BG107544A - Phenoxybenzylamine derivatives as selective serotonin re-uptake inhibitors - Google Patents

Abstract

A compound of general formula wherein R1 and R2 are H, C1-C6 alkyl or (CH2)d(C3-C6 cycloalkyl) wherein d = 0, 1, 2 or 3; or R1 and R2 together with the nitrogen to which they are attached from the azetidine ring; Z or Y is -SR3 and other Z or Y is halogen or -R3; wherein R3 is C1-C4 alkyl optionally substituted with fluorine; except that R3 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 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; R4 and R5, which may be the same or different, are: A-X, wherein A =-CH=CH- or -(CH2)p- where p is 0, 1 is 2; X is hydrogen, F, Br, I, CONR6R7, SO2NR6R7, SO2NHC(=O)R6, OH, C1-4 alkoxy, NR8SO2R9, NO2, NR6R11, CN, CO2R10, CHO, SR10, S(O)R9 or SO2R10; or a 5- or 6-membered heterocyclic ring containing 1, 2or 3 heteroatoms selected from N, S and O, optionally substituted independently from one or more R13; wherein R13 is hydroxy, C1-C4 alkoxy, F, C1-C6 alkyl, haloalkyl, haloalkoxy, -NH2, NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2. The compounds of general formula (I) inhibit monoamine reuptake and in particular exhibit activity as selective serotonin reuptake inhibitors. 32 claims

Description

Technical field

This invention relates to novel diphenyl ether compounds that inhibit monoamine reuptake. In particular, the compounds of the present invention exhibit activity as selective serotonin reuptake inhibitors (SSRTs) and are therefore useful in a variety of therapeutic areas. The compounds of the present invention are particularly useful in the treatment or prevention of a wide variety of disorders, including those that are affected by the regulation of monoamine transport function, such as depression, hyperactive attention deficit disorder, obsessive # compulsive disorder, post-traumatic stress disorder, disorders substance abuse and sexual dysfunction, including premature ejaculation, and pharmaceutical compositions containing such compounds.

According to the first aspect, the invention provides a compound of general formula (I), pharmaceutically acceptable salts, solvates or polymorphs thereof;

where:

R ¹ and R ² , which may be the same or different, are H, C 1 -C 6 alkyl or (CH 2 N 3 -C 6 cycloalkyl), where d = 0, 1,2 or 3; or R ¹ and R ² together with the nitrogen to which they are attached form an azetidine ring;

Z or Y is -SR 'and the other Z or Y is halogen or -R'; wherein R 'is independently C 1 -C ₄ alkyl which may be fluoro substituted; except that R ³ is not CF ₃ ; or Z and Y are joined so that together with the binding atoms Z and Y form a fused 5 to 7 membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, and where if Z and Y form a heterocyclic ring other than carbon atoms contains one or two heteroatoms selected independently from oxygen, sulfur and nitrogen; with the proviso that if R ⁵ is fluorine and R ² is methyl, 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, are:

A-X, where A = -CH = CH- or - (CH ₂ ) _P -, where p is 0, 1 or 2; X is hydrogen, F, Cl, Br, I, CONR ⁶ R ⁷ , SO2NR ⁶ R ⁷ , SO2NHC (= O) R ⁶ , OH, C, .4 alkoxy, NR ⁸ SO ² R ⁹ , NO 2, NR ⁶ R, CN , CO2R 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, are hydrogen or C 1-6 alkyl which may be substituted independently of one or more RR is C 1-6 alkyl which may be substituted independently of one or more R ¹² ; R ¹¹ is hydrogen, C 1-6 alkyl, which may be independently substituted by one or more R ¹² ; C (O) R ⁶ , CO2R ⁹ , C (O) NHR or SO ² NR ⁶ R ⁷ ; R ¹² is F (preferably up to 3), OH, CO ₂ H, C ₂ . ₆ cycloalkyl, NH ₂ , CONH ₂ , C _1-6 alkoxy, C 1-6. ₆ alkoxycarbonyl or a 5- or 6-membered heterocyclic ring containing 1,2 or 3 heteroatoms selected from N, S and O, which may be independently substituted by one or more R ¹¹ ; or R ⁶ and R ⁷ together with the nitrogen to which they are attached form a 4-, 5- or 6-membered heterocyclic ring which may be independently substituted by one or more R ¹ or

A 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O, which may be independently substituted by one or more R ¹ '; wherein R ¹ 'is hydroxy, C ₁ -C ₄ alkoxy, F, C 1 -C ₆ alkyl, haloalkyl, haloalkoxy, -NH ₂ , -NH (C 1 -C ₆ alkyl) or -X (C 1 -C ₆ alkyl) ₂ .

Unless otherwise indicated, the alkyl group throughout may be linear or branched and have from 1 to 6 carbon atoms, preferably from 1 to 4 and especially from 1 to 3 carbon atoms.

Unless otherwise indicated, each carbocyclyl group contains 3 to 8 ring atoms and may be saturated, unsaturated or aromatic. Preferred saturated carbocyclyl groups are cyclopropyl, cyclopentyl or cyclohexyl. Preferred unsaturated carbocyclyl groups contain up to 3 double bonds. A preferred aromatic carbocyclyl group is phenyl. The term carbocyclic should be interpreted similarly. In addition, the term carbocyclylene includes any condensed combination of carbocyclyl groups, for example, naphthyl, phenanthryl, indanyl and indenyl.

Unless otherwise stated, each heterocyclyl group contains 5 to 7 ring atoms, of which up to 4 may be heteroatoms such as nitrogen, oxygen and sulfur, and may be saturated, unsaturated or aromatic. Examples of heterocyclyl groups are furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl , dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanyl, tetrazolyl, triazinyl, azepinyl, oxazepinyl, thiazepinyl, diazepinyl, and thiazepinyl. In addition, the term heterocyclyl includes condensed heterocyclyl groups, for example, The term heterocyclic should be interpreted similarly.

Halogen means fluoro, chloro, bromo or iodo.

p

Preferably R ¹ and R ² , which may be the same or different, are hydrogen or C ₁ -C ₆ alkyl. More preferably, they are hydrogen or methyl.

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

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

Preferably, when 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, where 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 ^{I ()} , where R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as described in the first aspect, or

5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O (preferably oxadiazolyl, triazolyl, imidazolyl, oxzolyl, pyrazolyl, pyridinyl or pyrimidinyl).

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

- (CH ₂ ) _P -X, where p is 0 or 1; X is hydrogen, hydroxy, CONR ⁶ R ⁷ , SO ² NR ⁶ R 'or NR ^with SO ² R ⁹ , where R ⁶ and R ⁷ , which may be the same or different, are hydrogen or C ₁ -C ₃ alkyl which may be substituted with hydroxy, -COH ₂ or C ₁ -C ₃ alkoxy (preferably methoxy); R ⁸ is hydrogen, hydroxyethyl or methyl; or R ⁹ is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; or triazolyl, imidazolyl or pyrazolyl.

D *

Most preferably, R ⁴ is hydrogen.

Preferably R ⁶ and R ⁷ , which may be the same or different, are hydrogen, C ₁ -C ₃ alkyl which may be substituted by hydroxy, -CONH ₂ , or C 1 -C ₃ alkoxy (preferably methoxy). More preferably R ⁶ and R ⁷ , which may be the same or different, are hydrogen or methyl, most preferably hydrogen.

When present, R is preferably oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl. More preferred are triazolyl, imidosolyl or pyrazolyl.

In the case where R ⁶ and R 1, together with the nitrogen to which they are attached, form a heterocyclic ring, the preferred rings are pyrrolidine or piperidine rings, each of which may be substituted by OH or CONH ₂ or a morpholine ring which may be substituted by CONH ₂ .

Preferably R ¹¹ is hydrogen or C 1. ₆ alkyl.

Q

Preferably R1 is hydrogen, hydroxyethyl or methyl. Preferably it is hydrogen.

Preferably R ⁹ is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl. More preferably it is methyl or ethyl (most preferably methyl).

Preferably R ¹⁰ is methyl or ethyl.

Preferably p is 1 or 0, more preferably 0.

Preferred

R ¹ and R ² , which may be the same or different, are hydrogen or methyl;

when R ³ is methyl or ethyl; or Z and Y are bonded so that together with their bonding atoms Z and Y form a fused 5 to 7 membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, wherein if Z and Y form a heterocyclic ring other than carbon atoms, the bond contains one or two heteroatoms selected independently from oxygen, sulfur and nitrogen; and

R ⁴ and R ⁵ ', which may be the same or different, are (CH 2) P-X, where p is 0 or 1; X is hydrogen, hydroxy, CONR ⁶ R ⁷ , ^w SO ² NR ⁶ R ⁷ , NR ⁸ SO ² R ⁹ , SR ¹⁰ , SOR ⁹ or SO ² R ¹⁰ and where R ⁶ and

R, which may be the same or different, are hydrogen, C 1 -C ₂ alkyl which may be substituted by hydroxy, -CONH ₂ or C 1 -C ₂ alkoxy (preferably methoxy); or R ⁶ and R together with the nitrogen to which they are attached may form a morpholine, pyrrolidine or piperidine ring g, each of which may be substituted by OH or CONH ₂ ; R is hydrogen, hydroxyethyl or methyl (preferably hydrogen); R ⁹ is methyl, ethyl, isopropyl, trifluoromethyl or f 'methoxyethyl; and R ¹⁰ is methyl or ethyl; or an oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl group.

More preferred

R ¹ and R ² , which may be the same or different, are hydrogen or methyl;

when R ³ is methyl or ethyl; or Z and Y are joined so that together with their bonding atoms Z and Y form a fused 5 to 7 membered carbocyclic or heterocyclic ring containing 1 or 2 sulfur atoms; and

R ⁴ and R ³ , which may be the same or different, are

- (CH ₂ ) _P -X, where 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 , where R ⁶ and R ⁷ , which may be the same or different, are hydrogen, C 1 -C ₃ alkyl which may be substituted with hydroxy, -CONH ₂ or C 1 -C ₃ alkoxy (preferably methoxy); R ⁸ is hydrogen, hydroxyethyl or methyl; R ⁹ is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; or triazolyl, imidazolyl or pyrazolyl

Most preferred

R ¹ and R ² , which may be the same or different, are hydrogen or methyl;

when it has R ^? is methyl or ethyl; or Z and Y are joined so that together with their bonding atoms Z and Y form a fused 5 to 7 membered carbocyclic or heterocyclic ring containing 1 or 2 sulfur atoms; and

R ⁴ is hydrogen, and

R ⁵ is

- (CH ₂ ) _p -X, where p is 0 or 1; X is hydrogen, hydroxy, CONR ⁶ R ^Z , SO ² NR ⁶ R ⁷ or NR ^with SO ² R ⁹ , where R ⁶ and R ⁷ , which may be the same or different, are hydrogen, C 1 -C ₃ alkyl which may be substituted with hydroxy, -CONH ₂ or C ₁ -C ₃ alkoxy (preferably methoxy); R is hydrogen, hydroxyethyl or methyl; R ⁹ is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; or triazolyl, imidazolyl or pyrazolyl.

Preferably R ⁴ and R ⁵ are not both hydrogen.

Preferred compounds are:

4- (2,3-dihydro-1-benzothien-5-yloxy) -3 - [(metiamino) 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 - [(dimethyl amino) 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);

N 3 - [(dimethylamino) 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-13 - [(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-MeTwi-N-13 - [(methylamino) methyl] -4- [3-methyl-4 (methylsulfanyl) phenoxy] phenyl} methanesulfonamide (Example 1 16) and

N-14- (2,3-dihydro-1,4-benzoxathin-7-yloxy) -3 - [(dimethyl amino) methyl] phenyl | methanesulfonamide (Example 124).

According to the second aspect, the invention provides a compound of formula (I) or (XIX)

and pharmaceutically acceptable salts or solvates thereof, wherein (in this aspect): R ¹ and R ^{2 are} independently H, C 1 -C ₆ alkyl or (CH ₂ ) and (C ₃ C ₆ cycloalkyl), where d = 0, 1 , 2 or 3, or wherein NR ¹ R ² taken together are a 4-membered ring, wherein R ¹ and R ² together are C 3 alkyl; Z and Y are both independently -SR ³ , where if Z = -SR ³ , το Y = halogen, -OR ^a , -R ^a or -SR ^a ; or if Y = -SR ³ , το Z = halogen, -OR ^a , R ^a wiH -SR ^a ; and R ³ and R ^{a are} independently: C 1 -C 4 alkyl (may be substituted by fluorine atoms, for example, -CF ₃ ); or Z and Y taken together may be a fused 5 to 7 membered ring, as illustrated by the general formula XIX, where the given 5 to 7 membered ring may be saturated, unsaturated or aromatic, and where the given 5 to 7 membered ring may contains one or more heteroatoms P and Q, where P and Q = may be independently O, S or N, and where E, F or G are independently CH or CH ₂ and where k and p can independently be = O, 1,2 or 3, and m = 1, 2 or 3; and

R ⁴ and R 2 are independently A-X, where A = - (CH 2) N -, where η is 0, 1 or 2 and where X is: H, F, Cl, Br, I, CONR ⁶ R ⁷ or SO 2 NR ⁶ R ⁷ , OH, NR ⁸ SO ² R ⁹ , NO 2, NR ⁶ R ^h , CN, CO2R ¹⁰ , CHO, S (O) mR ¹⁰ , where m = 0, 1 or 2 and where R ⁶ , R ⁷ , R ⁸ and R ^{10 are} independently H or C 1-6 alkyl, where R ⁹ is C 1-6 alkyl, R ¹¹ is H, C 1-6 alkyl, C (O) R ⁶ , CO ₂ R ⁹ ,

C (O) NHR ⁶ or SO ² NR ⁶ R ⁶ and where a C 1 6 alkyl group may be substituted by one or more groups selected from OH, CO ₂ H, C 3-6 cycloalkyl, NH ₂ , CONH ₂ , C 6b. alkoxy, C 1-6 alkoxycarbonyl and a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O; or provided that when P = Q = oxygen, then both k and p are not zero; provided that Z and Y together do not form a fused phenyl ring; R ⁴ or R ⁵ may be representative of a 5- or 6-membered heterocyclic ring containing 1,2 or 3 heteroatoms selected from N, S and O; and furthermore, R 'and R may, together with the nitrogen atom to which they are attached, be a 5- or 6-membered heterocyclic ring which may be substituted; and pharmaceutically acceptable salts or solvates thereof, provided that both R ⁴ and R ⁵ are not H.

For the sake of doubt, unless otherwise stated, the term substituted means substituted with one or more defined groups. If the groups are selected from a number of alternative groups, the selected groups may be the same or .D different.

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

According to a third aspect, the invention provides a compound of general formula I and pharmaceutically acceptable salts thereof, wherein R ¹ , R ² , R ¹ , Z and Y are as defined in the first aspect; and R ⁴ and R ³ , which may be the same or different, are - (CH ₂ ) _P -A ', where p is 0, 1 or 2 and A' is a polar group. In this respect, polar groups can be defined as having negative values (see C Hansch and A Leo, “Substituent Constants for Correlation Analysis in Chemistry and Biology”, Wiley, New York, 1979). In this system H has a π-value of 0.00, -OCH ₃ has a 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. ibid], the more preferred polar groups have a more negative value: so, the preferred groups have a greater negative π-value of -0.1, the more preferred ones have a greater negative value of -0.5, and the most preferred ones have a larger a negative value of -1.0. Even when p is not zero in the above definition, the definition of A 'is based on the above comparison as if p is zero.

Unless specifically indicated, the compounds of the first, second and third aspects are hereinafter defined as compounds of the invention.

The compounds of the invention have the advantage of being selective serotonin reuptake inhibitors (SRIs) (and as such are likely to have reduced side effects), they have a rapid onset of action (making them suitable for administration immediately before the desired effect), they have the desired potency and related properties. Compounds that selectively inhibit serotonin reuptake and do not inhibit noradrenaline or dopamine are preferred.

We have found that compounds of formula I having such properties have a relatively polar group at R ⁴ / R ⁵ .

Pharmaceutically or veterinarily acceptable salts of compounds of formula I having a basic center are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydrochloric, sulfuric, and phosphoric acids, with carboxylic acids or with organosulfonic acids. There are examples of HCl, HBr, HI, sulfate or bisulfate, nitrate, phosphate or acid phosphate, acetate, benzoate, succinate, sugar, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, ethanesulfonate, ethanesulfonate, toluenesulfonate and pamoate salts. The compounds of the invention may also form pharmaceutically or veterinarily acceptable metal, in particular non-toxic alkali and alkaline earth metal salts with bases. Examples are sodium, potassium, aluminum, calcium, magnesium, zinc, diolamin, olamine, ethylenediamine, tromethamine, chloin, megulamine and diethanolamine salts. For reviews on suitable pharmaceutical salts, see Berge et al, J. Pharm. Sci., 66, 1-19, 1977; P L Gould, International Journal of Pharmaceutics, 33 (1986), 201217; and Bighley et al, Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York 1996, Volume 13, page 453-497.

Hereinafter, the compounds, their pharmaceutically acceptable salts, their solvates and polymorphs, defined in each aspect of the invention (with the exception of intermediates in chemical processes) are referred to as compounds of the invention.

The pharmaceutically acceptable solvates of the compounds of the invention include their hydrates.

The compounds of the invention may have one or more chiral centers and different stereoisomeric forms may exist. All stereoisomers and mixtures thereof are within the scope of the invention. The racemic compounds can be separated either by preparative HPLC and a column of chiral stationary phase or separated into individual enantiomers by methods well known in the art. In addition, chiral intermediates can be separated and used to prepare the chiral compounds of the invention.

Ί.ίί '

Where the compounds of the invention exist as E and N isomers, the invention includes the individual isomers as well as mixtures thereof.

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

Where the compounds of the invention exist as diastereomers, the invention includes the individual diastereomers as well as mixtures thereof.

Separation of diastereomers or E and Z isomers can be achieved by conventional methods, for example, fractional crystallization, chromatography or H.P.L.C. An individual enantiomer of a compound of the invention may be obtained from the corresponding optically pure intermediate or by separation, such as by H.P.L.C. of the corresponding racemate using a suitable chiral carrier or by fractional crystallization of the diastereomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base as appropriate.

The compounds of the invention may exist in one or more tautomeric forms. All tautomers and mixtures thereof are within the scope of the present invention. For example, the claim for 2hydroxypyridinyl also applies to the tautomeric form, apyridonyl.

It will be appreciated by those skilled in the art that certain protected derivatives of the compounds of the invention obtained prior to the last phase of deprotection may not in themselves have pharmacological activity, but may in some cases be taken orally or parenterally and thereafter metabolize in the body to form compounds of the invention that are pharmacologically active. Such derivatives can therefore be described as a "pre-medication". In addition, compounds of the invention may act as pre-drugs of other compounds of the invention.

All protected derivatives and prodrugs of the compounds are within the scope of the invention. Examples of suitable prodrugs of the compounds of the invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499-538 and in Topics in Chemistry, Chapter 31, pp 306-316 and in Design of Prodrugs by H. Bundgaard, Elsevier, 1985, Chapter 1 (parts of these documents are incorporated herein by reference).

Specialists will also note that some moieties known to those skilled in the art as "pre-structures", such as those described by N. Bundgaard in Design of Prodrugs (this part of this document is provided here as a citation) engage in appropriate functionality when such functionality is present in the compounds of the invention.

Preferred drugs for the compounds of the invention are: esters, carbonate esters, chemiesters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo compounds, phosphamides, glycosides, ethers, acetals and ketals.

The invention also includes all suitable isotope variants of the compounds of the invention. Isotope variation is defined as one in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass from the atomic mass that is commonly found in nature. Examples of isotopes that may be included in the compounds of the invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ^{| 3} C, ^{| 4} C, ^b N, ^{| 7} O, ^l8 O, ^3I P, ³² P, ³⁵ S, ^l3 F and ^3b C1. Certain isotope variations of the invention, for example, which include radioactive isotopes such as ³ H or ^{| 4} C, are useful in investigating the tissue distribution of a drug and / or substrate. Tritium isotopes, i. ^? H, and carbon-14, i. ⁴ C are especially preferred for their ease of preparation and measurement. Furthermore, isotope substitution such as deuterium, i. H, gives certain therapeutic advantages due to greater metabolic stability, for example, greater half-life in vivo or use of lower doses, and therefore may in some circumstances be preferred. Isotopic variations of the invention are generally prepared by conventional methods such as, for example, the examples and preparations described below, using suitable isotope variants of the corresponding reagents.

The compounds of the invention can be prepared in various ways. In the following reaction schemes, unless otherwise stated, R ¹ to R ¹³ , Z and Y are as described in the first aspect. These processes are covered in further aspects of the invention.

Throughout the specification, the general formulas are indicated by Roman numerals I, II, III, IV etc. Subgroups of these general formulas are referred to as la, lb, ic etc, .... IVa, IVb, IVc etc.

Compounds of general formula (I) may be prepared from compounds of formula (II) by reaction with an amine of general formula HNR ¹ R ² , or a suitable salt form thereof, together with a hydride reducing agent in a suitable solvent (see Scheme 1). When either R ¹ or R ² is hydrogen, suitable solvents are protic solvents such as ethanol, and sodium borohydride is a suitable reducing agent as given here in Example 36. If neither R ¹ nor R ² is hydrogen, the appropriate solvent system is tetrahydrofuran / dichloromethane and a suitable reducing agent is sodium triacetoxyboro hydride. In these reactions, the use of a salt form of HNR'R ² , such as hydrochloride, is preferable, and an auxiliary base such as triethylamine together with acetic acid as given in Example 25 may be added to improve the solubility of the salt of HNR'R.

SCHEME 1

Compounds of formula (II) may in turn be obtained by coupling the compounds of general formula (IV) with an aldehyde compound of general formula (III), wherein L is a suitable leaving group such as halogen (F, Cl, Br or I) or a sulfonate ester such as trifluoromethane sulfonate or methanesulfonate, preferably L is F or Cl. Such a coupling reaction may be carried out by methods known to those skilled in the art, such as by reaction with potassium carbonate in a suitable solvent such as dimethylformamide under suitable conditions for carrying out the inert and inert atmosphere.

reaction as fever

According to a further aspect, the invention provides a process for the preparation of compounds of general general formula (II).

formula (I) from compounds of

Otherwise R ⁴ and / or R? can be introduced after ether coupling (see Scheme 2).

Compounds of general formula (I) may be prepared from compounds of general formula (Ia), i.e. compounds of general formula (I) in which R ⁴ and R ^? are hydrogen. Compounds of general formula (1a) can be prepared from (IIa) in a similar manner to the preparation of preparation (I) of (II) (see Scheme 1), whereas compounds of general i

of formula (IIa) can be prepared (IV) and (IIIa) in a similar manner to the preparation of preparation (II) (see Scheme 1).

SCHEME 2

Thus, in a further aspect, the invention provides a method for preparing compounds of general formula (I) from compounds of general formula (Ia).

Methods for introducing R ⁴ and / or R ⁵ into compounds of formula (Ia) include:

i) When R ⁴ / R ⁷ are halogen, by reaction of (1a) with a suitable halogenating agent in an inert solvent which does not adversely affect the reaction. Suitable halogenating agents are trifluoromethanesulfonic acid and N-iodosuccinamide, and a suitable inert solvent is dichloromethane.

j) when R ⁴ / R ³ are -NO ₂ , by reaction of (1a) with a suitable nitrating agent such as an alkali metal nitrate in a solvent which does not adversely affect the reaction. Suitable nitrating agents are trifluoromethanesulfonic acid / potassium nitrate and a suitable inert solvent is 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 ⁶ R ⁷ in a suitable solvent. Suitable solvents are a mixture of water and dichloromethane and are usually carried out at or below room temperature. Intermediate sulfonyl chlorides may be prepared from compounds of formula (Ia) by reaction with chlorosulfonic acid under low temperature conditions in the presence of a solvent which does not adversely affect the reaction, with or without further treatment with a chlorinating agent such as phosphorus oxychloride, phosphorus pentach , oxalyl chloride or thionyl chloride in a solvent which does not adversely affect the reaction. A suitable reaction solvent is trifluoroacetic acid at a typical reaction temperature of 0 ° C. Suitable solvents for reaction with chlorinating agents are acetonitrile and suitable conditions are reflux, as further illustrated in Example 12.

For example, a compound of formula (Iq) wherein R ⁵ is

Z

-SCFNR'R, may be prepared by intermediate sulfonyl chlorides (XVIII) from compounds of formula (1a) by reaction of (1a) with chlorosulfonic acid, with or without further treatment with a chlorinating agent such as phosphorus pentachloride, oxalyl chloride or thionyl chloride followed by reaction with HNR ⁶ R ⁷ (see Scheme 2a). A typical condition for the reaction is low temperature. The reaction can be carried out in mass, i. E. in the absence of a solvent, or in the presence of an inert solvent that does not adversely affect the reaction. The intermediate sulfonyl chloride (XVII) can be isolated, purified and then reacted with HNR ⁶ R ⁷ , or it may be formed in situ without isolation, and then reacted with HNR ⁶ R ⁷ .

SCHEME 2a

Thus, according to a further aspect, the invention provides a method for preparing compounds of general formula (I) from compounds of general formula (II). In a preferred embodiment, there is provided a process for the preparation of compounds of general formula (Iq) by reaction of compounds of formula (1a) in a suitable solvent with chlorosulfonic acid, with or without subsequent treatment with a chlorinating agent such as phosphorus oxachloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride to give compounds of formula (XVIII), followed by reaction with HNR ⁶ R ⁷ to give compounds of formula (Iq). Preferably, compounds of formula (XVIII) are formed in situ and reacted with HNR'R ⁷ without isolation.

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

i) when R ⁴ / R ⁵ is halogen such as chloro, bromo or iodo, it can be converted to cyano by reaction with the cyanide salt in the presence of Pd (O) or (II) catalyst in high boiling solvent at elevated temperatures. Suitable Pd catalysts are palladium tetrakis (triphenylphosphine), a suitable cyanide salt is Zn (CN) ₂ and a suitable high boiling solvent that does not adversely affect the reaction is dimethylformamide, which is further illustrated in Example 78;

n) when R ⁴ / R ^? is halogen such as chloro, bromo or iodo, it can be converted to the corresponding -CO ₂ R ester by reaction with high pressure carbon monoxide with Pd (O) or (II) catalyst in an alcoholic solvent (ROH, where R is C (-C ₄ alkyl) in the presence of a base at elevated temperatures. For example, the reaction may be carried out at a pressure of about 100 psi and the appropriate Pd catalyst is dichlorobis (triphenylphosphine) palladium (II), a suitable base is triethylamine and a suitable alcoholic solvent is methanol, as further illustrated in Example 50;

iii) when R ⁴ / R is nitro, it can be reduced to the corresponding -NH ₂ group by reaction with a reducing agent in a protic solvent at room or higher temperature. A suitable reducing agent is iron powder / calcium chloride, a suitable protic solvent is aqueous ethanol, a typical reaction temperature is about 70 ° C to about 100 ° C, preferably about 90 ° C, as further illustrated in Example 103 ;

iv) when R ⁴ / R? is -NH ₂ , 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 that does not adversely affect the reaction, at or below room temperature. A suitable sulfonylating agent is methanesulfonyl chloride, a suitable base is triethylamine and a suitable inert solvent is dichloromethane, as further illustrated in Example 128;

ν) when R ⁴ / R ³ is an -NHSO ² R ⁹ group, it may be converted to the corresponding NR 1 SO 2 R by treatment with an alkylating agent and base in a suitable inert solvent. An example of a suitable alkylating agent is methyl iodide, a suitable base is potassium carbonate, and a suitable inert solvent is acetonitrile, as further illustrated in Example 88;

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

(vii) when R ⁴ / R ⁵ is an -CO ₂ R ester, it can be reduced to the corresponding alcohol group -CH ₂ OH by treatment with a hydride reducing agent such as lithium aluminum hydride, as further illustrated in Example 69;

(viii) when R ⁴ / R ⁵ is an -CO ₂ R ester, it can be converted to the corresponding CO ₂ H acid by treatment with suitable hydroxide in the presence of water and a suitable co-solvent. Suitable hydroxide is lithium hydroxide and a suitable co-solvent is tetrahydrofuran, as further illustrated in Example 55;

ix) when R'Vr ² 'is an acid -CO ₂ H, it can be converted to the corresponding amide CONR ⁶ R ⁷ by reaction with a coupling agent, base and amine HNR ⁶ R ⁷ in a suitable inert solvent that does not adversely affect the reaction. A suitable coupling agent is 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride in the presence of 1-hydroxy-benzotriazole, a suitable base is triethylamine and a suitable solvent is dichloromethane, as further illustrated in Example 59;

x) when R ⁴ / R 5 is halogen such as chloro, bromo or iodo, it can be converted to α, β-unsaturated amide by reaction with an acrylamide, Pd (O) or (II) catalyst and a suitable base in an inert solvent, which does not adversely affect the reaction at elevated temperature. A suitable Pd catalyst is palladium (II) acetate in the presence of three (o-tolyl) phosphine, a suitable base is triethylamine and a suitable inert solvent is acetonitrile, as further illustrated in Example 50;

xi) when R ⁴ / R5 is α, β-unsaturated amide, it can be converted into CH2CH2CO2NH2 by reaction with a suitable reducing agent at an appropriate temperature in a suitable solvent which does not adversely affect the reaction. A suitable reducing agent is samarium diode at room temperature and a suitable solvent is tetrahydrofuran containing some water, as further illustrated in Example 51;

xii) when R ⁴ / R ³ is -CH ₂ OH, it can be converted to CH2NR SO2R by the Mitsunobu reaction at the appropriate temperature in a suitable solvent which does not adversely affect the reaction. Suitable reagents are diethyl azodicarboxylate, triphenylphosphine and tert-butyl methylsulfonylcarbamate, 0 ° C is a suitable reaction temperature and tetrahydrofuran is a suitable solvent, as further illustrated in Example 72;

Alternatively, compounds of general formula (I) with a specific NR'R ² group may be converted to other compounds of general formula (I) with a different NR'R ² group. For example:

i) Compounds of general formula (Ib), wherein either R or R is hydrogen, may be converted to compounds of formula

2 (Ic) wherein neither R nor R is hydrogen by reaction of a compound of formula (Ib) with an aldehyde and a hydride reducing agent. A suitable aldehyde is formaldehyde, a suitable reducing agent is three (acetoxy) boronic hydride and the reaction is preferably carried out in a solvent that does not interfere with the reaction as dichloromethane at or at room temperature, as further illustrated in Example 12.

WI 2 (ii) Compounds of formula (Ib) wherein R or R is hydrogen may be converted to a compound of formula (Ic) wherein R ¹ or R ² is methyl by reaction of the compounds of formula (Ib) with formylating agent in a suitable solvent followed by reduction of the intermediate Nformyl compound with a hydride reducing agent in an inert solvent, preferably at elevated temperature. A suitable formylating agent is pentafluorophenyl formate (formed from formic acid, pentafluorophenol and dicyclohexylcarbodiimide) and a suitable formylation solvent is dichloromethane. A suitable reducing agent is boron tetrahydrofuran complex and a suitable inert solvent for reduction is tetrahydrofuran, as further illustrated in Example 110.

Alternatively, compounds of general formula (I) may be prepared from compounds of formula V (see Scheme 3), where L is as defined for Scheme 1 and T is a group that can be

7 is converted to CH ₂ NR R '. Examples of suitable T substituents are: -CO ₂ R 1, -CN, and -C (O) NR ¹ R ² .

SCHEME 3

The procedures for converting compounds of formula (V) into (I) are:

i) when T is -CO ₂ R 'and R ^{i ()} = methyl or ethyl, by reaction with an amine of the general formula NHR R 2 an amide is formed, which is then reduced to an amine.

i) When T = -CN, by reduction to the corresponding amine of formula CH ₂ NH ₂ .

iii) When T = -C (O) NR'R ² , by reduction to an amine.

Compounds of general formula (V) can be prepared in turn by coupling compounds of general formula (VI) and compounds of general formula (IV).

The reagents and conditions for such coupling reactions are as previously defined for coupling compounds of general formulas (IV) and (III) in Scheme 1.

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

SCHEME 4

(VII)

(Vi) are obtained by flavoring

Compounds of formula (VI) can electrophilically substitute compounds of formula (VII) for the direct preparation of compounds of formula (VI). Alternatively, compounds of formula (VI) may be prepared in two or more steps; aromatic electrophilic substitution of compounds of formula (VII) to give intermediates, which are then subsequently converted to compounds of formula (VI). The intermediates can be isolated or formed in situ without isolation. The preferred route is shown in Scheme 5.

SCHEME 5

C1SO

(VII) (VIII)

Compounds of formula (VII) are reacted with sulfonyl chloride to give compounds of formula (VIII) and then reacted with NHR ⁶ R ⁷ to give compounds of formula (Via).

According to other aspects, the invention provides compounds of formulas (II), (IIa) and (V) as defined above.

The compounds of formulas (III), (IIIa), (IV), (VI) or (VII) are either known and commercially available or commercially available by known methods (see Examples below).

Those skilled in the art will appreciate that sensitive functional groups need to be protected and deprotected during the synthesis of a compound of formula I. This is done using 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 a protecting group strategy for the synthesis of a compound of the present invention.

The experienced chemist will appreciate that diaryl ethers can be prepared using various synthetic procedures. For a review of the methodologies, see J Sawyer, Tetrahedron, 56 (2000) 50455065, cited here.

The compounds of the invention are useful because they have pharmacological activity in mammals, including humans. In particular, they are useful for the treatment and prevention of disorders that affect the regulation of monoamine transport function. Mention may be made of conditions such as hypertension, depression (e.g., depression in cancer patients, depression in patients with Parkinson's, depression after myocardial infarction, sub-syndromic symptomatic depression, depression in infertile women, pediatric depression, major depression, depression triggered by childhood abuse, postpartum depression, and post-partum old-age syndrome, generalized Cr anxiety disorder, phobias (e.g., agoraphobia, social phobia and common phobias), post- rheumatic stress syndrome, personality disorder, premature ejaculation, eating disorders (e.g., anorexia nervosa and bulimia neurosis), fullness, chemical dependencies (eg, alcohol, cocaine, heroin, feiobarbital, zone nicotinobionic and bencinolipine, nicotine and binocular) migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, memory disorders (eg / dementia, amnesia disorders, age-related cognitive decline (AR.CD)), Parkinson's diseases (e.g., e Parkinson's disease, neuroleptically induced parkinsonism and delayed dyskinesias), endocrine disorders (eg, hyperprolactinemia), vasospasm (especially in the brain vasculature), cerebral ataxia (cerebella ataxia), digestive disorders secretion), negative symptoms of schizophrenia, pre-menstrual syndrome, fibromyalgia syndrome, stress dropout, Tourette syndrome, trichloomania, kleptomania, male impotence, hyperactive disorder of attention (ADHD) onic paroxysmal hemicrania, headache (associated with vascular disorders), emotional lability, pathological crying, sleep disorders (cataplexy) and shock.

Disorders of particular interest are depression, hyperactive attention deficit disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders, and sexual dysfunction, including (especially) premature ejaculation.

Premature ejaculation can be defined as prolonged or periodic ejaculation before, during or shortly after the penetration of the penis of the sexual partner. It can also be defined as ejaculation that occurs before the individual desires [see “The Merck Manual”, 16 ¹¹¹ edition, ρ 1576, published by Merck Research Laboratories, 1992].

Accordingly, in accordance with the following aspects, the invention provides:

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

(j) use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of a disorder that interferes with the regulation of monamine transport function, for example, depression, hyperactive disorder of attention, obsessive-compulsive disorder, post-traumatic stress disorder, disorders caused by substance abuse and sexual dysfunction, including premature ejaculation;

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

(iv) a method of treating or preventing depression,

hyperactive disorder of attention, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders, and sexual dysfunction, including premature ejaculation, which consists of administering to a patient in need of treatment or prevention a therapeutic amount a compound of the invention;

(v) a method for increasing ejaculatory latency, which consists in the administration by an effective amount of a compound of the invention from men who desire increased ejaculatory latency; and vi) a compound of the invention for the treatment or prevention of a disorder related to the regulation of monoamine transport function, such as depression, hyperactive attention deficit disorder, obsessive-compulsive depression, post-traumatic stress disorder, substance abuse disorders , or sexual dysfunction, including premature ejaculation.

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

It should be noted that any mention of treatment here includes curative, palliative and prophylactic treatment.

The compounds of the invention may be administered alone or as part of combination therapy. If a combination of active agents is used, they can be taken simultaneously, individually or sequentially. In particular, the compounds of the invention may be combined to treat PE with the following agents:

i) alpha-blockers (eg, phentolamine, doxazazime, tamsulazine, terazazine, prazazine and Example 19 of WO9830560). Possible considerations for using beta-blockers to treat premature ejaculation are as follows. The muscular activity of the expelling smooth muscle (vas deferens, seminal vesicles and urethra) is controlled by the sympathetic nervous system by separation

of norepinephrine. Norepinephrine acts on the alpha 1 adrenergic receptors, stimulating muscle contraction, which leads to semen and subsequent ejaculation. Therefore, blocking these receptors will inhibit ejaculation. (1 ·) Apomorphine - The use of apomorphine as a medicament can be found in US-A-5945117. F * · (iii) Dopamine D2 agonists (eg, Premiprixal, Pharmacia Upjohn compound number PNU95666). (iv) Melanocortin receptor agonists (eg, Melanotan Π) (V) PGE1 receptor agonists (e.g., alprostadil). (VI) Monoamine transport inhibitors, especially norepinephrine reuptake inhibitors (NRIs) (eg, Reboxetine), other serotonin reuptake inhibitors (SRIs) (eg, paroxetine) or dopamine reuptake inhibitors (DRIs). (vii) 5-HTZ antagonists (eg, ondansetron and granisetron). A possible explanation for the treatment of premature ejaculation with 5-HT3 antagonists is the following. 5-HT3 receptors located in the lumen of the posterior urethra (urethra) are stimulated by 5-HT in the semen during

sperm separation leading to sensitization of the spinal relex pathway causing ejaculation. Therefore, an antagonist will prevent this sensitization and thus delay ejaculation.

(viii) PDE inhibitors such as PDE2 (e.g., erythro-9- (2hydroxyl-3-nonyl) adenine) and Example 100 of EP 0771799, which is cited herein), and in particular the PDE5 inhibitor (e.g., 1 - {[3- (3 , 4-Dihydro-5-methyl-4-oxo-7-propylimidazo [5,1-f] -5-trazin-2-yl) -4-ethoxyphenyl] sulfonyl} 4-ethylpiperazine i.e. vardenafil (vardenafil) / Bayer BA 38-9456 or IC351 (see structure below, Icos Lilly). A possible explanation for the effect of PDE inhibitors on premature ejaculation is the following. cAMP and CGMP levels in the ejector smooth muscle regulate the muscle tone of these ejector muscle and thus delay ejaculation.

(ix) Potassium channel openers (x) P2X purinergic receptor antagonists.

(xi) Endothelin receptor antagonists.

For use in humans, the compounds of the invention may be administered alone, but in the treatment of humans, mixtures with a suitable pharmaceutical excipient, diluent or carrier are usually used, selected according to the intended route of administration and standard pharmaceutical practice.

For example, the compounds of the invention may be administered orally, through the oral cavity or under the tongue in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, with use, aimed at immediate, delayed, prolonged, double, controlled release of the drug. The compounds of the invention can also be administered by intra-cavernous injection. The compounds of the invention may also be administered as fast-dispersing or rapidly dissolving forms.

Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine, and starch (preferably maize, potato or tapioca starch), disintegrators such as sodium starch glycolate, granulate binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

Solid compositions of this kind can also be used as fillers in gelatin capsules.

Preferred excipients in this respect are lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols. In aqueous suspensions and / or elixirs, the compounds of c, the invention and their pharmaceutically acceptable salts may be combined with various sweetening and flavoring agents, coloring agents or dyes, with emulsifying and / or suspending agents, and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

Modified release and pulsatile release dosage forms may contain excipients such as those considered for immediate release dosage forms together with additional excipients that act as modifiers of the release rate and may be coated and / or incorporated internally. Modifiers of release rate are hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, xanthan gum, carbomer, ammonium methacrylate copolymer, anhydrous, annealed , a copolymer of methacrylic acid and mixtures thereof. Modified release and pulsed release dosage forms may contain one or a combination of rate-modifying excipients. The rate-modifying excipients may be within the dosage form, i. E. in the matrix and / or on the dosage form, i.e. on the surface or as a coating.

Fast-dispersing or dissolving dosage formulations with (FDDFs) may contain the following ingredients: aspartame, potassium acesulfame, citric acid, croscarmellose sodium, crospovidone, diasorbic acid, ethyl acrylate, ethyl cellulose hydroxyetalose, ethyl cellulose hydrolysose, ethyl cellulose hydroxyethanol methyl methacrylate, mint flavoring, polyethylene glycol, fumed silica, silica, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The terms dispersing or dissolving used herein to describe FDDFs depend on the solubility of the drug substance, i. E. when the drug is insoluble, dispersible dosage forms are made and when the drug substance is soluble, rapidly dissolving dosage forms are prepared.

The compounds of the invention may also be administered parenterally, for example, intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion methods. For such parenteral administration, it is best used in the form of a sterile aqueous solution that may contain other substances, for example, sufficient salts or glucose to make the solution isotonic with blood. The aqueous solutions should be appropriately buffered (preferably at pH 3 to 9) if necessary. The preparation of suitable parenteral compositions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

The following dosage forms and other dosage levels given herein refer to a human individual weighing in the range of about 65 to 70 kg. One skilled in the art can readily determine the dose levels required for an individual whose weight is outside this range, such as children or the elderly.

For oral and parenteral administration to humans, the daily dose level of the compounds of the invention or their salts or solvates * is usually from 10 to 500 mg (as a single dose or divided doses).

For example, tablets or capsules of the compounds of the invention may contain from 5 mg to 250 mg of active compound for administration once or twice or more. In each case, the physician determines the actual most appropriate dose for the patient and varies depending on the age, weight and susceptibility of the particular patient. Higher or lower doses may be administered in various cases in accordance with the invention. One skilled in the art will appreciate that in the treatment of certain diseases (including PE), the compounds of the invention may be administered as a single dose based on the "required" dose (required or desired).

An example of a tablet composition

Typically, the tablet composition contains between about 0.01 mg and 500 mg of a compound of the invention while the tablet filler is from 50 mg to 1000 mg. Illustration of an example tablet composition:

Ingredient% w / w

Compound of the Invention 10,000 *

Lactose 64.125

Starch 21.375

Croscarmellose sodium 3.000

Magnesium stearate 1.500 * This amount is selected depending on the activity of the drug.

The compounds of the invention may also be administered intravenously or by inhalation and for this purpose are available as a dry powder or aerosol spray inhaler, pump, spray or nebulizer using a suitable propellant, for example dichlorodifluoromethane, trichlorofluoroethane, hydrofluoroalkane such as 1,1,1,2tetrafluoroethane (HFA 134A [trademark]) or 1,1,1,2,3,3,3 heptafluoroheptane (HFA 227EA [trademark]), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the required dose is determined by means of a valve which releases an accurately measured amount. The pressure vessel, pump, spray or nebulizer may contain a solution or suspension of the active compound, for example, a mixture of ethanol and propellant, the solvent may further comprise a lubricant, for example, sorbitan trioleate. Capsules and cartridges (for example, made from gelatin) for use in an inhaler or insufflator may contain a composition that is a mixture of the compound of the invention and a suitable powder such as lactose or starch.

The aerosol or dry powder formulations are preferably formulated such that the measured dose of each patient administration buffer contains from 1 to 50 mg of a compound of the invention. The total daily dose of aerosol is in the range of 1 to 50 mg, which can be administered as a single dose or more often divided into several doses throughout the day.

The compounds of the invention may be used in compositions intended for administration with an atomizer.

Atomizer compositions may contain the following ingredients, such 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 topically administered in the form of gel, hydrogel, lotion, solution, cream, ointment or powder. The compounds of the invention may also be administered dermally or transdermally, e.g. use of skin patches. They can also be administered by ophthalmic, pulmonary or rectal route. For ophthalmic use, the compounds should be formulated as micronized suspensions in isotonic, fixed pH, sterile cooking salt solution, or preferably as solutions in isotonic, fixed pH, sterile cooking salt solution, optionally in combination with a preservative such as benzylalkonium. chloride. Alternatively, it may be included in an ointment composition such as petrolatum.

'Whose » For topical application to the skin, the compounds of the invention may participate in compositions for a suitable ointment containing the active compound dissolved or suspended in it, for example, a mixture of one or more of the following components: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsified wax and water. They may be dissolved or suspended in lotion or cream formulations, for example, a mixture of one or more of the following components:

mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters, wax, cetaryl 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 (inclusion) complexes and non-inclusion complexes with drug molecules. The formation of a drug-cyclodextrin complex may alter the solubility, dissolution rate, bioavailability and / or stability of the drug molecule. Drug-cyclodextrin complexes are commonly used for most types of dosage forms and routes of administration. An alternative possibility of direct complexation with the drug is the use of cyclodextrin as an excipient, for example, a carrier, diluent, or solubilizer. The most commonly used are alpha-, beta- and gamma-cyclodextrins as described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

For oral and parenteral administration in humans, the daily dose levels of the compounds of the invention will be 0.01 to 30 mg / kg (single or divided dose) and preferably be in the range of 0.01 to 5 mg / kg. Thus, the tablets will contain 1 mg to 0.4 g of compound for administration once or twice or more daily. In all cases, the physician determines the actual dose that will be most appropriate for the particular patient and varies depending on the age, weight and sensitivity of that patient. The aforementioned doses are, of course, exemplary of a mediocre case, and there may be cases of administration of higher or lower doses, which are also within the scope of the invention.

Oral administration is preferred. It is preferable for the effect to occur rapidly after administration of the drug.

For veterinary use, the compound of the invention is administered in a suitable acceptable composition in accordance with normal veterinary practice, and the veterinarian determines the dose interval and route of administration that is most appropriate for the particular animal.

Thus, according to another aspect, the invention provides

a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable adjuvant, diluent or carrier.

The invention is illustrated without limitation by examples using the following abbreviations and definitions:

Arbocel® filtering agent no wide Here tert-butoxycarbonyl CDI carbonyldiimidazole δ chemical displacement d doublet Δ heat

DCCI

DCM

DMF

DMSO

ES ⁺

ES ~

Ex h

HOBt

HPLC m / z min

MS

NMR

Prec

Prep q

s

C t

Tf

TFA

TLC

TS ⁺

WSCDI dicyclohexylcarbodiimide dichloromethane

Ν, Ν-dimethylformamide dimethyl sulfoxide electrospray ionization positive scan electrospray ionization negative scan example hours

-h-hydroxybenzothiazole liquid chromatography high-pressure peak of mass spectra nuclear magnetic resonance drug quartet singlet triplet trifluoromethane sulfonyl trifluoroacetate minute (s) min. spectra in all cases correspond to the structures proposed. Characteristic chemical shifts (δ) are given in parts per million in less field than tetramethylsilane using conventional abbreviations to denote major signals: for example, s, singlet; d, doublet; t, triplet; q, quartet; t, multiplet; br, wide.

The following abbreviations are used for conventional solvents: CDC1 ₃ , deuterochloroform; DMSO, dimethyl sulfoxide. The abbreviation psi means pounds per square inch and LRMS means low resolution mass spectrometry. When thin layer chromatography is used, it refers to TLC with silica gel using 60 F ₂₅₄ silica gel plates, Rf is the distance traveled by the compound divided by the distance traveled by the solvent front on the TLC plate. Melting points were determined using a Perkin Elmer DSC7 at a heating rate of 20 ° C / minute.

Where indicated, the compounds are characterized as their hydrochloride salts. A typical procedure for the preparation of hydrochloride salts is given in Example 12. The procedure can also be used with other solvents, for example diethyl ether or DCM.

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

EXAMPLE 1

3 - [(methylamino) methyl)] - 4- [3-methyl-4-methylsulfanyl) phenoxy] benzene sulfonamide cp.

The amide of Preparation 8 (760 mg, 2.07 mmol) was stirred in THF (10 mL) and the resulting suspension was treated with boron tetrahydrofuran complex (1 M solution in THF, 6.22 mL, 6.22 mmol) at room temperature. The resulting solution was refluxed for 5 hours under dry nitrogen. The reaction mixture was cooled to room temperature and treated carefully with 6M FIC1 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), which gave a precipitate in the organic layer and the aqueous layer was further extracted with DCM (2 x 20 mL). The EtOAc fraction was washed with 2M NaOH (20 mL) to give a pure biphasic separation and the base layer was extracted with DCM (4 x 25 mL). All organic fractions were collected and washed with saturated aqueous brine (brine) (20 mL), dried (MgSO ₄ ) and evaporated to give a colorless oil. Purification by column 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, d6-DMSO) 2.26 (3H, d), 2.32 (3H, d), 2.45 (3H, d), 3.75 (2H, d), 6.90 (3H, m), 7.25 (3H, br ), 7.67 (1H, t) 7.98 (1H, d); MS m / z (TS ⁺ ) 353 (MH ⁺ ).

Compounds of formula Id, i.e. compounds of general formula I, wherein R ¹ is methyl, R ² is hydrogen and R ³ is -SO ₂ NH ₂ given in Table 1 were prepared in a manner analogous to Example 1 of said precursors.

Table 1

An example Precursor p. 7 Data 2 Prep. 9 HCl salt: δ _Η (CD ₃ OD, 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 ⁺ ) (MH ⁺ 3 Prep. 12 1 T. SMe HCl salt: δ _Η (CD ₃ OD, 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 ⁺ ) 373 (MH ^{< +} & gt ^; )

An example Precursor Z Data 4 Prep. 11 ΙΊ SMe HCl salt: δ _Η (CD ₃ OD, 400 MHz) 2.45 (3H, s), 2.73 (3H, s), 5.44 (2H, s), 6.97 (3H, m), 7.42 (1H, m), 7.89 ( 1H, m), 8.03 (1H, s); MS m / z (ES ⁺ ) 357 (MH ^{< +} & gt ^; ) 5 Prep.10 (λ uh HCl salt: δ _Η (CD ₃ OD, 400 MHz) 2.79 (3H, s), 3.18 (2H, m), 4.38 (2H, s), 4.41 (2H, m), 6. 68 (2H, m). 6.97 (1H, d), 7.13 (1H, d), 7. 91 (1H, d), 8.03 (1H, s); MS m / z (TS ⁺ ) 367 (MH ^{< +} & gt ^; ) 6 Prep. 13 ίΊ Ο HCl salt: δ _Η (CD ₃ OD, 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 (ESA 367) 7 Prep. 14 ίΊ k-G HCl salt: δ "(CD ₃ OD, 400 MHz) 2.81 (3H, s), 4.43 (2H, s), 5.09 (4H, s), 6.93 (1H, d), 7.12 (2H, s + d). 7.40 (1H, d), 7.90 (1H, d), 8.08 (1H, s); MS m / z (TS ⁺ ) 335 (MH ⁺ 8 Prep. 15 ιΑ S— ' HCl salt: δ _Η (CD ₃ OD, 400 MHz) 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 Wz (TS ⁺ ) 333 (MH + 9 Prep. 16 0 Me HCl salt: δ _Η (CD ₃ OD, 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, 7.89 (1H, d), 8.05 (1H, s); MS m / z (ES ⁺ ) 352 (MH ⁺ ) 10 Prep. 17 A HCl salt: δ _Η (CD ₃ OD, 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 (MH ^{< +} & gt ^; )

An example Precursor Z Data 11 Prep. 18 % δ _Η (CD ₃ OD, 400 MHz) 2.76 (3H, s), 3.30 (2H, m), 3.42 (2H, m), 4.33 (2H, s), 6.90 (1H, d), 6.94 (1H, d ), 7. 00 (1H, s), 7.29 (2H, d), 7.89 (1H, d), 8.04 (1H, s); MS m / z (ES ⁺ ) 351 (MH ⁺ ), (ES ~) 349 (MIL)

EXAMPLES 12 and 13

3 - [(Dimethylamino) methyl) -4-N3-methyl-4 (methylsulfanyl) phenoxy] -benzenesulfonamide (Example 12) and

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

Formaldehyde (37% aqueous solution, 282 L, 3.76 mmol) was added to a secondary amine suspension of Example 1 (409 mg, 1.16 mmol) in DCM (20 mL) at room temperature under nitrogen. The resulting mixture was stirred for 15 min before the addition of triacetoboric anhydride (984 mg, 4.64 mmol). The resulting reaction mixture was stirred for 5 hours, then basified with saturated NaHCO ₃ solution (10 mL) and extracted with DCM (3x20 mL). The organic layers were washed with brine (10 mL), dried (MgSO ₄ ) and evaporated to a yellow oil. It was purified by HPLC (Phenomonex Luna C, ₈ 75 x 4.6 mm column, CH ₃ CN, H ₂ O, TFA). The fractions containing the basic product were evaporated and the residue was treated with us. NaHCO ₃ solution (5 mL), and extracted with DCM (3x30 mL). The combined organic fractions were washed with brine (30 mL), dried (MgSO ₄ ) and evaporated to give a white foam (155 mg, 36%) of Example 12; δ _Η (300 MHz, CDC1 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 ⁺ ) 367 (MH ⁺ ).

After HPLC purification, a smaller product was obtained. The corresponding fractions were evaporated and the residue was treated with us. NaHCO ₃ solution (5 mL), and extracted with DCM (2x30 mL). The combined organic fractions were washed with saturated brine (30 mL), dried (MgSO ₄ ) and evaporated to a gum. It was dissolved in DCM (5 mL), treated with 1M ether HCl (2 mL) and evaporated to give a white powder (39 mg, 9%) of Example

H »» ·

13; δ _Η (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) 381 (MH ⁺ ).

Repeated reaction using 1 equivalent of formaldehyde against the amine of Example 1, Example 12 yields 78% after column chromatography [SiO ₂ ; 95: 5: 0.5 to 90: 10: 1 (EtOAc / MeOH / 880 NH ₃ )]. It was dissolved in EtOAc and converted into the HCl salt by the addition of 1M ether HCl. The resulting precipitate was filtered off and dried in vacuo to give Example 12 as the HCl salt; mp 188 ° C.

Another way to prepare Example 12 is from the amine of Example 1 by the method of Example 110.

Example 12 was prepared as follows.

A solution of the hydrochloride salt of Example 94 (20 g) in trifluoroacetic acid (100 mL) was added slowly to a solution of chlorosulfonic acid (72 g), maintaining the temperature between 0 ° C and 5 ° C. After one hour, the reaction mixture was slowly poured into water (200 mL) at 0-20 ° C. The mixture was then extracted with dichloromethane (200 mL) and partitioned. The aqueous layer was extracted again 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 phosphorous oxychloride (28.8 mL) was added to the mixture. The solution was then refluxed overnight. The reaction mixture was cooled to room temperature and transferred to a stirred mixture of ammonia (90 mL), dichloromethane (240 mL) and water (100 mL) while maintaining the temperature between 0 ° C and 10 ° C. With ammonia the pH of the mixture was adjusted to pH 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. It was dissolved in acetone (100 mL) and stirred with charcoal (Norit SX plus, 50% w / w). This mixture was filtered again and the solution was concentrated by substitution with water (200 mL). The slurry was granulated, filtered and dried under vacuum overnight to give the title product as a creamy white substance (40% yield).

EXAMPLES 14 and 15

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

4- (2,3-Dihydro-1,4-benzoxathin-7-yloxy) -3 - [(dimethylamino) methylphenylbenzenesulfonamide

These compounds were prepared in a manner analogous to that of Examples 12 and 13 starting from the secondary amine of Example 5. EXAMPLE 14. HCl salt: δ _Η (CD ₃ OD, 400 MHz) 2.97 (6H, s), 3.18 ( 2H, m), 4.42 (2H. M), 4.52 (2H, s), 6.68 (2H, d), 6.99 (1H, d), 7.14 (1H, d), 7.94 (1H, d), 8.07 (1H , s); MS m / z (ES ^T ) 381 (MH ^{< +} & gt ^; ).

EXAMPLE 15. HC1 salt: δ _Η (CD ₃ OD, 400 MHz) 2.56 (3H, s), 2.80 (6H, s), 3.17 (2H, m), 4.35 (2H, s), 4.41 (2H, m) , 6.68 (2H, m), 6.98 (1H, d), 7.13 (1H, d), 7.81 (1H, d), 8. 00 (1H, s); MS m / z (ES ⁺ ) 395 (MH ⁺ ).

Compounds of formula Ia, i.e. compounds of general formula I in which R ¹ and R ² are methyl and R ³ is -SO ₂ NH ₂ shown in Table 2 were prepared as in Example 12 of said precursors. In this reaction, N-methyl sulfonamides analogous to Example 13 are not isolated and HPLC purification is not required.

Table 2

An example Precursor Ζ Data 16 Example 2 1 ^ 1 S— / HCl salt: δΗ (CD ₃ OD, 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 ^{< +} & gt ^; ) 17 Example 3 MS! SMe HCl salt: δΗ (CD ₃ OD, 300 MHz) 2.54 (3H, s), 2.98 (6H, s), 4.53 (2H, s), 7.01 (1H, d), 7.20 (1H, dd), 7.33 (1H , s), 7.42 (1H, d), 7.99 (1H, d), 8.04 (1H, s); MS m / z (TS ⁺ ) 387 (MH ^{< +} & gt ^; ) 18 Example 4 ф, SMe HCl salt: δΗ (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 +) 371 (MH ⁺ ) 19 Example 6 Ο HCl salt: δΗ (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 ^{< +} & gt ^; )

An example Precursor ф, Z Data 20 Example 7 Yu HCl salt: δΗ (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 ^{< +} & gt ^; ) 21 Example 8 u) HCl salt: δΗ (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 ') 22 Example 10 HCl salt: δΗ (CD ₃ OD, 400 MHz) 2.93 (6H, s), 4.21 (4H, s), 4.50 (2H, s), 6.91 (1H, d), 7.02 (1H, d), 7.09 (1H , s), 7.37 (1H, d), 7.91 (1H, d), 8.05 (1H, s); MS m / z (TS ') 365 (MH ^- ) 23 Example 11 \ ^S HCl salt: δ _Η (DMSO-d ₆ , 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), 10.23 (1H, br); MS m / z (TS ⁺ ) 365 (MH ^{< +} & gt ^; )

EXAMPLE 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 (3H, 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 (TS ⁺ ) 367 (MH ⁺ ).

EXAMPLE 25

N- {5-Methoxy-2- [3-methyl-4 (methylsulfanyl) phenoxybenzyl} N, T4-dimethylamine

i

Dimethylamine hydrochloride (424 mg, 5.2 mmol), Et ₃ N (725 pL, 5.2 mmol), AcOH (298 pL, 5.2 mmol) and sodium triacetoboric hydride (1.10 g, 5.2 mmol) were added to a solution of aldehyde from 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 hours. After removal of the solvent in vacuo, the residue was dissolved in 2M HCl (20 mL) and washed with ether (2x15 mL). The aqueous layer was basified with NaOH pellets and extracted with DCM (4x20 mL). The combined DCM extracts were washed with saturated brine, dried (MgSO ₄ ) and evaporated. The residue was dissolved in a small amount of DCM and treated with 1M ether HCl to give the HCl salt. It was filtered, washed with ether and dried, yielding a white solid (936 mg) contaminated with triethylamine hydrochloride. It was dissolved in 1 M NaOH (10 mL) and extracted with EtOAc (3x15 mL). The organic extracts were washed with saturated brine (10 mL), dried (MgSO ₄ ) and evaporated, then redissolved in EtOAc and evaporated again. The residue was dissolved in DCM and treated with 1M ether HCl to precipitate the HCl salt, which was filtered, washed with ether and dried to give a white solid (635 mg, 52%); δΗ (CDCL, 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 If, i.e., compounds of general formula I, wherein R ¹ and R ¹ are methyl, shown in Table 3, were prepared according to the procedure in Example 25 of said precursors.

Table 3

An example Smoke- sort R ⁵ " R- ά. ζ Data » 26 Prev.25 N. F ίι ιΓι HCl salt: δ _Η (CDCl ₃ , 300 MHz) 2.23 (6Η, 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 ^{< +} & gt ^; ) 27 39 n -no ₂ / HC1 salt: δ _Η (CDCl ₃ , 300 MHz) 2.32 (6H, s), 2.36 (3H, s), 2.47 (3H, s), 3.60 (2H, 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 38 n -no ₂ '7 Taken from crude product at -75% purity; δ _Η (CDC1 ₃ , 300 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 (1H, d), 8.00 (1H, dd), 8.37 (1H, d) 29 26 n Η δ _Η (CDC1 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 ^{< +} & gt ^; ) 30 _ Prel.27 n Η [Γ ^ Ί ΐΓ ^ Ί ^Ν \> - ^Ν HCl salt: δ _Η (d ₆ -DMSO, 300 MHz) 2.77 (6H, d), 4.38 (2H, d), 7.08 (1H, d), 7.36 (1H, t), 7.52 (1H, t), 7.62 (1H, s), 7.80 (1H, d), 7.91 (1H, dd), 8.10 (1H, d), 9.25 (1H, s), 9.52 (1H, s); MS m / z (TS ⁺ ) 280 (MH ^{< +} & gt ^; )

An example Smoke- sort In R ³ Z Data 31 29 N. N. 4 Maleate salt: δ _Η (d ₆ -DMSO, 300 MHz) 2.77 (6H, s), 4.33 (2H, s), 5.98 (2H, s), 6.87 (1H, d), 7.21 (1H, 7.30 (1H, 7H). dd), 7.41 (1H, dt), 7.58 (1H, dd), 7.88 (1H, d), 8.11 (1H, d), 9.32 (1H, s); MS m / z 285 (MH ⁺ ) 32 REP n Br A \ ^s HCl salt: δ _Η (d ₆ -DMSO, 400 MHz) 2.77 (6H, d), 3.23 (3H, m), 3.39 (2H, m), 4.32 (2H, d), 6.75 (2H, m), 7 03 (1H, s), 7.26 (1H, d), 7.57 (1H, dd), 7.87 (1H, s), 10.06 (1H, br, s); MS m / z (ES ⁺ ) 366 (MH ^{< +} >) 33 32 Br N. ί δ _Η (CDCl ₃ , 400 MHz) 2.22 (6H, s), 2. 30 (3H, s), 2.41 (3H, s), 3.41 (2H, s), 6.76 (2H, m), 6.94 (1H. s), 7. 18 (1H, s), 7.21 (1H, obs), 7.30 (1H, d); MS m / z (TS ⁺ ) 366/368 (MH ^{< +} >)

EXAMPLE 34

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

Chlorosulfonic acid (106 pL, 1.6 mmol) was added to a solution of Example 29 (50 mg, 0.16 mmol) in DCM (2 mL) and the mixture

stirred for 3 hours at room temperature. Water (2 mL) was added and the mixture was brought to pH 6 with saturated aqueous NaHCO ₃ solution and extracted with DCM (2x5 mL). The organic extracts were dried (MgSO ₄ ) and filtered, then 8M methylamine in EtOH (0.3 mL) was added. After 1 hour of standing, the solvent was removed in vacuo and the residue was purified by column chromatography [SiO ₂ ; 95: 5: 0.5 (DCM / MeOH / 880 NH ₃ )]. The product was transferred to EtOAc and converted to the HCl salt by the addition of ether HCl. The desired product was obtained as a hygroscopic solid (3 mg, 5%); δ _Η (CD ₃ OD, 300 MHz) 2.60 (3H, s), 2.99 (6H, s), 4.60 (2H, s), 7.21 (1H, d), 7.96 (1H, d), 8.04 (3H, m ), 8.19 (1H, s), 8.38 (1H, d), 9.03 (1H, d), 9.18 (1H, d); MS / 77 / z (TSJ 371 (MH)).

EXAMPLE 35

3-D (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 ₂ Cl ₂ (15 mL) at 0 ° C and the mixture was stirred for 5 min. The solvent was removed in vacuo and the residue partitioned between CH ₂ Cl 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 dissolved in CH ₂ Cl ₂ (20 mL), cooled to 0 ° C and CSO ₃ H (2.4 mL, 36.1 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 4 hours, then poured into ice water. The mixture was extracted with CH ₂ Cl ₂ (50 mL) and the organic layer was treated with saturated NH ₃ solution in MeOH (10 mL). After 4 hours of stirring, IM LiOH (20 mL) was added and stirring was continued overnight. TLC analysis indicated that the reaction was not complete and therefore, IM LiOH (50 mL) was added and the mixture was stirred for another 2 hours. The mixture was acidified to pH 8 with 2M HCl and extracted with CH ₂ Cl ₂ (3x200 mL). The combined organic extracts were dried (MgSO ₄ ) and evaporated and the residue triturated with ether to give the title compound (500 mg, 43%) as a yellow solid; δ _Η (CD ₃ OD, 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 ~)

344 (MH ^{< +} & gt ^; ).

EXAMPLE 36

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

The aldehyde of Preparation 19 (1.10 g, 3.28 mmol) was dissolved in 8M methylamine in EtOH (4.1 mL, 32.8 mmol) and stirred for 5 hours, then NaBH ₄ (372 mg, 9.83 mmol) was added portionwise over 30 min. ). EtOH (100 mL) was added and the reaction mixture was stirred for 16 hours, then concentrated in vacuo. The residue was treated with 6M HCl to 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%); δ _Η (CD ₃ OD, 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 ⁺ ) 350.352 (MH ⁺ ).

Compounds of formula Ig, i.e. compounds of general formula I, wherein R ¹ and R ⁴ are hydrogen and R ² is methyl, shown in Table 4, were prepared according to the procedure in Example 36 of said precursors. These compounds, which were isolated as free bases, were obtained by partitioning the reaction mixture between 2M HCl and ether after removal of the reaction solvent in vacuo. The aqueous layer was basified and extracted with DCM, the DCM layer was dried (MgSO ₄ ) and evaporated to give the desired secondary amine.

(ig)

Table 4

An example Smoke- sort R ⁵ ζ Data 37 Prep.20 Br M-F SMe ' HCl salt: δ _Η (d ₆ -DMSO, 300 MHz) 2.48 (3H, s), 2.59 (3H, s), 4.18 (2H, s), 6.88 (1H, 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 ⁺ ) 356.358 (MH ⁺ ) 38 Prel.21 Br γ ^ ο Μ HC1 salt: 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 ⁺ ) 366.368 (MH ⁺ ) 39 Prel.22 Br fk-ι SMe HC1 salt: 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 ⁺ ) 372, 374 (MH ^{< +} & gt ^; ) 40 38 -νο ₂ hh s — J HCl salt: δ _Η (CDC1 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 ⁺ ) 317 (MH ⁺ 41 Prel.36 -νο ₂ γΤ. δ _Η (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 ^{< +} & gt ^; )

An example Smoke- sort R ⁵ 0, Z Data 42 Rev. 40 -NO, 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 (MH ^{< +} & gt ^; ) 43 24 -Ome [Γί SMe HCl salt: δ _Η (CDCl ₃ , 300 MHz), 2.35 (3H, 2.45 (3H, s), 2.60 (3H, s), 3.84 (3H,! 4.17 (2H, s), 6.80 (1H, d). 6.82 (1H, 6.88 (2H, s), 7.15 (1H, d), 7.42 (1H, 9.85 (2H,: brs); MS m / z (TS ⁺ ) 304 (MH ⁺ ) 44 23 Br [Γί SMe δ _Η (CDCI 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 ⁺ ) 352.354 (MH ⁺ ) 45 REP N. ίΓ ^ Ί SMe HCl salt: (d ₆ -DMSO, 400 MHz) 2.22 (3H, s), 2.42 (3H, s), 2.58 (3H, s), 4.18 (2H, s), 6.78 (1H, d), 6.96 (1H , d), 6.99 (1H, s), 7.18 (1H, t), 7.25 (1H, d), 7.38 (1H, t), 7.60 (1H, d); MS m / z (ES +) 274 (MH ^{< +} & gt ^; ) 46 Ref. 31 N. Ζ HCl salt: δ _Η (CDCl ₃ , 300 MHz), 2.55 (3H, brs), 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 (1H, d); MS m / z (ES ⁺ ) 272 (MH ^{< +} & gt ^; ) 47 28 N. V ^ N and Maleate salt: (DMSO-df, 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 (MH ^{< +} & gt ^; )

An example Smoke- sort R ⁵ 6, Z Data 48 26 N. / H (CDCl ₃ , 300 MHz) 2.64 (3H, s), 4.25 (2H, s), 6.89 (1H, d), 7.19 (1H, t), 7.30 7.41 (2H, t), 7.45 (1H, s) ), 7.49 (1H, d), 7.69 (1H, d), 8.08 (1H, d), 8.16 (1H, d), 8.87 (1H, d); MS m / z (ES ⁺ ) 529 (2M + H ^& lt ^{; +} & gt ^; ) 49 34 -CN A HCl salt: δ _Η (CDCl ₃ , 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 ⁺ ) 290 (MH ^{< +} & gt ^; )

^a - 2M Methylamine in MeOH (2 eq) and Ti (Oi-Pr) ₄ (2 eq) in EtOH (-0.1M aldehyde solution) were used instead of methylamine in EtOH. After isolation of the free base, it is converted into maleate salt by standard methods.

EXAMPLE 50 (2E) -3-14- (2,3-dihydro-1-benzothien-6-yloxy) -3- (dimethylamino)

methyl] phenyl] -2-propenamide

A mixture of bromide from 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 tri-o-tolylphosphine (33.4 mg, 0.11

mmol) (15 mL) was refluxed for 72 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue partitioned between EtOAc (50 mL) and 2M HCl (50 mL). The aqueous phase was basified with 2M NaOH and extracted with EtOAc (3x50 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 the polarity to 90: 10: 1] to give the title compound (196 mg, 50%) as a cream foam; δ _Η (CDC1 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) , 6.59 (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 ⁺ ) 355 (MH ⁺ ).

EXAMPLE 51

3- {4- (2,3-Dihydro-1-benzothien-6-yloxy) -3-N (dimethyl amino) methyl] phenyl-2-propanamide

A solution of SmL in THF (0.1 M, 21.9 mL, 2.19 mmol) was added under nitrogen to a solution of the alkene of Example 50 (194 mg, 0.55 mmol) in THF (5 mL), then water (1 mL) was added. After stirring for 10 min at room temperature, 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 (2x20 mL). Gathered

The IQ 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 / 880NH ₃ ), increasing the polarity to 90: 10: 1] to give the title compound (90 mg, 46%); δ _Η (CDC1 ₃ , 400 MHz) 2.25 (6H, s), 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 (1H, d), 6.73 (1H, s), 6.81 (1H, d), 7.05 (2H, m), 7.31 (1H, s); MS m / z (TS ⁺ ) 357 (MH ⁺ ).

Compounds of formula If, i.e. compounds of general formula I wherein R and R are methyl shown in Table 5 were prepared according to the procedure of Preparation 50 of said precursors.

Table 5

When- | Smoke- R ⁴ R ' ά 1 7. Data mayor sort 52 An example 32 N. -CO ₂ Me - δ _Η (CDC1 ₃ , 400 MHz) 2.29 (6H, s), 3.26 (3H, m), 3.39 (2H, m), 3. 54 (2H, s), 3.89 (3H, 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 ⁺ ) 344 (MH ^{< +} & gt ^; )

53 An example - N. 33 CO ₂ Me e _ SMe

δ _Η (CDC1 ₃ , 400 MHz) 2.24 (6H, s), 2.33 (3H, s), 2.42 (3H, s), 3.48 (2H, s), 3.82 (3H, 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 (MH ^{< +} & gt ^; )

Compounds of formula If, i.e., compounds of general formula I, wherein R ¹ and R ² are methyl shown in Table 6, were prepared according to the method in Preparation 55 of said precursors.

Table 6

When- mayor Smoke- sort R ⁴ R ⁵ 7. Data 54 An example 52 N. -CO ₂ H δ _Η (CDCl ₃ , 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 (1H, s); MS Wz (TS ') 330 (ΜΙΓ) 55 (-80% number- Thoth An example 55 -CO ₂ H N. SMe δ _Η (CDCl ₃ , 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 If, i.e., compounds of general formula I wherein R ¹ and R ² are methyl shown in Table 7 were prepared according to the method in Preparation 59 of said precursors.

Table 7

When- : measure Precursor R ⁴ R ⁵ z Data 56 i When- mayor 54 N. -CO ₂ NH ₂ .1 '* 6 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, d), 7.92 (1H, s); MS m / z (TS) 329 (ΜΙΓ) ; 57 When- mayor 55 CO ₂ NH ₂ Η I S \ 1e HCl salt: δ _Η (CDCl ₃ , 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 w / z (TS ⁺ ) 331 (MH ^{< +} & gt ^; )

Compounds of formula If, i.e., compounds of general formula I wherein R ¹ and R ² are methyl shown in Table 8 are prepared according to the method in Preparation 69 of said precursors.

Table 8

When- mayor Pre- kur- sort R ⁵ ξι. Z Data ! 58 When- mayor 52 n -CH ₂ OH * HCl salt: δ _Η (DMSO-d ₆ , 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), 7.37 (1H, d), 7.60 (H, s) , 10.07 (1H, br); MSWz (TS ⁺ ) 316 (MH ^{< +} & gt ^; ) 59 At mayor 53 -CH ₂ OH N. SMe HCl salt: δ _Η (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 ^{< +} & gt ^; )

EXAMPLE 60

4- (2,3-Dihydro-1-benzothien-5-yloxy) -3 - [(methylamino) methylbenzamide

s

The protected amine of Preparation 59 (317 mg, 0.76 mmol) was dissolved in saturated HCl solution in DCM (25 mL) at 0 ° C, left for one hour and neutralized by the 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 ether HCl (1 mL). The white precipitate was isolated by filtration and dried in vacuo to give the desired product (211 mg, 77%); δ _Η (CD ₃ OD, 400 MHz) 2.77 (3H, s), 3.35 (2H, obs), 3.39 (2H, t), 4.34 (2H, s), 6.79 (1H, 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 ⁺ ) 315 (MH ⁺ ).

Compounds of formula Ig, i.e. compounds of general formula I wherein R and R are hydrogen and R is methyl, are shown in Table 9, were prepared according to the method in Example 60 from said precursors.

(ig)

Table 9

When- mayor Smoke- sort R? 4-- Z Data _ 61 Ref. 61 0 nHa c OMe HCl salt :: δ _Η (CDC1 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 ^- ) 373 (MH ^{< +} & gt ^; ) 62 Ref. 60 0 nhA 1 Me HCl salt :: δ _Η (CDCl ₃ , 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, d), 7.78 (1H, d), 7. 96 (1H, s); MS m / z (TS ⁺ ) 329 (MH ^{< +} & gt ^; ) 63 62 0 „.A SMe HCl salt :: δ _Η (d ₆ -DMSO, 300 MHz) 2.52 (3H, obs), 2.61 (3H, s), 4.21 (3H, s), 6.90 (1H, d), 7.07 (1H, d), 7.19 (1H, 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) 321 (MNH?) 64 63 0 1 Me 4. SMe HCl salt: δ _Η (d ₆ -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 (1H, d); MS m / z (TS ⁺ ) 335 (MH ^{< +} & gt ^; ) 65 64 1) HN ' 1 Ί OMe ¢ 1, SMe HCl salt: δ _Η (d ₆ -DMSO, 300 MHz) 2. 52 (3H, obs), 2.60 (3H, s), 3.27 (3H, s), 3.46 (4H, m), 4.22 (2H, s) , 6.91 (1H, d), 7.08 (1H, d), 7.20 (1H, d), 7.50 (1H, t), 7.89 (1H, d), 8.10 (1H, s), 8.58 (1H, br ); MS m / z (TS ⁺ ) 379 (MH ^{< +} & gt ^; )

When- mayor Precursor R? Z Data i 1 66 65 0 ά .. SMe HCl salt: δ _Η (d ₆ -DMSO, 300 MHz) 2.52 (3H, obs), 2.60 (3H, t), 4.11 (2H, s + H2O), 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 ⁺ ) 337 (MH ^{< +} & gt ^; ) 67 Ref.66 0 , A 1 Me I c ί Γ ^C1 S \ lc HCl salt: δ _Η (d ₆ -DMSO, 300 MHz) ¹ 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 (1H, d); MSW- (ES) 351 (MIS 68 Prep. 67 0 uh δ _Η (CDCh, 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 3 331 (MH +) 69 Prep. 68 () L n \ ^k ί 0MS A Λ THAT, A HC1 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) 390 (MH ^{< +} & gt ^; ) 70 Prep. 70 hH 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, s); MS m / z (TS ⁺ ) 308 (MH ^{< +} & gt ^; )

An example Precursor R ⁵ ξι, Z Data i 71 Prep. 69 on 1 1 '1 Ύ ^C1 SMe HCl salt: δ _Η (d ₆ -DMSO, 300 MHz) 2.52 (3H, obs), 2.58 (3H, t), 4.10 (2H, s + H2O), 4.48 (2H, s), 6.94 (1H. d), 7.1 d (1H, d), 7.21 (1H, s), 7.25 (2H, m), 7.57: (1H, s); MS m / z (ES ⁺ ) 324 (MH ^{&lt; +} & gt ^; ) 72 Prep. 49 ! A SMe HCl salt: δ _Η (d ₆ -DMSO, 300 MHz) 2.52 (3H, s), 2.60 (3H, s), 4.24 (2H, s), 6.94; (1H, 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 ⁺ ) 303 (MH ^{&lt; +} & gt ^; ) 73 Prep. 73 W m / \ ^ \ n ¹ SMe δ _Η (CDC1 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 ⁺ ) 385 (MH ⁺ ), (ES ~) 383 (MH) 74 Prep. 71 i / h 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) 6,886.92 (2H, m), 7.24 (1H, d), 7.37 (1H, d), 7.46 (1H, s); MS m / z (ES ⁺ ) 304 (MH ^{&lt; +} & gt ^; ) 75 Prep. 72. 'W ⁰ M. · \ a II ¢ 1 ,,. SMe HCl salt: δ _Η (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 (1H, d), 7.57 (1H, s); MS m / z (ES) > 381 (MH &lt; + &gt;, (ES) 379 (M N &lt; + &gt;) 76 Prep. 75 <4 ^ 0 n i ¢ 1, .. SMe HCl salt: δ _Η (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 ⁺ ) 435 (MH ⁺ ), (ES ~) 433 (MH) i

EXAMPLE 77

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

Example 77 was obtained from the Boc sulfonamide protected from Preparation 74 by the method of Example 60; IC1 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), 7.24 (1H, d), 7.48 (1H, d); MS m / z (TS ⁺ ) 395 (MH ⁺ ).

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 a solution of the bromide of Example 44 (3.0 g, 8.52 mmol) in

DMF (20 mL) and the mixture was heated at 100 ° C for 17 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ether (2x100 mL and then 3x50 mL). The combined organic layers were washed with water (3x50 mL), dried (MgSCL) and evaporated to give a yellow oil. Initial purification by column chromatography [SiO ₂ ; 95: 5: 0.5 (DCM / MeOH / 880 NH ₃ )] failed and the product was chromatographed [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%) as a pale yellow oil. The sample was taken in DCM (5 mL) and treated with 1M ether HCl to give the HCl salt as a white powder which was isolated by filtration; δ _Η (CDC1 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 ⁺ ) 299 (MH ⁺ ).

EXAMPLE 79

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

A mixture of the nitriles of Example 78 (404 mg, 1.35 mmol) and KOH (304 mg, 5.42 mmol) in tert-butanol (10 mL) was refluxed for 1 hour under nitrogen. After cooling to room temperature, the solvent was removed in vacuo and the residue 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 washed with saturated 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%) as a white foam; 6Hz (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, t ), 7.19 (1H, d), 7.70 (1H, d), 7.90 (1H, s); MS m / z (TS *) 317 (MH ⁺ ).

The compounds of formula Ih, i.e., compounds of general formula I, wherein R ¹ and R ² are methyl and R ⁴ is hydrogen, shown in Table 10, were prepared according to the procedure in Example 12 of said precursors.

Table 10

When- mayor Smoke- sort R ⁵ Z Data 80 An example 60 0 δ _Η (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 ⁺ ) 329 (MH ^{&lt; +} & gt ^; ) 81 An example 62 0 L. NOT ME T. δ _Η (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 +) 343 (MH ^{&lt; +} & gt ^; ) 82 An example 61 Fr. ^) Me V) δ _Η (CDC1 ₃ , 400 MHz) 2.90 (6H, brm), 3.35 (2H, obs), 3.37 (2H, brm), 3.51 (4H, brm), 4. 43 (2H, brs), 6.80-6.94 ( 2H, brd), 7.01 (1H, brs), 7.20 (1H, brs), 7.82 (1H, brs), 7.98 (1H, brs); MS m / z (TS ⁺ ) 387 (MH ^{&lt; +} & gt ^; ) 83 An example 63 0 SMe δ _Η (CDCl ₃ , 300 MHz) 2.29 (6H, s), 2.47 (3H, s), 3.51 (2H, s), 6.73 (2H, 6.97 (1H, d), 7.30 (1H, t), 7.79 ( 1H, d), 7.97 (1H, s); MS m / z (TS ~) 335 (MNH4 ⁺ ) 84 An example 0 “A ride SMe δ _Η (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 +) 349 (MH ^{&lt; +} & gt ^; )

When- mayor Smoke- cop R? ф ,. Z Data; ! 85 An example 65 0 "A ^ Me 9 ' SMe HCl salt: δ _Η (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 (1H, t), 7.39 (1H, brs), 7.98 (1H, d), 8.68 (1H, s); MS m / z (TS +) 393 (MH &lt; + &gt;) 86 An example 66 0 H ₂ N ^ A f. 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 ⁺ ) 351 (MH ^{&lt; +} & gt ^; ) 87 An example 67 0 l nk LA _C | SMe δ _Η (CDCl ₃ , 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, s); MS m / z (ES ⁺ ) 365 (MH ⁺ 88 An example 68 0 uh HCl salt: δ _Η (CDC1 ₃ , 400 MHz) 2.25 (6H, s), 3.07 (2H, s), 3.49 (2H, s), 4.37 (2H, m), 5.47-6.22 (2H, brd), 6.44 (1H, s), 6.49 (1H, d), 6.86 (1H, d), 6.95 (1H, d), 7.68 (1H, d), 7.87 (1H, s); MS m / z (TS ⁺ ) 346 (MH ^{&lt; +} & gt ^; ) 89 An example 69 0 "A ^) Me ./¼ aA> aJ HCl salt: δ, ι (CD ₃ OD, 400 MHz) 2.91 (6H, s), 3.13 (2H, s), 3.27 (3H, s), 4.39 (2H, s), 4.46 (2H, s), 6.64 (2H, s + d), 6.87 (1H, d), 7.08 (1H, d), 7.95 (1H, d), 8.00 (1H, s); MS m / z (TS ~) 403 (MH ⁺ ) 90 An example 70 SMe 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 ⁺ ) 322 (MH ^{&lt; +} & gt ^; )

When- mayor Smoke- sort R? ψ. Data ί j 91 An example 71 Vki SMe HCl salt: δ _Η (d ₆ -DMSO, 400 MHz) 2.52 (3H, obs), 2.76 (6H, s), 4.09 (2H, s), 4.49 (2H, s), 5.32 (1H, brs). 6.87 (1H, d), 7.08 (1H, d), 7.26 (1H, s), 7.38 (2H, m), 7.60 (1H, s); MS m / z (ES ⁺ ) 338 (MH ^{&lt; +} & gt ^; ) 92 An example 78 -ON xC. 'Me SMe HCl salt: δ _Η (CDCl3, 400 MHz) 2.35 (3H, s), 2.48 (3H, s), 2.87 (6H, d), 4.39 (2H, d), 6.85 (1H, d), 6.90 (1 H, d), 6.93 (1H, dd), 7.21 (1H, d), 7.60 (1H, d), 8.17 (1H, s); MS m / z (TS ⁺ ) 313 (MH ^{&lt; +} & gt ^; ) 93 An example 72 -ON C SMe HCl salt: δ _Η (d ₆ -DMSO, 300 MHz) 2.49 (3H, obs), 2.79 (6H, s), 4.41 (2H, s), 6.97 (1H, d), 7.14 (1H, d), 7.32 (1H, d), 7.49 (1H, t), 7.87 (1H, d), 8.22 (1H, s); MS m / z (TS ⁺ ) 317 (MH ^{&lt; +} & gt ^; ) 94 An example 45 Η - / '' Me 1 SMe HCl salt: δ _Η (d ₆ -DMSO, 400 MHz) 2.23 (3H, s), 2.42 (3H, s), 2.76 (6H, s) 4. 34 (2H, s), 6.80 (1 H, d) , 7.97 (1H, dd), 7.00 (1H, s), 7.19 (1H, t), 7.24 (1H, d), 7.40 (1H, t), 7.67 (1H, d); MS m / z (ES ⁺ ) 288 (MH ⁺ 95 An example 46 Η b HCl salt: δ _Η (CDC1 ₃ , 400 MHz) 2.74 (6H, s), 3.22 (2H, m), 3.38 (2H, m), 4.26 (2H, s), 6.71 (1H, d), 6.80 (2H , brm), 7.15 (2H, brm), 7.32 (1H, d), 7.79 (2H, d); MS m / z (ES ') 286 (MH + 96 An example 73 Η 0. SMe HCl salt: δ _Η (CD ₃ OD, 300 MHz) 2.46 (3H, s), 3.93 (6H, s), 3.97 (3H, s), 4.24 (2H, s), 4.42 (2H, s), 6.91- 7.00 (3H, m), 7.41-7.54 (2H, m), 7.61 (1H, s); MS m / z (TS ⁺ ) 399 (MH ⁺ ), (ES “) 397 (M“ H ⁺ )

'War

When- mayor Smoke- sort R? (f Z Data 97 An example 75 O., R Me N> · N f. SMe HCl salt: δ _Η (CD ₃ OD, 400 MHz) 2.31 and (3H, s), 2.43 (3H, s), 2.86-2.94 (9H, im), 4.22 (2H, s), 4.39 (2H, s) , 6.83 (1H, d) 6.89-6.94 (2H, m), 7.26 (1H, d), 7.40 (1H, d), 7.54 (1H, s); MS m / z (ES ~) 393 (M'H ⁺ ) 98 An example 74 f. ! SMe HCl salt: δ _Η (CD ₃ OD, 300 MHz) 2.36 (3H, s), 2.47 (3H, s), 2.98 (6H, s), 4.43 (2H, s), 4.63 (2H, s), 6.89 ( 1H, d), 6.91-7.00 (2H, m), 7.30 (1H, d), 7.43 (1H, d), 7.55 (1H, s); MS m / z (ES ') 318 (MH &lt; + &gt;) 99 An example 76 () O >> CT-y ^Sx N '^ ^x * n ... SMe HCl salt: δ _Η (CD ₃ OD, 300 MHz) 2.39 (3H, s), 2.47 (3H, s), 2.85 (6H, s), 4.32 (2H, s), 4.44 (2H, s), 6.80- 6.86 (3H, m), 7.21 (1H, d), 7.35 (1H, d), 8.08 (1H, s); MS m / z (TS ⁺ ) 449 (MH ^{&lt; +} &gt;), (ES) 447 (M ^& apos ^; H ⁺ ) 100 An example 102 0 t ί ιΓ'ί δ _Η (CD ₃ OD, 400 MHz) 2.26 (6H, s), 3.58 (2H, s), 6.97 (1H, d), 7.35 (1H, 7.46 (1H, dd), 7.54 (1H, d), 7.80 (1H, d), 8.03 (2H, m), 8.20 (1H, d), 8.74 (1H, d); MS m / z (TS +) 322 (MH *)

Example 94 was prepared as follows.

A solution of the product from Preparation 30 (200 g, 0.78 mol) in DCM (1.4 L) was added to THF (1.4 L). Dimethylamine dihydrochloride (69.5 g, 0.85 mol) and triethylamine (235 g, 2.33 mol) were added sequentially to this mixture. The temperature was adjusted to 20 ° C and after 3 hours triacetoxyboro hydride (246 g, 1.16 mol) was added (after 20 hours if the reaction was continued with the treatment and if not - see the note below). Add dichloromethane (2

L) and a solution of 8% sodium bicarbonate (0.9 L) for 0.5 hours. The layers were separated and the organic layer was washed with water (1 L). The layers were separated again and the organic phase concentrated. Ethyl acetate (0.27 L) was added and the separated solvent was replaced with fresh ethyl acetate (800 mL). The solution was then cooled below 5 ° C and 7.02M HCl / IPA (0.117 L, 0.82 mol) was added while maintaining the temperature below 10 ° C. After stirring for 1 hour at below 5 ° C, the mixture was filtered, washed 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 powder (141.5 g, 56 %). [Note: if the reaction is not complete after 20 hours. New portions of dimethylamine hydrochloride (13g, 0.16mol) and triethylamine (43.4g, 0.43mol) were added successively. After 2 hours at room temperature, sodium triacetoxyboro hydride (46g, 0. 22mol) was added. It is left for 20 hours and then treated as described above.]

The compounds of formula Ii, i.e., compounds of general formula I, wherein R is methyl, R is hydrogen and R is -C (= O) NH ₂ shown in Table 11 were prepared according to the procedure in Example 79 of said precursors.

Table 11

When- mayor Smoke- sort R? ¢ 4 Z Data 101 An example 92 Me SMe δ _Η (CDC1 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 (1H, s); MS m / z (TS ⁺ ) 331 (MH ^{&lt; +} & gt ^; ) 102 An example 49 N. 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 (1H, d); MS m / z (ES ⁺ ) 309 (MH ^{&lt; +} & gt ^; )

EXAMPLE 103

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

A mixture of the nitro compound of Example 27 (2.0 g, 6 mmol), Fe 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. refrigerator for 20 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue partitioned between saturated brine (100 mL) and ether (100 mL). The aqueous layer was extracted with ether (50 mL) and the combined organic layers were dried (MgSO ₄ ) and evaporated, yielding the product (1.47 to 81%) as an orange oil; 6H (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, w ), 6.78 (1H, dd), 6.94 (1H, s), 7.10-7.20 (3H, m); MS m / z (ES ⁺ ) 303 () ′).

EXAMPLE 104

N- [5-Ethyl-2- (2,3-dihydro-1-benzothien-5-yloxy-1H, N-dimethylamine

The title compound was obtained from the nitro compound of Example 28 by the method of Example 103; δ _Η (CDC1 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 ⁺ ) 301 (MH &apos;).

EXAMPLE 105

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

The nitrile of Preparation 95 (720 mg, 1.99 mmol) was dissolved in a 1M solution of BH ₃ THF in THF (10 mL, 10 mmol) and the mixture was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was deactivated by careful addition of MeOH (10 mL). The solvent was evaporated, the residue was treated with 6M HCl (10 mL) and refluxed for 1 hour. After cooling, the mixture was basified with 2M NaOH and the pH was adjusted to 7 with saturated aqueous NH ₄ Cl. The mixture was extracted with EtOAc (3x50 mL) and DCM (2x50 mL) and the combined organic layers were dried (MgSO ₄ ) and evaporated to give a cream foam (685 mg, 94%), which was used without further purification; 5 _H (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 ⁺ ) 367 (MH ⁺ ).

The compounds of formula Ij, i.e. compounds of general formula I, wherein R ¹ , R ² and R ⁴ are hydrogen and R ⁵ is -NR ⁸ -SO ₂ Me, shown in Table 12, were prepared according to the procedure in Example 105 of the precursors indicated.

dj)

Table 12

When- mayor Smoke- sort L R ⁸ Data 106 Prep. 96 SMe Η δ _Η (CDC1 ₃ , 300 MHz) 2.47 (3H, s), 3.02 (3H, s), 3.08 (3H, br), 3.85 (2H, s), 6.87 (2H, m), 6.99 (1H, d) , 7.15 (1H, dd), 7.20 (1H, d), 7.30 (1H, d); MS m / z (ES ~) 371 (MH ⁺ ) 107 Prep. 97 (V Η The crude product used in the next 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 Prep. 100 SMe Me The crude product used in the next step: δ _Η (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 Prep. 99 ^ A ^ SMe Me Η δπ (CD ₃ OD, 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 ⁺ ) 353

(MND, (ES ~) 351 (M ND

EXAMPLE 110

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

0,

Dicyclocarbodiimide (460 mg, 2.23 mmol) was added to a solution of pentafluorophenol (413 mg, 2.24 mmol) in ether (10 mL), then formic acid (95 pL, 2.5 mmol) was added. The mixture was stirred for 2 hours and filtered, the residue was washed with ether. The filtrate was concentrated to 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 hours and then concentrated to give an oily residue. This crude oil was taken up in a solution of BH ₃ THF in THF (1 M, 20 mL, 20 mmol) and refluxed for 1.5 hours under nitrogen. After cooling to room temperature, the reaction was quenched by careful addition of MeOH (10 mL) and concentrated in vacuo. The oily residue was treated with 6M HCl and refluxed for 30 min. After cooling to room temperature, the mixture was basified with aqueous K ₂ CO ₃ 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 dissolved in EtOAc (20 mL) and treated with 1M ether HCl (2 mL). After stirring for 1.5 hours, the solid was filtered to give the title product (282 mg, 60%); δ _Η (CD ₃ OD, 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 ), 6.80-6.90 (3H, m), 7.22 (1H, d), 7.44 (1H, s); MS m / z (TS ⁺ ) 381 (MH ⁺ ).

The compounds of formula Ik, i.e., compounds of general formula I, wherein R ¹ and R ⁴ are hydrogen and R ² is methyl and R ⁵ is -NHSO ₂ Me, shown in Table 13, were prepared according to the procedure in

Example 110 of said precursors.

(Ik)

Table 13

When- mayor Smoke, cop h D. i 'ζ Data 111 Example it 107 ¹ CX γΜ SMe δΗ (CDCl ₃ , 400 MHz) 2.40 (6H, s), 2.99 (3H, s), 3.70 (2H, s), 6.64 (2H, t), 6.88 (1H, d), 7.15 (1H, d). 7.25 (2H, s); MS m / z (TS ⁺ ) 371 (MH ⁺ 112 An example. ¹⁰⁶ (1 and γ \ ι SMc HCl salt: δΗ (CD ₃ OD, 400 MHz) 2.55 (3H, s), 3. 82 (3H, s), 3.04 (3H, s), 4.32 (2H, s), 6.97 (1H, d), 7.11 (1H, d), 7.23 (1H, s), 7.30 (1H, d), 7.39 (1H, d), 7.56 (1H, s); MS m / z (TS ⁺ ) 387 (MH ^{&lt; +} & gt ^; ) 113 An example 109 i Me HCl salt: δΗ (CD ₃ OD, 400 MHz) 2.24 (3H, s), 2.39 (3H, s), 2.76 (3H, s), 2.93 (3H, s), 4.25 (2H, s), 6.69 (1H , d), 6.82 (1H, d), 6.93 (1H, s), 7.17 (1H, d), 7.21 (1H, d), 7.43 (1H, s); MS m / zi (ES ⁺ ) 367 (MH ⁺ ), (ES ~) 365 (MH ⁺ )

Compounds of formula Im, i.e., compounds of general formula I, wherein R ¹ and R ⁴ are hydrogen, R ² is methyl, and R ³ is -N ⁸ SO ₂ Me, shown in Table 14, were prepared according to the procedure in Example 110 of these precursors.

Table 14

When- mayor Smoke- sort R ⁸ '1 ^ Ζ Data 114 85 N. % HCl salt: δΗ (CDCl ₃ , 400 MHz) 2.09 (2H, 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 ⁺ ) 347 (MH ⁺ ) 115 84 N. fs SMe HCl salt: δΗ (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 (1H, s); MS m / z (TS +) 367 (MH ^{&lt; +} & gt ^; ) 116 ^a 88 Me ¢. SMe δΗ (CDCl ₃ , 300 MHz) 2.17 (3H, s), 2.37 (3H, s), 2.48 (3H, s), 2.62 (3H, s), 2.97 (3H, s), 3.34 (3H, s ), 4.23 (2H, s), 6.79 (1H, d), 6.94 (2H, s), 7.35 (2H, m), 7.81 (1H, s); MS m / z (TS ⁺ ) 381 (MH ⁺

When- mayor Smoke- sort R ⁸ ф ,. Z Data 117 89 he C- " SMe HCl salt: δΗ (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 ⁺ ) 410 (MH ^{&lt; +} & gt ^; ) 118 87 n 457 HCl salt: δΗ (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 ⁺ ) 381 (MH ^{&lt; +} & gt ^; ) 119 Prep. 86 n 1 HCl salt: δΗ (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), 6.85 (2H , m), 7.00 (1H, s), 7.20 (1H, d), 7.24 (1H, dd), 7.47 (1H, d); MS m / z (TS ⁺ ) 365 (MIT)

^a - also obtained from Example 108 by the method of Example 110.

The compounds of formula In, i.e., compounds of general formula I, wherein R ¹ and R ² are methyl, R 4 is hydrogen and R ⁵ is -N ⁸ SO ₂ Me, shown in Table 15, were prepared according to the procedure in Example 12 of the precursors indicated.

γ

Table 15

When- mayor Smoke- sort R ⁸ _In Ζ Data 120 An example 111 N. ψ, SMe HCl salt: δΗ (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 ( 1H, d), 7.28 (1H, d), 7.39 (1H, t), 7.48 (1H, s); MS m / z (TS ⁺ ) 385 (MH ^{&lt; +} & gt ^; ) 121 (by the first amine) An example 105 n δΗ (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 ') 367 (MH + 122 (by the first amine) An example 106 n T Zxs SMe HCl salt: δΗ (CD ₃ OD, 400 MHz) 2.49 (3H, s), 2.93 (6H, s), 3.00 (3H, s), 4.41 (2H, s), 6. 95 (1H, d). 7.07 (1H, d), 7.21 (1H, s), 7.33 (2H, m), 7.54 (1H, s); MS m / z (TS ⁺ ) 395 (MH ⁺ 123 An example 114 n a HCl salt: δΗ (CDCl ₃ , 400 MHz) 2.12 (2H, m), 2.81 (6H, s), 2.91 (4H, t), 3.13 (3H, s), 4.25 (2H, s), 6.73 (1H. d) 6.83 (2H, m), 7.10 (1H, d), 7.39 (1H, d), 7.90 (1H, s); MS Wz (TS ⁺ ) 360 (MH ^{+ 1} 124 An example 118 n V δΗ (CDCl ₃ , 400 MHz) 2.22 (6H, s), 2.98 (3H, s), 3.07 (2H, m), 3.41 (2H, s), 4.38 (2H, m), 6. 36 (1H, s) ), 6.45 (1H, d), 6.86 (1H, d), 6.92 (1H, d), 7.12 (1H, d), 7.27 (1H, s); MS m / z (TS ⁺ ) 395 (MH ⁺ 125 An example 117 he Mr φ. SMe HCl salt: δΗ (CDCl ₃ , 300 MHz) 2.38 (3H, s), 2.48 (3H, s), 2.86 (6H, 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 ⁺ ) 425 (MH ^{&lt; +} & gt ^; )

When- mayor Smoke- sort ф ,. Z Data 126 (by the first amine) An example 108 Me p. SMe HCl salt: δΗ (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 (1H, d); MS m / z (TS ') 395 (MH ^{&lt; +} & gt ^; ) 127 (by the first amine) An example 109 N. Me HCl salt: δΗ (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 (1H, s); MS m / z (TS ⁺ ) 381 (MH ⁺ ), (ES ~) 379 (M “H ⁺ )

EXAMPLE 128

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

Methanesulfonyl chloride (371 pL, 4.79 mmol) was added to a solution of the aniline of Example 103 (371 mg, 4.79 mmol) and Et ₃ N (1 mL, 7.17 mmol) in DCM (10 mL) at 0 ° C. After stirring for 1 hour at 0 ° C, the reaction mixture was allowed to warm to room temperature and then the solvent was removed in vacuo. 2M NaOH (10 mL) was added to the residue and the mixture was stirred overnight. The resulting clear solution was neutralized by the addition of saturated aqueous NH ₄ Cl and extracted with DCM (2x30 mL). The combined organic extracts were dried (MgSO ₄ ) and evaporated to give an oil. It was dissolved in EtOAc (10 mL), after the addition of 1M ether HCl, the HCl salt precipitated and the product (669 mg, 67%) was isolated 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), 4.38 (2H, s), 6. 84 (1H , d), 6.93 (1H, d), 6.98 (1H, s), 7.17-7.25 (2H, m), 7.50 (1H, s); MS m / z (ES ⁺ ) 381 (MH ⁺ ).

The compounds of formula Ip, ie compounds of general formula I, wherein R ¹ and R ² are methyl, R ⁴ is hydrogen and R ³ is -NHSO ₂ R ⁹ shown in Table 16 were prepared according to the procedure in Example 128 of the precursors indicated.

(1p)

Table 16

When- mayor Smoke- sort R ⁹ ά γ Ζ Data 129 An example 104 Me HCl salt: δ _Η (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), 6.88 ( 2H, d) 7.00 (1H, s), 7.10 (1H, d), 7.27 (1H, d), 7.50 (1H, s); MS m / z (TS ⁺ ) 381 (MH ⁺ ) I 130 An example 103 Et Α Λ ! ίΙ 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 ⁺ ) 395 (MH ^{&lt; +} & gt ^; )

PREPARATIONS

PREPARATION 1

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

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 hours, a solution of methylamine in THF (2M, 70 mL, 140 mmol) was added dropwise and the reaction mixture was stirred for an additional 18 hours. The crude reaction mixture was concentrated in a small volume and EtOAc (150 mL) was added to the resulting thick oil. This mixture was stirred and the precipitate formed was isolated by filtration. This crude imidazole-contaminated product was suspended in DCM (300 mL) and refluxed for 5 hours. After cooling to room temperature, the mixture was filtered to give the desired product (19.8 g, 81%) containing <2% w / w. imidazole; 1 H NMR δ _Η (300 MHz, d ₄ -MeOH) 2.97 (3H, s), 7.40 (1H, t), 8.05 (1H, m), 8.29 (1H, d); MS m / z (TS ⁺ ) 250 (MNH ₄ ').

PREPARATION 2

3-Chloro-4- (methylsulfanyl) phenol

Cl

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) at room temperature was added 5-tert. butyl-4-hydroxy-2-methylphenyl sulfide (100 mg), then sodium thiomethoxide (NaSMe) (10 g, 143 mmol) and the reaction mixture was stirred for 6 hours. The DMF was removed in vacuo and the residue partitioned between ether (1 L) and water (1 L). The ether layer was washed with water (1 L) and saturated brine (1 L), dried (MgSO ₄ ) and the solvent was removed 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%) as a yellow solid; 5h (400 MHz, CDCl3) 2.53 (3H, s), 7.20 (1H, d), 8.09 (1H, dd), 8.20 (1H, d).

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

To a mixture of the above compound (14.08 g, 69 mmol) in acetic acid (300 mL) and water (60 mL) was added Fe powder (23 g, 412 mmol) and the reaction mixture was stirred until the starting material was completely dissolved. The mixture was allowed to stand for 1.5 hours and the acetic acid was removed under reduced pressure. The residue was taken up in saturated aqueous NaHCO3 (500 mL) and EtOAc (500 mL) and filtered through Arbocel (R). The layers were separated, the aqueous phase extracted with EtOAc (300 mL) and the combined organic layers washed with saturated brine, dried (MgSO ₄ ) and the solvent removed in vacuo to give the title compound (11.52 g, 96% ) as a beige solid 5n (400 MHz, CDCl3) 2.38 (3H, s), 3.66 (2H, br), 6.53 (1H, dd), 6.70 (1H, d), 7.12 (1H, d); MS / and / z (ES ⁺ ) 174 (MH ⁺ ).

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

The above aniline (11.5 g, 66.2 mmol) was dissolved in a minimum of THF (~ 15 mL) and water (500 mL) was added with vigorous stirring, then KOHn.H ₂ SO ₄ (25 mL) was added. The mixture was cooled in an ice water bath and a solution of NaNO ₂ (5.0 g, 72.5 mmol) in ice water (10 mL) was added using a pipette below the surface of the reaction mixture. The reaction mixture was stirred at 0 ° C for 1.5 hours and the resulting yellow / brown solution was decanted from the remaining precipitate in a separating funnel containing ice (-200 g). This solution was added at a constant rate for 7 min to a vigorously stirred mixture of Cu (NO ₃ ), (230 g, 0.99 mol) and Cu ₂ O (8.52 g, 67.4 mmol) in water (1 L) at room temperature. . After the addition was complete, the mixture was stirred for a further 15 min then extracted with ether (500 mL). The residual red / brown solid in the reaction vessel was dissolved in MeOH (100 mL) and diluted with ether (300 mL) and then poured into the upper aqueous layer. The ether layer was separated and the combined organic layers were extracted with 1 N NaOH (3 x 100 mL). The aqueous extracts were acidified with concentrated HCl, then extracted with ether (2 x 150 mL). The ether layers were washed with saturated brine, dried (MgSO ₄ ) and the solvent removed in vacuo to give phenol (5.465 g, 47%) 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).

101

PREPARATION 3

3-fluoro-4- (methylsulfanyl) phenol

This compound was prepared by a similar method to that described above in Preparation 2, based on the commercially available 3,4-difluoronitrobenzene; bn (CDCl ₃ , 300 MHz) 2.40 (3H, s), 5.03 (1H, br), 6.60 (2H, 1H), 7.27 (1H, m masked); MS m / z (ES ~) 157 (MIG).

PREPARATION 4

2,3-Dihydro-1,4-benzoxathin-6-ol

1,2-Dibromoethane (2.3 mL, 26.7 mmol) and K ₂ CO ₃ (8.21 g, 59.4 mmol) were stirred in acetone (250 mL) and a solution of 2-sulfanyl 1.4 was added to the stirred mixture for 4 hours. -benzenediol (prepared according to J. Org. Chem. 1990, 55, 2736) (4.22 g, 29.7 mmol) in acetone (50 mL). After completion of the addition, stirring was continued for a further 10 hours, after which time the solvent was removed in vacuo. The residue was partitioned between water (50 mL) and EtOAc (50 mL), the aqueous solution 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%) as

102 pale orange oil; bz (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 Wz (ES *) 167 (ΜΊΗ +).

PREPARATION 5

2,3-Dihydro-1,4-benzoxathin-7-ol

The title compound was prepared by a similar method to that used above in Preparation 4, starting from 4-sulfanyl-

1,3-benzenediol (prepared according to J. Org. Chem. 1979, 26, 49714973); δ _Η (CDCl 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 ⁺ ) 169 (MH ⁺ ).

PREPARATION 6

1,3-Dihydro-1,4-benzofuran-5-ol

1,3-Dihydro-2-benzofuran-5-amine (prepared according to US 4,000,286) (2.7 g, 20 mmol) was dissolved in a mixture of water (300 mL) and kohh.H ₂ SO ₄ (21 mL), cooled to 0 ° C and NaNO ₂ (1.43 g, 20.7 mmol) in water (10 mL) was added over 15 min. After stirring at 0 ° C for 1 hour, the mixture was stirred at 10 ° C for 30 min and then urea was added until a negative starch / KI test was observed. The solution was then poured for more than 2 min into a mixture of water (180 mL) and kohh.H ₂ SO ₄ (12.6 mL) at 90 ° C and at

103 this temperature was stirred for 1.5 hours. The hot mixture was filtered and allowed to cool to room temperature. The aqueous mixture was extracted with EtOAc (2 x 100 mL) and the combined organic layers were dried (MgSO ₄ ) and evaporated to give the title phenol (974 mg, 36%) as a cream solid; 5h (CDCl3, 400 MHz) 5.03 (4H, s), 6.71 (2H, m), 7.08 (1H, d).

PREPARATION 7

2,3-Dihydro-1-benzothiophen-1-ol

(1) Preparation of 2,3-dihydro-1-benzothiophen-6-ol 1,1,1-dioxide Suspension of 2,3-dihydro-1-benzothiophen-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 kohh.H ₂ SO ₄ (35 mL) was heated to give a solution. The mixture was cooled to 0 ° C and a solution of NaNO ₂ (6.22 g, 90 mmol) in water (15 mL) was added over 5 min. After stirring the reaction mixture at 0 ° C for 1 hour, urea was added to remove excess nitrite to obtain a negative starch test / K.1. The mixture was then allowed to warm to room temperature and a mixture of kohu.H ₂ SO ₄ (55 mL) and water (750 mL) at 90 ° C was added with stirring. The reaction mixture was reheated to 90 ° C and stirred at this temperature for 30 min. The hot reaction mixture was filtered through Arbocel® and then stirred at room temperature overnight. The aqueous mixture was extracted with ether (2.5 L) and then with EtOAc (5 x 500 mL) and

104 combined organic layers were dried (MgSO ₄ ) and evaporated to give the desired phenol (12.7 g, 80%), which was used without further purification; bn (CD ₃ OD, 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 (MFC).

(ii) Preparation of 2,3-dihydro-1-benothiophen-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 heated to reflux. refrigerator 16 hours. After cooling to room temperature, EtOH (75 mL) and then water (100 mL) were added gently with stirring. 6M HCl was added to the resulting slurry 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 a cream solid. After purification by column chromatography [SiO ₂ ; DCM / MeOH / 880 NH3 (97: 3: 0.25) increasing polarity to (95: 5: 0.5)] gave the title phenol as a cream solid (1.85 g, 53%); δ, ι (CD ₃ OD, 400 MHz) 3.13 (2H, t), 3.30 (2H, m), 6.41 (1H, d), 6.60 (1H, s), 6.98 (1H, d); MS m / z (ES) 151 (M ~ H ⁺ ).

PREPARATION 8

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

Me

105

The fluoroamide of Preparation 1 (732 mg, 3.15 mmol) was treated with 4- (methylthio) -t-cresol (commercial) (535 mg, 3.47 mmol) and potassium carbonate (457 mg, 3.31 mmol) in DMF (10 mL). . The mixture was heated at 100 ° C for 5 hours. The solvent was removed under reduced pressure and the residue treated with 2M HCl (10 mL). The resulting suspension was extracted several times with dichloromethane. The combined layers of dichloromethane contain the suspension and evaporate to a solid residue. The residue was triturated with ether (5 mL) and the remaining solid was washed with ether (3x10 mL) to give an off-white solid (765 mg, 66%). bz (300 MHz, d ₆ DMSO) 2.28 (3H, s), 2.48 (3H, s), 2.70 (3H, d), 6.90 (1H, d), 7.02 (1Η, d), 7.03 (1H, s ), 7.30 (1H, d), 7.35 (2H, s), 7.79 (1H, d), 8. 10 (1H, d), 8.30 (1H, m); MS W 2 (TS ⁺ ) 367 (MH ⁺ ), 385 (MNH ₄ ⁺ ).

PREPARATIONS 9-18

Compounds of formula Va, i.e., compounds of general formula I, where T is -C (= O) NHMe, R ⁴ is hydrogen and R? is -SO ₂ NH ₂ shown in Table 17 were prepared according to the procedure in Preparation 8 using the sulfonamide of Preparation 1 and said phenol.

, Me (Va)

106 '^ w

Table 17

Drug Precursor phenol X Z Data 9 Synth. Sottype. 1991.21. 959-964 2, 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 ⁺ ) 365 (MH ^{&lt; +} & gt ^; ) 10 References 5 0, uh 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 ⁺ ) 381 (MH ^{&lt; +} & gt ^; ) 11 Referral i! ' SMc 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 ~) 371 (MH ⁺ ) 12 Prep.2 ά, S \ le 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 (1H, s). 7.37 (1H, d), 7. 92 (1H, d), 8.28 (1H, s); MS w / z (ES ⁺ ) 387 (MH ⁺ 13 Refer 4 X 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 (1H, s ), 8.28 (1H, brs); MS m / z (ES) 381 (MH + 14 Prep.6 / δ _Η (d ₆ -DMSO, 400 MHz) 2.79 (3H, s), 4.98 (4H, brs), 6.92 (1H, d), 7.04 (1H, d), 7.09 (1H, s), 7.37 (3H. m), 7.79 (1H, m), 8.10 (1H, s), 8.30 (1H, s); MS m / z (TS ⁺ ) 349 (MH ^{&lt; +} & gt ^; ) 15 Commercial 2, 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 (1H, d), 7.81 (1H , d), 8.31 (1H, s); MS m / z (TS +) 347 (MH ^{&lt; +} & gt ^; )

107

Drug Precursor phenol ά ,. Ζ Data 16 Tetrahedron 1982.38 2721 & Synthesis 1982.475 4% Me The product was used without purification 17 Prep. 101 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 (1H, d), 7. 81 (1H , d), 8.31 (1H, s); MS m / z (TS ⁺ ) 347 (MNH ₄ ^{&lt; + &gt;} ) 18 Prep. 7 ά 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 (1H, br, d); MS m / z (ES) 363 (M'ND

PREPARATION 19

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

A mixture of 5-bromo-2-fluorobenzaldehyde (1.08 g, 5.32 mmol), 5hydroxy-2,3-dihydrobenzothiophene (prepared as described in Synth. Commun. 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 at 90 ° C for 16 hours. After cooling to room temperature, the mixture was partitioned between water (50 mL) and ether (50 mL), the aqueous layer was extracted with ether (50 mL). The combined organic extracts were washed

Wb *

108 watts with water (50 mL), dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography [SiO ₂ ; 9: 1 (pentane / EtOAc)] then triturated with ether to give the product (1.1 g, 62%) as a pale yellow solid; δ _Η (CDCl ₃ , 400 MHz), 3.28 (2H, t), 3.41 (2H, 6.78 (1 Η, 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).

The compounds of general formula II shown in Table 18 were prepared according to the procedure in Preparation 19 by reacting said phenol with the required 2-fluorobenzaldehyde.

In most cases, the crude reaction product after treatment with water is used directly in the following steps without further purification.

Table 18

Prepa- rat Smoke- phenol R ⁴ R ⁵ Z Data 20 Referral N. Br T. SMe δ _Η (CDCl ₃ , 300 MHz) 2.48 (3H, s), 6.81 (3H, m), 7.37 (1H, t), 7.64 (1H, d), 8.06 (1H, s), 10.39 (1H, s) ; MS m / z (TS ⁺ ) 358.360 (MNH ₄ ⁺ )

109

Prepa- rat Precursor phenol R ⁴ R ⁵ “In Z Data 21 References 5 N. Br δ _Η (CDCl ₃ , 400 MHz) 3.13 (2H, m), 4.42 (2H, m), 6.55 (1H, s), 6.59 (1H, d), 6.81 (1H, d), 7.04 (1H, d) , 7.59 (1H, d), 8.01 (1H, s), 10. 40 (1H, s) 22 Prep.2 N. Br SMe 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) , 8.00 (1H, s) 23 Trade- ski N. Br p. SMe δ _Η (CDC1 ₃ , 300 MHz) 2.35 (3H, s), 2.49 (3H, s), 6.78 (1H, d), 6.90 (2H, s), 7.22 (1H, d), 7.59 (1H, d) , 8.05 (1H, s), 10.45 (1H, s); MS m / z (TS ⁺ ) 356.354 (MNH ₄ ⁺ ) 24 Trade- ski N. MeO SMe δ _Η (CDCl ₃ , 300 MHz) 2.35 (3H, s), 2.45 (3H, s), 3.87 (3H, s), 6.82 (1H, d), 6.83 (1H, s), 6.92 (1H, d) , 7.13 (1H, dd), 7.19 (1H, d), 7.40 (1H, d), 10.40 (1I, s); MS m / z (TS ⁺ ) 389 (MH ^{&lt; +} & gt ^; ) : -5 Trade- ski N. F A <4 δ _Ν (CDC1 ₃ , 300 MHz) 7.02 (1H, dd), 7.21 (1H, s), 7.30 (1H, m), 7.40 (1H, m), 7.54 (1H, d), 7.66 (1H, dd) , 8.0C1H, d), 8.18 (1H, d), 8.88 (1H, d), 10.43 (1H, s); MS m / z (ES ⁺ ) 268 (MH ^{&lt; +} &gt;) 26 Trade- ski n N. 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), 7.928.01 (2H, m), 8.11 (1H, d), 8.83 (1H, d), 10.50 (1H. s); MS m / z (ES ⁺ ) 272 (MNa ⁺ ), (ES “) 248 (M“ H ⁺ )

110

P

W · '

Prepa- rat Smoke- phenol R ⁴ R ⁵ A ζ Data 27 J. Chem. Soc. 1952 4985-4993 Η Η φ. δ _Η (CDC1 ₃ , 300 MHz) 7.08 (1Η, 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 ⁺ ) 251 (MH ^{&lt; +} & gt ^; ) 28 Trade- ski Η Η δ _Η (CDCl ₃ , 400 MHz) 7.09 (1H, d), 7.28 (1H, m), 7.35 (1H, m), 7.40 (1H, m), 7.50 (1H, br), 7.59 (1H, m) , 7.86 (1H, dd), 7.99 (1H, dt), 8.15 (1H, d), 8.86 (1H, m), 10.46 (1H, s); MS m / z 250 (MH ^{&lt; +} & gt ^; ) 29 Chem. Pharm. Bull .. 1978. 26.1443 Η Η φ. A 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 ), 10.5 (1H, s); MS m / z 256 (MH ^{&lt; +} & gt ^; ) 30 Trade- ski Η Η C ..... 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 ⁺ ) 259 (MH ^{&lt; +} & gt ^; ) pl Synth. Com type. 1991.21. 959-964 Η Η τ 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) , 7.92 (1H, d), 10.51 (1H, s); MS w / z (TS ^) 257 (MH) 32 Trade- ski Nr Η φ. SMe δ _Η (CDCl ₃ , 400 MHz) 2.36 (3H, s), 2.44 (3H, s), 6.88 (2H, m), 6.96 (1H, s), 7.18-7.25 (2H, obs), 7.77 (1H. d), 10.43 (1H, s)

Ill

Drug Precursor phenol R ⁵ Z Data 33 7 n Br 'λ δ _Η (CDCl ₃ , 400 MHz) 3.27 (2H, m), 3.42 (2H, m), 6.67 (1H, d), 6.80 (1H, d), 6.90 (1H, s), 71.6 (1H, d) , 7.58 (1H, d), 8.01 (1H, s), 10.41 (1H, s); MS m / z (TS ⁺ ) 354 (MNH?) 34 ^a Trade- ski n CN ι ^ Ί 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 (ES ”) 273 (MH), (ES ⁺ ) 275 (MH ⁺ )

¹¹ - 4-Fluoro-3-formylbenzonitrile was synthesized according to Synth.Commun. 1997, 27 (7), 1199 and J.Org.Chem. 1961, 26, 2522.

The product from Preparation 30 was obtained as follows.

Potassium carbonate (334.1 g, 2.42 mol) and 4- (methylthio) -1H-cresol (273.4 g, 1.77 mol) were added sequentially to DMF (2 L). 2-Fluorobenzaldehyde (200 g, 1.61 mol) was then added and the Г mixture was heated at 100-110 ° C. After 48 hours, the mixture was allowed to cool to room temperature and water (1.2 L) was added. The solution was cooled to below 10 ° C and the pH was adjusted to 5 with concentrated HCl (0.37 L) while maintaining 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 azeotropically to remove water. The dried dichloromethane solution was concentrated in vacuo to give the crude product as an oil (422 g, 100%).

112

The compounds of formula IX shown in Table 19 were prepared according to the procedure in Preparation 19 using 2-chloro 5-nitrobenzaldehyde or 2-chloro-5-nitrobenzonitrile with said phenol. These reactions usually require shorter times to achieve good conversion. In most cases, the crude reaction product after treatment with water is used directly in the following steps without further purification.

Table 19

Prepa- rat Smoke- sort W ά, Ζ Data 35 Referral -C = N 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 (1H, s) 36 Prep. 5 Fr. Ah, X uh 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 ⁺ ) 318 (MH ^{&lt; +} & gt ^; )

113

Prepa- rat Smoke- sort W ζ Data 37 Prep.2 -C = N φ ,. 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 ⁺ ) 338 (MNH ₄ ^{&lt; + &gt;} ) 38 Synth. Comrmtn. 1991.21. 959-964 0 Λ, 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, d), 8.26 (1H, d) , 8.75 (1H, s), 10.54 (1H, s) 39 Trade- ski ο Λ, 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 (1H, dd) ), 8.78 (1H, d), 10.57 (1H, s) 40 Trade- Ski ο Λ. V) 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, d), 8.79 (1H, s) , 10.59 (1H, s); MS m / z (TS ⁺ ) 301 (MNH ₄ ^{&lt; + &gt;} ) 41 Refer 4 -CAN ίϋ 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 ⁺ ) 332 (MNH ₄ ^{&lt; + &gt;} ) 42 Trade- ski -C = N "" SMe δ _Η (CDCl ₃ , 400 MHz) 2.32 (3H, s), 2.47 (3H, s), 6.87 (1H, d), 6.94 (2H, m), (1H, d), 8.26 (1H, dd). 8.51 (1H, d); MS m / z (TS ⁺ ) 318 (MNH ₄ ⁺ ) 43 Tetrahedron 1982. 38. 2721 & Synthesis 1982.475 -CAN ό ....... Me 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 ⁺ ) 318 (MNH ₄ ⁺ )

114

PREPARATION 44

Tert-Butyl-5-bromo-2- (2,3-dihydro-1-benzothien-5-yloxy)

benzyl (methyl) carbamate 0 Λ '/ ^x N OtBu A Me 0 AA s— /

The hydrochloride salt of Example 36 (1.04 g, 2.7 mmol) was mixed with DCM (12 mL) and Et ₃ N (750 pL, 5.38 mmol) was then added, and then ditret-butyl dicarbonate (766 mg, 3.51 mmol). After stirring at room temperature for 20 min, the reaction was quenched by the addition of 0.2M HCl (20 mL). The well shaken mixture was separated and the aqueous layer extracted with DCM (10 mL). The combined organic extracts were dried (MgSO ₄ ) and evaporated to give the product (quantitative yield) as a colorless oil, which was used without purification: δ _Η (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 (1H, d). 7.29 (1H, d), 7.39 (1H, s).

The compounds of formula X shown in Table 20 were prepared according to the procedure in Preparation 44 based on the precursors indicated.

115

(X)

Table 20

Prepa- rat Smoke- sort ά, 1 Ζ Data 45 An example 38 m 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, d), 7.34 (1H, s); MS m / z (ES ⁺ ) 468 (MH ^{&lt; +} & gt ^; ) 46 An example 39 / H γ4 · ι 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 (ES) 474 (MH &lt; + & gt ^; ) 47 An example 37 SMe δ _Η (CDC1 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 (ES ⁺ ) 458 (MH ^{&lt; +} & gt ^; ) 48 An example 44 ί ^ Ί ^^ TMe SMe δ _Η (CDC1 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), 7.24-7.58 (2H, m)

116

PREPARATION 49 tert-Butyl-5-cyano-2- [3-fluoro-4 (methylsulfanyl) phenoxybenzyl- (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 (3H, s), 2.93 (3H, brs), 4.55 (2H, brs), 6.79 (2H, m), 6.88 (1H, d) , 7.35 (1H, t), 7.53 (1H, d), 7.59 (1H, s); MS m / z (TS ⁺ ) 403 (MH).

PREPARATION 50

Methyl 3- [(tert-butoxycarbonyl) (methyl) amino] methyl} -4 (2,3-dihydro-1-benzothien-5-yloxy) benzoate

OtBu

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 at 80 At 100 psi CO for 18 hours. TLC analysis indicated that the reaction was not complete, so

117 A further catalyst (190 mg, 0.27 mmol) was added and the mixture was heated at 100 ° C under a pressure of 100 psi of CO for 24 hours. The mixture was diluted with EtOAc (20 mL) and filtered through a pad of silica gel, eluting with EtOAc. The solvent was removed in vacuo and the residue partitioned between EtOAc (50 mL) and a 2: 1 mixture of water: 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)] afforded the product (970 mg, 84%) as an oil; δ _Η (CDC1 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 ') 430 (MH ^T ).

The compounds of formula XI shown in Table 21 were prepared according to the procedure in Preparation 50 based on the precursors indicated.

Oh

MeO

Y (XI)

Oh

OtBu

118

Table 21

Prepa- rat Smoke- sort V '· ζ Data 51 Prep.45 Uh- δ _Η (CDCl ₃ , 400 MHz) 1.42 (9H, s), 2.86 (2H, m), 3.07 (2H, m), 3.85 (3H, s), 4.37 (2H, m), 4.48 (2H, m) , 6.48 (2H, tn), 6.79 (1H, d), 6.97 (1H, d), 7.83 (1H, d), 7.95 (1H, s); MS m / z (ES ⁺ ) 446 (MH ^{&lt; +} & gt ^; ) 52 Prep.46 SMe δ _Η (CDC1 ₃ , 400 MHz) 1.43 (9H, brs), 2.47 (3H, s), 2.88 (3H, brd), 3.90 (3H, s), 4.51 (2H, brd), 6.81 c (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 ⁺ ) 469 (MNHf) 53 Prep. 4 7 SMe δ _Η (CDC1 ₃ , 400 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 (1H, d), 7.35 (1H, m), 7.92 (1H, d), 8.02 (1H, brs); MS m / z (TS ⁺ ) 453 (MNH2) 54 Prep. 4 8 ^c 1 δ _Η (CDCl ₃ , 300 MHz) 1.44 (9H, s), 2.37 (3H, s), 2.47 (3H, s), 2.94 (3H, br), 3.90 (3H, 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 ⁺ ) 454 (MNa)

PREPARATION 55

3 - {[(tert-Butoxycarbonyl) (methyl) aminomethyl} -4- (2,3-dihydro-1-benzothien-5-yloxy) benzoic acid

119

A solution of the ester from Preparation 50 (970 mg, 2.26 mmol) in THF (20 mL) and IM LiOH (20 mL) was refluxed for 16 hours. After cooling to room temperature, THF was removed in vacuo, the residue was neutralized with saturated aqueous NH ₄ Cl and the extract was extracted with DCM (100 mL) and then with (100 mL). The combined organic layers were dried (MgSO ₄ ) and evaporated to give a white foam (960 mg) which was used without purification; bn (CDCL, 400 MHz) 1.30 (9H, s), 2.78 (3H, brs), 3.20 (2H, brs), 3.38 (2H, t), 4.41 (2H, t), 6.62 (2H, t), 6.78 (1H, m), 7.10 (1H, m), 7.84 (1H, m), 7.99 (1H, m); MS m / z (ES ^_) 414 (M-H).

Compounds of formula XII shown in Table 22 were prepared according to the procedure in Preparation 55 of said precursors.

(XI)

120

Table 22

Prepa- rat Smoke- sort 6, Z Data 56 Prep. 51 CA A 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), 6.64 (1H, d) , 6.87 (1H, d), 7.68 (1H, brs), 7.78 (1H, brs); MS m / z (ES ^_ ) 430 (MAT ') 57 Prep. 52 Λ, 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 (M “ET) 58 Prep. 53 A% SMe δ _Η (CDC1 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) 420 (M ~ H ⁺ )

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

S

121

Et ₃ N (267 pL, 1.92 mmol), HOBt.H ₂ O (129 mg, 0.84 mmol) and

WSCDI (191 mg, 1.0 mmol) was added to a solution of acid from Preparation 55 (318 mg, 0.77 mmol) in DCM (10 mL) and the mixture was stirred for 1 hour, then saturated NH ₃ solution in THF (2 was added). mL). After stirring for an additional 16 hours, the reaction mixture was diluted with water (50 mL), 0.2M HCl (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 (quantitative yield), which was used without C 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 (3H, m), 7.18 (1H, d), 7.68 (1H, d), 7.74 (1H, s) .

The compounds of formula XIII shown in Table 23 were prepared according to the procedure in Preparation 59 of said precursors.

OtBu (XIII)

122

Table 23

Prepa- rat Smoke- sort R ⁵ 0, Z Data 60 Prep. 55 0 Med n T. δ _Η (CDCl ₃ , 400 MHz) 1.43 (9H, s), 2.83-3.00 (6H, m), 3.24 (2H, t), 3.39 (2H, t), 4.51 (2H, brs), 6.70 6.85 (3H , m), 7.15 (1H, d), 7.62 (1H, d), 7.68 (1H, s) 61 Prep. 55 L. S OMe δ _Η (CDCl ₃ , 400 MHz) 1.46 (9H, s), 2.89 (3H, br), 3.24 (2H, t), 3.37 (5H, m), 3.56 (2H, t), 3.63 (2H, m) , 4.54 (2H, br), 6.46 (1H, br), 6.75-6.86 (3H, m), 7.16 (1H, d), 7.62 (1H, d), 7.69 (1H, s) ' 62 Prep. 58 O L NL ⁴ SMe δ _Η (d ₆ -DMSO, 400 MHz) 1.29 (9H, br), 2.40 and (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 (T8D 438 (MNH ₄ ⁺ ) 63 Prep. 58 0 n 1 SMe δ _Η (CDC1 ₃ , 400 MHz) 1.41 (9H, s), 2.40 (3H, s), 2.92 (3H, brs), 2.98 (3H, d), 4.45 (2H, and brs), 6.10 (1H, brs) ), 6.67 (2H, m), 6.88 (1H, d), 7.27 (1H, obs), 7.63 (2H, m); MS m / z (TS ⁺ ) 452 (MNH ₄ ^{&lt; + &gt;} ) 64 Prep. 58 0 1 5 OMe A 1 SMe δ _Η (CD ₃ OD, 400 MHz) 1.40 (9H, s), 2.40 (3H, s), 2.81 (3H, brs), 3.35 (3H, s), 3.53 (2H, m), 3.61 (2H, m ), 4.44 (2H, brs), 6.45 (1H, brs), 6.66 (2H, m), 6.87 (1H, d), 7.29 (1H, d), 7.64 (1H, d), 7.72 (1H, s) ; MS m / z (TS ') 479 (MH + 65 Prep. 57 0 "L. SMe δ _Η (CDC1 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 ^_) 435 (MH ⁺⁾ 66 Prep. 57 n 0 ,. SMe δ _Η (CDC1 ₃ , 400 MHz) 1.42 (9H, brs), 2.47 (3H, s), 2.88 (3H, brd), 3.00 (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 (M'H ⁺ )

123

Prepa- rat Smoke- sort R ⁵ 0, Z Data 67 Prep. 56 o L n ₂ \ ⁴ '—O δ _Η (CDCl ₃ , 400 MHz) 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 Prep. 56 "A OMe 0 ,. uh 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), 6.64 (1H, d) , 6. 87 (1H, d), 7.68 (1H, brs), 7.78 (1H, brs); MS m / z (ESM 430 (M'H ⁺ )

PREPARATION 69 tert-Butyl 2-3-chloro-4- (methylsulfanyl) phenoxy 1-5 (hydroxymethyl) benzyl (methyl) carbamate

A solution of LiAlH ₄ in THF (1M, 2 mL, 2 mmol) was added dropwise to a solution of the ester of Preparation 52 (452 mg, 1 mmol) in THF (10 mL) under nitrogen. After the TLC was determined to be complete, ether (10 mL) was added and excess LiAlH _{4 was} deactivated by carefully adding 2M NaOH. The organic layer was separated, washed with saturated brine, dried (MgSO ₄ ) and evaporated. Purification of the residue by column chromatography [SiO ₂ ; 39: 1 (DCM / MeOH)] is desired

124% alcohol (200 mg, 47%) as a gummy white substance; δ _Η (CDC1 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 ⁺ ) 446 (MNa *).

Compounds of formula XIV shown in Table 24 were prepared according to the procedure in Preparation 69 of said precursors.

OtBu (XIV)

Table 24

Drug Smoke- sort Z Data 70 Prep. 53 SMe δ _Η (CDC1 ₃ , 400 MHz) 1.39 (9H, brs), 1.99 (1H, brs), 2.39 (3H, s), 2.78 (3H, brd), 4.39 (2H, brs), 4.62 (2H, d) , 6.61 (2H, t), 6.88 (1H, d), 7.20-7. 30 (3H, m + CHCl ₃ ); MS m / z (TS ⁺ ) 408 (MH ^{&lt; +} & gt ^; ) 71 Prep. 54 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), 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 ⁺ ) 404 (MH ^{&lt; +} & gt ^; )

125

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

Me '

OtBu

SMe

A solution of diethyl azodicarboxylate (505 pL, 3.21 mmol) in THF (5 mL) was added dropwise 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) at 0 ° C. The reaction mixture was stirred for 2 hours at 0 ° C and then diluted with EtOAc (80 mL) and washed with 10% aqueous K ₂ CO ₃ (100 mL). The organic layer was washed with saturated 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%) as a colorless oil; δ _Η (CDC1 ₃ , 300 MHz) 1.45 (9H, s), 1.52 (9H, s), 2.38 (3H, s), 2.44 (3H, s), 2.83 (3H, s), 3.22 (3H, s) , 4.49 (2H, s), 4.85 (2H, s), 6.74-6.83 (3H, m), 7.18-7.29 (3H, obs); MS m / z (TS ') 481 (MH + -BOC).

126

PREPARATION 73

Tert-Butyl 3-1G (tert-butoxycarbonyl) (methyl) amino) methyl} 4- [3-fluoro-4- (methylsulfanyl) phenoxy} benzyl (methylsulfonyl) carbamate

The title compound was obtained from the alcohol of Preparation 70 by the method of Preparation 72; δ _Η (CDC1 ₃ , 300 MHz) 1.44 (9H, s), 1.52 (9H, s), 2. 44 (3H, s), 2.82 (3H, s), 3.23 (3H, s), 4.45 (2H, s), 4.87 (2H, s), 6.61-6.70 (2H, m), 6.90 (1H, d), 7.25-7.33 (3H, m); MS m / z (ESD 607 (MNa &apos;).

PREPARATION 74

Tert-Butyl 4- {(dimethylamino) methyl] -3- [3-methyl-4- (methylsulfanyl) phenoxy] benzyl (methylsulfonyl) carbamate

SMe

127

The title compound was obtained from the alcohol of Preparation 59 by the method of Preparation 72. The crude product was not purified by column chromatography but used directly for the next step; δ _Η (CDC1 _?, 400 MHz) 1.39 (9H, s), 2.22 (6H, s), 2.28 (3H, s), 2.38 (3H, s), 3.07 (3H, s), 3.42 (2H, s) , 4.76 (2H, s), 6.72 (2H, m), 6.79 1H, s), 7.07 (1H, d), 7.12 (1H, d), 7.40 (1H, obs).

PREPARATION 75

Tert-Butyl methyl [2- [3-methyl-4- (methylsulfanyl) phenoxy] -5 ({[(trifluoromethyl) sulfonyl] amino [methyl] benzyl] carbamate

The title compound was obtained from the alcohol of Preparation 71 by the method of Preparation 72 using trifluoromethanesulfonamide instead of tert-butyl methylsulfonylcarbamate. The desired product is tainted with tert-butyl 5- ({{3 {(tert-butoxycarbonyl) (methyl)} 4- [3-methyl-4- (methylsulfanyl) phenoxy] benzyl} [(trifluoromethyl) sulfonyl] amino) methyl) -2 - [- methyl-4-methylsulfanyl) phenoxy] benzyl (methyl) carbamate and was used as a mixture; MS m / z (ES ~) 533 (M ~ H ⁺ ).

The compounds of formula XV shown in Table 25 were prepared according to the procedure in Preparation 44 of said precursors.

128

(XV)

Table 25

Prepa- rat Smoke- sort Ζ Data 76 An example 41 9- uh 5H (CDCl ₃ , 400 MHz) (major 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 ⁺ ) 433 (ΜΗ) 77 An example 40 δ _Η (CDC1 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 An example 42 X δ _Η (CDCl ₃ , 400 MHz) 1.56 (9H, s), 2.15 (2H, m), 2.85-3.00 (7H, m), 4.60 (2H, m), 6.78 (2H, m), 6.87 (1H. s), 7.12 (1H, d), 8.03 (1H, d), 8.10 (1H, s); MS m / z (TS) 399 (MH ^{&lt; +} & gt ^; )

PREPARATION 79

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

129

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

To a suspension of the aldehyde of Preparation 39 (21.0 g, 69.2 mmol) in EtOH (100 mL) was added 8M methylamine in EtOH (86.5 mL, 692 mmol). The resulting solution was stirred and a precipitate formed after a short time. It was dissolved by the addition of THF (100 mL), the solution was cooled to 0 ° C and NaBH ₄ (7.85 g, 208 mmol) was added. The reaction mixture was allowed to warm slowly to room temperature and allowed to stir overnight, after which the solvent was evaporated in vacuo. The residue V was mixed with water (150 mL) and ether (150 mL) and carefully added

2M HCl to pH 1. The layers were separated and the aqueous layer was washed with ether (2 x 100 mL). The combined organic layers were dried and evaporated to give {2- [3-methyl-4 (methylsulfanyl) phenoxy] -5-nitrophenyl) methanol (18.9 g, 89%) as a yellow solid; 5H (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 above aqueous solution was neutralized by pouring on an excess of solid K ₂ CO ₃ . The basic solution is extracted with

130 ether (2x100 mL) and these 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%) as an orange oil; MS m / z (ES ⁺ ) 319 (MH ⁺ ).

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

Methanesulfonyl chloride (4.81 mL, 61.9 mmol) was added slowly to a solution of {2- [3-methyl-4- (methylsulfanyl) phenoxy] -5nitrophenyl} 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 hours and poured into water, then extracted with DCM (3 times). The combined organic extracts were dried (MgSO ₄ ) and evaporated to give a dark viscous oil. The oil was dissolved in DCM (50 mL) and 8M methylamine in EtOH (200 mL, 1.6 mol), then Et ₃ N (10 mL, 71.7 mmol) was added. After stirring for 18 hours, the mixture was concentrated in vacuo to give the crude amine, which was used without further purification.

Tert-Butyl methyl {2- [~ 3-methyl-4- (methylsulfanyl) phenoxy] -5nitrobenzylcarbamate

The above crude amine was dissolved in DCM (100 mL) at 0 ° C and Et ₃ N (11.4 mL, 81.8 mmol) was added, then di-tert-butyl dicarbamate (15.0 g, 68.7 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours, then concentrated in vacuo. The residue was partitioned between EtOAc and water and the aqueous layer was extracted with

131

EtOAc (2 times). The combined organic layers were dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (SiO ₂ ; first column - 3% MeOH in DCM; second column EtOAc: pentane 1: 3) to give the title compound (14.2 g, 54%) as a yellow oil; 5H (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 ⁺ ) 419 (MH ⁺ ).

Compounds of formula XVI shown in Table 26 were prepared according to the procedure in Example 103 of the precursors indicated.

(XVI)

H * »- ^!

132

Table 26

Prepa- rat Smoke- sort γ ..... Z Data 80 77 S— / δ _Η (CDC1 ₃ , 300 MHz) 1.50 (9H, br), 2.80 (3H, br), 3.20 (2H, m), 2.37 (2H, m), 3.60 (2H, (2H, br), 4.40 (2H , s), 6.50- 6.80 (5H, m), 7.05 (1H, d); MS m / z (ES ⁺ ) 387 (MH ⁺ ) 81 78 t 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 (ES ⁺ ) 369 (MH ^{&lt; +} & gt ^; ) 82 76 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), 4.36 (2H, m) , 6.32 (1H, s), 6.40 (1H, d), 6.49-6. 65 (2H, m), 6.75 (1H, d), 6.88 (1H, d); MS m / z (ES ⁺ ) 403 (MH ^{&lt; +} & gt ^; ) 83 79 a. S.Mc 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 (ES) 389 (MES

PREFERENCE 84

Tert-Butyl methyl} 2- [3-methyl-4- (methylsulfanyl) phenoxy] -5 [(methylsulfonyl) aminobenzyl} carbamate

133

Methanesulfonyl chloride (4.16 mL, 53.7 mmol) was added dropwise to a solution of aniline from Preparation 83 (9.5 g, 24.5 mmol) and Et ₃ N (7.5 mL, 53.8 mmol) in DCM (50 mL) at 0 ° C. After stirring at 0 ° C for 30 min, the reaction mixture was allowed to warm to room temperature and then the solvent was removed in vacuo. To the residue was added 2M NaOH (50 mL) and the mixture was stirred for 30 min. The mixture was extracted with EtOAc and the organic layer was washed with saturated brine, dried (MgSO ₄ ) and evaporated to give an oil. After purification by column chromatography [SiO ₂ ; 97.5: 2.5: 0.25 (DCM / MeOH / 880 NH ₃ )] gave the product (9.0 g, 79%) as a brown foam; δ _Η (CDC1 ₃ , 300 MHz) 1.43 (9H, brs), 2.35 (3H, s), 2.42 (3H, s), 2.88 (3H, brs), 3.01 (3H, 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 ⁺ ) 467 (MH ⁺ ).

The compounds of formula XVII shown in Table 27 were prepared according to the procedure in Preparation 84 of said precursors.

134

Table 27

Prepa- rat Smoke- sort C ', Z Data 85 81 5c (CDCl ₃ , 400 MHz) (rotamers) 1.44 and 1.48 (9H, 2xs), 2.10 (2H, quintet), 2.88 (7H, t), 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 (3H, m); MS m / z (TS ⁺ ) 347 (MH ' -Boc) 86 80 Fr. The product was used without purification 87 82 δ ₍ | (CDC1 ₃ , 400 MHz) (rotamers) 1.40 and 1.44 (9H, 2xs), 2.80 and 2.85 (3H, 2xs), 2.95 t (3H, s), 3.07 (2H, t), 4.38 (2H, m), 6.36 (1H, s), 6.44 (1H, d), 6.84 (1H, d), 6.92 (1H, d), 7.12 (2H, t); MS m / z (TS ⁺ ) 498 (MNH ₄ ⁺ )

135

PREPARATION 88

Tert-butyl methyl {2- [3-methyl-4- (methylsulfanyl) phenoxy] -5 [methyl (methylsulfonyl) amino] benzyl} carbamate

Mel (1.07 mL, 17.2 mmol) was added dropwise to a mixture of sulfonamide from Preparation 84 (2.0 g, 4.3 mmol) and K ₂ CO ₃ (592 mg, 4.3 mmol) in CH ₃ CN (10 mL) under nitrogen. The mixture was stirred for 16 hours, then partitioned between EtOAc (50 mL) and 2M NaOH (50 mL). The organic layer was washed with saturated 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 product (1.23 g, 60%) as a yellow oil; 5Hz (CDC] 3, 300 MHz) 1.45 (9H, s), 2.34 (3H, s), 2.42 (3H, s), 2.86 (3H, s), 2.90 (3H, s), 3.28 (3H, s) , 4.49 (2H, s), 6.80 (3H, br), 7.18 (3H, m); MS m / z (TS ⁺ ) 498 (MNH ₄ ⁺ ).

PREPARATION 89

Tert-Butyl 5-N (2-hydroxyethyl) (methylsulfonyl) amino] -2- [3methyl-4- (methylsulfanyl) phenoxy] benzyl (methyl) carbamate

136

2-Bromoethanol (1.34 mL, 18.9 mmol) was added to a mixture of sulfonamide from 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) under nitrogen. The mixture was refluxed for 16 hours, cooled and then partitioned between EtOAc (50 mL) and 2M NaOH (50 mL). The organic layer was washed with saturated 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 product (524 mg, 24%) as a pink foam; δ _Η (CDC1 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), 7.19 (3H, m); MS m / z (TS ') 528 (MNH ₄ ⁺ ).

PREPARATION 90

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

ο.

137

Fe 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 hours. The solvent was removed in vacuo, the residue dissolved in EtOAc (50 mL) and 10% aqueous K ₂ CO ₃ (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%), which was used without

additional purification; δ ₁₄ (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) 302 (ΜΝΗ /).

Compounds of formula Vb, i. compounds of formula V where T is cyano, R ⁴ is hydrogen and R? is the amino shown in Table 28 were prepared according to the procedure in Preparation 90 of said precursors.

***** .CN

(Vb)

138

Table 28

Prepa- rat Smoke- sort A γ γ Ζ Data 91 35 A 1 ^g SMe δ _Η (CDC1 ₃ , 400 MHz) 2.40 (3H, s), 6.62 6.72 (2H, t), 6.80-6.90 (3H, t), 7.28 (1H, d) 92 37 A ^X C1 SMe δ, (CDCl ₃ , 300 MHz) 2.47 (3H, s), 3.83 (2H, br), 6.83-6.94 (4H, m), 7.01 (1H, s), 7.19 (1H, d); MS m / z (TS ⁺ ) 308 (MNHf) 92 42 ό Υ Me SMe 5h (CDCl ₃ , 400 MHz) 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 (MNHf) _

PREPARATION 94

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

The title compound is obtained from the nitro compound of

Preparation 43 according to the method of Example 103; (CDCl ₃ , 400 MHz) 2.27 (3H, s), 2.41 (3H, s), 3.66 (2H, br), 6.62 (1H, d), 6.79 (2H, s), 6.82

139 (1H, s), 6.89 (1H, s), 7.08 (1H, d); MS m / z (ES ⁺ ) 293 (MNa ⁺ ), (ES ^_ )

269 (M ⁺ H ⁺ ).

Compounds of formula Vc, i. compounds of formula V where T is cyano, R ⁴ is hydrogen and R? is -NHSO ₂ Me shown in Table 29 were prepared according to the procedure in Preparation 84 of said precursors.

Table 29

Prepa- rat Smoke- sort Data 95 9.90 «-J Δ 5 (CDCl ₃ , 400 MHz) 2.98 (3H, s), 3.10 (2H, m), 4.39 (2H, m), 6.67 (1H, dd), 6.76 (1H, s), 6.81 (1H, d) , 7.33 (1H, dd), 7.49 (1H, s); MS m / z (TS ⁺ ) 380 (MNHf) 96 92 t / H ci SMe δ _Η (CDCl ₃ , 300 MHz) 2.51 (3H, s), 3.06 (3H, s), 6.52 (1H, br), 6.92 (1H, d), 7.02 (1H, dd), 7.14 (1H, d) , 7.24 (1H, d), 7.41 (1H, dd), 7.57 (1H, d); MS m / z (ES ⁺ ) 391 (MNa ⁺ ) 97 91 T 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 (9H, d), 7.28 (1H. t), 7.38 (1H, d), 7.51 (1H, s); MS m / z (ES ⁺ ) 351 (MH ^{&lt; +} & gt ^; )

140

Prepa- rat Smoke- cop ψ, Z Data 98 93 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 ⁺ ) 366 (MNHf) 99 94 Λ Me δ _Η (CDCl ₃ , 400 MHz) 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 (MNH?)

PREPARATION 100

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

The title compound was prepared from the sulfonamide of Preparation 98 by the method of Preparation 88; δ _(Ι (CDC1 ₃ , 400 MHz) 2.31 (3H, s), 2.44 (3H, s), 2.83 (3H, s), 3.27 (3H, s), 6.79 (1H, d), 6.88 (2H, t ), 7.17 (1H, d), 7.44 (1H, dd), 7.58 (1H, d); MS m / z (ES ⁺ ) 385 (MNa ⁺ ).

141

PREPARATION 101

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

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

Dimethyl 4- (allyloxy) phthalate [obtained according to Inouye, M .; Tsuchiya, K .; Kitao, T. Angew. Chem. 1992, 104, 198-200 (see also Angew. Chem., Int. Ed. Engl., 1992, 204-205)] (9.9 g, 38 mmol)] was dissolved in THF (40 mL) and cooled to 0 ° C, then lithium aluminum hydride (IM in THF, 77 mL, 77 mmol) was added dropwise over 10 min. The mixture was stirred at room temperature for 3 hours, then quenched by careful addition of water (1.4 mL) and then NaOH (1.4 mL). Then excess MgSO ₄ was added and then water was formed to form a granular precipitate (ca.5 mL). The mixture was filtered and evaporated to give Q brown oil (7.1 g, ca. 95%). &Lt; 1 &gt; H NMR shows are. 85% purity of the material. It is used directly in the next step without further cleaning; bz (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 diode of step (i) was dissolved in DCM (60 mL) and treated with Et ₃ N (10 mL, 72 mmol), after which the solution was cooled to 0 ° C. Methanesulfonyl chloride (4.2 mL, 54 mmol) was added dropwise and the solution was stirred for 1 hour, allowing the solution to reach room temperature. Through

142 addition of water and then the 2M HCl (50 mL) was quenched. The DCM layer was isolated and the aqueous layer was extracted with DCM (50 mL). The combined organic fractions were washed with water (50 mL), dried (MgSO ₄ ) and concentrated to volume. 30 mL. Benzyltriammonium chloride (1 g) was then added and a solution of sodium sulfide (5 g, 91 mmol) in water (50 mL) was added. The mixture was stirred vigorously under a nitrogen atmosphere for 15 hours. 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. After column chromatography, two fractions were obtained; the first is a pure product and the second fraction is contaminated with a dimeric compound. Trituration of the second fraction results in crystallization of the dimer product, which is removed by filtration. The filtrate was added to the first chromatographic fraction, which represented the desired product (800 mg, 23%); δ _Η (CD ₃ OD, 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 of step (j) (800 mg, 4.16 mmol) was dissolved in THF (10 mL) and reacted with palladium tetrakis (triphenylphosphine) (481 mg, 0.42 mmol) and then with sodium boron hydride (944 mg, 25 mmol). The mixture was heated to 45 ° C and stirred at this temperature for 15 hours. After cooling to room temperature, the THF was evaporated and the residue partitioned between a solution of 2M NaOH (25 mL) and diethyl ether (25 mL). The combined aqueous layers were neutralized to pH 7-8 s

143 concentrated hydrochloric acid and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried (MgSO ₄ ) and evaporated to give a clear oil of the title phenol, which solidified upon standing (540 mg, 85%); 4.14 (2H, s), 4.17 (2H, s), 6.636.68 (2H, m), 7.04 (1H, d).

Biological activity

A number of compounds have been tested for biological activity by their ability to inhibit serotonin uptake by human serotonin transporters as follows.

(i) Cell culture

Human embryonic kidney cells (HEK-293) stably transfected with the human serotonin transporter (hDAT) are cultured according to standard cell culture procedures (cells are grown at 37 ° C and 5% CO? In DMEM culture medium (to which is added 10% dialysed fetal calf serum (FCS), 2mM 1-glutamine and 250 pg / ml geneticin). The cells were harvested for analysis to give a cell suspension of 750,000 cells / ml.

(ii) Determination of inhibitor potency

All test compounds were dissolved in 100% DMSO and diluted with the buffer used in the assay to the appropriate test concentrations. Analyzes are conducted in

144

96-well plates with filter bottom. Cells (7500 cells / well) were pre-incubated for 5 min in standard buffer solution containing either the test compound, standard inhibitor or carrier of the compound (1% DMSO). Reactions begin with the addition of ³ H-serotonin, ³ H-noradrenaline, or ³ Ndopamine substrates. All reactions were carried out at room temperature in a shaking incubator. The incubation time is 5 minutes for hSERT and hDAT analyzes and 15 minutes for hNET analysis. The reactions were stopped by separation of the reaction mixture using a vacuum manifold followed by rapid washing with ice buffer. The ³ Nsubstrate incorporated into the cells was quantified.

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

(iii) Standard composition of assay buffer:

Trisma hydrochloride (26mM) NaCl (124mM)

KS1 (4.5mM)

KN ₂ RO ₄ (1.2tM)

MgCl ₂ . 6H ₂ O (1.3mM)

145

Ascorbic acid (1.136µM)

Glucose (5.55mM) pH 7.40

CaCl ₂ (2.8tM)

Pargillin (100 M)

Note: pH of the buffer was adjusted to 7.40 with IM NaOH prior to the addition of SaS1 ₂ and pargyline.

(iv) Summary of parameters in the test

HSERT test HDAT test HDAT test Cell concentration to the nest 75,000 75,000 75,000 Concentration of ^J H-5HT 'H-dopamine ³ H-noradrenaline the substrate (50pM) (200pM) (200pM) Incubation time (minutes) 5 5 15

Compounds with an IC _{5 ()} serotonin reuptake inhibitory value (SRI) of less than or equal to 1 OOPM and which are more than 10 times more potent in inhibiting serotonin reuptake than inhibiting serotonin reuptake. dopamine reuptake and norepinephrine reuptake inhibition are the title compounds of Examples 1-6, 9-13, 16-19, 21, 22, 25,

146

26, 29-32, 34-36, 43, 45, 47-49, 51, 57-88, 90-102, 109-121, 123, 124, 127, 129.

Compounds with an IC ₅₀ value of serotonin reuptake inhibition (SRI) value less than or equal to 100 nM and which are more than 100 times more potent in inhibiting serotonin reuptake than inhibition of reuptake inhibition of dopamine and the inhibition of noradrenaline reuptake are the title compounds of Examples 1, 2, 4, 5, 9, 12, 13, 16-19, V 21, 22, 25, 26, 29-32, 34, 36, 43, 45, 48, 49, 58-80, 83-88, 90, 9297,99-102, 111-113, 115-1 18, 120, 123, 124, 127.

Compounds with an IC _{5 ()} value of serotonin reuptake inhibition (SRI) less than or equal to 50nM and which are more than 100 times more potent in inhibiting serotonin reuptake than inhibiting reverse serotonin dopamine uptake and norepinephrine reuptake inhibition are the title compounds of Examples 1, 2, 4, 9, 12, 17, 18, 26, 29, 30, 36, 43, 45, 48, 49, 60-66, 68-75, 78, 79, 90, 92-94, 100, 102, 116, 118,124.

In particular, the title compound of Example 16 has an inhibition of serotonin reuptake (SRI) IC ₅₀ of 4.7 nM; the title compound of Example 29 had an inhibition of serotonin reuptake (SRI) IC ₅₀ of 2.0 nM; and the title compound of Example 62 had serotonin reuptake inhibition (SRI) IC ₅₀ of 3.7 nM.

Claims (32)

Claims A compound of general formula (I), its pharmaceutically acceptable salts, solvates or polymorphs; (I) where: R ¹ and R ² , which may be the same or different, are H, C ₁ -C ₆ alkyl or (CH ₂ ) a (C 3 -C ₆ cycloalkyl), where d = 0, 1, 2 or 3; or R ¹ and R ² together with the nitrogen to which they are attached form an azetidine ring; Z or Y is -SR ³ and the other Z or Y is halogen or -R ³ ; wherein R ³ is independently C 1 -C 4 alkyl which may be fluoro substituted; except that R ³ is not CF 3; or Z and Y are bonded so that together with their bonding atoms Z and Y form a fused 5 to 7 membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, and where if Z and Y form a heterocyclic ring, except carbon atoms contain one or two heteroatoms selected independently from oxygen, sulfur and nitrogen; with the proviso that if 148 R? is fluorine 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 ³ , which may be the same or different, are: A-X, where A is -CH = CH- or - (CH ₂ ) _P -, where p is 0, 1 or 2; X is hydrogen, F, Cl, Br, I, CONR ⁶ R ⁷ , SO ² NR ⁶ R ⁷ , SO 2 NHC (= O) R ⁶ , OH, C 1-4 alkoxy, NR ⁸ SO ² R ⁹ , NO 2, NR ⁶ R, CN. CO2R ¹⁰ , CHO, SR ¹⁰ , S (O) R ⁹ or SO ² R ¹⁰ ; R ^6, R ^7, R ^s and R ^H), which may be identical or different, are hydrogen or C | _6 alkyl which may be optionally substituted independently with one or more R ^i2; R ⁹ is C 1-6 alkyl which may be independently substituted by one or more R ¹² ; R ¹¹ is hydrogen, C 1-6 alkyl which may be independently substituted by one or more R ¹² ; C (O) R ⁶ , CO2R ^y , C (O) NHR or SO ² NR ⁶ R ⁷ ; R ¹² e F, OH, CO ₂ H, C ₃ . ₆ cycloalkyl, NH ₂ , CONH ₂ , C 1. _b alkoxy, C _1-6 alkoxycarbonyl or a 5- or 6 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O, which may be substituted independently with one or more R ¹³ ; or R ⁶ and R ⁷ together with the nitrogen to which they are attached form a 4-, 5- or 6-membered heterocyclic ring which may be independently substituted by one or more R ¹³ ; or A 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O, which may be independently substituted by one or more R ¹³ ; where R ¹³ is hydroxy, C 1 -C ₄ alkoxy, F, C 1 -C ₆ alkyl, 149 haloalkyl, haloalkoxy, ~ MH ₂ , -T ₄ H (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? and R ² , which may be the same or different, are hydrogen or C 1 -C ₆ alkyl. A compound according to claims 1 or 2, its pharmaceutically acceptable salts, solvates or polymorphs, wherein when Z or Y is -SR ³ , R ³ is methyl or ethyl. A compound according to claims 1 or 2, its pharmaceutically acceptable salts, solvates or polymorphs, characterized in that when Z or Y is attached in a ring, the ring is a heterocyclic ring. A compound according to claim 4, its pharmaceutically acceptable salts, solvates or polymorphs, characterized in that it contains one or two sulfur atoms in addition to carbon atoms. A compound according to any one of the preceding claims, its pharmaceutically acceptable salts, solvates or polymorphs, characterized in that R ⁶ and R ⁷ , which may be the same or different, are hydrogen, C 1 -C ₃ alkyl which may to be replaced by hydroxy, -CONH? or C ₁ -C ₃ alkoxy. 150 A compound according to any one of the preceding claims, pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein R ⁵ is hydrogen, hydroxyethyl or methyl. A compound according to any one of the preceding claims, pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein R ⁹ is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl. 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, its pharmaceutically acceptable salts, solvates or polymorphs, characterized in that R ⁴ and R ⁵ , which may be the same or different, are - (CH ₂ ) _P -X, where p is 0, 1 or 2; 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 wherein R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ^{1 ()} are as defined in claim 1, or or a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O. A compound according to any one of the preceding claims, pharmaceutically acceptable salts, solvates or polymorphs thereof, 151, characterized in that R ⁴ and R ⁵ , which may be the same or different, are - (CH ₂ ) _p -X, where p is 0 or 1; X is hydrogen, hydroxy, CONR ⁶ R ⁷ , SO? NR ⁶ R ⁷ or NR ^with SO ² R ⁹ , wherein R ⁶ and R ⁷ , which may be the same or different, are hydrogen or C 1 -C 3 alkyl which may be substituted with hydroxy, -CONH ₂ or C 1 -C ₃ alkoxy (preferably methoxy); R is hydrogen, hydroxyethyl or methyl; or R ⁹ is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; or triazolyl, imidazolyl or pyrazolyl. A compound according to any one of the preceding claims, pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein R ⁴ and R ⁵ are not both hydrogen. A compound according to any one of the preceding claims, pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein R ⁴ is hydrogen. A compound according to claim 1, its pharmaceutically acceptable salts, solvates or polymorphs, selected from the group: 4- (2,3-dihydro-1-benzothien-5-yloxy) -3 - [(metiamino) 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); 152 3 - [(dimethylamino) methyl] -4- [3-fluoro-4 (methylsulfanyl) phenoxy-benzenesulfonamide (Example 18); N, N-dimethyl-4- [2- (6-quinolinyloxy) benzyl] amine (Example 29); 3- [(dimethylamino) methyl] -4- (6-quinolinyloxy) benzenesulfonamide (Example 35); 4- (2,3-dihydro-1-benzothien-5-yloxy) -3 - [(methyl amino) 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 J-methanol (Example 90); 3 - [(dimethylamino) methyl] -4- (6-quinolinyloxy) benzamide (Example 100); 3 - [(methylamino) methyl] -4- (6-quinolinyloxy) benzamide (Example 102); N-Meran-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). 15. Compound as defined in any of the foregoing 153 claims, pharmaceutically acceptable salts, solvates or polymorphs thereof, for use as a medicament. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 14, or pharmaceutically acceptable salts, solvates or polymorphs thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier. Use of a compound as defined in any one of claims 1 to 14, or pharmaceutically acceptable salts, solvates or polymorphs thereof, for the manufacture of a medicament for the treatment or prevention of disorders affecting the regulation of monoamine transport function. Use according to claim 17, characterized in that the disorder is depression, hyperactive disorder of attention, obsessive-compulsive disorder, post-traumatic stress disorder, disorder due to substance abuse or sexual dysfunction. Use according to claim 17, characterized in that the disorder is premature ejaculation. Use of an effective amount of a compound as defined in any one of claims 1 to 14, or pharmaceutically acceptable salts, solvates or polymorphs thereof, for the treatment or prevention of a disorder affecting 154 regulation of monoamine transport function in a patient in need of such treatment or prevention. Use of an effective amount of a compound as defined in any one of claims 1 to 14, or pharmaceutically acceptable salts, solvates or polymorphs thereof, for the treatment or prevention of premature ejaculation in a patient in need of such treatment or prevention. Use of an effective amount of a compound as defined in any one of claims 1 to 14, or pharmaceutically acceptable salts, solvates or polymorphs thereof, to increase ejaculation latency in a patient in need of increased ejaculation latency. 23. A method for preparing a compound of the general formula: wherein R ¹ , R ² , R ⁴ , R ⁵ , X and Z are as defined in any one of claims 1 to 14, consisting of the reaction of a compound of general formula 1a 155 under suitable reaction conditions to form a compound of formula I, suitable reaction conditions being: (i) when R ⁴ / R? are halogen by reaction of (1a) with a suitable halogenating agent in an inert solvent which does not adversely affect the reaction; (n) when R ⁴ / R ⁵ are -NO ₂ , by reaction of (1a) with a suitable nitrating agent in an inert solvent that does not adversely affect the reaction at or below room temperature; or (iii) when R ⁴ / R ⁵ are -SO ₂ NR ⁶ R ⁷ , by reaction of an intermediate sulfonyl chloride with the corresponding amine of formula HNR ⁶ R ⁷ in a suitable solvent. A method according to claim 23 for the preparation of a compound of formula (Iq), i.e. a compound of formula I wherein R ⁵ is -SO ₂ NR ⁶ R ⁷ and R ⁴ is hydrogen, 156 consisting of a) reaction of a compound of formula Ia, optionally in a suitable solvent, with chlorosulfonic acid to give a compound of formula XVIII followed by B) reaction with HNR ⁶ R ⁷ to give the compound of formula (Iq). A method according to claim 24, wherein the compound of formula XVIII is formed in situ and reacted with HNR ⁶ R ⁷ without isolation. 157 A method according to any one of claims 23 to 25, further comprising the step of preparing compounds of formula (Ia) by reaction of compounds of formula (IIa) with a compound of formula HNR R, or a suitable salt thereof, together with a hydride reducing agent in a suitable solvent to give a compound of formula (Ia). An intermediate of formula (IIa) or (XVIII) as defined in claims 23 to 26, provided that (IIa) cannot be 2 ((3 ', 4' - methylenedioxy) phenoxy) benzaldehyde. A process for the preparation of a compound of formula I 158 wherein R ¹ , R ² , R ⁴ , R ⁵ , X and Z are as defined in any one of claims 1 to 14, comprising reacting compounds of formula II with a compound of formula HNR'R ² or a suitable salt thereof together with a hydride reducing agent in a suitable solvent. The method of claim 28, further comprising coupling a reaction under suitable reaction conditions of a compound of formula III, wherein L is a suitable leaving group such as halogen or a sulfonate ester such as trifluoromethylsulfonate or methanesulfonate, with a compound of formula IV 159 to give a compound of formula II. 30. An intermediate of formula II as defined in claim 28, provided that (II) cannot be 2 ((3 ', 4' methylenedioxy) phenoxy) benzaldehyde or 2 ((3 ', 4' - methylenedioxy) phenoxy) 5-fluorobenzaldehyde. A compound of general formula (I) or pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein R, R, Y and Z are as defined in claim 1; and R ⁴ and R ⁵ , which may be the same or different, are - (CH ₂ ) _P -A ', where p is 0, 1 or 2 and A' is a polar group. The compound of claim 23, wherein the polar group has a π-value that is less than -0.1.