was warmed to room temperature and then refluxed for 2 hours. Cool the reaction mixture to room temperature

106 was quenched by the addition of 6 M HCl (15 mL). The reaction mixture was strongly basified by addition of 7.5 M NaOH (aq) and extracted with EtOAc. The combined organic fractions were dried (Na ₂ SO 4) and evaporated to dryness to afford 320 mg (70%) of the product. The product is worked up by Method A (using piperidine as the amine). Mp 209-211 ° C.

Compound 128

3-Cyclohexyl-8- (piperidinosulfonyl) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide DL-Cyclohexylglycine: To NaCN solution (15.9 g; 0.32 mol) ) in H ₂ O (60 mL) was added NH 4 Cl (17 g; 0.32 mol) followed by a solution of cyclohexanecarboxaldehyde (37 mL; 0.31 mol) in MeOH (60 mL). The reaction mixture was stirred vigorously for 2 hours at room temperature. The reaction mixture was diluted with H ₂ O (100 mL) and extracted with toluene (2 x 70 mL). The combined organic phases were washed with H ₂ O (2 x 50 mL) and extracted with 6 M HCl (2 x 90 mL). The acidic aqueous phases and the precipitate formed after acidification are combined and refluxed for 24 hours. The reaction mixture was cooled to room temperature and gently basified (using 25% NH 3 (aq)). The precipitate formed is collected by filtration, washed with cold H ₂ O and air dried to give 13 g (26%) of the free amino acid.

Compound 128 was synthesized according to the method used for compound 127 (using DL-cyclohexylglycine as the amino acid).

Compound 129 3-Cyclohexyl-7-cyclopentylsulfinyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Amino-5-cyclopentylthiobenzenesulfonamide: A mixture of 5-iodo-2-aminobenzenesulfonamide (1.192 g; 4 mmol), triethylamine (750 μΐ; 10 mmol), CU1 (76 mg; 0.4 mmol); cyclopentyl mercaptan (590 μΙ; 6 mmol) and Pd (Ph ₃ ) 4 (462 mg; 0.4 mmol) in dry dioxane (10 mL) were stirred under N ₂ in a sealed vial at 130 ° C overnight. The reaction mixture was cooled to room temperature, diluted with H ₂ O, basified (using 4 M NaOH) and filtered through Celite. The filtrate was neutralized to pH 8.5 and evaporated to dryness. Column chromatography gave 327 mg (30%) of the product.

3-Cyclohexyl-7-cyclopentylsulfinyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (129): 2-Amino-5-cyclopentylthiobenzenesulfonamide is brominated at the 3-position of the ring and S -oxidizes under

107 titles described by Ali and Bohnert (in Synthesis, (1998) 1238), using 2 equivalents of Br ₂ . The product was reduced at 1 bar using 5% Pd / C in 96% EtOH and worked up by Method G (using cyclohexanecarboxaldehyde).

The following tables summarize the compounds described:

108

3,7-disubstituted single bonded compounds

- about Xp 3,6-disubslilui oo 3,3-disubstituted -J hJ Xu B. S O “W r * <- * pq - 3-mono-substitution P · ΙΛ O WHAT O M WHAT O M n II o WHAT About it WHAT ίΛ _M o o II O After n II o Q & 0 FROM. FROM FROM about from from x ABOUT about from FROM 0 W jednod Jednod. n g · o Q- Jednod. l__ Jednod. Jednod. J Jednod. 1 | Jednod. | jednod S * g · g. | Jednod. type of binding X X x x X x x x x x * cyclohexyl n π o 5 x n X o · * n x s w Q X 'C) phenyl WITH* £ about x w | phenyl n? r Q »* About X · <· X x x g o. N 1 ituované x ituované x x 1 T X x <i CD * N & X x x tičeniny sj Simplyc x compounds with one x compounds with one x x x x X x účeniny sj simplec Ut P P P α <F by hammers x in unusual ties x in unusual ties x x x x x x by hammers 53 A x x x x x x x x x x x n M x x X x X x x x x x x JO

109

hJ w N) M M about \ c 00 Σ5 with LH U) ts> rx B O bJ WHAT O bj CO O n> GQ O K) tn O frJ WHAT F / 3 .P (Λ P WHAT .P w O n » with. M O N> n FROM FROM FROM FROM from FROM from from from FROM from FROM ABOUT H jednod jednod jednod jednod 'Jednod. jednod Jednod. Jednod. jednod jednod Jednod. jednod type of binding X X X X x X X X X X X ΣΕ WITH M cyclohexyl cyclohexyl O se X g · fp x cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyl * < F SP o x se. cyclohexyl w X X x X x x X X X X x X X X x X x x X X x x hr j; pM IN" x x x X x x X x x x x x n ž v) <? o <? p o «F Ά P P / ^ZI ° = <of phenyl Q z m Y * about c? with Y 8 x x X x x X x x x x x x M A * •ABOUT

110

GJ GJ GJ Gj NJ GJ GJ ABOUT \about WHAT N> NJ O \ NJ Ul ro Q < CO O CO p> CO _w o CO o WHAT CO _w o WHAT WHAT WITH CO s> with. WHAT ABOUT from from from from from from FROM 2 from from from about N Jednod. Jednod. Jednod. Jednod. Jednod. Jednod. Jednod. Jednod. Jednod. Jednod. Jednod. x X X X X X X X X x X 50 »4 cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyl w X X X x X X X X X X X 50 x x x X x X x X X »-U X » x x x x x X x x X X x 90 Ot P o J Q P P P After P • ω z o x 90 • 4 T X x x x x x x x x x 90 «

111

.u • * 4 • U Os wl .For -U N) N> Ό about \about U3 00 u> axis OJ Lh about ΙΛ s> o ►? WHAT O w CO P n II o n of NJ 03 P 03 ABOUT M 03 O nj 03 O hu 03 P 03 P 03 P 03 P n from from FROM from from FROM FROM FROM from from from from from from o M Jednod. re & o Q. o & o Q. ίο Q. 5 O Q. c. <P Q. 3 O Q. u (D § · o Q. c. (P Q. 3 O Q. <(P Q. 3 O p. c. (P Q. 3 O Q. πΓ & about Q. C. (D Q. 3 O Q. C (D Q. 3 O Q. c. CP Q. 3 O Q. CD Q. 3 O from FROM • T * from from from from from from from from from from from w cyclohexyl «2 x c y CP x n of «Ρ o * < X ABOUT 5 rp x * <. n * <x * o o * n x * < n * < x * o y n x n * < xF 5 rt x n * < X * ABOUT 3 CP X o * < x · o sr (P x * <_ * <o D * CP x n about sr fp x * <_ n ? r & CP x n VÉ x · ABOUT CP x * <_ n * < π ABOUT 3 · CP X <<, from at FROM from from from from from from T ^- from from from from from X FROM from from from from from from from from from from from from from 93 ui from from from from from from from from from from from from from from 93 • t J _and X \ _Z O T * 8 rU Ae J z CO o M ►F of CO P X of CO M ^O TJ 3 * CO o N % ° = _M oz n x 03 P from x n from U) n o z z y , ² « _? in 93 «4 from from FROM FROM FROM FROM FROM from from from from from from from 93 «6

112

vn O Vi u * IN) U) Ml M in* Lh O Ä. within 00 Q * CO O WHAT P CO O bJ CO O h> Ui About »» WHAT .P CO P> (Λ o M to O N) ABOUT FROM from FROM FROM from FROM FROM FROM FROM ft W Jednod. Jednod. Jednod. Jednod. Jednod. Jednod. Jednod. 1 Jednod. Jednod. type of binding from X FROM FROM X FROM x X X 'WITH. cyclohexyl Cyclopenlyl n J = •in B propyl isopropyl cyclopropyl 2 cyclohexyl cyclohexyl % FROM X WITH X X X x X X from FROM x X rr X x X x * from from from from from x from x from Q. Q. O 0 0 * Q, Q. Q _and \ <P wí Q. Q. trie m / m-z ~ \ A3 from from x x x x x x X x 00

113

O Ul

3,7-disubstituted compounds with double bonds

£ o CJ o * tu i> Os G Ul \ s Ul OG WI * 4 r> co O M WHAT O K> WHAT OK) What about here WHAT WHAT ° F CO O w about from FROM from FROM from FROM from FROM n M Jednod. Φ § o Q. c. (D & about CL cd Q. 3 O □. c. CD & ABOUT P- c CD 3 · O p. CD & o p. « & o Q. H <3? X X x x x - · · 7Z hj c * <sr w G X n 5 cľ c? x n * <gr n x ¹ cyclolxyxy r. * < 7Γ E G x r. E £ G X * <_ r, * 55Γ with X * <_ p * · * W X j; n- x • M X • T " Λ. x X «Μ u- u. χ X X x X ul x x x x X - X = X c * CZ n 0 _° \><° in (A í <χ a cP «« » « K.e * ή'ο about <N < Q, £ tn x «J X x - - = • T " X x oc

114

* 4 O \ xj Ml * 4 * 4 UJ • xj N) -4 -xj o about σ * 00 O \ • U ch Q * WHAT CO O NJ CO o CO _M o tA O M c = o Q II O c = o 1 After 9 about n II O n to » FROM FROM FROM FROM FROM from FROM from from from FROM ABOUT H double nondef. double nondef. double nondef. double nondef. double nondef. double) Sunday. double nondef. double nondef. double nondef. double nondef. double nondef. type of binding z— \ X x * W * z> x </ x &apos; x Z-> x 0x x 'M' X z * x x Z * x X z * x x <z x n * n W o, x u> n x UJ n J 2 M cyclohexyl • n L · » n Ί1 ω about T) ω n .u UJ o n ω x z — x X v ** x x x * X Z “X x z — x X X z-x x x x * x x x x x x x x x X X x x x x x x X X X x x & f s V » "9 X 0 o 0 ' f ^{- -} * <° %% x N * FROM ΙΛ O txj x Ν » from CZ) O N) O _o ' _w * ° «/ ^ 0 Q \ <O « hi » nF z F / 3 O N> x X x X x X x x x x X £ 5 M>

115

double (H) CFj (H) HH HOSO _{2 no} def. ______'___

116

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117

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Claims (30)

PATENT CLAIMS 1. A compound represented by the general formula (I): where X is C = O or CH ₂ ; and Y is CH (R ⁴ ), N (R ⁴ ) or N (R ⁴ ) -CH ₂ or O; aa Λ R is hydrogen, alkyl, cycloalkyl, aryl, benzyl, or -CO-R, wherein R ⁹ is alkyl, cycloalkyl, benzyl, or aryl; or R ^{2, taken} together with R ³ and the atoms to which they are attached, forms a 4 to 7 membered ring which is optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy , amino groups, thio groups and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R ³ represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR ¹³ R ¹⁴ or alkyl-SR ¹³ , wherein R ¹³ and R ¹⁴ independently represent an atom hydrogen, alkyl or cycloalkyl; or R ¹³ and R ¹⁴ together with the nitrogen to which they are attached form a 3 to 8 membered heterocyclic ring structure; or R ³ represents a carbocyclic 7-membered to 12-membered ring, 121 which is optionally substituted with halogen, alkyl, hydroxy or alkoxy; or R ³ represents a heterocyclic 3-membered to 8-membered ring which is optionally substituted by halogen, alkyl, hydroxy or alkoxy and optionally the heterocyclic ring is fused to aryl; or R ³ represents benzyl which is optionally substituted with one or more substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino, thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio and alkylamino; or R ³ represents aryl which is optionally substituted by one or more substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino, thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio and alkylamino; or R ^{3, taken} together with the substituent R ² or R ⁴ and the atoms to which they are attached, forms a 4-membered to 7-membered ring which is optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy , alkoxy groups, amino groups and thio groups and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R ⁴ represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R ¹⁰ or -CO 2 R ¹⁰ , wherein R ¹⁰ represents hydrogen, cycloalkyl, alkyl, aryl or benzyl; or R ^{4, taken} together with R ³ and the atoms to which they are attached, forms a 4-membered or 7-membered ring, 122 which is optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino and thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R ⁵ represents a hydrogen atom, halogen, alkyl, alkenyl, alkynyl or aryl; or R ⁵ represents -SO 2 -NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R ¹¹ and R ¹² together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted by halogen, alkyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, - SO 2 -alkyl, -SO ₂ -aryl, or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl; and R ⁶ represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl or cyclohalogenoalkyl; or R ⁶ represents -NR ¹⁵ R ¹⁶ , -NHSO ₂ -R ¹⁵ or -NHSO ₂ -aryl, wherein the aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, -CF 3, -OCF 3, -NO 2, and aryl; wherein R ¹⁵ and R ¹⁶ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure which is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio a group, aryl, benzyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl and the optionally heterocyclic ring is fused to aryl; or 123 R ⁶ represents aryl which is optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl and amino; or R ⁶ represents HET, which is optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and haloalkoxy; or ^; Rf is - (alkyl) mSR ^15; - (alkyl) m-SO-R ¹⁵ ; - (alkyl) m -SO 2 -R ¹⁵ ; - (alkyl) m SO ₂ OR ^15; - (alkyl) m-SO 2 -NR ¹⁵ R ¹⁶ ; - (alkyl) m-NHCOR ¹⁵ ; - (alkyl) m-CONR ^{, 5} R ^{, <5} ; - (alkyl) m-CR '= NOR; - (alkyl) _m -CO-R ¹⁵ ; - (alkyl) _m -CO ₂ -R ¹⁵ , wherein the index m is 0 or 1; and R 'and R' independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl or benzyl; and R ¹⁵ and R ¹⁶ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl , benzyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl; and R ⁷ represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl or cyclohalogenoalkyl; or R ⁷ represents -NR ¹⁷ R ¹⁸ , -NHSO 2 -R ¹⁷ or -NHSO 2 -aryl, wherein the aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF ₃ , -OCF ₃ , -NO ₂ , aryl; or 124 R ⁷ represents - (alkyl) mSR ¹⁷ ; - (alkyl) m-SO 2 -R ^17; - (alkyl) m-SO 2 -R ¹⁷ ; - (alkyl) m SO ₂ OR ^17; - (alkyl) in-SO 2 -NR ¹⁷ R ¹⁸ ; - (alkyl) m-NHCOR ¹⁷ ; - (alkyl) m-CONR ¹⁷ R ¹⁸ ; - (alkyl) m-CR 1 = NOR '- (alkyl) _m -CO-R ¹⁷ or - (alkyl) _m -CO 2 -R ¹⁷ , wherein the index m is 0 or 1; and R 'and R' are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl , benzyl, SCh-alkyl, SO2-aryl or SCh-benzyl; and optionally the heterocyclic ring is fused to aryl; or R ⁷ represents HET, which is optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, -SO- alkyl, -SO-aryl, -SO2alkylu, -SO 2 aryl, -SO 2 NR ¹⁷ or R ^18; or R ⁷ represents aryl which is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, -NHCOalkyl, nitro, -OCF _3, or - SO 2 -NR ¹⁷ R ¹⁸ wherein R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl , benzyl, -SO2-alkyl, -SC2-aryl or -SO2-benzyl; and optionally the heterocyclic ring is fused to aryl; or 125 R ⁷ together with R ⁶ , or together with R ⁸ , forms a 5- to 7-membered ring having one of the following structures -O- (CH ₂ ) _n -O-; wherein n is 1, 2 or 3; -SO ₂ -NR- (CH ₂ ) _n -, wherein R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and the index n is 1 or 2; -SO-NR- (CH ₂ ) _n - wherein R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and n is 1 or 2; -SO ₂ - (CH ₂ ) _n - wherein the index n is 2 or 3; -SO- (CH ₂ ) _n - wherein the index n is 2 or 3; -CO-CH = CH-NH-; -CO-CH = CH-O-; -CO- (CH ₂ ) n -N-, wherein the index n is 1 or 2; -CO-NH- (CH ₂ ) n -, wherein the index n is 1 or 2; -CO- (CH ₂ ) ₂ -O-; or -O- (CH ₂ ) _n -O-; wherein n is 1, 2 or 3; and R ⁸ represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro or nitroalkyl; or R ⁸ represents aryl, optionally substituted with one or more substituents selected from the group consisting of halogen, -CF ₃ , -OCF ₃ , -NO ₂ , alkyl, cycloalkyl and alkoxy; or R ⁸ represents HET, optionally substituted with one or more substituents selected from the group consisting of halogen, -CF ₃ , -OCF ₃ , -NO ₂ , alkyl, cycloalkyl and alkoxy; or R ⁸ is - (alkyl) mSR ¹⁹ ; - (alkyl) m-SO-R ¹⁹ ; - (alkyl) m -SO 2 -R ¹⁹ ; - (alkyl) m SO ₂ OR ^19; - (alkyl) m -SO 2 -NR ¹⁹ R ²⁰ ; - (alkyl), n-NHCOR ¹⁹ ; - (alkyl) m-CONR ¹⁹ R ²⁰ ; - (alkyl) m-CR '= NOR; - (alkyl) _m -CO-R ¹⁹ ; or - (alkyl) _m -CO ₂ -R ¹⁹ , wherein 126 the index m is 0 or 1; and R 'and R' independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl or benzyl; and R ¹⁹ and R ²⁰ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl, or R ¹⁹ and R ²⁰ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl; or a compound represented by the general formula I, wherein X represents SO ₂ ; and Y is CH (R ⁴ ), N (R ⁴ ), N (R ⁴ ) -CH ₂ or O; and R represents a hydrogen atom; and R ³ represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, alkyl-NR ¹³ R ¹⁴ or alkyl-SR ¹³ , wherein R ¹³ and R ¹⁴ independently represent hydrogen, alkyl or cycloalkyl; or R ¹³ and R ¹⁴ together with the nitrogen to which they are attached form a 3 to 8 membered heterocyclic ring structure; or R ³ represents a carbocyclic 7-membered to 12-membered ring optionally substituted by halogen, alkyl, hydroxy or alkoxy; or R ³ represents a heterocyclic 3- to 8-membered ring optionally substituted by halogen, alkyl, hydroxy or alkoxy; and optionally the heterocyclic ring is fused to aryl; or 127 R ³ represents benzyl which is optionally substituted with one or more substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino, thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio and alkylamino; or R ^{3, taken} together with R ⁴ and the atoms to which they are attached, forms a 4 to 7-membered ring which is optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy , amino groups and thio groups and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R ⁴ represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R ¹⁰ or -CO 2 R ¹⁰ , wherein R ¹⁰ represents hydrogen, cycloalkyl, alkyl, aryl or benzyl; or R ⁴ together with R ³ and the atoms to which they are attached form a 4 to 7 membered ring which is optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy , amino groups and thio groups and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R ⁵ is H, halogen, alkyl, alkenyl, alkynyl, and aryl, or -SO-NR ¹ ^ ^'2, wherein R ¹¹ and R ¹² independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R ¹¹ and R ¹² together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted by halogen, alkyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, - C1-C8-alkyl, -SC2-aryl or -SC2-benzyl; and optionally the heterocyclic ring is fused to aryl; 128 R ⁶ is H, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, or cyclohaloalkyl; or R ⁶ is -NR ^{1 S} R ^16, -NHSO 2 R ¹⁵ or -NHSCfe-aryl, wherein the aryl is optionally substituted by one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, - CF 3, -OCF 3, -NO 2, and aryl; wherein R ¹⁵ and R ¹⁶ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure which is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio a group, aryl, benzyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO 2 -benzyl and the optionally heterocyclic ring is fused to aryl; or R ⁶ represents aryl which is optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl and amino; or R ⁶ represents HET, optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, and haloalkoxy; or R ⁶ represents - (alkyl) mSR ¹⁵ ; - (alkyl) m-SO-R ¹⁵ ; - (alkyl) m -SO 2 -R ¹⁵ ; - (alkyl) mSO ² OR ¹⁵ ; - (alkyl) m-SO 2 -NR ¹⁵ R ¹⁶ ; - (alkyl) m-NHCOR ¹⁵ ; - (alkyl) m-CONR ¹⁵ R ¹⁶ ; - (alkyl) m-CR '= NOR "; - (alkyl) _m -CO-R ¹⁵ ; or - (alkyl) _m -CO ₂ -R ¹⁵ , wherein m is 0 or 1; and R 'and R' independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl or benzyl; and 129 substituents R ¹⁵ and R ¹⁶ independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl , benzyl, -SO-alkyl, _-SO2 -aryl and _-SO2-benzyl; and optionally the heterocyclic ring is fused to aryl; and R ⁷ represents halogen, alkyl, cyano, cyanoalkyl, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl or cyclohalogenoalkyl; or R ⁷ represents -NR ¹⁷ R ¹⁸ , -NHSO 2 -R ¹⁷ or -NHSO 2 -aryl, wherein the aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF 3, -OCF 3, -NO 2, and aryl; or R ⁷ represents - (alkyl) mSR ¹⁷ ; - (alkyl) ^{m-SO-R, 7} ;-( alkyl) ^m-SO2-R17; - (alkyl) mSO 2 OR ¹⁷ ; - (alkyl) m-NHCOR ¹⁷ ; - (alkyl) m-CONR ¹⁷ R ¹⁸ ; - (alkyl) m -CR '= NOR; - (alkyl) m-CO-R * ⁷ or - (alkyl) m-CO ₂ -R ¹⁷ , wherein the index m is 0 or 1; and R 'and R' independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl or benzyl; and R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl , benzyl, -SC2-alkyl, -SO2-aryl or -SO2-benzyl; and optionally the heterocyclic ring is fused to aryl; or 130 R ⁷ is - (alkyl) _m -SO 2 -NR ¹⁷ R ¹⁸ , wherein m is 0 or 1; and R ¹⁷ and R ¹⁸ independently of each other represent alkyl, cycloalkyl, benzyl or aryl; or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl , benzyl, -S0 ₂ -alkyl, -SO 2 -aryl and -SO 2 benzyl; and optionally the heterocyclic ring is fused to aryl; or R ⁷ represents HET, which is optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, -SO- alkyl, -SO 2 aryl, -SO ₂ alkyl, -SO ₂ -aryl and -SO ₂ NR ¹⁷ R ¹⁸ ; or R ⁷ represents aryl which is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, -NHCOalkyl, nitro, -OCF 3 and -SO ₂ -NR ¹⁷ R ¹⁸ wherein R and R independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl , benzyl, -SC2-alkyl, -SO2-aryl or -SC2-benzyl; and optionally the heterocyclic ring is fused to aryl; or 131 7 7 · 8 R together with R, or together with R, forms 5-membered to 7-membered ring having one of the following structures -O- (CH ₂ ) _n -O-; wherein n is 1, 2 or 3; -SO ₂ -NR- (CH ₂ ) _n -, wherein R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and the index n is 1 or 2; -SO-NR- (CH ₂ ) _n - wherein R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and n is 1 or 2; -SO ₂ - (CH ₂ ) _n - wherein the index n is 2 or 3; -SO- (CH ₂ ) _n - wherein the index n is 2 or 3; -CO-CH = CH-NH-; -CO-CH = CH-O-; -CO- (CH ₂ ) _n -NH-, wherein the index n is 1 or 2; -CO-NH- (CH ₂ ) _n wherein the index n is 1 or 2; -CO- (CH ₂ ) ₂ -O-; or -O- (CH ₂ ) _n -O-, wherein the index n is 1, 2 or 3; and R ⁸ represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro or nitroalkyl; or R ⁸ represents aryl, optionally substituted with one or more substituents selected from the group consisting of halogen, -CF 3, -OCF 3, -NO ₂ , alkyl, cycloalkyl and alkoxy; or R ⁸ represents HET, optionally substituted with one or more substituents selected from the group consisting of halogen, -CF 3, -OCF ₃ , -NO ₂ , alkyl, cycloalkyl and alkoxy; or R ⁸ represents - (alkyl), "- SR ¹⁹ ; - (alkyl) _m -SO-R ¹⁹ ; - (alkyl) m -SO 2 -R ¹⁹ ; - (alkyl) m SO ₂ OR ^19; - (alkyl) _m -SO ₂ -NR ¹⁹ R ²⁰ ; - (alkyl) _m -NHCOR ¹⁹ ; - (alkyl) m-CONR ¹⁹ R ²⁰ ; - (alkyl) m-CR '= NOR "; - (alkyl) _m -CO-R ¹⁹ ; or - (alkyl) _m -CO ₂ -R ¹⁹ , 132 wherein m is 0 or 1; and R 'and R' are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl or benzyl; and R ¹⁹ and R ²⁰ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl, or R ¹⁹ and R ²⁰ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO-alkyl, -SO2-aryl and _-SO2-benzyl; and optionally the heterocyclic ring is fused to aryl; but provided that when X is SO 2 and Y is NR ⁴ , and when one of R ⁵ , R ⁶ , R ⁷ or R ⁸ is halogen or an alkyl or alkoxy group, then one or more of the remaining R ⁵ , R ⁷ substituents ⁶ , R ⁷ or R ⁸ is not / are not also halogen or alkyl, and then one or more of the remaining substituents R ⁵ , R ⁶ , R ⁷ or R ⁸ is not / are not hydrogen. A compound according to claim 1 which is a 1,2,4-benzothiadiazine derivative having the general formula (II) wherein: 133 R ³ represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, alkoxy, carbocyclic 7-membered to 10-membered ring, heterocyclic 5-membered to 6-membered ring, or benzyl; or R ³ together with R ⁴ forms a 5-membered to 6-membered ring; and R ⁴ represents a hydrogen atom or an alkyl group; R ⁴ together with R ³ and the atoms to which they are attached form a 5 to 6 membered ring which is optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy , amino groups and thio groups and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R ⁵ is H, halogen, alkyl, alkenyl, alkynyl, phenyl, or Soya-NR ^2, wherein R ¹¹ and R ¹² independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R and R together with the nitrogen to which they are attached form a 5-membered to 6-membered heterocyclic ring structure; R ⁶ represents a hydrogen atom, Br, F, I, cycloalkyl, alkyl, alkoxy or alkoxyalkyl; or R ⁶ represents phenyl, which is optionally substituted with one or more substituents selected from the group consisting of alkyl and alkoxy; or R ⁶ represents HET; or R ⁶ is -SR ^15, -SO-R ^15, -SO 2 R ^15, -SO2OR ^15, -SO 2 NR ¹⁵ R ^16, -NHCOR ^15, CONR ¹⁶ R ^I5, -CR '= N0R, -CO- R ¹⁵ or -CO 2 -R ¹⁵ , wherein R 1 and R 3 independently represent hydrogen, alkyl, cycloalkyl, phenyl or benzyl; and R ¹⁵ and R ¹⁶ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl , benzyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl; and R ⁷ represents Br, F, I, alkyl, cyano, cyanoalkyl, nitroalkyl; alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohalogenoalkyl, - (alkyl) m-NR ¹⁷ R ¹⁸ , -NHSO 2 -R ¹⁷ , -SR ¹⁷ ; -SO-R ^17; -SO 2 -R ¹⁷ ; -SO2OR ¹⁷ ; -NHCOR ¹⁷ ; -CONR ¹⁷ R ¹⁸ ; -CR 1 = NOR -CO-R ¹⁷ or -CO ₂ -R ¹⁷ ; wherein m is 0 or 1; and R 'and R' independently represent hydrogen, alkyl, cycloalkyl, phenyl or benzyl; and R and R independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or the radicals R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached forms a heterocyclic 3-to 8 membered ring structure optionally substituted with alkyl, _-SO2 -alkyl, _-SO2 -aryl, _-SO2-benzyl, and optionally the heterocyclic ring is fused to aryl; or R ⁷ represents - (alkyl) _m -SO ₂ NR ¹⁷ R ¹⁸ wherein m is 0 or 1; and R ¹⁷ and R ¹⁸ independently of each other represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio 135, aryl, benzyl, -SC2-alkyl, -SO2-aryl or -SC2-benzyl; and optionally the heterocyclic ring is fused to aryl; or R ⁷ represents HET, optionally substituted with one or more substituents selected from halogen, alkyl, phenyl and -SO 2 NR ¹⁷ R ¹⁸ ; or R ⁷ represents phenyl, optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, halogen, haloalkyl, amino, -NHCO-alkyl, nitro, -OCF 3, or -SO 2 -NR ¹⁷ R ¹⁸ , wherein R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, -SO 2 alkyl, -SC-aryl or -SC-benzyl; and optionally the heterocyclic ring is fused to aryl; or R ⁷ together with R ⁶ , or together with R ⁸ , forms a 5-membered to 7-membered ring having one of the following structures -O- (CH ₂ ) _n -O-, wherein the index n is 1, 2 or 3; -SO ₂ -NR- (CH ₂ ) _n -, wherein R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and n is 1 or 2; -SO-NR- (CH 2) _n -, wherein R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and n is 1 or 2; -SO ₂ - (CH 2) _n - wherein the index n is 2 or 3; -SO- (CH ₂ ) _n - wherein the index n is 2 or 3; -CO-CH = CH-NH-; -CO-CH = CH-O-; -CO- (CH 2) _n -NH- wherein the index n is 1 or 2; -CO-NH- (CH 2) _n wherein n is 1 or 2; 136 -CO- (CH ₂ ) ₂ -O-; or -O- (CH ₂ ) _n -O-, wherein the index n is 1, 2 or 3; and R ⁸ represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro or nitroalkyl; or R ⁸ represents phenyl, optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl and alkoxy; or R ⁸ represents HET; or R ⁸ is -SR ¹⁹ ; -SO-R ¹⁹ ; -SO 2 -R ¹⁹ ; -SO 2 O-R ¹⁹ ; -SO ₂ -NR ¹⁹ R ²⁰ ; -NHCOR ¹⁹ ; -CONR ¹⁹ R ²⁰ ; -CR '= NOR "; -CO-R ¹⁹ or -CO ₂ -R ¹⁹ , wherein R 'and R' are independently hydrogen, alkyl, cycloalkyl, phenyl or benzyl; and R ¹⁹ and R ²⁰ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁹ and R ²⁰ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl , benzyl, -SO ₂ -alkyl, -SO ₂ -aryl, -SO ₂ -benzyl, and optionally a heterocyclic ring is fused to aryl. A compound of formula I according to claim 1, wherein R is hydrogen, alkyl, cycloalkyl, phenyl or benzyl. A compound according to any preceding claim, wherein R ³ represents a hydrogen atom, a cycloalkyl, an alkyl, a haloalkyl, an alkoxy group, a carbocyclic 7-membered to 10-membered ring, a heterocyclic 5-membered to 6-membered ring, or benzyl; or 137 R ³ together with R ⁴ forms a 5-membered to 6-membered ring, optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, and thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups. A compound according to any preceding claim, wherein R ⁴ represents a hydrogen atom or an alkyl; or R ⁴ together with R ³ and the atoms to which they are attached form a 5 to 6 membered ring which is optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy , amino groups and thio groups and optionally containing one or more heteroatoms and optionally containing carbonyl groups. A compound according to any preceding claim, wherein R ⁵ represents a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, phenyl or -SO 2 -NR ¹¹ R ¹² , wherein R and R independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹¹ and R ¹² together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure. A compound according to any preceding claim, wherein R ⁶ represents a hydrogen atom, halogen, cycloalkyl, alkyl, alkoxy or alkoxyalkyl; or R ⁶ represents aryl, optionally substituted with one or more substituents selected from the group consisting of alkyl and alkoxy; or 138 R ⁶ represents HET; or R ⁶ is -SR ^15, -SO-R ^15, -SO 2 R ^15, -SO 2 R ^15, -SO 2 NR ¹⁵ R ^16, -NHCO-R ^15, -CONR ¹⁵ R ^16, -CR '= NOR , -CO-R ¹⁵ or -CO 2 -R ¹⁵ , wherein R 'and R' independently represent hydrogen, alkyl, cycloalkyl, phenyl or benzyl; and R ¹⁵ and R ¹⁶ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁵ and R ^{16, taken} together with the nitrogen to which they are attached, form a heterocyclic 3- to 8-membered ring structure optionally substituted by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl , benzyl, -SO ₂ alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl. A compound according to any preceding claim, wherein R ⁷ represents halogen, alkyl, cyano, cyanoalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, - (alkyl) _m -NR ¹⁷ R ¹⁸ , -NHSO 2 -R ¹⁷ , -SR ¹⁷ ; -SO-R ^17; -SO 2 -R ¹⁷ ; -SO 2 O-R ¹⁷ ; -NHCOR ¹⁷ ; -CONR ¹⁷ R ¹⁸ ; -CR '= NOR; -CO-R ¹⁷ or -CO ₂ -R ¹⁷ , wherein R 'and R' independently represent hydrogen, alkyl, cycloalkyl, phenyl or benzyl; and R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted by alkyl, -SO ₂ -alkyl, -SO ₂ -aryl, -SO ₂ -benzyl, and optionally the heterocyclic ring is fused to aryl; R ⁷ represents - (alkyl) _m -SO ₂ -NR ¹⁷ R ¹⁸ wherein 139 the index m is 0 or 1; and R ¹⁷ and R ¹⁸ independently represent alkyl, cycloalkyl, benzyl or aryl; or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted by alkyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl and optionally the heterocyclic ring is fused to aryl; or R ⁷ represents HET, optionally substituted with one or more substituents selected from halogen, alkyl, phenyl or -SO ₂ NR ¹⁷ R ¹⁸ , wherein R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted by halogen, alkyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl ; and optionally the heterocyclic ring is fused to aryl; or R is phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, halogen, haloalkyl, amino, -NHCO-alkyl, nitro, -OCF _3, or -SO ₂ -NR ¹⁷ R ¹⁸ , wherein R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted by halogen, alkyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl , and optionally the heterocyclic ring is fused to aryl; or R ⁷ together with R ⁶ , or together with R ⁸ , forms 5-membered to 7-membered ring having one of the following structures -O- (CH ₂ ) _n -O-; wherein n is 1, 2 or 3; -SO ₂ -NR- (CH ₂ ) _n -, wherein R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and the index n is 1 or 2; 140 -SO-NR- (CH 2) _n -, wherein R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and n is 1 or 2; -SO ₂ - (CH ₂ ) _n - wherein the index n is 2 or 3; -SO- (CH 2) _n - wherein the index n is 2 or 3; -CO-CH = CH-NH-; -CO-CH = CH-O-; -CO- (CH 2) n -NH- wherein the index n is 1 or 2; -CO-NH- (CH 2) _n wherein n is 1 or 2; -CO- (CH ₂ ) 2 -O-; or -O- (CH 2) _n -O-; wherein n is 1, 2 or 3. A compound according to any preceding claim, wherein A R is hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro or nitroalkyl; or R ⁸ represents phenyl, optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl or alkoxy; or R ⁸ represents HET; or R ⁸ is -SR ¹⁹ ; ^{-SO-R 9,} -SO 2 R ^19; -SO 2 O-R ¹⁹ ; -SO ₂ -NR ¹⁹ R ²⁰ ; -NHCOR ¹⁹ ; ^{-CONR 9} R ^20; -CR '= NOR; -CO-R ¹⁹ ; or -CO 1 -R ¹⁹ , wherein R 'and R' independently represent hydrogen, alkyl, cycloalkyl, phenyl or benzyl; and R ¹⁹ and R ²⁰ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁹ and R ²⁰ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl , benzyl, 141 -SO 2 alkyl, -SO ₂ -aryl and -SO-benzyl; and optionally the heterocyclic ring is fused to aryl. A compound according to any preceding claim, wherein X represents SO2; Y is N; and R ² is H; and R ³ represents a cycloalkyl, carbocyclic 7-membered to 10-membered ring; a heterocyclic 5-membered to 6-membered ring; and R ⁴ represents H; and R ⁵ represents H; and R ⁶ represents a hydrogen atom, an alkyl or a halogen; and R ⁷ represents cyanoalkyl, nitroalkyl, haloalkyl or - (alkyl) _m -SO-R ¹⁷ ; - (alkyl) _m -SO ₂ -R ¹⁷ ; - (alkyl) m-CONR ¹⁷ R ¹⁸ ; - (alkyl) m-CR '= NOR "; - (alkyl) _m -COR ¹⁷ ; or - (alkyl) _m -CO ₂ -R ¹⁷ , wherein m is 0 or 1, and R 'and R' independently represent hydrogen, alkyl, cycloalkyl, phenyl or benzyl; and R and R independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted by alkyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl; or 142 R ⁷ is - (alkyl) _m -SO ₂ -NR ¹⁷ R ¹⁸ wherein m is 0 or 1; and R ¹⁷ and R ¹⁸ independently represent alkyl, cycloalkyl, benzyl or aryl; or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted by alkyl, -SC-alkyl, -SO ₂ -aryl or -SO ₂ -benzyl and optionally heterocyclic the ring is fused to aryl; or R ⁷ represents HET; or R together with R, or together with R, forms A 5-membered to 7-membered ring having one of the following structures -O- (CH ₂ ) _n -O-; wherein n is 1, 2 or 3; -SO ₂ -NR- (CH ₂ ) _n -, wherein R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and the index n is 1 or 2; -SO-NR- (CH ₂ ) n -, wherein R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and n is 1 or 2; -SO ₂ - (CH ₂ ) _n - wherein the index n is 2 or 3; -SO- (CH ₂ ) _n - wherein the index n is 2 or 3; -CO-CH = CH-NH-; -CO-CH = CH-O-; -CO- (CH ₂ ) _n -NH-, wherein the index n is 1 or 2; -CO-NH- (CH ₂ ) _n wherein the index n is 1 or 2; -CO- (CH ₂ ) ₂ -O-; or -O- (CH ₂ ) _n -O-; wherein n is 1, 2 or 3; and Q R represents alkyl, halogen, cyanoalkyl, nitroalkyl, haloalkyl, - (alkyl) _m -SO-R ¹⁷ ; - (alkyl) mSO 2 -R ¹⁷ ; - (alkyl) m-SO ₂ -NR ¹⁷ R ¹⁸ ; - (alkyl) m-CONR ¹⁷ R ¹⁸ ; - (alkyl) m-CR '= NOR; - (alkyl) _m -CO-R ¹⁷ ; or - (alkyl) _m -CO ₂ -R ¹⁷ , 143 wherein m is 0 or 1; R 'and R' are independently hydrogen, alkyl, cycloalkyl, phenyl or benzyl; and R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with alkyl, -SC-alkyl, -SC-aryl or -SC-benzyl; and optionally the heterocyclic ring is fused to aryl; or R ⁸ represents HET. A compound according to any preceding claim, wherein o R represents a hydrogen atom, cyclopropyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, CF ₃ , ethoxy, norbomylene, norborane, adamantane or benzyl; or R ³ together with R ⁴ and the atoms to which they are attached form a 5-membered ring. A compound according to any preceding claim, wherein R ⁴ represents a hydrogen atom, methyl or ethyl; or R ⁴ together with R ³ and the atoms to which they are attached form a 5-membered ring. A compound according to any preceding claim, wherein R ⁵ represents a hydrogen atom, chlorine, bromine, methyl or phenyl. 144 A compound of formula I according to any one of the preceding claims, wherein R ⁶ represents a hydrogen atom, 2-methoxyphenyl, 2-pyridyl, 3-pyridyl, methyl, methoxy, chloro or bromo. A compound of formula I according to any one of the preceding claims, wherein R ⁷ represents chloro, bromo, methyl, 1-hydroxyethyl, acetyl, - (CH ₃ ) C = N-OH, -CONH ₂ , -CO ₂ -ethyl, cyano, phenyl, 2-N-acetylaminophenyl, 2-nitrophenyl . 2-methoxyphenyl, 4-trifluoromethyl-2-methoxyphenyl, 2,4-dimethoxyphenyl, 2-N, N-dimethylsulfamoylphenyl, 2-chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-furyl, 3-furyl, 2-thienyl, 2- (N-methyl) -imidazolyl, 5-triazolyl, 4-phenyl-triazol-5-yl, 5-methyl-1, 2,4-oxadiazol-3-yl, CH ₃ CONH-, CH ₃ SO ₂ NH-, -SO ₂ OH, phenyl-SO ₂ -, N, N-dimethylsulfamoyl,,-diethylsulfamoyl, N-phenyl-N-methylsulfamoyl or a -SO ₂ -heterocyclic ring, wherein the heterocyclic rings are selected from piperidine, pyrrolidine, 1,2,5,6-tetrahydropyridine, tetrahydroquinoline, N -methylpiperazine, N -sulfonylmethylpiperazine and morpholine. A compound of formula I according to any one of the preceding claims, wherein a R is hydrogen, methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl or methoxy. A compound of formula Π according to claim 2, wherein R ² is H or CH 3; and R represents a cyclohexyl, cyclopentyl, norbomylene, norbomane, adamantane, or ethoxy group; and R ⁴ represents a hydrogen atom or CH ₃ ; and R ⁵ represents a hydrogen atom, CH 3, phenyl, sulfamoyl, chlorine or bromine; and R ⁶ represents a hydrogen atom, CH ₃ , 2-methoxyphenyl, methoxy, chloro, bromo, 2-pyridyl, 3-pyridyl; and R ⁷ represents chloro, bromo, methyl, 1-hydroxyethyl, acetyl, - (CH ₃ ) C = N-OH, -CONH ₂ , -CO ₂ -ethyl, cyano, phenyl, 2-7-acetylaminophenyl, 2-nitrophenyl . 145 2-methoxyphenyl, 4-trifluoromethyl-2-methoxyphenyl, 2,4-dimethoxyphenyl, 2-N, N-dimethylsulfamoylphenyl, 2-chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-furyl, 3-fluoryl, 2-thienyl, 2- (N-methyl) -imidazolyl, 5-triazolyl, 4-phenyl-triazol-5-yl, 5-methyl-1, 2,4-oxadiazol-3-yl, CH 3 CONH-, CH 3 SO ₂ NH-, NO 2, SO ₂ OH, phenyl-SO ₂ -, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N-phenyl-N-methylsulfamoyl or -SO ₂ heterocyclic books, wherein the heterocyclic rings are selected from the group of piperidine, pyrrolidine, 1,2,5,6-tetrahydropyridine, tetrahydroquinoline, N -methylpiperazine, Ύ-sulfonylmethylpiperazine and morpholine; and R is methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl or methoxy. A compound of formula I according to claim 1, wherein X is C = O; and Y is N, O or CH; and R ² is H; and R ³ represents a hydrogen atom, CH ₃ , CF ₃ , cyclohexyl, norbornylene, phenyl or ethyl; and R ⁷ represents a hydrogen atom, ΛζΎ-dimethylsulfamoyl, N-cyclohexylsulfamoyl, tetrahydropyrid-1-yl-sulfonyl, morpholin-4-yl-sulfonyl, sulfamoyl, bromine; and R ⁵ represents a hydrogen atom or a bromine atom; and R ⁴ , R ⁶ and R ⁸ are hydrogen. A compound of formula I according to claim 1, wherein X represents CH ₂ ; and Y is N; and R is cyclohexyl or norbornylene; and R ⁵ represents a hydrogen atom or a bromine atom; and R ⁷ is bromo or sulfamoyl; and R ^2, R ^4, R ⁶ and R ⁸ are hydrogen. 146 A compound of formula I according to claim 1, wherein X is SO ₂ ; and Y is -NHCH ₂ -; R ³ represents 3-methylbut-2-yl, phenyl or cyclohexyl; and R ⁷ is 1-piperidinylsulfonyl. A compound of formula I according to claim 1 which is: 2-Cyclohexyl-4-oxo-1,2,3,4-tetrahydroquinazoline; 2-phenyl-4-oxo-1,2,3,4-tetrahydroquinazoline; 2-Methyl-3,4-dihydro-1,3-benzoxazin-4-one; 2-phenyl-3,4-dihydro-l, 3-benzoxazin-4-one; 2-ethyl-2-methyl-3,4-dihydro-1,3-benzoxazin-4-one; 2-methyl-4-oxo-3,4-dihydro-6-quinazoline-N, N-dimethyl sulfonamide; 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline sulfonamide; 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline Ν, Ν-dimethylsulfonamide; 2-Trifluoromethyl-4-oxo-3,4-dihydro-8-quinazoline-1 ', 2', 3 ', 6'-tetrahydropiperidinosulfone amide; 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline N-cyclohexylsulfonamide; 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline morpholinosulfonamide; 2-Cyclohexyl-4-oxo-3,4-dihydro-6-quinazoline-N, N-dimethyl sulfonamide; 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline sulfonic acid; 2-Cyclohexylmethylamino-5-N, N-dimethylsulfamoylbenzenesulfonamide; or 2-ethylamino-7- (1 ', 2 ^' , 3 ^' , 6'-tetrahydropiperidino) sulfonylbenzene sulfonamide, or a pharmaceutically acceptable salt thereof. The 1,2,4-benzothiadiazine derivative according to claim 2, which is: 3-Bicyclo [2.2.1] hept-5'-en-2'-yl 1-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; l, 2,3,5,10,10a-hexahydrobenzo [e] pyrrolo [l, 2-6] -l, 2,4-thiadiazine 5,5-dioxide; 3-Cyclohexyl-6- (2-methoxyphenyl) -l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide; 3-Cyclohexyl-6- (2-pyridyl) -l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide; 3-Cyclohexyl-6- (3-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 147 3-Cyclohexyl-7- (1-hydroxyethyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-acetyl-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide; 3-Cyclohexyl-7- (1-hydroxyiminoethyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-carbamoyl-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide; 3-Cyclohexyl-7-ethoxycarbonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-cyano-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Bicyclo [2.2.1] hept-5'-en-2'-yl-7-phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (2'-acetamidophenyl) -l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l-dioxide; 3-Cyclohexyl-7- (2'-nitrophenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (2'-methoxyphenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; S-Cyclohexyl-N-C 1 -methoxy-N 1 -trifluoromethylphenyl-1,1,1-tetrahydro-1 H -benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (2 ', 4'-dimethoxyphenyl) -1,2,3,4 tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (2 '- (N, N-dimethylsulfamoyl) phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (2'-chlorophenyl) -l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide; 3-Cyclohexyl-7- (2'-fluorophenyl) -l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide; 3-Cyclohexyl-7- (3'-hydroxyphenyl) -l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide; 3-Cyclohexyl-7- (2'-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (3'-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (2'-pyrimidinyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (2'-furyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (3'-furyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (2'-thienyl) -l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide; 3-Cyclohexyl-7- (1-methyl-1H-2-imidazolyl) -1,2,3,4 tetrahydro-1,2,4-benzothiadiazine 1,1-dioxide; 3-Cyclohexyl-7- ( ', 2', ^{3-triazol-4-yl)} -l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l-dioxide; 3-Cyclohexyl-7- (5'-phenyl-2 ^{', 3'-triazol-4-yl)} -1,2,3,4-tetrahydro-1,2,4-benzotiadiazín1,1-dioxide; 148 3-Cyclohexyl-7- (5'-methyl-1 ', 4', 1'-oxadiazol-S-yl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-acetamido-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-methylsulfonylamino-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide; 3-Cyclohexyl-7-phenylsulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline sulfonamide; 3-Methyl-7-dimethylsulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 2-cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline Ν, Ν-dimethylsulfonamide; 3-Cyclohexyl-7-dimethylaminosulfonyl-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l-dioxide; 3-Cyclohexyl-7- (N, N-diethylamino) sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-pyrrolidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Methyl-7-piperidinosulfonyl-2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide; 3-Cyclopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Isopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-propyl-7-piperidinosulfonyl-2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide; 3-Benzyl-7-piperidinosulfonyl-2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide; 3-Cyclopentyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-piperidinosulfonyl-2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide; 3-Bicyclo [2.2.1] hept-5'-en-2'-yl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (1 ', 2 ^' , 3 ^' , 6'-tetrahydropiperidino) sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (N-methyl-N-phenylamino) sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (1 '- (1', 2 ', 3', 4'-tetrahydroquinolinyl)) sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (4'-methylpiperazino) sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine- 1,1-dioxide; 3-Cyclohexyl-7- (4'-methylsulfonylpiperazino) sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 149 3-Methyl-7-dimethylsulfamoyl-l, 2-dihydro-l, 2,4-benzothiadiazine-l, l-dioxide; 3-Methyl-7- (1 ', 2', 3 ', 6'-tetrahydropiperidino) sulfonyl-1,2-dihydro-1,2,4-benzothiadiazine- 1,1-dioxide; 3-Trifluoromethyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-8-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-8-hydroxymethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-8- (2-methoxyphenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-8- (3-methoxyphenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-8- (2-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-8-methoxy-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l, l-dioxide; 5,7-Dibromo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-2-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-4-methyl-7-morpholinosulfonyl-l, 2,3,4-tetrahydro-l, 2,4-benzothiadiazine-l-dioxide; 7-methylsulfonylamino-l, 2,3,3a, 4,5-hexahydro-benzo [e] pyrrolo [2, l-c] -l, 2,4-thiadiazine-5,5dioxid; 7-sulfamoyl-l, 2,3,3a, 4,5-hexahydro-benzo [e] pyrrolo [2, l-c] -l, 2,4-thiadiazine 5,5-dioxide; 7-Methylsulfamoyl-l, 2,3,3a, 4,5-hexahydro-benzo [e] pyrrolo [2, l-c] -l, 2,4-thiadiazine-5,5dioxid; 7-dimethylsulfamoyl-l, 2,3,3a, 4,5-hexahydro-benzo [e] pyrrolo [2, l-c] -l, 2,4-thiadiazine-5,5dioxid; 7-dimethylsulfamoyl-l, 2,3,5-tetrahydro-benzo [e] pyrrolo [2-c] -l, 2,4-thiadiazine 5,5-dioxide; 7 (I ', ^2', 3 ', ^6, -Tetrahydropiperidino) sulfonyl-l, 2,3,5-tetrahydro-benzo [e] pyrrolo [2-c] l, 2,4-thiadiazine 5,5-dioxide; 3-Bicyclo [2.2.1] hept-5'-en-2'-yl-5,7-dimethyl-1,2,3,4 tetrahydro-1,2,4-benzothiadiazine- 1,1-dioxide; 3-Cyclohexyl-7- (N, N-diethylsulphamoyl) -5-methyl-l, 2,3,4-tetrahydro-2,4-benzotiadiazín- 1,1-dioxide; 3-bicyclo [2.2.1] ^{hept-5'-en-2-yl-5,7-diphenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine} 1,1-dioxide; 3-Cyclohexyl-6-methyl-7- (2'-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 150 3-Cyclohexyl-6-methyl-7- (4'-triazolyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine 1,1-dioxide; 3-Cyclopentyl-6-methyl-7-piperidinosulfonyl-2,3,4-tetrahydro-2,4-benzotiadiazín- 1,1-dioxide; 3-Cyclohexyl-6-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine 1,1-dioxide; 3-Cyclohexyl-6- (2-methoxyphenyl) -7-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-6-methoxy-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzotiadiazín- 1,1-dioxide; 3-Cyclohexyl-7,8-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-cyclohexyl-6,7-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; or 3-Isobutyl-8- (piperidinosulfonyl) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide; or a pharmaceutically acceptable salt thereof. A compound having the general formula (ΠΙ) wherein Y is CH (R ⁴ ), N (R ⁴ ) or N (R ⁴ ) -CH ₂ or O; and R ³ represents a carbocyclic 7-membered to 12-membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; R ⁶ represents haloalkyl, and R represents halogen, alkyl, cyano, cyanoalkyl, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl or cyclohalogenoalkyl, or R ⁷ is -NR ¹⁷ R ¹⁸ , -NHSO 2 -R ¹⁷ or -NHSO 2 -aryl, 151 wherein the aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, -CF ₃ , -OCF ₃ , -NO _2, and aryl; or R ⁷ represents - (alkyl) mSR ¹⁷ ; - (alkyl) m-SO-R ¹⁷ ; - (alkyl) m -SO 2 -R ¹⁷ ; - (alkyl) m SO ₂ OR ^17; - (alkyl) m-NHCOR ¹⁷ ; - (alkyl) ^{m-CONR 7} R ^18; - (alkyl) m-CR '= NOR; - (alkyl) m-CO-R ¹⁷ or - (alkyl) m-CO ₂ -R ¹⁷ ; wherein m is 0 or 1; and R 'and R' independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl or benzyl; and R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, aikenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl , benzyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl and the optionally heterocyclic ring is fused to aryl; or R ⁷ represents - (alkyl) _m -SO ₂ -NR ¹⁷ R ¹⁸ where m is 0 or 1; and R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted by halogen, alkyl, aikenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl , benzyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl; or R ⁷ represents HET, optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio 152 groups, aryl, -S-alkyl, -S-aryl, -SO-alkyl, -SO-aryl, -SO ₂ -alkyl, -SO ₂ -aryl and -SO ₂ NR ¹⁷ R ¹⁸ ; or R ⁷ represents aryl, optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, -NHCO-alkyl, nitro, -OCF _3, and - SO ₂ -NR ¹⁷ R ¹⁸ wherein R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl , benzyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl, and optionally the heterocyclic ring is fused to aryl; or R ⁷ together with R ⁶ , or together with R ⁸ , forms 5-membered to 7-membered ring having one of the following structures -O- (CH ₂ ) _n -O-; wherein n is 1, 2 or 3; -SO ₂ -NR- (CH ₂ ) _n -, wherein R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and the index n is 1 or 2; -SO-NR- (CH ₂ ) _n - wherein R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and n is 1 or 2; -SO ₂ - (CH ₂ ) _n - wherein the index n is 2 or 3; -SO- (CH ₂ ) _n - wherein the index n is 2 or 3; -CO-CH = CH-NH-; -CO-CH = CH-O-; -CO- (CH ₂ ) _n -NH-, wherein the index n is 1 or 2; -CO-NH- (CH ₂ ) _n wherein the index n is 1 or 2; -CO- (CH ₂ ) ₂ -O-; or -O- (CH ₂ ) _n -O-; wherein n is 1, 2 or 3. 153 A pharmaceutical composition comprising an effective amount of a chemical compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, optionally a pharmaceutically acceptable excipient, carrier or diluent. The use of a compound of claim 1 for the preparation of a medicament for the treatment of a disorder or disease of living animal subjects, including humans, wherein the disorder or disease is susceptible to modulation of the AMPA receptor complex of the central nervous system. The use of claim 25 for the preparation of a medicament for the treatment of a disorder or disease of living animal subjects, including humans, wherein the disorder or disease is susceptible to modulation of the AMPA receptor complex of the central nervous system. Use according to any one of claims 25 to 26, wherein the disorders or diseases are selected from memory or learning disorders, psychotic disorders, sexual dysfunctions, intellectual disorders, schizophrenia, depression, autism, Alzheimer's disease, learning deficit, attention deficit, memory loss or senile dementia; or disorders or diseases resulting from trauma, stroke, epilepsy, Alzheimer's disease, neurotoxic agents, aging, neurodegenerative disorders, alcohol intoxication, substance abuse, cardiac bypass surgery or brain ischemia. A method of treating a disorder or disease of a living animal subject, including humans, characterized in that the disorder or disease is susceptible to modulation of the central nervous system AMPA receptor complex, the method comprising administering a therapeutically effective amount of a chemical compound according to any one of the claims 1 to 23. 154 The method of claim 28, wherein the disorder or disease is susceptible to modulation of the central nervous system AMPA receptor complex. The method of any one of claims 28 to 29, wherein the disorder or disease is selected from memory or learning disorders, psychotic disorders, sexual dysfunction, intellectual disorders, schizophrenia, depression, autism, Alzheimer's disease, learning deficit, attention deficit disorder. memory loss or senile dementia; or disorders or diseases resulting from trauma, stroke, epilepsy, Alzheimer's disease, neurotoxic agents, aging, neurodegenerative disorders, alcohol intoxication, substance abuse, cardiac bypass surgery or brain ischemia.