SK2012003A3 - Phenoxybenzylamine derivatives as selective re-uptake inhibitors - Google Patents

Abstract

A compound of general formula (I) wherein R<1> and R<2> are H, C1-C6alkyl or (CH2)d(C3-C6cycloalkyl) wherein d = 0, 1, 2 or 3; or R<1> and R<2> together with the nitrogen to which they are attached from an azetidine ring; Z or Y is -SR<3> and the other Z or Y is halogen or -R<3>; wherein R<3> is C1-C4 alkyl optionally substituted with fluorine; except that R<3> is not CF3; or Z and Y are linked so that, together with the interconnecting atoms, Z and Y form a fused 5 to 7-membered carbocyclic or heterocyclic ring, and wherein when Z and Y form a heterocyclic ring, in addition to carbon atoms, the linkage contains one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; R<4> and R<5>, which may be the same or different, are: A-X, wherein A = -CH=CH- or -(CH2)p- where p is 0, 1 or 2; X is hydrogen, F, CI, Br, I, CONR<6>R<7>, SO2NR<6>R<7>, SO2NHC(=O)R<6>, OH, C1-4alkoxy, NR<8>SO2R<9>, NO2, NR<6>R<11>, CN, CO2R<10>, CHO, SR<10>, S(O)R<9> or SO2R<10>; or a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O, optionally substituted independently by one or more R<13>; wherein R<13> is hydroxy, C1-C4alkoxy, F, C1-C6alkyl, haloalkyl, haloalkoxy, -NH2, NH(C1-C6alkyl) or -N(C1-C6alkyl)2. The compounds of general formula (I) inhibit monoamine reuptake and in particular exhibit activity as selective serotonin reuptake inhibitors.

Description

Technical field

The invention relates to novel diphenyl ether compounds which inhibit the re-uptake of monoamine. In particular, the compounds of the invention act as selective serotonin reuptake inhibitors (SSRIs) and are therefore of use in various therapeutic fields. Of note is the use of the compounds of the invention in the treatment or prevention of a variety of disorders, including those implicated in the regulation of monoamine transporter function, such as depression, attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder, post-traumatic stress disorder, substance abuse and sexual dysfunction, including premature ejaculation. The invention further relates to pharmaceutical compositions comprising these compounds.

SUMMARY OF THE INVENTION

In a first category of Formula I, solvates or polymorphs thereof, the invention provides a compound of pharmaceutically acceptable salts,

where

R ¹ and R ² , which may be the same or different, represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a (CH ₂ ) d (C ₃ -C ₆ cycloalkyl group), wherein d represents 0, 1, 2 or 3; or R ¹ and R ² together with the nitrogen atom to which they are attached represent an azetidine ring;

Z or Y is -SR ³ and the other of Z or Y is halogen or -R ³ ; wherein R ³ is independently C 1 -C 4 alkyl optionally substituted with fluoro; with the exception that R ^{3 is} not CF ₃ ;

or Z and Y are joined to form a fused 5- to 7-membered carbocyclic or heterocyclic ring, which may be saturated, unsaturated or aromatic, with the interconnecting atoms, and where, when Z and Y form a heterocyclic ring, the bond contains one or two carbon atoms in addition heteroatoms independently selected from oxygen, sulfur and nitrogen provided that when R ⁵ is fluoro and R ² is methyl, the fused ring is not 1,3-dioxolane and Z and Y together do not form a fused phenyl ring;

R ⁴ and R ⁵ , which may be the same or different, mean:

AX wherein A is -CH = CH- or - (CH ₂ ) _p - wherein p is 0, 1 or 2; X is H, F, Cl, Br, I, CONR ^with R ^7, SO 2 NR ⁶ R ^7, SO2NHC (= 0) R ^6, hydroxy, C 1 -C 4 alkoxy, NR ⁸ SO 2 R ^9, kto2t, NR ⁶ R ^14, CN, CO 2 R ^10, CHO, SR ^10, S (0) R ⁹ or SO 2 R ^10; R ⁶ , R ⁷ , R ⁸ and R ¹⁰ , which may be the same or different, represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms optionally independently substituted by one or more R ¹² , - R ⁹ represents an alkyl group having 1 to 6 carbon atoms optionally independently substituted with one or more R ¹² ; R ¹¹ is hydrogen, C 1 -C 6 alkyl optionally independently substituted with one or more R ¹² , C (O) R ⁶ , CO ² R ⁹ , C (O) NHR ⁶ or SO ² NR ⁶ R ⁷ ; R ¹² is fluoro (preferably up to 3), OH, CO ₂ H, C 3 -C 6 cycloalkyl, NH ₂ , CONH ₂ , C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl or 5-membered or a six membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from nitrogen, sulfur and oxygen, optionally independently substituted with one or more R ¹³ ; or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a four-membered, five-membered or six-membered heterocyclic ring optionally independently substituted with one or more R ^{13 's} ; or a five- or six-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from nitrogen, sulfur and oxygen optionally independently substituted with one or more R ¹³ ; wherein R ¹³ is hydroxy, C 1 -C 4 alkoxy, fluoro, C 1 -C 6 alkyl, haloalkyl, haloalkoxy, -NH ₂ ,

NH (C 1 -C 6 alkyl) or -N (C 1 -C 6 alkyl) ₂ .

Unless otherwise stated, any alkyl group may be straight or branched and may have 1 to 6 carbon atoms, preferably 1 to 4, and especially 1 to 3, carbon atoms.

Unless otherwise stated, any carbocyclic group contains 3 to 8 ring atoms and may optionally be saturated, unsaturated or aromatic. Preferred saturated carbocyclic groups are cyclopropyl, cyclopentyl or cyclohexyl. Preferred unsaturated carbocyclic groups contain up to 3 double bonds. A preferred aromatic carbocyclic group is phenyl. In addition, the term carbocyclic includes any fused combination of carbocyclic groups, for example, naphthyl, phenanthryl, indanyl and indenyl.

Unless otherwise specified, any heterocyclic group contains 5 to 7 ring atoms, up to 4 of which may be heteroatoms such as nitrogen, oxygen and sulfur, and may be saturated, unsaturated or aromatic. Examples of heterocyclic groups are furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolinyl, pyrazolinyl isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidyl, piperazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl , triazinyl, azepinyl, oxazepinyl, thiazepinyl, diazepinyl and thiazolinyl. In addition, the term heterocyclic groups include fused heterocyclic groups, for example, benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, benzoquinoline, quinoxalinyl, quinoxalinyl, quinoxalinyl, quinoxalinyl, quinoxalinyl, a benzodiazepinyl group, an indolyl group and an isoindolyl group.

Halogen means fluorine, chlorine, bromine or iodine.

Preferably R ¹ and R ² , which may be the same or different, represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. More preferably, a hydrogen atom or a methyl group.

When Z or Y is -SR ³ , then R ³ is preferably methyl or ethyl.

If Z and Y form a fused ring, then the ring is preferably a heterocyclic ring. More preferably, a bond containing one or two sulfur atoms.

Preferably R ⁴ and R ^{5 are} not both hydrogen.

Preferably R ⁴ and R ⁵ , which may be the same or different, are

- (CH ₂ ) _p -X, wherein p is 0, 1 or 2 (preferably 0 or 1); X is hydrogen, hydroxy, CONR ⁶ R ⁷ , SO ² NR ⁶ R ⁷ , NR ⁸ SO ₂ R ⁹ , SR ¹⁰ , SOR ⁹ or SO ₂ R ¹⁰ , where R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ have higher as defined above or a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from nitrogen, sulfur and oxygen (preferably oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl or pyrimidinyl).

More preferably, R ⁴ and R ⁵ , which may be the same or different, mean:

- (CH ₂ ) _p -X, wherein p is 0 or 1; X is hydrogen, hydroxy, CONR ⁶ R ⁷ , SO ² NR ⁶ R ⁷ or NR ⁸ SO ² R ⁹ ; wherein R ⁶ and R ⁷ , which may be the same or different, represent a hydrogen atom or a C 1 -C 3 alkyl group optionally substituted by a hydroxy group, -CONH ₂ or a C 1 -C 3 alkoxy group (preferably a methoxy group); R ⁸ represents a hydrogen atom, a hydroxyethyl group or a methyl group; or R ⁹ represents a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group or a methoxyethyl group; or a triazolyl group, an imidazolyl group or a pyrazolyl group.

Even more preferably, R ⁴ is a hydrogen atom.

Preferably, R ⁶ and R ⁷ , which may be the same or different, represent a hydrogen atom, a C 1 -C 3 alkyl group optionally substituted by a hydroxyl group, -CONH ₂ or a C 1 -C 3 alkoxy group (preferably a methoxy group). More preferably, R ⁶ and R ⁷ , which may be the same or different, represent a hydrogen atom or a methyl group, even more preferably a hydrogen atom.

When present, the R ¹² is preferably oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl. More preferably, a triazolyl group, an imidazolyl group or a pyrazolyl group.

When R ⁶ and R ⁷ , together with the nitrogen atom to which they are attached, form a heterocyclic ring, then the preferred rings are a pyrrolidine ring or a piperidine ring, both of which may be substituted by OH or CONH ₂ , or a morpholine ring which may be substituted with CONH ₂ .

Preferably R ¹¹ is H or alkyl having 1 to 6 carbon atoms.

Preferably R ⁸ is hydrogen, hydroxyethyl or methyl. More preferably, a hydrogen atom.

Preferably R ⁹ represents a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group or a methoxyethyl group. More preferably methyl or ethyl (preferably methyl).

Preferably R ¹⁰ is methyl or ethyl.

Preferably p is 1 or 0, more preferably 0.

preferably

R ¹ and R ² , which may be the same or different, represent a hydrogen atom or a methyl group;

when present, the R ³ is a methyl or ethyl radical, · or Z and Y are linked so that, together with the interconnecting atoms form a fused five to seven membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, and wherein when Z and Y forms a heterocyclic ring, then the bond contains, in addition to carbon atoms, one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; and

R ⁴ and R ⁵ , which may be the same or different, represent (CH 2) PX, wherein p is 0 or 1; X is H, OH, CONR ⁶ R ^7, SO 2 NR ^p R ^7, NR ⁸ SO 2 R ^9, SR ^10, SOR ⁹ or SO 2 R ¹⁰ and wherein R ⁶ and R ^7, which may be the same or different, are H, C C 1 -C 3 optionally substituted by hydroxy, -CONH 2 or C 1 -C 3 alkoxy (preferably methoxy); or R ⁶ and R ⁷ , together with the nitrogen atom to which they are attached, may form a morpholine ring, a pyrrolidine ring or a piperidine ring, each of which may be substituted with OH or CONH 2; R ⁸ represents a hydrogen atom, a hydroxyethyl group or a methyl group (preferably a hydrogen atom); R ⁹ is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; and R ¹⁰ is methyl or ethyl; or oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl.

Advantageous

R ¹ and R ² , which may be the same or different, represent a hydrogen atom or a methyl group;

when present, the R ³ is methyl or ethyl; or Z and Y are joined to form a fused 5- to 7-membered heterocyclic ring containing 1 or 2 sulfur atoms with the interconnecting atoms; and

R ⁴ and R ⁵ , which may be the same or different, are - (CH ₂ ) _p -X, wherein p is 0 or 1; X is H, OH, CONR ⁶ R ^7, SO 2 NR ^p R ⁷ or NR ⁸ SO 2 R ^9; wherein R ⁶ and R ⁷ , which may be the same or different, represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms substituted by a hydroxy group, -CONH ₂ or a 1 to 3 carbon atoms (preferably; R ⁸ represents a hydrogen atom, hydroxyethyl methyl) R ⁹ is isopropyl or alkoxy (methoxy) or methyl, ethyl, trifluoromethyl or or methoxyethyl;

triazolyl, imidazolyl lyl.

or a pyrazole is more preferably

R ¹ and R ² , which may be the same or different, represent a hydrogen atom or a methyl group;

when present, the R ³ is methyl or ethyl; or Z and Y are joined to form a fused saturated 5- to 7-membered heterocyclic ring containing 1 or 2 sulfur atoms with the interconnecting atoms;

R ⁴ represents a hydrogen atom, and

R ⁵ represents

- (CH ₂ ) _p -X, wherein p is 0 or 1; X is hydrogen, hydroxy, CONR ^e R ⁷ , SO ² NR ⁶ R ⁷ or NR ⁸ SO ² R ⁹ ; wherein R ^s and R ^7, which may be the same or different, are H, alkyl having 1 to 3 carbon atoms optionally substituted by hydroxy, -CONH ₂ or C 1 -C 3 alkoxy (preferably methoxy); R ⁸ represents a hydrogen atom, a hydroxyethyl group or a methyl group; R ⁹ is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; or a triazolyl group, an imidazolyl group or a pyrazolyl group.

Even more preferably, R ⁴ and R ⁵ are not both hydrogen.

Preferred compounds are:

4- (2,3-dihydro-1-benzothien-5-yloxy) -3 - [(methylamino) methyl] benzenesulfonamide (Example 2);

3 - [(dimethylamino) methyl] -4- [3-methyl-4- (methylsulfanyl) phenoxy] benzenesulfonamide (Example 12);

4- (2,3-dihydro-1-benzothien-5-yloxy) -3 - [(dimethylamino) methyl] benzenesulfonamide (Example 16);

4- [3-chloro-4- (methylsulfanyl) phenoxy] -3 - [(dimethylamino) methyl] benzenesulfonamide (Example 17);

3 - [(dimethylamino) methyl] -4- [3-fluoro-4- (methylsulfanyl) phenoxy] benzenesulfonamide (Example 18);

N, N-dimethyl-N- [2- (6-quinolinyloxy) benzyl] amine (Example 29);

3 - [(methylamino) methyl] -4- (6-quinolinyloxy) benzenesulfonamide (Example 35);

4- (2,3-dihydro-1-benzothien-5-yloxy) -3 - [(methylamino) methyl] benzamide (Example 60);

4- (2,3-dihydro-1-benzothien-5-yloxy) -N-methyl-3 - [(methylamino) methyl] benzamide (Example 62);

N- (3 - [(methylamino) methyl] -4- [3-methyl-4- (methylsulfanyl) phenoxy] benzyl] methanesulfonamide (Example 75);

3 - [(methylamino) methyl] -4- [3-methyl-4- (methylsulfanyl) phenoxy] benzamide (Example 79);

4- (2,3-dihydro-1,4-benzoxathin-7-yloxy) -3 - [(dimethylamino) methyl] benzamide (Example 88);

{3 - [(dimethylamino) methyl] -4- [3-fluoro-4- (methylsulfanyl) phenoxy] phenyl} methanol (Example 90);

3 - [(dimethylamino) methyl] -4- (6-quinolinyloxy) benzamide (Example 100);

3 - [(methylamino) methyl] -4- (6-quinolinyloxy) benzamide (Example 102);

N-methyl-N- {3 - [(methylamino) methyl] -4- [3-methyl-4- (methylsulfanyl) phenoxy] phenyl} methanesulfonamide (Example 116); and

N- {4- (2,3-dihydro-1,4-benzoxathin-7-yloxy) -3 - [(dimethylamino) methyl] phenyl} methanesulfonamide (Example 124).

In a second category, the invention provides a compound of formula I or XIX

(D and pharmaceutically acceptable salts or solvates thereof, wherein (in this category): R ¹ and R ² independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or (CH ₂ ) d (C ₃ 11)

(C ₆ cycloalkyl), wherein d is 0, 1, 2 or 3, or wherein NR ¹ R ² , when taken as a whole, represents a four membered ring, wherein R ¹ and R ² together represent an alkyl group of 3 carbon atoms; Z and Y independently represent -SR ³ wherein, when Z is -SR ³ , then Y is halogen, -OR ^a , -R a ^, or -SR ^a ; or when Y is -SR ^3, then Z is halogen, -OR ^a , R ^a or -SR ^a ; wherein R ³ and R ^a independently represent: C 1 -C 4 alkyl (optionally substituted with fluorine atoms, for example -CF ₃ ); or Z and Y, taken together, may then represent a fused 5- to 7-membered ring, as illustrated by formula XIX, wherein said 5- to 7-membered ring may be saturated, unsaturated or aromatic, and wherein said 5- to 7-membered ring may optionally contain one or a plurality of P and Q heteroatoms, wherein P and Q can independently be oxygen, sulfur or nitrogen, wherein E, F, or G independently represent CH or CH ₂ and wherein cap can independently be 0, 1, 2 or

3, and m is 1, 2 or 3; and

wherein R ⁴ and R ⁵ independently represent AX, where A is

- (CH 2) n - »wherein n represents 0, 1 or 2 and wherein X represents: hydrogen, fluorine, chlorine, bromine, iodine, CONR ⁶ R ⁷ or SO ² NR ⁶ R ⁷ , OH, NR ⁸ SO ² R ⁹ , NO 2, NR ⁶ R ^{1: 1} , CN, CO ² R ¹⁰ , CHO, S (O) m R ¹⁰ , where m is 0, 1 or 2 and wherein R ⁶ , R ⁷ , R ⁸ and R ¹⁰ independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein R ⁹ represents an alkyl group having 1 to 6 carbon atoms, R ¹¹ represents H, an alkyl group having 1 to 6 carbon atoms, C (O) R ⁶ , CO ² R ⁹ , C (O) NHR ⁶ or SO 2 NR ^{6 with} R ⁶ and wherein said C 1 -C 6 alkyl is optionally substituted with one or more groups selected from OH, CO 2 H, C 3 -C 6 cycloalkyl, NH ₂ , CONH ₂ , alkoxy (C 1 -C 6), (C 1 -C 6) alkoxycarbonyl, and (5-membered or 6-membered) heterocyclic ring containing 1, 2 or 3 heteroatoms selected from d sulfur, sulfur and oxygen; or with the proviso that if P = Q = an oxygen atom, then both k and p are not zero; with the proviso that Z and Y together do not form a fused phenyl ring; R ⁴ or R ⁵ may be represented by a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from nitrogen, sulfur and oxygen; and in addition, R ⁶ and R ⁷ , together with the nitrogen atom to which they are attached, may represent a five or six membered heterocyclic ring which may be optionally substituted; and pharmaceutically acceptable salts or solvates thereof, provided that both R ⁴ and R ^{5 are} not hydrogen.

For the avoidance of doubt, unless otherwise stated, the term "substituted" means substituted with one or more defined groups. Where groups can be selected from a number of alternative groups, the groups selected may be the same or different.

For the avoidance of doubt, the term "independently" means that when one substituent is selected from a number of possible substituents, the substituents may be the same or different.

In a third category, the invention provides a compound of formula I and pharmaceutically acceptable salts thereof, wherein R ¹ , R ² , R ³ , Z and Y have the same meaning as in the first category of the invention; and R ⁴ and R ⁵ , which may be the same or different, represent - (CH ₂ ) _p -A ', wherein p represents 0, 1 or 2 and A' represents a polar group. In this category, polar groups can be defined as having negative π-values (see C Hansch and A Leo, "Substituent Constants for Correlation Analysis in Chemistry and Biology, Wiley, NY, 1979)." In this system, the hydrogen atom has a π-value of 0.00, -OCH ₃ has a π-value of -0.02, and -SO ₂ NH ₂ has a π-value of -1.82, for example [see Table VI-I, " Well-Characterized Aromatic Substituents, p. 49 et seq.]. More preferably, the polar groups have negative π values, therefore the preferred groups have π values more negative than -0.1, more preferably more negative values than -0.5, and most preferably negative values than -1.0. Although in the above definition p is other than 0, the definition of A 'is the same as p would be zero.

Unless otherwise defined, the compounds of the first, second and third embodiments are further defined as compounds of the invention.

The advantage of the compounds of the invention is that they are selective re-uptake inhibitors (they limit side effects), they should consider their possible serotonin faster (which makes them suitable to have an onset of effect as desired), its associated properties. Preferred for administration shortly before the desired efficacy α s are compounds that selectively inhibit the re-uptake of serotonin but not noradrenaline or dopamine.

It has been found that compounds of formula I which exhibit these properties have relatively polar groups on R ⁴ / R ⁵ .

Pharmaceutically or veterinarily acceptable salts of the compounds of formula I which contain a basic center are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydrobromic acid, sulfuric acid and phosphoric acid with carboxylic acids or with organosulfonic acids. Examples include HCl, HBr,

H1, sulfate or hydrogen sulphate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, glucose, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, p-toluenesulfonate and p-toluenesulfonate. The compounds of the invention may also be provided as pharmaceutically or veterinarily acceptable metal salts, in particular non-toxic alkali metal and alkaline earth metal salts, with bases.

Examples include sodium salt, potassium salt, aluminum salt, calcium salt, magnesium zinc salt, diolamine, olamine, ethylenediamine, tromethamine, chloin, megulamine diethanolamine. An overview of suitable pharmaceutical salts can be found in U.S. Pat

Berge et al., J. Pharm.

Sci., 66, p

19, 1977; P

L Gould, International

Journal of Pharmaceutics, 33 (1986), pages 201-217; and

Bighley et al., Encyclopedia of Pharmaceutical Technology,

Marcel Dekker Inc., New York 1996, Vol. 13, pages 453 to 497.

Furthermore, the compounds, their pharmaceutically acceptable salts, their solvates and polymorphs, as defined in any of the embodiments of the invention (except for intermediate compounds in chemical processes) will be referred to as compounds of the invention.

Pharmaceutically acceptable solvates of the compounds of the invention include hydrates of these compounds.

The compounds of the invention may have one or more chiral centers and may exist in a variety of stereoisomeric forms. All stereoisomers and mixtures thereof are also within the scope of the invention. Racemic compounds can either be separated using preparative HPLC and a chiral stationary phase column or resolution to give the individual enantiomers by procedures known to those skilled in the art. In addition, it is possible to isolate chiral intermediate compounds and use them to prepare the chiral compounds of the invention.

In cases where the compounds of the invention exist as E and Z isomers, the invention includes the individual isomers as well as mixtures thereof.

In cases where the compounds of the invention exist as tautomeric isomers, the invention includes the individual tautomers as well as mixtures thereof.

In cases where the compounds of the invention exist as optical isomers, the invention includes the individual isomers as well as mixtures thereof.

In cases where the compounds of the invention exist as diastereoisomers, the invention includes the individual diastereoisomers as well as mixtures thereof.

Separation of diastereoisomers or E and Z isomers may be achieved by conventional techniques, for example, fractional crystallization, chromatography or HPLC. The individual enantiomer of a compound of the invention may be prepared from the corresponding optically pure intermediate or resolution, for example, by HPLC of the corresponding racemate using a suitable chiral carrier or by fractional crystallization of the diastereoisomeric salts prepared by reaction of the corresponding racemate with a suitable optically active acid or base.

The compounds of the invention in a plurality of tautomeric forms fall within the scope of 2-hydroxypyridinyl is α-pyridonyl.

invention.

they may exist in one or all tautomers and mixtures thereof For example, it would also cover a claim for its tautomeric form,

However, it will be appreciated by those skilled in the art that certain protections that may be derivatives prior to the final step in which they are subsequently deprived of may not show parenteral and compounds according to some of the following pharmacological activity per se, orally administered or metabolized in the body to form the invention, the compounds of the invention

Thus, these derivatives may be described as being pharmacologically active.

prodrugs. In addition, certain compounds of the invention may act as prodrugs of other compounds of the invention.

All protected derivatives and prodrugs of the compounds of the invention are within the scope of the invention. Examples of suitable prodrugs of the compounds of the invention are described in "Drugs of Today, Vol. 19, No. 9, 1983, p. 499-538 and in "Topics in Chemistry, Chapter 31," p. 306-316 and in Design of

Pro-drugs H. Bundgaard, Elsevier, 1985, Chapter 1 (the contents of which are incorporated herein by reference only).

It will further be apparent to those skilled in the art that certain parts known to those skilled in the art as pre-parts, for example described by H. Bundgaard in Design of Pro.drugs (the contents of which are incorporated herein by reference), may be placed at appropriate functionalities. groups, if such functional groups are present in the compounds of the invention.

Preferred prodrugs of the compounds of the invention include: esters, carbonate esters, hemi-esters, phosphate esters, nitroesters, sulfate esters, sulfoxides, amides, carbamates, azo compounds, phosphamides, glycosides, ethers, acetals and ketals.

The invention also encompasses all suitable isotopic variations of the compounds of the invention. Isotopic variation is defined as a variation in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass than that found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ 0, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, respectively. ³⁶ C1. Certain isotopically labeled compounds of the invention, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and / or tissue substrate distribution assays. Particularly preferred for their ease of preparation and easy detectability are tritiated, i.e. ³ H, and carbon-14, i.e. ¹⁴ C, isotopes. The ³¹ C and ¹⁵ F isotopes are particularly useful in PET (positron emission tomography) and the ^12S I isotopes are particularly useful in SPECT (single photon emission computed tomography) and all are useful in brain imaging. In addition, substitution with heavier isotopes such as deuterium, i.e., ² H, may confer certain therapeutic advantages resulting from greater metabolic stability, for example, prolongation of the in vivo half-life or reduction of the required dose, and thus may be advantageous in certain circumstances. Isotopically labeled compounds of formula I according to the invention can generally be prepared using the procedures described in the reaction schemes and / or in the Examples below, by replacing the non-isotopically labeled reagent with a readily available isotopically labeled reagent.

The compounds of the invention can be prepared in a variety of ways. In the following reaction schemes, and further unless otherwise stated, R ¹ to R ¹³ , Z and Y have the same definitions as in the first embodiment of the invention. These methods represent a further embodiment of the invention.

Throughout the description, all general formulas are indicated by the Roman numerals I, II, III, IV, etc. The subsets of these formulas are defined as Ia, Ib, Ic etc., ... IVa, IVb, IVc, etc.

Compounds of formula (I) may be prepared from compounds of formula (II) by reaction with an amine of formula HNR ¹ R ² , or a suitable salt thereof, together with a hydride reducing agent in a suitable solvent (see Reaction Scheme 1). When either R ¹ or R ² is a hydrogen atom, suitable solvents include protic solvents such as ethanol, and sodium borohydride is a suitable reducing agent, as shown in Example 36. If neither R ¹ or R ² is a hydrogen atom, it is a suitable solvent. tetrahydrofuran and dichloromethane and a suitable reducing agent is sodium triacetoxyborohydride. In such reactions, it is preferred to use a salt form of ENR -R ^{2, 19,} such as the hydrochloride, and can be optionally together with acetic acid, add auxiliary base, to aid solubility HNRX ² salt, such as triethylamine, see, for example, are an example of the 25th

Reaction scheme 1

Compounds of formula II may in turn be prepared by coupling compounds of formula IV with aldehyde compounds of formula III wherein L is a suitable leaving group such as a halogen atom (fluorine, chlorine, bromine or iodine) or a sulfonate ester such as trifluoromethanesulfonate or methanesulfonate, preferably L represents a fluorine atom or a chlorine atom. Such a coupling reaction may be carried out by techniques known in the art, such as by reaction with potassium carbonate in a suitable solvent, such as dimethylformamide, under suitable reaction conditions, such as at elevated temperature and under an inert atmosphere.

Thus, in a further aspect, the invention provides a process for the preparation of compounds of formula I from compounds of formula II.

Alternatively, R ⁴ and / or R ^{5 can} be introduced after the ether has been bound (see Reaction Scheme 2). Compounds of formula I may be prepared from compounds of formula Ia, i.e. from compounds of formula I, wherein R ⁴ and R ⁵ are hydrogen. Compounds of formula Ia may be prepared from compounds of formula IIa in a manner analogous to the method for preparing a compound of formula I from a compound of formula II (see Reaction Scheme 1), while compounds of formula IIa may be prepared from compounds of formula IV and compounds of formula (IIa) in a manner analogous to the method for preparing compounds of formula (II) (see reaction scheme 1).

Reaction scheme 2

(Ha) (Ia) (D

Accordingly, in a further aspect, the invention provides a process for preparing compounds of formula I from compounds of formula Ia.

Methodologies for introducing R ⁴ and / or R ⁵ into compounds of formula Ia include:

i) when R ⁴ / R ⁵ is a halogen atom, reacting a compound of formula Ia with a suitable halogenating agent in an inert solvent which does not adversely affect the reaction. Suitable halogenating agents include trifluoromethanesulfonic acid and N-iodosuccinimide, and suitable inert solvents include dichloromethane;

ii) when R ⁴ / R ⁵ is -NO ₂ , reacting a compound of formula Ia with a suitable nitrating agent such as an alkali metal nitrate in a solvent that does not adversely affect the reaction at room temperature or below room temperature. Suitable nitrating agents include trifluoromethanesulfonic acid / potassium nitrate and suitable solvents include trifluoroacetic acid;

iii) when R ⁴ / R ⁵ is -SO ₂ NR ⁶ R ^{7 by} reaction of an intermediate sulfonyl chloride with the desired amine of formula HNR ^e R ⁷ in a suitable solvent; suitable solvents include a mixture of water and dichloromethane, and the reactions are generally carried out at or below room temperature; Intermediate sulfonyl chlorides can be prepared from compounds of Formula Ia by reaction with chlorosulfonic acid at low temperature in the presence of a solvent that does not adversely affect the reaction, either with or without subsequent treatment with a chlorinating agent such as phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride. a solvent which does not adversely affect the reaction; suitable solvents for reaction with chlorosulfonic acid include trifluoroacetic acid and a typical reaction temperature is 0 ° C; suitable solvents for reaction with the chlorinating agents include acetonitrile and suitable conditions include the reaction at reflux as illustrated in Example 12 herein.

For example, compounds of formula Iq wherein R ⁵ is -SO ₂ NR ⁶ R ⁷ may be prepared via the intermediate sulfonyl chlorides of formula XVIII from compounds of formula Ia by reacting a compound of formula Ia with chlorosulfonic acid, either with or without subsequent treatment with a chlorinating agent, such as phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride, followed by reaction with HNR ^S R ⁷ (see Reaction Scheme 2a). Reaction conditions generally include low temperature. The reaction may be carried out either in the absence of a solvent or in the presence of an inert solvent which does not adversely affect the reaction. The intermediate sulfonyl chloride (XVII) can be isolated, purified and then reacted with HNR ⁶ R ⁷ , alternatively generated in situ, without isolation, and then reacted with HNR ⁶ R ⁷ .

Reaction Scheme 2a

Accordingly, in a further aspect, the invention provides a process for the preparation of compounds of formula I from compounds of formula II. In a preferred embodiment, the method provides the preparation of compounds of formula Iq by reacting compounds of formula Ia in a suitable solvent with chlorosulfonic acid either with or without subsequent treatment with a chlorinating agent such as phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride to form compounds of formula XVIII; followed by treatment with an amine of formula HNR ^S R ⁷ to give compounds of formula Iq. Preferably, compounds of formula XVIII are generated in situ and reacted with an amine of formula HNR ^S R ⁷ without isolation.

Alternatively, using known techniques, a compound of formula I having a particular R ⁴ / R ⁵ substituent can be converted to other compounds of formula I. For example:

i) where R ⁴ / ^R is a halogen, such as chlorine, bromine or iodine atom, then it may be converted to cyano by treatment with a cyanide salt in the presence of Pd (0) or Pd (II) catalyst in a solvent with a high boiling point at elevated temperature.

Suitable Pd catalysts include palladium tetrakis (triphenylphosphine), suitable cyanide salts include Zn (CN) _2, and suitable high boiling solvents that do not adversely affect the reaction include dimethylformamide, as exemplified by Example 78 herein;

(ii) when R ⁴ / R ⁵ represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, then it can be converted to the corresponding ester-CO ₂ R by treatment with high pressure carbon monoxide with Pd (0) or (II) a catalyst, in an alcoholic solvent (ROH, wherein R is C 1 -C 4 alkyl), in the presence of a base at an elevated temperature; for example, the reaction may be carried out at pressures ranging from about 0.7 MPa, while suitable Pd catalysts include dichlorobis (triphenylphosphine) palladium (II), suitable bases include triethylamine, and suitable alcohol solvents include methanol, as exemplified by Preparation 50 herein. ;

iii) when R ⁴ / R ⁵ represents a nitro group, it can be reduced to the corresponding -NH ₂ group by treatment with a reducing agent in a protic solvent at room temperature or higher. Suitable reducing agents include powdered iron / calcium chloride, suitable protic solvents include aqueous ethanol, and a typical reaction temperature is from about 70 ° C to about 100 ° C, preferably about 90 ° C, as exemplified by Example 103 herein;

iv) when R ⁴ / R ⁵ is -NH ₂ , then it can be converted to the corresponding -NHSO ₂ R ⁹ group by reaction with a sulfonylating agent in the presence of a base in an inert solvent which does not adversely affect the reaction at room temperature or below. Suitable sulfonylating agents include methanesulfonyl chloride, suitable bases include triethylamine, and suitable inert solvents include dichloromethane, as exemplified by Example 128 herein;

v) when R ⁴ / R ⁵ represents an -NHSO ² R ⁹ group, then it can be converted to the corresponding -NR ⁸ SO 2 R ⁹ group by treatment with an alkylating agent and a base in a suitable inert solvent. Examples of suitable alkylating agents include methyl iodide, a suitable base includes potassium carbonate, and suitable inert solvents include acetonitrile as exemplified by Preparation 88 herein;

vi) when R ⁴ / R ⁵ represents a nitrile -CN, then it can be converted to the corresponding -C (O) NH ₂ group by hydrolysis under basic, oxidative or acidic conditions. The basic hydrolysis is preferably carried out with a hydroxide such as potassium hydroxide in a protic solvent such as tert-butanol at elevated temperature, as illustrated in Example 79.

vii) when R ⁴ / R ⁵ is an ester -CO ₂ R, then it can be reduced to the corresponding alcohol group -CH ₂ OH by treatment with a hydride reducing agent such as aluminum hydride as exemplified by Preparation 69 herein; viii) when R ⁴ / R ⁵ represents an ester -CO ₂ R, it can be converted to the corresponding acid -CO ₂ H by treatment with a suitable hydroxide in the presence of water and a suitable co-solvent; a suitable hydroxide includes lithium hydroxide and suitable co-solvents include tetrahydrofuran, as exemplified by Preparation 55 herein;

ix) when R ⁴ / R ⁵ is -CO ₂ H acid, then it can be converted to the corresponding amide -CONR ^S R ^{7 by} treatment with a binder, base and amine HNR ⁵ R ⁷ in a suitable inert solvent which does not adversely affect the reaction; suitable binders include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole, a suitable base comprising triethylamine and suitable solvents include dichloromethane, as exemplified by Preparation 59 herein;

(x) when R ⁴ / R ⁵ represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, it may be converted to an α, β-unsaturated amide by treatment with acrylamide, a Pd (O) or (II) catalyst, and a suitable base, in an inert solvent which does not adversely affect the reaction, at elevated temperature; suitable Pd catalysts include palladium (II) acetate in the presence of tri (o-tolyl) phosphine, suitable bases include triethylamine, and suitable inert solvents include acetonitrile, as exemplified by Example 50 herein;

(xi) where R ⁴ / R ⁵ is α, β-unsaturated amide, then it can be converted to -CH ₂ CH ₂ CO ₂ NH ₂ , by treatment with a suitable reducing agent at a suitable temperature, in a suitable solvent which does not adversely affect the reaction ; suitable reducing agents include room temperature iodide and suitable solvents include tetrahydrofuran containing a small amount of water, as exemplified by Example 51 herein;

xii) when R ⁴ / R ⁵ is -CH 2 OH, then it can be converted to -CH ² NR ⁸ SO ² R ⁹ by means of a Mitsunobu reaction at a suitable temperature, in a suitable solvent that does not adversely affect the reaction; suitable reagents include diethyl azodicarboxylate, triphenylphosphine and tert-butyl methylsulfonylcarbamate, wherein a suitable reaction temperature is 0 ° C and a suitable solvent is tetrahydrofuran as exemplified by Preparation 72 herein;

Alternatively, compounds of formula I having a particular ΝΙΝΙ Ή ² group can be converted to other compounds of formula I having another NR / R ² group. For example:

i) compounds of formula 1b wherein either R ¹ or R ² is hydrogen can be converted to compounds of formula Ic wherein neither R ¹ or R ² is hydrogen by reacting the compound of formula 1b with an aldehyde and a hydride reducing agent ; suitable aldehydes include formaldehyde, suitable reducing agents include sodium tri (acetoxy) borohydride, and the reaction is preferably carried out in a solvent that does not affect the reaction, for example, dichloromethane, at room temperature or below, as exemplified by Example 12 herein;

ii) compounds of formula 1b wherein R ¹ or R ² is hydrogen may be converted to compounds of formula Ic wherein R ¹ or R ² is methyl by reacting a compound of formula 1b with a formulation agent in a suitable solvent, followed by by reducing the intermediate Ν'-form of the compound with a hydride reducing agent in an inert solvent, preferably at elevated temperature. Suitable formulating agents include pentafluorophenyl formate (formed from formic acid, pentafluorophenol and dicyclohexylcarbodiimide) and suitable solvents for formylation include dichloromethane. Suitable reducing agents include borane-tetrahydrofuran complex and suitable inert solvents for reduction include tetrahydrofuran, as exemplified by Example 110 herein.

Alternatively, compounds of formula I may be prepared from compounds of formula V (see Scheme 3) wherein L is as defined above in Reaction Scheme 1 and T is a group which can be converted to R ^ CH ^ · ^second

Examples of suitable T substituents include:

-CO ₂ R ¹⁰ , -CN and -C (O) NR ^X R ² .

Reaction scheme 3

Methodologies for converting a compound of Formula V to I include:

i) when T is -CO ₂ R ¹⁰ and R ¹⁰ is methyl or ethyl, reacting with an amine of formula NHR ¹ R ² to form an amide, followed by reduction to give the amine;

ii) when T is -CN, reduction to the corresponding amine of formula -CH ₂ NH ₂ ;

iii) when T is -C (O) NR ¹ R ² , an amine-providing reduction.

Compounds of formula (V) may in turn be prepared by the coupling of compounds of formula (VI) and compounds of formula (IV). The reagents and conditions for such coupling reactions are the same as those defined for the coupling of compounds of formulas IV and III in Reaction Scheme 1.

Compounds of formula VI can in turn be prepared from compounds of formula VII (see Reaction Scheme 4).

Reaction scheme 4

Compounds of formula VI may be prepared by aromatic electrophilic substitution of compounds of formula

VII immediately provides compounds of formula

Alternatively, compounds of formula (I) are possible

Prepare VI in two or more steps; that is, an aromatic electrophilic substitution of compounds of formula VII to give intermediate compounds, which are then subjected to a further reaction to give compounds of formula VI. The intermediate compounds may be isolated or generated in situ without isolation. The preferred route is shown in Reaction Scheme 5.

Reaction scheme 5

Compounds of formula VII are reacted with a sulfonyl chloride to form a compound of formula VII, followed by reaction with NHR ^S R ⁷ to give a compound of formula VIa.

In further aspects, the invention provides compounds of formula II, IIa and V as defined above.

Compounds of formula III, IIIa, IV, VI or VII are either known or available from commercial sources or can be prepared from commercial materials using known techniques (see the following examples).

It will be apparent to those skilled in the art that, during the synthesis of a compound of Formula I, it may be necessary to protect more sensitive functional groups and subsequently deprive them of their protection. This can be accomplished by conventional techniques such as those described in "Protective Groups in Organic Synthesis, 3rd Edition by TW Greene and PGM Wuts, John Wiley and Sons Inc., 1999. Example 35 provides one such example of using a group protecting strategy in compound synthesis. according to the invention.

It will be apparent to those skilled in the art that diaryl ethers can be prepared using a variety of synthetic methods. An overview of these methods can be found, for example, in J S Sawyer, Tetrahedron, 56 (2000) p. 5045-5065, the contents of which are incorporated herein by reference.

The compounds of the invention are useful because of their pharmacological activity in mammals, including humans. More particularly, they are useful in the treatment or prevention of a disorder involved in the regulation of monoamine transporter function. Diseases that may be mentioned in this regard include hypertension, depression (e.g., depression of cancer patients, depression of patients suffering from Parkinson's disease, depression following myocardial infarction, subsyndrome symptomatic depression, depression of infertile women, pediatric depression, minor depression, minor depression, minor depression, minor depression, minor depression, minor depression) , recurrent depression, childhood abuse depression, postpartum depression, and annoying old man syndrome), generalized anxiety disorder, phobias (such as agoraphobia, social phobia, and simple phobia (persistent and irrational fear of a particular subject or situation), post trauma personality avoidance, premature ejaculation, eating disorder (eg anorectic neurosis and bulimic neurosis), obesity, chemical dependence (eg alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepine), h istamine cefalalgia, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory impairment (e.g. dementia, amnestic disorder, and aging-related impairment of cognitive function (ARCD)), Parkinson's disorder (e.g. dementia in Parkinson's disease, neuroleptically induced) parkinsonism and tardive dyskinesia), endocrine disorders (e.g. hyperprolactinaemia), vasospasm (especially in cerebral vasculature), cerebral ataxia, gastrointestinal tract disorders (including changes in motility and secretion), negative symptoms of schizophrenia, stress syndrome, premenstrual syndrome, premenstrual syndrome, premenstrual syndrome, , trichothilomania, cleptomania, male impotence, attention deficit hyperactivity disorder (ADHD) (ADHD), chronic paroxysmal hemicrania, headache (related to vascular disorders), emotional lability, pathological tear, sleep disorders (cataplexy) and shock.

Of particular interest are disorders including depression, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, post-traumatic stress disorder, substance-related disorders and sexual dysfunctions including (particularly) premature ejaculation. Premature ejaculation can be defined as permanent or recurrent ejaculation before, after or shortly after penetration of the penis into the body of the sexual partner. It can also be defined as an ejaculation that occurs before the individual wishes to do so [see "The Merck Manual, 16th edition, p. 1576, published by Merck Research Laboratories, 1992].

Accordingly, in other aspects, the invention provides:

i) a compound of the invention for use as a medicament;

(ii) the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of a disorder in which the regulation of monoamine transport function is involved, such as depression, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, post-traumatic stress disorder; substance or sexual dysfunction, including premature ejaculation;

iii) use of a compound of the invention in the manufacture of a medicament for treating or preventing premature ejaculation;

iv) a method of treating or preventing depression, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, post-traumatic stress disorder, substance-related disorder or sexual dysfunction, including premature ejaculation, which comprises administering a therapeutically effective amount of a compound of the invention to a patient treatment or prevention needs;

v) a method of increasing ejaculatory latency, comprising administering to a male in need thereof an effective amount of a compound of the invention in need of increasing ejaculatory latency; and vi) a compound of the invention for the treatment or prevention of a disorder in which the regulation of monoamine transport function is involved, such as depression, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorder or sexual dysfunction including premature ejaculation.

vii) a compound of the invention for the treatment of premature ejaculation.

All references to treatment are to be understood as referring to curative, palliative and prophylactic treatment.

The compounds of the invention may be administered alone or as part of a combination therapy. When a combination of active ingredients is administered, they can be administered simultaneously, separately or sequentially. In particular, the compounds of the invention may be combined with the following substances, preferably in the treatment of PE:

i) With alpha-blockers (e.g. phentolamine, doxazasim, tamsulosin, terazasin, prazasin and Example 19 of WO 9 830 560. A possible rational consideration for treating premature ejaculation with alpha-blockers is as follows. Muscular activity of ejaculatory smooth muscle and urethra) is controlled by the sympathetic nervous system through the release of norepinephrine. Norepinephrine acts on alpha 1 adrenoreceptors, stimulating muscle contractions, leading to semen emission and subsequent ejaculation, and blocking these receptors will lead to inhibition of ejaculation.

ii) Apomorphine, wherein reference to the use of apomorphine as a medicament can be found in U.S. Patent 5,945,117.

iii) Dopamine D2 agonists (e.g. Premiprixal, Pharmacia Upjohn Compound No. PNU95666).

iv) Melanocortin receptor agonists (e.g. Melanotan II).

v) PGE1 receptor agonists (e.g. alprostadil).

vi) Monoamine transport inhibitors, in particular noradrenaline re-uptake inhibitors (NRIs) (e.g. reboxetine), other serotonin re-uptake inhibitors (SRIs) (e.g. paroxetine) or dopamine reuptake inhibitors (DRIs).

vii) With 5-HT 3 antagonists (for example ondansetron and granisetron). The possible rational consideration for treating premature ejaculation with 5-HT 3 antagonists is as follows. receptors

The 5-HT3 present in the lumen of the posterior urethra is stimulated by 5-HT in the semen during seed emission, resulting in sensitization of the spinal release pathway, which in turn leads to ejaculation. Thus, the antagonist would prevent this sensitization and thus delay ejaculation.

viii) PDE inhibitors such as PDE2 (e.g. erythro-9- (2-hydroxyl-3-nonyl) adenine) and Example 100 of EP 0 771 799, incorporated herein by reference) and in particular a PDE5 inhibitor (e.g. sildenafil 1 - {[3- (3,4-dihydro-5-methyl-4-oxo-7-propylimidazo [5,1- f] -as-trazin-2-yl) -4-ethoxyphenyl] sulfonyl} -4 -ethylpiperazine is vardenafil / Bayer BA 38-9456 or IC351 (see structure below, Icos Lilly)). The possible rational consideration for treating premature ejaculation with PDE inhibitors is as follows. C AMP and CGMP levels in ejaculatory smooth muscles regulate the muscle tone of these ejaculatory muscles, and thus may delay ejaculation.

ο

1C351 (Ics Ulyl) (ix) With potassium channel opener.

x) Purinergic P2X receptor antagonists.

xi) With endothelin receptor antagonists

When used in human medicine, the compounds of the invention may be administered alone, but in human medicine they will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with respect to the intended route of administration and standard pharmaceutical practice.

For example, the compounds of the invention may be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gel capsules), eggs, elixirs, solutions or suspensions which may contain flavoring or coloring agents for immediate, delayed, modified, long-term, dual or controlled release or pulsating delivery. The compounds of the invention may also be administered by intracavernosal injection. The compounds of the invention may also be administered by rapidly dispersing or rapidly dissolving dosage forms.

Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, glycine, and starch (preferably corn starch, potato starch or tapioca starch), disintegrating agents such as sodium starch glycolate, croscarmellose sodium. granulating binders such as hydroxypropylmethylcellulose (HPC), sucrose, gelatin included in the lubricating magnesium tablets, stearic acid and certain complex silicates, and, for example, polyvinylpyrrolidone, (HPMC), hydroxypropylcellulose and acacia. Further, there may be agents such as stearate. glyceryl behenate and talc.

Solid compositions of a similar type may also be used as fillers in gelatin capsules. Preferred excipients in this case are, for example, lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycol. In the case of aqueous suspensions and / or elixirs, the compounds of the invention and their pharmaceutically acceptable salts may be combined with various sweetening or flavoring agents, coloring agents or coloring agents, emulsifying and / or suspending agents and diluents such as water, ethanol, propylene glycol and glycerin. and their combinations.

The drug release form of the modified release form may comprise excipients such as and pulsating as, for example, the excipient release excipients described in the context of dosage forms that act as immediately together with other release rate modifiers these are part of and / or are released from the body.

include, but are not limited to, rate modifiers such as hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, polyethylene oxide, xanthan gum, carbomer, ammonium methacrylate copolymer, hydrogenated castor oil, paraffin oil, paraffin oil, paraffin oil, paraffin oil, propyl methylcellulose, methacrylic acid copolymer and mixtures thereof. Modified release and pulsatile release dosage forms may comprise one or a combination of release rate modifying excipients. Release rate modifying excipients may be. present both within the dosage form, that is, within the matrix, and on the dosage form, that is, on the surface or in the coating.

Rapid or dispersible formulations (FDDFs) may contain dissolving agents as follows aspartame, acesulfame potassium, croscarmellose ethyl acrylate, cellulose, drug ingredients:

citric acid, diaskorbic acid, sodium acid, crospovidone, ethylcellulose, gelatin, hydroxypropyl methyl stearate magnesium, mannitol, methyl methacrylate, mint silica, sodium stearyl fumarate, flavor, silica, sorbitol polyethylene glycol xylene, sodium glycol.

fuming starch, dispersing the context of or

FDDFs, dissolving, are dependent as

As used herein, the terms are used in the solubility of the pharmaceutically active drug substance used, i.e., if the drug is insoluble, a rapidly dispersing dosage form can be prepared, and if the drug is soluble, the pharmaceutically active drug dissolving form can be prepared.

The compounds of the invention may also be administered parenterally, for example, intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracrally, intramuscularly or subcutaneously, or may be administered by infusion techniques.

For such parenteral administration, the most commonly used form is a sterile aqueous solution, which may contain other substances, such as sufficient salts or glucose, to form a solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of about 3 to 9) if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques known to those skilled in the art.

The following dosage levels and other dosage levels herein are calculated for an average adult having a body weight of from about 65 kg to about 70 kg. A person skilled in the art will then be able to determine the dosage levels necessary to treat a subject whose weight lies outside the indicated weight range, for example, for children and the elderly.

For oral and parenteral administration to a human, the daily dosage level of the compounds of the invention or salts or solvates thereof will generally range from 10 mg to 500 mg (in single or divided doses).

Thus, for example, tablets or capsules of the compounds of the invention may contain from 5 mg to 250 mg of active compound when administered, as required in a single dose or in two or more doses as appropriate. The attending physician will, in a particular case, be able to determine the particular dose that will be most suitable for any individual patient, depending, for example, on the age, weight, and response of the particular patient. The above dosages are examples of the average dosage. Of course, there may be particular instances where higher or lower doses may be preferred, and these will also be within the scope of the invention. One of ordinary skill in the art will also appreciate that in the treatment of a condition (including PE), the compounds of the invention may be administered in a single dose based on "particular need."

Example of tablet formulation

Generally, a tablet formulation could contain about 0.01 mg to 500 mg of a compound of the invention, while the tablet fill weight can range from 50 mg to 1000 mg. An illustrative example of a 10mg tablet formulation is:

Folder% w. A compound of the invention 10 000 * lactose 64 125 starch 21 375 Croscarmellose sodium 3000 Magnesium stearate 1500

This amount is generally adjusted depending on the efficacy of the pharmaceutically active ingredient.

The compounds of the invention may also be administered intranasally or by inhalation and are conveniently supplied as a dry powder inhaler or aerosol spray presentation from a pressurized container, pump, spray or nebulizer using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane,

1,1,1,2-tetrafluoroethane hydrofluoroalkane such as (HFA 134A [Trade Mark]) or

1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. The pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, for example in the form of a mixture of ethanol and a propellant as a solvent, which may further comprise a lubricant, for example sorbitan trioleate. Capsules and cartridges (made, for example, of gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and suitable powder bases such as lactose or starch.

Aerosol or dry powder formulations are preferably adapted so that each metered dose, or even breath, containing 1 mg to 50 mg of a compound of the invention for delivery to the patient. The total daily dose for an aerosol will range from 1 mg to 50 mg and can be administered in a single dose or, more usually, in divided doses throughout the day.

The compounds of the invention may also be formulated for atomizing dosing. Atomizer formulations may contain the following components as solubilizers, emulsifiers or suspending agents: water, ethanol, glycerol, propylene glycol, low molecular weight polyethylene glycols, sodium chloride, fluorocarbons, polyethylene glycol ethers, sorbitan trioleate, oleic acid.

Alternatively, the compounds of the invention may be administered in the form of suppositories or pessaries, or may be administered topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or powder. The compounds of the invention may also be administered dermally or transdermally, for example using patches. They can also be administered by the ocular, pulmonary or rectal route.

For ophthalmic use, the compounds may be formulated as micronized suspensions in an isotonic sterile saline solution at a suitably adjusted pH value, or, preferably, as solutions in an isotonic sterile saline solution at a suitably adjusted pH value, optionally in combination with a preservative such as for example, benzylalkonium chloride. Alternatively, they may be formulated as ointments, for example as petrolatum.

For topical skin applications, the compounds of the invention may be formulated as suitable ointments containing the active compound suspended or dissolved, for example, in admixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they may be formulated as suitable lotions or creams, suspended or dissolved, for example, in admixture with one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters, wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water .

The compounds of the invention may also be used in combination with cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with the active compound molecules. Formation of the active agent-cyclodextrin complex can modify the solubility, dissolution rate, bioavailability and / or stability of the active agent molecule. The active compound-cyclodextrin complexes are generally useful in most dosage forms and routes of administration. An alternative to direct complexing with the active ingredient can be the use of cyclodextrin as an auxiliary additive, for example, as a carrier, diluent or solubilizing agent. Α-, β- and γ-cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

For oral or parenteral administration to patients in human medicine, the daily doses of the compound of the invention will range from 0.01 mg / kg to 30 mg / kg (in single or divided doses) and preferably will be in the range of 0.01 mg / kg to 5 mg / kg. Thus, the tablets will contain 1 mg to 0.4 g of the compound to be administered, administered as needed in one administration or divided into two or more administrations. The attending physician will, in each particular case, determine the particular dose that will be most appropriate for a particular patient and will depend on the age, body weight, and response of the particular patient. Obviously, the above dosages are merely exemplary of the average case and, if preferred, higher or lower dosages are also within the scope of the invention, as are values within the above ranges.

Oral administration is preferred. Preferably, the administration is carried out shortly before the desired effect.

For veterinary use, the compounds of the invention are administered as suitably acceptable formulations in accordance with normal veterinary practice and the veterinary surgeon will determine the dosage regimen and route of administration that will be most appropriate for a particular animal.

Accordingly, in a further aspect, the invention provides a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable adjuvant, diluent or carrier.

The invention will be further elucidated by way of illustrative examples, which are illustrative only and are not intended to limit the scope of the invention, which is clearly defined by the appended claims. The following abbreviations and expressions have been used in the Examples:

Arbocel filtering agent

br broad Boe tert CDI carbonyldiimidazole δ chemical shift D doublet δ heat DCCI dicyclohexylcarbodiimide DCM dichloromethane DMF N, N-d imethylformamide; DMSO dimethyl sulfoxide ES ⁺ electron ionization positive mass spectrometry EC ' electron ionization negative mass spectrometry ex example h lesson HOBt 1-hydroxybenzotriazole HPLC high pressure liquid chromatography m / z mass spectrum peak min minute MS mass spectrum NMR nuclear magnetic resonance imaging Prek prodrug

Preparation

q quartet with s T triplet obs some time tf trifluoromethanesulfonyl TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TS ⁺ thermo-spray ionization positive scan

WSCDI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide ^{hydrochloride; H} nuclear magnetic resonance spectra (NMR) spectra were in all cases consistent with the proposed structures. The characteristic chemical shifts (δ) are given in parts per million downstream of tetramethylsilane using conventional abbreviations to denote the principal peaks: for example, s denotes a singlet; d denotes a doublet; t denotes a triplet; q denotes a quartet; m denotes a multiplet; br denotes broad. The following abbreviations were used for common solvents: CDCl ₃ , deuterochloroform; DMSO, dimethylsulfoxide. Psi stands for pounds per square inch and LRMS stands for low resolution mass spectrometry. Thin layer chromatography (TLC) was performed on silica gel. TLC uses silica gel 60 F ₂₅₄ plates, R _f is the distance traveled by the compound divided by the distance traveled by the solvent on the TLC plate. Melting points were determined using a functional Perkin Elmer DSC7 generator at a heating rate of 20 ° C / min).

When indicated, the compounds are characterized as hydrochloride salts. A typical procedure for preparing the hydrochloride salt is given in Example 12. Other solvents such as diethyl ether or DCM may also be used.

Commercial starting materials were obtained from Aldrich Chemical Co., Lancaster Synthesis Ltd or Acros Organics.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

3 - [(Methylamino) methyl] -4- [3-methyl-4-methylsulfanyl) phenoxy] benzenesulfonamide

The amide from Preparation 8 (760 mg, 2.07 mmol) was suspended in THF (10 mL) and the resulting suspension was treated with a borane-tetrahydrofuran complex (1M solution in THF, 6.22 mL, 6.22 mmol) at room temperature. The resulting solution was refluxed under a nitrogen atmosphere for 5 h. The reaction mixture was cooled to room temperature and carefully treated with 6M HCl solution (6 mL). The resulting mixture was refluxed for 30 min. After cooling to room temperature, the mixture was diluted with water (10 mL) and basified by careful addition of solid potassium carbonate. The aqueous layer was extracted with EtOAc (20 mL) resulting in a precipitate in the organic layer and the aqueous layer was further extracted with DCM (2 x 20 mL). EtOAc The fraction was washed with 2M NaOH solution (20 mL) to give a clear two-phase separation and the basic layer was extracted with DCM (4 x 25 mL). All organic fractions were combined and washed with brine (20 mL), dried (MgSO ₄ ) and evaporated to give a colorless oil. Purification by flash chromatography [SiO ₂ ; 95: 5: 0.5 to 90: 10: 1 (EtOAc / MeOH / 880 NH ₃ )] gave a white powder of the desired amine (646 mg, 89%). δ _Η (300 MHz, d ₆ DMSO) 2.26 (3H, d), 2.32 (3H, d), 2.45 (3H, d), 3.75 (2H, d),

6.90 (3 H, m), 7.25 (3 H, br), m / z (TS ⁺ ) 353 (MH ⁺ ).

7.67 (1H, t); 7.98 (1H, d); MS

Compounds of formula (Id), i.e. compounds of formula (I) wherein R ¹ is methyl, R ² is hydrogen and R ⁵ is -SO ₂ NH ₂ listed in Table 1 were prepared in an analogous manner to the title compound of Example 1 from the indicated precursors.

Table 1

Example

precursor

Prípr. 9

Data

HCl salt: 1 H (CD 3 CD, 400 MHz) 2.80 (3H, s), 3.42 (2H, m), 4.41 (2H, s), 6.86-7.00 (2H,

m), 7.09 (1H, s), 7.23 (1H, d), 7.90 (1H, d), 8.05 (1H, s), MS m / z (TS) 351 (MH + ⁾ )

Prípr. 12

SMe

HCl salt: 1 H (CD 3 CD, 300 MHz) 2.54 (3H, s),

2.82 (3H, s), 4.43 (2H, s), 7.00 (1H, d),

7.20 (1H, d), 7.34 (1H, s), 7.42 (1H, d),

7.95 (1H, d); 8.11 (1H, s); MS m / z (TS ³ )

373 (MH ⁴⁾

Prípr. 11

SMA

HCl salt: OH (CDCl 3, 400 MHz) 2.45 (3H, s),

2.73 (3H, s), 5.44 (2H, s), 6.97 (3H, m),

7.42 (1H), 7.89 (1H, m), 8.03 (1H, s); MS m / z (ES ⁴⁾ H r 357 (MH ⁴⁾

Prípr. 10

HCl Sol: oh (CDjCD, 400 vjHz) 2.79 (3H, with), 3.18 (2H, m), 4.38 (2H, with); 4.41 (2H, m), 6.68 (2H, m), 6.97 (1 H, d), 7.13 (1 H, d), 7.91 (1 H, d), 8.03 (1Ή. with), MS m / z (TS ³ ) 367 (MH ⁴ )

Prípr. 13

Prípr. 14

HCl salt: 1 H (CD 3 CD, 400 MHz) 2.78 (3H, s), 3.15 (2H, m), 4.38 (4H, m), 6.79 (1H, d), 6.85 ( 3H, m), 7.84 (1H, d), 8.00 (1H, s); MS m / z (ES ⁴⁾ 367 (MH ⁴⁾

HCl salt: δh (CD 3 CD, 400 MHz) 2.81 (3H, s), 4.43 (2H, s), 5.09 (4H, s), 6.93 (1H, d),

7.12 (2H, s-td), 7.40 (1H, d), 7.90 (1H, d), 8.08 (1H, s); MS m / z (TS ⁴⁾ 335 (MH ⁴⁾

8 Prípr. 15 HCl salt: OH (CDCl 3, 400 MHz) 2.16 (2H, m), 2.80 (3H, s), 2.92 (4H, t), 4.40 (2H, s), 6.86 ( 1H, d), 6.94 (1H, d), 7.03 (1H, s), 7.30 (1H, d), 7.88 (1H, d), 8.03 (1H, s); MS m / z ( ^{+ 5} ) 333 (MHT) 9 Prípr. 16 d .. Me HCl salt: OH (CDCl 3, 400 MHz) 2.32 (3H, s), 2.43 (3H, s), 2.81 (3H, s), 4.41 (2H, s), 6.84 (1H, d), 6.91 (1H, d), 7.06 (1H, s), 7.24 (1H, d), 7.89 (1H, d), 8.05 (1H, s); MS m / z (ES +) 352 (MH +) 10 Prípr. 17 HCl salt: OH (CDCl 3, 400 MHz) 2.78 (3H, s), 4.21 (4H, s), 4.39 (2H, s), 6.89 (1H, d), 7.01 (1H, d), 7.08 (1H, s), 7.38 (1H, d), 7.85 (1H, d), 8.02 (1H, s); MS m / z (TS) 351 (*) 11 Prípr. 18 PART δ (CD 3 OD, 400 MHz) 2.76 (3H, s), 3.30 (2H, m), 3.42 (2H, m), 4.33 (2H, s), 6.90 (1Ή, d), 6.94 (1 H, d), 7:00 (1 H, s), 7.29 (2 H, d), 7.89 (1H, d), 8.04 (1H, s); MS m / z (ES *) 351 (M +), (ES ') 349 (M-H *)

Examples 12 and 13

3 - [(Dimethylamino) methyl] -4- [3-methyl-4- (methylsulfanyl) phenoxy] benzenesulfonamide (Example 12); and

3 - [(dimethylamino) methyl] -N-methyl-4- [3-methyl-4- (methylsulfanyl) phenoxy] benzenesulfonamide (Example 13)

SMe SMe

To suspension secondary of the amine of Example 1 (409 mg 1.16 mmol) in DCM (20 ml) was added at room temperature Come nitrogen added formaldehyde (37% aqueous solution, 282 μΐ,

3.76 mmol). The resulting mixture was stirred for 15 min before sodium triacetoxyborohydride (984 mg, 4.64 mmol) was added. The resulting reaction mixture was stirred for 5 h, then basified with saturated NaHCO ₃ (10 mL) and extracted with DCM (3 x 20 mL). The organic layers were washed with brine (10 mL), dried (MgSO ₄ ) and evaporated to give a yellow oil. This was purified by HPLC (Phenomonex Luna C ₁₈ 75x4.6 mm column, CH ₃ CN, H ₂ O, TFA). Fractions containing the main product were evaporated and the residue was treated with saturated NaHCO ₃ solution (5 mL), and extracted with DCM (3x 30 mL). The combined organic fractions were washed with brine (30 mL), dried (MgSO ₄ ) and evaporated to give a white foam (155 mg, 36% yield) from Example 12; δ _H (300 MHz, CDCl ₃ ) 2.30 (6H, s), 2.35 (3H, s),

2.48 (3H, s), 3.60 (2H, s), 6.83 (3H, m), 7.20 (1H, m), 7.28 (2H, s), 7.74 (1H) d) 8.08 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 367 (MH &lt; ^{+ &gt;} ).

Minor product was also obtained after HPLC purification. Relevant fractions were evaporated and the residue was treated with saturated NaHCO ₃ solution (5 mL) and extracted with DCM (2x30 mL). The combined organic fractions were washed with brine (30 mL), dried (MgSO ₄ ) and evaporated to give a gum which was taken up in DCM (5 mL), treated with 1M ethereal HCl (2 mL) and evaporated to give a white powder (39 mg). 9%) of Example 13; HCl salt: OH (CDCl ₃ , 300 MHz) 2.30 (6H, s), 2.35 (3H, s), 2.48 (3H, s), 3.60 (2H, s), 6.83 (3H, m), 7.20 (1H, m), 7.28 (2H, s), 7.74 (1H, d), 8.08 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 381 (MH &lt; ^{+ &gt;} ).

By repeating the reaction using 1 equivalent of formaldehyde per amine of Example 1, the product of Example 12 was obtained in 78% yield after purification by column chromatography [SiO ₂ ; 95: 5: 0.5 to 90: 10: 1 (EtOAc / MeOH / 880 NH ₃ )]. This product was taken up in EtOAc and converted to the HCl salt by addition of 1M ethereal HCl solution. The resulting precipitate was filtered and dried in vacuo to give the product of Example 12 as the HCl salt; mp 188 ° C.

Alternatively, the product of Example 12 can also be prepared from the amine of Example 12 by the method of Example 110.

The product of Example 12 was also prepared as follows.

A solution of the hydrochloride salt of Example 94 (20 g) in trifluoroacetic acid (100 mL) was slowly added to the chlorosulfonic acid solution (72 g) while maintaining the temperature between 0 ° C and 5 ° C. After 1 h, the reaction mixture was slowly poured into water (200 mL) at 0 ° C to 20 ° C. The mixture was then extracted with dichloromethane (200 mL) and separated. The aqueous layer was then extracted with dichloromethane (60 mL) and separated. The combined organic layers were washed with water (200 mL). The layers were separated and the dichloromethane was removed in vacuo to give a solid. Acetonitrile (240 mL) was added and phosphorus oxychloride (28.8 mL) was added to this suspension. The resulting solution was then refluxed overnight. The reaction mixture was cooled to room temperature and poured into a stirred mixture of ammonia (90 mL), dichloromethane (240 mL) and water (100 mL), maintaining the temperature between 0 ° C and 10 ° C. The mixture was adjusted with ammonia (if necessary) to a pH greater than 8. After 15 min, the reaction mixture was allowed to warm to room temperature and the layers were separated. The organic layer was concentrated in vacuo to give a thick brown oil. This was dissolved in acetone (100 mL) and suspended with carbon (Norit SX plus, 50% w / w) filtered and treated with a second portion of carbon (Norit SX plus, 50% w / w). The mixture was filtered again, the solution was concentrated and water (200 mL) was added again. The suspension was granulated, filtered and dried under vacuum overnight to give the title product as a cream-white solid (40% yield).

Examples 14 and 15

4- (2,3-Dihydro-1,4-benzoxathin-7-yloxy) -3 - [(dimethylamino) methyl] benzenesulfonamide; and

4- (2,3-dihydro-1,4-benzoxathiin-7-yloxy) -3 - [(dimethylamino) methyl] -N-methyl-benzenesulfonamide

These compounds were prepared in an analogous manner to that described in Examples 12 and 13 and the secondary amine of Example 5 was used as the starting product.

Example 14

HC1 sol: δ _Η (CD ₃ OD, 400 MHz) 2.97 (6H, s) 3.18 (2H, m) 4.42 (2H, m) 4.52 (2H, with) , 6.68 (2H, d), 6.99 (1H, d), 7.14 (1 H, d), 7.94 (1 H, d), 8.07 (1 H, with) ; M N / z (ES ⁺ ) 3 81 (MH &lt; ^{+ &gt;} ). Example 15 HC1 sol: CH (C ! D ₃ OD, 400 MHz) 2.56 (3H, s) 2.80 (6H, s) 3.17 (2H, m) 4.35 (2H, with) , 4.41 (2H, m), 6.68 (2H, m), 6.98 (1 H, d), 7.13 (1 H, d), 7.81 (1 H, d), 8.00 (1 H, s); MS m / z (ES ⁺ ) 395 (MH &lt; ^{+ &gt;} )

Compounds of formula Ie, i.e. compounds of formula I wherein R ¹ and R ² are methyl and R ⁵ is -SO ₂ NH ₂ , which are listed in Table 2, were prepared as described in Example 12 from the precursors mentioned. N-Methylsulfonamides analogous to the compound of Example 13 were not isolated in these reactions and no HPLC purification was performed.

(Ie)

Table 2

Example precursor FROM Data 16 Example 2 HCl salt: δ _Η (CDaOD, 400 MHz) 2.98 (6H, s), 3.41 (2H, m), 4.58 (2H, s), 6.95 (2H, m), 7.08 (1H, s), 7.25 (1H, d), 7.95 (1H, d), 8.05 (1H, s); MS m / z (ES ⁺ ) 365 (MH +) 17 Example 3 (Y. SMe HC1 salt: _δ Η (CD 3 OD, 300 MHz) 2.54 (3H, s), 2.98 (6H, s), 4.53 (2H, s), 7.01 (1 H, d), 7.20 (1 H dd), 7.33 (1H, s), 7.42 (1H, d), 7.99 (1H, d), 8.04 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 387 (MET) 18 Example 4 ά. SMG HCl salt: δ _Η (CD ₃ OD, 400 MHz) 2.43 (3H, s), 2.88 (6H, s), 4.42 (2H, s), 6.99 (3H, m), 7 42 (1H, t), 7.92 (1H, d), 8.06 (1H, s); MS m / z (ES ^&lt; ^{+ &gt;} ) 371 (MH &lt; ⁺ &gt;) 19 Example 6 x HCl salt: δ _Η (CD ₃ OD, 400 MHz) 2.89 (3H, s), 3.17 (2H, m), 4.39 (2H, m), 4.47 (2H, s), 6 78 (1H, d), 6.87 (3H, m), 7.89 (1H, d), 8.01 (1H, s); MS m / z (TS ⁺ ) 367 (MH ⁺ )

20 Example 7 TFA salt: δ _Η (CDCl ₃ , 400 MHz) 2.22 (6H, s), 3.60 (2H, t), 5.05 (4H, d), 6.75-6.90 (3H, m) 7.20 (1H, d), 7.60 (1H, m), 8.00 (1H, m); MS m / z 349 (MH +) 21 Example 8 4 HCl salt: δ _Η (CD 3 OD, 400 MHz) 2.10 (2H, m), 2.85-3.00 (10H, m), 4.30 (1H, brs), 4.50 (2H, s) 6.80-6.95 (2H, m), 7.05 (1H, s), 7.25 (1H, d), 7.80 (1H, d), 8.10 (1H, s); MS m / z (ES ⁺ ) 347 (MH +

Example precursor from Data 22 Example 10 HCl salt: δκ (CD ₃ OD, 400 MHz) 2.93 (6H, s), 4.21 (4H, s), 4.50 (2H, s), 6.91 (1H, d), 7, O 2 (1H, d), 7.09 (1H, s), 7.37 (1H, d), 7.91 (1H, d), 8.05 (1H, s); MS m / z (TS ^&lt; ^{+ &gt};) 365 (MH ⁺ ) 23 Example 11 HCl salt: 5h (DMSO-d6, 400 MHz) 2.76 (6H, s), 3.21 (2H, t), 3.38 (2H, t), 4.39 (2H, S), 6, 80 (1H, d), 6.86 (1H, d), 7.10 (1H, s), 7.28 (3H, m), 7.80 (1H, d), 8.06 (1H, s) 11.23 (1H, br); MS m / z (TS ⁺ ) 365 (+)

Examples 24

3 - [(Dimethylamino) methyl] -4- [4-methyl-3- (methylsulfanyl) phenoxy] benzenesulfonamide

The title compound was prepared from the secondary amine of Example 9 by the method of Example 110; δ _Η (CD ₃ OD, 400 MHz) 2.27 (3Η, S), 2.41 (3H, S), 2.61 (6H, s), 4.19 (2H, s), 6.76 ( 1H, d), 6.88-6.93 (2H, m), 7.20 (1H, d), 7.82 (1H, d), 8.03 (1H, d); MS m / z (T +) 367 (MH ⁺ ).

Examples 25

N- {5-Methoxy-2- [3-methyl-4- (methylsulfanyl) phenoxy] benzyl} -N, N-dimethylamine

Dimethylamine hydrochloride (424 mg, 5.2 mmol), Et ₃ N (725 μΐ, 5.2 mmol), AcOH (298 μΐ, 5.2 mmol) and sodium triacetoxyborohydride (1.10 g, 5.2 mmol) were added to the of a solution of the aldehyde of Preparation 24 (1.00 g, 3.47 mmol) in THF (15 mL) and DCM (15 mL) and the mixture was stirred at room temperature for 16 h. After removal of the solvent in vacuo, the residue was taken up in 2M HCl solution (20 mL) and washed with ether (2 x 15 mL). The aqueous layer was basified with NaOH pellets and extracted with DCM (4 x 20 mL). The combined DCM extracts were washed with brine, dried (MgSO ₄ ) and evaporated. The residue was taken up in a small amount of DCM and treated with 1M ethereal HCl to precipitate the HCl salt. This was filtered, rinsed with ether and dried to give a white solid (936 mg) contaminated with triethylamine hydrochloride. This solid was dissolved in 1M NaOH solution (10 mL) and extracted with EtOAc (3 x 15 mL). The organic extracts were washed with brine (10 mL), dried (MgSO ₄ ) and evaporated before being carefully dissolved in EtOAc and evaporated again. The residue was taken up in DCM and treated with 1M ethereal HCl to precipitate the HCl salt, which was filtered, washed with ether and dried to give a white solid (635 mg, 52%); δ _Η (CDCl ₃ , 300 MHz) 2.35 (3H, s), 2.45 (3H, s), 2.79 (6H, s), 3.90 (3H, s), 4.21 (2H s, 6.70 (1H, d), 6.73 (1H, s), 6.90 (2H, m), 7.18 (1H, d), 7.65 (1H, s), 12 .83 (1H, brs); MS m / z (TS ⁺ ) 318 (MH ⁺ ) Compounds of formula (I), i.e., compounds of formula (I) wherein R ¹ and R ² are the methyl groups shown in Table 3 were prepared as described in Example 25 of the above. precursors.

Table 3 (If)

Example precursor R ⁴ R ⁵ from Data 26 Prípr. 25 H F HCl salt: δκ (CDCl ₃ , 300 MHz) 2.23 (6H, s), 3.41 (2H, s), 6.98 (2H, m), 7.34 (2H, m), 7.48 (1H, dd), 7.98 (1H, d), 8.08 (1H, d), 8.80 (1H, s); MS m / z (TS ⁺ ) 297 (MH &lt; ⁺ &gt;) 27 Prípr. 39 H -NO? ý .. SMe δ _Η (CDCl ₃ , 300 MHz) 2.32 (6H, S), 2.36 (3H, s), 2.47 (3H, s), 3.60 (2H, s), 6.80 (1H d), 6.87 (2H, d), 7.19 (1H, d), 8.03 (1H, d), 8.40 (1H, d); MS m / z (ES ⁺ ) 333 (MH +) 28 Prípr. 3 8 H -NO 2 Taken from crude at 75% purity; δκ (CDCl 3, 400 MHz) 2.33 (6H, s), 3.24 (2H, m), 3.38 (2H, m), 3.66 (2H, s), 6.76 (2H, m), 6.86 (1H, m),

7.17 (1 H, d), 8.00 (1 H, dd), 8.37 (1 H, d)

Example.

precursor

R ⁴

Prípr. 26

Data δ _Η (CDCl ₃ , 300 MHz) 2.28 (6H, s), 3.50 (2H, s), 7.03 (2H, m), 7.20-7.40 (3H, m), 7.52 (2H, m), 7.98 (1H, d), 8.09 (1H, d), 8.81 (1H, m);

MS m / z (TS ⁺ ) 279 (MH ⁺ )

Prípr. 27

HCl salt: Sh (dg-LMSO, 30 0 MHz) 2.77 (6H, d) , 4.38 (2H, d), 7.08 (1 H, d) , 7.36 (1 H, t), 7.52 (1 H, t) , 1.62 (1 H, with) , 7.80 (1 H, d) , 7.91 (1 H, dd), 8.10 (1 H, d) , 9.25 (1 H, with) , 9.52 (1 H, with) ; MS m / z (TS ^&lt; ^{+ &gt;} ) 280 (MH +)

Prípr. 29

Maleate salt: δ _Η (ds-EMSO, 300 MHz) 2.77 (6H, s), 4.33 (2H, s), 5.98 (2H, s), 6.87 (1H, d), 7 21 (1H, dt), 7.30 (1H, dd), 7.41 (1H, dt), 7.58 (1H, dd), 7.88 (1H, d), 8.11 (1H, d) 9.32 (1 H, s); MS m / z 285 (MH &lt; ^{+ &gt;} )

Prípr. 33 H

br

HCl salt: δ _Η (CMSO-d '400 MHz 2.77 (6H, d) , 3.23 (3H, m), 3.39 (2H, m) , 4.32 (2H, d), 6.75 (2H, m) , 7.03 (1 H, with), 7.26 (1 H, d) , 7.57 (1 H, dd), 7.87 (1 H, with) , 10.06 (1 H, br,

with) ; MS m / z (ES ^&lt; ^{+ &gt;} ) 366 (*)

Prípr. 32 Br

SMe

δ _Η (CDC1 ₃ , 400 MHz) 2.22 (6H, with) , 2.30 (3H, s), 2.41 (3H, with) , 3.41 (2H, s), 6.76 (2H, m), 6.94 (1 H, s), 7.18 (1 H, with) , 7.21 (1 H, obs), 7.3 0 (1H, d); MS m / of (TS ⁺ ) 366/368 (MP1)

Example 34

3 - [(Dimethylamino) methyl] -N-methyl-4- (6-quinolinyloxy) benzenesulfonamide

(106 μΐ, 1.6 mmol) was added to

0.16 mmol) in DCM (2 mL) and mixture

Chlorosulfonic acid solution of Example 29 (50 mg, stirred for 3 h at room temperature. Water (2 mL) was added, the mixture was adjusted to pH 6 with saturated aqueous solution.

The organic extracts were added

NaHCO ₃ and extracted with DCM (2 x 5 mL)

The 8M standing solution was purified, removed by column drying (MgSO ₄ ), filtered with methylamine in EtOH (0.3 mL). After solvent in vacuo and residue chromatographed [SiO ₂ ; 95: 5: 0.5 (DCM / MeOH / 880 NH ₃ )]. The product was taken up in EtOAc and treated with HCl solution. This afforded the substance on the HCl salt by adding the desired product (3 mg, 5% yield);

ethereal in the form of δ _Η (CD ₃ OD, hygroscopic solid

300 MHz) 2.60 (3H, with) , 2.99 (7H, s) 4.60 (2H, s), 7.21 d), 7.96 (1 H, d), 8.04 (3H, m) 8 19 (1 H, s), 8.38 (1 H, 9.03 (1 H, d), 9.18 (1 H, d); MS m / z (TS ⁺ ) 371 (MH &lt; ^{+ &gt;} ).

d), (1H,

Example 35

3 - [(Methylamino) methyl] -4- (6-quinolinyloxy) benzenesulfonamide

Trifluoroacetic anhydride (0.96 mL, 6.8 mmol) was added to a solution of the amine of Example 48 (900 mg, 3.4 mmol) and triethylamine (1.9 mL, 13.6 mmol) in CH at 0 ° C. ₂ Cl ₂ (15 mL) and stirred for 5 min. The solvent was evaporated in vacuo and the residue was partitioned between CH ₂ C1 ₂ and water. The organic layer was washed with brine, dried (MgSO ₄ ) and evaporated to give a yellow oil which was used without further purification. This crude oil was taken up in CH ₂ Cl ₂ (20 mL), cooled to 0 ° C, and ClSO ₃ H (2.4 mL, 36.1 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 4 h before being poured into ice water. The mixture was extracted with CH ₂ Cl ₂ (50 mL) and the organic layer was treated with a saturated solution of NH ₃ in MeOH (10 mL). After stirring for 4 h, 1 M LiOH solution (20 mL) was added and stirring was continued overnight. TLC analysis indicated that the reaction was incomplete, so an additional amount of 1M LiOH solution (50 mL) was added and stirred for 2 h. The mixture was acidified to pH 8 with 2M HCl solution and extracted with CH ₂ Cl ₂ (3 x 200 mL). The combined organic extracts were dried (MgSO ₄ ) and evaporated and the residue was triturated with ether to give the title compound (500 mg, 43% yield) as a yellow solid, _δδ (CDCl 3, 400 MHz) 2.46 (3H, s), 3.87 (2H, s), 6.93 (1H, d), 7.25 (1H, s), 7.39 (1H, t), 7.42 (1H, d), 7, 78 (1H, d), 8.00-8.08 (2H, m), 8.12 (1H, d), 8.86 (1H, s); MS m / z (ES ^&lt; ^{+ &gt;} ) 344 * (MH &lt; ^{+ &gt;} ).

Example 36

N- [5-Bromo-2- (2,3-dihydro-1-benzothien-5-yloxy) benzyl] -N-methylamine

The aldehyde of Preparation 19 (1.10 g, 3.28 mmol) was dissolved in an 8M solution of methylamine in EtOH (4.1 mL, 32.8 mmol) and stirred for 5 h before NaBH ₄ (372 mg) was added portionwise. , 9.83 mmol) over 30 min. EtOH (100 mL) was added and the reaction mixture was stirred for 16 h before being concentrated in vacuo. A 6M HCl solution was poured into the residue until pH 1 and the precipitated HCl salt was collected by filtration, washed with water (100 mL) and dried in vacuo to give a crystalline solid (1.04 g, 82% yield); δ _Η (CDCl ₃ , 400 MHz) 2.62 (3H, s), 3.26 (2H, t), 3.41 (2H, t), 4.18 (2H, s), 6.66 (1H) d), 6.90 (1H, d), 7.03 (1H, s), 7.19 (1H, d), 7.39 (1H, d), 7.80 (1H, s); MS m / z (ES ^&lt; ^{+ &gt;} ) 350, 352 (MH &lt; ^{+ &gt;} ).

Compounds of formula (Ig), i.e. compounds of formula (I) wherein R ¹ and R ⁴ are hydrogen and R ² is the methyl group shown in Table 4, were prepared as described in Example 36 from the precursors mentioned. For compounds that were isolated as the free base, the reaction mixture was partitioned between 2M HCl solution and ether after removal of the reaction solvent in vacuo. The aqueous layer was then basified and extracted with DCM, the DCM layer was dried (MgSO ₄ ) and evaporated to give the desired secondary amine.

Table 4

Example precursor R ⁵ from Data 37 Prípr. 20 br SMe HCl salt: B, J (d, -DMSO, 300 MHz) 2.48, (3H, s), 2.59 (3H, s), 4.18 (2H, s), 6.88 (1H, s, d), 7.01 (1H, d), 7.16 (1H, d), 7.45 (1H, t), 7.59 (1H, d), 7.91 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 356, 358 (MH &lt; ^{+ &gt;} ) 38 Prípr. 21 br δ _Η (CDCl ₃ , 400 MHz) 2.43 (3H, s), 3.11 (2H, t), 3.78 (2H, s), 4.41 (2H, t), 6.44 (1H s), 6.51 (1H, d), 6.77 (1H, d), 6.98 (1H, d), 7.31 (1H, d), 7.55 (1H, s); MS m / z (ES &lt; + &gt;) 366, 368 (MH &lt; + &gt;) 39 Pripr. 22 br ï SMe δ _Η (CDCl ₃ , 400 MHz) 2.41 (3H, s), 2.45 (3H, s), 3.72 (2H, s), 6.77 (1H, d), 6.85 (1H d), 6.99 (1H, s), 7.18 (1H, d), 7.36 (1H, d), 7.59 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 372, 374 (*) 40 Prípr. 38 -no ₂ 4 δ _Η (CDCl ₃ , 300 MHz) 2.55 (3H, s), 3.30 (2H, m), 3.43 (2H, m), 3.95 (2H, s), 6.80 (2H m), 6.91 (1H, s), 7.22 (1H, d), 8.05 (1H, d), 8.40 (1H, s); MS m / z (ES ^&lt; ^{+ &gt;} ) 317 (MH &lt; ⁺ &gt;)

41 Prípr. 36 -no ₂ Δ (CDCl ₃ , 400 MHz) 2.45 (3H, S), 3.10 (2H, m), 3.86 (2H, s), 4.40 (2H, m), 6.53 (2H m), 6.80 (1H, d), 7.01 (1H, d), 8.00 (1H, d), 8.27 (1H, s); MS m / z (TS ⁺ ) 333 (MH ⁺ )

Example precursor R ⁵ from Data 42 Prípr. 40 -N0 ₂ δ _Η (CDCl ₃ , 400 MHz) 2.14 (2H, m), 2.52 (3H, s), 2.93 (4H, t), 3.92 (2H, s), 6.78 (1H d), 6.81 (1H, d), 6.91 (1H, s), 7.22 (1H, d), 8.02 (1H, dd), 8.29 (1H, s); MS m / z (TS ⁺ ) 299 (*) 43 Prípr. 24 -CMe ý. SMe HC1 salt: 5 H (CDC1 _3, 300 MHz) 2.35 (3H, s), 2.45 (3H, s), 2.60 (3H, s), 3.84 (3H, s), 4.17 (2H, s), 6.80 (1H, d), 6.82 (1H, s), 6.88 (2H, s), 7.15 (1H, d), 7.42 (1H, s) 9.85 (2H, brs); MS m / z (TS ⁺ ) 304 (Copper) 44 Prípr. 23 br about. SMe δ _Η (CDCl ₃ , 300 MHz) 2.35 (3H, s), 2.45 (6H, s), 3.77 (2H, s), 6.73 (2H, m), 6.80 (1H s), 7.19 (1H, d), 7.32 (1H, d), 7.57 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 352, 354 (MH &lt; + &gt;) 45 Prípr. 30 H SMe HCl salt: δ (dg-DMSO, 400 MHz) 2.22 (3H, s), 2.42 (3H, s), 2.58 (3H, s), 4.18 (2H, s), 6, 78 (1 H, d), 6.96 (1 H, d), 6.99 (1 H, s), 7.18 (1 H, t), 7.25 (1 H, d), 7.38 (1 H, t) 1.60 (1H, d); MS m / z (ES ^&lt; ^{+ &gt;} ) 274 (MH) 46 Prípr. 31 H HC1 salt: _δ Η (CDC1 _3, 400 MHz) 2.55 (3H, br s), 3.21 (2H, t), 3.32 (2H, m), 4.17 (2H, s), 6. 76 (1H, d), 6.84 (1H, d), 6.99 (1H, s), 7.04 (1H, m), 7.12 (1H, d), 7.28 (1H, obs 7.61 (1 H, d); MS m / z (ES ^&lt; ^{+ &gt;} ) 272 (*)

47 Pripr. 28 H % Maleate salt: δ _Η (LCMS-dg, 400 MHz) 2.60 (3H, s), 4.19 (2H, s), 5.99 (2H, s), 7.03 (1H, d), 7.29 (1H, m), 7.37 (1H, s), 7.45 (3H, m), 7.60 (1H, d), 8.06 (1H, d), 8.37 (1H, d), 8 74 (2H, br); 8.83 (1H, dd); MS m / z 264 (M)

Example precursor R ⁵ 2 Data 48 Pripr. 26 H δ _Η (CDCl ₃ , 300 MHz) 2.64 (3H, s), 4.25 (2H, s), 6.89 (1H, d), 7.19 (1H, t), 7.30-7 Δ1.4 (2Η, m), 7.45 (1H, s), 7.49 (1H, d), 7.69 (1H, d), 8.08 (1H, d), 8.16 (1H, d), d) 8.87 (1 H, d); MS m / z (ES ^&lt; ^{+ &gt;} ) 529 (2M + H &lt; + &gt;) 49 Pripr. 34 CN HCl salt: δπ (CD ₃ OD, 400 MHz) 2.81 (3H, s), 3.30 (1H, br), 4.42 (2H, s), 7.17 (1H, br), 7, 82 (1H, br), 8.06 (1H, br), 8.11 (3H, br), 8.39 (1H, br), 9.18 (1H, br), 9.21 (1H, br) ); MS m / z (ES ^&lt; ^{+ &gt;} ) 290 (MH)

^and -2M Methylamine in MeOH (2 eq) and Ti (O ^x Pr) ₄ (2 eq) in

EtOH (approximately 0.1M solution in aldehyde) was used instead of methylamine in EtOH. After isolation of the free base, it was converted to the maleate salt by standard methods.

Example 50 (2E) -3- [4- (2,3-Dihydro-1-benzothien-6-yloxy) -3 - [(dimethylamino) methyl] phenyl} -2-propenamide

A mixture of the bromide of Example 32 (400 mg, 1.10 mmol), acrylamide (156 mg, 2.19 mmol), triethylamine (0.38 mL, 2.74 mmol), palladium II acetate (12.5 mg, 0, 06 mmol) and trio-tolylphosphine (33.4 mg, 0.11 mmol) in acetonitrile (15 mL) was heated at reflux for 72 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was partitioned between EtOAc (50 mL) and 2M HCl solution (50 mL). The aqueous phase was basified with 2M NaOH solution and extracted with EtOAc (3 x 50 mL). The combined basic extracts were dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography [SiO ₂ ; 96: 4: 0.5 (DCM / MeOH / 880 NH ₃ ) increasing polarity to 90: 10: 1] to give the title compound (196 mg, 50% yield) as a beige foam; δ _Η (CDCl ₃ , 400 MHz) 2.28 (6H, s), 3.24 (2H, t), 3.38 (2H, t), 3.51 (2H, s), 5.73 (2H , br), 6.42 (1H, d), 6.69 (1H, dd), 6.82 (2H, m), 7.10 (1H, d), 7.32 (1H, d), 7 60 (1H, d); 7.69 (1H, s); MS m / z (ES ^&lt; ^{+ &gt;} ) 355 (MH &lt; ^{+ &gt;} ).

Example 51

3- {4- (2,3-Dihydro-1-benzothien-6-yloxy) -3 - [(dimethylamino) methyl] phenyl] propanamide with nitrogen added

0.55 mmol) in THF

Sml ₂ solution

2.19 mmol) is added to

of solution of Example 50 (194 mg, mL) followed by addition of water (1 mL). After stirring at room temperature for 10 min, the reaction was quenched with 6M NaOH (10 mL) and stirred for 30 min. The organic phase was separated and the aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (MgSO ₄ ) and evaporated to give an oil which was purified by column chromatography [SiO ₂ ; 93: 7: 1 (DCM / MeOH / 880 NH ₃ ) increasing polarity to 90: 10: 1] to give the title compound (90 mg, 46% yield);

δ _Η (C dci ₃ , 400 MHz) 2.25 (6H , with) , 2.54 (2H, t) 2.97 (2H, t), 3 22 (2H, t), 3.36 (2H, t), 3.42 (2H, s), 5.20-5.46 (2H, br), 6. 54 (1 H, d), 6.73 (1 H, with) , 6.81 (1 H, d), 7.05 (2H, m), 7.31

(1 H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 357 (MH &lt; ^{+ &gt;} ).

Compounds of formula (I), i.e. compounds of formula (I) wherein R ¹ and R ² are the methyl groups shown in Table 5, were prepared according to Preparation 50 of the above precursors.

Table 5

Example precursor R ⁴ R ⁵ Data 52 Example 32 H -CX ^ Me 6H (CDCl ₃ , 400 MHz) 2.29 (6H, s), 3.26 (3H, m), 3.39 (2H, m), 3.54 (2H, s), 3.89 (3H, m, s), 6.62 (1H, d), 6.84 (2H, m), 7.13 (1H, d), 7.86 (1H, d), 8.12 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 344 (MH &lt; ⁺ &gt;) 53 Example 33 -COsMe H SMe δ _Η (CDCl ₃ , 400 MHz) 2.24 (6H, s), 2.33 (3H, s), 2.42 (3H, s), 3.48 (2H, s), 3.82 (3H, s) s), 6.73 (2H, m), 7.14 (1H, d), 7.50 (1H, s), 7.55 (1H, d), 7.78 (1H, d); MS m / z (TS ⁺ ) 346 (M)

Compounds of formula (I), i.e. compounds of formula (I) wherein R ¹ and R ² are the methyl groups listed in Table 6, were prepared according to Preparation 55 of the above precursors.

Table 6

Example precursor R ⁴ R ⁵ from Data 54 Example 52 H -CO2H δπ (CD 3 OD, 400 MHz) 2.95 (6H, s), 3.29 (2H, m), 3.42 (2H, m), 4.52 (2H, s), 6.80 (1H, d) ), 6.89 (1H, d), 7.03 (1H, s), 7.29 (1H, d), 8.06 (1H, d), 8.23 (11-1, s); MS m / z (TS ⁺ ) 330 (M)

55 (80% purity) Example 55 - after ₂ h H A SMe δ _Η (CD ₃ OD, 400 MHz) 2.27 (3H, s), 2.42 (3H, s), 2.88 (6H, s), 4.43 (2H, s), 6.95 ( 2H, m), 7.26 (1H, m), 7.42 (2H, m), 7.72 (1H, m)

Compounds of formula (I), i.e. compounds of formula (I) wherein R ¹ and R ² are the methyl groups shown in Table 7, were prepared according to Preparation 59 of the above precursors.

Table 7

Example precursor R ⁴ R ⁵ from Data 56 Example 54 H -C0NH ₂ δ _Η (CDCL ₃ , 400 MHz) 2.27 (6H, s), 3.25 (2H, m), 3.38 (2H, m), 3.54 (2H, s), 5.90-6 38 (2H, br), 6.59 (1H, d), 6.80 (1H, s), 6.86 (1H, d), 7.11 (1H, d), 7.71 (1H, s), d) 7.92 (1 H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 329 (MH &lt; ⁺ &gt;) 57 Example 55 -CONH; H ý. SMe HCl salt: δ _Η (CD 3 OD, 400 MHz) 2.32 (3H, S), 2.43 (3H, s), 2.94 (6H, s), 4.47 (2H, s), 6.98 (2H, br), 7.27 (1H, br), 7.36 (1H, br), 7.62 (1H, br); MS m / z (TS ^&lt; ^{+ &gt;} ) 331 (MH &lt; ⁺ &gt;)

Compounds of formula (I), i.e. compounds of formula (I) wherein R ¹ and R ² are the methyl groups shown in Table 8, were prepared according to Preparation 69 of the above precursors.

Table 8

Example precursor R ⁴ R ⁵ OJ from Data 58 Example 52 H -CH ₂ OH HCl salt: OH, (DMSO-d6, 400 MHz) 2.76 (6H, s), 3.22 (2H, m), 3.40 (2H, m), 4.30 (2H, s), 4 49 (2H, S), 5.27 (1H, br, s), 6.68 (1H, d), 6.83 (1H, d), 6.97 (1H, s), 7.25 (1H, d) 1 H, d), 7.37 (1 H, d), 7.60 (1 H, s), 10.07 (1 H, br); MS m / z (TS ⁺ ) 316 (*) 59 Example 53 -CH ₂ OH H ý. SMe HCl salt: OH, (CD ₃ OD 400 MHz) 2.34 (3H, s), 2.46 (3H, s), 2.90 (6H, s), 4.40 (2H, s), 4, 55 (2H, s), 6.89 (1H, s), 6.95 (2H, m), 7.18 (1H, d), 7.28 (1H, d), 7.50 (1H, d) ); MS m / z (TS ⁺ ) 318 (MH &lt; ⁺ &gt;)

Example 60

4- (2,3-dihydro-l-benzothiophen-5-yloxy) -3 - [(methylamino) methyl] benzamide

The protected amine from Preparation 59 (317 mg, 0.76 mmol) was dissolved in a saturated solution of HCl in DCM (25 mL) at 0 ° C and allowed to stand for 1 h before being neutralized by addition of 10% aqueous K ₂ CO ₃ ( 25 ml). Water (50 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (25 mL) and the combined organic layers were dried (MgSO 4 and evaporated. The resulting oil was dissolved in EtOAc (10 mL) and treated with 1M ethereal HCl solution (1 mL). to give the desired product (211 mg, 77%); _δ Η (CD ₃ 0D, 400 MHz) 2.77 (3H, s), 3.35 (2H, obs), 3.39 (2H, t); 4.34 (2 H, s), 6.79 (1 H, d),

6.90 (1H, dd), 7.02 (1H, s), 7.21 (1H, d), 7.83 (1H, d), 8.00 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 315 (MH &lt; ^{+ &gt;} ).

Compounds of formula (Ig), i.e., compounds of formula (I) wherein R ¹ and R ⁴ are hydrogen and R ² is methyl, which are listed in Table 9, were prepared as described in Example 60 from the above precursors.

Table 9

Pr. Prípr. R ⁵ from Data 61 Pripr. 61 Λ OMe and HCl sol: δ _Η (CDCl ₃ , 400 MHz) 2.77 (3H, d), 3.35 (2H, obs), 3.36 (3H, s), 3.39 (2H, t), 3, 51 (4H, s), 4.35 (2H, s), 6.80 (1H, d), 6.90 (1H, dd), 7.01 (1H, s), 7.21 (1H, d) 7.79 (1H, d), 7.96 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 373 (MH &lt; ^{+ &gt;} )

Pr.

Prípr.

R ⁵

Data

Me

HCl salt: δ _Η (CD ₃ OD, 400 MHz) 2.77 (3H, s), 2.88 (3H, s), 3.35 (2H, obs), 3.39 (2H, t), 4 35 (2H, s), 6.79 (1H, d), 6.90 (1H, dd), 7.01 (1H, s), 7.20 (1H, dd)

d), 7.78 (1H, d), 7.96 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 329 (MH &lt; ^{+ &gt;} )

Prípr. 62

SMe

HC1 salt: _δ Η (d ₆ -DMSO, 300 MHz) 2.52 (3H, obs), 2.61 (3H, s), 4.21 (3H, s), 6.90 (1 H, d), 7.07 (1 H, d), 7.19 (1 H, d),

7.40 (1H, brs), 7.48 (1H, t), 7.92 (1H, d), 7.96 (1H, s), 8.21 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 321 (MNHJ)

Prípr. 63

Me

SMe

HCl salt: δ _Η (d _with -DMSO, 300 MHz) 2.52 (3H, obs), 2.60 (3H, s), 2.79 (3H, d), 4.21 (2H, S), 6.89 (1H, d), 7.07 (1H, d), 7.19 (1H, d), 7.48 (1H, t), 7.85 (1H, d), 8.19 (1H) s) 8.48 (1 H, d); MS m / z (TS ^&lt; ^{+ &gt;} ) 335 (MH &lt; ^{+ &gt;} )

Prípr. 64

SMe

HC1 salt: _δ Η (EMSO-de, 300 MHz) 2.52 (3H, obs), 2.60 (3H, s), 3.27 (3H, s), 3.46 (4H, m), 4 22 (2H, s), 6.91 7.08 (1H, d), 7.20 (1H, d),

t), 7.89 (1H, d), 8.10 (1H, (1H, brs)), - MS m / z (TS ⁺ ) 379 (1H, d),

7.50 (1 H, s), 8.58 (MH ⁺ )

HCl sol: δ _Η (d _with -DMSO, 300 MHz) 2.52 (3H, obs), 2.60 (3H, t), 4.11 (2H, s + H ₂ O), 6.82 (1H , d), 7.21 (1H, d), 7.40 (3H, s + d), 7.88 (1H, d), 7.96 (1H, brs), 8.21 (1H, s) ; MS m / z (ES ^&lt; ^{+ &gt;} ) 337 (MH &lt; ^{+ &gt;} )

Prípr. 66

SMe

HCl salt: δ _Η (d ₆ -DMSO, 300 MHz) 2.52 (3H, obs), 2.60 (3H, t), 2.79 (3H, d), 4.22 (2H, t), 6.94 (1H, d), 7.22 (1H, d), 7.40 (2H, S + d), 7.83 (1H, d), 8.19 (1H,

d) 8.46 (1 H, d); MS m / z (ES ^&lt; ^{+ &gt;} ) 351 (MH &lt; ^{+ &gt;} )

Prípr. 67

δ _Η (CDCl 3, 400 MHz) 2.41 (3H, s), 3.08 (2H, m), 3.80 (2H, s), 4.37 (2H, m), 5.94-6, 36 (2H, brd), 6.46 (1H, s), 6.49 (1H, d), 6.81 (1H, d), 6.96 (1H, d), 7.65 (1H, d) ), 7.86 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 331 (MH &lt; ^{+ &gt;} )

Prípr. 68

HCl salt: δ _Η , (CDCl 3, 400 MHz) 2.42 (3H, s), 3.08 (2H, m), 3.44-3.50 (4H, m), 3.80 (2H, s) 4.40 (2H, m), 6.45 (1H, s), 6.49 (1H, d), 6.62 (1H, brs), 6.83 (1H, d), 6.96 (1H, d), 7.62 (1H, d), 7.78 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 390 (MH &lt; ^{+ &gt;} )

Pr. Prípr. R ⁵ 6. FROM Data 70 Prípr. 70 about· SMe HCl salt: δ _Η (d ₆ DMSO, 300 MHz) 2.48 (3H, s), 2.58 (3H, s), 4.12 (2H, s), 4.50 (2H, d), 5 32 (1H, t), 6.92 (2H, m), 7.03 (1H, dd), 7.39 (1H, dd), 7.46 (1H, d), 7.60 (1H, with); MS m / z (TS ^&lt; ^{+ &gt;} ) 308 (MH &lt; ^{+ &gt;} ) 71 Prípr. 69 HO ^ SMe HC1 salt: _δ Η (d ₆ -DMSO, 300 MHz) 2.52 (3H, obs), 2.58 (3H, t), 4.10 (2H, s + H ₂ O), 4.48 (2H, S), 6.94 (1H, d), 7.11 (1H, d), 7.21 (1H, s), 7.25 (2H, m), 7.57 (1H, S); MS m / z (ES ^&lt; ^{+ &gt;} ) 324 (MH &lt; ^{+ &gt;} ) 72 Prípr. 49 -ČSN about, SMe HC1 salt: _δ Η (d ₆ -DMSO, 300 MHz) 2.52 (3H, s), 2.60 (3H, s), 4.24 (2H, s) 6.94 (1 H, d), 7 04 (1H, d), 7.28 (1H, d), 7.50 (1H, t), 7.86 (1H, d), 8.08 (1H, s); MS m / z (TS ⁺ ) 3 03 (MH &lt; ^{+ &gt;} ) 73 Prípr. 73 M C ^ Xj. SMe HCl sol: δ _Η (CDCl ₃ , 300 MHz) 2.48 (3H, s), 2.64 (3H, s), 2.99 (3H, s), 4.23 (2H, s), 4, 30 (2H, d), 6.40 (1H, br), 6.81-6.89 (3H, m), 7.26-7.35 (2H, obs), 7.92 (1H, s) ; MS m / z (ES ^&lt; ^{+ &gt;} ) 385 (MH &lt; ^{+ &gt;} ), (ES &lt; ^{+ &gt};) 383 (MH &lt; ^{+ &gt;} ) 74 Prípr. 71 SMe HCl salt: δ _Η (CD ₃ OD, 400 MHz) 2.30 (3H, s), 2.44 (3H, s), 2.73 (3H, s), 4.25 (2H, S), 4 59 (2H, S); 6.81 (1H, d); 6.88-6.92 (2H, m); 7.24 (1H, d); 7.37 (1H, d); 46 (1 H, s); MS m / z (ES ^&lt; ^{+ &gt;} ) 304 (MH &lt; ^{+ &gt;} ) 75 Prípr. 72 (> 0 * _e ^ ^ Me SMe HCl salt: δ _Β (CD ₃ OD, 300 MHz) 2.37 (3H, s), 2.48 (3H, s), 2.78 (3H, s), 2.96 (3H, S), 4 27 (2H, s), 4.31 (2H, s), 6.85 (1H, d), 6.92-7.00 (2H, m), 7.31 (1H, d), 7, 41 (1 H, d), 7.57 (1 H, s); MS m / z (ES ^&lt; ^{+ &gt;} ) 381 (MH &lt; ^{+ &gt;} ), (ES &lt; ^{+ &gt};) 379 (MH &lt; ^{+ &gt;} ) 76 Prípr. 75 ¢. SMe HC1 salt: 5 H (CD ₃ OD, 400 MHz) 2.29 (3H, s) 2.41 (3H, s), 2.43 (3H, s), 3.76 (2H, s), 4.30 (2H, s), 6.72-6.79 (3H, m), 7.12 (1H, br), 7.27 (2H, obs); MS m / z (ES ^&lt; ^{+ &gt;} ) 435 (MH &lt; ^{+ &gt;} ), (ES &lt; ^{+ &gt};) 433 (MH &lt; ^{+ &gt;} )

Example 77

N- [4 - [(Dimethylamino) methyl] -3- [3-methyl-4- (methylsulfanyl) phenoxy] benzyl} methanesulfonamide

The product of Example 77 was prepared from the Boe protected sulfonamide of Preparation 74 by the method of Example 60; HC1 salt: _δ Η (CD ₃ OD, 400 MHz) 2.29 (3H, s), 2.42 (3H, s), 2.82 (3H, s);

2.89 (6H, s), 4.17 (2H, s), 4.39 (2H, s), 6.39 (3H, m), 7.19 (1H, d), 7.48 (1H , d); MS m / z (TS ^&lt; ^{+ &gt;} ) 395 (MH &lt; ^{+ &gt;} ).

Example 78

3 - [(Methylamino) methyl] -4- [3-methyl-4- (methylsulfanyl) phenoxy] benzonitrile

Zn (CN) ₂ (700 mg, 5.96 mmol) and Pd (PPh ₃ ) ₄ (1.97 g, 1.7 mmol) were added to the bromide solution of Example 44 (3.0 g, 8.52 mmol). ) in DMF (20 mL), heated to 100 ° C and held at this temperature for 17 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ether (2 x 100 mL then 3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL), dried (MgSO ₄ ) and evaporated to give a yellow oil. Initial purification by column chromatography [SiO ₂ ; 95: 5: 0.5 (DCM / MeOH / 880 NH ₃ )] was unsuccessful, so the material was chromatographed once more [SiO ₂ ; 50% pentane in 95: 5: 0.5 (DCM / MeOH / 880 NH ₃ ) increasing polarity to 0% pentane] to give the product (1.275 g, 50% yield) as a pale yellow oil. A sample was taken up in DCM (5 mL) and treated with 1M ethereal HCl to give the HCl salt as a white powder which was collected by filtration; δ _Η (CDCl ₃ , 300 MHz) 2.35 (3H, s), 2.47 (6H, s), 3.88 (2H, s),

6.79 (1H, d), 6.87 (2H, m), 7.20 (1H, d), 7.46 (1H, d), 7.72 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 299 (MH &lt; ^{+ &gt;} ).

Example 79

3 - [(Methylamino) methyl] -4- [3-methyl-4- (methylsulfanyl) phenoxy] benzamide

A mixture of the nitrile of Example 78 (404 mg, 1.35 mmol) and KOH (304 mg, 5.42 mmol) in tert-butanol (10 mL) was boiled for 1 h under

N ₂ under reflux. After cooling to room temperature, the solvent was removed in vacuo and the residue was partitioned between water (10 mL) and DCM (10 mL). The aqueous layer was extracted with DCM (4 x 20 mL) and the combined organic layers were washed with brine, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography [SiO 2; 93: 7: 1 (DCM / MeOH / 880 NH ₃ )] to give the desired product (376 mg, 88% yield) as a white foam; δ _Η (CDCl ₃ , 300 MHz) 2.35 (3H, s), 2.47 (3H, s), 2.49 (3H, s), 3.88 (2H, s), 5.90-6 30 (2H, brs), 6.82 (3H, m), 7.19 (1H, d), 7.70 (1H, d), 7.90 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 317 (MH &lt; ^{+ &gt;} ).

Compounds of formula Ih, i.e. compounds of formula I, wherein R ¹ and R ² are methyl and R ⁴ is hydrogen, as shown in Table 10, were prepared as described in Example 12 from the above precursors.

Table 10

Example precursor R ⁵ ï from Data 80 Example 60 «Λ s) 5 _h (CD 3 OD, 400 MHz) 2.91 (6H, s), 3.35 (2H, obs), 3.38 (2H, t), 4.45 (2H, s), 6.81 (1H d), 6.90 (1H, d), 7.03 (1H, s), 7.21 (1H, d), 7.86 (1H, d), 8.03 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 329 (MH &lt; ^{+ &gt;} ) 81 Example 62 Λ Me Δ (CD 3 OD, 400 MHz) 2.90-2.99 (9H, m), 3.35 (2H, obs), 3.43 (2H, t), 4.50 (2H, S), 6, 88 (1H, d), 6.97 (1H, d), 7.07 (1H, s), 7.28 (1H, d), 7.85 (1H, d), 8.03 (1H, S) ); MS m / z (TS &lt; ^{+ &gt};) 343 (MH &lt; ^{+ &gt;} )

δ '(CDCl 3,

Data

MHz (2.90 obs), 3.37 brm), 4.43

2H, brd 7.01 brs), 7.32 brs), - MS ( _δΗ , (2H, (2H,

H (1 H, m / z)

δ _Η (CDCl 3, 300 MHz) 2.29 (6H,

S), 2.47 (3H, s), 3.51 (2H, s), 6.73 (2H, S), 6.97 (1H, d), 7.30 (1H, t), 7, 79 (1 H, d), 7.97 (1 H,

with) ; MS m / z (TS ^&lt; ^{+ &gt;} ) 335 (MNH _& ^lt ; ₄ ^&gt; )

^Δ H (CDCl 3, 300 MHz) 2.29 (6H,

s), 2.46 (3H, s), 3.02 (3H, d),

3.54 (2H, s), 6.20 (1H, brs),

6.69 (2H, m), 6.97 (1H, d), 7.30 (1H, t), 7.75 (1H, d), 7.91 (1H, S); MS m / z (TS ⁴⁾ 349 (MH ⁴⁾

HCl salt: 5 _h (CDCl ₃ , 300 MHz) 2.49 (3H, s), 2.94 (6H, s), 3.42 (3H, s), 3.65 (4H, m), 4, 33 (2H,

S), 6.79 (2H, d), 6.96 (1H, d),

7.35 (1 H, t), 7.39 (1 H, brs),

7.98 (1 H, d), 8.68 (1 H, s); MS m / z (TS ⁴⁾ 393 (MH ⁴⁾

Example 66 o

Example 67

Me

SMe δ _Η (CDCl 3, 400 MHz) 2.38 (6H,

s), 2.47 (3H, s), 3.53 (2H, s),

6.88 (2H, d), 7.03 (1H, s), 7.19 (1H, d), 7.77 (1H, d), 7.95 (1H, S); MS m / z (ES ⁴⁾ 351 (MH ⁴⁾ _δ Η (CDCl, 400 MHz) 2.27 (6H,

S), 2.46 (3H, s), 3.01 (3H, d),

3.50 (2H, s), 6.19 (1H, brs),

6.88 (2H, m), 7.00 (1H, s), 7.19 (1H, d), 7.72 (1H, d), 7.85 (1H,

WITH); MS m / z (ES ⁴⁾ 365 (MH ⁴⁾

Example 68

HC1 Sol: δ _Η (CDCl 400 MHz) 2.25 (6H, s) 3.07 (2H, s), 3.49 (2H, s), 4.37 (2H, m), 5.47 to 6.22 (2H, brd), 6.44 (1 H, s), 6.49 (1 H, d), 6.86 (1 H, d), 6.95 (1 H, d), 7.68 (1 H, d), 7.87 (1 H, s);

MS m / z (TS ⁴⁾ 346 (MH ⁴⁾

precursor

Example 69

Example 70

Example 71

Example 78

Example 72

Example 45

HCl salt:

2.91 (6H, (3H, s), 4.39, 6.64 (2H, 7.08 (1H,

8.00 (1 H, s);

(MH ⁺ ) (CD 3 OD,

3.13 (2H, (2H, s)), 4.46

S + d), 6.87

d) 7.95 (1H,

MS m / z (TS ^&lt; ^{+ &gt;} )

MHz)

3.27 (2H, (1 H, d), 403)

HCl salt: δ _Η (d ₆ -DMSO, 300 MHz) 2.46 (3H, s), 2.74 (6H, s), 4.29 (2H, s), 4.51 (2H, s), 5.32 (1H, brs), 6.93 (2H, d), 7.08 (1H, d), 7.41 (2H, m), 7.63 (1H, s);

MS m / z (TS ^&lt; ^{+ &gt;} ) 322 (MH &lt; ⁺ &gt;)

HC1 sol: δ _Η (d ₆ -DMSO, 400 MHz) 2.52 (3H, obs), 2.76 (6H, WITH) , 4.09 (2H, with) , 4.49 (2H, WITH) , 5.32 (1 H, brs) , 6, 87 (1 H, d), 7.08 (1 H, d), 7.26 (1 H, WITH) , 7.38 (2H, m), 7.60 (1 H, s ⁺ ; MS m / z (ES ⁺ ) 338 (MH ⁺ ) HC1 sol: δ _Η (cr Cl ₃ , 400 MHz) 2.35 (3H, with) , 2.48 (3H, with) , 2.87 (6H, d), 4.39 (2H, d), 6.85 (1 H, d), 6.90 (1 H, d), 6, 93 (1 H, dd), 7.21 (1 H, d), 7.60 (1 H, d), 8.17

(1 H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 313 (MH &lt; ^{+ &gt;} )

HC1 sol: δ _Η (d _{6 -} DMSO, 300 MHz) 2.49 (3H, obs), 2.79 (6H, with) , 4.41 (2H, s) 6.97 (1H d), 7.14 (1 H, d) 7.32 (1 H, d). 7.49 (1 H, t), 7.87 (1 H, j d), 8.22 (1 H, with) ; MS m / z (TS ^&lt; ^{+ &gt;} ) 317 (MH &lt; ^{+ &gt;} )

HC1 sol: δ _Η (d ₆ -DMSO, 400 MHz) 2.23 (3H, with) , 2.42 (3H, s) 2.76 (6H, with) , 4.34 (2H, s), 6.80 (1 H, d), 7.97 (1 H, dd), 7.00 (1 H, with) , 7.19 (1 H, t), 7.24 (1 H, d), 7.40 (1 H, t), 7.67 (1 H, d); MS m / z (ES ⁺ ) 288 (MH ⁺ ) HC1 sol δ _Η (Article Cl ₃ , 400 MHz) 2.74 (6H, with) , 3.22 (2H, m) 3.38 (2H, m), 4.26 (2H, s), 6.71 (1 H, d), 6.80 (2H, br m), 7.15 (2H, BRM) 7 32 (1 H, d), 7.79 (2H,

(3H,

Example 73

Example 75

Example 74

Example 76

Product way.

HC1 SOľ: δ _Η (CD ₃ OD, 300 MHz) 2.46 (3H, with) , 3.93 (6H, s), 3.97 (3H, with) , 4.24 (2H, s), 4.42 (2H, with) , 6,91- 7.00 (3H, m) 7.41-7.54 (2H, m), 7.61 (1H, H) ; MS m / z (TS ⁺ ) 399 (MH ⁺ ) , (ES -) 397 (MH ⁺ ) HC1 SOľ: 5H (CD 3 OD, 400 MHz) 2.31 (4H, S) , 2.43 (3H, s) 2.86 -2.94 (9H, m), 4.22 (2H, s), 4.39 (2H, with) , 6.83 (1 H, d) 6,89- 6.94 (2H, m), 7.26 (1 H, d), 7.40 (1 H, d), 7.54 (1H, s) ; MS m / z (ES) 393 (MH ⁺ ) HC1 salt: δ _Η (CD 3 OD, 300 MHz) 2.36 (3H, with) , 2.47 (3H, s), 2.98 (6H, with) , 4.43 (2H, s), 4.63 (2H, with) , 6, 89 (1 H, d), 6,91- 7.00 (2 H, m), 7.30 (1 H, d), 7.43 (1 H, d), 7.55 (1 H with) ; MS m / z (ES ⁺ ) (MH ⁺

(CD ₃ OD,

2.47

MHz)

2.85

(6H, s), d). MS ir (M-H s), 4.32 6.80-6.86 7.35 (1H, / z (ES ⁺ ) 4 ⁺ ) (2H, s) (3H, m) 4.44 (2H, 7.21 (1H, d) 49 8 (MH ⁺⁾ 08 (1 H, , (ES) with) ; 447 δ _Η (CD3OD, 4 00 MHz) 2.26 (6H, with) , 3.58 (2H, with) , 6, 97 (1 H, d), 7.35 (1H, d) / 7.46 (1 H, dd), 7.54 (1 H, d), 7.80 (1 H, d), 8.03 (2H, m), 8.20 (1H, d) , 8.74 (1 H, d); MS m / z (TS ⁺ ) 322 (MH ⁺ )

from Example 94 was also prepared by the following

A solution of the product of Preparation 30 (200 g, 0.78 mol) in DCM (1.4 L) was added to THF (1.4 L). To this mixture were gradually added dimethylamine hydrochloride (69.5 g, 0.85 mol) and triethylamine (235 g, 2.33 mol). The temperature was set at 20 ° C and after 3 h sodium triacetoxyborohydride (246 g, 1.16 mol) was added. (After 20 h, if the reaction was complete, work-up continued; otherwise see note below). Dichloromethane (2 L) was added, followed by 0.5% sodium bicarbonate solution (0.9 L) over 0.5 h. The layers were separated and the organic layer was washed with water (1 L). The layers were separated again and the organic layer was concentrated. Ethyl acetate (0.27 L) was added and the solvent was removed by extrusion with ethyl acetate (800 mL). The resulting solution was then cooled to below 5 ° C and 7.02 M HCl / IPA (0.117 L, 0.82 mol) was added while keeping the temperature below 10 ° C. After stirring at below 5 ° C for 1 h, the suspension was filtered, rinsed with ethyl acetate (3 x 0.2 L) and dried in a vacuum oven at 50 ° C overnight to give the desired product as a powdery solid (141.5). g, 56% yield). [Note: if the reaction is not complete after 20 h, then a further portion of dimethylamine hydrochloride (13 g, and triethylamine (43,4 g,

0.43 mol). After 2 h at room temperature sodium triacetoxyborohydride (46

0.22 mol). It was allowed to react for another 20 h and then worked up as above.

Compounds of formula (Ii), i.e. compounds of formula (I) wherein R ² is methyl, R ⁴ is hydrogen, and R ⁵ is -C (= O) NH ₂ , which are listed in Table 11, were prepared as described in the Example. 79 of these precursors.

(Η)

Table 11

Example Prekurzo r R ¹ Data 101 Example 92 Me SMe δ _Η (CDCl 3, 300 MHz) 2.30 (6H, s), 2.35 (3H, s), 2.46 (3H, s), 3.58 (2H, s), 5.60-5, 80 (1H, brs), 6.00-6.20 (1H, brs), 6.32 (3H, m), 7.19 (1H, m), 7.71 (1H, d), 7.90 (1 H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 331 (MH &lt; ^{+ &gt;} ) 102 Example 49 H δ _Η (CDCl ₃ , 400 MHz) 2.43 (3H, s), 3.84 (2H, s), 6.94 (1H, d), 7.20 (1H, d), 7.34-7 39 (1H, m), 7.43 (1H, dd), 7.70 (1H, d), 7.91 (1H, s), 7.99 (1H, d), 8.09 (1H, d) 8.82 (1 H, d); MS m / z (ES ^&lt; ^{+ &gt;} ) 309 (MH &lt; ^{+ &gt;} )

Example 103

N- {5-Amino-2- [3-methyl-4- (methylsulfanyl) phenoxy] benzyl} -N, N-dimethylamine

SMe

A mixture of the nitro compound of Example 27 (2.0 g, 6 mmol), iron powder (2.51 g, 44.9 mmol) and CaCl 2 (300 mg, 2.7 mmol) in EtOH (20 mL) and water (4 mL) ) was refluxed for 20 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was partitioned between brine (100 mL) and ether (100 mL). The aqueous layer was extracted with ether (50 mL), the combined organic layers were dried (MgSO ₄ ) and evaporated to give the product (1.47 g, 81% yield) as an orange oil; δ _Η (CDCl ₃ , 300 MHz) 2.22 (6H, s), 2.32 (3H, s), 2.40 (3H, s), 3.33 (2H, s), 6.59 (1H dd), 6.60-6.75 (2H, m), 6.78 (1H, dd), 6.94 (1H, s), 7.10-7.20 (3H, m); MS m / z (ES ^&lt; ^{+ &gt;} ) 303 (MH &lt; ^{+ &gt;} ).

Example 104

N- [5-Amino-2- (2,3-dihydro-1-benzothien-5-yloxy) benzyl] -N, N-dimethylamine

The title compound was prepared from the nitro compound of Example 28 by the method of Example 103; δ _Η (CDCl ₃ , 400 MHz) 2.20 (6H, s), 3.16 (2H, t), 3.30 (4H, m), 3.54 (2H, br), 6.53 (1H dd), 6.60 (1H, d), 6.71 (2H, m), 6.79 (1H, d), 7.01 (1H, d);

MS m / z (ES ^&lt; ^{+ &gt;} ) 301 (MH &lt; ^{+ &gt;} ).

Example 105

N- [3- (Aminomethyl) -4- (2,3-dihydro-1,4-benzoxathiin-6-yloxy) phenyl] methanesulfonamide

The nitrile from Preparation 95 (720 mg, 1.99 mmol) was dissolved in

1M solution of BH ₃ .THF in THF (10 mL, 10 mmol) and the mixture was refluxed for 3 h. After cooling to room temperature, the reaction was quenched by careful addition of MeOH (10 mL). The solvent was evaporated, the residue was treated with 6M HCl (10 mL) and refluxed for 1 h. After cooling, the mixture was basified with 2M NaOH solution and the pH was adjusted to 7 with saturated aqueous NH ₄ Cl solution. The mixture was extracted with EtOAc (3 x 50 mL) and DCM (2 x 50 mL), the combined organic layers were dried (MgSO ₄ ) and evaporated to give a beige foam (685 mg, 94% yield) which was used without further purification. ; δ _Η (CDCl ₃ , 400 MHz) 3.00 (3H, s), 3.13 (2H, m), 3.87 (2H, s), 4.40 (2H, m), 6.62 (1H d), 6.67 (1H, s), 6.79 (2H, d), 7.08 (1H, d), 7.25 (1H, d); MS m / z (TS ^&lt; ^{+ &gt;} ) 367 (MH &lt; ^{+ &gt;} ).

Compounds of formula Ij, i.e. compounds of formula I wherein R ¹ , R ² and R ⁴ are hydrogen and R ⁵ is -NR ⁸ -SO ₂ Me, which are listed in Table 12, were prepared as described in Example 105 of said precursors

(Ij)

Table 12

Example Prekurzo r from R ⁸ Data 106 Pripr. 96 SMe H δ _Η (CDCl 3, 300 MHz) 2.47 (3H, s), 3.02 (3H, s), 3.08 (3H, br), 3.85 (2H, s), 6.87 (2H, s, m), 6.99 (1H, d), 7.15 (1H, dd), 7.20 (1H, d), 7.30 (1H, d); MS m / z (ES +) 371 (MH ⁺ ) 107 Prípr. 97 SMe H Used crude in the following step: δ _Η (CD ₃ OD, 400 MHz) 2.37 (3H, s), 2.95 (3H, s), 3.75 (2H, s), 6.58 (1H, d 6.71 (2H, m), 6.89 (1H, d), 7.15 (1H, dd), 7.28 (1H, obs) 108 Pripr. 100 SMe Me Use crude in the next step: 5H (CDCl 3, 300 MHz) 2.36 (3H, s), 2.46 3H, s), 2.90 (3H, s), 3.36 (3H, s), 3, 93 (2H, s), 6.83 (3H, m), 7.20 (2H, m), 7.42 (1H, d), 109 Prípr. 99 A s ^ SMe Me H _δ Η (CD ₃ 0D, 400 MHz) 2.24 (3H, s), 2.40 (3H, s), 2.97 (3H, s), 3.80 (2H, s), 6.60 ( 1H, d), 6.81-6.87 (2H, m), 7.08-7.17 (2H, m), 7.29 (1H, d); MS m / z (ES ^&lt; ^{+ &gt;} ) 353 (MH &lt; ^{+ &gt;} ), (ES &lt; ^{+ &gt};) 351 (MH &lt; ^{+ &gt;} )

Example 110

N- {4- (2,3-Dihydro-1,4-benzoxathiin-6-yloxy) -3 - [(methylamino) methyl] phenyl} methanesulfonamide

Dicyclohexylcarbodiimide (460 mg, 2.23 mmol) was added to a solution of pentafluorophenol (413 mg, 2.24 mmol) in ether (10 mL) followed by the addition of formic acid (95 µL, 2.5 mmol). The mixture was stirred for 2 h and then filtered, and the residue was washed with ether. The filtrate was concentrated to approximately 5 mL and a solution of the primary amine of Example 105 (411 mg, 1.1 mmol) in DCM (10 mL) was added. The mixture was stirred for 16 h and then concentrated to an oily residue. This crude oil was taken up in a solution of BH 3 .THF in THF (1M, 20 mL, 20 mmol) and refluxed under N _{2 for} 1.5 h. After cooling to room temperature, the reaction was quenched by careful addition of MeOH (10 mL) and then concentrated in vacuo. The oily residue was treated with 6M HCl solution and refluxed for 30 min. After cooling to room temperature, the mixture was basified with aqueous K ₂ CO _{3 solution} and extracted with DCM (3x). The combined organic extracts were dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography [SiO ₂ ; 90: 10: 1 (DCM / MeOH / 880 NH ₃ )] to give a colorless oil which was taken up in EtOAc (20 mL) and treated with 1M ethereal HCl (2 mL). After stirring for 1.5 h, the solid was collected by filtration to give the title product (282 mg, 60% yield); _δ Η (CD ₃ 0D, 400 MHz) 2.78 (3H, s), 2.98 (3H, s), 3.18 (2H, m), 4.29 (2H, s), 4.39 ( 2H, m), 6.74 (1H, d), 6.806.90 (3H, m), 7.22 (1H, d), 7.44 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 381 (MH &lt; ^{+ &gt;} ).

Compounds of formula Ik, i.e. compounds of formula I, wherein R ¹ and R ⁴ are hydrogen, R ² is methyl, and R ⁵ is -NHSO ₂ Me, which are listed in Table 13, were prepared as described in Example 110 of said precursors.

Table 13

precursor 'ý from Data Example 111 δ _Η (CDCl 3, 400 MHz) 2.40 (6H, s), 2.99 (3H, s), 3.70 (2H, s), 6.64 (2H, t), 6.88 (1H, s, d), 7.15 (1 H, d), 7.25 (2 H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 371 (MH &lt; ^{+ &gt;} ) Example 112 SMe HC1 salt: _δ Η (CD ₃ OD, 400 MHz) 2.55 (3H, s), 3.82 (3H, s), 3.04 (3H, s), 4.32 (2H, 6.97 ( 1 H, s), d), 7.11 (1 H, d), 7.23 (1 H, s), 7.30 (1 H, d), 7.39 (1 H, d), 7.56 (1 H, s), with) ; MS m / z (TS ^&lt; ^{+ &gt;} ) 387 (MH &lt; ^{+ &gt;} ) Example 113 A Me HC1 salt: _δ Η (CD ₃ OD, 400 MHz) 2.24 (3H, s), 2.39 (3H, s), 2.76 (3H, s), 2.93 (3H, 4.25 ( 2H, s), S), 6.69 (1H, d), 6.82 (1H, d), 6.93 (1H, s), 7.17 (1H, d), 7.21 (1H, d) 7.43 (1 H, s); MS m / z (ES ^&lt; ^{+ &gt;} ) 367 (MH &lt; ^{+ &gt;} ), (ES) 365 (MH &lt; ^{+ &gt;} )

Compounds of formula (I), i.e. compounds of formula (I) wherein R ¹ and R ⁴ are hydrogen, R ² is methyl, and R ⁵ is -NR ⁸ SO ₂ Me, which are listed in Table 14, were prepared as described in Example 110 of said precursors.

(Im)

Table 14

Example precursor R ⁸ FROM Data 114 Prípr. 85 H HCl salt: δ _Η (CDCl 3, 400 MHz) 2.09 (2H, µl), 2.73 (3H, s), 2.88 (4H, t), 3.00 (3H, s), 4.21 (2H, s), 6.80 (2H, m), 6.88 (1H, s), 7.19 (1H, d), 7.34 (1H, d), 7.75 (1H, s) ; MS m / z (TS ^&lt; ^{+ &gt;} ) 347 (MH &lt; ^{+ &gt;} ) 115 Prípr. 84 H ý. SMe HCl salt: δ _Η (d ₆ -DMSO, 400 MHz) 2.20 (3H, s), 2.40 (3H, s), 2.55 (3H, s), 2.97 (3H, s), 4.08 (2H, s), 6.80 (1H, d), 6.87 (1H, d), 6.91 (1H, s), 7.14 (1H, d), 7.20 (1H d) 7.39 (1 H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 367 (MH &lt; ^{+ &gt;} ) 116 ^a Prípr. 88 Me (k SMe δ _Η (CDCl ₃ , 300 MHz) 2.17 (3H, s), 2.37 (3H, s), 2.48 (3H, s), 2.62 (3H, s), 2.97 I ( 3H, s), 3.34 (3H, s), 4.23 (2H, s), 6.79 (1H, d), 6.94 (2H, s), 7.35 (2H, m), 7.81 (1 H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 381 (MH &lt; ^{+ &gt;} ) 117 Pripr. 89 f ^r ý. SMe HCl salt: δ _Η (CDCl ₃ , 400 MHz) 2.29 (3H, s), 2.39 (3H, s), 2.42 (3H, s), 2.94 (3H, s), 3, 60 (2H, t), 3.74 (2H, t), 3.79 (2H, s), 6.78 (3H, m), 7.14 (2H, m), 7.41 (1H, s) ); MS m / z (TS ^&lt; ^{+ &gt;} ) 410 (MH &lt; ^{+ &gt;} )

Example precursor R ⁸ ý FROM Data 118 Prípr. 87 H 5h (CDCl ₃ , 400 MHz) 2.42 (3H, s), 2.58 2.79 (2H, br), 2.94 (3H, s), 3.08 (2H, m), 3.71 (2H, s), 4.38 (2H, m), 6.39 (1H, s), 6.47 (1H, d), 6.82 (1H, d), 6.94 (1H, d) 7.07 (1H, d); 7.18 (1H, S); MS m / z (TS ^&lt; ^{+ &gt;} ) 381 (MH &lt; ^{+ &gt;} ) ¹¹⁹ Prípr. 86 δ _Η (CD 3 OD, 400 MHz) 2.80 (3H, s), 3.00 (3H, s), 3.27 (2H, m), 3.40 (2H, m), 4.28 (2H, m, m), 6.85 (2H, m), 7.00 (11H, s), 7.20 (1H, d), 7.24 (1H, dd), 7.47 (1H, d); MS m / z (TS ⁺ ) 375 (MH &lt; ^{+ &gt;} )

^and - Also prepared from the product of Example 108 as described in Example 110.

Compounds of formula (I), i.e. compounds of formula (I) wherein R ¹ and R ² are methyl, R ⁴ is hydrogen, and R ⁵ is -NR ⁸ SO ₂ Me, which are listed in Table 15, were prepared as described above. in Example 12 of the above precursors.

Table 15

Example

precursor

R ⁸

Data

120

Example 111

SMe

HCl salt: _δ Η (CD ₃ OD, 400 MHz) 2.42 (3H s), 2.89 (6H, s), 2.98 (3H, s), 4 , 37 (2H, s), 6.88 (2H, m) 6.97 (1 H, d), 7.28 (1 H, d), 7.39 (1 H, t), 7.48 (1 H,

with) ; MS m / z (TS ^&lt; ^{+ &gt;} ) 385 (MH &lt; ^{+ &gt;} )

121 (from primary amine)

Example 105

δ _Η (CDCl ₃ , 400 MHz) 3.00 (3H, s), 3.13 (2H, m), 3.87 (2H, s), 4.40 (2H, m), 6.62 (1H d), 6.67 (1H, s), 6.79 (2H, d), 7.08 (1H, d), 7.25 (1H, d); MS m / z (TS ^&lt; ^{+ &gt;} ) 367 (MH &lt; ^{+ &gt;} )

122 (from primary amine)

Example 106

SMe

123

Example 114 H

HC1 salt: _δ Η (CD ₃ OD 4 00 MHz) 2.49 (3H, with) , 2.93 (6H, s), 3.00 (3H, s), 4 , 41 (2H, with) , 6.95 (1 H, d), 7.07 (1 H, d), 7.21 (1 H, with) , 7.33 (2H, m), 7.54 (1 H, with) ; MS m / z (TS ⁺ ) 395 (M ^{@ +} ) H ⁺ ) HC1 SOl: δ _Η (C DC1 _3, 400 MHz) 2.12 (2H, n), 2.81 (6H, s), 2.91 (4H, t), 3 , 13 (3H, with) , 4.25 (2H, s), 6, 73 (1 H, d), 6.83 (2H, m), 7.10 (1 H, d), 7.39 (1 H, d), 7.90 (1 H, with) ; MS m / z (TS ^&lt; ^{+ &gt;} ) 36 0 (MH ⁺ )

124 Example 118 H

δ _Η (CDCl 3, 400 (3H, s), 3.07 4.38 (2H, m), d), 6.86 (1H, (1H, d), 7.27 (MH ⁺ ))

MHz) 2.22 (6H, s), 2.98 (2H, m), 3.41 (2H, s), 6.36 (1H, S), 6.45 (1H, d), 6.92 (1 H, d), 7.12 (1 H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 395

125

Example 117

SMe

HCl salt: δ _CD (CDCl 3, 300 MHz) 2.38 (3H, s), 2.48 (3H, s), 2.86 (δ _Η , brs), 3.15 (3H, s), 3, 73 (2H, brs), 3.87 (2H, brs), 4.35 (2H, brs), 6.82 (3H, brs), 7.20 (2H, m), 7.41 (1H, d) ); MS m / z (TS ^&lt; ^{+ &gt;} ) 425 (MH &lt; ^{+ &gt;} )

126 (from primary amine)

Example 108

Me

SMe

HCl salt: δ _Η (CD ₃ OD, 400 MHz) 2.29 (3H, s), 2.43 (3H, s), 2.89 (3H, s), 2.91 (6H, s), 3 26 (3H, s), 4.42 (2H, s), 6.84 (1H, d), 6.97 (2H, m), 7.27 (1H, d), 7.47 (1H, dd) 7.60 (1 H, d); MS m / z (TS ^&lt; ^{+ &gt;} ) 395 (MH &lt; ^{+ &gt;} )

127 (From primary amine) Example 109 H And y ^ SMe Me HC1 salt: _δ Η (CD ₃ OD, 400 MHz) 2.27 (3H, s), 2.42 (3H, s), 2.94 (6H, s), 2.99 (3H, s), 4 42 (2H, s), 6.77 (1H, d), 6.89 (1H, d), 6.99 (1H, s), 7.19 (1H, d), 7.28 (1H, dd) 7.50 (1 H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 381 (MH &lt; ^{+ &gt;} ), (ES ^&lt; ^{+ &gt;} ) 381 (MH &lt; ^{+ &gt;} )

Example 128

N- {3 - [(Dimethylamino) methyl] -4- [3-methyl-4- (methylsulfanyl) phenoxy] phenyl} methanesulfonamide

Methanesulfonyl chloride (371 μΐ, 4.79 mmol) was added to a solution of the aniline of Example 103 (725 mg, 2.4 mmol) and Et ₃ N (1 mL, 7.17 mmol) in DCM (10 mL) at 0 ° C. . After stirring at 0 ° C for 1 h, the reaction mixture was allowed to warm to room temperature and then the solvent was removed in vacuo. 2M NaOH solution (10 mL) was added to the residue and the mixture was stirred overnight. The resulting clear solution was neutralized by addition of saturated aqueous NH ₄ Cl solution and extracted with DCM (2 x 30 mL). The combined organic layers were dried (MgSO ₄ ) and evaporated to give an oil. This oil was taken up in EtOAc (10 mL), the HCl salt precipitated by the addition of 1M ethereal HCl and the product (669 mg, 67%) was collected by filtration; δ _Η (d ₆ -DMSO, 400 MHz) 2.23 (3H, s), 2.42 (3H, s), 2.75 (6H, s), 3.04 (3H, s)

s), 4.38 (2H, s), 6.84 (1H, d), 6.93 (1H, d), 6.98 (1H, s), 7.17-7.25 (2H, m) 1.50 (1H, s); MS m / z (ES ^&lt; ^{+ &gt;} ) 381 (MH &lt; ^{+ &gt;} ).

Compounds of formula Ip, i.e. compounds of formula I, wherein R ¹ and R ² are methyl, R ⁴ is hydrogen, and R ⁵ is -NHSO ₂ R ⁹ , which are listed in Table 16, were prepared as described in Example 128 of the above precursors.

Table 16

Example precursor R ⁹ FROM Data 129 Example 104 Me HCl salt: 5 H (CD ₃ OD, 400 MHz) 2.92 (6H, s), 2.99 (3H, s), 3.26 (2H, t), 3.40 (2H, t), 4. 41 (2H, s), 6.98 (2H, d), 7.00 (1H, s), 7.10 (1H, d), 7.27 (1H, d), 7.50 (1H, s) ); MS m / z (TS ^&lt; ^{+ &gt;} ) 381 (MH &lt; ^{+ &gt;} ) 130 Example 103 et ý. SMe HCl salt: δ _Η (d ₆ -DMSO, 400 MHz) 1.21 (3H, t), 2.23 (3H, s), 2.42 (3H, s), 2.74 (6H, s), 3.16 (2H, q), 4.26 (2H, s), 6.92 (1H, d), 6.92 (1H, d), 6.98 (1H, s), 7.18-7 25 (2H, m); 7.51 (1H, s); MS m / z (ES &lt; ^{+ &gt};) 395 (MH &lt; ^{+ &gt;} )

Preparations

Preparation 1

5- (aminosulfonyl) -2-fluoro-N-methylbenzamide

NHMe

To a solution of 5- (aminosulfonyl) -2-fluorobenzoic acid [prepared according to Chem. Pharm. Bull. 1995, 43, 582-7] (22.98 g, 105 mmol) in THF (500 mL) at room temperature under nitrogen was added carbonyldiimidazole (17 g, 105 mmol). After stirring for 2.25 h, a solution of methylamine in THF (2M, 70 mL, 140 mmol) was added dropwise and the reaction mixture was allowed to stir for 18 h. The crude reaction mixture was concentrated to a small volume and EtOAc (150 mL) was added to the resulting thick oil. This mixture was stirred and a precipitate formed in the form of granules, which was collected by filtration. This crude product contaminated with imidazole was suspended in DCM (300 mL) and refluxed for 5 h. After cooling to room temperature, the mixture was filtered to give the desired product (19.8 g, 81% yield) containing less than 2% w / w. imidazole; ^{Χ Η} NMR δΗ (300 MHz, d 4 -MeOH) 2.97 (3H, s), 7.40 (1H, t), 8.05 (1 H, m), 8.29 (1H, d); MS m / z (TS ^&lt; ^{+ &gt;} ) 250 (MNH4 ^&lt; ^{+ &gt;} ).

Preparation 2

3-Chloro-4- (methylsulfanyl) phenol

OH

SMe (i) Preparation of 2-chloro-1- (methylsulfanyl) -4-nitrobenzene

To a solution of 4-fluoro-3-chloronitrobenzene (27 g, 156 mmol) in DMF (150 mL) was added at room temperature

5-tert-butyl-4-hydroxy-2-methylphenylsulfide (100 mg) followed by sodium thiomethoxide (NaSMe) (10 g, 143 mmol) and the reaction mixture was stirred for 6 h. The DMF was evaporated in vacuo and the residue was partitioned between ether (1 L) and water (1 L). The ether layer was washed with water (1 L) and brine (1 L), dried (MgSO ₄ ) and freed of solvent under reduced pressure. The residue was purified by column chromatography (SiO ₂ ; DCM: pentane 1: 5 increasing polarity to 3: 7) to give the title compound (15.22 g, 49% yield) as a yellow solid; δ _Η (400 MHz, CDCl ₃ ) 2.53 (3H, s), 7.20 (1H, d), 8.09 (1H, dd), 8.20 (1H, d).

(ii) Preparation of 3-chloro-4- (methylsulfanyl) aniline

To a mixture of the above compounds (14.08 g, 69 mmol) in acetic acid (300 mL) and water (60 mL) was added iron powder (23 g, 412 mmol) and the reaction mixture was stirred until all of the starting material had dissolved. . The mixture was allowed to stand for 1.5 h and the acetic acid was subsequently removed under reduced pressure. The residue was taken up in saturated NaHCO ₃ (aq) (500 mL) and EtOAc (500 mL) and filtered through

Arbocel. The layers were separated, the aqueous phase was extracted with EtOAc (300 mL), and the combined organic phases were washed with brine, dried (MgSO ₄ ) and the solvent evaporated in vacuo to give the title compound (11.52 g, 96% yield) as a beige solid. substances; δ _Η (400 MHz, CDCl 3) 2.38 (3H, s), 3.66 (2H, br), 6.53 (1Η, dd), 6.70 (1Η, d), 7.12 (1H, d); MS m / z (ES ^&lt; ^{+ &gt;} ) 174 (MH &lt; ^{+ &gt;} ).

(iii) Preparation of 3-chloro-4- (methylsulfanyl) phenol

The above aniline (11.5 g, 66.2 mmol) was dissolved in a minimum amount of THF (approximately 15 mL) and water (500 mL) was added with vigorous rinsing followed by concentrated H ₂ SO ₄ (25 mL). The mixture was cooled in a water / ice bath and a solution of NaNO ₂ (5.0 g, 72.5 mmol) in ice water (10 mL) was pipetted underneath the reaction mixture. The reaction mixture was stirred at 0 ° C for 1.5 h and the resulting yellow-brown solution was decanted from the solid residue into an ice-dropping funnel (approximately 200 g). This solution was added at room temperature at a constant rate over 7 min to a vigorously stirred mixture of Cu (NO ₃ ) ₂ (230 g, 0.99 mol) and Cu ₂ O (8.52 g, 67.4 mmol) in water (1 mL). 1). After the addition was complete, the mixture was stirred for an additional 15 min and then extracted with ether (500 mL). The remaining red-brown solid in the reaction flask was taken up in MeOH (100 mL) and diluted with ether (300 mL), then poured from above into the aqueous layer. The ether layer was separated and the combined organic layers were extracted with 1M NaOH (3 x 100 mL). The aqueous extracts were acidified with concentrated HCl and then extracted with ether (2 x 150 mL). The ether layers were then washed with brine, dried (MgSO ₄ ) and the solvent evaporated in vacuo to give phenol (5.465 g, 47% yield) as a brown crystalline solid; δ _Η (400 MHz, CDCl ₃ ) 2.44 (3H, s),

5.08 (1H, br), 6.77 (1H, d), 6.93 (1H, d), 7.18 (1H, d); MS m / z (ES +) 173 (MH ⁺ ).

Preparation

3-Fluoro-4- (methylsulfanyl) phenol

OH

This compound was prepared using a method similar to that described in Preparation 2 above and using commercially available 3,4-difluoronitrobenzene as a starting material; δ _Η (CDCl ₃ , 300 MHz) 2.40 (3H, s), 5.03 (1H, br), 6.60 (2H, m), 7.27 (1H, m not visible); MS m / z (ES ^- )

157 (MH &lt; ^{+ &gt;} ).

Preparation 4

2,3-dihydro-1,4-benzoxathiin-6-ol

OH

1,2-Dibromoethane (2.3 mL, 26.7 mmol) and K ₂ CO ₃ (8.21 g, 59.4 mmol) were suspended in acetone (250 mL) and a solution was added to the stirred mixture over 4 h. 2-sulfanyl-1,4-benzenediol (prepared according to J. Org. Chem. 1990, 55, 2736) (4.22 g,

29.7 mmol) in acetone (50 mL). After the addition was complete, stirring was continued for a further 10 h before the solvent was removed in vacuo. The residue was partitioned between water (50 mL) and EtOAc (50 mL), the aqueous layer was extracted with EtOAc (50 mL), and the combined organic layers were dried (MgSO ₄ ) and evaporated. Purification of the residue by column chromatography [SiO ₂ ; 9: 1 (pentane / EtOAc)] gave the title compound (2.48 g, 55% yield) as a pale orange oil; 5h (CDCl 3, 400 MHz) 3.08 (2H, m), 4.31 (2H, m), 4.44 (1H, s), 6.42 (1H, d), 6.49 (1H, s 6.66 (1H, d); MS m / z (ES &lt; ^{+ &gt};) 167 (MH &lt; ^{+ &gt;} ).

Preparation

2,3-dihydro-1,4-benzoxathiin-7-ol

OH

The title compound was prepared in a similar manner to the compound of Preparation 4 using 4-sulfanyl-1,3-benzenediol as a starting material (prepared according to J. Org. Chem. 1979, 26, 4971-4973); _δ Η (CDC1 _3, 400 MHz)

3.05 (2H, t), 4.37 (2H, t), 6.32 (1H, s), 6.35 (1H, d), 6.84 (1H, d); MS m / z (TS ^&lt; ^{+ &gt;} ) 169 (MH &lt; ^{+ &gt;} ).

Preparation 6

1,3-dihydro-2-benzofuran-5-ol

OH

1,3-Dihydro-2-benzofuran-5-amine (prepared according to US Patent No. 4,000,286) (2.7 g, 20 mmol) was dissolved in a mixture of water (300 mL) and concentrated H ₂ SO ₄ (21 mL), cooled to 0 ° C and NaNO ₂ (1.43 g, 2.7 mmol) in water (10 mL) was added over 15 min. After stirring at 0 ° C for 1 h, the mixture was allowed to stir at 10 ° C for 30 min and urea was added until a negative starch / KI paper test was found. The resulting solution was then poured at 90 ° C for 2 min into a mixture of water (180 mL) and concentrated H ₂ SO ₄ (12.6 mL) and stirred at this temperature for 1.5 h. The hot mixture was filtered and then left

Cool to room temperature. water the mixture is extracted EtOAc (2 x 100 mL), combined organic layers the dried _(MgSO4) and evaporated to give title phenol (974 mg, 3 6% extract) in the form of a cream solid substances; δ _Η (CDC1 ₃ , 400 MHz) 5.03 (4H, s), 6.71 (2H, m), 7.08 (1H, d)

Preparation 7

2,3-dihydro-1-benzothiophen-6-ol

OH

(i) Preparation of 2,3-dihydro-1-benzothiophen-6-ol-1,1-dioxide

A suspension of 2,3-dihydro-1-benzothiophene-6-amine-1,1-dioxide [prepared according to J. Am. Chem. Soc. 1955, 77, 5939] (15.73 g, 85.8 mmol) in water (500 mL) and concentrated H ₂ SO ₄ (35 mL) was heated until a solution was obtained. The mixture was cooled to 0 ° C and then a solution of NaNO ₂ (6.22 g, 90 mmol) in water (15 mL) was added over 5 min. The reaction mixture was stirred at 0 ° C for 1 h and then urea was added to remove excess nitrite until a negative starch / KI paper test was obtained. The mixture was allowed to warm to room temperature and then added to a mixture of concentrated H ₂ SO ₄ (55 mL) and water (750 mL) with stirring at 90 ° C. The reaction mixture was again heated to 90 ° C and stirred at this temperature for 30 min. The hot reaction mixture was filtered through Arbocel and then stirred overnight at room temperature. The aqueous mixture was extracted with ether (2.5 L) then EtOAc (5 x 500 mL), the combined organic layers were dried (MgSO ₄ ) and evaporated to give the desired phenol (12.7 g, 80% yield) which was used. without further purification; δ _Η (CDCl ₃ , 400 MHz) 3.30 (2H, m), 3.50 (2H, m), 7.05 (1H, m), 7.14 (1H, s), 7.23 (1H , m); MS m / z (ES -) 183 (MH ⁺ ).

(ii) Preparation of 2,3-dihydro-1-benzothiophen-6-ol

A solution of the sulfone from step (i) (4.84 g, 26.3 mmol) in toluene (100 mL) and THF (70 mL) was added to a solution of DIBAL in toluene (1M, 100 mL, 100 mmol) and the mixture was then boiled under reflux for 16 h. After cooling to room temperature, EtOH (75 mL) was carefully added with stirring followed by water (100 mL). To the resulting thick suspension was added 6M HCl and the organic layer was separated. The aqueous layer was extracted with EtOAc (3 x 150 mL) and the combined organic layers were dried (MgSO ₄ ) and evaporated to give a beige solid.

Purification by column chromatography [SiO ₂ ; DCM / MeOH / 880 NH ₃ desired title phenol as a beige solid (1.85 g, 53%); _δ Η (CD ₃ OD, 400 MHz) 3.13 (2H, t), 3.30 (2H,

151 (MH &lt; ^{+ &gt;} ).

Preparation

5- (Aminosulfonyl) -2- [3-methyl-4- (methylsulfanyl) phenoxy] -N-

methylbenzamide

The fluoramide from Preparation 1 (732 mg, 3.15 mmol) was treated with 4 (methylthio) -m-cresol (commercially available) (535 mg, 3.47 mmol) and potassium carbonate (457 mg, 3.31 mmol) in DMF. (10 mL). The mixture was heated to 100 ° C and held at that temperature for 5 hours. The solvent was removed by evaporation under reduced pressure and the residue was treated with 2M HCl solution (10 mL). The resulting suspension was extracted several times with dichloromethane. The combined dichloromethane layers contained a suspension and evaporated until a solid residue was obtained. The residue was triturated with ether (5 mL) and the remaining solid was collected

flushed with ether (3 x 10 ml) to form no quite white solid (765 mg 66% yield). δ _Η (300 MHz, d ₆ -DMSO) 2.28 (3 H, s), 2.48 (3H, with) , 2.70 (3 H, d), 6,9C i (1H, d) 7.02 (1H, d) 7.03 (1 H, with) , 7.30 (1H, d) 7.35 (2H, s), 7.79 (1 H,

d), 8.10 (1H, (mnh ₄ ⁺ )). d), 8.30 (1H, m); MS m / z (TS ^&lt; ^{+ &gt;} ) 367 (MH ⁺ ) 385 Preparation 9 to 18 compounds of formula Va, it is a compound wherein T means -C (= O) NHMe, R ⁴ is hydrogen atom and R ⁵ represents -SO ₂ NH ₂ , which They are listed in Table 17, with prepared as prepared 8 using

sulfonamide from Preparation 1 and the indicated phenol.

Table 17

preparation Precursor phenol ý from Data 9 Synth, Commun, 1991, 21, 959-964 δ _Η (d ₆ -DMSO, 400 MHz) 2.80 (3H, d), 3.20 (2H, t), 3.40 (2H, t), 6.90 (1H, m), 7.05 (1H, s), 7.25 (1H, d), 7.35 (1H, s), 7.80 (1H, m), 8.10 (1H, s), 8.30 (1H, brs) ; MS m / z (TS ^&lt; ^{+ &gt;} ) 365 (MH &lt; ^{+ &gt;} ) 10 Prípr.5 δ _Η (CD 3 OD, 400 MHz) 2.92 (3H, s), 3.17 (2H, m), 4.41 (2H, m), 6.60-6.70 (2H, m), 6, 97 (1H, d), 7.18 (1H, d), 7.90 (1H, d), 8.31 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 381 (MH &lt; ^{+ &gt;} ) 11 Prípr.3 SMe δ _Η (CD ₃ OD, 400 MHz) 2.43 (3H, s), 2.97 (1H, s), 6.89 (2H, m), 7.00 (1H, d), 7.39 ( 1H, br), 7.88 (1H, brd), 8.23 (1H, s); MS m / z (ES ^&lt; ^{+ &gt;} ) 371 (MH &lt; ^{+ &gt;} )

12 Prípr.2 p. SMe δ _Η (CD ₃ OD, 400 MHz) 2.85 (3H, s), 2.99 (3H, s), 6.99 (1H, d), 7.09 (1H, d), 7.22 ( 1 H, s), 7.37 (1 H, d), 7.92 (1 H, d), 8.28 (1 H, s); MS m / z (ES ^&lt; ^{+ &gt;} ) 387 (MH &lt; ^{+ &gt;} ) 13 Prípr. 4 Á δ _Η (CD ₃ OD, 400 MHz) 2.87 (3H, brs), 3.13 (2H, brs), 4.37 (2H, brs), 6.73 (1H, brs), 6.82 ( 3H, m), 7.82 (1 H, s), 8.28 (1 H, brs); MS m / z (ES ^&lt; ^{+ &gt;} ) 381 (MH &lt; ^{+ &gt;} ) 14 Prípr. 6 δ _Η (d ₆ -DMSO, 400 MHz) 2.79 (3H, 4.98 brs), S), 6.92 (1H, (4H, d), 7.04 (1H, d), 7.09 7.37H, (3H, (1m), s), 7.79 (1H, m), 8.10 (1H, s), 8.30 (1H, s), MS m / z (TS ⁺ ) 349 (MH &lt; ^{+ &gt;} ) preparation Precursor phenol Data 15 commercial ιΓί δ _Η (CD ₃ OD, 400 MHz) 2.08 (2H, m), 2.90 (7H, m), 6.84 (2H, m), 6.97 (1H, s), 7.23 ( 1 H, d), 7.81 (1 H, d), 8.31 (1 H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 347 (MH &lt; ^{+ &gt;} ) 16 Tetrahedron 1982, 38, 2721 & Synthesis 1982, 475 / .. Me The product was used without purification 17 Prípr. 101 δ _Η (CD ₃ OD, 400 MHz) 2.88 (3H, s), 4.20 (4H, s), 6.89 (1H, d), 6.97 (1H, d), 7.01 (1H, s), 7.30 (1H, d), 7.84 (1H, d), 8.28 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 382 (MNH4 _& ^lt ; ^{+ &gt;} ) 18 Prípr. 7 A δ _Η (DMSO-d ₆ , 400 MHz) 2.78 (3H, d), 3.23 (2H, m), 3.40 (2H, m), 6.75 (1H, dd), 6.90 (1H, d), 7.02 (1H, s), 7.27 (1H, d), 7.34 (1H, d), 7.80 (1H, d), 8.10 (1H, s) 8.26 (1 H, br, d); MS m / z (ES &lt; ^{+ &gt};) 363 (MH &lt; ^{+ &gt;} )

Preparation 19

5-Bromo-2- (2,3-dihydro-1-benzothien-5-yloxy) benzaldehyde

5-Bromo-2-fluorobenzaldehyde mixture. (1.08 g, 5.32 mmol), 5-hydroxy-2,3-dihydrobenzothiophene (prepared as described in Synth. Conrnun. 1991, 21, 959-964) (808 mg, 5.31 mmol) and K ₂ CO ₃ (1.47 g, 10.6 mmol) in DMF (5 mL) was heated to 90 ° C and held at this temperature for 16 h. After cooling to room temperature, the mixture was partitioned between water (50 mL) and ether (50 mL), and the aqueous layer was extracted with ether (50 mL). The combined organic extracts were washed with water (50 mL), dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography [SiO ₂ ; 9: 1 (pentane / EtOAc)] and then triturated with ether to give the product (1.1 g, 62% yield) as a pale yellow solid; δ _Η (CDCl ₃ , 400 MHz) 3.28 (2H, t), 3.41 (2H, t), 6.78 (1H, d), 6.84 (1H, d), 6.92 (1H s, 7.20 (1H, d), 7.58 (1H, d), 8.00 (1H, s), 10.43 (1H, s).

Compounds of formula II which are listed in Table 18 were prepared according to Preparation 19 by reaction of the indicated phenol with the desired 2-fluorobenzaldehyde.

In most cases, the crude reaction product after aqueous work-up was used directly in subsequent steps without further purification.

preparation

Precursor phenol

Prípr.

Prípr. 5

Prípr. 2

commercial

commercial

commercial

Table 18

br

br

br

br

MeO

SMe

SMe

SMe

SMe

Data δ _Η (CDCl 3, 300 MHz) 2.48 (3H, s), 6.81 (3H, m), 7.37 (1H, t),

7.64 (1 H, d), 8.06 (1 H, s),

10.39 (1 H, s); MS m / z (TS ^&lt; ^{+ &gt;} )

358,360 (MNH ₄ ⁺ )

δ _Η (CDCl 400 MHz) 3.13 (2H, m) , 4.42 (2H, m), 6 55 1H, s) 6. 59 (1 H, d), 6.81 (1 H, d), 7 04 (1 H, d), 7.59 (1 H, d), 8 01 (1 H, with) , 10.40 (1 H, with)

δ _Η (CDCl 3, 400 MHz) 2.43 (3H,

s), 6.78 (1H, d), 6.94 (1H, d), 7.08 (1H, s), 7.19 (1H, d), 7.59 (1H, d), 8, 0 (1H, s)

5h (CDC1 ₃ , 300 MHz) 2.35 (3H, with) , 2.49 (3H, with) , 6, 78 (1H, d) 6. 90 (2H, with) , 7.22 (1 H, d), 7 _z 59 (1 H, d), 8, 05 (1 H, with) ,

10.45 (1 H, s); MS m / z (TS ^&lt; ^{+ &gt;} )

356, 354 (MNH ₄ ⁺⁾

δ _Η (CDC1 ₃ , 300 MHz) 2.35 (3H, with) , 2.45 (3H, with) , 3.87 (4H, s) 6. 82 (1 H, d), 6.83 (1 H, with) , 6. 92 (1 H, d), 7.13 (1 H, dd), 7, 19 (1 H, d), 7.40 (1 H, d),

10.40 (1 H, s); MS m / z (TS ⁺⁾ 389 (MH ⁺⁾ _δ Η (CDC1 _3, 300 MHz) 7.02 (1H, dd), 7.21 (1H, s), 7.30 (1 H,

m), 7.40 (1 H, m), 7.54 (1 H, d),

7.66 (1 H, dd), 8.01 (1 H, d),

8.18 (1 H, d), 8.88 (1 H, d),

10.43 (1 H, s); MS m / z (ES ^&lt; ^{+ &gt;} ) 268 (MH &lt; ^{+ &gt;} )

100

commercial

δ _Η (CDCl 3, 400 MHz) 6.97 (1H,

d), 7.21-7.27 (2H, m), 7.38 (1H, dd), 7.49-7.58 (2H, m), 7.92-8.01 (2H, m) 8.11 (1H, d), 8.83 (1H, d), 10.50 (1H,

with) ; MS m / z (ES ^&lt; ^{+ &gt;} ) 272 (MNa &lt; + ^&gt; ), (ES &lt; ^{+ &gt};) 248 (MH &lt; ^{+ &gt;} )

J. Chem. Soc. 1952, 4985-4993

δ _Η (CDCl ₃ , 300 MHz) 7.08 (1H, d), 7.36 (2H, m), 7.65 (1H, m), 7.79 (1H, dd), 8.01 (1H d), 8.13 (1H, d), 9.29 (1H, d), 10.45 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) (TS ^&lt; ^{+ &gt;} ) 251 (MH &lt; ^{+ &gt;} )

commercial

δ _Η (CD 400 MHz) 7.09 (1H, d)

7.28 (1 H, m), 7.35 (LH, m), 7.40 (1 H, m), 7.50 (1H, br) 7.59 (1 H, m), 7.86 (LH, dd) 7.99 (1 H, dt) 8.15 (1H, d) 8.86 (1 H, m), 10.46 (1H, s)

m / z 250 (MH &lt; ^{+ &gt;} )

Chem, Pharm. Bull, 1978;

26.1443

δ _Η (CDCl ₃ , 400 MHz) 6.91 (1H,

d), 7.25 (2H, m), 7.55 (2H, m), 7.96 (1H, m), 8.12 (1H, d), 8.95 (1H, s), 10, Δ (1H, s); MS m / z 256 (MH &lt; ^{+ &gt;} )

commercial

SMe

δ _Η (CDCl 3, 300 MHz) 2.35 (3H, s), 3.44 (3H, s), 6.87 (3H, m), 7.17 (2H, m), 7.50 (1H, t) 7.92 (1H, dd, 10.52 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 259 (MH &lt; ^{+ &gt;} )

Synth, Commun, 1991, 21, 959-964

δ _Η (CDCl ₃ , 400 MHz) 3.26 (2H, t), 3.39 (2H, m), 6.85 (2H, t), 6.92 (1H, s), 7.18 (2H m, 7.48 (1H, t), _x 7.92 (1H, d), 10.51 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 257 (MH &lt; ^{+ &gt;} )

commercial

br

SMe _δ Η (CDCl, 400 MHz) 2.36 (3H, s), 2.44 (3H, s), 6.88 (2H, m), 6.96 (1H, s), 7.18 to 7 25 (2H, Obs), 7.77 (1 H, d), 10.43 (1 H, s)

Prípr.

br

δ _Η (CDC1 ₃ ) 400 MHz) 3.27 (2 H m), 3.42 (2H, m), 6 67 1H, 6.80 (1 H, d), 6.90 (1 H, WITH) , 71.6 (1 H, d), 7.58 (1 H, d), 8.01 (1 H, with) , 10.43 (1 H, with) m / z (TS ⁺ ) 354 (MNH ₄ ^(tr )

101

34 ^a commercial H CN δ _Η (DMSO-d ₆ , 300 MHz) 6.26 (1H, d), 6.43 (1H, d), 7.49 (1H, d), 7.65-7.71 (2H, m) 7.88 (1H, d), 8.07 (1H, d), 8.17 (1H, s), 8.73 (1H, d), 8.89 (1H, s); MS m / z (ESU 273 (MH &lt; ⁺ &gt;), (ES ⁺ ) 275 (MH &lt; ^{+ &gt;} )

^and -4-Fluoro-3-formylbenzonitrile was synthesized according to Synth.

Commun. 1997, 27 (7), 1199 and J. Org. Chem. 1961, 26, 2522.

The product of Preparation 30 was also prepared as follows.

Potassium carbonate (334.1 g, 2.42 mol) and 4- (methylthio) m-cresol (273.4 g, 1.77 mol) were added sequentially to DMF (2 L). 2-Fluorobenzaldehyde (200 g, 1.61 mol) was then added to the suspension and the mixture was heated to 100 ° C to 110 ° C. After 48 h, the reaction mixture was allowed to cool to room temperature and water (1.2 L) was added. The resulting solution was cooled to less than 10 ° C and the pH was adjusted to 5 with conc. HCl (0.37 L) keeping the temperature below 10 ° C. Water (0.15 L) and dichloromethane (0.9 L) were added and the mixture was stirred. The layers were separated and the organic layer was washed with water (4 x 0.75 L). The solvent was distilled to azeotropically remove water. Fresh dichloromethane was added as needed. The anhydrous dichloromethane solution was then concentrated in vacuo to give the crude product as an oil (422 g, 100% yield).

Compounds of formula IX, which are listed in Table 19, were prepared according to Preparation 19, either using 2-chloro-5-nitrobenzaldehyde or 2-chloro-5-nitrobenzonitrile with the phenol indicated. A shorter reaction time (approximately 2 h to 3 h) is generally sufficient to achieve good conversion for these reactions. In most cases, the crude reaction product is used directly in subsequent steps after aqueous work-up without further purification.

102

Table 19

preparation precursor W from Data 35 Prípr. 3 -ČSN SMe δ _Η (CDCl 3, 400 MHz) 2.48 (3H, s), 6.85-6.95 (3H, m), 7.28 (1H, t), 8.30 (1H, d), 8, 52 (1 H, s) 36 Prípr. 5 0 A. IN δ _Η (CDCl 3, 400 MHz) 3.14 (2H, d), 4.43 (2H, d), 6.62 (2H, m), 6.92 (1H, d), 7.08 (1H, d), 8.27 (1H, d), 8.72 (1H, s), 10.51 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 318 (MH &lt; ^{+ &gt;} ) 37 Prípr. 2 -ČSN ψ. SMe δ _Η (CDCl 3, 300 MHz) 2.55 (3H, s), 6.94 (1H, d), 7.09 (1H, dd), 7.22 (1H, d), 7.27 (1H, d), 8.36 (1H, dd), 8.60 (1H, d); MS m / z (TS ^&lt; ^{+ &gt;} ) 338 (MNH _& ^lt ; ₄ ^&gt; ) 38 Synth, Commun, 1991, 21, 959-964 0 A. δ _Η (CDCl 3, 400 MHz) 3.29 (2H, m), 3.42 (2H, m), 6.88 (2H, m), 6.96 (1H, s), 7.23 (1H, m, d), 8.26 (1H, d), 8.75 (1H, s), 10.54 (1H, s) 39 commercial 0 And, SMe δ _Η (CDCl ₃ , 400 MHz) 2.38 (3H, s), 2.50 (3H, s), 6.92 (1H, d), 6.99 (2H, m), 7.24 (1H , d), 8.28 (1 H, dd), 8.78 (1 H, d), 10.57 (1 H, s) 40 commercial 0 δ _Η (CDCl 3, 400 MHz) 2.18 (2H, m), 2.95 (4H, t), 6.90 (2H, m), 7.29 (1H, d), 8.27 (1H, m, d), 8.79 (1H, s), 10.59 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 301 (MNH _& ^lt ; ₄ ^&gt; ) 41 Prípr. 4 -ČSN at δ _Η (CDCl ₃ , 400 MHz) 3.18 (2H, t), 4.44 (2H, t), 6.76 (1H, d), 6.86 (1H, s), 6.92 (2H d), 8.32 (1H, d), 8.57 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 332 (MNH _& ^lt ; ₄ ^&gt; ) 42 commercial -ČSN SMe δ _Η (CDCl 3, 400 MHz) 2.32 (3H, s), 2.47 (3H, s), 6.87 (1H, d), 6.94 (2H, m), 7.21 (1H, d), 8.26 (1H, dd), 8.51 (1H, d); MS m / z (TS ^&lt; ^{+ &gt;} ) 318 (MNH _& ^lt ; ₄ ^&gt; )

103

preparation precursor W from Data 43 Tetrahedron 1982, 38, 2721 & Synthesis 1982,475 -ČSN about,. SMe δ _Η (CDCl 3, 400 MHz) 2.31 (3H, s), 2.41 (3H, s), 6.76 (1H, dd), 6.85 (2H, m), 7.19 (1H, d), 8.24 (1H, dd), 8.53 (1H, d); MS m / z (TS ^&lt; ^{+ &gt};) 318 (MNH4 _& ^lt ; ^{+ &gt;} )

Preparation 44 tert -Butyl 5-bromo-2- (2,3-dihydro-1-benzothien-5-yloxy) benzyl (methyl) carbamate

The hydrochloride salt of Example 36 (1.04 g, 2.7 mmol) was suspended in DCM (12 mL) and Et ₃ N (75 0 µΐ, 5.38 mmol) was added followed by di-tert-butyl dicarbonate (766 mg, 3 , 51 mmol). After stirring at room temperature for 20 min, the reaction was quenched by the addition of 0.2 M HCl solution (20 mL). The vigorously shaken mixture was separated and the aqueous layer was extracted with DCM (10 mL). The combined organic layers were dried (MgSO ₄ ) and evaporated to give the product (in quantitative yield) as a colorless oil which was

used without further purification; δ _H (CDCl ₃ , 400 MHz) 1.56 (9H, s), 2.82-2.98 (3H, brd), 3.23 (2H, t), 3.40 (2H, t), 4.44 (2H, brd), 6.71 (2H, d), 6.79 (1H, s), 7.12 (1 H, d), 7.29

(1H, d), 7.39 (1H, s).

104

Compounds of formula (X) listed in Table 20 were prepared according to Preparation 44 using the above precursors as starting materials.

Table 20

preparation precursor ý from Data 45 Example 38 at δ _Η (CDCl ₃ , 400 MHz) 1.41 (9H, brs), 2.81 (3H, m), 3.07 (2H, m), 4.36 (4H, m), 6.38 (1H s), 6.43 (1H, d), 6.71 (1H, d), 6.92 (1H, d), 7.26 (1H, 7.34 d), (1H, s); MS m / z (ES ^&lt; ^{+ &gt;} ) 468 (MH &lt; ^{+ &gt;} ) 46 Example 39 SMe δ _Η (CDCl 3, 400 MHz) 1.48 (9H, s), 2.41 (3H, s), 2.82 (3H, brd), 4.39 (2H, brd), 6.73 (1H, d), 6.80 (1H, d), 6.93 (1H, s), 7.04 (1H, d), 7.32 (1H, d), 7.39 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 474 (MH &lt; ^{+ &gt;} ) 47 Example 37 SMO δ _Η (CDC) ₃ , 300 MHz) 1.46 (9H, brs), 2.46 (3H, s), 2.89 (3H, brs, 4.41 (2H, brs), 6.68 (2H) m, 6.82 (1H, d), 7.27 (1H, obs), 7.40 (1H, d), 7.43 (1H, s) MS m / z (TS ⁺ ) 458 ( MH ⁺ ) 48 Example 44 SMe δ _Η (CDCl 3, 300 MHz) 1.45 (9H, br) 2.38 (3H, s), 2.44 (3H, s), 2.90 (3H, br), 4.47 (2H, br) 6.70-6.81 (3H, m) 7.20 (1H, d), 7.247.58 (2H, m)

105

Preparation 49 tert -Butyl 5-cyano-2- [3-fluoro-4- (methylsulfanyl) phenoxy] benzyl (methyl) carbamate

The title compound was prepared from the bromide of Preparation 47

by the method of Example 78; δ _Η (CDC1 ₃ ) 300 MHz) 1.48 (9H, brs) 2.50 (3 H, s), 2.93 (3H, brs), 4.55 (2H, brs), 6, 79 (2 H, m), 6.88 (1 H, d), 7.35 (1 H, t), 7.53 (1H, d) 7.59 (1 H, s); MS m / z (TS ⁺ ) 403 (MH &lt; ^{+ &gt;} ).

Preparation

Methyl 3 - {[(tert-butoxycarbonyl) (methyl) amino] methyl} -4- (2,3-dihydro-l-benzothiophen-5-yloxy) benzoate

A mixture of bromide from Preparation 44 (1.22 g, 2.7 mmol), Et ₃ N (1.13 mL, 8.11 mmol) and dichlorobis (triphenylphosphine) palladium (II) (190 mg, 0.27 mmol) in MeOH (14 mL) was heated to 80 ° C under a carbon monoxide pressure of 0.69 MPa at this temperature.

The temperature and pressure were maintained for 18 h. TLC analysis indicated that the reaction was incomplete, so additional catalyst (190 mg, 0.27 mmol) was added and the mixture was heated to 100 ° C under a carbon monoxide pressure of 0.69 MPa and maintained at this temperature and pressure for a period of time. 24 h. The mixture was diluted with EtOAc (20 mL) and filtered through a silica gel pad, using excess EtOAc as eluent. The solvent was evaporated in vacuo and the residue was partitioned between EtOAc (50 mL) and a 2: 1 mixture of water and 880 NH ₃ (50 mL). The aqueous layer was extracted with EtOAc (25 mL) and the combined organic layers were dried (MgSO ₄ ) and evaporated. Purification by column chromatography [SiO ₂ ; 4: 1 (pentane / EtOAc)] gave the desired product (970 mg, 84% yield) as an oil; δ _Η (CDCl ₃ , 400 MHz) 1.42 (9H, s), 2.90 (3H, brs), 3.22 (2H, t),

3.38 (2H, t), 3.84 (3H, s), 4.50 (2H, brd), 6/74 (2H, d),

6.82 (1H, s), 7.13 (1H, d), 7.82 (1H, d), 7.93 (1H, brd); MS m / z (ES ^&lt; ^{+ &gt;} ) 430 (MH &lt; ^{+ &gt;} ).

Compounds of formula XI which are listed in Table 21 were prepared according to Preparation 50 using the above precursors as starting materials.

107

Table 21

preparation

precursor

Data

Prípr. 45

δ _κ (CDCl ₃ , 400 MHz) 1.42 (9H, s), 2.86 (2H,

m), 3 07 (2H, m), 3.85 (3H, with) , 4.37 (2H, m), 4. 48 (2H, τη), 6.48 (2H, m), 6.79 (1 H, d), 6. 97 (1 H, d), 7.83 (1 H, d), 7.95 (1 H,

with) ; MS m / z (ES &lt; ^{+ &gt};) 446 (MH &lt; ^{+ &gt;} )

Prípr. 46

SMe _δ Η (CDCl, 400 MHz) 1.43 (9H, br s), 2.47 (3H, s), 2.88 (3H, br d), 3.90 (3H, s), 4.51 (2H , brd), 6.81 (1H, d), 6.91 (1H, d), 7.06 (1H, s), 7.20 (1H, d), 7.89 (1H, d), 7 .98 (1H, brd); MS m / z (TS ^&lt; ^{+ &gt;} ) 469 (MNH4 _& ^lt ; ^{+ &gt;} )

Prípr. 47

SMe

δ _Η (CDCl 3, 300 MHz) 1.47 (9H, brs), 2.46 (3H, s), 2.91 (3H, brs) 3.94 (3H, S), 4.52 (2H, brs), 6 78 (2H, m); 6, 91 (1 H, d), 7.35 (1 H, m), 7.92 (1H, d) .delta 02 (1H, brs); MS m / z (TS ⁺ ) 453 (MNH /)

Prípr. 48

SMe _δ Η (CDCl, 300 MHz) 1.44 (9H, s), 2.37 (3H, s), 2.47 (3H, s), 2.94 (3H, br), 3.90 (3 H s, 4.73 (2H, br), 6.79-6.87 (3H, m), 7.20 (1H, d), 7.86 (1H, d), 8.00 (1H, br); MS m / z (ES ^&lt; ^{+ &gt;} ) 454 (MNa ^&lt; ^{+ &gt;} )

Preparation

3 - {[(tert-butoxycarbonyl) (methyl) amino] methyl} -4- (2,3-dihydro-1-benzothien-5-yloxy) benzoic acid

A solution of the ester of Preparation 50 (970 mg, 2.26 mmol) in THF (20 mL) and 1M LiOH solution (20 mL) was refluxed for 16 h.

108 cooler. After cooling to room temperature, THF was evaporated in vacuo, the residue neutralized with saturated aqueous NH ₄ Cl solution, and the mixture was extracted with DCM (100 mL) followed by ether (100 mL). The combined organic layers were dried (MgSO ₄ ) and evaporated to give a white foam (960 mg) which was used without further purification; δ _Η (CDCl ₃ , 400 MHz) 1.30 (9H, s), 2.78 (3H, brs), 3.20 (2H, brs), 3.38 (2H, t), 4.41 (2H m), 6.62 (2H, m), 6.78 (1H, m), 7.10 (1H, m), 7.84 (1H, m), 7.99 (1H, m); MS m / z (ES -) 414 (MH +).

Compounds of formula XII which are listed in Table 22 were prepared according to Preparation 55 of the above precursors.

Table 22

preparation precursor ý from Data 56 Prípr. 51 δ _Η (CDCl 3, 400 MHz) 1.26 (9H, s), 2.74 (3H, s), 3.02 (2H, m), 4.31 (4H, m), 6.38 (2H, m, m), 6.64 (1H, d), 6.87 (1H, d), 7.68 (1H, brs), 7.78 (1H, brs); MS m / z (ES +) 430 (MH ⁺ ) 57 Pripr. 52 ý. SMe δ _Η (CDCl ₃ , 400 MHz) 1.44 (9H, brs), 2.49 (3H, s), 2.92 (3H, brd), 4.57 (2H, brd), 6.82 (1H d), 6.94 (1H, d), 7.08 (1H, s), 7.21 (1H, d), 7.97 (1H, d), 8.04 (1H, brd); MS m / z (ES +) 436 (MH ⁺ ) 58 Prípr. 53 ý SMe Δ (CDCl ₃ , 300 MHz) 1.46 (9H, brs), 2.49 (3H, s), 2.93 (3H, brs), 4.57 (2H, brs), 6.77 (2H m), 6.92 (1H, d), 7.32 (1H, t), 7.99 (1H, d), 8.08 (1H, brs); MS m / z (ES +) 42 0 (MH ⁺ )

109

Preparation 59 tert -Butyl 5- (aminocarbonyl) -2- (2,3-dihydro-1-benzothien-5-yloxy) benzyl (methyl) carbamate

To a solution of the acid of Preparation 55 (318 mg, 0.77 mmol) in

DCM (10 mL) was added Et ₃ N (267 µL, 1.92 mmol), HOBt-H ₂ O (129 mg, 0.84 mmol) and WSCDI (191 mg, 1.0 mmol) and the mixture was stirred for 1 h. h before adding a saturated solution of NH ₃ in THF (2 mL). After stirring an additional 16 h, the reaction mixture was diluted with water (50 mL), 0.2 M HCl solution (20 mL) and DCM (25 mL).

The organic layer was separated and the aqueous layer was extracted with DCM (25 mL). The combined organic layers were dried (MgSO ₄ ) and evaporated to give a white foam (predicted quantitative yield) which was used without further purification; δ _Η (CDC1 ₃ )

400 MHz) 1.44 (9H, s), 2.91 (3H, br), 3.27 (2H, t), 3.40 (2H, t), 4.54 (2H, br), 6.75-6.88 (1 H, m) 7.18 (1 H, d), 7.68 (1 H, d), 7.74 (1 H, with) .

Compounds of formula (XII) listed in Table 23 were prepared according to Preparation 59 of the above precursors.

110

(XIII)

Table 23

preparation

precursor

R ⁵

Data

Prípr.

δ _Η (CDCls, 400 MHz) 1.43 (8H, s), 2, 83 -3.00 (6H, m), 3.24 (2 H, t), 3.39 (2H, t), 4.51 (2H, brs), 6.70 6, 85 (3H, m), 7.15 (1 H, d), 7.62 (1 H, d), 7.68 (1 H, with)

Prípr. 55

δ _Η (CDCl 3, 400 MHz) 1.46 (9H, s), 2.89 (3H, br), 3.24 (2H, t), 3.373.43 (5H, m), 3.56 (2H, t), 3.63 (2H, m), 4.54 (2H, br), 6.46 (1H, br), (16.75-6.86 (3H, m), 7.16 (1H) d), 7.62 (1 H, d), 7.69 (1 H, s)

SMe _δ Η (d ₆ -DMSO, 400 MHz) 1.29 (9H, br), 2.40 (3H, s), 2.75 (3H, s), 4.39 (2H, s), 6. 78 (1H, d), 6.91 (2H, m), 7.23 (1H, br), 7.36 (1H, t), 7.78 (2H, m), 7.90 (1H, br) ); MS m / z (TS ⁺ ) 438 (MNH4 _& ^lt ; ^{+ &gt;} )

Prípr.

SMe δ _Η (CDCl ₃ , 400 MHz) 1.41 (9H, s),

2.40 (3H, s), 2.92 (3H, brs), 2.98 (3H, d), 4.45 (2H, brs), 6.10 (1H, brs), 6.67 (2H) m) 6.88 (1 H, d),

7.27 (1H, obs); 7.63 (2H, m); MS m / z (TS ⁺ ) 452 (MH +)

Prípr. 58

SMe δ _Η (CDCl 3, 400 MHz) 1.40 (9H, s),

2.40 (3H, s), 2.81 (3H, brs) , 3, 35 (3H, with) , 3.53 (2H, m), 3.61 (2H, m), 4.44 (2H, brs), 6 45 (1 H, br with) , 6.66 (2H, m), 6.87 (1 H, d), 7.29 (1 H, d), 7, 64 (1 H, d), 7.72 (1 H, s); MS m / z (TS ⁺ ) 479 (MH ⁺ )

lll

preparation precursor R ⁵ from Data 65 Prípr. 57 A ά, SMe Δ H (CDCl 3, 400 MHz) 1.43 (9H, brs), 2.47 (3H, s), 2.90 (3H, brd), 4.52 (2H, brs), 6.87 (1H, d) ), 6.91 (1H, d), 7.03 (1H, s), 7.10 (1H, d), 7.72 (1H, d), 7.78 (1H, s); MS m / z (ES &lt; ^{+ &gt};) 435 (MH &lt; ^{+ &gt;} ) 66 Prípr. 57 0 H X SMe δ _Η (CDCl 3, 400 MHz) 1.42 (9H, brs), 2.47 (3H, s), 2.88 (3H, brd), 3.0C (3H, d), 4.48 (2H, brs), 6.16 (1H, brd), 6.85 (2H, m), 7.01 (1H, s), 7.19 (1H, d), 7.67 (2H, m); MS m / z (ES ^- ) 449 (MH &lt; ^{+ &gt;} ) 67 Prípr. 56 á in δ _Η (CDCl 3, 400MHz) 1.42 (9H, s), 2.86 (3H, m), 3.08 (2H, m), 3.97 (2H, m), 4.48 (2H, brs ), 5.86-6.27 (2H, brs), 6.45 (1H, s), 6.49, (1H, d), 6.82 (1H, d), 6.96 (1H, d) ), 7.64 (1H, d), 7.71 (1H, s); MS m / z (TS ⁺ ) 331 (MH &lt; ^{+ &gt;} -Boc) 68 Prípr. 56 0 OMe "il δ _Η (CDCl 3, 400 MHz) 1.26 (9H, s), 2.74 (3H, s), 3.02 (2H, m), 4.31 (4H, m), 6.38 (2H, m, m), 6.64 (1 H, d), 6:87 (1 H, d), 7.68 (1 H, brs), 7.78 (1 H, brs); MS m / z (ES ^- ) 430 (MH &lt; ^{+ &gt;} )

Preparation 69 tert -Butyl 2- [3-chloro-4- (methylsulfanyl) phenoxy] -5- (hydroxymethyl) benzyl (methyl) carbamate

A solution of LiAlH ₄ in THF- (1M, 2 mL, 2 mmol) was added dropwise under nitrogen to the ester solution of Preparation 52 (452 mg,

112 mmol) in THF (10 mL). After analysis showed completion of the reaction, ether (10 mL) was added and excess LiAlH ₄ was quenched by careful addition of 2M NaOH solution. The organic layer was separated, washed with brine, dried (MgSO ₄ ) and evaporated to remove volatiles. Purification of the residue by column chromatography [SiO ₂ ; 39: 1 (DCM / MeOH)] gave the desired alcohol (200 mg, 47%) as a gummy white solid; δ _Η (CDCl ₃ , 400 MHz) 1.41 (9H, brs), 1.80 (1H, brs), 2.43 (3H, s), 2.81 (3H, brd), 4.42 (2H , brd), 4.66 (2H, s), 6.82 (1H, d), 6.88 (1H, d), 6.96 (1H, s), 7.16 (1H, d), 7 27 (2H, obs); MS m / z (ES ^&lt; ^{+ &gt;} ) 446 (MNa ^&lt; ^{+ &gt;} ).

Compounds of formula XIV shown in Table 24 were prepared according to Preparation 69 using the above precursors as starting materials.

Table 24

preparation precursor ý from Data 70 Prípr. 53 ú SMe δ _Η (CDCl ₃ , 400 MHz) 1.39 (9H, brs), 1.99 (1H, brs), 2.39 (3H, s), 2.78 (3H, brd), 4.39 ( 2H, br s), 4.62 (2H, d), 6.61 (2H, t), 6.88 (1H, d), 7.20-7.30 (3H, m + _CHCl3); MS m / z (TS ^&lt; ^{+ &gt;} ) 408 (MH &lt; ^{+ &gt;} ) 71 Prípr. 54 here SMe δ _Η (CDCl 3, 300 MHz) 1.45 (9H, s), 2.34 (3H, s), 2.46 (3H, s), 2.90 (3H, br), 4.49 (2H, s, s), 4.67 (2H, s), 6.72-6.81 (2H, m), 6.85 (1H, d), 7.18 (1H, d), 7.21-7 30 (2H, obs); MS m / z (TS ^&lt; ^{+ &gt;} ) 404 (MH &lt; ^{+ &gt;} )

113

Preparation 72 tert -Butyl 3 - {[(tert-butoxycarbonyl) (methyl) amino] methyl} -4- [3-methyl-4- (methylsulfanyl) phenoxy] benzyl (methylsulfonyl) carbamate

A solution of diethyl azodicarboxylate (505 μΐ, 3.21 mmol) in THF (5 mL) was added dropwise at 0 ° C to a solution of tert-butyl methylsulfonylcarbamate (synthesized according to Tetrahedron Lett. 1994, 35, 379- 380) (655 mg, 3.36 mmol), the alcohol of Preparation 71 (1.226 g, 3.04 mmol) and triphenylphosphine (880 mg, 3.36 mmol) in THF (15 mL). The reaction mixture was stirred at 0 ° C for 2 h, then diluted with EtOAc (80 mL) and washed with 10% aqueous K ₂ CO ₃ (100 mL). The organic layer was washed with brine, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography [SiO ₂ ; 1: 4 EtOAc: pentane] to give the title compound (1.406 g, 80% yield) as a colorless oil; δ _Η (CDCl ₃ , 300 MHz)

1.45 (8H, s), 1.52 (9H, s) 2.38 (3 H , with) , 2.44 (3H, s) 2.83 (3H, s) 3.22 (1 H, s), 4.49 (2H, with) , 4.85 (2H, s), 6.74-6.83 (3H, m), 7.18- -7.29 (3H, obs); MS m / z (TS ⁺ ) 481 (MH ⁺ -BOC).

Preparation 73 tert -Butyl 3 - {[(tert-butoxycarbonyl) (methyl) amino] methyl} -4- [3-fluoro-4- (methylsulfanyl) phenoxy] benzyl (methylsulfonyl) carbamate

114

The title compound was prepared from the alcohol of Preparation 70 by the method of Preparation 72; δ _Η (CDCl ₃ , 300 MHz) 1.44 (9H, s),

1.52 (8H, s), 2.44 (3 H, s) , 2.82 (3H, with) , 3.23 (3H, s), 4.45 (2H, s), 4.87 (2H, s), 6.61-6.70 (2H, m), 6.90 (1 H, d), 7,25- 7.33 (3 H, m); MS m / z (ES ^&lt; ^{+ &gt;} ) 607 (MNa ^{@ +} ).

Preparation 74 tert -Butyl 4 - [(dimethylamino) methyl] -3- [3-methyl-4- (methylsulfanyl) phenoxy] benzyl (methylsulfonyl) carbamate

The title compound was prepared from the alcohol of Example 59 by the method of Preparation 72. The crude product was not purified by column chromatography but used directly in the following:

step; δ _Η (CDCl ₃ , 400 MHz) 1.39 (9H, s), 2.22 (6H, s), 2.28 (3H, p 2.38 (3H, s), 3.07 (3H, s); with) , 3.42 (2H, s), 4.76 (2H, s), 6, 72 (2H, m), 6.79 (1H, s), 7.07 (1 H, d), 7.12 (1 H, d),

7.40 (1 H, obs).

115

Preparation 75 tert -Butylmethyl [2- [3-methyl-4- (methylsulfanyl) phenoxy] -5 - ({[(trifluoromethyl) sulfonyl] amino} methyl) benzyl] carbamate

The title compound was prepared from the alcohol of Preparation 71 by the method of Preparation 72 using trifluoromethanesulfonamide in place of tert-butylmethylsulfonylcarbamate. The desired product was contaminated with tert-butyl-5 - {{3 - {[(tert-butoxycarbonyl) (methyl) amino] (methyl} -4- [3-methyl 4- (methylsulfanyl) phenoxy] benzyl} [(trifluoromethyl) (sulfonyl) amino} methyl) -2- [3-methyl-4- (methylsulfanyl) phenoxy] benzyl (methyl) carbamate and used as a mixture; MS m / z (ES +) 533 (MH ⁺ ).

Compounds of formula (XV) listed in Table 25 were prepared according to Preparation 44 using the indicated precursors.

116

Table 25

preparation precursor from Data 76 Example 41 δ _Η (CDCl 3, 400 MHz) (main rotamer) 1.51 (9H, s), 2.92 (3H, s), 3.10 (2H, m), 4.40 (2H, m), 4, 52 (2H, br), 6.53 (2H, m), 6.81 (1H, m), 7.03 (1H, d), 7.97-8.21 (2H, m); MS m / z (TS ^&lt; ^{+ &gt;} ) 433 (MH &lt; ^{+ &gt;} ) 77 Example 40 δ _Η (CDCl ₃ , 300 MHz) 1.50 (9H, br), 2.99 (3H, s), 3.29 (2H, m), 3.43 (2H, m), 4.60 (2H , br), 6.81 (2H, m), 6.91 (1H, s), 7.22 (1H, d), 8.04 (1H, d), 8.21 (1H, br) 78 Example 42 5 _h (CDCl 3, 400 MHz) 1.56 (9H, s), 2.15 (2H, m), 2.85-3.00 (7H, m), 4.60 (2H, brd), 6, 78 (2H, m), 6.87 (1H, s), 7.12 (1H, d), 8.03 (1H, d), 8.10 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 399 (MH &lt; ^{+ &gt;} )

Preparation 79 tert -Butylmethyl {2- [3-methylsulfanyl) phenoxy] -5-nitrobenzyl} carbamate

N-Methyl-N- {2- [3-methyl-4- (methylsulfanyl) phenoxy] -5-nitrobenzyl} amine and {2- [3-methyl-4- (methylsulfanyl) phenoxy] -5-nitrophenyl} methanol

117

To a suspension of the aldehyde from Preparation 39 (21.0 g, 69.2 mmol) in EtOH (100 mL) was added an 8M solution of methylamine in EtOH (86.5 mL, 692 mmol). The solution was stirred for a short time and a precipitate was observed. This precipitate was redissolved by the addition of THF (100 mL), the solution was cooled to 0 ° C, then NaBH ₄ (7.85 g, 208 mmol) was added. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight before evaporating the solvent in vacuo. The residue was taken up in water (150 mL) and ether (150 mL) and 2M HCl solution was carefully added until pH 1. The layers were separated and the aqueous layer was washed with ether (2 x 100 mL). The combined organic extracts were dried and evaporated to give {2- [3-methyl-4- (methylsulfanyl) phenoxy] -5-nitrophenyl} methanol (18.9 g, 89% yield) as a yellow solid; δ _Η (CDCl ₃ , 400 MHz) 2.35 (3H, s), 2.48 (3H, s), 4.90 (2H, s), 6.79 (1H, d), 6.89 (1H s), 6.91 (1H, d), 7.22 (1H, d), 8.07 (1H, dd), 8.41 (1H, d).

The aqueous layer from the above product was neutralized by pouring to excess solid K ₂ CO ₃ . The basic solution was extracted with ether (2 x 100 mL), the obtained ether extracts were dried (MgSO ₄ ) and evaporated to give

N-methyl-N- {2- [3-methyl-4- (methylsulfanyl) phenoxy] -5-nitrobenzyl] amine (1.65 g, 7.5% yield) as a yellow oil; MS m / z (ES ^&lt; ^{+ &gt;} ) 319 (MH &lt; ^{+ &gt;} ).

N-Methyl-N- {2- [3-methyl-4- (methylsulfanyl) phenoxy] -5-nitrobenzyl} amine from {2- [3-methyl-4- (methylsulfanyl) phenoxy] -5-nitrophenyl} methanol

Methanesulfonyl chloride (4.81 mL, 61.9 mmol) was slowly added to a solution of {2- [3-methyl-4- (methylsulfanyl) phenoxy] -5

118

-nitrophenyl [methanol (18.9 g, 61.9 mmol) and Et ₃ N (9.5 mL, 68.2 mmol) in DCM (60 mL). The mixture was stirred at room temperature for 3 h, then poured into water and extracted with DCM (3 times). The combined organic extracts were dried (MgSO ₄ ) and evaporated to give a dark viscous oil. This oil was taken up in DCM (50 mL) and 8M solution of methylamine in EtOH (200 mL, 1.6 mol) was added followed by Et ₃ N (10 mL, 71.7 mmol). After stirring for 18 h, the mixture was concentrated in vacuo to give the crude amine, which was used without further purification.

tert -Butylmethyl {2- [3-methyl-4- (methylsulfanyl) phenoxy] -5-nitrobenzyl} carbamate

The crude amine from the above preparation was dissolved in DCM (100 mL) at 0 ° C and Et ₃ N (11.4 mL, 81.8 mmol) was added followed by di-tert-butyl dicarbonate (15.0 g, 68.7 mmol). ).

The reaction mixture was stirred for 16 h, allowed to warm to room temperature and then concentrated in vacuo. The residue was partitioned between EtOAc and water and the aqueous layer was extracted

EtOAc (2 times). The combined organic layers were dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (SiO ₂ ; 1st column 3% MeOH in DCM; 2nd column EtOAc / pentane 1: 3) to give the title compound (14.2 g, 54% yield) as a yellow oil; δ _H (CDCl ₃ , 400 MHz) 1.44 (9H, s), 2.32 (3H, s), 2.44 (3H, s), 2.95 (3H, s), 4.56 (2H) , br),

6.75 (1H, d), 6.84 (2H, m), 7.17 (1H, d), 8.00 (1H, d), 8.18 (1H, br); MS m / z (TS ^&lt; ^{+ &gt;} ) 419 (MH &lt; ^{+ &gt;} ).

Compounds of formula (XVI) listed in Table 26 were prepared as described in Example 103 from the above precursors.

119

(XVI)

Table 26

preparation precursor 'FROM from Data 80 Prípr. 77 δ _Η (CDCl 3, 300 MHz) 1.50 (9H, br), 2.80 (3H, br), 3.20 (2H, m), 2.37 (2H, m), 3.60 (2H, m, br), 4.40 (2H, s), 6.50-6.80 (5H, m), 7.05 (1H, d); MS m / z (ES ⁺ ) 387 (MH ⁺ ) 81 Pripr. 78 δ _Η (CDCl 3, 400 MHz) 1.42 (9H, s), 2.05 (2H, m), 2.80 (7H, m), 4.37 (2H, s), 6.50-6, 65 (3H, m), 6.69 (1H, s), 6.78 (1H, d), 7.08 (1H, d); MS m / z (TS ^&lt; ^{+ &gt;} ) 369 (MH &lt; ^{+ &gt;} ) 82 Prípr. 76 in δ _Η (CDCl 3, 400 MHz) 1.43 (9H, s), 2.88 (3H, br), 3.07 (2H, m), 3.59 (2H, br), 4.30 (2H, s), s), 4.36 (2H, m), 6.32 (1H, s), 6.40 (1H, d), 6.49-6.65 (2H, m), 6.75 (1H) H, d), 6.88 (1H, d); MS m / z (TS ^&lt; ^{+ &gt;} ) 403 (MH &lt; ^{+ &gt;} ) 83 Prípr. 79 SMe δ _Η (CDCl ₃ , 300 MHz) 1.47 (9H, s), 2.33 (3H, s), 2.40 (3H, s), 2.82 (3H, br), 3.60 (2H , s), 4.35 (2H, s), 6.50-6.77 (4H, m), 6.80 (1H, d), 7.16 (1H, d), MS m / z (TS ⁺⁾ 389 (MH)

Preparation 84 tert -Butylmethyl {2- [3-methyl-4- (methylsulfanyl) phenoxy] -5 - [(methylsulfonyl) amino] benzyl] carbamate

120

Methanesulfonyl chloride (4.16 mL, 53.7 mmol) was added dropwise at 0 ° C to a solution of the aniline of Preparation 83 (9.5 g, 24.5 mmol) and Et ₃ N (7.5 mL, 53.8 mmol). mmol) in DCM (50 mL). After 3 0 min. After stirring at 0 ° C, the reaction mixture was allowed to warm to room temperature and then the solvent was evaporated in vacuo. 2M NaOH solution (50 mL) was added to the residue and the mixture was stirred for 30 min. The mixture was extracted with EtOAc and the organic layer was washed with brine, dried (MgSO ₄ ) and evaporated to give an oil. Purification by column chromatography [SiO ₂ ; 97.5: 2.5: 0.25 (DCM / MeOH / OH / 880 NH ₃ )] gave the desired product (9.0 g, 79% yield) as a brown foam; δ _Η (CDCl ₃ , 300 MHz) 1.43 (9H, brs), 2.35 (3H, s), 2.42 (3H, s), 2.88 (3H, brs), 3.01 (3H, s) , s), 4.46 (2H, brs), 6.76 (2H, d + s), 6.83 (1H, d), 7.16 (1H, s), 7.20 (2H, brs) ; MS m / z (ES ^&lt; ^{+ &gt;} ) 467 (MH &lt; ^{+ &gt;} ).

compounds of of formula XVII, which are listed in Table 27, with prepared by preparations 84 of listed precursors.

121

Table 27

preparation precursor ý. from Data 85 Pripr. 81 D δ _Η (CDCl ₃ , 400 MHz) (rotamers) 1.44 and 1.48 (9H, 2xs), 2.10 (2H, quintet), 2.88 (7H, m), 3.00 (3H, s ), 4.49 (2H, br), 6.23 (1H, br), 6.72 (1H, d), 6.81 (1H, s), 6.83 (1H, d), 7.13 (3 H, m); MS m / z (TS +) 347 (MH + -Boc) 86 Prípr. 80 The product was used without purification 87 Pripr. 82 δ _Η (CDCl ₃ , 400 MHz) (rotamers) 1.40 and 1.44 (9H, 2xs), 2.80 and 2.85 (3H, 2xs), 2.95 (3H, s), 3.07 (2H, m), 4.38 (2H, m), 6.36 (1H, s), 6.44 (1H, d), 6.84 (1H, d), 6.92 (1H) H, d), 7.12 (2 H, m); MS m / z (TS &lt; + &gt;) 498 (MNH &_lt; _{4 &gt};)

Preparation 88 tert -Butylmethyl {2- [3-methyl-4- (methylsulfanyl) phenoxy] -5- [methyl (methylsulfonyl) amino] benzyl} carbamate

To a mixture of the sulfonamide of Preparation 84 (2.0 g, 4.3 mmol) and K ₂ CO ₃ (592 mg, 4.3 mmol) in CH ₃ CN (10 mL) was added Mel (1.07) dropwise under nitrogen. ml, 17.2 mmol). The mixture was stirred for 16 h and then partitioned between EtOAc (50 mL) and 2M

122 NaOH solution (50 mL). The organic layer was washed with brine, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography [SiO ₂ ; 590: 10: 1 (DCM / MeOH / 880 NH ₃ )] to give the desired product (1.23 g, 60% yield) as a yellow oil; δ _Η (CDCl ₃ , 300 MHz) 1.45 (9H, s), 2.34 (3H, s), 2.42 (3H, s), 2.86 (3H, s), 2.90 (3H, s) s), 3.28 (3H, s), 4.49 (2H, s), 6.80 (3H, br), 7.18 (3H, m); MS m / z (TS ^&lt; ^{+ &gt;} ) 498 (MNH4 _& ^lt ; ^{+ &gt;} ).

Preparation 89 tert -Butyl 5 - [(2-hydroxyethyl) (methylsulfonyl) amino] -2- [3-methyl-4- (methylsulfanyl) phenoxy] benzyl (methyl) carbamate

2-Bromoethanol (1.34 mL, 18.9 mmol) was added under nitrogen to a mixture of sulfonamide of Preparation 84 (2.0 g, 4.3 mmol) and K ₂ CO ₃ (2.605 g, 18.8 mmol) in CH ₃ CN (10 mL). The mixture was refluxed for 16 h, cooled and then partitioned between EtOAc (50 mL) and 2M NaOH solution (50 mL). The organic layer was washed with brine, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography [SiO ₂ ; 390: 10: 1 (DCM / MeOH / 880 NH ₃ )] to give the desired product (524 mg, 24% yield) as a pink foam; δ _Η (CDCl ₃ , 300 MHz) 1.42 (9H, s), 2.37 (3H, s), 2.43 (3H, s), 2.91 (3H, s), 2.98 (3H) s), 3.68 (2H, brs), 3.79 (2H, d), 4.49 (2H, s), 6.81 (3H, m); MS m / z (TS ^&lt; ^{+ &gt;} ) 528 (MNH4 _& ^lt ; ^{+ &gt;} ).

123

Preparation

5-Amino-2- (2,3-dihydro-1,4-benzoxatin-6-yloxy) benzonitrile

Iron powder (930 mg, 16.7 mmol) was added to the nitro compound of Preparation 41 (740 mg, 2.38 mmol) in AcOH (5 mL) and water (1 mL), and the mixture was stirred at room temperature for 16 h. The solvent was evaporated in vacuo, the residue taken up in EtOAc (50 mL) and 10% aqueous K ₂ CO ₃ solution (50 mL) and filtered through Arbocel. The organic layer was separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic extracts were dried (MgSO ₄ ) and evaporated to give a brown foam (670 mg, 99% yield) which was used without further purification; δ _Η (CDCl ₃ , 400 MHz) 3.18 (2H, m), 4.36 (2H, m),

6.60-6.70 (2H, m), 6.70-6.80 (3H, m), 6.85 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 302 (MNH4 _& ^lt ; ^{+ &gt;} ).

Compounds of formula Vb, i.e. compounds of formula V, wherein T is cyano, R ⁴ is hydrogen and R ⁵ is amino, as shown in Table 28, were prepared according to Preparation 90 of the above precursors.

124

(Vb)

Table 28

preparation precursor from Data 91 Prípr. 35 δ _Η (CDCl 3, 400MHz) 2.40 (3H, s), 6.62-6.72 (2H, m), 6.80-6.90 (3H, m), 7.28 (1H, d) 92 Prípr. 37 ψ, SMe δ _κ (CDCl 3, 300 MHz) 2.47 (3H, s), 3.83 (2H, br), 6.83-6.94 (4H, m), 7.01 (1H, S), 7, 19 (1 H, d); MS m / z (TS ⁺ ) 308 (MH +) 93 Prípr. 42 SMe δ _Η (CDCl ₃ , 400MHz) 2.30 (3H, s), 2.40 (3H, s), 3.84 (2H, br), 6.77 (4H, m), 6.85 (1H, s), 7.13 (3H, d); MS m / z (TS ⁺ ) 288 (MH +)

Preparation

5-Amino-2- [4-methyl-3- (methylsulfanyl) phenoxy] benzonitrile

Me

125

The title compound was prepared from the nitro compound of

Preparation 43 by the method of Example 103; δ _Η (CDC1 ₃ , 400 MHz) 2.27 (3H, s) 2.41 (3H, s) 3.66 (2H, (br), 6 , 62 (1 H, d), 6.79 (2H, s), 6.82 (1 H, s), 6, 89 (1 H, s) , 7.08 (1 H, d), ; MS m / z (ES ⁺ )

293 (MNa ^{@ +} ), (ES @ ⁺ ) 269 (MH ^{@ +} ).

Compounds of formula Vc, i.e. compounds of formula V, wherein T is cyano, R ⁴ is hydrogen and R ⁵ is -NHSO ₂ Me listed in Table 29, were prepared according to Preparation 84 of the above precursors.

Table 29

preparation precursor about, from Data 95 Pripr. 90 δ _Η (CDCl ₃ , 400 MHz) 2.98 (3H, s), 3.10 (2H, m), 4.39 (2H, m), 6.67 (1H, dd), (1H, s) 6.81 (1H, d), 7.33 (1H, 6.76, dd), 7.49 (1H, s); MS m / z (TS ^&lt; ^{+ &gt;} ) 380 (MNH _& ^lt ; ₄ ^&gt; ) 96 Pripr. 92 d. SMe δ _Η (CDCl ₃ , 300 MHz) 2.51 (3H, s), 3.6'6 '(3H, s), 6.52 (1H, br), 6.92 (1H, d), 7, O 2 (1H, dd), 7.14 (1H, d), 7.24 (1H, d), 7.41 (1H, dd), 7.57 (1H, d); MS m / z (ES ^&lt; ^{+ &gt};) 391 (MNa ^&lt; ^{+ &gt;} ) 97 Pripr. 91 d. SMe δ _Η (CDCl ₃ , 400 MHz) 2.43 (3H, s), 3.02 (3h, S), 6.41 (1H, brs), 6.72-6.85 (2H, m), 6 92 (1H, d), 7.28 (1H, t), 7.38 (1H, d), 7.51 (1H, s); MS m / z (ES &lt; ^{+ &gt};) 351 (MH &lt; ^{+ &gt;} )

126

preparation precursor Ψ-. from Data 98 Prípr. 93 about- SMe δ _Η (CDCl 3, 400 MHz) 2.19 (3H, s), 2.42 (3H, S), 2.99 (3H, s), 6.81 (1H, d), 6.86 ( 2H, m), 7.15 (1H, d), 7.33 (1H, d), 7.51 (1H, S); MS m / z (TS ^&lt; ^{+ &gt;} ) 366 (MNHJ) 99 Prípr. 94 Me δ _Η (CDCl 3, 400MHz) 2.31 (3H, s), 2.43 (3H, s), 3.02 (3H, s), 6.61 (1H, s), 6.72 (1H, dd) 6.83 (1H, d), 6.88 (1H, S), 7.17 (1H, d), 7.37 (1H, dd), 7.55 (1H, s); MS m / z (TS ⁺ ) 366 (MH +)

100 ALIGN!

N- {3-Cyano-4- [3-methyl-4- (methylsulfanyl) -phenoxy] phenyl} -N-methylmethanesulfonamide

The title compound was prepared from the sulfonamide of

preparation 98 way of preparation 88; δ _Η (CDC1 ₃ ) 400 MHz) 2.31 (3H, s) 2.44 (3 H, s), 2.83 (3H, with) , 3.27 (3 H, with) , 6.79 (1 H, d), 6.88 (2H, m) 7.17 (1 H, d), 7.44 (1 H, dd), 7.58 (1 H, d);

MS m / z (ES ⁺ ) 385 (MNa ⁺ ).

127

Preparation

1,3-dihydro-2-benzothiophen-5-ol

OH

(i) Preparation of [4- (allyloxy) -2- (hydroxymethyl) phenyl] methanol

Dimethyl 4- (allyloxy) phthalate [prepared according to Inouy, M .;

Tsuchiya, K .; Kitao, T. Angew. Chem. 1992, 104, p. 198 to

200 (see also Angew. Chem., Int. Ed. Engl, 1992, pp. 204-205)] (9.9 g, 38 mmol) was dissolved in THF (40 mL) and cooled to 0 ° C as lithium aluminum hydride (1M in THF, 77 mL, 77 mmol) was added dropwise over 10 min. The mixture was then allowed to stir at room temperature for 3 h and then quenched by carefully adding water (1.4 mL) followed by 2M NaOH solution (1.4 mL). Excess MgSO ₄ was added and water was added until a precipitate formed (approximately 5 mL). The resulting mixture was then filtered and evaporated to give a brown oil (7.1 g, approximately 95% yield). ¹ H NMR confirmed the material to be approximately 85% pure. Thus, the obtained material was used directly in the next step without further purification; δ _Η (CDCl ₃ , 400 MHz) 2.63 (1H, brs), 2.91 (1H, brs), 4.52 (2H, m), 4.67 (4H, m), 5.26 (1H (dd), 5.38 (1H, dd), 5.97-6.09 (1H, m), 6.80 (1H, dd), 6.92 (1H, d), 7.22 (1H, d).

(ii) Preparation of 5- (allyloxy) -1,3-dihydro-2-benzothiophene

The crude diol from step (i) (3.5 g, 18 mmol) was dissolved in

DCM (60 mL) and treated with Et ₃ N (10 mL, 72 mmol) and the resulting solution

128 was cooled to 0 ° C. Methanesulfonyl chloride (4.2 mL, 54 mmol) was added dropwise and the solution was stirred for 1 h while allowing to reach room temperature. The reaction was then quenched by the addition of water followed by 2M HCl solution (50 mL). DCM The layer was separated and the aqueous layer was re-extracted with DCM (50 mL). The combined organic fractions were washed with water (50 mL), dried (MgSO ₄ ) and concentrated to approximately 30 mL. Benzyltriethylammonium chloride (1 g) and a solution of sodium sulfate (5 g, 91 mmol) in water (50 mL) were added. The resulting mixture was stirred rapidly under stirring for 15 h. The organic layer was separated and the aqueous layer was re-extracted with DCM (50 mL). The combined organic layers were dried (MgSO ₄ ) and evaporated to give a yellow oil. Flash chromatography gave two fractions; the first was a pure product and the second was contaminated with dimeric material. Trituration of the second fraction caused crystallization of the dimeric material which was removed by filtration. The filtrate was combined with the first chromatographic fraction to give the desired product (800 mg, 23% yield); δ _Η (CDCl ₃ , 400 MHz) 4.16 (2H, s), 4.19 (2H, s), 4.48 (2H, m), 5.26 (1H, d), 5.37 (1H d), 5.95-6.06 (1H, m), 6.74 (2H, m), 7.09 (1H, d).

(iii) Preparation of 1,3-dihydro-2-benzothiophen-5-ol

The allyl ether from step (ii) (800 mg, 4.16 mmol) was dissolved in THF (10 mL) and treated with tetrakis (triphenylphosphine) palladium (481 mg, 0.42 mmol) followed by sodium borohydride (944 mg, 25 mmol). ). The resulting mixture was then heated to 45 ° C and stirred at this temperature for 15 h. After cooling to room temperature, THF was evaporated and the residue was partitioned between 2M NaOH solution (25 mL) and diethyl ether (25 mL). The aqueous layer was separated and the organic layer re-extracted with 2M NaOH solution (25 mL). Merged water

The 129 layers were neutralized to pH 7-8 by addition of concentrated hydrochloric acid and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried (MgSO ₄ ) and evaporated to give the title phenol as a clear oil which solidified on standing (540 mg, 85% yield); 4.14 (2H, s), 4.17 (2H, s), 6.63-6.68 (2H, m), 7.04 (1H, d).

Biological Activity

For a number of compounds, biological activity was tested for their ability to inhibit serotonin uptake by human serotonin transporters as follows.

(i) Cell culture

Human embryo kidney cells (HEK-293) stably transfected with either human serotonin transporter (hSERT), human noradrenaline transporter (hNET) or human dopamine transporter (hDAT) were cultured using standard cell culture techniques (cells were grown at 37 ° C and at 5 ° C). % CO ₂ concentration in DMEM-culture medium (enriched with 10% dialyzed fetal calf serum (FCS), 2 mM 1-glutamine and 250 µg / ml geneticin)). Cells were harvested for analysis at a cell suspension yield of 750,000 cells / ml.

(i) Determination of inhibitor potency

All test compounds were dissolved in 100% DMSO and diluted with assay buffer to give appropriate test concentrations. Assays were performed in 96-well filter bottom plates. wells

130 (7500 cells / well) were preincubated in standard assay buffer containing either test compound, standard inhibitor or vehicle only (1% DMSO) for 5 min. Reactions were initiated by the addition of ³ H-serotonin, ³ H-noradrenaline or ³ Hdopamine substrate. All reactions were carried out at room temperature in a shaking incubator. The incubation time was 5 min for hSERT and hDAT assays and 15 min for hNET assay. The reaction was terminated by isolating the reaction mixture using a vacuum line followed by rapid flushing with ice-cold assay buffer. Subsequently, the amount of ³ H-substrate incorporated into the cells was determined.

The test plates were dried in a microwave oven, scintillation fluid was added, and radioactivity was measured. The potency of the test compound was quantified as IC ₅₀ values (the test compound concentration required for 50% inhibition of the specific uptake of the radiolabeled substrate in the cells).

(iii) Composition of standard assay buffer

Trizma hydrochloride (26 mM)

NaCl (124 mM)

KCl (4.5 mM)

KH ₂ PO ₄ (1.2 mM)

MgCl ₂ -6H ₂ O (1.3 mM)

Ascorbic acid (1.136 mM)

Glucose (5.55 mM) pH 7.40

CaCl ₂ (2.8 mM)

Pargyline (100 μΜ)

131

Note: The pH of the buffer was adjusted to 7.40 by addition

1M NaOH solution before adding CaCl ₂ and pargyline.

(iv) Summary of test parameters

hSERT test hDAT test hNET test Concentration of cells per well 75 000 75 000 75 000 Substrate concentration ³ H-5HT (50 nm) ³ H-Dopamine (200 nm) ³ H-Noradrenaline (200 nM) Incubation period (Min) 5 5 5

Compounds having IC ₅₀ serotonin re-uptake inhibition (SRI) values less than or equal to 100 nM include the title compounds of Examples 1 to 6, 8 to 23, 25, 26, 29 to 32, 34 to 36, 43, 45 to 49, 51, 56 to 102, 109 to 130.

Compounds that exhibit IC ₅₀ serotonin re-uptake inhibition (SRI) values less than or equal to 100 nM and which are more than 10 times more potent in inhibiting serotonin re-uptake than in inhibiting dopamine re-uptake or norepinephrine reuptake include the title Examples 1 to 6, 9 to 13, 16 to 19, 21, 22, 25, 26, 29 to 32, 34 to 36, 43, 45, 47 to 49, 51, 57 to 88, 90 to 102, 109 to 121, 123, 124, 127, 129.

Among compounds that exhibit IC ₅₀ values of serotonin re-uptake inhibition (SRI) less than or equal to 100 nM and which are more than 100 times more potent in inhibiting serotonin re-uptake than in inhibiting dopamine re-uptake or noradrenaline re-uptake, Include the title compounds of Examples 1, 2, 4, 5, 9, 12, 13, 16-19, 21, 22, 25, 26, 29

132 to 32, 34 to 36, 43, 45, 48, 49, 58 to 80, 83 to 88, 90, 92 to 97, 99 to 102, 111 to 113, 115 to 118, 120, 123, 124, 127.

Among compounds that exhibit IC ₅₀ serotonin re-uptake inhibition (SRI) values less than or equal to 50 nM and which are more than 100 times more potent in inhibiting serotonin re-uptake than in inhibiting dopamine re-uptake or noradrenaline re-uptake, Include the title compounds of Examples 1, 2, 4, 9, 12, 17, 18, 26, 29, 30, 36, 43, 45, 48, 49, 60 to 66, 68 to 75, 78, 79, 90, 92 to 94, 100, 102, 116, 118, 124.

In particular, the title compound of Example 16 showed an IC ₅₀ inhibition of serotonin (SRI) re-uptake of 4.7 nM; the title compound of Example 29 showed an IC ₅₀ inhibition of serotonin (SRI) re-uptake of 2.0 nM; and the title compound of Example 62 showed an IC ₅₀ inhibition of serotonin (SRI) re-uptake of 3.7 nM.

Claims (31)

PATENT CLAIMS A compound of formula I, pharmaceutically acceptable salts or solvates thereof, or polymorphs thereof; (I) where R ¹ and R ² , which may be the same or different, represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or (CH ₂ ) d (C ₃ -C ₆ cycloalkyl), wherein d represents 0, 1, 2 or 3; or R ¹ and R ² together with the nitrogen atom to which they are attached represent an azetidine ring; Z or Y is -SR ³ and the other of Z or Y is halogen or -R ³ ; wherein R ³ is independently C 1 -C 4 alkyl optionally substituted with fluoro; with the exception that R ^{3 is} not CF ₃ ; or Z and Y are joined to form a fused 5- to 7-membered carbocyclic or heterocyclic ring, which may be saturated, unsaturated or aromatic, with the interconnecting atoms and where, when Z and Y form a heterocyclic ring, the bond contains one or two carbon atoms in addition to the carbon atoms heteroatoms independently selected from oxygen, sulfur and nitrogen provided that: 134 that when R ⁵ represents a fluorine atom and R ² represents a methyl group, then the fused ring is not 1,3-dioxolane and Z and Y together do not form a fused phenyl ring; R ⁴ and R ⁵ , which may be the same or different, mean: AX wherein A is -CH = CH- or - (CH ₂ ) _p - wherein p is 0, 1 or 2; X is hydrogen, fluorine, chlorine, bromine, iodine, CONR ⁶ R ⁷ , SO ² NR ⁶ R ⁷ , SO 2 NHC (= O) R ⁶ , hydroxy, C 1 -C 4 alkoxy, NR ⁸ SO ² R ⁹ , NO 2, NR ¹¹ , CN, CO ₂ R ¹⁰ , CHO, SR ¹⁰ , S (O) R ⁹ or SO ² R ¹⁰ ; R ⁶ , R ⁷ , R ⁸ and R ¹⁰ , which may be the same or different, represent a hydrogen atom or a C 1-6 alkyl group optionally independently substituted with one or more R ^{12 's} ; R ⁹ is C 1 -C 6 alkyl optionally independently substituted with one or more R ^{12 's} ; R ¹¹ represents a hydrogen atom, a C 1 -C 6 alkyl group optionally independently substituted with one or more R ¹² , C (O) R ⁶ , CO ² R ⁹ , C (O) NHR ⁶ or SO ₂ NR ⁶ R ⁷ ; R ¹² is fluoro (preferably up to 3), OH, CO ₂ H, C 3 -C 6 cycloalkyl, NH ₂ , CONH ₂ , C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl or 5-membered or a six-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from nitrogen, sulfur and oxygen, optionally independently substituted with one or more R ¹³ ; or R ⁶ and R ^{7 taken} together with the nitrogen atom to which they are attached form a four, five or six membered heterocyclic ring optionally independently substituted with one or more R ¹³ ; or 135 a five or six membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from nitrogen, sulfur, and oxygen optionally independently substituted with one or more R ¹³ ; wherein R ¹³ is hydroxy, C 1 -C 4 alkoxy, fluoro, C 1 -C 6 alkyl, haloalkyl, haloalkoxy, -NH ₂ , -NH (C 1 -C 6 alkyl) or -N (C 1 -C 6 alkyl) ₂ . A compound according to claim 1, pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein R ¹ and R ² , which may be the same or different, represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. A compound according to claim 1 or 2, pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein when Z or Y represents -SR ³ , then R ³ represents a methyl group or an ethyl group. A compound according to claim 1 or 2, pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein when Z and Y are attached to form a fused ring, the ring is a heterocyclic ring. ^{5 * *} A compound according to claim 4, pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein the bond contains one or two sulfur atoms in addition to the carbon atoms. 136 G. A compound according to any one of the preceding claims, pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein R ^p and R ^7, which may be the same or different, are H, alkyl having 1 to 3 carbon atoms optionally substituted by hydroxy, - CONH ₂ or (C 1 -C 3) alkoxy. A compound according to any one of the preceding claims, pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein R ⁸ represents a hydrogen atom, a hydroxyethyl group or a methyl group. A compound according to any one of the preceding claims, pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein R ⁹ represents a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group or a methoxyethyl group. A compound according to any one of the preceding claims, pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein p is 1 or 0. A compound according to any one of the preceding claims, pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein R ⁴ and R ⁵ , which may be the same or different, represent - (CH ₂ ) _p -X, wherein p is 0, 1 or 2; X is H, OH, CONR ^with R ^7, SO 2 NR ^e R ^7, NR ⁸ SO 2 R ^9, SR ^10, SOR ⁹ or SO ₂ R ^10, wherein R ^6, R ^7, R ^8, R ⁹ and R ¹⁰ have the same as defined in claim 1, or 137 a heterocyclic ring containing 1, selected from nitrogen, sulfur, 5- or 6-membered 2 or 3 heteroatoms and an oxygen atom. A compound according to claims, pharmaceutically acceptable polymorphs thereof, wherein R ⁴ and R ⁵ , which may be: any of the foregoing salts, solvates or the same or different, - (CH ₂ ) _p -X, wherein p is 0 or 1; X is hydroxy, CONR ⁶ R ⁷ , SO ₂ NR ⁶ R ⁷ R ⁷ , which may be the same or different, is hydrogen or a C 1 -C 3 alkyl group optionally substituted by a hydroxy group, a C 1 -C 3 alkoxy group, preferably a methoxy group; R ⁸ represents a hydrogen atom, a hydroxyethyl group or a methyl group; or R ⁹ represents a hydrogen atom, or NR ⁸ SO ₂ R ⁹ ; wherein R ^6a represents a carbon atom -CONH ₂ or methyl, ethyl, trifluoromethyl or isopropyl methoxyethyl,; or a triazolyl group, an imidazolyl lyl group. group or pyrazo- A compound according to any one of the preceding claims, pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein R ⁴ and R ⁵ do not simultaneously represent a hydrogen atom. A compound according to any one of the preceding claims, pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein R ⁴ is a hydrogen atom. 138 A compound according to claim 1, pharmaceutically acceptable salts, solvates or polymorphs thereof, selected from the group consisting of: 4- (2,3-dihydro-1-benzothien-5-yloxy) -3 - [(methylamino) methyl] benzenesulfonamide (Example 2); 3 - [(dimethylamino) methyl] -4- [3-methyl-4- (methylsulfanyl) phenoxy] benzenesulfonamide (Example 12); 4- (2,3-dihydro-1-benzothien-5-yloxy) -3 - [(dimethylamino) methyl] benzenesulfonamide (Example 16); 4- [3-chloro-4- (methylsulfanyl) phenoxy] -3 - [(dimethylamino) methyl] benzenesulfonamide (Example 17); 3 - [(dimethylamino) methyl] -4- [3-fluoro-4- (methylsulfanyl) phenoxy] benzenesulfonamide (Example 18); N, N -dimethyl-N- [2- (6-quinolinyloxy) benzyl] amine (Example 29); 3 - [(methylamino) methyl] -4- (6-quinolinyloxy) benzenesulfonamide (Example 35); 4- (2,3-dihydro-1-benzothien-5-yloxy) -3 - [(methylamino) methyl] benzamide (Example 60); 4- (2,3-dihydro-1-benzothien-5-yloxy) -2H-methyl-3 - [(methylamino) methyl] benzamide (Example 62); N- {3 - [(methylamino) methyl] 4- [3-methyl-4- (methylsulfanyl) phenoxy] benzyl] methanesulfonamide (Example 75); 3 - [(methylamino) methyl] -4- [3-methyl-4- (methylsulfanyl) phenoxy] benzamide (Example 79); 139 4- (2,3-dihydro-1,4-benzoxathin-7-yloxy) -3 - [(dimethylamino) methyl] benzamide (Example 88); {3 - [(dimethylamino) methyl] -4- [3-fluoro-4- (methylsulfanyl) phenoxy] phenyl} methanol (Example 90); 3 - [(dimethylamino) methyl] -4- (6-quinolinyloxy) benzamide (Example 100); 3 - [(methylamino) methyl] -4- (6-quinolinyloxy) benzamide (Example 102); N-methyl-N- {3 - [(methylamino) methyl] -4- [3-methyl-4- (methylsulfanyl) phenoxy] phenyl] methanesulfonamide (Example 116); and N- (4- (2,3-dihydro-1,4-benzoxathiin-7-yloxy) -3 - [(dimethylamino) methyl] phenyl} methanesulfonamide (Example 124). A compound according to any preceding claim, pharmaceutically acceptable salts, solvates or polymorphs thereof for use as a medicament. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate or polymorph thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier. Use of a compound according to any one of claims 1 to 14, pharmaceutically acceptable salts, solvates or polymorphs thereof in the manufacture of a medicament for the treatment or prevention of a disorder implicated in the regulation of monoamine transporter function. 140 Use according to claim 17, wherein the disorder is depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance-related disorder and sexual dysfunction. The use of claim 18, wherein the disorder is premature ejection. A method of treating or preventing a disorder implied by regulating the function of a monoamine transporter, comprising administering to a patient in need of such treatment or prevention an effective amount of a compound according to any one of claims 1 to 14, a pharmaceutically acceptable salt, solvate or polymorph thereof. She needs. 21. A method of treating or preventing premature ejaculation comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 14, pharmaceutically acceptable salts, solvates or polymorphs thereof. A method of increasing ejaculatory latency, comprising administering to a male in need thereof an effective amount of a compound according to any one of claims 1 to 14, a pharmaceutically acceptable salt, solvate or polymorph thereof, in need thereof. 141 A process for preparing a compound of formula I; wherein R ^1, R ^2, R ^4, R ^5, X and Z have the same meanings as in claims 1 to 14, characterized in that it comprises reacting a compound of formula Ia under suitable reaction conditions to form a compound of formula I, wherein suitable reaction conditions are understood to mean: i) when R ⁴ / R ⁵ is halogen, the reaction of compound Ia with a suitable halogenating agent in an inert solvent which does not adversely affect the reaction; (ii) where R ⁴ / R ⁵ is -NO ₂ , the reaction of Ia with a suitable nitrating agent in an inert solvent which does not adversely affect 142 reaction at room temperature or below; or ii) when R ⁴ / R ⁵ is -SO ₂ NR ⁶ R ⁷ , then reacting the intermediate sulfonyl chloride with the desired amine HNR ⁶ R ⁷ in a suitable solvent. A process according to claim 23 for the preparation of a compound of formula Iq, that is, wherein R ⁵ represents -SO ₂ NR ⁶ R ⁷ and R ⁴ represents a hydrogen atom, characterized in that it comprises a) reacting a compound of formula Ia, optionally in a suitable solvent, with chlorosulfonic acid to form a compound of formula XVIII, and then 143 b) reacting the obtained intermediate of formula XVIII with HNR ⁶ R ⁷ to give a compound of formula Iq. A process according to claim 24, wherein the formula (XVIII) is generated in situ and reacted with HNR ⁶ R ⁷ without isolation. A method according to any one of claims 23 to 23 25, further comprising the step of preparing a compound by reacting the compound of Formula Ia, a compound of the general salt together with a hydride of a suitable solvent to form HNR ¹ R ² or a reducing agent in the compound of Formula Ia. 27. An intermediate of the formula Or of the general formula XVIII according to claims 23 to 26, provided that Intermediate IIa is not methylenedioxy) phenoxybenzaldehyde. 144 A process for the preparation of compounds of formula I wherein R ¹ , the claims of the compounds R ^2, R ^4, R ^5, X are 1 to 14, characterized in that it has the same meaning as in reacting with a compound of the formula HNR ¹ R ² or a suitable salt thereof, together with a hydride reducing agent in a suitable solvent. 29. The process of claim 28, further comprising reacting with a compound of formula III under suitable reaction conditions 145 ((Η)) wherein L represents a suitable leaving group such as a halogen atom or a sulfonate ester such as trifluoromethanesulfonate or methanesulfonate with a compound of formula IV HO, (IV) to give a compound of formula II. The intermediate of formula II according to claim 28, provided that the intermediate of formula II is not 2 - ((3 ', 4'-methylenedioxy) phenoxy) benzaldehyde or 2 - ((3', 4'-methylenedioxy) phenoxy) -5 fluoro-benzaldehyde. A compound of formula I, or a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein R ¹ , R ² , Y and Z have the same meanings as in claim 1; and R ⁴ and R ⁵ , which may be the same or different, represent - (CH ₂ ) _p -A ', wherein p represents 0, 1 or 2 and A' represents a polar group. The compound of claim 23, wherein the polar moiety has a greater negative value than -0.1.