CZ20002896A3 - Novel compounds and their use as positive modulators of AMPA receptor - Google Patents

Abstract

The novel compounds of formula I wherein the bond is depicted the dashed line may be single, double, or non-broken and if the bond is absent, then nitrogen is substituted with hydrogen and R2; X represents SO 2, C = O or CH 2; Y represents -CH (R4) -, - N (R 4) - or -N (R 4) -CH 2 -, O; and the other substituents R 2, R 3, R 4, R 5, R 6, R 7 and R 8 are of particular significance. The compounds are effective as positive AMPA receptor modulators, for example in the treatment of memory or learning disorders, psychotic disorders, sexual dysfunction, intellectual disorders, schizophrenia, depression or autism.

Description

NEW COMPOUNDS AND THEIR USE AS POSITIVE MODULATORS

AMPA RECEPTOR

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.

A glutamatergic neurotransmission disorder has been demonstrated in the learning and memory loss observed in many neurological diseases such as Alzheimer's disease, senile dementia, stroke (McEntee and Crook, Psychopharmacology 111: 391-401 (1993)). It is widely accepted that learning and memory refers to inducing long-term potentiation (LTP), which represents a stable increase in synaptic strength and subsequent repetitive high frequency stimulation. Experimental studies have shown that an increase in 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 sharp desensitization of the receptor; ie. the receptor channel does not resist the continuous presence of the agonist. Thus, it is possible to obtain an increase in synaptic strength by alleviating desensitization of the AMPA receptor by normally induced endogenous nerve mediator Lglutamate.

In 1990, Ito et al. reported (J. physiol., 424: 533-543) that the nootropic drug aniracetam (γ-anisoyl-2-pyrrolidine) increases the flows of AMPA-induced oocytes 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 animals used to * *. experiments at very high doses of 120 mg / kg (Staubli et al., Proc. Natl. Acad. Sci.

USA, 91: 11158-11162 (1994)).

• ·

Cyclothiazide benzothiadiazide is a potent and effective in vitro flow modulator of AMPA receptors than aniracetam (Johansen et al., Mol. Pharmacol. 48: 946-95 (1995)). The effect of cyclothiazide 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 has no therapeutic efficacy for modulating AMPA receptors since it cannot cross the blood-brain barrier and after peripheral administration. The known compounds have lower efficacy because they impose high solubility requirements at higher doses.

BACKGROUND OF THE INVENTION

US 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 galvanizing bath.

Synthesis (10), 183, p. 851 describes a process for the preparation of benzothiadiazine-1,1-dioxide. The compounds are described as effective antihypertensive and antimicrobial agents.

J. Med. Chem. (15, No. 4), 1972. Str. 400-403, benzothiadiazine-1,1-dioxides are investigated for their π-substituent constants as a study of structural activity for antihypertensive activity.

WO 9812185 discloses benzothiadiazines 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 treating diseases or disorders in mammals, including humans, and in particular in treating diseases and disorders that are susceptible to modulation of AMPA receptors in the brain.

• ·

AND

Another object of the present invention is to provide a method of treating diseases or disorders of mammals, including humans, sensitive to AMPA receptor modulators, which comprises administering to a 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 treating diseases or disorders in mammals, including humans, sensitive to AMPA modulators.

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, but is not limited to, the following, alone or in combination:

Compound represented by the general formula:

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

X represents 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 , where

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 by halogen, alkyl, hydroxy or alkoxy; or

Heterocyclic 3- 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 with 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 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 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R ¹⁰ or CO 2 R ¹⁰ , wherein R ¹⁰ is 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 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 ⁿ 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-membered up to 8-membered ring structures 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, cyclohalogenalkyl,

-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, 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) mSO 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, SO ₂ alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl;

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

-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;

99 ·· 9 · • 99 8

9 99

9 9

9999 99 ·

- (alkyl) _m -SR ¹⁷ ; - (alkyl) ^m-SO-R17 ;-( alkyl) m-SO ₂ -R ^17; - (alkyl) m-SO 2 OR ¹⁷ ; - (alkyl) mSO 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 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 with halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring 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 ⁷ 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, SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

or · · φφ · · · · · φφ

ΦΦΦ · φ · φ · φ · φ ·

Φ φ Φ 9 · ·· ΦΦΦ Φφ φ

ΦΦΦ ΦΦΦΦ

ΦΦΦΦΦ ΦΦ ΦΦ

R ⁷ together with R ⁶ or R ⁸ 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; -CONH- (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 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) m -SO 2 O-R ¹⁹ ; - (alkyl) mSO 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 I; and R a 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-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 a heterocyclic ring fused to aryl;

if the dashed 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

• 0 0 • 0 0 ·· 00 • 0 0

0 00 mono substituted with R ³ representing OCH ₃ , methyl, pentyl, t-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, sec-butyl, t-butyl, cyclobutyl, 2,2-dimethylpropyl, phenyl;

and if the compound is disubstituted then it is not disubstituted with 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;

And if 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 when the dashed line in formula I represents a single bond and X represents SO ₂ and Y represents NH

Then, the compound is not disubstituted with R ⁷ or R ⁶ substituents which are chlorine and R is alkyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclohexene, norbornylene, norbornanyl, ethylthiomethyl, ethyloxymethyl, ethyloxyethyl, methyloxymethyl, methylamino, 2-chloroethyl, chloromethyl , dichloromethyl, trifluoromethyl, amino;

and the compound is not trisubstituted by 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;

A pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound together with pharmaceutically acceptable carriers or excipients;

Use of a compound represented by the general formula

* · ·· φφ ··

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

X represents 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 by halogen, alkyl, hydroxy or alkoxy; or

Heterocyclic 3- 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 with 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 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 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R ¹⁰ or CO 2 R ¹⁰ , wherein R ¹⁰ is 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 or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups.

• • 9 # 9 9 • · · · · ··· ···

9 9

9 9 9

9 9 9

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

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

-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, halogen, haloalkyl, haloalkoxy;

- (alkyl) _m -SR ¹⁵ ; - (alkyl) m-SO-R ¹⁵ ; - (alkyl) m-SO ₂ -R ¹⁵ ; - (alkyl-m-SO 2 -R ¹⁵ ) - (alkyl) mSO 2 -NR ¹⁵ R ¹⁶ - (alkyl) m -NHCO-R ¹⁵ - (alkyl) _m -CONR ¹⁵ R ¹⁶ - (alkyl) m-CR (Alkyl) m-CO-R ¹⁵ - (alkyl) m-CO ₂ -R ¹⁵ , where m is 0 or 1, and R and R 'are independently hydrogen, alkyl, cycloalkyl, alkenyl , alkynyl, aryl, benzyl;

»« ·· • · · ·· ·· • · • * · « « • « • · • • ·· • · • • • • · • • · • · • • • • · • ·· · • · • · · ·· • · ··

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- 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 a heterocyclic ring fused to aryl;

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

-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) mSO 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 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 with halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl;

HET optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio

ΦΦΦ · φφφφ ··

Φ Φ Φ Φ Φ Φ Φ Φ · · Φ Φ,,, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SO-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-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;

or

R ⁷ together with R ⁶ or R ⁸ 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 ) ₁₁ -NH-, wherein the index n is 1 or 2; -CONH- (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 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;

«0

0

0 * 0 ·· • 000 • · 0

0 0

0000 00

0 * 0 0 0 0 0 0 0

0 0 0

0 0 0

0 0 0

0 0 ·

- (alkyl) _m -SR ¹⁹ ; - (alkyl) m-SO-R ¹⁹ ; - (alkyl) m-SO ₂ -R ¹⁹ ; - (alkyl) m -SO 2 O-R ¹⁹ ; - (alkyl) mSO 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-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 a heterocyclic ring fused to aryl;

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

A method for treating disorders and diseases sensitive to modulation of the AMPA receptor complex, wherein a therapeutically effective amount of a compound represented by the general formula is administered

R ³ wherein the bond represented by the dotted line may be single, double bond or absent; and if the bond is absent, then nitrogen is substituted with hydrogen and R ² ;

Φ · Φ · φ · V φφφφ φφφ φφφ φφφφ φφ

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 by halogen, alkyl, hydroxy or alkoxy; or

Heterocyclic 3- 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;

ΦΦ · * · · φ φ φ φ φ φ φ «« φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

Aryl 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; 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 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R ¹⁰ or CO 2 R ¹⁰ , wherein R ¹⁰ is 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 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 ⁿ 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-membered up to 8-membered ring structures 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, cyclohalogenalkyl,

-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, halogen, haloalkyl, haloalkoxy;

- (alkyl) _m -SR ¹⁵ ; - (alkyl) m-SO-R ¹⁵ ; - (alkyl) _n -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 a heterocyclic ring fused to aryl;

• • <2,

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

-NR ¹⁷ R ¹⁸ , NHSO 2 -R ¹⁷ , NHSCh-aryl, wherein 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-R ¹⁷ ; - (alkyl)] n-SO ₂ -R ¹⁷ ; - (alkyl) m -SO 2 O-R ¹⁷ ; - (alkyl) mSO 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 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 with halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring 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 R, wherein R @ 1 and R @ 2 independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or R @ ¹⁷ and R @ ¹⁸ together with nitrogen, to which they are attached form heterocyclic 3-membered 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;

or

R ⁷ together with R ⁶ or R ⁸ 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; -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;

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 ^I9 ;-( alkyl) m-SO ₂ -R ^19; - (alkyl) m -SO 2 O-R ¹⁹ ; - (alkyl) mSO ₂ -NR ¹⁹ R ²⁰ ; - (alkyl) m-NHCOR ¹⁹ ; - (alkyl) m-CONR ²⁰ R ^I9; - (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-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 a heterocyclic ring 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 »00 • 0

0 groups or thio groups and optionally containing one or more heteroatoms and optionally containing carbonyl groups.

0 0 00

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

-SO ₂ NR ⁿ 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 5-membered up to 6-membered ring structure;

R ⁶ represents a hydrogen atom, Br, F, I, 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 1 = 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 a heterocyclic ring fused to aryl;

R ⁷ represents a hydrogen atom, Br, F, I, alkyl, cyano, cyanoalkyl, nitro, nitroalkyl; alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohalogenalkyl, - (alkyl) _m -NR ¹⁷ R ¹⁸ , NHSO 2 -R ¹⁷ , -SR ¹⁷ ; -SO-R ^17; -SO 2 -R ¹⁷ ; SO2O-R ^17; -SO 2 -NR ¹⁷ R ¹⁸ ; -NHCOR ¹⁷ ; -CONR ¹⁷ R ¹⁸ ; -CR '= NOR; -CO-R ^17; -CO ₂ R ¹⁷ , where R a and R a 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- to 8-membered ring structure optionally substituted with alkyl SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring 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 is 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, 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

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; -CO • Β Β Β> · Β

Β ΒΒΒ

-NH- (CH _{2) n,} where index η 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 ²⁰ ; -NHCOR ¹⁹ ; -CONR ¹⁹ R ²⁰ ; CR -NOK; -CO-R ¹⁹ ; -CO 2 -R ¹⁹ , where R a and R a 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-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 a heterocyclic ring fused to aryl;

when X is SO ₂ and Y is N and the dashed line represents a single bond, then either R ⁷ or R ⁶ is chloro, when R ² , R ⁴ , R ⁵ , R ⁸ and the remaining R ⁶ and R ⁷ are all a hydrogen atom; and provided that R ³ can represent CH 3 only when R ⁵ is hydrogen or R ⁷ is not sulfamoyl;

and when X is SO ₂ and Y is N and the dotted line represents a double bond, then either R ⁷ or R ⁶ is chloro, where R ² , R ⁴ , R ⁵ , R ⁸ and the remaining R 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 the substituent 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;

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

-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;

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;

R ³ represents a hydrogen atom, a cycloalkyl, an alkyl, a haloalkyl, an alkoxy group, and a 7 to 10-membered carbocyclic 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.

9

9

999 9

98 • 9 9 9

9 9 9

9 9 9

9 9 ·

And another preferred embodiment is wherein

R ⁴ represents a hydrogen atom, an alkyl, or 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, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups.

And another preferred embodiment is wherein

R ⁵ represents a hydrogen atom, 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 3-membered up to 8-membered ring structure;

And another preferred embodiment is wherein

R ⁶ represents hydrogen, 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,

• • •

φ • · · · · · · · ·

SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl;

A further preferred embodiment is wherein R ⁷ is hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohalogenalkyl, - (alkyl) _r -NR ¹⁷ R ¹⁸ , NHSO 2 -R ¹⁷ , -SR ¹⁷ ; -SO-R ^17; -SO 2 -R ¹⁷ ; SO2O-R ^17; -SO 2 -NR ¹⁷ R ¹⁸ ; -NHCOR ¹⁷ ; -CONR ¹⁷ R ¹⁸ ; -CR '= NOR; -CO-R ^17; -CO ₂ wherein 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- to 8-membered ring structure optionally substituted with alkyl SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring 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 is 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, 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-; where n is 1, 2

ΦΦ φ • φ • φ φ φ φ φ φ φ φ φ φ φ φ «• • • • φ φ φ φ φ φ φ φ φ nebo nebo nebo nebo nebo nebo nebo 3 3 3 3 3 nebo -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 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 wherein

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 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-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 a heterocyclic ring fused to aryl;

Particularly preferred embodiments are compounds of the above formula I wherein X is SO ₂ ; Y is N and the dotted line represents a single bond;

R ² represents H;

«* * 9 9

9 9

9999 »«

999

• 9 9

9 «9 9

R ³ represents cycloalkyl, a 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, alkyl or 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) m -CR-NOR; - (alkyl) _m -CO-R ¹⁷ ; (alkyl) _m -CO ₂ -R ¹⁷ , wherein the index m is 0 or 1 and R a 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- to 8-membered ring structure optionally substituted with alkyl SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl;

HET or

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

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 the index 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) m-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;

»»

. · ♦ * ♦ · • · • V

The substituents R a and R 8 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- to 8-membered ring structure optionally substituted with alkyl SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl; or

HET;

Special embodiments of the present invention are all of the following which relate to formula I above.

An embodiment of the invention is wherein R ³ represents a hydrogen atom, cyclopropyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl,

CF ₃ , ethoxy group, norbomylene, norborane, 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 wherein R ⁴ is hydrogen, 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 wherein

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

Another embodiment of the invention is wherein R ⁶ represents a hydrogen atom, 2-methoxyphenyl, 2-pyridyl, 3-pyridyl, methyl, methoxy, chloro or bromo;

Another embodiment of the invention is wherein

R ⁷ is hydrogen, chloro, bromo, methyl, 1-hydroxyethyl, acetyl, - (CH ₃ ) C = N-OH, CONH ₂ ,

CO ₂ -ethyl, cyano, phenyl, 2-7-acetylaminophenyl, 2-nitrophenyl, 2-methoxyphenyl, »·φφφφφφφ

4-trifluoromethyl-2-methoxyphenyl, 2,4-dimethoxyphenyl, 2-N, N-dimethylsulfamoylphenyl,

2-chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-turyl,

3-furyl, 2-thienyl, 2- (γ-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 -dimethylsulfamoyl, N-diethylsulfamoyl, N -phenyl-Y-methylsulfamoyl, Ncyclohexylsulfamoyl, -SO ₂ - a heterocyclic ring, wherein the heterocyclic rings are selected from piperidine, pyrrolidine, 1,2,5,6-tetrahydropyridine, tetrahydroquinoline, N -methylpiperazine, N -sulfonylmethylpiperazine, morpholine;

A further embodiment of the invention is wherein

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, norbomylene, norboman, 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-Y> A-dimethylsulíamoylfenyl,

2-chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-furyl,

3-furyl, 2-thienyl, 2- (γ-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 -A-diethylsulfamoyl, N-phenyl-N-methylsulfamoyl, Ncyclohexylsulfamoyl, -SO ₂ -heterocyclic a ring wherein the heterocyclic rings are selected from piperidine, pyrrolidine, 1,2,5,6-tetrahydropyridine, tetrahydroquinoline, N-methylpiperazine, N -sulfonylmethylpiperazine, morpholine;

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

Another special preferred embodiment 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 7V-methylsulfamoyl, Λζ / V-dimethylsulphamoyl, 7V-cyclohexyl sulfamoyl, tetrahydropyridyl-sulfonyl; SO ₂ OH, sulfamoyl;

Another special preferred embodiment 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 represents a hydrogen atom; and

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

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

R ⁵ represents a hydrogen atom or bromine; and

R ⁴ , R ⁶ and R ⁸ are hydrogen;

Another special preferred embodiment 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 norbornylene; and

R ⁵ represents a hydrogen atom or bromine; and

R ⁷ is bromo or sulfamoyl; and

R ^2, R ^4, R ⁶ and R ⁸ are hydrogen;

Another special preferred embodiment 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 ² , R ⁴ , R ⁵ and R ⁸ are hydrogen;

R ³ represents cyclohexyl, methyl or hydrogen; and

R ⁷ is N-dimethylsulfamoyl, tetrahydropyridylsulfonyl, bromine; and

R ⁶ represents bromo or hydrogen;

Another special preferred embodiment 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-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-1,3-benzoxazin-4-one;

-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;

1,2,3,5,10,10a-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;

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

-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;

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

-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;

-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;

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

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

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

-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;

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

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

·· · 0 ·

0 0 0

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

-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;

-Cyclohexyl-7- (3-furyl) -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-177-2-imidazolyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

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

-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;

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

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

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

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

2-Cyclohexyl-l, ^{2,3,4-tetrahydro-6-quinazoline-N,} 7V-dimethylsulfonamide;

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

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

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

-Methyl-7-piperidinosulfones of 1,1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

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

-Isopropyl-7-piperidinesulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

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

-Benzyl-7-piperidinosulfones of 1,1,2,3,4-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-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-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- (r, 2 ^{', 3',} 6'-tetrahydropiperidino) sulfonyl-l, 2,3,4-tetrahydro-1,1-dioxide 2,4benzothiadiazin;

3-Cyclohexyl-7- (N-methyl-N-phenylamino) sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7- (R- (R *, 2 ^', 3', 4'-tetrahydroquinolinyl)) sulfonyl-l, 2,3,4-tetrahydro-1,1-dioxide 2,4benzothiadiazin;

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

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

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

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

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

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

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

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline-1,2 ', 3', 5'-tetrahydropiperidinosulfonamide;

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-dimethylsulfonamide;

-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- (R, 2 ', 3', ^6, -tetrahydropyridines) sulfonyl-1,2-dihydro-1,2,4-benzothiadiazine 1,1-dioxide;

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

- Trifluoromethyl-7-dimethylsulfamoyl-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;

-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;

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · φ · ·· φφφφ φφ φφ · · ··

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

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

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

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

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

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

7-Methylsulfamoyl-1,2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide;

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

7-Cyclohexylsulfamoyl-1,2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide;

7- (1 ', 2', 3 ', 6'-Tetrahydropiperidino) sulfonyl-1,2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-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 -diethylsulfamoyl) -5-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-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-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;

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

• · · · φφφφφφφφφφφφφφφφφ · · φ · · · · φφ φφφφφφφφφφφ «« «« «« «

...... ··· ·· · ♦ ··

2-Bicyclo [2.2.1] hept-5'-en-2'-yl-6,8-dibromo-1,2,3,4-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 [2.2.1] heptan-2'-yl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

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

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

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

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

-Methyl-5,7-dibromo-1,2-dihydro-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;

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

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

-Cyclopentyl-6-methyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

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

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

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

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

3-Cyclohexohexyl-6,7-ethylndioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-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;

-Cyclohexyl-6-bromo-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

2-cyclohexylmethylamino-5-N, N-dimethylsulfamoylbenzenesulfonamide;

2-Ethylamino-7- (1 ', 2', 3 ', 6'-tetrahydropiperidino) sulfonylbenzenesulfonamide;

3-Isobutyl-8- (piperidinosulfonyl) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide;

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

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

-Cyclohexyl-7-cyclopentylsulfinyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-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 pharmaceutically (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, nontoxic inorganic and organic acid addition salts such as acetic acid derived acetate, aconitic acid aconitate, ascorbic acid ascorbate, benzenesulfonic acid derived benzenesulfonate, benzoate derived benzoate from benzoic acid, cinnamate derived from cinnamic acid, citrate derived from citric acid, embonate derived from emonic acid, enanthate derived from enanthic acid, formate derived from formic acid, fumarate derived from filmic acid, glutamate derived from glutamic acid, glycollate derived from glycolic acid acids, hydrochloride derived hydrochloride, hydrobromide derived from hydrobromic acid, lactate derived from lactic acid, maleate derived from maleic acid, malonate derived from malonic acid, mandelate derived from mandelic acid, methanesulfonate derived from methanesulfonic acid, naphthalene-2-sulfonate derived from naphthalene-2-sulfonic acid, nitrate derived from nitric acid, 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, sulfate derived from sulfuric acid, tartrate derived from tartaric acid, toluene-psulfonate derived from p-toluenesulfonic acid, etc. Such salts may be prepared by methods known and described in the prior art.

Other acids such as 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 the sodium salt of the chemical compound of the invention containing a carboxy group.

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

Definition of substituents

Halogen is fluorine, chlorine, bromine or iodine.

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

Haloalkyl means the above-mentioned alkyl substituted one or more times with the above-defined halogen. 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 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 _3rd

6-cycloalkyl; _4- alkyl such as - (CH ₂ ) -cyclopropyl, -cyclopropyl- (C 1-4 -alkyl), - (CH ₂ ) n -cyclohexyl, -cyclohexyl- (C _1-4 -alkyl), (C _1-4 -alkyl) -cyclobutyl, -cyclobutyl (C _1-4 -alkyl) - (C _1-4 alkyl) cyclopentyl, -cyclopentyl (C _1-4 -alkyl), - (C _1-4 -alkyl) cyclohexyl, cyclohexyl (C _1-4 -alkyl);

Halocycloalkyl means the above-mentioned cyclic alkyl which is substituted one or more times with the above-mentioned halogen including, but not limited to, chlorocyclopropyl, fluorocyclopropyl, iodocyclopropyl, dichlorocyclopropyl, difluorocyclopropyl, chlorocyclobutyl, fluorocyclobutyl, chlorocyclopentyl, fluorocyclopentyl, iodocyclopenyl; Chlor♦ • chlor chlor chlor chlor • φ φ chlor chlor chlor chlor chlor chlor chlor chlor chlor chlor chlor chlor c c c c chlor chlor chlor chlor chlor chlor chlor chlor chlor chlor chlor chlor chlor chlor chlor chlor chlor c c chlor chlor c c chlor chlor c c c c c Preferred embodiments are monosubstituted and disubstituted cycloalkyl having 3 to 6 carbon atoms such as dichlorocyclopropyl, difluorocyclopropyl, chlorocyclohexyl, fluorocyclohexyl, iodocyclohexyl, chlorocyclopentyl, fluorocyclopentyl.

Alkenyl means a straight 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 by CN;

The nitro group is -NO ₂ ;

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

Β · · Β * * * * * * * * * * * * * * * * * * ΒΒΒ ΒΒΒ ΒΒΒ ΒΒΒ ΒΒΒ

ΒΒΒ · · Β ·· ·· ««

Thio 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 with 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 1 and R 2 together with (CH ₂ ) _m wherein m is 2, 3, 4, 5, or 6; or R c is benzyl; or NR ⁱⁿ R ^IV are each independently hydrogen or alkyl or wherein R ^IV and R ⁿⁱ together are (CH ₂₎ p wherein p is 2, 3,4, 5 or 6th

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

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

HET is a 5-membered 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, thiazole -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-thiadiazol-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 -foranyl, 3-foranyl, 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, foryl, 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.

ΏΌΌ Φ φ φ • φ φ φ φ φ φ φ φ φ φ • φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ heteroc heteroc heteroc heteroc heteroc heteroc heteroc heteroc a saturated heterocyclic ring structure such as aziridine, pyrrolidine, piperidine, piperazine, homopiperidine, homopiperazine, azacyclooctane, 1,3-diazacyclooctane, 1,4-diazacyclooctane, tetrahydrofuran, tetrahydrothiophene, morpholine, tetrahydropyridine and compounds such as e.g.

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

The described 4-membered to 7-membered rings fused to ring structures 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 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 this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water,

• · 9 99 99 99 • 9 • 99 9 9 9 ♦ • • • 9 9 9 • • »» « « • 9 9 9 9 9 • • • • 9 9 999 99 99 ··

ethanol, etc. 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 may thus be resolved into their optical antipodes, eg, 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 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).

Moreover, some of the chemical compounds of the invention which are oximes may exist in two forms, the syn- and anti-forms (Z-form and E-form), depending on the arrangement of the substituents on the -C = N- 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.

Pharmaceutical preparations ·· Φ · · φ φ φ φ φ φ Φ

ΦΦ

· ΦΦ • ·

ΦΦ

Φ Φ Φ

ΦΦ

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 treating specific diseases and disorders;

While the chemical compound of the invention for use in therapy may be administered in the form of an untreated 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 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 as 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 form of pharmaceutical compositions and unit doses thereof. Such forms include solids and in particular tablets, filled capsules, powder and pellet forms, and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, medicinal drinks, and capsules filled in the same way, 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 ingredients in conventional doses 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 apparent to those skilled in the art that the following dosage forms may contain, as the active ingredient, either a chemical compound of the invention or a pharmaceutically acceptable salt of the chemical compound of the invention.

For preparing pharmaceutical compositions from a chemical compound of the present invention, the carriers may be either liquid or solid. Solid form preparations include

* «0 0 00 00 00 0 0 00 0 0 0 0 0 0 • 000 0 0 0 0 0 0 0 • Φ 0 0 00 0 0 0 0 0 00 0 0 00 0 0 0 00

powders, tablets, pills, capsules, capsules, rectal suppositories and dispersible granules. The solid carrier may be one or more substances which may function as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents after ingestion, or a microencapsulating agent.

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 properties in suitable dosages and compressed in 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 carboxymethylcellulose, low melting waxes, cocoa fat, and the like. The term formulation refers to the association of the active ingredient with the microencapsulation agent 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, lozenges can be used as solid forms suitable for oral administration.

To prepare rectal suppositories, low melting point waxes, such as fatty acid glyceride or cocoa fat, are first dissolved and the active ingredient dispersed homogeneously by stirring. The liquid homogeneous mixture is then poured into a suitably 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, eg, water or water-propylene glycol solutions. For example, parenteral 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 (eg, by injection, eg, by bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules, prefilled syringes, mild infusion or multi-dose containers with added preservative. . The compositions may take such forms as, for example, suspensions, solutions, or emulsions in an oily or aqueous carrier, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in the form prior to use

4 · ΦΦ • Φ Φ

Φ ΦΦΦ

Φ Φ ΦΦΦΦ φφ

Φ ΦΦ ΦΦ Φ Φ

ΦΦΦ

ΦΦΦ ΦΦΦ ΦΦ

ΦΦ ΦΦ

· Φ φ ·

Φ Φ Φ Φ

Φ Φ φ Φ

Φ Φ Φ Φ

Šku šku powder to be prepared with a suitable carrier, eg sterile pyrogen-free water, obtained by aseptic isolation of sterile solid or by lyophilization from solution.

Aqueous solutions suitable for oral use can 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 can be made by dispersing the finely divided active ingredient in water with a viscous substance, such as 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, stabilizers, 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, for example, with an aqueous or oily base with the addition of a suitable thickening agent and / or gelling additives. The lotion may be prepared 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 acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerol or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier.

The 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. Later, in the case of drops or pipettes, dosing may be accomplished by applying a suitable, predetermined volume of solution or suspension. In the case of a spray, the dosing can be carried out by means of a spray pump with dosing spraying.

Administration to the respiratory tract may also be achieved by aerosol administration in which the active ingredient is provided in a pressurized pack with a suitable propellant such as freon (CFC), e.g. dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane,

* ♦ «00 • 0 00 • « 0 0 «« 0 0 • 0 « • 00 « 0 0 0 0 « * « 0 • 0 0 0 0 0 0 0 0 0000 0 0 • 0 0 00 00 00

carbon dioxide or other suitable gases. The aerosol may suitably also contain a surfactant such as lecithin. The dose of the drug may be controlled by providing a dispensed closure.

In another method, the active ingredients may be provided in the form of a dry powder, eg a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as 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, e.g. gelatin, or soft transparent packages from which the powder may be delivered 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. of the order of 5 microns or less. Such a particle size can be obtained by means known in the art, for example by grinding the rental particle.

If desired, formulations adapted to provide sustained release of the active ingredient may be employed.

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

Preferred formulations are tablets or capsules for oral administration and fluids for intravenous administration and continuous 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 mode of administration, dosage form and regimen, and the desired result.

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 pg / 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 pg / kg to about 10 mg / kg / day i.v. and from about lpg / kg to about 100 mg / kg / day p.o.

Method of treatment

·· «· * ·· ·· * · • • Φ · • • • • 4 • ♦ · • • • • · • • · «· • · · · ♦ • • • · • • · ··

The compounds of the present invention are AMPA receptor stimulators, and therefore useful in the treatment of a region of disorders and diseases sensitive to AMPA receptor modulators. As an embodiment of the invention, the diseases are responsible for positive modulation of the AMPA receptor. The compounds may be used in the treatment, prevention, profilaxis or amelioration of diseases, disorders or conditions of the central nervous system such as: neurodegenerative disorders, cognitive or memory dysfunction, memory and learning disorders, attention deficit, memory or learning disorders due to old age, trauma, stroke, epilepsy; Alzheimer's disease, depression, schizophrenia, memory loss, AIDS dementia, senile dementia, learning deficit, cognitive deficit, sexual dysfunction, psychotic disorders, sexual dysfunction, 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 in particular 10-70 milligrams per day, administered once or twice daily depending generally on the correct route of administration, form of administration, indication of the route of administration chosen, the subject and body weight of the subject, and other priorities. and the practice of a doctor or veterinarian.

I.p. means intraperitoneally, a well known route of administration.

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

The invention includes the following, alone or in combination:

Use of the above compound for the manufacture of a medicament for the treatment of diseases that are responsible for modulating the AMPA receptor.

The above uses wherein the diseases are memory or learning disorders, psychotic disorders, sexual dysfunction, intellectual disorders, schizophrenia, depression or 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

·· * · • ·· * · • · « • · · • • • • • ··· • · • • • « • • • • · • · • • • • 9 • · * * »· ·· · ·· • · ··

Determination of in vitro inhibition of ³ H-AMPA binding

L-glutamate (GLU) is the major exiting nerve mediator in the mammalian central nervous system. Electrophysiological and binding studies have shown that at least three GLU receptor subtypes, provisionally designated N-methyl-D-aspartate (NMDA), chischalate, and kainate receptors. The subtypes of GLU receptors sensitive to chischalate and kainate are often referred to as nonNMDA receptors as a group. Binding studies of ³ H-AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor (for chischalate receptors) and ³ H-kainate (for kainate receptors) receptor agonists have shown different antagonist selectivity and local incidence. For several years, AMPA has been known to be 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 the activated metabotropic type of chischalate receptors associated with the metabolism of inositol triphosphate and diacylglycerate. 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, strong and competitive antagonists of CNQX and NBQX non-NMDA receptors have been described and it has been reported that CNQX does not block the effect of chischalate on the metabotropic receptor subtype. ³ H-AMPA is a selective radioligand for the labeling of ionotropic chischalates (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 of 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 frozen. and stored at -20 ° C.

φφ φφ φ

• φ

φ · · • 0 0 0 0 0 0

φ • · · · · ·

Determination

The membrane preparation is thawed and centrifuged at 2 ° C for 10 minutes at 27,000 xg for 10 minutes. The pellets are 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 for binding determination. Aliquots of 0.5 (0.2) ml are added to 25 (20) μΐ of test solution and 25 (20) μΐ of ³ H-AMPA (5nM, 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, add 5 ml of ice-cold buffer to 550 μΐ samples and pour directly into Whatman GF / C glass fiber filters with suction turned on and immediately wash with 5 ml of ice-cold buffer. Wash the filters 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.

Results

The test results will be reported as IC50 (concentration (μΜ) of the control that inhibits the specific binding of ³ H-AMPA by 50%)

Test results

Compound numbers correspond to those in the table below.

Compound IC ₅₀ (pM) 13 22.0 14 45.0 15 Dec 39.0 44 3.5 47 5.3 48 4.4 49 17.0 57 26.0

00 • 00 • 0 00 • 0 • 00 0 • 0 0 € 0 • 000 • 0 • • 0 • • 0 • • 0 • 0 • 0 0 0 0 ···· · < ··· ·· 00 00

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 the exiting 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 exiting amino acid receptors. This means that they can be stimulated with potassium (55 mM) or with the exiting 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 the exiting amino acid receptors.

Ways

Cell culture

The cortex of 15-16 day old NMRI mouse embryos is trimmed to 0.4 x 0.4 mm cubes and the tissue dissociates by weak trypsinization (0.1% (w / v) trypsin, 37 ° C, 10 min) . An additional cell suspension (3 mill / ml) is inoculated into Petri dishes (3 ml / dish) coated with 30 mm poly-L-lysine containing slightly 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 cytosinarbinoside (5μΜ) from day 2 to prevent glial proliferation. Drejer et al (Exp. Brain Res. 47, 259 (1982)).

Experiments for determining release

Release experiments are performed using the model described by Drejer et al. (Life Sci. 38: 2077 (1986)). 10 mM γ-vinyl-GABA was added to brain cortex neurons cultured in Petri dishes (30 mm) one hour prior to the experiment to inhibit GABA degradation in neurons. Minutes before the experiment, 5 gCi 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 buffered solution (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. Medium smoothly U is concentrated ⁱⁿ the lower part of the dish and delivered to a fraction collector. Initially, cells are superfused with HBS for 30 minutes (flow rate 2 ml / min), then stimulated for 30 seconds every 4 minutes by changing the superphosphate medium from HBS to the corresponding medium containing 5 μΜ AMP A with or without modulators.

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

Results

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

The potency of the test substance AMP A response is expressed as a ratio to the potentiation of cyclothiazide-induced AMP A response (30 μΜ).

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 potentiation induced by 30 μΜ cyclothiazide.

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 potentiation induced by 30 μΜ cyclothiazide.

Artificial maintenance of 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 is removed under sterile conditions. Tissue is treated by slicing on a 0.4 mm cube and triturated with trypsin (12.5 µg / 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) are placed in the dishes before covering. After culturing 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: EPC-9 amplifier (HEKA-electronics,

Lambrect, Germany) running on the Power Macintosh G3 via the ITC-16 interface. The experimental conditions were set by the Pulse software connected to the amplifier. Data was slowly discharged and taken directly to the hard disk at a speed of 3x 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 for experiments. Just prior to sealing, the electrodes were zeroed with an open pipette in the bath.

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

The cells were maintained at a holding voltage of -60 mV and at the beginning of each experiment the current was continuously measured for at least 30 seconds to ensure stable current leakage. Solutions containing AMPA were fed into the chamber by a weight-driven custom-made feed line, a tip that was placed approximately 50 µm from the cell. The application started when the pipe connected to the inlet pipe was compressed by a pulse controlled valve. AMPA (30 pM) 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 repeatable amplitudes were received.

The sampling interval in all experiments was 310 pse seconds.

All experiments were performed at room temperature (20-25 ° C).

Substances

Pregnant (9 days) NMRO mice were obtained from 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-isoxazollepropionic acid) was synthesized in NeuroSearch A / S. 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.

• · · ·

Results

The results are shown in Figure 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. It can be seen that potentiation in each case is 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: 40 pA / sec. In these experiments the concentration of compounds 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 in the graph of 200 pA / 5 sec) (Fig. 8).

Links

Drejer J., Honon T. and Schousboe A. (1987) Excitatory amino acid-induced release ³ HGABA from cultured cerebral cortex intemeurons. 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 cells and cell-free membrane patches. Plugers Arch. 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 cortical neurones. Eur. J Pharmacol. 353: 159-157.

Iontophoretic applications

Purpose

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

Principle

Hippocampal single neuron pulse activity is strongly influenced by the exit input and iontophoretic application of AMPA induces pulse activity in vivo in a dose-dependent manner (Mathiesen et al. 1998). The activity of AMPA-induced pulses is

inhibited by intravenous (/ v.) administration of a broad spectrum of AMP A receptor antagonists (Mathiesen et al. 1998), indicating that excitation is primarily mediated through AMP A receptors. PAM potentiates activation of AMPA receptors in vitro, and if this mechanism also works in vivo, it should i.v. injection of PAM to increase the activity of the impulses induced by AMPA. Thus, the aim of this study was to test the in vivo effect of an in vitro active PAM group. 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 (Μ & 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 ). If the rat responded to a squeeze of the hind paw, another anesthetic was administered. The trachea was cannulated and the rats were placed in a stereotaxic skeleton and ventilated with 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 portions of the parietal bone were removed by craniotomy and the hard diaper contracted by exposing the vascular diaper and the underlying brain, covered with 0.9% NaCl.

Compounds / Reagent

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. Cyclothiazide, 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 pulse activity was analyzed on-line by a computer, storing individual pulse values and event duration. Neuronal pulse activity (number of action potentials') was monitored on a pulse rate histogram along with indicators for AMPA, COMPOUND 61, and transmitter application.

·· ··

I · 4 · 1 · 9 · 9

9 44

Method

Extracellular records of single 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 end. The individual cylinders were filled with 5 M NaCl (recording), 400 mM NaCl (buffer), 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, transmitter) 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 iontophoretic application of AMPA for 10-15 s with 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 at 1401p / ws (Cambridge Electronic Design Limited, England). The computational program also recorded mean arterial blood pressure and monitored and controlled iontophoretic application.

AMPA expelled into the hippocampus in standard cycles of 100-105 seconds. If the neuronal responses are stable (unless the AMPA responses deviate by more than 10%, measured at 10 second interval) for at least 30 minutes, then a single dose of either cyclothiazide, 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 microiontophoretic application of COMPOUND 61 (20 nA, Fig.).

Results

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

Giant. 9. Ionophoretic application of COMPOUND 61 increases the activity of individual AMPA-induced neuronal pulses.

ΦΦ · ·

I · · ΦΦΦ φ φ φ φ φφ φφ

Giant. 10. Cyclothiazide (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 seconds 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 induced by low AMPA stimulation intensity, but has only a marginal effect on large AMPA responses induced by 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). The figure shows the increase in AMPA responses by COMPOUND 56 (10 mg kg ¹ ). The onset appears approximately 10 minutes after application (Fig. 12).

Giant. 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). After 1500 seconds of recording, 10 mg kg ^{1 of} COMPOUND 63 was administered. The injection time is indicated by a shaded box above the AMPA2 entry line.

Giant. 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 time of injection is indicated by a shaded box above the AMPA line.

Giant. 13. Shows an example of an increase in AMPA pulse activity following iv administration of COMPOUND 115 (10 mg kg ^-1 ). Effect began 2 min. after iv administration and lasted more than 2 hours. COMPOUND 61 (10 mg kg ¹ ) also enhanced AMPA responses in the hippocampus. A 3-fold increase in the activity of AMPA-induced pulses induced by COMPOUND 61 starts 20 minutes after administration and lasts more than 2 hours (Figure 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 pulse- ¹ responses, medium response, Fig. 15), while only a smaller increase with higher control response is observed. (from 124 to 204 pulses' responses ¹ , Fig. 16).

· * 9 9 9 9 9 9 9 9 9 9 9

9 9 9

99

Giant. 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 recording. The effect of COMPOUND 115 lasted longer than 2 hours.

Giant. 14. COMPOUND 61 increases 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.

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

Giant. 16. COMPOUND 114 (10 mg kg ¹ ) approximately doubles the AMPA responses. The compound is administered 3900 s after the start of the recording, indicated by a shaded box above the AMPA entry line.

The results show cyclothiazide does not show any 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.

Links

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

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

Passive revocation

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

Principle: Mice are placed in a bright chamber with access to a dark chamber. If they enter the dark chamber they get elect. foot shock (0.4 mA). After a 24 hour delay, • • <is tested

• · ι • t ··

• ♦ * • · ♦♦ • · · • · · · • · « AND • · · • · · · · · • «· ··· •

association to risk unpleasant elect. Shock the foot by re-entering the dark chamber.

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

Apparatus: Devices for passive deprivation consisted of modular test chambers (ENV-307, MED-Associates, US). The light and dark chambers consisted of plexiglass boxes of uniform size (15 x 17 x 13 cm; width x length x depth) with metal grid floors. The movable guillotine door was placed in an opening connecting two chambers. To obtain 0.4 raA electr. A foot scrambler network (ENV-412, MED-Associates, US) was used.

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

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 opened. When the mouse enters the dark chamber with all four paws, it receives one elect. a paw shock (0.4 mA) and removed to your home cage. Test. After a 24-hour delay, the mouse re-enters the light chamber and the waiting time to enter the dark chamber is measured with a timeout of 2 minutes. If the mouse does not enter the darkroom within the specified time to test (2 minutes), it is assigned a waiting time of 2 minutes.

Port: 10% Tween80.

Dose volume: 10 ml / kg

N = 10;

Results; The mean (± SEM) input latency for each group is shown.

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

T ♦♦ t φ t t t · φ · · · · · · · · · · ·

Brief description of the pictures

Giant. 1 and 2 show potentiation of AMP A induced [ ³ H] GABA release from cultured cortical neurons of the compounds of the invention.

Giant. Figures 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 AMP A.

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

Giant. 9-16 are iontophoresis experiments.

Giant. 9. lontophoretic application of COMPOUND 61a iontophoretic application of the transmitter;

Giant. 10. Cyclothiazide is administered in the hippocampus.

Giant. 11. Application of COMPOUND 63;

Giant. 12. COMPOUNDS Application 56.

Giant. 13. Application of COMPOUND 115;

Giant. 13. COMPOUND 115 in the hippocampus.

Giant. 14. COMPOUND 61 in the hippocampus.

Giant. 15. COMPOUND 114;

Giant. 16. COMPOUND 114;

Giant. 17. Passive Deprivation Assay for Compound 61.

· · Φ · · · · · · · · · ·

Φ · φφ

General methods of synthesis

Method A

General sulfamoylation

i. HNR ' _{2 R.} in ^R y ^s >

X 'NR _Z NR ₂ • φφ φφ · · · · ·

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 into 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 is scaled to TLC].

Method B o -Sulfamoylation of anilines

i. CISOjNCO θν® Τ / θ ajj. AlCl, A IfeSO, (6M, aqueous)

NHR ^Δ _r A ^ NHR

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 ClSO ₂ NCO (275 mmol) in nitroethane or nitromethane (75 mL) such that the reaction temperature did not exceed -30 ° C. Remove the cooling bath and warm the thick reaction mixture 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 MH ₂ SO ₄ (or concentrated HCl only) (500 mL) and heated to reflux overnight.

0 · 00 »

9 9 9

9999 99

00 * ř •

0 »· 0

The reaction mixture was cooled to room temperature, filtered and 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? The yields range from 10% to 75%.

see also Girard Y., Atkinson J.G. and Rokach J., J. Chem. Soc., Perkinl, (1979) 1043.

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

Method C

Application of a trifluoroacetyl protecting group

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. All 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 adjusted to 7 using concentrated HCl (aq). The reaction mixture was quenched

• «♦ ·· ·· ·· • « • • * · • ♦ ♦ • « • ·· * • fl • • • • • • • «· • · • • • • • ····  · ·· · « • Φ

Cool to 0 ° C and filter. The isolated solid was washed with water and air dried. The yields are mostly in the range of 85-95%.

Method E

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

i. R'-COCl, DMAP, TEA li. 1 M NaOH, Δ

IN

N {H)

A, (H)

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. The resulting precipitate is isolated and recrystallized from z-PrOH, all yields being in the range of 80-90%.

Method F

Reduction of dihydrobenzothiadiazines-1,1-dioxide to tetrahydrobenzo-thiadiazines-1,1-dioxides in a, N (H) DIBALH 'NH

N- (R) ^M (H) ^R H

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%.

* [If 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

00

00 · 0

0 00

0 0

0 · 0000 00

0

0

0 0 t 0

00

0 0 · 0 0 * 0 0 0 0 00

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 all 2-aminobenzenesulfonamide derivative (mostly 12). - 36 hours). The reaction mixture was filtered, and the precipitate was 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 Pd + Metal Catalyst / Heterocene Catalyst Cross Coupling. - Pd additives

Helaryl / Aryt

R

Suzuki coupling: A mixed mixture of aryl halide (2 mmol), aryl or hetarylboric acid, boric acid ester or dialkylborane (6 mmol), K2CO3 (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 were heated at 70 ° C for 3 hours. 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 gave the pure product. The yields range from 40-100%.

Method I

Formation of compounds having triazolyl substitution

X = Br, I

·· 99 • 99 99 · « • 9 9 99 9 9 • · • 9 9 999 9 9 9 • 9 • 9 « • 9 9 9 9 9 9 9 • « 999 · 99 999 99 99 99

Sonogashira coupling, a mixture of aryl iodide or aryl bromide (2 mmol); acetylene (10 mmol); Pd (PPh 3) 2 Cl 2 (140 mg; 0.2 mmol); Cul (40 mg; 0.1 mmol) and triethylamine (10 mL) were stirred at room temperature overnight under N ₂ atmosphere (prolonged heating at 60 ° C for aryl bromides). THF was added and the reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. Column chromatography gave the ethynylated arene. The yields range from 40-53% for aryl bromides to 97% for aryl iodides.

Detrimethylsilylation for R 'TMS: To a solution of ethynylated arene (1.7 mmol) in MeOH (8 mL) was added 1 1 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 triazolir. Ethynylarene (0.7 mmol) and TMS-N3 (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 an 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%.

44 9 9

4 ·

4494 94 • ·· 44 4 9

9 4

4

9 9

494 44

4 9

4 4

4 ·

4 ·

DETAILED DESCRIPTION OF THE INVENTION

Compound 1

2-Cyclohexyl-4-oxo-1,2,3,4-tetrahydroquinazoline

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

Compound 2

2-Phenyl-4-oxo-1,2,3,4-tetrahydroquinazoline

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

Compound 3

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

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

Compound 4

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

2-Hydroxybenzamide is treated by Method G (using benzaldehyde). M.p. 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 2-Aminobenzenesulfonamide is treated with Method G (using an endo / exo racemic mixture of 2-norbornylenecarboxaldehyde). Mp 206-209 ° C.

Compound 6

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

2-Aminobenzenesulfonamide was treated by Method G (using benzaldehyde). Melting point 125.5-128.5 ° C.

Compound 7

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

• a ·· 9 99 99 99 • · • 9 9 9 9 9 • • and • 9 99 9 9 9 9 • • 9 • and • 9 9 9 9 • 9 • • • * · · · 99 999 99 ·· ··

2-Aminobenzenesulfonamide was used as 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 heated at 100 ° C for 72 hours and precipitated in ice) . Mp 149-154 ° C.

Compound 8

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

2-Hydroxybenzamide was treated by Method G (using 2-butanone). Mp 7678 ° C.

Compound 9

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

3- Bromoaniline was treated via Method B (see Compound 121) to give 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 Of 2-dimethoxyethane (30 mL) and Na ₂ CO ₃ (2M, 3 mL, 6 mmol) was 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 of the colorless powder. The product is further processed by Method G (using cyclohexanecarboxaldehyde). Melting point 219-221 ° C.

Compound 10

-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%). 3- (2)

· 9 · 9

9 9 9 • 9

The pyridyl) aniline is treated by Method B and Method G (using cyclohexanecarboxaldehyde). Mp 213-216 ° C.

Compound 11

-Cyclohexyl-6- (3-pyridyl) -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 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 silica gel column chromatography using EtOAc; n-hexane (1; 1, v / v) as eluent to give 240 mg (96%) of 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

-Cyclohexyl 1-7- (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 all at once. 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 extracted 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 / w) 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

-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 t-BuLi (1.7 M in pentane, 25 mL, 40 mmol) and the yellow mixture was stirred for for 1 hour at

9 9 9 9 9 9 9 9 9 9

9 · 9 · 999 · 9 * · 9 9 · 999 · 9 99 ··· · Temperature -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. It will be added

5-iodo-2-aminobenzenesulfonamide (see compound 37) (1.8 g, 6 mmol) and Pd (PPh ₃ ) ₄ (0.2 g, 3 mol%) and the mixture was refluxed for 6 hours. The THF was evaporated and the residue was boiled in 1 M hydrochloric acid (30 mL) and MeOH (30 mL) for 30 min. EDTA (14.6 g, 50 mmol) was added and basified slightly (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 cyclohexanecarboxaldehyde). Mp 224-226 ° C (dec.).

Compound 14

-Cyclohexyl 1-7- (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). Melting point 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) was heated at 80 ° C for 5 hours and over overnight at 50 ° C. The reaction mixture was poured on 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 Compound 16 Compound 16 Compound 16 Compound 16 Compound 16 Compound 16 Compound 16 Compound 16 Compound 16 Compound 16 Compound 16 Compound 16 Compound

··· · «·· ··

-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) were 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) was 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; 10 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).

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

Compound 19

-Cyclohexyl-7- (2'-acetamidophenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Nitrophenylboronic acid: Phenylboronic acid solution (10 g; 82 mmol) in acetic anhydride (100 mL) at -15 ° C add fuming HNO 3 (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 = l0 / 0.5) gave 4.8 g (35%) of pure product as an oil.

9 9

9 9

9 9

9 9 ·· ··

9 • 9 9 • 9

9

9999 99

99

9 9 • 9 9 9 9 9

999 99

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 indicated 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'-acetamidophenyl) -1,2,3,4-tetrahydro-7,2,4-benzothiadiazine-1,1-dioxide (19): 5-Iodo-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 with 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 had 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 was added a solution of 2.5 M nBuLi in hexane ( 20 mL; 50 mmol). The reaction mixture was stirred for 1 hour at -30 ° C, then cooled to -70 ° C and B (Oz-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 THF was removed by evaporation. 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 with Method H (using 2-methoxy-5-trifluoromethylphenylboronic acid) and Method G (using cyclohexanecarboxaldehyde). M.p. 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) phenylboronic acid: To a solution of benzenesulfonyl chloride (10 mL; 78 mmol) in THF (100 mL) was added a 40% solution of dimethylamine in H ₂ O (20 mL; 160 mmol) to bring the temperature reaction maintained 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 N-dimethylbenzenesulfonamide.

A solution of N, 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; 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 extracted M NaOH (4x 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-benzathiadiazine 1,1-dioxide (24): 5-Iodo-2 The aminobenzenesulfonamide (see compound 37) is treated with Method H (using 2- (N, N-dimethylsulfamoyl) phenylboronic acid) and Method G (using cyclohexanecarboxaldehyde). Melting point 290-300 ° C.

Compound 25

-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 as follows: H (using 2-chlorophenylboronic acid) and Method G (using cyclohexanecarboxaldehyde). Mp 233-236 ° C.

Compound 26

-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 as follows: H (using 2-fluorophenylboronic acid) and Method G (using cyclohexanecarboxaldehyde). Mp 249-250 ° C.

Compound 27

-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 was added NaNCE solution (2.5 g; 36.3 mmol) in H ₂ O (20 mL).

The reaction mixture was slowly added to a stirred solution of concentrated H2SCE (25 mL) in ft.

H ₂ O (20 mL) at reflux. After the addition was complete, the reaction mixture was refluxed for 30 min, cooled, charcoal added, 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.

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

Compound 28

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

4- (2'-Pyridyl) -2-aminobenzenesulfonamide: A stirred 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 H ₂ O / 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 column chromatographed 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- The aminobenzenesulfonamide is treated by Method G (using cyclohexanecarboxaldehyde). Melting point 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 with Method H (using diethyl 3-pyridylborane) and Method G (using cyclohexanecarboxaldehyde). Mp 240-242 ° C.

Compound 30

-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 was added t- BuLi (1.5 M in pentane, 13.3 mL, 20 mmol) and the yellow mixture was stirred for 1 hour at -78 ° C under an atmosphere. Φ · · φ · * * * φ φ φ

Ν ₂ . 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 off and dried, yielding 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%), 1,2-dimethoxyethane (40 mL) and Na ₂ CO ₃ (2 M, 7 mL, 14 mmol) were refluxed under N ₂ atmosphere for 5 hours. 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) after for 2 hours. The mixture was cooled and strongly basified with NaOEl (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 pale yellow powder. The product is further processed by Method B and Method G (using cyclohexanecarboxaldehyde). Mp 236-238 ° C.

Compound 31

-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 with 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 with Method H (using furyl-3-boronic acid) and Method G (using cyclohexanecarboxaldehyde). Mp 204-205 ° C.

Compound 33

• ·· ·· ··

3-Cyclohexyl-7- (2'-thienyl) -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 thienyl-2-boronic acid) and Method G (using cyclohexanecarboxaldehyde). Mp 234-236 ° C.

Compound 34

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

To a 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 Stir for 45 minutes at -78 ° C. A solution of ZnCl ₂ (2 M in THF, 75 mL, 150 mmol) was added slowly 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 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). Melting point> 250 ° C (dec.).

Compound 35

-Cyclohexyl-7- (1 ', 2', 3'-triazol-4'-yl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Iodine The 2-aminobenzenesulfonamide (see compound 37) is treated with Method I (using trimethylsilylacetylene) and Method G (using cyclohexanecarboxaldehyde). Mp 230-234 ° C (dec.).

Compound 36

-Cyclohexyl-7- (5'-phenyl-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 with Method I (using phenylacetylene) and Method G (using cyclohexanecarboxaldehyde). Mp 231232 ° C (dec.).

Compound 37 0 00 0 0 0 0 0 0

-Cyclohexyl-7- (5'-methyl-1 ', 2', 4'-oxadiazol-3-yl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-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 mL) over 1 h. 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 a filter with CHCl ₃ (3x 20 mL), NaHCO ₃ (sat. Aq., 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-aminobenzenesulfonamide: 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 hours. The reaction mixture was poured into NaHCO 3 (sat. Aq., 600 mL) and extracted with EtOAc (9x 200 mL). The combined organic fractions were washed with NaHCO ₃ (sat. Aq.) And NaCl (sat. Aq.), 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; 11 mmol) and NaOMe (616 mg; 11.4 mmol) in MeOH (10 mL) was stirred at room temperature for 1 hour, then add 5-cyano-2-aminobenzenesulfonamide (1 g; 5 mmol). 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-hydroxyamidine)} -2-amino-benzenesulfonamide (200 mg; 0.9 mmol), NaOMe (50 mg, 1 mmol), EtOAc (5 mL), comminuted MS3 (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 249251 ° C.

Compound 38 Compound 38 Compound 38 Compound 38 Compound 38 Compound 38 Compound 38 Compound 38 Compound 38 Compound 38 Compound 38 Compound 38 Compound 38 Compound 38 Compound 38 Comp. ··· ··································

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 . 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. The combined filtrates are adsorbed onto silica gel. 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 μΐ; 0.29 mol) and triethylamine (42 μΐ; 0.3 mmol) are stirred for 2 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 27a. Melting point 202206 ° C.

Compound 39

3-Cyclohexyl-7-methylsulfonylamino-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Cyclohexyl-1,2-dihydro-1,2,4-benzathiadiazine-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 3cyclohexyl-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 is 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: 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) was hydrogenated at 1 bar. After reacting • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · »• • · · · ·» the calculated amount of H _2, the reaction mixture was 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 re-suspended in EtOAc / iPrOH 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 C1 _2: acetone = 9: 1) yielded 210 mg of product.

-Cyclohexyl-7-methylsulfonylamino-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (3 9): 7-Methylsulfonylamino-3-cyclohexyl-1,2-dihydro-1 The 2,4-benzothiadiazine-1,1-dioxide is treated by Method F. M.p. 255-258 ° C.

Compound 40

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

-T-difluoromethyl-1,2,4-benzothiadiazine-1,1-dioxide:

The trifluoroacetyl protecting group was applied to 2-aminobenzenesulfonamide using Method C. To this solution (1 g; 4 mmol) in H ₂ SO 4 (16 mL) at 0 ° C was added KNO 3 solid (4.4 mmol). 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 afford 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 was treated 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 treated with Method A (using 25% NH ₃ (aqueous) as the amine) and Method G (using cyclohexanecarboxaldehyde). Melting point 178-180 ° C.

Compound 43

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

4-Sulfamoylanthranilamide: To a stirred solution of ClSO ₃ H (20 mL) was added anthranilamide (7.5 g; 55 mmol) in small portions. 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 product.

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

4- Sulfamoylanthranilamid was treated as G (using cyclohexanecarboxaldehyde) FAB + ^310,! HNMR (DMSO-d6): 8.1 (1H, br,), 8.0 (1H, d), 7.58 (1H, 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

-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 The benzothiadiazine-1,1-dioxide is reduced using Method F. Melting point 210-212 ° C.

• 0 · · ♦♦

0 00

0 ·

0 0

0000 00

00

0 0 f

0 0 0 0

0 0 0

0 «0 ·

Compound 46

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

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 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 (1H, m).

Compound 47

-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. Melting point 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

-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 TsOH], mp 255-256 ° C.

Compound 51

-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 (use piperidine as amine), Method D, Method G [using cyclopropanecarboxaldehyde], mp 228-231 ° C.

Compound 52

-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 (use piperidine as amine), Method D, Method G [using isobutyraldehyde]. Mp 237-239 ° C.

Compound 53

-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 (use piperidine as amine), Method D, Method G [using butyraldehyde]. Melting point 147.4-151.2 ° C.

Compound 54

-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 processing procedure: Method C, Method A (use piperidine such as amine), Method D, Method G [using phenylacetaldehyde]. Melting point 242-244 ° C.

Compound 55

-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 is cooled to 0 [deg.] 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 (sat. Aq.), 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 afforded the pure aldehyde which was used as a solution in CH ₂ C1 _2nd

* [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 an 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. Melting point 262-264 ° C.

Compound 57

3-Bicyclo [2.2.1] hept-5'-en-2'-yl-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 processing procedure: Method C, Method A (using piperidine as an amine), Method D, Method G [using endo / exo racemic 2-norbornylenecarboxaldehyde mixture] Two separate diastereoisomeric mixtures were isolated at temperature melting point (A) 240-242 ° C and melting point (B) 234-238 ° C.

Compound 58

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

ΦΦ ΦΦ ΦΦ ΦΦ

Φ Φ Φ ΦΦ Φ

ΦΦΦ ΦΦΦΦ

ΦΦ ΦΦΦ ΦΦ 9

ΦΦΦ ΦΦΦΦ

ΦΦΦ Φ · φ · · · ·

ΦΦ Φ ΦΦΦΦ ΦΦ

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 the amine), Method F. Melting point: 237-239 ° C.

Compound 59

3-Cyclohexyl-7- (X-methyl-X-phenylamino) 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 X-methylaniline as the amine), Method F. Melting point 210-212 ° C.

Compound 60

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

2-Aminobenzenesulfonamide was used as 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

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

2-Aminobenzenesulfonamide was used as 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 was checked by HPLC for stability compared to the free base. Under these conditions, the salt was found to be stable to hydrolysis and to have a water solubility of 10 mg / ml.

Compound 62

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

9φ 99

9 9 9

9

9 9 9

99 * 9 • 9

9

9 · 9 • 9

99 · · *

9

9

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-mesylpiperainium 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. treatment: Method E (using cyclohexanecarbonylphosphide), Method A (using N-Mesylpiperazinium chloride as amine (1.5 equiv.), using 3 equiv. K ₂ CO ₃ for neutralization), Method F. Melting point 272-274 ° C .

Compound 63

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

2-Aminobenzenesulfonamide was used as starting material for the following work-up procedure: Method E (using cyclohexanecarbonyl chloride), Method A (using morpholine as the 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 200204 ° 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 (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.

»9 9 9 9 9 9 • ·· 99 9 * 99 • 9 99 9 9 • 999 9 9 9 9 9 9 9 • 9 9 · 9 9 • • • 9 9 99 9 9 * 9 999 99 • * 9 9

Compound 66

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline sulfonamide

2-Trifluoroacetamidobenzamide (see compound 68) was treated by Method A (using 0.5 Μ NH ₃ in THF as the amine). Melting point 311-314 ° C.

Compound 67

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline Ν, Ν-dimethylsulfonamide

2-Trifluoroacetamidobenzamide (see Compound 68) was treated by Method A (using dimethylamine as the amine). M.p. 257-258 ° C.

Compound 68

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline-1,2 ', 3', 6'-tetrahydropiperidinosulfonamide To a stirred mixture of anthranilamide (13.6 g; 100 mmol) in THF (100 mL) at trifluoroacetic anhydride (15.2 mL; 110 mmol) was added at 0 ° C, allowed to warm to room temperature and stirred overnight. The reaction mixture was 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. 2-Trilfluoroacetamidobenzamide was 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-Trifluoroacetamidobenzamide (see compound 68) was treated by Method A (using cyclohexylamine as the amine). Melting point 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 the 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 an

ΦΦ • ♦ * φ φ φφ φφ • · φ φ · φ φ • κ φ • φφφ φ · φ φ • φ • φ φ φ φ φ φ φ φ φ φ · φ « φφ φφφ φφ φφ φφ

5,7-disulfonamide, which are separated by chromatography) Method G (using cyclohexanecarboxaldehyde. Aminal autooxidizes to atomatic hydroxy quinazoline). 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 0.5 M NH 3 in THF as the amine). Mp 295-297 ° C.

Compound 73

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

2-Aminobenzenesulfonamide (17.2 g; 100 mmol) was refluxed in AcOH for 5 days. The formed precepitate was isolated by filtration and washed with water to give 17.8 g (91%) of 3-methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide. 3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide was treated by Method A (using dimethylamine as the amine). Melting point 260-261 ° C.

Compound 74

-Methyl-7- (1 ', 2', 36'-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-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 cyclohexylamine as the amine). Mp 239-242 ° C.

Compound 76

-Trifluoromethyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was used as the starting material for the following processing procedure: Method C and Method A (using dimethylamine as amine) . Mp 240-242 ° C.

Compound 77

99 9 · · · «I I I I I I

9. »9

9 9 9 9 9

9999 99 999 99 99 99

2-Fluoromethyl-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 in place of the amine). Mp> 330 ° C.

Compound 78

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

-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 (1.3 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 in m.p. in the form of colorless crystals.

-Cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide-8-carboxylic acid: 5-chloro-3-cyclohexyl-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 hours 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.

• 0 0

000

0 0 0000 00

0 * 00 00 00 0 0 0 0 0 0

0 0 0 0 0 0

000 000 · 0 0 0 0 0 0 0

000 00 00 00

-Cyclohexyl-8-hydroxymethyl-1,2,2,3,4-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 min. 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 temperature -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 silica gel column chromatography using EtOAc: n-hexane (2.T, 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

-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 the 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-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

5-Chloro-3-cyclohexyl-8- (2-methoxyphenyl) -1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide:

A 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) are refluxed under atmosphere N ₂ for 2 hours. Solvents were removed under reduced pressure and the residue was extracted with water. · * ·· ··

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-methoxyphenyls) 1) -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 mL) 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 was worked up by Method F. Mp 100-105 ° C.

Compound 81

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

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

Compound 82

-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 with} BuLi of 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. Remove the cooling bath and warm to 0 ° C and stir 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) -1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

5-Chloro-3-cyclohexyl-8- (2-pyridyl) -1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: 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 1.292

·· · » 9 44 44 44 • · Φ 44 4 4 4 4 • « • 4 4 4 9 4 • « 4 • • 41 4 4 9 4 4 • • »» • » 49 4 44 44 ··

dimethoxyethane (30 mL) and Na ₂ CO ₃ (2M, 3 mL, 6 mmol) were 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 silica gel column chromatography using EtOAc: n-hexane (2: 1, v / v) as eluent to give 280 mg (58%) of 5-chloro-3-cyclohexyl-8- (2-pyridyl) ) 1,2-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. Filter the mixture through a pad of Celite ™ and remove the solvent 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 as colorless crystals. The product is further processed by Method F. Melting point 200-203 ° C.

Compound 83

-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-6] -methoxybenzenesulfonamide is separated from 2-amino-4-methoxybenzenesulfonamide by flash chromatography (EtOAc / hexane)] and then Method G (using cyclohexanecarboxaldehyde). 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). 289-292 ° C.

Compound 85 and Compound 86

-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 (8 6) * 99 9 99 99 9 9 999 999 · Β

9 9 9 9 9

9999 99,999 9 9 9 9 99

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

-Cyclohexyl-2-methyl-7-morpholinosulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide and

3-Cyclohexyl-4-methyl-7-morpholinosulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide; A mixture of 3-cyclohexyl-7-morpholinosulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (2 g;

mmol), DEAD (2.35 mL; 15 mmol), PPh ₃ (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 obtain the 2-methyl isomers in the filtrate and the 4-methyl isomers as a precipitate.

The 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 1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide was reduced according to Method F. Melting point 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-1 1,2-Dihydro-1,2,4-benzothiadiazine-1,1-dioxide was 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 [2,1c] -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

· * ·· 9 ·· • 9 ·· • * ·· · • 9 9 • 4 • * ·· «· • ♦ · • • 4 • • · «· • • · • 4 «1 ·» ·· ·· · ·· ·· **

ml). The reaction 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 LiAfflU (115 mg; 3 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture 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 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 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 was used as 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). Melting point 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 starting material for the following: treatment method: method E (using 4-chlorobutanoyl chloride), method A (using methylamine as amine), method F (using L1AlH4 and at room temperature). Mp 244-245 ° C.

Compound 90

7-Cyclohexylsulfamoyl-1,2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide φ «· · · · · · · · · · · · φ φ

2-Aminobenzenesulfonamide was used as starting material for the following work-up procedure: Method E (using 4-chlorobutanoyl chloride), Method A (using cyclohexylamine as amine), Method F (using LiAlH 4 and at room temperature). M.p. 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 work-up procedure: Method E (using 4-chlorobutanoyl chloride), Method A (using dimethylamine as 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). Melting point 151-153 ° C.

Compound 95

7- (1 ', 2', 3 ', 6'-Tetrahydropiperidino) sulfonyl-1,2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5- tt tt tt ttttttttt · · tttt tt tt tt tt ttt ttt «· · ttt tttt tt tt tttt • tttt tt

2-Aminobenzenesulfonamide was used as 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 [2.2.1] hept-5'-en-2'-yl-5,7-dimethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-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 column chromatography was obtained diastereomeric fractions, each being a mixture of diastereoisomers]. Isomeric mixture A, m.p. 160-165 ° C; isomer 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 amine). To the product of this work-up (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 ml, 3.2 mmol). The yellow mixture was stirred at -78 ° C for 25 minutes. The reaction was quenched with dry DMF (0.3 mL, 4 mmol) and the mixture was stirred at -78 ° C for 20 min. 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-forms of 1,1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as 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- (N, 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) ). For complete hydrogenation, hydrochloric acid is added in small drops. The mixture was hydrogenated using Pd / C (10%, 10 mg) at 4 bar for 24 hours. The mixture was filtered through Celite ™ and evaporated to dryness. The residue was dissolved in EtOAc (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-1,2,4-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

3,5-Dibromo-2-aminobenzenesulfonamide (see alucine 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 mixture ). Melting point 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 was treated with Method A (using 25% NH 3 (aq) as the amine) and Method G (using the endo / exo racemic bicyclo [2.2.1] hept-5-ene-2-carboxaldehyde mixture). M.p. 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-1,1-dioxide

2,4-Dichloroaniline was 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 was 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: Stirred suspension 2-amino-4 -chloro-5sulfamoylbenzenesulfonamide (11.4 g; 40 mmol) and 10% Pd / C (750 mg) in EtOH (300 mL) was hydrogenated at 1 bar until hydrogen was 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 afford 9.58 g (95%) of the product.

2-Amino-3-bromo-5-sulfamoylbenzenesulfonamide: To a stirred solution of 2-amino-5sulfamoylbenzenesulfonamide (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 3-methyl-, 3-bromomethyl-, 3-dibromomethyl and 3-tribromomethyl-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.

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 [2.2.1] hept-5'-en-2'-yl-6,8-dibromo-1,2,3,4-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 was 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 by Method G (using an endo / exo racemic mixture of 2-norbornylene carboxaldehyde). 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-Dibromanthranilamide: 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 (approx. 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-Dibromanthranilamide is processed 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) was treated by Method G (using an endo / exo racemic mixture of bicyclo [2.2.1] hept-5-ene-2-carboxaldehyde). The mixture of diastereomers is purified by column chromatography to obtain three of 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 l] Heptane-2-carboxaldehyde: To a stirred suspension of 2-norbornylene methanol (0.5 mL; 5.8 mmol) and PCC on Al 2 O 3 * in CH 2 Cl 2 (25 mL) is stirred at 2-3 ° C for 1 hour, it is then allowed to warm slowly to room temperature. The reaction mixture was filtered and the solid 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-3,5-dibromobenzenesulfonamide (see compound 125) is treated as follows: G (using bicyclo [2.2.1] heptane-2-carboxaldehyde). M.p. 182-183 ° C.

Compound 106

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

100 ALIGN!

2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was treated by Method G (using cyclohexanecarboxaldehyde). Melting point 166-167 ° C.

Compound 107

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

1-Adamantanecarboxaldehyde: 1-Adamanthylmethanol 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) is treated with Treated by Method G (using 1-adamantylcarboxaldehyde). Melting point 270-273 ° C.

Compound 108

-Phenyl 1-5,7-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 was evaporated to dryness and column chromatography was performed. Melting point 9698 ° C.

Compound 110

3-Methyl-5,7-dibromo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-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 on ice and filtered. The isolated solid was washed with Et ₂ O. Mp 287-289 ° C.

Compound 111

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

To a solution of t-BuLi (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, 60 mmol) was added slowly, the cooling bath was removed and warmed to 20 ° C. 5-Iodo-2-aminobenzenesulfonamide (see compound 37) (1.0 g, 3.2 mmol) and Pd (PPh ₃ ) ₄ (0.3 g, 8 mol%) were added and the mixture was refluxed for 6 hours. THF was evaporated and the residue 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 nhexane. 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- aminobenzenesulfonamide: n-Toluidine was treated by Method B and 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). The reaction mixture was stirred at 0 ° C until complete reaction of the starting material was observed by 1 H NMR. 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 treated 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

3-Cyclohexyl-6-methyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide N-Acetyl-3-methylaniline: n-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%).

102 · · · · · · · · · · · · · ·

3-Cyclohexyl-6-methyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide: N-acetyl-3-methylaniline was treated by Method A (using 25 % NH ₃ (aqueous) as 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) was 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.

-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 work-up procedure: Method B [2-Amino-6-methylbenzenesulfonamide is separated from 2-amino-4-methylbenzenesulfonamide by recrystallization (EtOAc / hexane)], Method E (using cyclopentanecarbonyl chloride), Method A (using piperidine as amine), Method F. Melting point 229-230 ° C.

Compound 115

3-Cyclohexyl-6-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide t-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)], Method E (using cyclohexanecarbonyl chloride), Method A (using morpholine as amine), Method F. Melting point 268-271 ° C .

Compound 116

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

3-Bromo-4-methylaniline was treated by 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 • 44)

103

4444 49

44 44 44

9 4 4 4 9 4 5

4 4 9 4 4 9 4

4 4 4 4 4 5

444 44 49 44 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (13 mg, 5 mol%) in 1,2-dimethoxyethane (20 mL) and Na ₂ CO ₃ (2 Μ, 1 mL, 2 mmol) are refluxed under N ₂ atmosphere 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 silica gel column chromatography using EtOAc: n-hexane (1: 1, v / v) as eluent to give 100 mg (90%) of 2-amino-4- (2-methoxyphenyl) -5-methylbenzenesulfonamide as colorless powder. The product is further processed by Method G (using cyclohexanecarboxaldehyde). M.p. 172-175 ° C.

Compound 117

-Cyclohexyl-6-methoxy-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide z-Anisidine was used as the 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

-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 was used as the starting material and was processed to a mixture of isomers of ethylenedioxy-2-aminobenzenesulfonamide using Method B. Two isomers were separated by column chromatography.

3-Cyclohexyl-6,7-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (118): 2 amino-5,6-ethylenedioxybenzenesulfonamide was treated according to Method G ( using cyclohexanecarboxylaldehyde). Melting point 196-200 ° C.

-Cyclohexyl-7,8-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (122): 2-amino-7,8-ethylenedioxybenzenesulfonamide is treated according to Method G (using cyclohexanecarboxylaldehyde). M.p. 268-270 ° C.

Compound 119 • 0 00 ·· • 0 9 9 0 0

0 0 0 0 0 «0 · 0 0 0>

0 0 0 0 0

00 00

104 • 9 9

000 • · 9 9

-Cyclohexyl-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 cyclohexanecarboxaldehyde). Mp 274-276 ° C.

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 / n-Bromaniline was used as 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 was allowed to stir overnight at room temperature with DIBALH). Melting point 123-125 ° C.

Compound 124

2-Ethylamino-7- (1 ', 2', 3 ', 6'-tetrahydropiperidino) sulfonylbenzenesulfonamide

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 LiAlH 4 and at room temperature). Melting point 175-177 ° C.

Compound 125 • ·

105

9 »·

9 9 9 9 9 9 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

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 gel and purified by column chromatography to afford 11.1 g (67%) of the product. 165169 ° C.

Compound 126

2-Acetamidobenzenesulfonamide

To a stirred solution of 2-aminobenzenesulfonamide (1.72 g; 10 mmol) and triethylamine (1.53 mL; 11 mmol) in THF (25 mL) at 0 ° C was added AcCl (0.85 mL; 12 mmol) and allow 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. 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: A solution of 2-nitrobenzenesulfonyl chloride (lig; 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. 4 M NaOH (12.5 mL) was added to the reaction mixture and filtered. 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: Stirred suspensions 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.

«· 9 9 • 9 9

9 99

106

99 ··

999 · 9,999 9

9 9 9 9 9

989 99 9

9 9 9 9 9

999 · «99

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. The reaction mixture was cooled to room temperature, carefully 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 was 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 was 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 dlcyclohexylglycine as the amino acid).

Compound 129

-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), CUI (76 mg; 0.4 mmol); cyclopentyl mercaptan (590 μΐ; 6 mmol) and Pd (Ph ₃ ) 4 (462 mg; 0.4 mmol) in dry dioxane (10 mL) under N ₂ atmosphere 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 is Φ Φ ♦ · φ · φ φ φ φ φ φ φ φ φ φ φ φ φ · φ φ φ φ φ φ φ φ

107

φφ φ

ί φ

neutralize to ρΗ 8.5 and evaporate 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 and A- oxidizes under the conditions described by Mr Ali and Bohnert (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:

«Φ φ φ

108

ΦΦΦ

ΦΦΦΦ φφ • φ φ

• φ Φ :: :: ::

Φ φ φ φφ φφ

109

«* • * · ·· 99 * * • • · · 9 9 9 9 ♦ « «· · • · 9 9 9 • « • • • ♦ • · b 9 • • « ·· «· 99 · 9 99 99 · ♦

it u> it it it it O 3 00 3 Lh 4a. w it O < ΙΛ O bJ LO O sj LO bP LO O SJ LO O SJ LO P> WHAT O tsí LO O it WHAT O SJ WHAT O SJ LO O what O O OF . of of of of of of of of of OF of O s> Jednod. sr Ř G. cT and Cu r CL E- O G- oT ¹ f G- F G- {? r O- ir r O- r G. o ⁴ ø CL o ¹ § ”o G- type ties X X X X X X X X X X X 50 s> cyclohexyl cyclohexyl and § · δ cyclohexyl cyclohexyl 'ir cyclohexyl cyclohexyl O & • a> x << * cyclohexyl cyclohexyl n * < π C π 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 W tzi X X X X X X X X X X X X w OX AND 6 O <? J ¹ 8 i? R <j P P / 21 o = ^ o r (? □ O of m > ° cf O <ř γ « Bye % X X X X X X X X X X X X

9 · 9

9 9

9 99 99

110 • 99

9 9 9 9 9 9 9

9

99 9 9 9 9 9 9 9 9 9

LU lu LU LU M uo LU O it kD bU oo ŘO bU O\ bU LA it Q < LO Ο here it O here it kP 00 O here it O JU it O here it O here it O here it O here it O IU it O here 0 of of of of of OF OF of of of of 0 kU Jednod. Jednod. Jednod. Jednod. Jednod. t CD O. 3 O p. Jednod. and Jednod. Jednod. Jednod. Jednod. type ties X X X X X X X X X X X cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexy! cyclohexyl cyclohexyl cyclohexyl X Cm X X X X X X X X X X X x X X X X X X X X X X X X AT) X X X X X X X X X X X X F ^w \ ^] P / ^ 1 o Ί O P P P P P 'CA O ro OF O AND X X X X X X X X X X X X 09 /

112

• · • · • 99 « • ·· 9 9 · 99 9 9 ·· • • 9 9 9 9 9 • • • • 9 • • • · 9 · • * • • • 99 · 9 9 9 99 * ·· 99 ··

LA O\ CA CA Ca 45w CA U> CA Ni CA CA O 4 ^ kQ -fa. 00 o < (Λ (OF) O N) ω κΡ what O hj WHAT O Ν » WHAT O IQ WHAT O it WHAT O WITH) what O sj O OF OF of of OF OF of of of O Ν » Jednod. (X CD O Q. C CD Q. □ O p. C CD Q. 3 O Q. C. CD Q. 3 O Q. C. CD Q. 3 O p. C- CD Q. 3 O Q. C_ CD Q. 3 O Q. C_ CD Q. 3 O p. X and and and and and and and and AFTER K> cyclohexyl cyclopentyl O and K> ►3 sr ό 3 Ό 55 ’ O * 3 3 cyclopropyl ......... O X UJ cyclohexyl cyclohexyl w w and and and and and and and and and AFTER AND. and and and and and and and and and AFTER tn and and and and and and and and and * O _o \ χ, Ο <nd O C0 < O y ^ o O \ <P cn < y »> o Q, wr Q _o \ xP tni y ^ o Q _o \ X0 y7o Q _o CD <y70 m / rn — z \ xP ω < and and and and and and and and and %

• φ

Φ φ φ φ φ φ φ φ φ

113 φ φφ φφφ φ

Φ φ φ φ φ φ φ φ φ · · · · · · · · · · · φ φ

3,4,7-Frisubstituted Single-Binding Compounds 1-H 1 -cyclohexyl I CH, I-H

116 • * φφ • * · · · * * * *

φ · φ · φ · φ · «· • · φ

\C ο 3,5,7-trisubstituted compounds with single bonds \O <-Λ ve? •AT \C ca va 3,4,7-trisubstituted double bonded compounds VO M5 O oc VC 00 oc OO -at Q < ιη S> WHAT what , P what O here what O here WHAT O here WHAT sP what O here what 0 here what 0 here O Ζ of of of of of of of of of O Κ » Jednód. Q. - ¹ ° Q) « ^ω □ Q) « -g ^w 3 'Ol · Q. O 0) ' C CD Q. 3 O· Q. C_ CD CL □ O· Q. C_ CD Q. □ O· Q. C CD Q. □ O Q. C- CD O. 3 O CL íš X 1 t 1 and X X ►Τ ’ »-Ht X X »» here Ρ & & & & & ¢ / Cy % X the JL Γ5 X X X X X X X X X X X «Λ X X X X X X X X X X 50 O\ ο X u> Q _o \ <.0 tni P 12 " \ 0 ° th 54¾ š o — z ^Z I \ 02 “5 ^ o X'o / ^X2 \ 5? * O X% QZ _Λ <? 54¾ P ¹² Z, \ / tZli 54¾ X o / xz _Λ 54¾ X here of what , P Π X LU WHAT 0 fj of X se at X X X X X X X X X X ?O 00

• ·

• 0

9

0 «

• *

117 * 0 0 0 0 0 9 0 0

• ·

9 ··

118

• · • • * *

• • • • • • 9 9 • ·

3,7,8-trisubstituted single bonded compounds 120 ^ 0 00 ^ 4 116 115 £ OJ here 3,6,7-trisubstituted single bonded compounds Q < the P the O here the O KJ LO O KJ 00 O i.e the O the 00 P what C ts> what P 00 0 Her 00 0 here O OF of OF of of of of of of of of O the C. CD CL 3 O p. t_ what Q. 3 O Q. C_ (0 and. 3 0 p. C_ CD Q. 3 O Q. c ^ CD and. 3 8. C_ CD Q. 3 O p. C_ CD and. 3 and C. CD Q. 3 O p. C_ CD CL 3 p. C_ C_ CD Q. ? b * < and X X X X X X X X X »» N> cyclohexyl C? 3 << 22nd and 2T CD X cyclohexyl 0 Uí 3Γ O 3- CD X * <_ C5 E 0 3 * CD X 0 * < E 0 3Γ η » X Π * < 0 3 CD X * <. <0 3Γ O 3Γ CD X * < E O 3 ” 8 n << E 0 3- CD X X w AND X X X X X X X X X X X «. X tfl X X X X X X X X X what * » q and r ~ \ 0 O X O X w O * T * 0 , x UJ n X Uí Whose X % O UJ < ν-Ασ X IU 2 00 0 it X w 2 what 0 here 0 0 X UJ 0 ^λ —z _Λ \ <P cn < Q _o γΛο X ba 2 CZ5 P P X AT X X X X X X X X X X X

• · · · ···· <

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

119 ··

μ it o < what O NJ O of O Jednod. type ties X w cyclohexyl »» Hive X 73 <u X % X oQ •> c y. 73 oc

·· ·· · ·· ··

Claims (30)

PATENT CLAIMS 1. The 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; and R ² represents a hydrogen atom, alkyl, cycloalkyl, aryl, benzyl, or -CO-R ⁹ wherein R ⁹ represents alkyl, cycloalkyl, benzyl or aryl; or R ² together with R ³ and the atoms to which they are attached form a 4-membered 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 121 linked, 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-membered to 8-membered ring which is optionally substituted with halogen, alkyl, hydroxy or alkoxy and the optionally 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 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 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 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 a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R ¹⁰ or -CO ² R ¹⁰ , wherein R ¹⁰ represents hydrogen, cycloalkyl, alkyl, aryl or benzyl; or 122 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · R ⁴ together with R ³ and the atoms to which they are attached form a 4-membered or 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 represents a hydrogen atom, halogen, alkyl, alkenyl, alkynyl or aryl; or R ⁵ represents -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- to 8-membered ring structure optionally substituted by halogen, alkyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, - C 1-6 -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 cyclohalogenalkyl; or R ⁶ represents -NR ¹⁵ R ¹⁶ , -NHSOR ¹⁵ or -NHSOaryl 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; 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 by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio , aryl, benzyl, -SO2alkyl, -SCH-aryl or -SObenzyl and the optionally heterocyclic ring is fused to aryl; or »0 0 • 0 • · ·· 123 · · · · · · · · · · · · 0 0 0 0 0 0 · 00 000 00 0 0 0 0 0 0 0 0 000 00 00 00 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, halogen, haloalkyl, and haloalkoxy; or R ⁶ represents - (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 ¹⁵ R ¹⁶ ; - (alkyl) mCR '= 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-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; and R ⁷ represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl or cyclohalogenalkyl; 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, 4 cycloalkyl, hydroxy groups, alkoxy groups, amino groups, thio groups, -CF ₃ , OCF ₃ , -NO ₂ , aryl; or 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) 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 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, 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 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 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 or -SO ₂ NR ¹⁷ R ¹⁸ ; or R ⁷ represents aryl which is 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 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, C 12 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 together with the R substituent or together with the R substituent form a 5-membered to 2-membered group A 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 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 φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ ·· * 126 φφφφ Φ · • · φφ R ⁸ represents - (alkyl) mSR ¹⁹ ; - (alkyl) m-SO 2 -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) mCR '= NOR; - (alkyl) m-CO-R ¹⁹ ; or - (alkyl) _m -CO ₂ -R ¹⁹ , wherein 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 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 a compound represented by the general formula I, wherein X represents SO ₂ ; and Y represents CH (R ⁴ ), N (R ⁴ ), N (R ⁴ ) -CH ₂ or O; and R ² is hydrogen; and R ³ represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, 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 ΦΦ «« · · 127 ΦΦ Φ Φ Φ ΦΦ ΦΦ 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 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 together with R ⁴ and the atoms to which they are attached form a 4 to 7 membered ring 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 a hydrogen atom, 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 optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino a group or thio group and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R ⁵ represents a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, aryl; or -SO ₂ -NR ⁿ R ¹² wherein R ¹¹ and R ¹² independently represent hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or 128 tt · • φ * * φ φ φ φ φ φ φ The substituents R and R 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, -SCh -alkyl, -SO2-aryl or -SO2-benzyl; and optionally the heterocyclic ring is fused to aryl; R ⁶ represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl or cyclohalogenalkyl; or R ⁶ is -NR ^{1 S} R ^16, -NHSO 2 R ¹⁵ or -NHSO 2 -aryl, wherein aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino groups, thio groups, - 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, -SCH-aryl or -SO ₂ -benzyl and an optionally heterocyclic ring fused to aryl; or R ⁶ aryl which is optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl and amino; or R ⁶ HET, optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, and haloalkoxy; or 99 99 99 «9 9 9 9 9 9 9 9 9999 99 129 9 9 * · 9 9 99 «99 99 99 R ⁶ represents - (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 ¹⁵ R ¹⁶ ; - (alkyl) mCR '= NOR; - (alkyl) _m -CO-R ¹⁵ ; or - (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-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; and R ⁷ represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl or cyclohalogenalkyl; 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 2 -R ¹⁷ ; - (alkyl) m-SO 2 -R ¹⁷ ; - (alkyl) m-SO ₂ OR 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 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 130 00 00 00 00 00 00 00 0 0 0 0 · · 00 ·· 0 00 000 0000 0000 00 000 00 00 00 R 1 and R 1 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, -SO2alkyl, -SC2-aryl or -SCb-benzyl; and optionally the heterocyclic ring is fused to aryl; or R ⁷ represents - (alkyl) m-SO ₂ -NR ¹⁷ R ¹⁸ wherein the index 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, -SO ₂ alkyl, -SO ₂ -aryl or -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 or -SO ₂ NR ¹⁷ R ¹⁸ ; or R ⁷ represents aryl which is 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 or -SO ₂ -NR ¹⁷ R ¹⁸ wherein 131 φ φ · · · · · · · · φ • • • φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ nezávisle nezávisle nezávisle φ 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, -SC-alkyl, -SC-aryl or -SObenzyl; and optionally the heterocyclic ring is fused to aryl; or R ⁷ together with R ⁶ or R ⁸ form a 5- to 7-membered ring having one of the following structures -O- (CH 2) _n -O-; wherein the index n is 1, 2 or 3; -SONR- (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 the index n is 1 or 2; -CO- (CH ₂ ) ₂ -O-; -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 132 ΦΦ φ · · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ 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) mSR ¹⁹ ; - (alkyl) m-SO 2 -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) mCR '= NOR; - (alkyl) _m -CO-R ¹⁹ ; or - (alkyl) _m -CO ₂ -R ¹⁹ , wherein 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 by halogen , alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO ₂ alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl; but provided that if X is SO ₂ and Y is NR ⁴ and if 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, R, R or R is not / are also not halogen or alkyl and then one or more of the remaining R ⁵ , R ⁶ , R ⁷ or R ⁸ substituents are not / are not hydrogen. A compound according to claim 1, which is a 1,2,4-benzothiadiazine derivative having the general formula (II) 99 99 ·· ·· · 999 · 9 9 9 9999 99 133 9 9 99 99 where 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 or together with the substituent R ³ and together with the atoms to which they are attached form a 5-membered to 6-membered ring which is optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl , hydroxy, alkoxy, amino and thio groups and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R ⁵ represents hydrogen, halogen, alkyl, alkenyl, alkynyl, phenyl or -SO ₂ -NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² 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 5-membered to 6-membered ring structure; R ⁶ represents a hydrogen atom, Br, F, I, cycloalkyl, alkyl, alkoxy or alkoxyalkyl; or R ⁶ represents phenyl, 134 ·· • * • • • a · «· • ·· • • ·· • * • • * • • • • • and • • · • · • • • • • ···· • · ··· ·· which is optionally substituted with one or more substituents selected from the group consisting of alkyl and alkoxy; or R ⁶ 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 ¹⁵ R ^16, -CR '= NOR, -CO- R ¹⁵ or -CO 2 -R ¹⁵ , wherein the index m is 0 or 1; and 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 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, 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, cyclohalogenalkyl, - (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 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, -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 m is 0 or 1 135 99 99 9 99 99 99 9999 99 99 9 9 99 99 99 99 999 99 9,999,999,999 9999 99 999 99 99 99 R and R are independently hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R and R 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; 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 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 R ⁸ form 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; • Φ φφ ΦΦ φφ • φ φ • · φφ φ φ φ φ 136 • · · φφ φφ -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-; -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' 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, C 1-5 alkyl, -SC-aryl, -SC-benzyl; and optionally the heterocyclic ring is fused to aryl; A compound of formula I according to claim 1, wherein R ² represents hydrogen, alkyl, cycloalkyl, phenyl or benzyl. 137 «» 9 99 ·· • · 9 · · • 9 • • 1 • ··· • i • 9 • • and • 4 • • · • · • • • • AND • ·· * • » ·· »· A compound according to any one of the preceding claims wherein <3 R is hydrogen, cycloalkyl, alkyl, 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 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 one of the preceding claims wherein R ⁴ represents a hydrogen atom or an alkyl; or o together with the substituent R and together with the atoms to which they are attached form a 5-membered 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 hydrogen, halogen, alkyl, alkenyl, alkynyl, phenyl or -SO ₂ -NR ¹¹ R ¹² where R ⁶ and R ¹² 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. 0 «0» 0 0 0 0 000 0 0 0 0 0 0 · 0000 · 0 0 0 0 0 0 0 0 0 0 0 0 0 138 R ⁶ «0 t 0 • · 0 0 0 0 0 0 000 0F A compound according to any one of the preceding claims, wherein it represents a hydrogen atom, a halogen, a cycloalkyl, an alkyl, an alkoxy group or an alkoxyalkyl; or R ⁶ represents aryl 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, -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 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 one of the preceding claims, wherein R ⁷ represents halogen, alkyl, cyano, cyanoalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohalogenalkyl, - (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 139 R 17 and R 17 independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or the substituents R and R 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 -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- 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 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 140 substituted with 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 R ⁸ form 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 -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-; -O- (CH ₂ ) _n -O-; wherein n is 1, 2 or 3; and A compound according to any preceding claim, wherein 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 or alkoxy; or R ⁸ represents HET; or R ⁸ is -SR ¹⁹ ; -SO 2 -R ¹⁹ ; -SO 2 -R ¹⁹ ; -SO 2 O-R ¹⁹ ; -SO ₂ -NR ¹⁹ R ²⁰ ; -NHCOR ¹⁹ ; »·« I · · · · · · · 141 • · ·· • · 4 I · · · · · -CONR ¹⁹ R ²⁰ ; -CR '= NOR; -CO-R ¹⁹ ; or -CO ₂ -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, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl; A compound according to any preceding claim, wherein X represents SO ₂ ; Y is N; and R ² represents H; and R ³ represents cycloalkyl, a carbocyclic 7-membered to 10-membered ring; a heterocyclic 5- to 6-membered ring; and R ⁴ represents H; and R ⁵ represents H; and R ⁶ represents a hydrogen atom, alkyl or 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-CO-R ¹⁷ ; or - (alkyl) m-CO ₂ wherein the index m is 0 or 1 142 • 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, -SC-alkyl, -SC-aryl or -SC-benzyl; and optionally a heterocyclic ring fused to aryl; or R ⁷ is - (alkyl) _m -SO 2 -NR ¹⁷ R ¹⁸ , wherein 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- to 8-membered ring structure optionally substituted with alkyl, -SOalkyl, -SOaryl or -SO ₂ -benzyl and optionally a heterocyclic ring fused to aryl; or R ⁷ is HET; or R ⁷ together with R ⁶ or R ⁸ form a 5- to 7-membered ring having one of the following structures -O- (CH 2) _n -O-; wherein the index n is 1, 2 or 3; -SONR- (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; 143 -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 alkyl, halogen, cyanoalkyl, nitroalkyl, haloalkyl, - (alkyl) _m -SO-R ¹⁷ ; - (alkyl) m-SO 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 , wherein the index m is 0 or 1, 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 or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl; or R ⁸ represents HET. A compound according to any preceding claim, wherein R ³ represents a hydrogen atom, cyclopropyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, CF ₃ , ethoxy, norbomylene, norboman, adamantane or benzyl; or R ³ together with the substituent R ⁴ and together with the atoms to which they are attached form a 5-membered ring; A compound according to any preceding claim, wherein R ⁴ is 144 0 0 0 0 0 0 0 0 0 0 0 0 0 0 9 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 O is hydrogen, methyl or ethyl; or R ⁴ together with the substituent R ³ and together with the atoms to which they are attached form a 5-membered ring; A compound according to any one of the preceding claims, wherein R ⁵ represents a hydrogen atom, chlorine, bromine, methyl or phenyl. 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 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-TVs, ^r -dimethylsulfamoylfenyl, 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, 2,4-oxadiazol-3-yl, CH ₃ CONH- , CH ₃ SO ₂ NH-, -SO ₂ OH, phenyl-SO ₂ -, N, N -dimethylsulfamoyl, N-diethylsulfamoyl, N -phenyl-Y-methylsulfamoyl or -SO ₂ heterocyclic ring, wherein the heterocyclic rings are selected from piperidine, pyrrolidine, 1,2,5,6-tetrahydropyridine, tetrahydroquinoline, N -methylpiperazine, Nsulfonylmethylpiperazine and morpholine; A compound of formula I according to any one of the preceding claims, wherein R ⁸ represents a hydrogen atom, a methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl or methoxy group. 0 0 · · 0 00 00 00 • • 00 000 000 145 0 00 000 0000 0000 00 000 90 0 0 00 A compound of formula II according to claim 2, wherein R ² is hydrogen or CH 3; and R ³ represents a cyclohexyl, cyclopentyl, norbomylene, norboman, 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-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- (γ-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 -dimethylsulfamoyl, N, N -diethylsulfamoyl, JV -phenyl-N-methylsulfamoyl or -SC 2 -heterocyclic ring, wherein the heterocyclic rings are selected from piperidine, pyrrolidine, 1,2,5,6-tetrahydropyridine, tetrahydroquinoline, N -methylpiperazine, N -sulfonylmethylpiperazine and morpholine; and R ⁸ represents a methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl or methoxy group, A compound of formula I according to claim 1, X is C = O; Y is N, O or CH; and R ² is hydrogen; and R ³ represents a hydrogen atom, CH 3, CF 3, cyclohexyl, norbomylene, phenyl or ethyl; and 146 ·· ·· · ·· · · · · 9 9 9 99 · 9999 999 8 · 9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9999 99 99 99 99 99> ι R represents a hydrogen atom, N-dimethylsulfamoyl, N-cyclohexyl sulfamoyl, tetrahydropyrid-1-yl-sulfonyl, morpholin-4-yl-sulfonyl, sulfamoyl, bromine; and R ⁵ represents a hydrogen atom or bromine; 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; R ³ represents cyclohexyl or norbornylene; and R ⁵ represents a hydrogen atom or bromine; and R ⁷ is bromo or sulfamoyl; and R ^2, R ^4, R ⁶ and R ⁸ are hydrogen; A compound of formula I according to claim 1, wherein X is SO ₂ ; and N is -NHCH ₂ -; and R ³ represents 3-methylbut-2-yl, phenyl or cyclohexyl; and R ⁷ is 1-piperidinyl sulfonyl. 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-1,3-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-dimethylsulfonamide; 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'-tetrahydropiperidinosulfonamide; 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-dimethylsulfonamide; 9 9 9 9 9 9 9 • 9 9 999 147 9 · · · 9999 ·· 999 9 99 99 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-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 1,2,3,5,10,1 Oa-Hexahydrobenzo [e] pyrrolo [1,2- b] -1,2,4-thiadiazine-5,5-dioxide; 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-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) -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'-trifluoromethylphenyl) -1,2,3,4-tetrahydro-1,2,4-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) -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) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; ·· ·· • φ φ φ φ φ φ 148 φ φ φ φ φ φ · · · · · φ φ φ φ φ · · · · · · · · 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) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7- (1-methyl-177-2-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-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-dimethylsulfonamide; 3-Cyclohexyl-7-dimethylaminosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-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-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-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-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-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-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-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; 149 ♦ φ φ φ φ · · · · · φ φ φ φ • • φ φ φ φ φ φ φ ΦΦΦ ΦΦΦ φφφφ φφφφ φφ ΦΦΦ φφ φφ φφ 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; 3-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-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-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-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 7-Methylsulfonylamino-1,2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine 5,5-dioxide; 7-Sulfamoyl-1,2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide; 7-Methylsulfamoyl-1,2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide; 7-Dimethylsulfamoyl-1,2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide; 7-Dimethylsulfamoyl-1,2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine-5,5-dioxide; φφ φφφφφφ .φ φφφφφφφφφφ φ φ φ φ φ φ φ φ φ 150 φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ 7- (1 ', 2', 3 ', 6'-Tetrahydropiperidino) sulfonyl-1,2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1,2,4-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-diethylsulfamoyl) -5-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-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; 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-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-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-benzothiadiazine-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 (III) 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 • 9 99 • 9 9 • ··· 9 9 9 9999 99 151 9 99 99 99 98 9 9 9 9 9 9 9 9 9 9 9 9 99,999 99 9 9 9 9 9 9 9 9 ··· 99 9 · 99 optionally substituted by halogen, alkyl, hydroxy or alkoxy; and R ⁶ represents haloalkyl and R ⁷ represents halogen, alkyl, cyano, cyanoalkyl, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl or cyclohalogenalkyl, or R ⁷ represents -NR ¹⁷ R ¹⁸ , -NHSO 2 -R ¹⁷ or -NH-SO 2 -aryl, wherein the aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio groups , -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 ¹⁷ 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 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, -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 152 Φ ♦ * · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ alky alky alky alky alky alky alky alky alky alky alky alky alky alky alky alky 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, 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- 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 R ⁸ form 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; φ »φ φ φ φ φ φ φ φ φ φ 153 * φ φ • • φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ -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-; -O- (CH 2) _n -O-; wherein the index n is 1, 2 or 3. 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, or a pharmaceutically acceptable excipient, carrier or diluent. Use of a compound according to claim 1 for the preparation of a medicament for the treatment of disorders and diseases of living animal subjects, including humans, characterized in that the disorder or disease is susceptible to modulation of the central nervous system AMPA receptor complex. The use of claim 25 for the preparation of a medicament for the treatment of disorders and diseases 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, characterized in that 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; 154 9 · • 9 99 9 9 9 9 9 9 * 9 • 99 • 99 • • • 9 99 9 9 9 • 9 • • 4 * • ♦ 9 * • 9 9 • « • 9 * · ·· ♦ 99 9 9 9 9 99 A method of treating a disorder or disease of a living animal subject, including humans, wherein the disorder or disease is susceptible to modulation of the central nervous system AMPA receptor complex, wherein the method comprises administering a therapeutically effective amount of a chemical compound according to any one of claims 1 to 23 ; 29. 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 disorders or diseases are selected from memory or learning disorders, psychotic disorders, sexual dysfunctions, intellectual disorders, schizophrenia, depression or 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;