ES2370529T3 - DERIVATIVES OF BENZAMIDE AND PIRILAMIDE AS ANTIBACTERIAL AGENTS. - Google Patents

Abstract

The use of a compound that is a substituted benzamide or pyridylamide of the formula (I) or a salt, hydrate, or solvate thereof, in the production of a medicament for use in the treatment of bacterial infection: wherein R represents hydrogen or 1, 2 or 3 optional substitutes independently selected from (C1-C6) alkyl, (C2-C6) alkenyl, (C2-Ce) alkynyl, (C1-C6) alkoxide, hydroxide, hydroxide (C1-C6 ) alkyl, mercapto, mercapto (C1-C6) alkyl, (C1-C6) alkylthio, halo, (C1-C3) fully or partially fluorinated alkyl, (C1-C3) alkoxide or (C1-C3) alkylthio, nitro, nitrile , (-CN), oxo (= O), phenyl, phenoxide, monocyclic heteroaryl or heteroaryloxide with 5 or 6 ring atoms, - COOR A, -COR A, -OCOR A, -SO2R A, -CONR ARB, -SO2NR ARB, -NR ARB, -OCONR ARB, -NR B COR A, -NR B COOR A, - NR B SO2OR A or -NR A CONR ARB where RA and RB are independently hydrogen or a group (C1-C6 ) Alcilo or, in the case where RA and RB are in bonded to the same atom N, RA and RB taken together with said nitrogen can form a cyclic amino ring, and where the substitute is phenyl, phenoxide or heteroaryl or monocyclic heroaryloxide with 5 or 6 atoms, being its phenyl or heteroaryl anyl, itself, substituted by any of the preceding substitutes except phenyl, phenoxide, heteroaryl or heteroaryloxide; W is = C (R1) -or = N-: R1, is hydrogen and R2 is methyl, hydrogen or fluorine; or R1 and R2 taken together are -CH2-, -CH2CH2-, -O-, or, in any orientation, -O-CH2-, OCH2CH2-; R3 is a radical of the formula - (Alk 1) m- (Z) p- (Alk 2) nQ where m, pyn, are independently 0 or 1, provided that at least one of m, pyn is 1, Z is -O-, -S-, -S (O) -. -S (O2) -. -NH-, -N (CH3) -. -N (CH2CH3) -, -C (= O) -, -O-, - (C = O) -, -C (= O) -O-, an optionally substituted divalent monocyclic, carbocyclic or heterocyclic radical having atoms from 3 to 6 rings; or an optionally substituted divalent bicyclic heterocyclic radical having atoms of 5 to 10 rings; Alk 1 and Alq 2 are optionally substituted C 1 -C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkylene radicals, which may optionally end with or be interrupted by -O-, -S-, -S (O) -. -S (O2) -. -NH-, -N (CH3) -. -N (CH2CH3) -; and Q is hydrogen, halogen, nitrile (-CN), or hydroxyl or an optionally substituted monocyclic, carbocyclic or heterocyclic radical having 3 to 7 ring atoms; or an optionally substituted bicyclic heterocyclic radical having atoms of 5 to 10 rings; and in the definitions of 2 Alq 1, Alq 2 and Q the term -substituted- means substituted with up to four compatible substitutes, each of which is independently selected from (C1-C6) alkyl, (C2-C6) alkenyl , (C2-Ce) alkynyl, (C1-C6) alkoxide, hydroxide, hydroxide (C1-C6) alkyl, mercapto, mercapto (C1-C6) alkyl, (C1-C6) alkylthio, halo, (C1-C3) alkyl totally or partially fluorinated, (C1-C3) alkoxide or (C1-C3) alkylthio, nitro, nitrile, (-CN), oxo (= O), phenyl, phenoxide, monocyclic heteroaryl or heteroaryloxide with atoms of 5 or 6 rings, -COOR A, -COR A, -OCOR A, -SO2R, -CONR ARB, -SO2NR ARB, -NR ARB, - OCONR ARB, -NR B COR A, -NR B COOR A, -NR B SO2OR A or - NR A CONR ARB where RA and RB are independently hydrogen or a (C1-C6) alkyl group or, in the case where RA and RB are linked to the same atom N, RA and RB taken together with said nitrogen they can form a cyclic amino ring, and where the substitute is phenyl, phenoxide or heteroaryl or monocyclic heteroaryloxide with 5 or 6 atoms, being its phenyl or heteroaryl anil, itself, substituted by any of the preceding substitutes except phenyl, phenoxide, heteroaryl or heteroaryloxide.

Description

Benzamide and pyridylamide derivatives as antibacterial agents

R represents hydrogen or 1, 2 or 3 optional substitutes independently selected from (C1-C6) alkyl, (C2-C6) alkenyl, (C2-Ce) alkynyl, (C1-C6) alkoxide, hydroxide, hydroxide (C1- C6) alkyl, mercapto, mercapto (C1C6) alkyl, (C1-C6) alkylthio, halo, (C1-C3) fully or partially fluorinated alkyl, (C1-C3) alkoxide or (C1-C3) alkylthio, nitro, nitrile, (-CN), oxo (= O), phenyl, phenoxide, monocyclic heteroaryl or heteroaryloxide with 5 or 6 ring atoms, COORA, -CORA, -OCORA, -SO2RA, -CONRARB, -SO2NRARB, -NRARB, - OCONRARB, -NRBCORA, -NRBCOORA, NRBSO2ORA or -NRACONRARB where RA and RB are independently hydrogen or a group (C1-C6) alcilo or, in the case where RA and RB are linked to the same atom N, RA and RB taken together with said nitrogen can form a cyclic amino ring, and where the substituent is phenyl, phenoxide or heteroaryl or monocyclic heroaryloxide with 5 or 6 atoms, it can be its phenyl or heteroaryl anyl, itself, substituted by any of the preceding substituents except phenyl, phenoxide, heteroaryl or heteroaryloxide;

W is = C (R1) -Ó = N-:

R, is hydrogen and R2 is methyl, hydrogen or fluorine; or R1 and R2 taken together are â € “CH2-, -CH2CH2-, -O-, or, in any orientation, -O-CH2-, OCH2CH2-;

 R3 is a radical of the formula â € “(Alq1) m- (Z) p- (Alq2) n-Q where

m, p and n, are, independently, 0 or 1, provided that at least one of m, p and n is 1,

Z is â € “O-, -S-, -S (O) -. â € “S (O2) -. â € “NH-, -N (CH3) -. â € “N (CH2CH3) -, -C (= O) -, -O-, - (C = O) -, -C (= O) -O-, an optionally substituted divalent monocyclic, carbocyclic or heterocyclic radical that have atoms of 3 to 6 rings; or an optionally substituted divalent bicyclic heterocyclic radical having atoms of 5 to 10 rings;

Alq1 and Alq2 are optionally substituted C1-C6alkylene, C2-C6alkenylene or C2-C6alkylene radicals, which may optionally end with or be interrupted by â € “O-, -S-, -S (O) -. â € “S (O2) -. â € “NH-, -N (CH3) -. â € “N (CH2CH3); Y

Q is hydrogen, halogen, nitrile (-CN), or hydroxyl or an optionally substituted monocyclic, carbocyclic or heterocyclic radical having atoms of 3 to 7 rings; or an optionally substituted bicyclic heterocyclic radical having atoms of 5 to 10 rings; and in the definitions of 2 Alq1, Alq2 and Q the term â € œreplacedâ €? means substituted with up to four compatible substitutes, each of which is independently selected from (C1-C6) alkyl, (C2-C6) alkenyl, (C2-Ce) alkynyl, (C1-C6) alkoxide, hydroxide, hydroxide (C1C6) alkyl, mercapto, mercapto (C1-C6) alkyl, (C1-C6) alkylthio, halo, (C1-C3) fully or partially fluorinated alkyl, (C1-C3) alkoxide or (C1-C3) alkylthio, nitro , nitrile, (-CN), oxo (= O), phenyl, phenoxide, monocyclic heteroaryl or heteroaryl oxide with atoms of 5 or 6 rings, -COORA, -CORA, -OCORA, -SO2RA, -CONRARB, -SO2NRARB, -NRARB, OCONRARB, -NRBCORA, -NRBCOORA, -NRBSO2ORA or -NRACONRARB where RA and RB are independently hydrogen or a (C1-C6) alkyl group or, in the case where RA and RB are linked to same atom N, RA and RB taken together with said nitrogen may form a cyclic amino ring, and where the substitute is phenyl, phenoxide or heteroaryl or monocyclic heroaryloxide with 5 or 6 à volumes, may be its anilo phenyl or heteroaryl, in itself, substituted by any of the foregoing except substitute phenyl, fenóxido, heteroaryl or heteroarilóxido;

Some members of the class of compounds defined by formula (I) above are considered novel in their own right, and the invention includes all such novel members of the class.

Thus, the invention also includes novel compounds that are substituted benzamides or substituted pyridylamides of formula (IC) and salts, hydrates or solvates thereof:

 Where W is = C (R1) -Ó = N-; R1 is hydrogen and R2 is methyl, hydrogen or fluorine; or R1 and R2 taken together are â € “CH2-, -CH2CH2-, -O-, or, in any orientation, -O-CH2-, OCH2CH2-; R4 and R5 are, independently, fluorine or chlorine, or one of R4 and R5 is hydrogen while the other is fluorine or chlorine; and R3 is a radical selected from those of the following A-H formulas, in which any vacant ring position is optionally substituted:

Where Q is hydrogen, halogen, nitrile or hydroxyl or an optionally substituted monocyclic, carbocyclic or heterocyclic radical having atoms of 3 to 7 rings; or an optionally substituted bicyclic heterocyclic radical having atoms of 5 to 10 rings; and in the definitions of R3 and Q the term â € œoptionally substitutedâ €? It has the same meaning as in the definitions of Z, Alq1 and Q in relation to formula (1).

The invention also includes novel pyrirdyl amide compounds of the formula (ID) and salts, hydrates or solvates thereof:

Where R2 is hydrogen, methyl, or fluorine; and R3 is as defined in relation to the formula (IC).

Terminology

As used herein, the term â € œ (Ca-Cb) alkylâ € ?, where â € œaâ €? and â € œbâ €? are integers, refers to a straight or branched chain alcil radical having â € œaâ €? to â € œbâ €? Carbon atoms. So, when â € œaâ €? be 1 and â € œbâ €? 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and nhexyl.

As used herein, the term "radical of C1-C6 divalent alkylene"? , where â € œaâ €? and â € œbâ €? are integers, refers to a saturated hydrocarbon chain that has â € œaâ €? to â € œbâ €? Carbon atoms and two valences not satisfied. The term includes, for example, methylene, ethylene, n-propylene and n-butylene.

As used herein, the term â € œ (Ca-Cb) alkenylâ €? Where â € œaâ €? and â € œbâ €? are integers, refers to a straight or branched chain alcenyl functional group that has â € œaâ €? to â € œbâ €? Carbon atoms that have at least one double stereochemistry bond of E Ó Z where possible. The term includes, for example, vinyl, allyl, 1- and 2- butenyl and 2-methyl-2-propenyl.

As used herein, the term "radical of C1-C6alkenylene divalent" refers to a saturated hydrocarbon chain having "a"? to â € œbâ €? Carbon atoms, at least one double bond, and two valences not satisfied. The term includes, for example, -CH = CH- (vinyl), -CH = CH-CH2-, -CH2-CH = CH-, -CH = CH-CH2-CH2-, -CH = CH-CH2CH2 -CH2-, -CH = CH-CH = CH-, -CH = CH-CH = CH-CH2-, -CH = CH-CH = CH-CH2-CH2-, -CH = CH-CH2-CH = CH , and â € “CH = CH-CH2-CH2-CH = CH-.

As used herein, the term â € œCa-Cbalquinylâ €? Where â € œaâ €? and â € œbâ €? are integers, refers to a chain of straight chain or branched chain hydrocarbon groups that has â € œaâ €? to â € œbâ €? Carbon atoms and additionally have at least one triple bond. This term would include, for example, ethylino, 1-propylino, 1- and 2-butynyl, 2methyl-2-propynyl, 2-pentinyl, 4-pentinyl, 2-hexinyl, 3-hexinyl, 4-hexinyl and 5- hexinyl

As used herein, the term "radical of (C1-C6) divalent alkynylene"? , where â € œaâ €? and â € œbâ €? are integers, refers to a divalent hydrocarbon chain that has â € œaâ €? to â € œbâ €? Carbon atoms and at least one triple bond. The term includes, for example, -C = C-, - C- C-CH2-, and â € “CH2-C-CH-.

As used herein, the term "cycloalcil"? refers to a monocyclic or saturated carbocyclic monocyclic bridge radical having between 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and bicyclo [2.2.1] hept-1- ilo.

As used herein, the term unqualified "aryl" refers to a mono- or bicyclic carbocyclic aromatic radical. Illustrative examples of such radicals are phenyl and naphthyl.

As used herein, the term unqualified â € œheteroarylâ €? refers to a mono- or bi-cyclic aromatic radical containing one or more heteroaromas selected from S, N and O, and includes radicals having two monocyclic rings as well, or one monocyclic ring as well and one aryl ring monocyclic, which are fused or directly linked by a covalent bond. Illustrative of such radicals are thienyl, benzothienyl, furyl, benzofuryl, pyrrolyl, imidazolyl, benizimiadazolilo, thiazolyl, benzothiazolyl, thiazolopyridinyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benzotriazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrirmidinyl, pyridazinyl, triazinyl, indolyl and indazolyl.

As used herein, the term unqualified â € œheterocyclylâ €? or â € œheterocyclicâ €? includes â € œheteroarylâ €? as defined supra, and, additionally, means a mono- or bi-cyclic non-aromatic radical containing one or more heteroaromas

selected from S, N and O. Illustrative examples of such radicals are the pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thidiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl groups. , benzofuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, malimido and succinimido.

Unless otherwise indicated in the context in which it takes place, the term â € œreplacedâ € ?, as it applies to any functional group here means substituted with up to four compatible substitutes, each of which may be , independently, for example, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-Ce) alkynyl, (C1-C6) alkoxide, hydroxide, hydroxide (C1-C6) alkyl, mercapto, mercapto ( C1-C6) alkyl, (C1-C6) alkylthio, halo, (C1-C3) fully or partially fluorinated alkyl, (C1-C3) alkoxide or (C1-C3) alkylthio, nitro, nitrile, (-CN), oxo (= O), phenyl, phenoxide, monocyclic heteroaryl or heteroaryl oxide with atoms of 5 or 6 rings, -COORA, -CORA, -OCORA, -SO2RA, -CONRARB, SO2NRARB, -NRARB, -OCONRARB, -NRBCORA, - NRBCOORA, -NRBSO2ORA or -NRACONRARB where RA and RB are independently hydrogen or a (C1-C6) alkyl group or, in the case where RA and RB are linked to the same atom N, RA and RB taken as a whole with said nitrogen they can form a cyclic amino ring, and where the substituent is phenyl, phenoxide or heteroaryl or monocyclic heroaryloxide with 5 or 6 atoms, being able to be its phenyl or heteroaryl anyl, itself, substituted by any of the preceding substituents except phenyl, phenoxide, heteroaryl or heteroaryloxide. An optional substitute or â € œsubstituteâ €? It can be one of the groups specified above.

As used herein, the term â € œsalâ €? It includes basic addition, acid addition and quaternary salts. The compounds of the invention that are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, for example, sodium and potassium hydroxides; alkaline earth metal metal hydroxides, for example, calcium, barium and magnesium hydroxides; with organic bases, for example N-methyl-Dglucamine, tris (hydroxymethyl) amino methane, L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like. These compounds (I), which are basic, can form salts, including pharmaceutically acceptable salts with inorganic acids, for example, with hydrophilic acids, such as hydrochloric or hydrobromic acids, sulfuric acid, nitric acid or phosphoric acid and the like, and with organic acids, for example, with acetic, tartaric, succinic, fumaric, maleic, maleic acids , salicylic, citric, methanesulfonic, p-toluenesulfonic, benzoic, benzenesulfonic, glutamic, lactic and mandelic and the like. For a review of suitable salts, see Handbook of Pharmaceutical Salts: properties, Selection, and Use, by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

The term â € œsolvatoâ €? It is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term â € œhydrateâ €? It is used when said solvent is water.

The compounds of the invention that contain one or more potential or physical chiral centers, due to the presence of asymmetric carbon atoms, can exist as a number of enantiomers or diastereoisomers with stereochemicals R or S in Each chiral center. The invention includes all such enantiomers and diastereoisomers and mixtures thereof.

Aspects of the invention

A particular subclass of compounds for antibacterial use, according to the invention, consists of those of the formula (IA)

Where R4 and R5 are, independently, fluorine or chlorine, or one of R4 and R5 is hydrogen while the other is fluorine

or chlorine and R1, R2 and R3 are as defined in reference to formula (I) above.

Another particular subclass of compounds for antibacterial use, according to the invention, consists of those of the formula (IB)

In a reduced subclass of compounds for antibacterial use, according to the invention, including those of the formula (IA) supra, R1 and R2 are hydrogen; and in the compounds of the formula (IB) supra R2 is hydrogen. In the radical R3, p can be 0, and my / on can be 1. Alternatively, p can be 1, and Z can be an optionally substituted carbocyclic or heteroaryl radical having 3 to 6 ring-linked atoms or an optionally substituted bicyclic, carbocyclic or heteroaryl radical having 5 to 10 ring-linked atoms, which is linked to the â € “(Alc1) m-R3 part and to the â €" (Alc2) part ) nQ of R3 by means of ring-bound carbon or nitrogen atoms. Examples of divalent Z radicals in this embodiment include the

10 selected from the following, in each orientation: In another alternative embodiment, p is 1, and Z is an optionally substituted monocyclic non-aromatic carbocyclic or heterocyclic radical having 3 to 6 ring-linked atoms. an optionally substituted carbocyclic or non-aromatic bicyclic heterocyclic having 5 to 10 ring-shaped atoms, which is linked to the â € “(Alc1) m- part of R3 and to the â €" ( Alc2) nQ of R3 by means of ring-bound carbon or nitrogen atoms. Examples of Z radicals, which are optionally substituted, in this embodiment include those selected from the following, in each orientation:

In the compounds referred to in the invention, and in any of the subclasses or embodiments of such compounds discussed supra, Q may be hydrogen. However, Q may also be a radical selected from any of the divalent radicals specifically identified above but with one of the valencies not satisfied therewith satisfied with hydrogen or an optional substitute.

In the compounds to which the invention relates, and any of the subclasses or embodiments of such compounds discussed supra n and / or m may be 0.

In all the compounds and classes of compounds to which the invention relates, it is usual that the radical R3, when fully extended, does not exceed the length of a chain of saturated unbranched hydrocarbon of 14 carbon atoms, that is , do not exceed about 16 Angstroms.

In the compounds referred to in the invention, Alq1 and Alq2, when present, may be, for example,

20 C1-C6alkylene, C2-C6alkenylene or C2-C6 straight chain optionally substituted radicals, which may optionally end with or be interrupted by â € “0-, -S-, -S (O) -. â € “S (O2) -. â € “NH-, -N (CH3) -. â € “N (CH2CH3) -C (= O) -, -O- (C = O) -, -C (= O) -O-.

Any optional substitutes R and any optional substitutes present in Alq1, Alq2, Z and Q can be selected from, for example, methyl, -OCH3, -CF3, -OCF3, ethyl, cyclopropyl, oxo, hydroxyl, -F, -Cl , -Br,

Cyano, acetyl, amino, methylamino, acetylamino, carbamate, -CONH2, nitro, -COOH and â € “CH2OH.

Compounds of the formula (IC) per se, and salts, hydrates or solvates thereof constitute a different aspect of the invention:

Where W is = C (R1) -Ó = N-;

R1 is hydrogen and R2 is methyl, hydrogen or fluorine; or R1 and R2 taken together are â € “CH2-, -CH2CH2-, -O-, or, in any orientation, -O-CH2-, OCH2CH2-;

R4 and R5 are, independently, fluorine or chlorine, or one of R4 and R5 is hydrogen while the other is fluorine or chlorine;

 R3 is a radical selected from those of the following A-H formulas, in which any vacant position in the ring is optionally substituted:

Where Q is defined in relation to formula (I) above, and where any unsubstituted carbon in the ring is optionally substituted.

In compounds (IC) it is currently preferred that W is = CH- and R2 is hydrogen.

In the compounds (IC) the radical R3 can be hydrogen or optionally substituted phenyl.

In a peculiar set of compounds (IC), R3 is quinolin-2-yl, benzothiazol-2-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxadiazol-3-yl, oxadiazol-5- ilo, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl or optionally substituted thiazolopyridin-2-yl.

Optional substitutes that may be present in R3 in the aspect of the invention of the compound per include methyl, -OCH3, -CF3, -OCF3, ethyl, cyclopropyl, oxo, hydroxyl, -F, -Cl, -Br, cyano , acetyl, amino, methylamino, acetylamino, carbamate, -CONH2, nitro, -COOH and â € “CH2OH.

Compounds of the formula (IC) per se, and salts, hydrates or solvates thereof also constitute a different aspect of the invention:

Where R2 is hydrogen, methyl, or fluorine; and R3 is as defined in relation to the formula (IC).

Specific examples of compounds with which the invention relates relate to those of the examples herein.

There are multiple synthetic strategies for the synthesis of the compounds (I) with which the present invention relates, but all are based on known chemistry, known to the expert in synthetic organic chemistry. Thus, the compounds according to formula (I) can be synthesized according to procedures described in the standardized literature and are well known to the person skilled in the art. Typical literary sources are â € œAdvanced Organic Chemistryâ € ?, Fourth Edition (Wiley), J. March, â € œComprehensive Organic

10 Transformationâ € ?, Second Edition (Wiley), R.C. Larock, â € œHandbook of Heterocyclic Chemistryâ € ?, Second Edition (Pergamon), A.R. Katrizky), journal articles such as those found in â € œSynthesisâ € ?, â € œAcc.Chem.Revâ € ?, or primary sources of literature identified by searching for online standardized literature or secondary sources such as â € œChemical Abstractsâ € ? or â € œBeilsteinâ € ?.

The compounds (I) can be prepared, for example, by introducing the radical â € “(Alc1) m- (Z) p â €“ (Alc2) n-Q into the hydroxyl group of a compound (II)

Further details of the synthetic approaches and schemes for the preparation of the intermediary (II) are given in the examples of this document. As mentioned above, the compounds with which the invention relates are active against bacteria, as long as they inhibit bacterial growth. They are, consequently, of use in the

20 treatment of bacterial infections in human and non-human animals, such as other mammals, birds and fish. The compounds include those that inhibit the growth of Gram-positive organisms such as Bacillus subtilis and Staphylococcus aureus and some also show activity against certain Gram-negative organisms.

It will be understood that the specific dose level for each particular patient will depend on a variety of

25 factors including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, combination of substances and the severity of the disease in particular undergoing therapy. As required in the pharmaceutical technique, safe and authorized doses will be determined by clinical trial, but daily doses may vary within wide ranges and will be adjusted to individual needs in each specific case. However, generally, the

The dosage adopted for each route of administration when a compound is administered only to adult humans is 0.00001 to 150 mg / kg body weight. Such a dose can be given, for example, daily, 1 to 5 times. For intravenous injection, an adequate daily dose is 0.0001 to 150 mg / kg body weight. A daily dose may be administered as an individual dose or according to a fractional dosing schedule.

The compounds with which the invention relates can be prepared for administration by any route consistent with their pharmacokinetic properties, such as sterile oral, topical or parenteral solutions or suspensions. The orally administrable compositions may be in the form of tablets, capsules, powders, granules, rhombuses, liquid or gel preparations. Tablets and capsules for oral administration may be in the form of a unit dose presentation, and may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylopyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbit or glycine; tablet-forming lubricant, such as magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, or acceptable humidifying agents such as sodium lauryl sulfate. The tablets may be coated in accordance with procedures well known in normal pharmaceutical practice. Oral liquid preparations may have the form of, for example, aqueous or oleaginous suspensions, solutions, emulsions, syrups

or elixirs, or they may be presented as a dry product for reconstitution with water or other suitable carrier before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, methylcellulose syrup, glucose syrup, hydrogenated edible fats of

15 jelly; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous carriers (which may include edible oils), for example, almond oil, fractionated coconut oil, oil esters such as glycerin, propylene glycol, or ethyl alcohol; preservatives, such as methyl or propyl phydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.

For topical application on the skin, the substance can take the form of a cream, lotion or ointment. The

20 cream or ointment formulations that can be used for the substance are conventional formulas known in the state of the art, for example as those described in standardized Pharmacy textbooks, such as the British Pharmacopoeia.

For topical application to the eye, the substance may take the form of a solution or a suspension in a suitable sterile aqueous or non-aqueous carrier. Additives may also be included, for example buffers such

25 as sodium metabisulfite or disodium edeate; preservatives including bactericidal and fungicidal agents such as phenyl acetate or mercury nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose.

The active ingredient can also be administered parenterally in a sterile medium, either subcutaneously or intravenously, or intramuscularly, or in an intrasternal manner, or by infusion techniques, in the form of

30 sterile injectable aqueous or oleaginous suspensions. Depending on the carrier and the concentration used, the substance may either be suspended or dissolved in the carrier. Advantageously, helpers, such as a local anesthetic, preservatives and buffers, may be dissolved in the carrier.

As the compounds with which the invention relates are antibacterially active and inhibit bacterial growth, they are also used in the treatment of bacterial contamination of a substrate, such

35 as hospital instruments or work surfaces. In order to treat a contaminated substrate, the compounds may be applied to the area of said contamination in an amount sufficient to inhibit bacterial growth.

The following examples illustrate the synthesis of compounds with which the invention relates.

Analytical procedure

The analytical procedures used to characterize compounds included HPLC-MS and 1H NMR.

HPLC-MS Conditions - Procedure 1

Mobile phase: A = Acetonitrile

   B = 10mM aqueous ammonium acetate

gradient:

Time (minutes) % TO % B

0.00

twenty 80

0.30

twenty 80

4.00

90 10

5.00

90 10

5.03

twenty 80

Runtime:

7 minutes

Flow time

: 1 ml / min

sample

           Injection volume: variable depending on the concentration of the

5

Column temperature: 40º C

Column:

   50 x 4.6 mm Gemini C18; 5 Qm

 PDA Detector:

   220, 240, and 254 nm analyzed

HPLC-MS Conditions - Procedure 2

Mobile phase: A = Acetonitrile B = 10mM aqueous ammonium acetate

gradient:

Time (minutes) % TO % B

0.00

twenty 80

0.30

twenty 80

24.00

90 10

28.00

90 10

28.03

twenty 80

Runtime:

30 minutes

Flow time

: 1 ml / min

fifteen

sample            Injection volume: variable depending on the concentration of the

Column temperature:

40º C

 Column:

   50 x 4.6 mm Gemini C18; 5 Qm

 PDA Detector:

   220, 240, and 254 nm analyzed

twenty

HPLC-MS Conditions - Procedure 3

 Mobile phase: A = Acetonitrile + 0.1% Trifluoroacetic acid B = Water + 0.1% Trifluoroacetic acid

gradient:

Time (minutes) % TO % B

0.0

0 100

1.8

95 5

2.1

95 5

2.3

0 100

2.4

0 100

Execution time: 2.4 minutes Flow time: 1 ml / min Injection volume: 3 Ql

5 Column temperature: room temperature (20º C) Column: 50 x 2.0mm. Hypersil C18 BDS; 5 Qm UV detector: variable wavelength detector set a

215nm

10 HPLC-MS Conditions - Procedure 4

Mobile phase: A = Acetonitrile + 0.1% Formic acid B = Water + 0.1% Formic acid

gradient:

Time (minutes) % TO % B

0.0

0 100

2.5

100 0

2.7

100 0

2.71

0 100

3.0

0 100

fifteen

Runtime: 3.5 minutes

Flow time

: 1 ml / min

 Injection volume:

   3 ql

              Column temperature:

room temperature (20º C)

 Column:

   50 x 2.1mm Atlantis AD18; 5 Qm

twenty

 UV detector: variable wavelength detector set a

215nm

HPLC-MS Analysis Conditions â € “Procedure 5 HPLC-MS Analysis Conditions â €“ Procedure 6

Column

Purospher® star c-18

Mobile Phase

ACN: 0.1% Formic Acid (AF)

Flow mode

% ACN time

% AF

0.00

10.0 90.0

7.00

10.0 90.0

15.00

90.0 10.0

18.00

90.0 10.0

25.00

10.0 90.0

30.0

10.0 90.0

Flow

1.00 ml / min

UV maximum

Variable

Column Temperature

30º C

Injection Volume

Variable

Column

Discovery HSC-18 Column 250x4.6, 5.0 Qm

Mobile Phase

A â € “Acetonitrile B â €“ 0.1% Formic Acid

Flow mode

Weather

TO B

0.0

5.0 95.0

4.0

5.0 95.0

8.0

95.0 5.0

16.0

950 5.0

18.0 *

5 95.0

20.0

5.0 95.0

Flow

1.00 ml / min

UV maximum

Variable

Column Temperature

45 degrees

Sample preparation

Methanol

Injection Volume

Variable

HPLC-MS conditions - Procedure 8 Mobile phase: A = Acetonitrile + 0.1% Formic acid B = Water + 0.1% Formic acid

gradient:

Time (minutes) % TO % B

0.0

10 90

7.0

10 90

15.0

90 10

18.0

90 10

25.0

10 90

30.0

10 90

Execution time: 30.0 minutes Flow time: 1 ml / min Column temperature: room temperature (25º C) Column: 250 x 4.6mm. Xbridge AD18; 5 Qm 10 UV detector: 215nm variable wavelength detector set

HPLC-MS Conditions - Procedure 9

Mobile phase: A = Acetonitrile + 0.1% Formic acid B = Water + 0.1% Formic acid

gradient:

Time (minutes) % TO % B

0.0

10 90

7.0

10 90

15.0

90 10

18.0

90 10

25.0

10 90

30.0

10 90

Execution time: 30.0 minutes Flow time: 1 ml / min Column temperature: room temperature (25º C) Column: 250 x 4.6mm. Purospher Star dC18; 5 Qm UV detector: variable wavelength detector set a

262nm

NMR

The 1H NMR spectra were consistent with the required structures.

Melting points were measured on a Stuart Scientific SMP10 device and are not corrected.

The productions given are not optimized.

Experimental procedures

Scheme 1: (a) SOCl2, toluene, reflux; (b) aqueous NH3.

General Procedure for the Conversion of a Carboxylic Acid into a Carboxylic Amide (Procedure

TO). 3-Hydroxybenzenecarboxamide.

10 3-Hydroxybenzoic acid (110.5 g, 0.8 mol, 1 equiv.) Was suspended in toluene (500 ml) and thionyl chloride (88.0 ml, 1.2 mol, 1.5 equiv.) Was added slowly, at room temperature . The solution was heated to reflux, where it was kept for 5 hours. After this time, the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (300 ml) and cooled in an ice-cold methanol bath. Concentrated aqueous ammonia solution (-300 ml) was added slowly, dropwise, and the reaction mixture was

15 slowly heated to room temperature where it was stirred for 16 hours. The reaction mixture was concentrated in vacuo and the resulting solid was suspended in water and filtered. The collected solid was washed with additional water (x3) and then dried under vacuum to obtain 3-hydroxybenzamide as an off-white solid (79.9 g,

72.8%) mp 167-168 ° C. HPLC-MS (procedure 1): ml z 136 [M-H] -. Rt = 1.21 min. 1H NMR (d6-DMSO) δ = 9.53 (s, 1H), 7.78 (s, 1H), 7.30-7.15 (m, 4H), 6.88 (d, J = 8 Hz, 1H).

20 Scheme 2: (a) RX, K2CO3, Nal, DMF, 60º C

General Procedure for the alkylation of phenols using Alkyl Halides (Procedure B).

Example 1: 3-Nonyloxide-benzenecarboxamide

K2CO3 (302 mg., 2.19 mmol, 1.5 equiv.) And Nal (43.5 mg, 0.29 mmol, 0.2 equiv.) Were added to a solution of 3-hydroxybenzenecarboxamide (200 mg, 1.46 mmol, 1 equiv.) In DMF (3 ml) The suspension was stirred for 5 minutes before n-nonyl chloride (0.32 ml, 1.61 mmol, 1.1 equiv) was introduced: The resulting mixture was heated to 60 [deg.] C. where it was maintained for 16 hours. After this period, the reaction was cooled to room temperature and partitioned between EtOAc and water. The organic phase was separated, washed with additional water (x 2), dried (MgSO4), filtered and concentrated in vacuo until a colorless solid was revealed. In the case of 3-n-nonyloxybenzamide, this colorless solid was stirred for 5 minutes with MeOH (-0.5 ml) [Bene Note: 3-n-nonyloxybenzamide partially soluble in MeOH] and then filtered to reveal the desired compound as a colorless solid (116 mg, 30%). HPLC-MS (procedure 3): ml z 264 [M + H] +, Rt = 1.80 min. 1H NMR (d6-DMSO) δ = 7.95 (s, 1H), 7.44-7.31 (m, 4H),

10 7.06 (ddd, J = 8 Hz, J = 2 Hz, J = 1 Hz, 1H), 3.99 (t, J = 6.5 Hz, 2H), 1.72 (quintet, J = 6.5 Hz, 2H), 1.42 (m , 2H), 1.34

1.26 (m, 10H), 0.86 (t, J = 6.5 Hz, 3H).

Note Bene 1: The final stage of purification was dependent on the nature of group R. Other purification procedures used in the course of library synthesis were:

1. Recrystallization (eg, MeOH, EtOAc / hexane, CH3CH sorted).

15 2. Normal phase column chromatography (silica gel)

3. Preparatory HPLC or preparatory TLC.

Note Bene 2: In the case of compounds intended to be soluble in water, the aqueous phase was concentrated in vacuo and then washed with MeOH. The methanolic fractions were concentrated in vacuo and the crude product purified by preparative HPLC.

20 Examples 2 to 44 (Table A)

Examples 2 to 44 were synthesized according to procedure B, scheme 2

Example

2 3 4 5

Structure

HPLC-MS: Procedure no., M / z, ion

Rt (min)

1.10 1.05 1.11 1.78

Example

36 37

Structure

Performance (%)

70 70

Mp (ºC)

100-101 98-99

HPLC-MS: procedure no., M / z, ion

Rt (min)

4.72 3.62

Table of product compound names; Examples 2-44:

Example

Compound Name

2

3-Propoxybenzenecarboxamide

3

3-lsopropoxybenzenecarboxamide

4

3- (Cyclopropylmethoxy) benzenecarboxamide

5

3- (Pentyloxy) benzenocarboxamide

6

3- (Allyloxy) benzenecarboxamide

7

3-Butoxibenzenocarboxamide

8

3- (Hexyloxy) benzenecarboxamide

9

3- (2-Methoxyethoxy) benzenocarboxamide

10

 3- (4-phenoxybutyloxy) benzenecarboxamide

eleven

 3 - [(2-Methyl-2-propenyl) oxy] benzenocarboxamide

12

 3- (7-Octenyloxy) benzenecarboxamide

13

 3- (Isopentyloxy) benzenecarboxamide

14

3 - [(4-Methylpentyl) oxy] benzenocarboxamide

fifteen

 3- (5-Hexenyloxy) benzenecarboxamide

16

 3- (2-Propoxyethoxy) benzenocarboxamide

17

 3- (6-Heptenyloxy) benzenocarboxamide

18

 5- [3- (Aminocarbonyl) phenoxy] pentyl acetate

19

 3- (Octyloxy) benzenocarboxamide

twenty

 3- (4-Phenylbutoxy) benzenocarboxamide

twenty-one

3 - [(5-Phenylpentyl) oxy] benzenocarboxamide

22

3 - [(5-Methylhexyl) oxy] benzenocarboxamide

2. 3

3- (2-Quinolinylmethoxy) benzenocarboxamide

24

 3- (Heptyloxy) benzenecarboxamide

25

4- [3- (aminocarbonyl) phenoxy] ethyl butanoate

26

4- [3- (aminocarbonyl) phenoxy] methyl butanoate

27

Cyclohexyl 2- [3- (aminocarbonyl) phenoxy] acetate

28

 3- (2-Cycloheptylethoxy) benzenecarboxamide

29

 3 - [(3-Methylbenzyl) oxy] benzenocarboxamide

30

 3- [2-Butenyloxy] benzenecarboxamide

31

 3- (2-Octynyloxy) benzenecarboxamide

32

 3- (4-Nonynyloxy) benzenocarboxamide

33

 2- [3- (aminocarbonyl) phenoxy] ethyl acetate

3. 4

 3 - [(4-Fluorfenethyl) oxy] benzenocarboxamide

35

3 - [(4-Methoxyphenethyl) oxy] benzenocarboxamide

36

 3 - [(6-Phenylhexyl) oxy] benzenocarboxamide

37

6- [3- (aminocarbonyl) phenoxy] ethyl hexanoate

38

Methyl 10- [3- (aminocarbonyl) phenoxy] decanoate

39

 3 - [(2-Methylpentyl) oxy] benzenocarboxamide

40

3 - [(E) -3-Octenyloxy] benzenocarboxamide

41

 2- [3- (aminocarbonyl) phenoxy] butyl acetate

42

 3- (4-Hydroxybutyloxy) benzenocarboxamide

43

4- [3- (aminocarbonyl) phenoxy] butyl butanoate

44

 3- (4-Cyclohexylbutoxy) benzenecarboxamide

Scheme 3: (a) ROH, PPh3-PS, DIAD, Et3N, THF, r.t.

General Procedure for the Rental of Phenols Using Alcohols through a Mitsunobu reaction (Procedure C):

Diisopropylazodicarboxylate (0.47 ml, 2.4 mmol, 1.2 equiv.) Was added to a polymer-supported triphenyl phosphine suspension (1.4 g., 3 mmol, based on a 2.15 mmol / g load [purchased from Argonaut], 1.5 equiv.) thickened in THF (20 ml) at room temperature. The mixture was stirred for 5 minutes before 10-3-hydroxybenzamide (274 mg, 2 mmol, 1 equiv.), Triethylamine (0.28 ml, 2 mmol, 1 equiv.) And cis-5-decenol (313) were added mg, 2 mmol, 1 equiv.). The resulting suspension was stirred at room temperature for 16 hours and then filtered. The resin was washed with additional THF (x 3) and then, the filtrate and the wash, combined, were concentrated under reduced pressure, to obtain the crude product as a colorless semi-solid. It was purified by column chromatography on silica eluting with EtOAc / hexane (20% -40% gradient) to obtain the desired compound as a white solid (390 mg, 71%), mp 98-100 ° C. HPLC-MS (procedure 1): ml z 276 [M + H] +, Rt = 5.00 min. 1H NMR (CDCl3) δ = 7.35 (s, 1H), 7.32-7.28 (m, 2H), 7.08-7.02 (m, 1H), 6.18 (br, 2H), 5.41-5.32 (m, 2H), 3.98 ( t J = 6.4 Hz, 2H), 2.12-2.05 (m, 2H), 2.05-1.98 (m, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 1.34

1.28 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H).

Note Bene 1: In some cases, diethylazodicarboxylate (0.38 ml, 2.4 mmol, 1.2 equiv.) Was used instead of diisopropylazodicarboxylate.

Note Bene 2: In some cases, unsupported triphenyl phosphine was used. In the case of phenols containing fluorine atoms, no product could be detected when polymer supported triphenyl phosphine is used and, thus, the reactions were carried out with triphenyl phosphine.

Example

46 47

Structure

Performance (%)

3. 4 7.5

Mp (ºC)

94-96 93-94

HPLC-MS: procedure no., M / z, ion

Reaction time (min)

4.73 4.78

Table of product compound names; Examples 46-61:

Example

Compound number

46

3- (10-Undecyloxy) benzenecarboxamide

47

3 - [(Z) -2-Nonenyloxy] benzenocarboxamide

48

3- (5-Decinyloxy) benzenecarboxamide

49

3 - [(E) -2-Nonenyloxy] benzenocarboxamide

fifty

3- (2-Nonynyloxy) benzenecarboxamide

51

3- (3-Noninyloxy) benzenecarboxamide

52

3 - [(Z) -5-Octenyloxy] benzenocarboxamide

53

3- [2- (Pentyloxy) ethoxy] benzenocarboxamide

54

3- [2- (Hexyloxy) ethoxy] benzenecarboxamide

55

3 - {[(5E) -2,6,10-Trimethyl-5,9-undecadienyl] oxy} benzenecarboxamide

56

3 - [(2E, 6Z) -2,6-Nonadienyloxy] benzenocarboxamide

57

3- {3- [2- (tert-Butyl) -5- (trifluoromethyl) -1,3-oxazol-4yl] propoxy} benzenocarboxamide

58

3 - [(E) -5-Decenyloxy] benzenocarboxamide

59

3- (3-Octynyloxy) benzenecarboxamide

60

3 - [(3-Methylpentyl) oxy] benzenocarboxamide

61

3 - [(Z) -6-Nonenyloxy] benzenocarboxamide

Scheme 4: (a) Br (CH2) 6Br, K2CO3, CH3CH, 60 [deg.] C .; (b) PPh3, CH3CN, reflux; (c) (i) KHMDS, toluene, 0 ° C; (ii) RCHO, -78º C a r.t .; (d) H2, 10% Pd / C, MeOH, r.t.

3 - [(6-Bromohexyl) oxy] benzenocarboxamide.

(Procedure D) K2CO3 (1.38 g, 10 mmol, 1 equiv.) Was added to a suspension of 3-hydroxybenzamide (1.37 g, 10 mmol, 1 equiv.) In CH3CN (100 ml). The mixture was stirred for 10 minutes at room temperature, before 1,6-dibromo-hexane (9.76 g, 40 mmol, 4 equiv.) Was added. The resulting mixture was stirred at 60 ° C for 10 16 hours. After this time, the reaction was cooled to room temperature, some undissolved solids were filtered and the filtrate evaporated under reduced pressure to dryness. The residue was absorbed in EtOAc and water. The organic phase was separated and washed consecutively with K2CO3 solution, water and brine. Dried with MgSO4 and evaporated under reduced pressure to a small volume. The precipitated solid was filtered and washed with EtOAc / pentane, to obtain the desired compound as a white solid (2.0 g, 67%), mp 115-117 ° C. HPLC-MS

15 (procedure 1): m / z 300 [M] +, 302 [M + 2H] +, Rt = 4.08 min.

6- [3- (Aminocarbonyl) phenoxy] hexyl (triphenyl) phosphonium bromide

A mixture of 3 - [(6-Bromohexyl) oxy] benzenocarboxamide (2.10 g, 7 mmol, 1 equiv.) And triphenylphosphine (1.93 g, 7.35 mmol, 1.05 equiv.) In CH3CN (30 ml) was refluxed for 72 hours. The solvent was evaporated under reduced pressure and the residue was triturated with dry Et2O until it solidified. The solid was filtered

and dried in vacuo to obtain the desired compound as a white solid (4.0 g, 100%). HPLC-MS (procedure 1): m / z 482 [M-Br] +, Rt = 3.65 min.

5 (Procedure E) a solution of potassium bis (trimethylsilyl) amido (0.5 M; 7.1 ml, 3.55 mmol, 1.2 equiv.) In toluene was added, slowly, drop by drop, over a period of 15 minutes at 0 ° C under N2 to a stirred suspension of 6- [3- (amicarbonyl) phenoxy] hexyl (triphenyl) phosphonium bromide (2.0 g, 3.55 mmol, 1.2 equiv.) in anhydrous toluene (28 ml). The dark orange solution was stirred for another 20 minutes at 0 ° C and cooled to -78 ° C, at which time thiophene-3-carboxaldehyde was added instantly, and the temperature was allowed to rise from

10 78Â ° C at room temperature. The light yellow mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated aqueous NH4Cl (20 ml) and the solvent was evaporated under reduced pressure. The residue was taken to CH2Cl2 and H2O, the organic phase was separated, washed with brine and dried (Na2SO4). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica eluting with EtOAc / hexane (10% -50% gradient) to obtain the desired compound as a solid.

15 whitish (300 mg, 35%), mp 71-73 [deg.] C. By 1 H NMR analysis, it consisted of a mixture of Z: E (90:10). HPLC-MS (procedure 1): m / z 316 [M + H] +, Rt = 4.62 min.

10% Pd / C (30 mg) was added to an example solution 62 3 - {(Z) -7- (3-Thienyl) -6

Heptenyl] oxy} benzenocarboxamide (260 mg, 0.82 mmol) in MeOH (8 ml). The mixture was stirred under H2 at room temperature for 3 days. The catalyst was removed by filtration through a Celite buffer and the solvent was evaporated under reduced pressure, to a small volume. The precipitated solid was filtered and rinsed with Et2O / pentane to obtain the desired compound as a white solid (130 mg, 48%), mp 97100 [deg.] C. HPLC-MS (method 1): m / z 318 [M + H] + , Rt = 4.87 min.

Example 64: 3 - {[(Z) -7- (5-Chloro-2-furyl) -6-heptenyl] oxy} benzenecarboxamide

Synthesized from the bromide of 6- [3- (Aminocarbonyl) phenoxy] hexyl (triphenyl) phosphonium according to Procedure E. Production 72%, mp 53-56 [deg.] C. By 1 H NMR analysis, it consisted of a mixture of Z: E (81:19) .30 HPLC-MS (procedure 1): m / z 334 [M + H] +, Rt = 4.80 min.

Scheme 5: (a) Br (CH2) 6Br (n = 5, 8) K2CO3, CH3CH, 60 [deg.] C .; (b) ethylene diamine complex lithium acetyl [Lic = CH (H2NCH2CH2NH2)] DMSO, r.t.

3 - [(7-Bromoheptyl) oxy] benzenocarboxamide

Synthesized according to procedure D. HPLC-MS (procedure 1): m / z 314 [M] +, 316 [M + 2H] +, Rt = 4.37 min.

(Procedure F) a lithium acetyl ethylene diamine complex (305 mg, 3.3 mmol, 1.1 equiv.) Was placed in a triple neck bottle, degassed, washed with N2 and suspended in DMSO (2 ml). A solution of 3 [(7-Bromoheptyl) oxy] benzenecarboxamide (943 mg, 3 mmol, 1 equiv.) In DMSO (2 ml) was added, slowly, drop by drop, at room temperature, under N2, at agitated suspension. The reaction mixture was stirred at room temperature.

15 for 16 hours. After that time, it was diluted with 1 N HCl solution and extracted with EtOAc (x 3). The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography on silica eluting with 20% EtOAc / hexane, to obtain the desired compound as a white solid (100 mg, 13%), mp 82-83 ° C. HPLC-MS (method 1 ): m / z 260 [M + H] +, Rt = 4.26 min.

20 3 - [(7-Bromodecyl) oxy] benzenocarboxamide

Synthesized according to procedure D. Production 32%, mp 114-116 ° C, HPLC-MS (method 1): m / z 356 [M] +, 358 [M + 2H] +, Rt = 5.15 min.

Synthesized from 3 - [(7-Bromodecyl) oxy] benzenocarboxamide

Scheme 6: (a) lithium acetyl ethylenediamine complex [LiC = CH (H2NCH2CH2NH2)], DMSO, r.t., (b) ptoluenesulfonic acid, EtOH, reflux; (c) 3-hydroxybenzenecarboxamide, PPh3-PS, DIAD, Et3N, THF, r.t.

10-Undecin-1-ol

10 (1.0 g, 3.4 mmol, 1 equiv.) In DMSO (5 ml), slowly, drop by drop, at room temperature, under N2, to a stirred suspension of lithium acetyl ethylene diamine complex (350 mg, 3.8 mmol , 1.1 equiv.) In DMSO (5 ml). The reaction mixture was stirred at room temperature for 18 h and diluted with n-pentane (50 ml). The organic phase was washed with 1 N HCl solution (2x20 ml) and water (2x20 ml), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue (colorless liquid, 570 mg, 70% yield) was dissolved in 95% EtOH

15 (20 ml) together with p-toluenesulfonic acid (150 mg) and the mixture was heated at reflux for 2.5 hours. After being cooled, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with EtOAc / hexane (10% -30% gradient), to obtain the desired compound as a colorless oil (240 mg, 48% joint production).

Synthesized from 3-hydroxybenzenocarboxamide and 10-undecin-1-ol according to Procedure C, scheme 3; mp 111-112 [deg.] C., HPLC-MS (method 1): m / z 274 [M + H] +, Rt = 4.61 min.

Scheme 7: (a) SOCl2, toluene, reflux; (b) aqueous NH3, (c) n-Non-Br, K2CO3, Nal, DMF, 60 ° C; (d) 10-undecinol, PPh3-PS, DIAD, Et3N, THF, r.t.

2-Chloro-5-hydroxybenzenecarboxamide

Synthesized from 2-Chloro-5-hydroxybenzenecarboxylic acid, according to procedure A, scheme 1. Production 28%, mp 159-161 ° C, HPLC-MS (method 1): m / z 170 [MH] - , Rt = 1.48 min.

10 Synthesized from 2-Chloro-5-hydroxybenzenecarboxamide according to Method B, scheme 2. Production 80%, HPLC-MS (method 1): m / z 339 [M + H + CH3CH] +, Rt = 5.29 min.

Synthesized from 2-Chloro-5-hydroxybenzenecarboxamide according to procedure C, scheme 3. 15 Production 13%, HPLC-MS (method 1): m / z 322 [M + H] +, Rt = 4.94 min.

Scheme 8: (a) BBr3, CH2Cl2, r.t .; (b) R1-Br, K2CO3, Nal, DMF, 60 ° C; (c) R2-OH, PPh3-PS, DIAD, Et3N, THF, r.t.

2-Fluoro-5-hydroxybenzenecarboxamide

5 (Procedure H) a solution of boron tribromide (1.0 M in CH2Cl2, 23.6 ml, was added slowly, dropwise)

23.6 mmol, 2 equiv.) To a stirred solution of 2-Fluoro-5-methoxybenzenecarboxamide (2.0 g, 11.8 mmol, 1 equiv.) In CH2Cl2 (60 ml), at room temperature, under N2. The reaction mixture was stirred at room temperature for 48 hours. The solvent was removed under reduced pressure, the residue was dissolved in water (120 ml) and extracted with EtOAc (4x100 ml). The combined organic extracts were washed with water (2x100 ml), dried (Na2SO4) and filtered to

10 through a silica gel buffer. The filtrate was evaporated to dryness under reduced pressure, to obtain the desired compound as a gray solid (1.50 g, 82%).

Examples 70-75 (Table C)

Examples 70-72 were synthesized from 2-Fluoro-5-hydroxybenzenocarboxamide according to procedure B, scheme 2 and Examples 73-75 were synthesized from 2-Fluoro-5-hydroxybenzenocarboxamide 15 according to procedure C , scheme 3

Example

70 71

Structure

Performance (%)

- 40

Mp (ºC)

- 78-80

HPLC-MS: procedure no., M / z, ion

Rt (min)

2.42 5.69

Table of product compound names; Examples 70-75

Example

Compound name

70

2-Fluoro-5- (nonyloxy) benzenocarboxamide

71

2-Fluoro-5- (decyloxy) benzenocarboxamide

72

2-Fluoro-5- (undecyloxy) benzenocarboxamide

73

2-Fluor-5 - [(Z) -5-octenyloxylbenzenecarboxamide

74

2-Fluor-5 - [(E) -2-noneni) oxy] benzenocarboxamide

75

2-Fluoro-5- (10-undecinyloxy) benzenocarboxamide

Scheme 9: (a) SOCl2, toluene, reflux; (b) aqueous NH3; (c) BBr3, CH2Cl2, r.t .; (d) n-Non-Br, K2CO3, Nal, DMF, 60º C

6-Chloro-2-fluorine-3-methoxybenzenecarboxamide

Synthesized from 6-Chloro-2-fluorine-3-methoxybenzenecarboxylic acid, commercially available, according to Procedure A, scheme 1. Production 85%, mp 154-156 ° C, HPLC-MS (procedure 1) : m / z 245 [M + H + CH3CN] +, Reaction time = 2.37 min.

6-Chloro-2-fluorine-3-hydroxybenzenecarboxamide

Synthesized from 6-Chloro-2-fluorine-3-methoxybenzenecarboxamide according to Procedure H. Production: 90%.

Synthesized from 6-Chloro-2-fluorine-3-hydroxybenzenecarboxamide according to Procedure B, scheme 2. Production 73%, mp 75-77 [deg.] C., HPLC-MS (method 1): m / z 316 [M + H ] +, Rt = 5.27 min.

15 2-Chloro-6-fluorine-3-hydroxybenzenecarboxamide

Synthesized from 2-Chloro-6-fluorine-3-methoxybenzenecarboxamide, commercially available, according to the procedure H. Production: 78%.

Synthesized from 2-Chloro-6-fluorine-3-hydroxybenzenecarboxamide according to Procedure B, scheme 2. Production 30%, mp 66-68 [deg.] C., HPLC-MS (method 1): m / z 274 [M + H ] +, Rt = 2.78 min.

Synthesized from 2-Chloro-6-fluoro-3-hydroxybenzenecarboxamide according to Procedure B, scheme 2. Production 15%, mp 64-66 ° C, HPLC-MS (method 1): m / z 316 [M + H ] +, Rt = 5.13 min.

Scheme 11: (a) SOCl2, toluene, reflux; (b) aqueous NH3; (c) BBr3, CH2Cl2, r.t. (d) n-Hex-Br, K2CO3, Nal, DMF, 60 ° C.

2,4,6-Trifluor-3-methoxybenzenecarboxamide

Synthesized from commercially available 2,4,6-Trifluor-3-methoxybenzenecarboxylic acid, according to Procedure B, scheme 1. Production 85%, mp 102 ° C, HPLC-MS (method 1): m / z 206 [M + H] +, Rt =

15 2.40 min.

2,4,6-Trifluor-3-hydroxybenzenecarboxamide

Synthesized from 2,4,6-Trifluor-3-methoxybenzenecarboxamide, according to Procedure H. 100% Production, HPLC-MS (method 1): m / z 190 [M-H] -, Rt = 1.07 min.

Synthesized from 2,4,6-Trifluor-3-hydroxybenzenecarboxamide, according to Procedure B, scheme

2. Production 54%, mp 89-90 [deg.] C., HPLC-MS: m / z 276 [M + H] +, Rt = 4.36 min. Scheme 12:

2,4-Difluor-3-hydroxybenzenecarboxamide.

10 Synthesized from 2,4-Difluor-3- (hexyloxy) benzenocarboxamide, commercially available, according to Procedure H. Production 98%, HPLC-MS (procedure 1): m / z 172 [MH] - , Rt = 1.03 min.

Synthesized from 2,4-Difluor-3-hydroxybenzenecarboxamide, according to Procedure B, scheme 2. 15 Production 51%, mp 86-87º C.

Scheme 13: (a) SOCl2, toluene, reflux; (b) aqueous NH3; (c) BBr3, CH2Cl2, r.t. (d) R1-Br, K2CO3, Nal, DMF, 60 [deg.] C. (e) R2-OH, PPh3-PS, DIAD, Et3N, THF, r.t.

Example

81 82

Structure

Performance (%)

38 71

Mp (ºC)

93-95 76-78

HPLC-MS: procedure no., M / z, ion

Rt (min)

4.38 5.16

2,4-Difluor-3-methoxybenzenecarboxamide.

Synthesized from 2,4-Difluoro-3-methoxybenzenecarboxylic acid, commercially available, in accordance with Procedure A, scheme 1. Production 84%, mp 167-169 ° C, HPLC-MS (procedure 1): m / z 188 [M + H] +, Rt =

2.00 min.

2,6-Difluor-3-hydroxybenzenecarboxamide.

Synthesized from 2,6-Difluor-3-methoxybenzenecarboxamide according to Procedure H. Production 10 78%. HPLC-MS (procedure 1): m / z 172 [M-H] -, Rt = 1.25 min.

Examples 81-87 (Table D)

Examples 81-83 were synthesized from 2,6-Difluor-3-hydroxybenzenecarboxamide according to procedure B, scheme 2. Examples 84-88 were synthesized from 2,6-Difluor-3-hydroxybenzenecarboxamide according to procedure C, scheme 3.

Table of product compound names; Examples 81-88:

Example

Compound name

81

2,6-Difluor-3- (hexyloxy) benzenecarboxamide

82

2,6-Difluor-3- (nonyloxy) benzenocarboxamide

83

Butyl 2- [3- (aminocarbonyl) -2,4-difluorophenoxylacetate

84

2,6-Difluor-3 - [(E) -2-nonenitoxy] benzenocarboxamide

85

2,6-Difluor-3- [2- (hexyloxy) ethoxy] benzenecarboxamide

86

2,6-Difluor-3 - [(Z) -6-nonenyloxy) benzenocarboxamide

Example

Compound Name

87

2,6-Difluor-3 - [(Z) -5-decenyloxy) benzenecarboxamide

88

2,6-Difluor-3- (10-undecyloxy) benzenecarboxamide

Scheme 14: reflux;

2- [3- (aminocarbonyl) -2,4-difluorophenoxy] methyl acetate.

 A mixture of 2,6-difluoro-3-hydroxybenzenecarboxamide (1.2 g, 7 mmol, 1 equiv.), K2CO3 (2.87 g, 21 mmol, 3 equiv.) And methyl bromoacetate (.69 ml, 7.35 mmol, 1.05 equiv. ) in DMF (30 ml) was stirred at room temperature for 18 h. The mixture was diluted with water and extracted with EtOAc (4x80 ml). The combined organic extracts were dried (MgSO4) and evaporated to dryness under reduced pressure. The product was used raw in

10 the next phase. HPLC-MS (procedure 1): m / z 246 [M + H] +, Rt = 2.08 min.

Acetic 2- [3- (aminocarbonyl) -2,4-difluorphenoxy] acid

2- [3- (aminocarbonyl) -2,4-difluorophenoxy] methyl acetate (7 mmol, 1 equiv.) Was added to a solution of NaOH (1g, 25 mmol, 3.6 equiv.) In water (20 ml) and isopropyl alcohol (5 ml). The mixture was stirred at reflux for 1.5 h,

Diluted with water (40 ml) and extracted with CH2Cl2 (40 ml). The aqueous phase was acidified to pH 1 with conc. HCl The precipitated solid was filtered and dried in vacuo to obtain the desired compound (130 mg, 8%), mp 152153 ° C. HPLC-MS (procedure 1): m / z 312 [M-H + 2CH3CN] -, Rt = 0.91 min.

20 n-Bromohexane (0.077 ml, 0.55 mmol, 1.05 equiv.) Was added to a suspension of acetic 2- [3- (aminocarbonyl) -2,4-difluorophenoxy] acidic acid (120 mg, 0.52 mmol, 1 equiv.) and K2CO3 (215 mg, 1.56 mmol, 3 equiv.) in DMF (3 ml) and the mixture was stirred at 70 ° C for 1.5 h. After cooling to room temperature, the mixture was poured into water (25 ml) and the precipitating solid was filtered and washed with water (2x20 ml). After drying, the crude solid was crushed by stirring in hexane (10 ml), filtered and washed with hexane (3 x 10 ml), to obtain the compound.

25 desired as a white solid (99 mg, 60%), mp 108 ° C. HPLC-MS: m / z 316 [M + H] +, Reaction time = 4.09 min.

Scheme 15: (a) lithium acetyl ethylene diamine complex [LiC = CH (H2NCH2CH2NH2)], DMSO, r.t., (b) ptoluenesulfonic acid, EtOH, reflux; (c) CICH2COCl, CH2Cl2, r.t. (d) K2CO3, Nal, DMF, 60º C

7-Octin-1-ol.

Synthesized from available 2 - [(8-bromohexyl) oxy] tetrahydro-2H-pyran commercially available, in accordance with Procedure G. 55% global production, colorless oil.

7-Octinyl 2-chloroacetate.

Chloroacetyl chloride (0.16 ml, 2.0 mmol, 1 equiv.) Was added to a stirred solution of 7-Octin-1-ol (300 mg, 2.4 mmol, 1.2 equiv.) In CH2Cl2 (6 m-) at - 5 ° C. The reaction mixture was left calendar at room temperature, where

10 was stirred for 4 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica eluting with EtOAc / hexane (10%) to obtain the desired compound as a pale yellow liquid (450 mg, 100%).

15 Synthesized from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Procedure B, scheme 2. Production 13%, mp 130-132 ° C, HPLC-MS (method 1): m / z 340 [M + H] +, Reaction time = 3.93 min.

Scheme 16: (a) ZnEt2, CH2l2, toluene, r.t.

Example 91: 3- [4- (2-Ethylcyclopropyl) butoxy] benzenecarboxamide.

To a solution of example 52 (500 mg, 2.02 mmol, 1 equiv.) In dry toluene (1 ml) was added, at temperature

At room temperature, under N2, a solution of diethyl zinc (1.1 M in toluene, 1.84 ml, 2.02 mmol, 1 equiv.). Diiodomethane (0.244 ml, 3.03 mmol, 1.5 equiv.) Was added slowly, drop by drop, and the reaction mixture was stirred at room temperature for 5 days. The mixture was diluted with water (40 ml) and extracted with CH2Cl2 (4x40 ml). The combined organic extracts were dried (MgSO4) and the solvents were removed under reduced pressure. By HPLC-MS, the crude residue consisted of raw material (80%) and desired product (20%). The

The reaction was repeated in the same way, in toluene (15 ml) using diethyl zinc (1.1 M in toluene, 6.1 ml, 6.6 mmol,

3.3 equiv.) And diiodomethane (0.244 ml, 3.03 mmol, 1.5 equiv.). The reaction mixture was stirred at 50 ° C for 5 days, diluted with water (80 ml) and extracted with CH2Cl2 (4x50 ml). The combined organic extracts were dried (MgSO4) and the solvents were removed under reduced pressure. The residue was triturated by stirring in pentane (15 ml) and the precipitating solid was filtered and rinsed with pentane to obtain 196 mg of a compound.

15 white, mp 104-105 ° C. By HPLC-MS, it consisted of raw material (65%) and the desired product (35%). HPLC-MS (procedure 1): m / z 303 [M + H + CH3CN] +, Rt = 4.83 min.

Scheme 17: (a) Br (CH2) 9OH, K2CO3, Nal, DMF, 60 ° C; (b) toluenesulfonyl chloride, Et3N, CH2Cl2, r.t .; (c) NaCN, H2O / EtOH, 75 ° C.

20 3 - [(9-Hydroxynilyl) oxy] benzenocarboxamide

Synthesized according to Procedure B, scheme 2. Production 75%, mp 118-120 ° C, HPLC-MS (procedure 1): m / z 280 [M + H] +, Reaction time = 3.50 min.

Toluenesulfonyl chloride (410 mg, 2.15 mmol, 1.5 equiv.) And triethylamine (0.40 ml, 2.88 mmol, 2 equiv.) Were added to a solution of 3 - [(9-hydroxynonyl) oxy] benzenecarboxamide (400 mg, 1.43 mmol, 1 equiv.) In CH2Cl2 (4

5 ml) and the reaction mixture was stirred at room temperature for 6 days. A solution of saturated NaHCO3 (40 ml) was added and the mixture was extracted with CH2Cl2 (3x30 ml). The combined organic extracts were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with CH3OH / CH2Cl2 (2%), to achieve the desired compound as a solid solid (428 mg, 69%), mp 78-80 ° C. HPLC-MS (procedure 1): m / z 434 [M + H] +, reaction time = 4.90 min.

Example 93: 3 - [(9-Cyanononyl) oxy] benzenocarboxamide.

Sodium cyanide (60 mg, 1.22 mmol, 1.3 equiv.) Was added to a solution of 9- [3- (aminocarbonyl) phenoxy] nonyl 4

methylbenzenesulfonate (407 mg, 0.94 mmol, 1 equiv.) in water (10 ml) and 95% EtOH (8 ml), and the reaction mixture was stirred at 75 ° C for 2 days. After cooling to room temperature, the mixture was diluted with water (10

15 ml) and extracted with H2Cl2 (3x10 ml). The combined organic extracts were dried (MgSO4) and the solvent was removed under reduced pressure. The crude residue was purified by column chromatography on silica eluting with EtOAc / hexane (50%), to obtain the desired compound as a white solid (57 mg, 21%), mp 96-97 ° C. HPLC-MS (procedure 1): m / z 289 [M + H] +, Reaction time = 4.16 min.

Synthesized from 2-hydroxyisonicotinonitrile, commercially available, according to Procedure B. Production 30%, semi-solid, HPLC-MS (procedure 2): m / z 245 [M + H + CH3CN] +, time Reaction = 21.46 minutes. The reaction also gave, as a byproduct, 1-nonyl-2-oxo-1,2-dihydro-4-pyridinecarbonitrile, production 39%, mp 46-48 [deg.] C., HPLC-MS (method 1): m / z 288 [ M + H + CH3CN] +, Reaction time = 4.94 min.

A solution of 2- (nonyloxy) isonicotinonitrile (250 mg, 1.0 mmol, 1 equiv.) And sodium methoxide (10 mg, 10 mmol, 0.1 equiv) in dry CH3OH (10 ml) was stirred at room temperature for 2.5 hours. A solution of lithium hydroxide (24 mg, 1.0 mmol, 1 equiv.) In water (1 ml) was added and the reaction mixture was heated to reflux

10 for 3.5 h. After cooling to room temperature, the mixture was poured into water (40 ml). The precipitating solid was filtered and dried in vacuo at 50 ° C, to obtain the desired compound as a white solid (60 mg, 23%), mp 108-110 ° C. HPLC-MS (procedure 1): m / z 265 [M + H] +, Reaction time = 5.08 min.

Scheme 19: (a) Br2, CCl4, (b) K2CO3, CH3CN, 60 ° C, 5 days, (c) conc. H2SO4, H2O, 40º C.

15 1,2-Dibromoheptane

Bromine (1.9 ml, 377.28 mmol, 1.05 equiv.) Was added, slowly, drop by drop, to a 1-heptene solution (5 ml,

35.5 mmol, 1 equiv.) In CCl4 (7 ml) cooled to -10 ° C, under N2. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed by evaporation under reduced pressure. The residue was divided

20 between CH2Cl2 (200 ml) and 10% aqueous sodium metabisulfate solution (200 ml). The organic phase was separated, washed with brine and dried (Na2SO4). It was evaporated under reduced pressure to dryness, to obtain the desired compound as a colorless oil (8.94g, 98%).

3-Pentyl-2,3-dihydro-1,4-benzodioxine-6-carbonitrile and 2-pentyl-2,3-dihydro-1,4-benzodioxine-6-carbonitrile.

25 1,2-Dibromoheptane (5.11 g, 19.8 mmol, 1.1 equiv.) Was added to a mixture of benzonitrile dihydroxide (2.43 g, 18 mmol, 1 equiv.) And K2CO3 (12.4 g, 90 mmol, 5 equiv. .) in CH3CN (100 ml). The reaction mixture was heated at reflux for 4 days. After cooling to room temperature, the solvent was removed under reduced pressure; The residue was diluted with water (200 ml) and extracted with EtOAc (3x150 ml). The combined organic phases were washed with brine, dried (Na2SO4) and evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica eluting with EtOAc / hexane (5% -10% gradient) to obtain the desired compound as a colorless oil (390 mg, 9%); mixture of two regal isomers. HPLC-MS (procedure 1): m / z 230 [M-H] -, Ambient temperature = 5.28 min.

Example 95: 3-Pentyl-2,3-dihydro-1,4-benzodioxine-6-carboxamide and 2-pentyl-2,3-dihydro-1,4benzodioxine-6-carboxamide.

A mixture of the 3-pentyl-2,3-dihydro-1,4-benzodioxine-6-carbonitrile and 2-pentyl-2,3-dihydro-1,4- regio-isomers

Benzodioxin-6-carbonitrile (50 mg, 0.22 mmol) was vigorously stirred in conc. H2SO4 (0.5 ml) and heated to 40 ° C. Water (82 mg) was added dropwise, and the mixture was stirred for 45 min at 40 ° C. The mixture was cooled to -5 ° C, and ice (25 ml) was added quickly, with vigorous stirring. The mixture was stirred at room temperature for another two hours. The precipitating solid was filtered, washed with water and dried in vacuo at 40 ° C. It was

15 purified on a TLC preparation plate (Analtech, 2mm, 20x20) eluting with methyl-tert-butll-ether, to obtain the desired compound as a white solid (50 mg, 93%), HPLCMS (method 1): m / z 291 [M + H + CH3CN] +, Reaction time = 4.14 min.

Examples 96-99, 101-116, 117, 119, 122, 124, 128-134, 137-139, 142, 144-154, 156-159 and 161-163 (Table E)

The compounds of Examples 96-99, 101-116, 117, 119, 122, 124, 128-134, 137-139, 142, 144-154, 156-159 and

161 161-163 were synthesized according to the following general procedure: 2,6-difluoro-3-hydroxybenzamide (C) and potassium carbonate (D) were added to a reagent solution (A) in anhydrous DMF. The reaction mixture was stirred at room temperature or 25 ° C under a nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400P) using ethyl acetate / hexane as the eluent to obtain the product compound.

25 Table E

Example

96 97

Product

2,6-Difluor-3- (5-methyl-quinolin-2-ylmethoxide) benzamide 2,6-Difluor-3- (6-methyl-quinolin-2-methoxide) -benzamide

Reaction scheme

Reagent (A)

2-Bromomethyl-5-methyl-quinoline 2-Bromomethyl-6-methyl-quinoline

Quantities of A; B; C; D

Stirring Temperature / Time

Ethyl acetate / hexane ratio

Production

0.3 g, 43% off-white solid 0.039 g, 56% off-white solid

1H NMR (DMSO, 400 MHz, unless otherwise indicated)

2.51 (s, 3H), 5.42 (s, 2H), 7.06 (dt, 1H, J = 9.2 Hz (coupling-o), J = 1.6Hz (coupling), 7.31 (dt, 1H, J = 9.2 Hz (coupling -o), J = 5.2 Hz), 7.63 (d, 2H, J = 8.4 Hz (coupling-o) 7.76 (s, 1H), 7.87 (s, 1H) 7.91 2.51 (s, 3H), 5.42 (s, 2H), 7.06 (dt, 1H, J = 9.2 Hz (coupling-o), J = 1.6Hz (coupling-m), 7.31 (dt, 1H, J = 9.2 Hz (o-coupling), J = 5.2 Hz), 7.63 (d, 2H, J = 8.4 Hz (o-coupling) 7.76 (s, 1H),

(d, 1H, J = 8.8Hz (o-coupling), 8.16 (s, 1H), 8.34 (d, 1H, J = 8.8 Hz (o-coupling)

7.87 (s, 1H) 7.91 (d, 1H, J = 8.8Hz (o-coupling), 8.16 (s, 1H), 8.34 (d, 1H, J = 8.8 Hz (o-coupling)

HPLC Procedure Number, reaction time (minutes)

98

99

2,6-Difluor-3- (7-methoxy-quinolin-2-ylmethoxide) -benzamide

3- [4- (2-Chloro-phenyl) -thiazol-2-ylmethoxide] -2,6-difluorobenzamide

2-Bromomethyl-7-methyl-quinoline

2-Bromomethyl-4- (2-chloro-phenyl) -thiazole

0.012 g, 9% off-white solid

0.80 g, 17% yellowish brown solid

2.51 (s, 3H), 5.41 (s, 2H), 7.06 (m, 1H, J = 9.2 Hz (coupling-o), J = 1.2Hz (coupling-m), 7.35-7.32 (m, 2H), 7.39 (1H, J = 2.0 Hz (m-coupling), 7.51 (d, 1H J = 8.4Hz (o-coupling), 7.88 (d, 1H) 7.91 (s, 1H width), 8.16 (s, 1H), 8.33 (d, 1H, (d, 1H, J = 8.4 Hz (o-coupling)

5.59 (s, 2H), 7.13 (dt, 1H, J = 8.8 Hz (coupling-o), J = 2.0Hz (coupling-m), 7.39-7.48 (m, 3H), 7.57-7.59 (m, 1H) , 7.85-7.86 (m, 1H), 7.89 (width s, 1H), 8.17 (width s, 2H)

101

102

2,6-Difluor-3- (3-fluoro-benzyloxy) -benzamide

3- (biphenyl-3-ylmethoxide] -2,6-difluoro-benzamide

1-Bromomethyl-3-fluorine-benzene

3-Bromomethyl-biphenyl

0.058 g, 18% off-white solid

0.15 g, 44% off-white solid

5.21 (s, 2H), 7.07 (dt, 1H, J = 8.8 Hz (o-coupling), J = 1.6 Hz (m-coupling), 7.18 (dt, 1H, J = 8.8 Hz (o-coupling), J = 2.4 Hz (m-coupling), 7.257.31 (m, 3H), 7.43-7.49 (m, 1H), 7.86 (s width, 1H) 8.14 (s width, 1H)

5.26 (s, 2H), 7.07 (dt, 1H, J = 8.8 Hz (coupling-o), 7.31-7.36 (m, 1H), 7.39 (d, 1H, J = 7.2 Hz), 7.43-7.52 (m, 4H), 7.66 (t, 3H, J = 8.0 Hz (coupling-o), 7.74 (s, 1H), 7.85 (s, 1H), 8.13 (width s, 1H)

103

104

3- (7-Methylquinolin-2-ylmethoxy) -2,6-Difluor-benzamide

2,6-Difluor-3- (7-Chloro-benzothiazol-2-ylmethoxy) -benzamide

à † Stage-1

à † Stage-1

2-Bromomethyl-7-methyl-quinoline

2-Bromomethyl-7-chloro-benzothiazole

0.3 g, 43% off-white solid

0.02 g, 5% light yellow solid

2.53 (s, 3H), 5.42 (s, 2H), 7.05 (t, 1H, J = 8.8 Hz

5.73 (s, 2H), 7.12 (dt, 1H, J = 8.8 Hz (o-coupling),

(coupling-o), 7.30 (dt, 1H, J = 9.2 Hz (coupling), J = 5.2 Hz), 7.47 (d, 1H, J = 8.4 Hz (coupling-o) 7.59 (d, 1H, J = 8.4 Hz (coupling-o), 7.80 (s, 1H) 7.89 (d, 2H, J = 8.8Hz (coupling-o), 8.16 (s, 1H), 8.38 (d, 1H, J = 8.4 Hz (coupling-o )

J = 1.2 Hz (m-coupling), 7.41 (dt, 1H, J = 9.2 Hz (o-coupling) J = 5.2 Hz), 7.61 (dd, 2H, J = 7.6 Hz (o-coupling), 7.91 (width s, 1H), 8.04 (dd, 1H, J = 7.2 Hz (coupling-o), J = 1.6 Hz (coupling-m), 8.19 (width s, 1H)

105

106

3- [4- (7-Methoxyphenyl) thiazol-2-ylmethoxy] -2,6-Difluorobenzamide

2,6-Difluor-3- (7-Chloro-benzothiazol-2-ylmethoxy) -benzamide

à † Stage-1

à † Stage-1

2-Bromomethyl-4- (4-methoxy-phenyl) -thiazole

2-Bromomethyl-4- (4-chloro-phenyl) -thiazole

0.048 g, 42% white solid

0.35 g, 58% white solid

3.80 (s, 3H), 5.57 (s, 2H), 7.01 (d, 2H, J = 8.8Hz), 7.12 (m, 1H), 7.41 (m, 1H), 7.88 (width s, 2H), 7.90 ( s, 1H) 8.02 (s, 1H), 8.17 (s, 1H)

5.59 (s, 2H), 7.12 (dt, 1H, J = 8.8 Hz (o-coupling), J = 2.0 Hz (m-coupling), 7.41 (dt, 1H, J = 9.2 Hz (o-coupling) J = 5.2 Hz), 7.52 (d, 2H, J = 8.4 Hz (coupling-o), 7.89 (width s, 1H), 7.99 (d, 1H, J = 8.8 Hz (coupling-o), 8.17 (width s, 1H ), 8.26 (s, 1H)

107

108

2,6-Difluor-3- (3-trifluoromethoxybenzyloxy) benzamide

3- (3-Carbamoyl-2,4-difluorophenoxymethyl] -benzoic acid methyl ester

à † Stage-1

à † Stage-1

1-Bromomethyl-3-trifluoromethoxy-benzene

3-Bromomethyl-benzoic acid methyl ester

0.058 g, 18.4% white solid

0.055 g, 18.4% white solid

5.25 (s, 2H), 7.09 (dt, 1H, J = 8.8 Hz (o-coupling), J = 2.0 Hz (m-coupling), 7.29 (dt, 1H, J = 9.2 Hz (o-coupling), J = 5.2 Hz (m-coupling), 7.36 (t, 3H, J = 8.0 Hz), 7.48 (t, 3H, J = 8.0 Hz (o-coupling), 7.56 (t, 3H, J = 8.0 Hz (coupling- o), 7.86 (width s, 1H), 8.14 (s, 1H)

3.87 (s, 3H), 5.28 (s, 2H), 7.08 (d, 1H, J = 9.2 Hz (coupling-o), 7.27-7.33 (m, 1H), 7.58 (t, 1H, J = 7.6 Hz ( o-coupling), 7.73 (d, 1H, J = 7.6 Hz (o-coupling), 7.86 (s, 1H), 7.94 (d, 1H, J = 8.0 Hz (o-coupling), 8.06 (s, 1H) , 8.15 (s, 1H)

109

110

3- (6-Methoxyquinolin-2-ylmethoxy) -2,6-Difluorobenzamide

3- (6-Chloro-quinolin-2-ylmethoxy) -2,6-difluoro-benzamide

à † Stage-1

à † Stage-1

2-Bromomethyl-6-methoxyquinoline

2-Bromomethyl-6-chloro-quinoline

0.045 g, 33% yellow solid

0.02 g, 16% white solid

3.90 (s, 3H), 5.39 (s, 2H), 7.06 (m, 1H, J = 8.8 Hz (coupling-o), J = 1.6 Hz (coupling-m), 7.31 (dt, 1H, J = 9.2 Hz (o-coupling), J = 5.2 Hz), 7.73 (d, 1H, J = 8.4 Hz) 7.80 (dd, 1H, J = 2.4 Hz (m-coupling), 7.87 (s, 1H) 7.92 (d, 1H , J = 9.2Hz (o-coupling), 8.16 (s, 1H), 8.33 (d, 1H, J = 8.4 Hz (o-coupling)

5.45 (s, 2H), 7.06 (dt, 1H, J = 8.8 Hz (o-coupling), J = 1.6 Hz (m-coupling), 7.31 (dt, 1H, J = 9.2 Hz (o-coupling) J = 5.2 Hz), 7.73 (d, 1H, J = 8.4 Hz), 7.80 (dd, 1H, J = 2.4 Hz (m-coupling), 7.87 (s, 1H), 8.03 (d, 1H, J = 9.2 Hz ( o-coupling), 8.16 (2H, J = 2.4 Hz (m-coupling), 8.44 (d, 1H, J = 8.8 Hz (o-coupling)

111

112

3- (7-Chloro-quinolin-2-ylmethoxy) -2,6-Difluoro-benzamide

3- (8-Chloro-quinolin-2-ylmethoxy) -2,6-difluoro-benzamide

à † Stage-1

à † Stage-1

2-Bromomethyl-7-chloro-quinoline

2-Bromomethyl-8-chloro-quinoline

0.015 g, 94% white solid

0.038 g, 27% white solid

5.45 (s, 2H), 7.06 (m, 1H, J = 9.2 Hz (coupling-o), J = 1.6 Hz (coupling-m), 7.31 (dt, 1H, J = 9.2 Hz (coupling), J = 5.2 Hz), 7.68 (dd, 1H, J = 2.0 Hz (m-coupling), 8.8 Hz (o-coupling), 7.69 (d, 1H, J = 8.4 Hz (coupling), 7.87 (s, 1H width), 8.06-8.08 (m, 2H), 8.16 (width s, 1H), 8.50 (d, 1H, J = 8.8 Hz (coupling-o)

7.38 (dt, 1H, J = 9.2 Hz (coupling-o), J = 5.2 Hz), 7.61 (t, 1H, J = 8.0 Hz (coupling-o), 7.78 (d, 1H, J = 8.4 Hz (coupling -o)), 7.87 (width s, 1H), 7.98-8.03 (m, 2H), 8.16 (width s, 1H), 8.55 (d, 1H, J = 8.8 Hz (coupling-o)

113

114

2,6-Difluor-3- (naphthalen-2-ylmethoxy) -benzamide

2,6-Difluor-3- (5-phenyl-benzothiazol-2-ylmethoxy) -benzamide

à † Stage-1

à † Stage-1

2-Bromomethyl-Naphthalene

2-Bromomethyl-5-phenyl-benzothiazole

0.35 g, 49% off-white solid

0.012 g, 4% light yellow solid

5.36 (s, 2H), 7.07 (dt, 1H, J = 9.2 Hz (o-coupling), J = 2.0 Hz (m-coupling), 7.34 (dt, 1H, J = 9.2 Hz (o-coupling), J = 5.2 Hz), 7.53-7.55 (m, 2H), 7.58 (dd, 1H, J = 8.4 Hz (coupling-o), J = 2.4 Hz (coupling-m), 7.86 (width s, 1H), 7.92- 7.97 (m, 3H), 7.98 (width s, 1H), 8.143 (width s, 1H)

5.73 (s, 2H), 7.11 (dt, 1H, J = 9.2 Hz (coupling-o), J = 5.2 Hz), 7.36-7.43 (m, 2H), 7.51 (t, 2H, J = 7.6 Hz (coupling -o), 7.78-7.81 (m, 3H), 7.90 (width s, 1H), 8.16 (width s, 1H), 8.29 (d, 1H, J = 8.4 Hz (coupling) 8.28-8.29 (d, 1H, J = 1.6 Hz (coupling-m)

115

116

2,6-Difluor-3- (4-pyridin-2-yl-thiazol-2-ylmethoxy) -benzamide

2,6-Difluor-3- (3-methoxybenzyloxy) -benzamide

à † Stage-1

à † Stage-1

2- (2-Bromomethyl-thiazol-4-yl) -pyridine

1-Bromomethyl-3-methoxy-benzene

0.058 g, 18% light yellow solid

0.055 g, 18% white solid

3.75 (s, 3H), 5.15 (s, 2H), 6.90 (d, 1H, J = 8.0 Hz (coupling-o), 7.87 (width s, 1H), 7.05 (t, 2H, J = 8.8 Hz (coupling -o), 7.25-7.31 (m, 2H), 7.84 (width s, 1H), 8.13 (width s, 1H)

3.75 (s, 3H), 5.15 (s, 2H), 6.90 (d, 1H, J = 8.0 Hz (coupling-o), 7.87 (width s, 1H), 7.05 (t, 2H, J = 8.8 Hz (coupling -o), 7.25-7.31 (m, 2H), 7.84 (width s, 1H), 8.13 (width s, 1H)

117

119

2,6-Difluor-3- (5-nitro-benzothiazol-2-ylmethoxy) -benzamide

2,6-Difluor-3- (3-methoxy-benzothiazol-2-ylmethoxy) -benzamide

2-Bromomethyl-5-nitro-benzothiazole

2-Bromomethyl-5-methoxy-benzothiazole

Ambient temperature, overnight

0.040 g, 67% yellow solid

0.020 g, 33% yellow solid

δ 5.77 (s, 3H), 5.42 (s, 2H), 7.12 (t, 1H, J = 8.8 Hz (coupling-o), 7.42 (dt, 1H, J = 9.2 Hz (coupling-o), 7.90 (width s, 1H), 8.18 (width s, 1H), 8.32 (d, 1H, J = 8.8 Hz (coupling-o), 8.46 (d, 1H, J = 9.2 Hz (coupling-o), 8.83 (s, 1H )

δ 3.84 (width s, 3H), 5.66 (s, 2H), 7.08-7.12 (m, 2H), 7.38 (m, 1H, J = 8.4 Hz (coupling-o), 7.55-7.56 (m, 1H), 7.88 (width s, 1H), 7.99 (d, 3H, J = 9.2 Hz (coupling), 7.87 (width s, 1H), 7.05 (t, 2H, J = 8.8 Hz (coupling-o), 8.17 (width s , 1 HOUR)

122

124

2,6-Difluor-3- (4-phenethyl-thiazol-2-ylmethoxy) -benzamide

3- [1- (5-Chloro-benzothiazol-2-yl) -ethoxy] -2,6-difluoro-benzamide

à † Stage-1

2-Bromomethyl-4-phenethyl-thiazole

2- (1-Bromo-methyl) -5-chloro-benzothiazole

Ambient temperature, overnight

0.108 g, 41% white solid

0.1 g, 25% yellow solid

δ 2.98 (tt, 4H, J = 4.8 Hz), 5.48 (s, 2H), 7.08-7.15 (m, 1H), 7.17-7.28 (m, 4H), 7.33-7.38 (m, 2H), 7.87 (width s, 1H), 8.26 (width s, 1H)

δ 1.76 (d, 3H, J = 6.4 Hz), 6.01 (q, 1H, J = 6.4 Hz (o-coupling), 7.06 (dt, 1H, J = 8.8 Hz (o-coupling), 7.34 (dt, 1H , J = 9.2 Hz (coupling-o), 7.52 (dd, 1H, J = 7.2 Hz (coupling-o), 7.89 (width s, 1H), 8.11 (width s, 1H), 8.17 (d, 2H, J = 8.4 Hz (coupling-o)

128

129

2,6-Difluor-3- (2-fluorine-3-methyl-benzyloxy) -benzamide

-

1-Bromomethyl-2-fluorine-3-methyl-benzene

2-bromomethyl-5- (4-chloro-phenyl) -benzothiazole

Ambient temperature, overnight

25º C, overnight

0.112 g, 44% white solid

0.020 g, 54% white solid

δ 2.26 (s, 3H), 5.18 (s, 2H), 7.06-7.14 (m, 2H), 7.297.37 (m, 3H), 7.85 (width s, 1H), 8.14 (width s, 1H)

δ 5.72 (s, 2H), 7.11 (dt, 1H, J = 8.0 Hz (coupling-o & 8.4 Hz), 7.39 (m, 1H), 7.55 (d, 2H, J = 8.4 Hz (coupling-o), 7.78-7.83 (m, 3H), 7.89 (width s, 1H), 8.18 (width s, 1H), 8.23 (d, 2H, J = 8.0 Hz (coupling-o), 8.30 (s, 1H)

130

131

-

-

5-Bromo-2-bromomethyl-4-o-tolyl-thiazole

5-Bromo-2-bromomethyl-4-m-tolyl-thiazole

25º C, overnight

25º C, overnight

0.281 g, 44% off-white solid

0.371 g, 40% yellow solid

δ 5.53 (s, 2H), 7.11 (dt, 1H, J = 8.8 Hz (coupling-o), 7.38 (m, 5H), 7.89 (width s, 1H), 8.16 (width s, 1H)

1H NMR (MeOH, 400 MHz); δ 2.70 (s, 3H), 5.23 (s, 2H), 6.93 (dt, 1H, J = 8.8 Hz (coupling-o), 7.06 (dt, 1H, J = 8.8 Hz (coupling-o), & 2.0 Hz (m-coupling), 7.23 (dt, 1H, J = 4.8 Hz), 7.48 (d, 1H, J = 8.0 Hz (o-coupling), 7.49 (s, 1H), 7.80-7.82 (m, 1H), 7.93 (width s, 1H)

132

133

2,6-Difluor-3- (2-phenyl-oxazol-4-ylmethoxy) -benzamide

2,6-Difluor-3- (2-thiophen-2-yl-oxazol-ylmethoxy) -benzamide

4-bromomethyl-2-phenyl-oxazola

4-bromomethyl-2-thiophene-2-yl-oxazola

Ambient temperature, overnight

0.099 g, 30% white solid

0.020 g, 33% off-white solid

δ 5.15 (s, 2H), 7.12 (dt, 1H, J = 8.8 Hz (coupling-o), 7.42 (dt, 1H, J = 9.2 Hz J = 5.2 Hz (coupling-m), 7.55 (t, 3H, J = 3.2 Hz), 7.85 (width s, 1H), 7.98-8.00 (m, 2H), 8.13 (width s, 1H), 8.33 (s, 1H)

δ 5.11 (s, 2H), 7.09 (dt, 1H, J = 8.8 Hz (coupling-o), 7.23 (t, J = 4.8 Hz), 7.39 (dt, 3H, J = 5.2 Hz), 7.73 (dt, 3H, J = 5.2 Hz), 7.82 (dt, 3H, J = 5.2 Hz) (width s, 1H), 7.85 (width s, 1H), 8.13 (width s, 1H), 8.27 (s, 1H)

134

137

2,6-Difluor-3- (5-thiophen-2-yl- [1,2,4] oxadiazol-3-ylmethoxy) benzamide

3- (4-Benzyl-thiazol-2-ylmethoxy) -2,6-Difluoro-benzamide

4-bromomethyl-5-thiophene-2-yl- [1,2,4] oxadiazole

4-benzyl-2-bromomethyl-thiazole

Ambient temperature, overnight

0.020 g, 6% off-white solid

0.126 g, 35% white solid

δ 5.43 (s, 2H), 5.15 (s, 2H), 7.12 (dt, 1H, J = 9.2 Hz (coupling-o) & 1.6 Hz (coupling-m), 7.34-7.41 (m, 2H), 7.87 ( width s, 1H), 8.06 (d, 1H, J = 4.0 Hz), 8.12 (d, 1H, J = 4.8 Hz), 8.16 (width s, 1H)

δ 4.06 (s, 2H), 5.45 (s, 2H), 7.09 (dt, 1H, J = 7.6 Hz (coupling-o), 7.18 (t, J = 6.8 Hz), 7.23-7.36 (m, 2H), 7.37 (s, 1H), 7.86 (width s, 1H), 8.14 (width s, 1H)

138

139

-3- (5-Cyclopropyl- [1,2,4] oxadiazol-3-ylmethoxy) -2,6-Difluorobenzamide

3- (6-Chloro-thiazolo [5,4-b] pyridin-2-ylmethoxy) -2,6-Difluorobenzamide

3-bromomethyl-5-cyclopropyl- [1,3,4] thiadiazole

2-bromomethyl-6-chloro-thiazolo [5,4-b] pyridine

Ambient temperature, overnight

Ambient temperature, overnight

0.118 g, 38% pink solid

0.030 g, 22% yellow solid

δ 1.01-1.05 (m, 2H), 1.19-1.24 (m, 2H), 2.51-2.58 (m, 1H), 5.59 (s, 2H), 7.11 (dt, 1H, J = 9.2 Hz (o-coupling) , 7.37 (dt, 1H, J = 9.2 Hz (coupling-o), J = 1.2 Hz (coupling-m), 7.87 (width s, 1H), 8.15 (width s, 1H)

δ 5.72 (s, 2H), 7.12 (dt, 1H, J = 8.8 Hz (coupling), 7.37-7.43 (m, 1H), 7.90 (width s, 1H), 8.18 (width s, 1H), 8.68 (dt , 1H, J = 2.0 Hz (m-coupling), 8.73 (dt, 1H, J = 2.0 Hz (m-coupling)

142

144

-2,6-Difluor-3- (5-m-tolyl-benzothiazol-2-ylmethoxy) -benzamide

2,6-Difluor-3- (2-pyrazol-1-yl-ethoxy) -benzamide

3-bromomethyl-5-m-tolyl-benzothiazole

1- (2-Bromo-ethyl) -1H-pirazola

Ambient temperature, overnight

0.026 g, 10% white solid

0.112 g, 42% yellow solid

δ 2.82 (s, 3H), 5.28 (s, 2H), 7.08 (dt, 1H, J = 8.8 Hz (coupling-o), J = 1.2 Hz (coupling-m), 7.34-7.35 (m, 1H), 7.47 (dt, 1H, J = 7.2 Hz (o-coupling), 7.53 (t, 1H, J = 8.0 Hz (o-coupling), 7.71 (dd, 1H, J = 8.0 Hz (o-coupling), J = 1.2 Hz (coupling-m), 7.75 (d, 1H, J = 8.0 Hz (coupling-o), 7.85 (width s, 1H), 8.13 (d, 2H, J = 8.4 Hz), 8.18 (d, 1H, J = 1.2 Hz (coupling-m)

δ 4.39 (d, 2H, J = 4.8 Hz), 4.50 (d, 2H, J = 4.8 Hz), 6.24 (m, 1H), 7.03 (dt, 1H, J = 1.6 Hz (m-coupling), 7.17 ( dt, 1H), 7.46 (d, 1H, J = 2.0 Hz (m-coupling), 7.76 (d, 1H, J = 2.0 Hz (m-coupling), 7.83 (s width, 1H), 8.10 (s width, 1 HOUR)

145

146

-3- [5- (3,5-Dimethyl-isoxazol-4-yl) [1,2,4] oxadiazol-3-ylmethoxy) -2,6-Difluorobenzamide

2,6-Difluor-3- (8-methyl-quinolin-2-ylmethoxy) -benzamide

5- (3,5-Dimethyl-isoxazol-4-yl) -3-methyl [1,2,4] oxadiazole

2-bromomethyl-8-methyl-quinoline

Ambient temperature, overnight

0.098 g, 28% white solid

0.014 g, 8% white solid

δ 2.49 (s, 3H), 2.76 (s, 3H), 5.46 (s, 2H), 7.11 (dt, 1H, J = 8.8 Hz (o-coupling), 7.41 (dt, 1H, J = 8.8 Hz (coupling -o) & 5.2 Hz), 7.86 (width s, 1H), 8.14 (width s, 1H)

δ 2.71 (s, 3H), 5.46 (s, 2H), 7.06 (dt, 2H, J = 9.2 Hz (coupling) J = 1.6 Hz (coupling-m), 7.36 (dt, 1H, J = 9.2 Hz (coupling -o, J = 5.2 Hz), 7.51 (t, 1H, J = 7.6 Hz (coupling), 7.65 (t, 2H, J = 7.6 Hz (coupling-o), 7.82 (d, 1H, J = 8.0 Hz ( coupling-o), 7.86 (width s, 1H), 8.15 (width s, 1H), 8.41 (d, 1H, J = 8.0 Hz (coupling-o)

147

148

2,6-Difluor-3- (4-fluorine-3-methyl-benzyloxy) -benzamide

2,6-Difluor-3- (5-methyl-benzothiazol-2-ylmethoxy) benzamide

4-bromomethyl-1-fluorine-2-methyl-benzene

2-bromomethyl-5-methyl-benzothiazole

Ambient temperature, overnight

0.0973 g, 33% white solid

0.023 g, 27% yellow solid

δ 2.24 (s, 3H), 5.10 (s, 2H), 7.06 (dt, 1H, J = 8.8 Hz (coupling-o) J = 1.6 Hz (coupling-m), 7.15 (t, 1H, J = 8.4 Hz (coupling-o), 7.26-7.31 (m, 2H), 7.36 (d, 1H, J = 7.6 Hz (coupling-o), 7.84 (width s, 1H), 8.12 (width s, 1H)

δ 2.46 (s, 3H), 5.67 (s, 2H), 7.10 (dt, J = 8.4 Hz (o-coupling), 7.30 (d, 1H, J = 8.0 Hz (o-coupling, J = 5.2 Hz), 7.37 (dt, 1H, J = 5.2Hz, J = 9.2Hz), 7.83 (s, 1H), 7.88 (width s, 1H), 8.00 (d, 1H, J = 8.4 Hz (o-coupling), 8.17 ( width s, 1H)

149

150

2,6-Difluor-3- (5-styryl- [1,2,4] oxadiazol-3-ylmethoxy) benzamide

2,6-Difluor-3- (5-thiophen-3-yl- [1,2,4] oxadiazol-3-ylmethoxy) benzamide

3-bromomethyl-5-styryl- [1,2,4] oxadiazole

3-bromomethyl-5-thiophene-3-yl- [1,2,4] oxadiazole

0.089 g, 25% white solid

0.067 g, 20% white solid

δ 5.41 (s, 2H), 7.11 (dt, 1H, J = 8.4 Hz (coupling-o), 7.35-7.47 (m, 5H), 7.78-7.93 (m, 4H), 8.16 (width s, 1H)

δ 5.43 (s, 2H), 7.11 (dt, 1H, J = 8.8 Hz (coupling-o), 7.38 (dt, J = 5.2 Hz, J = 9.2 Hz), 7.70 (d, 1H, J = 5.2Hz) , 7.85-7.87 (m, 2H), 8.15 (width s, 1H), 8.64 (t, 1H, J = 1.2 Hz)

151

152

3- (5-Bromo-quinolin-2-ylmethoxy) -2,6-Difluoro-benzamide

2,6-Difluor-3- (5-thiophen-2-yl- [1,2,4] oxadiazol-2-ylmethoxy) benzamide

5-Bromo-2-bromomethyl-quinoline

2-bromomethyl-5-thiophene-3-yl- [1,3,4] oxadiazole

Ambient temperature, overnight

Ambient temperature, overnight

0.086 g, 22% white solid

0.0842 g, 25% off-white solid

δ 5.50 (s, 2H), 7.06 (dt, 1H, J = 8.4 Hz (o-coupling),

δ 5.55 (s, 2H), 7.14 (dt, 1H, J = 9.2 Hz (coupling-o),

7.30-7.31 (m, 1H), 7.73 (t, 1H, J = 8.0 Hz), 7.83 (d, 1H, J = 8.8 Hz (coupling-o), 7.87 (width s, 1H), 7.99 (d, 1H , J = 7.6 Hz (coupling-o), 8.06 (d, 1H, J = 8.8 Hz (coupling-o), 8.16 (width s, 1H), 8.60 (d, 1H, J = 8.8 Hz (coupling-o)

7.31 (dd, 1H, J = 4.8 Hz), 7.43 (dt, J = 9.2 Hz, J = 5.2 Hz), 7.86 (dd, 1H, J = 4.8Hz), 7.88 (width s, 1H), 7.99 (d , 1H, J = 5.2 Hz), 8.15 (width s, 1H)

153

154

2,6-Difluor-3- (3-thiophen-2-yl- [1,2,4] oxadiazol-5-ylmethoxy) benzamide

3- (3-Benzyloxy-benzyloxy) -2,6-Difluoro-benzamide

5-bromomethyl-3-thiophene-2-yl- [1,2,4] oxadiazole

3-benzyloxy-benzylbromide

0.045 g, 13% yellow solid

0.035 g, 10% off-white solid

δ 5.67 (s, 2H), 7.13 (dt, 1H, J = 8.8 Hz (o-coupling), J = 1.6 Hz (m-coupling), 7.28 (dd, 1H, J = 4.0 Hz (o-coupling), 7.38 (dt, 1H, J = 9.2 Hz (coupling-o), 5.2 Hz), 7.83 (dd, 1H, J = 3.6 Hz (coupling-o), 7.91 (width s, 1H), 7.92 (width s, 1H ), 8.18 (width s, 1H)

δ 5.10 (s, 2H), 5.15 (s, 2H), 6.98-7.09 (m, 4h), 7,227.28 (m, 3h), 7.39 (t, 2H, J = 7.2 Hz (coupling-o), 7.37 (d, 2H, J = 7.2 Hz (coupling-o), 7.85 (width s, 1H), 8.13 (width s, 1H)

156

157

3- (6-Chloro-thiazolo [5,4-c] pyridin-2-ylmethoxy) -2,6Difluor-benzamide

2,6-Difluor-3- [5- (2-hydroxy-phenyl) -benzothiazol-2-ylmethoxy) benzamide

2-bromomethyl-6-chloro-thiazolo [5,4-c] pyridine

2- (2-Bromomethyl-benzothiazol-5-yl) -phenol

25º C, all night

25º C, all night

0.012 g, 18% yellow solid

0.005 g, 10.0% yellow solid

δ 5.78 (s, 2H), 7.12 (dt, 1H, J = 8.8 Hz (coupling-o), 7.38-7.44 (m, 1h), 7.91 (width s, 1H), 8.20 (width s, 2H), 9.25 (s, 1H)

δ 5.71 (s, 2H), 6.91 (t, 2H, J = 5.6 Hz), 6.97 (d, 1H, J = 8.4 Hz (o-coupling), 7.11 (dt, 1H, J = 9.2 Hz (o-coupling ), 7.20 (t, 1H, J = 7.6 Hz), 7.35 (d, 1H, J = 8.8 Hz (coupling-o), 7.39-7.43 (m, 1h), 7.64 (d, 1H, J = 8.8 Hz ( o-coupling), 7.89 (width s, 1H), 8.13 (d, 2H, J = 8.4 Hz), 8.18 (width s, 1H)

158

159

3- [5-Bromo-4- (4-methoxy-phenyl) -thiazol-2-ylmethoxy] -2,6-Difluorobenzamide

3- [5-Bromo-4- (4-chloro-phenyl) -thiazol-2-ylmethoxy] -2,6Difluor-benzamide

5-Bromo-2-bromomethyl-4- (4-methoxy-phenyl) -thiazole

5-Bromo-2-bromomethyl-4- (4-chloro-phenyl) -thiazole

25º C, all night

25º C, all night

0.140 g, 10% off-white solid

0.280 g, 60% yellow solid

δ 3.81 (s, 3H), 5.54 (s, 2H), 7.06 (d, 2H, J = 8.4 Hz (o-coupling), 7.12 (dt, 1H, J = 9.2 Hz (o-coupling),

δ 5.55 (s, 2H), 7.13 (dt, 1H, J = 8.8 Hz (coupling-o), 7.40 (dt, 1H, J = 9.2 Hz

7.40 (dt, 1H, J = 9.2 Hz (coupling-o), 7.84 (dt, 1H, J = 8.8 Hz (coupling-o), 7.89 (width s, 1H), 8.16 (width s, 2H)

(coupling-o), 7.59 (d, 2H, J = 8.4 Hz (coupling-o), 7.91 (d, 1H, J = 8.4 Hz (coupling-o), 7.89 (s, 1H), 8.16 (width s, 1 HOUR)

161

162

2,6-Difluor-3- (3-pyrrol-1-yl-benzyloxy) -benzamide

2,6-Difluor-3- (3-phenoxy-benzyloxy) -benzamide

-1- (3-bromomethyl-phenyl) -1H-pyrrola

3-phenoxy benzyl bromide

25º C, all night

25º C, all night

0.140 g, 10% white solid

0.105 g, 31% white solid

δ 5.23 (s, 2H), 6.28 (t, 2H, J = 2.0 Hz (m-coupling), 7.07 (dt, 1H), 7.30 (d, 2H, J = 8.0 Hz (o-coupling), 7.37 (t , 2H, J = 2.0 Hz (m-coupling), 7.48 (t, 1H, J = 8.0 Hz (o-coupling), 7.56 (d, 1H, J = 9.2 Hz (o-coupling), 7.66 (s, 1H ), 7.85 (width s, 1H), 8.13 (width s, 2H)

δ 5.17 (s, 2H), 6.96-7.05 (m, 3H), 7.07 (d, 2H, J = 8.0 Hz), 7.16 (t, 1H, J = 7.6 Hz (o-coupling), 7.20 (d, 1H , J = 7.6 Hz (coupling-o), 7.25 (dt, 1H, J = 9.2 Hz (coupling-o), 7.38-7.43 (m, 3H), 7.85 (width s, 1H), 8.13 (width s, 1H )

163

2,6-Difluor-3- (5-phenyl-isoxazol-3-ylmethoxy) -benzamide

4-bromomethyl-2-thiophene-2-yl-thiazole

25º C, all night

0.105 g, 30% white solid

δ 5.25 (s, 3H), 7.09 (t, 2H, J = 8.4 Hz (o-coupling), 7.16-7.18 (m, 1H), 7.38 (m, 1H), 7.68 (d, 1H, J = 3.6 Hz (coupling-o), 7.74 (d, 1H, J = 4.8 Hz (coupling-o), 7.85 (width s, 1H), 8.13 (width s, 1H)

Example 100: 3- [4- (2-Bromo-5-methoxy-phenyl) -thiazol-2-ylmethoxy] -2,6-difluoro-benzamide

Zinc (0.06 g, .0001 mol) was added to a solution of 3- [5-Bromo-4- (2-bromo-5-methoxy-phenyl) -thiazol-2-ylmethoxy] -2,6-difluor-benzamide (0.06 g, .0001 mol) in 6 ml of acetic acid. The reaction mixture was refluxed for 30 min. The reaction mixture was allowed to reach 25 ° C. The reaction mixture was filtered on celite bed; The product was precipitated by the addition of water to the filtrate. The white solid was filtered and dried (0.006 g, 12%). 1 HOUR

10 NMR (DMSO, 400 MHz), 3.79 (s, 3H), 5.59 (s, 2H), 6.94 (dd, 1H, J = 8.8 Hz (coupling-o), J = 4.0 Hz), 7.09-7.15 (m , 1H), 7.27 (d, 1H, J-4.0 Hz), 7.40-7.43 (m, 1H), 7.63 (d, 1H, J = 8.8 Hz (coupling-o), 7.89 (broad s, 1H), 8.11 (s, 1H), 8.18 (s, 1H); MS ES + (455.08 & 457.08) HPLC (procedure 5) reaction time = 10.21 min.

Example 118: 2,6-Difluor-3- [4- (4-methoxy-phenyl) -5-propyl-thiazol-2-ylmethoxy] -benzamide

15 Stage-1

50 mg of dry Pd-C was added to a solution of 3- [5-allyl-4- (4-methoxy-phenyl) -thiazol-2-ylmethoxy] -2,6-difluorobenzamide (0.1 g, 0.02 mmol) in 5 ml of anhydrous methanol. The reaction mixture was stirred at 25 ° C for 12 h under hydrogen atmosphere. The reaction mixture was filtered on the celite bed. The filtrate was evaporated to dryness under reduced pressure and the residue was purified column chromatography on silica (230

400Q) using ethyl acetate / hexane (50:50) as the eluent to provide the title compound as a white solid (0.02 g, 2%). 1H NMR (DMSOd6, 400 MHz); δ 0.92 (t, 3H, J = 7.2 Hz), 1.63-1.65 (m, 2H), 2.8 (t, 2H, J = 7.6 Hz (o-coupling), 3.79 (s, 3H), 5.47 (s, 2H 7.02 (d, 2H, J = 8.8 Hz (o-coupling), 7.11 (m, 1H), 7.42 (m, 1H), 7.53 (d, 2H, J = 8.8 Hz (o-coupling), 7.88 ( s, 1H), 8.16 (s, 1H), 8.38 (d, 1H, J = 8.4 Hz (coupling-o) MS ES + (419.14), HPLC (procedure 5) reaction time = 16.58 min.

Example 120: 3- [5-Allyl-4- (4-methoxy-phenyl) -thiazol-2-ylmethoxy] -2,6-difluoro-benzamide

 Stage 1

Alil tributiltin (0.072 g, 0.0002 mol) was added to a solution of 3- [5-bromo-4- (4-methoxy-phenyl) -thiazol-2-ylmethoxy] 2,6-difluoro-benzamide (0.1 g 0.0002 mol) in 5 ml of anhydrous DMF and the reaction mixture was degassed for 10 minutes. Then Palladium tetraphenylphosphine (0) (0.025 g, 0.00002 mol) was added. The reaction mixture was heated at 120 [deg.] C. for 12 h under the nitrogen atmosphere. Then the reaction mixture was cooled to room temperature, 100 ml of water was added and the compound was extracted with ethyl acetate, the combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. . The compound was purified by column chromatography on silica (230-400P) using methanol / DCM

(2:98) as the eluent to obtain the title compound as a brown solid (0.120 g, 60%). 1H NMR (DMSO-d6, 400 MHz): δ 3.79 (s, 3H), 5.11-5.14 (m, 1H), 5.16 (s, 1H), 5.48 (s, 2H), 5.57 (s, 1H), 5.99 -6.06 (m, 1H),

15 7.03 (d, 2H, J = 8.4 Hz (o-coupling), 7.11 (dt, 1H, J = 9.2 Hz (o-coupling), 7.36-7.42 (m, 1H), 7.56 (d, 2H, J = 8.8 Hz (coupling-o), 7.88 (width s, 1H), 8.16 (width s, 1H) MS ES + (417.06), HPLC (procedure 5) ambient temperature = 16.96 min.

Example 121: 2,6-Difluor-3- [4- (4-methoxy-phenyl) -5-pyridin-3-ii-thiazol-2-ylmethoxy] -benzamide

20 Stage-1

Potassium phosphate (0.056 g 0.025 mmol) was added to a solution of 3- [5-bromo-4- (4-methoxy-phenyl) -thiazol-2-methoxy] -2,6-difluoro-benzamide (0.1 g, 0.02 mmol) in DMF: H2O (2: 1), 3-pyridine boronic acid (0.054 g, 0.04 mmo)). The reaction mixture was degassed for 10 min and then dichlorobis [(triphenylphosphine) -Palladium (II) (0.023g, 0.003 mmol) was added and degassed again for 10 min. The reaction mixture was heated at 25-120 ° C for 12 h under nitrogen atmosphere. DMF was distilled off after cooling to room temperature, water was added in the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by chromatography on silica (230-400P) using ethyl acetate / hexane (50:50) as the eluent to obtain the title compound as a yellow solid (0.050 g, 50%). 1H NMR (DMSO-d6, 400 MHz): δ 3.75 (s, 3H), 5.59 (s, 2H), 6.92 (d, 30 2H, J = 8.8 Hz (coupling-o), 7.14 (dt, 1H, J = 9.2 Hz (o-coupling), 7.36 (d, 2H, J = 8.4 Hz (o-coupling), 7.45 (dt, 2H, J = 9.2 Hz (o-coupling) J = 5.2 Hz (o-coupling), 7.79 (m, 1H), 7.88 (width s, 1H), 8.16 (width s, 1H),

8.53 (d, 1H, J = 2.0 Hz (m-coupling), 8.57 (d, 1H, J = 4.8 Hz) MS ES + (454.10), HPLC (procedure 5) Reaction time = 15.26 min.

Example 123: 3- (5-Bromo-benzothiazol-2-ylmethoxy) -2,6-difluoro-benzamide

 Stage 1

2,6-Difluoro-3-hydroxybenzamide (0.620 g, 0.22 mol) and potassium carbonate (1.73 g, 1.25 mmol) were added to a solution of 5-bromo-2-bromomethyl-benzothiazole (1.1 g, 0.358 mmol ) in 5 ml of anhydrous DMF. The reaction mixture was stirred at 25 ° C for 24 hours under a nitrogen atmosphere. Water was added to the reaction mixture, the compound was precipitated, filtered and washed with diethyl ether to obtain the title compound as a yellow solid (1.1 g, 76%). 1H NMR (DMSO-d6, 400 MHz): δ 5.71 (s, 2H), 7.11 (dt, 1H J = 8.8 Hz (o-coupling), 7.38

7.39

(m, 1H), 7.65 (d, 1H, J = 8.8 Hz (coupling-o), 7.90 (width s, 1H), 8.13 (d, 1H, J = 8.8 Hz (coupling-o),

8.18

 (s, 1H), 8.26 (width s, 1H). MS ES + (400.9), HPLC (procedure 5) reaction time = 16.57 min.

Example 125: 2,6-Difluoro-3- [4- (4-methoxy-phenyl) -5-pyridin-2-yl-thiazol-2-ylmethoxy] -benzamide

  Stage 1

2-Tributylstanyl pyridine (0.081 g, 0.02 mmol) was added to a solution of 3- [5-bromo-4- (4-methoxy-phenyl) -thiazol2-ylmethoxy] -2,6-difluoro-benzamide ( 0.1 g, 0.02 mmol) in 5 ml of anhydrous DMF and was degassed for 10 min. Palladium Tetrakis (triphenylphosphine) (0) (0.026 g, 0.002 mmol) was added to the reaction mixture and degassed again 10 times for 10 min. and then heated at 120 [deg.] C. for 12 h under nitrogen atmosphere. Then the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400Q) using ethyl acetate

(40:60) as eluent to obtain the title compound as a white solid (0.120 g, 60%). 1H NMR (DMSO

15 d6, 400 MHz): δ 3.80 (s, 3H), 5.55 (s, 2H), 6.99 (d, 2H, J = 8.8 Hz (coupling-o), 7.12 (dt, 1H, J = 8.8 Hz (coupling -o), 7.23 (d, 1H, J = 8.0 Hz (o-coupling), 7.29-7.32 (m, 1H), 7.44 (d, 2H, J = 8.8 Hz (o-coupling), 7.62 (m, 1H ), 7.69 (dt, 1H, J = 8.0 Hz (o-coupling), 7.88 (width s, 1H), 8.17 (width s, 1H),

8.60 (d, 1H, J = 4.0 Hz), MS ES + (454.18), HPLC (procedure 5) Reaction time = 15.6 min.

Example 126: 3- (5-Allyl-benzothiazol-2-ylmethoxy) -2,6-difluoro-benzamide

 Stage 1

Allyl tributylethane (0.083 g, 0.025 mol) was added to a solution of 3- (5-bromo-benzothiazol-2-ylmethoxy) -2,6-difluorobenzamide (0.1 g, 0.025 mol) in 5 ml of anhydrous DMF and The reaction mixture was degassed for 10 minutes. Tetrakis palladium (triphenylphosphine) (0) (0.029 g, 0.0025 mol) was added and degassed again for 10 min. The reaction mixture was heated at 120 ° C for 1 h under a nitrogen atmosphere and then cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was crystallized with ethyl acetate / hexane to obtain the title compound as a brown solid.

(0.050 g, 55%). 1H NMR (DMSO-d6, 400 MHz): δ 3.52 (d, 2H, J = 6.4 Hz), 507-5.13 (m, 1H) 5.68 (s, 2H) 5.98-6.05 (m,

30 1H), 7.10 (dt, 1H, J = 8.4 Hz (o-coupling), 7.31 (d, 1H, J = 8.4 Hz (o-coupling), 7.38 (dt, 1H, J = 9.2 Hz (o-coupling) ), J = 5.2 Hz), 7.83 (s, 1H), 7.89 (width s, 1H), 8.05 (d, 1H, J = 8.4 Hz (coupling-o), 8.17 (width s, 1H) MS ES + (361.05 ), HPLC (procedure 5) Reaction time = 16.74 min.

Example 127: 2,6-Difluor-3- [4- (4-methoxy-phenyl) -5-pyridin-4-yl-thiazol-2-ylmethoxy] -benzamide

35 Stage-1

Boronic acid 4-pyridine acid (0.108 g, 0.87 mmol), and potassium phosphate (0.112 g, 0.51 mmol) was added to a solution of 3- [5-bromo-4- (4-methoxy-phenyl) ) -thiazol-2-ylmethoxy] -2,6-difluoro-benzamide (0.2 g, 0.43 mmol) in 5 ml of DMF: H2O (2: 1) anhydrous. After degassing the reaction mixture for 10 minutes, and palladium dichlorobis [(triphenylphosphine) (II) (0.046 g, 0.06 mmol) was added and degassed again for 10 min. The reaction mixture was heated at 120 ° C for 12 h under a nitrogen atmosphere. DMF was distilled after cooling to

room temperature, water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by chromatography on silica (230-400Q) using ethyl acetate / hexane (50:50) as eluent to obtain the title compound as a white solid (0.045g, 49%). 1H NMR (DMSO-d6, 400 MHz): δ

3.80 (s, 3H), 5.59 (s, 2H), 6.94 (d, 2H, J = 8.8 Hz (coupling-o), 7.14 (dt, 1H), 7.34 (d, 1H, J = 6.0 Hz (coupling) , 7.38 (d, 2H, J = 8.8 Hz (coupling-o), 7.41-7.45 (m, 1H), 7.89 (width s, 1H), 8.17 (s, 1H), 8.60 (dd, 1H) MS ES + ( 454.12), HPLC (procedure 5) Reaction time = 13.55 min.

Example 135: 2,6-Difluor-3- (5-propyl-benzothiazol-2-ylmethoxy) -benzamide

10 Stage-1

20 mg of dry Pd-C was added to a solution of 3- (5-allyl-benzothiazol-2-ylmethoxy) -2,6-difluoro-benzamide (0.1 g, 0.27 mmol) in 5 ml of anhydrous methanol. The reaction mixture was stirred at 25 ° C for 12 h under hydrogen atmosphere. The reaction mixture was filtered on the celite bed. The filtrate was evaporated to dryness under reduced pressure and the compound was crystallized with ethyl acetate / hexane to obtain the title compound.

15 as a light yellow solid (0.014g, 14%). 1H NMR (DMSO-d6, 400 MHz): δ 0.92 (t, 3H, J = 7.2 Hz), 1.62-1.68 (m, 2H), 2.71, 2H, J = 7.2 Hz), 5.67 (s, 2H), 7.12 (dt, 1H, J = 8.8 Hz (coupling-o) J = 1.6 Hz), 7.32 (d, 1H, J = 8.4 (coupling-o), 7.38 (dt, 1H, J = 9.2 Hz (coupling-o ), J = 5.2 Hz), 7.83 (s, 1H), 7.89 (width s, 1H), 8.01 (d, 1H, J = 8.4 Hz (coupling-o). 8.17 (width s, 1H). MS ES + ( 363.08), HPLC (procedure 5) Reaction time = 17.64 min.

Example 136: 2,6-Difluor-3- [5- (3-hydroxy-phenyl) -benzothiazol-2-ylmethoxy] -benzamide

Stage 1

Boron tribromide (0.493 g, 1.9 mmol) was added dropwise at -78 [deg.] C. to a suspension of 2,6-difluoro-3- [5- (3-methoxy-phenyl) -benzothiazol-2-ylmethoxy ] -benzamide (0.14 g, 0.3 mmol) in 15 ml of anhydrous DCM. The reaction mixture was stirred at -78 ° C for 3 h under a nitrogen atmosphere. 5 ml of water at 0 ° C was added to the reaction mixture. The compound was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400Q) using ethyl acetate (40:60) as the eluent to obtain the title compound as a yellow solid (0.020 g, 14%). 1H NMR (DMSO-d6, 400 MHz): δ 5.71 (s, 2H), 6.80 (dd, 30 1H, J = 9.6 Hz (coupling-o), 7.11 (dt, 1H, J = 8.0 Hz (coupling-o ), 7.17 (dt, 1H, J = 8.0 Hz (o-coupling),

7.29 (t, 1H, J = 8.0 Hz (coupling-o), 7.39-7.43 (m, 1H), 7.71 (dd, 1H, J = 9.6 Hz) 7.89 (width s, 1H), 8.18-8.22 (m, 2H) MS ES + (413.01), HPLC (procedure 5) Reaction time = 14.95 min

Example 140: 2,6-Difluor-3- [5- (4-hydroxy-phenyl) -benzothiazol-2-ylmethoxy] -benzamide

The compound 2,6-Difluor-3- [5- (4-methoxy-phenyl) -benzothiazol-2-ylmethoxy] -benzamide (0.095g, 0.223 mmol) was dissolved in 5 ml of DCM and cooled to -70 ° C. To this, BBr3 (0.1 ml 0.156 mmol) was added dropwise. After its complete addition, the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was softened with MeOH. The reaction mixture was concentrated and purified by column chromatography to obtain 0.0025g, 3% of compound as a white solid. 1H NMR (DMSO-d6, 400 MHz); δ 5.70 (s,

2H), 6.88 (d, 1H, J = 8.4 Hz (o-coupling), 7.10 (m, 1H), 7.41 (m, 2H), 7.60 (d, 2H, J = 8.8 Hz, (o-coupling),

7.71 (d, 2H), 7.89 (width s, 1H), 8.13-8.17 (m, 2H), 9.62 (width s, 1H); MS ES + (413.0).

Example 141: 3- [5- (2-Amino-phenyl) -benzothiazol-2-ylmethoxy] -2,6-difluoro-benzamide

5 To the solution of compound 3- (5-bromo-benzothiazol-2-ylmethoxy) -2,6-difluoro-benzamide (0.3g 0.755 mmol) in

DMF: dry H2O (5 mL: 2.5 mL), phenylamine-2 boronic acid (0.260g, 1.5mmol) and K2CO3 (0.125g, 0.9 mmol) were added under a nitrogen atmosphere at room temperature. After that, said reaction mixture was degassed for half an hour. Palladium Dichlorobis [(triphenylphosphine) (II) was added to the reaction mixture (0.080g,

0.113 mmol) and was again degassed for half an hour and the reaction mixture was heated to 120 ° C

10 for 2 hrs under nitrogen atmosphere. DMF was distilled off after cooling to room temperature, water was added in the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by chromatography on silica (230-400Q) using ethyl acetate / hexane (50:50) as the eluent to obtain the title compound as a yellow solid (0.025g, 8%). 1H NMR (DMSO-d6, 400 MHz); δ 4.86 (width s, 2H), 5.71

15 (s, 2H), 6.66 (dt, 1H, J = 8.4 Hz (o-coupling), 6.78 (d, 1H, J = 7.2 Hz (o-coupling), 7.04-7.13 (m, 3H), 7.37

7.44 (m, 1H), 7.51 (dd, 1H, J = 8.4 Hz (coupling-o), J = 1.6 Hz (coupling-m), 7.89 (width s, 1H), 8.00 (width s, 1H), 8.18 (d, 2H, J = 4.0 Hz); MS ES + (412.16), HPLC (procedure 5) Ambient temperature = 15.33 min.

Example 143: 2,6-Difluor-3- [5- (3-methoxy-phenyl) -benzothiazol-2-ylmethoxy] -benzamide

3-Methoxyphenyl boronic acid (0.228g, 1.5 mmol) and K3PO4 (0.190g, 0.9 mmol) were added to the solution of compound 3- (5-bromo-benzothiazol-2-ylmethoxy) -2,6- difluor-benzamide (0.300g, 0.755mmol) in DMF: dry H2O (5mL: 2.5 mL) under inert condition at room temperature and was degassed for half an hour. Then palladium dichlorobis [(triphenylphosphine) (II) (0.078g, 0.075mmol) was added to the reaction mixture and was degassed again for 25 half an hour. The reaction mixture was heated at 120 ° C for 2 hrs under a nitrogen atmosphere. DMF was distilled off after cooling to room temperature, water was added to the reaction mixture and it was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by chromatography on silica (230-400Q) using ethyl acetate / hexane (50:50) as the eluent to obtain the title compound as a white solid (0.140 g, 43%).

1 H NMR (DMSO-d6, 400 MHz); δ 3.85 (s, 3H), 5.72 (s, 2H), 6.97 (t, 1H, J = 6.8 Hz (coupling-o), 7.11 (t, 1H, J = 8.8 Hz (coupling-o), 7.30 (width s, 1H), 7.34 (d, 1H, J = 8.8 Hz (o-coupling), 7.40 (dd, 2H, J = 8.0 Hz (o-coupling), 7.79 (d, 1H, J = 8.0 Hz (coupling- o), 7.90 (width s, 1H), 8.18 (width s, 1H), 8.21 (d, 1H, J = 8.0 Hz); MS ES + (427.14), HPLC (procedure 5) Ambient temperature = 16.48 min.

Example 155: 2,6-Difluor-3- [4â € ™ - (4-methoxy-phenyl) - [2,5â € ™] bitiazolyl-2â € -ylmethoxy] -benzamide

 Stage 1

2-tributylstanyl thiazole (0.071 g, 0.2 mmol) was added to a solution of 3- [5-bromo-4- (4-methoxy-phenyl) -thiazol-2-methylmethoxy] -2,6-difluoro-benzamide (0.1 g, 0.2 mmol) in 5 ml of anhydrous DMF and the reaction mixture was degassed for 10 minutes. Then palladium tetraphenylphosphine (0) (0.026 g, 0.2 mmol) was added. The reaction mixture was heated at 120 [deg.] C. for 12 h under the nitrogen atmosphere. Then the reaction mixture was cooled to room temperature, 100 ml of water was added and the compound was extracted with ethyl acetate, the combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under pressure. reduced The compound was purified by column chromatography on silica (230-400Q) using ethyl acetate (40:60) as the eluent to obtain the title compound as a yellow solid (0.003 g, 3%). 1H NMR (DMSO-d6, 400 MHz): δ 3.82 (s, 3H), 5.57 (s, 2H), 7.06 (d, 1H, J = 8.4 Hz (coupling-o), 7.13 (dt, 1H), 7.3910 7.47 (m, 1H), 7.51 (d, 2H, J = 8.4 Hz (o-coupling), 7.52-7.58 (m, 1H), 7.59-7.86 (m, 2H), 7.68 (d, 1H, J = 3.2 Hz),

7.84 (d, 1H, J = 3.2 Hz), 7.89 (width s, 1H), 8.18 (width s, 1H), 9.12 (s, 1H); MS ES + (460.01), HPLC (procedure 5) Ambient temperature = 15.64 min.

Example 160: 2,6-Difluor-3- [3- (6-methyl-2-phenyl-thiazol-4-yl) -propoxy] -benzamide

15 3- (5-Methyl-2-phenyl-thiazol-4-yl) -propan-1-ol. 2,6-Difluoro-3-hydroxybenzamide (0.173g, 1.0 mmol), PPh3 (0.262g, 1.0 mmol) and diisopropyl azodicarboxylate (0.202g, 1.0 mmol) were added to a solution of 3- (5-methyl- 2-phenyl-thiazol-4il) -propan-l-ol (0.219g, 1.0 mmol) in 5 ml of anhydrous DMF. The reaction mixture was stirred at 80 ° C overnight under a nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400Q) using ethyl

20 acetate / hexane (35:65) as the eluent to obtain the title compound as a white solid (0.050g, 13%). 1H NMR (DMSO-d6, 400 MHz): δ 2.44 (width s, 3H), 3.14 (t, 2H, J = 6.4 Hz), 4.35 (t, 2H, J = 6.4 Hz), 7.04 (dt, 1H, J = 9.2 Hz (o-coupling), 7.22-7.28 (m, 1H), 7.43-7.49 (m, 3H); 7.83-7.86 (m, 3H), 8.10 (s, 1H); MS ES + (375.15), HPLC (procedure 5) Ambient temperature = 10.67 min.

Example 164: 2,6-Difluor-3- [4- (4-methoxy-phenyl) - [5,5â € ™] bitiazolyl-2-ylmethoxy] -benzamide

[5,5â € ™] bitiazolyl-2-ylmethoxy] -benzamide (0.100g, 0.2 mmol) in 5 ml of anhydrous DMF. The reaction mixture was stirred at 80 ° C overnight under a nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400Q) 30 using ethyl acetate / hexane (35:65) as the eluent to obtain the title compound as a white solid (0.025g, 25%). 1H NMR (DMSO-d6, 400 MHz): δ 3.78 (s, 3H), 5.57 (s, 2H), 6.97 (d, 2H, J = 8.8 Hz (o-coupling),

7.13 (t, 1H), 7.44 (d, J = 8.8, (coupling-o, 3H), 7.89 (width s, 1H), 8.05 (s, 1H), 8.17 (width s, 1H), 9.12 (s, 1H); MS ES + (459.94), HPLC (procedure 5) Ambient temperature = 15.21 min.

Example 165: 2-Fluoro-3-Hexoxy-benzamide

Potassium carbonate (0.213, 1.4 mmol) was added to the solution of 2-fluorine-3-Hydroxy-benzamide (0.12 g, 0.774 mmol) in 20 mL DMF 1-bromohexane (0.13 mL, 1.0 mmol). The reaction mixture was stirred at 90 ° C for 4 h. The DMF was distilled off and the reaction mixture was extracted with EtOAc. The crude compound obtained was purified by column chromatography on silica (230-400Q) using ethyl acetate / hexane (50:50) as the eluent to obtain the title compound (0.05g, 28%). 1H NMR (DMSO-d6, 400 MHz with D2O): δ 0.82-0.99 (m, 3H), 1.10-1.33 (m, 6H), 1.67-1.71 (m, 2H), 3.99-4.15 (t, 2H, J = 8.0 Hz), 7.08-7.24 (m, 2H). MS ES + (214.33), HPLC (procedure 6) Reaction time = 11.15 min.

Example 166: 2-Hydroxy-3-Hexoxy-benzamide

10 A mixture of 2-fluor-3-Hexoxy-benzamide (0.30 g, 1.2 mmol), copper sulfate (0.10 g, 0.4 mol), copper (0.015g,

0.2 mmol) and NaOH (2.5 ml) was stirred at 100 ° C for 14 hrs. After completion of the reaction, the reaction mixture was acidified and extracted with EtOAc. The crude compound obtained was purified by column chromatography on silica (230-400Q) us column using ethyl acetate / hexane (50:50) as eluent to obtain the title compound as yellow (0.15g, 50%). 1H NMR (DMSOd6, 400 MHz with D2O): δ 3.9 (s, 3H), 7.11-7.18

15 (m, 2H), 7.53-7.58 (m, 1H). MS ES + (229.0 M + 2H adduct). HPLC (Procedure 7) Reaction time = 11.16 min.

Example 167: Synthesis of 3-Fluoro-5-hexyloxy benzamide

A solution of sodium nitrite (0.315 mg, 4.6 mmol) in water (5 ml) at 0 ° C was added to a solution of 3-amino-5

hexyloxy benzamide (0.9 g, 3.8 mmol) in tetrafluoroboric acid (20 ml), and was stirred for 1 hr. Subsequently, 20 was allowed to reach room temperature and was stirred for 1 hr followed by heating at 60 ° C for

2hrs It was then basified to pH = 14 using a saturated NaOH solution and extracted with dichloromethane.

(3x30ml). The solvent was evaporated to produce a crude product, which was purified by chromatography of

column using silica gel (230-400 mesh) and dichloromethane as eluent (100 mg, 11%). 1H NMR (DMSO-d6,

400 MHz with D2O): δ 0.88 (t, J = 7.2Hz, 3H), 1.32 (m, 2H), 1.41 (m, 4H), 1.72 (m, 2H), 4.0 (t, J = 7.2Hz, 2H ), 6.97 (m, 25 1H), 7.22 (m, 1H), 7.28 (m, 1H), 7.52 (width s, 1H), 8.03 (width s, 1H). MS ES + (238.0, 239.0), HPLC

(procedure 7) Reaction time = 11.34 min.

Example 168: Synthesis of 3- (Pirazol-1-ylmethoxy) -benzamide

Methyl esters of 3- (Pirazol-1-ylmethoxy) -benzoic acid (250 mg, 1.1 eq.) Were carried in a pressure vessel with 5

30 ml of aqueous ammonia, heated at 110 ° C for 12 hr. The reaction mixture was then poured into water (25 ml), and extracted with dichloromethane (25 ml x 4). The organic layer was dried over sodium sulfate and concentrated to obtain crude solid. The product was purified by column chromatography using 80% EtOAc-DCM as an eluent on 230-400 silica gel mesh. Crude product was obtained as a solid powder (50 mg, 19%). 1H NMR (DMSO-d6, 400 MHz with D2O): δ 6.12 (s, 2H), 6.33 (m, 1H), 7.25 (m, 1H), 7.37 (m, 1H), 7.41 (m, 1H),

35 7.51 (m, 1H), 7.56 (m, 2H), 7.95 (width s, 1H), 7.99 (m, 1H). MS ES + (218.0, 235.0-ammonium adduct), HPLC (procedure 7) Reaction time = 9.08 min.

Example 169: 3 - [(2-Methylcyclopropyl) methoxy] benzenecarboxamide.

Synthesized according to procedure C, scheme 3. Production 27%, mp 119-121 ° C, HPLC-MS (procedure 1): m / z 206 [M + H] +, Reaction time = 3.47 min.

Example 170: 3 - [(5-Methyl-3-pyridinyl) methoxy] benzenecarboxamide.

N-Bromosuccinimide (2.13 g, 12 mmol) and the subsequent α, α-azoisobutyronitrile (16 mg, 0.1 mmol) were added to a solution of 3,5-lutidine (1.14 ml, 10 mmol) in CCl4 ( 40 ml) The reaction mixture was stirred at reflux for 10 2 hrs. After cooling, the succinimide was removed by filtration and the filtrate was evaporated to a smaller volume (10 ml). A mixture of 3-hydroxybenzenecarboxamide (550 mg, 4 mmol) and K2CO3 (830 mg, 6 mmol) in DMF (5 ml) was added to this filtrate, and the new reaction mixture was stirred at 60 ° C for 24 h. After diluting with CH2Cl2 (100 ml), the solution was washed with Na2CO3 solution (40 ml) and water (40 ml), dried (Na2SO4) and evaporated to dryness, under reduced pressure. The brown oil residue was extracted by crushing with

Et2O (2x10 ml), and from the Et2O extracts, the solid precipitant was filtered and washed with pentane, to obtain 70 mg (7.2% production) of the desired product. Mp 152-154 ° C, HPLC-MS: m / z 243 [M + H] +, Reaction time = 2.28 min.

Example 171: 3 - [(3-Bromobenzyl) oxy] benzenocarboxamide.

20 Synthesized according to procedure B, scheme 2. Production 54%, mp 129-131 ° C, HPLC-MS (procedure 1): m / z 347 [M + H + CH3CN] +, Reaction time = 3.99 min .

3-3 (Hydroxymethyl) phenyl acetate.

Ice (4g) was added, followed by acetic anhydride (0.95 ml, 10 mmol, 1.25 equiv.) To a stirred solution of 3-hydroxybenzyl alcohol (1.0 g, 8 mmol, 1 equiv.) In 6.4N KOH solution ( 1.86 ml, 12 mmol, 1.5 equiv.) At room temperature. The reaction mixture was stirred at room temperature for 3h. Water (50 ml) was added and the mixture was stirred for 30 min, before being extracted with CH2Cl2 (2x50 ml). The combined organic extracts were washed with brine (50 ml), dried (Na2SO4) and evaporated to dryness, under reduced pressure. The oleaginous residue, transparent, was purified by column chromatography on silica, eluted with EtOAc / hexane (1: 2), to give the desired product as a clear oil (714 mg, 54% yield). HPLC-MS (method 1): m / z 165 [M-H] -. Rt = 2.52 min.

Example 172: Acetate 3- [3- (Aminocarbonyl) phenoxy] methylphenyl.

Synthesized according to Method Method C, scheme 3. Production 32%, HPLC-MS (procedure 1): m / z 286 [M + H] +. Reaction time = 3.44 min.

Example 173: 3 - [(3-Hydroxybenzyl) oxy] benzenocarboxamide.

A solution of K2CO3 (500 mg, 3.62 mmol, 5.75 equiv.) In water (5 ml) was added to a solution of 3- [3 (aminocarbonyl) phenoxy] methylphenyl acetate (180 mg, 0.63 mmol, 1 equiv .) and the mixture was stirred at room temperature, under N2, for 3 h; The mixture was acidified with 10% HCl solution to pH 1, and extracted with EtOAc (2x30 ml). The combined organic extracts were washed with water (30 ml), dried (Na2SO4) and evaporated to dryness under reduced pressure, to obtain a clear oil residue which, after its

After trituration with Et2O, it solidified to form a white solid (70 mg, 46% production). Mp 122-123Â ° C, HPLCMS (procedure 1): m / z 244 [M + H] +. Reaction time = 2.92 min.

3-Chloro-2- (hexyloxy) isonicotinic acid.

A solution of sodium hydride (60% in mineral oil, 600 mg, 15.0 mmol, 3 equiv.) In hexanol (10 ml) was stirred at room temperature for 2 h. 2,3-Dichloro-isonicotinic acid (960 mg, 5.0 mmol, 1 equiv.) Was added and the reaction mixture was stirred at 100 ° C for 16 h. The mixture was diluted with water (100 ml) and pentane (300 30 ml), and the two phases were separated. The aqueous phase was neutralized with 1 N HCl solution to pH 6.0 and extracted with EtOAc (3x80 ml). The combined EtOAc extracts were dried (MgSO4) and evaporated under reduced pressure to dryness. The residue was triturated with pentane, cooled to 0 ° C and the precipitating solid was filtered, to obtain 410 mg of a white compound (32% yield). By 1HNMR analysis, it consisted of about 80% of the desired product, which was used until the next phase without further purification. HPLC-MS: m / z 256 [M-H] -,

35 Reaction time = 2.94 min.

Example 174: 3-Chloro-2- (hexyloxy) isonicotinamide.

Synthesized from 3-chloro-2- (hexyloxy) isonicotinic acid according to Procedure A. Production 85% (crude); subsequently purified by preparative TLC, mp 75-77 ° C, HPLC-MS: m / z 298 [M + H + CH3CN] +, Rt = 4.16 5 min.

2-fluorine-3-hydroxybenzenecarboxamide.

Synthesized from commercially available 2-fluorine-3-methoxybenzenecarboxamide according to Procedure H. Production 82%, mp 196-197 ° C, HPLC-MS (procedure 1): m / z 154 [MH] -, Reaction time 10 = 1.24 min.

Example

175 176

Structure

Performance (%)

62 70

Mp (ºC)

76-77 91-92

HPLC-MS: procedure no., M / z, ion

Reaction time (min)

4.78 3.52

Table of product compound names; Examples 175-178:

Example

Compound Name

175

2-Fluoro-3- (nonyloxy) benzenocarboxamide

176

2- [3- (aminocarbonyl) -2-fluorophenoxy] Butyl acetate

177

2-Fluoro-3- (10-undecinyloxy) benzenocarboxamide

178

2,6-Difluor-3- (4-hydroxybutyloxy) benzenecarboxamide

Scheme 22: (a) Methyl 4-bromochronate, K2CO3, DMF, room temperature; (b) NaOH, IPA / H2O, reflux; (c) n-BuBr, K2CO3, DMF, 50 [deg.] C .; (d) H2, 5% Rh / C, BuOH, room temperature

Example 179: Methyl 4- [3- (aminocarbonyl) -2,4-difluorophenoxy] -2-butenoate.

Synthesized from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Procedure B, scheme 2. 10 Production 41%, mp 122-123 ° C, HPLC-MS (method 1): m / z 272 [M + H] +, Reaction time = 2.80 min.

4- [3- (aminocarbonyl) -2,4-difluorophenoxy] -2-butenoic acid. A solution of Methyl 4- [3- (aminocarbonyl) -2,4-difluorophenoxy] -2-butenoate (1.25 g, 4.61 mmol, 1 equiv.) And NaOH

(0.75 g, 18.44 mmol, 4 equiv.) In isopropanol (10 ml) and H2O (20 ml) was heated at reflux for 1 h. After

After cooling to room temperature, the mixture was acidified with concentrated HCl until pH 1. The white precipitating solid was filtered and washed with Et2O (50 ml), to obtain 568 mg, 48% of production, mp 187-188 ° C, HPLC-MS (procedure 1): m / z 258 [M + H] +, Reaction time = 0.98 min. By 1 H-NMR analysis, it was determined to be a mixture of isomers in a ratio (3: 2) E: Z.

The aqueous phase was extracted with Et2O (2x50 ml) and the combined extracts were dried (Na2SO4) and evaporated to dryness under reduced pressure, to obtain a light orange solid, 418 mg, 35% production, mp 127128 ° C, HPLC-MS (procedure 1): m / z 258 [M + H] +, Reaction time = .0.99 min. By 1 H-NMR analysis, it was determined to be a mixture of isomers in a ratio (3:40) E: Z.

Example 180: Butyl 4- [3- (aminocarbonyl) -2,4-difluorophenoxy] -2-butenoate.

5 - 4- [3- (Aminocarbonyl) -2,4-difluorophenoxy] -2-butenoic acid, mixture of isomers (3: 2) E: Z, (526 mg, 2 mmol, 1

equiv.) was dissolved in dry DMF (5 ml). K2CO3 (850 mg, 6 mmol, 3 equiv.) And n-butyl bromide (0.23 ml, 2.1 mmol, 1.05 equiv.) Were added and the reaction mixture was heated for 70 h at 50 ° C and for 1.5 h at room temperature . After cooling to room temperature, the mixture was diluted with H2O (50 ml) and extracted with EtOAc (3 x 40 ml). The combined organic extracts were washed with H2O (6x30 ml), dried (MgSO4) and evaporated to dryness under reduced pressure. The oil residue was purified by column chromatography on silica, eluted with CH2Cl2 and MeOH / CH2Cl2 (1%), to obtain 364 mg, 57% production, mp <40 [deg.] C. HPLC-MS (procedure 1): m / z 314 [M + H] +, Reaction time = 3.88 min. By 1 H-NMR analysis, it was determined to be a mixture of isomers in a ratio (5: 7) E: Z. When the same reaction was carried out on the mixture of isomers (3:40) E: Acid Z, the product obtained was determined to be a mixture of isomers in a ratio (1: 4)

15 E: Z.

Example 181: Butyl 4- [3- (aminocarbonyl) -2,4-difluorophenoxy] butanoate.

4- [3- (Aminocarbonyl) -2,4-difluorophenoxy] -2-butenoic acid (100 mg, 0.32 mmol) with 5% Rh / C (5 mg) was stirred

20 in butanol (5 ml) under H2, at room temperature for 21 hours. The reaction mixture was filtered through a celite buffer and rinsed with CH2Cl2 (3x5 ml). The filtrate was evaporated to dryness, under reduced pressure, to obtain 88 mg of the desired product, yield: 87%, mp 53-55 ° C. HPLC-MS (procedure 1): m / z 316 [M + H] +, Reaction time = 3.49 min.

Example 182-197 (Table G)

Examples 182 - 197 were synthesized from 2,6-difluoro-3-hydroxybenzenecarboxamide: examples 182, 190, 192, 193 and 195, according to Procedure B, scheme 2 and Examples 183-189, 194 and 196-197 according to Procedure C, scheme 3.

Example

182 183 184

Structure

Performance (%)

eleven 4 10

Mp (ºC)

130-132 86-88 -

HPLC-MS: procedure no., M / z, ion

Reaction time (min)

2.84 3.15 3.11

Table of product compound names; Examples 182-197:

Example

Compound Name

182

2,6-Difluor-3 - [(5-methyl-3isoxazolyl) methoxy] benzenecarboxamide

183

2,6-Difluor-3- (2-furylmethoxy) benzenecarboxamide

184

2,6-Difluor-3- (3-furylmethoxy) benzenecarboxamide

185

2,6-Difluor-3 - [(5-methyl-2-furyl) methoxy] benzenecarboxamide

186

2,6-Difluor-3- (2-thienylmethoxy) benzenecarboxamide

187

2,6-Difluor-3 - [(4-methyl-2-thienyl) methoxy] benzenocarboxamide

188

2,6-Difluor-3- (3-thienylmethoxy) benzenecarboxamide

189

2,6-Difluor-3- (1,3-thiazol-5-ylmethoxy) benzenocarboxamide

190

2,6-Difluor-3 - [(2-methyl-1,3-thiazol-4-yl) methoxy] benzenecarboxamide

191

2,6-Difluor-3- (1,3-thiazol-2-ylmethoxy) benzenocarboxamide

192

2,6-Difluor-3 - [(5-methyl-1,3-thiazol-2yl) methoxy] benzenecarboxamide

193

2,6-Difluor-3 - [(4-methyl-1,3-thiazol-2yl) methoxy] benzenecarboxamide

194

2,6-Difluor-3 - [(1-methi) -1H-imidazol-2il) methoxy] benzenecarboxamide

195

2,6-Difluor-3 - [(3-methylbenzyl) oxy] benzenocarboxamide

196

3 - [(3-Ethoxybenzyl) oxy] -2,6-difluorobenzenecarboxamide

197

2,6-Difluor-3 - [(6-methyl-2-pyridinyl) methoxy] benzenecarboxamide

Scheme 23: (a) n-BuLi, Et2NH, THF; (b) NalO4, MeOH; (c) NaBH4, MeOH; (d) PPh3, DIAD, Et3N, THF, room temperature.

Example 198: 2,6-Difluor-3 - [(2-methyl-4-pyridinyl) methoxy] benzenecarboxamide.

Synthesized from 2,6-difluoro-3-hydroxybenzenocarboxamide according to Procedure C, scheme 3. The required building block, 4-hydroxymethyl-2-methylpyridine, was synthesized according to the literature procedure, shown in Scheme 23 (Ragan, JA, Jones, BP, Meltz, CN, Teixeira JJJr .; Synthesis 2002, 483-486. Production 34%, mp 185-186 ° C, HPLC-MS (procedure 1): m / z 279 [ M + H] +, Reaction time = 2.50 min.

Example 199: 2,6-Difluor-3 - ([1,3] oxazolo [4,5-b] pyridin-2-ylmethoxy) benzenecarboxamide.

Synthesized from 2,6-difluoro-3-hydroxybenzenecarboxamide according to procedure B, scheme 2. 10 Production 8%, mp 180-181 ° C, HPLC-MS (method 1): m / z 306 [M + H) +, Reaction time = 2.30 min.

Example 200: 2,6-Difluor-3- (2-quinolinylmethoxy) benzenocarboxamide.

Synthesized from 2,6-difluoro-3-hydroxybenzenecarboxamide according to procedure B, scheme 2. Production 48%, mp 216-218 ° C, HPLC-MS (method 1): m / z 315 [M + H ] +, Reaction time = 3.43 min.

Example 201: 3- (1-Benzothiophene-5-ylmethoxy) -2,6-difluorobenzenecarboxamide.

Synthesized from 2,6-difluoro-3-hydroxybenzenocarboxamide according to procedure B, scheme 2. The required basic element, 5- (chloromethyl) -1-benzothiophene, was synthesized by chlorination of 1-benzothiophene-5-methanol , commercially available, with thionyl chloride. Production 10%, mp 146-148Â ° C, HPLC-MS

20 (procedure 1): m / z 320 [M + H] +, Reaction time = 3.95 min.

Examples 202-207 (Table H)

Examples 202-207 were synthesized from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Procedure C, scheme 3.

Example

202 203 204

Structure

Performance (%)

29 9 13

Mp (ºC)

154-156 - 84-86

HPLC-MS: procedure no., M / z, ion

Reaction time (min)

3.97 2.52 3.73

Table of product compound names; Examples 202-207:

Example

Compound Name

202

3- (1-Benzothiophene-3-ylmethoxy) -2,6-difluorobenzenecarboxamide

203

2,6-Difluor-3- (imidazo [1,2-a] pyridin-2-ylmethoxy) benzenocarboxamide

204

3- (2,3-Dihydro-1,4-benzodioxin-2-ylmethoxy) -2,6-difluorobenzenecarboxamide

205

2,6-Difluor-3 - [(5-methyl-1-benzothiophene-2-yl) methoxy] benzenecarboxamide

206

3- (1-Benzothiophene-2-ylmethoxy) -2,6-difluorobenzenecarboxamide

207

3- (1-Benzofuran-2-ylmethoxy) -2,6-difluorobenzenecarboxamide

[5- (Trifluoromethyl) -1-benzothiophene-2-yl] methanol.

Pyridine (0.37 ml, 4.72 mmol, 1.5 equiv.) And the subsequent cyanuric fluoride (0.53 ml, 6.3 mmol, 2) were added

10 equiv.) To a stirred solution of 5- (trifluoromethyl) -1-benzothiophene-2-carboxylic acid (776 mg, 3.15 mmol, 1 equiv.) In CH2Cl2 (16 ml), commercially available, kept low N2, at -20 to -10 ° C. A precipitation of cyanuric acid occurred and gradually increased as the reaction proceeded. After stirring the key at -20 to -10 ° C for 2 h, ice water was added together with 100 ml CH2Cl2. Undissolved solids were filtered; The organic phase was separated from the filtrate and the aqueous layer was extracted once more with CH2Cl2 (50 ml). The combined organic layers were washed with ice water (50 ml), dried (Na2SO4) and concentrated under reduced pressure to a small volume (15 ml). NaBH4 (240 mg, 6.3 mmol, 2 equiv.) Was added in one part, and then MeOH (6.5 ml) was added dropwise over 15 minutes at room temperature. Reaction mixture

5 was neutralized with 1 N H2SO4, and the organic solvents were evaporated under reduced pressure.

The residue was taken to EtOAc (80 ml) and water (40 ml); The organic layer was separated, and the aqueous layer was extracted with EtOAc (2x60 ml). The combined organic layers were washed with 1 N H2SO4 and brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica, using EtOAc / hexane (10-20% gradient) as eluent, to obtain 400 mg (54.6% production) of the

10 product required as a white solid. HPLC-MS (procedure 1) produced a maximum with reaction time = 4.02 min, but no ionization

Example 208: 2,6-Difluor-3- [5- (trifluoromethyl) -1-benzothiophene-2-yl] methoxybenzenecarboxamide.

Synthesized from 2,6-difluor-3-hydroxybenzenecarboxamide and [5- (trifluoromethyl) -1-benzothiophene-2-yl] methanol according to procedure C, scheme 3. Production 3%, mp150-152 ° C , HPLC-MS (procedure 1): m / z 386 [MH] -, Reaction time = 4.39 min.

Examples 209-217 (Table I)

Examples 209-217 were synthesized from 2,6-difluoro-3-hydroxybenzenecarboxamide according to procedure B, scheme 2.

Example

209 210 211

Structure

Performance (%)

37 62 16

Mp (ºC)

138-139 - 172-173

HPLC-MS: procedure no., M / z, ion

Reaction time (min)

3.28 3.72 3.60

Table of product compound names. Examples 209-217:

Example

Compound Name

209

3- (1,3-Benzoxazol-2-ylmethoxy) -2,6-difluorobenzenecarboxamide

210

3 - [(5-Chloro-1,3-benzoxazol-2-yl) methoxy] -2,6-difluorobenzenecarboxamide

211

2,6-Difluor-3 - [(6-methyl-1,3-benzoxazol-2-yl) methoxy] benzenocarboxamide

212

2,6-Difluor-3 - [(5-methyl-1,3-benzoxazol-2-yl) methoxy] benzenocarboxamide

213

3- [5- (tert-Butyl) -1,3-benzoxazol-2-yl] methoxy-2,6-difluorobenzenecarboxamide

214

2,6-Difluor-3 - [(5-nitro-1,3-benzoxazol-2-yl) methoxy] benzenocarboxamide

215

3- (1,3-Benzothiazol-2-ylmethoxy) -2,6-difluorobenzenecarboxamide

216

2,6-Difluor-3 - [(5-fluorine-1,3-benzothiazol-2-yl) methoxy] benzenecarboxamide

217

2,6-Difluor-3- [5- (trifluoromethyl) -1,3-benzothiazol-2-yl] methoxybenzenecarboxamide

5-Chloro-2- (chloromethyl) -1,3-benzothiazole.

4-Chloro-2-amino-benzothiol (4.05 g, 25.4 mmol, 1 equiv.) And 2-chloro-1,1,1-trimethoxy ethane (5.0 ml, 37 mmol, 1.45 equiv.) Were heated while being stirred at 60 ° C for 2 h. The reaction mixture was cooled to room temperature and triturated with diethyl ether (10 ml). The undissolved solid was filtered and rinsed with Et2O and pentane, to obtain 1.54 g (28% yield) of the desired product. The starter liquors were evaporated until the

After drying, the solid orange residue was dissolved in Et2O (50 ml) and washed consecutively with 1 N HCl (25 ml), water (25 ml), 5% NaHCO3 solution (25 ml) and brine (25 ml). The organic layer was dried (MgSO4) and evaporated to a lower volume, under reduced pressure. The precipitating solid was filtered and washed with

Et2O and pentane, to obtain a second fraction of the desired product 1.88 g (34% production). Total production 62%, mp 102-104 ° C, HPLC-MS (procedure 1): m / z 260 [M + H + CH3CN] +, Reaction time = 4.52 min.

10 Examples 218-221 (Table J)

Examples 218-221 were synthesized from 2,6-difluoro-3-hydroxybenzenecarboxamide and 5-chloro-2 (chloromethyl) -1,3-benzothiazole according to procedure B, scheme 2.

Example

218 219

Structure

Performance (%)

81 67

Mp (ºC)

235-236 204-205

HPLC-MS: procedure no., M / z, ion

Reaction time (min)

3.89 392

Table of product compound names; Examples 218-221:

Example

Compound Name

218

3 - [(5-Chloro-1,3-benzothiazol-2-yl) methoxy] -2,6-difluorobenzenecarboxamide

219

3 - [(5-Chloro-1,3-benzothiazol-2-yl) methoxy] -2-fluorobenzenecarboxamide

220

6-Chloro-3 - [(5-chloro-1,3-benzothiazol-2-yl) methoxy] -2-fluorobenzenecarboxamide

221

2-Chloro-3 - [(5-chloro-1,3-benzothiazol-2-yl) methoxy] -6-fluorobenzenecarboxamide

2 - [(5-Chloro-1,3-benzothiazol-2-yl) methoxy] isonicotinonitrile.

2-Hydroxy-4-cyano-pyridine (240 mg, 2 mmol, 1 equiv.) Was dissolved in DMF (6 ml), K2CO3 (415 mg, 3 mmol, 1.5 equiv.) And Nal (60 mg were added , 0.4 mmol, 0.2 equiv.) And the mixture was stirred at room temperature for 10 minutes. 5-Chloro-2- (chloromethyl) -1,3-benzothiazole (436 mg, 2 mmol, 1 equiv.) Was added and the reaction mixture was stirred at 60 ° C for 3 h and at room temperature throughout the entire night. By adding H2O, a brown solid precipitated, which was filtered, rinsed with H2O, dried and re-crystallized from CH3CN. Production 280 mg (46%), mp 224-227 ° C, HPLC-MS (procedure 1): m / z 302 [M + H] +, Reaction time = 3.80 min. The N-alkylated derivative (Scheme 25) was identified by 13C-NMR analysis. The DMF-H2O initiator liquors were evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica, eluted.

15 with EtOAc / hexane (10% -100% gradient) to obtain 45 mg (7.5% production) of a brown solid, HPLC-MS (method 1): m / z 302 [M + H] +, Reaction time = 4.86 min. By 13C-NMR analysis, it was identified as the desired O-alkylated derivative (Scheme 24).

Example 222: 2 - [(5-Chloro-1,3-benzothiazol-2-yl) methoxy] isonicotinamide.

20 2 - [(5-Chloro-1,3-benzothiazol-2-yl) methoxy] isonicotinonitrile (40 mg, 0.13 mmol) was dissolved in concentrated H2SO4

(0.36 ml) and the solution was heated to 40 ° C, under vigorous stirring. Water (50 mg) was added dropwise, and the mixture was stirred at 40 ° C for 3 h. After cooling to -5 ° C, crushed ice (25 ml) was added quickly, with vigorous stirring, and the mixture was stirred at room temperature for two more hours. An ammonia solution (pH 10) was added and the precipitating solid was filtered, rinsed with H2O and dried. The solid brown was

25 purified by preparative TLC, eluted with EtOAc, to obtain 20 mg (47% production), mp 220-222 ° C, HPLCMS (method 1): m / z 320 [M + H] +, Reaction time = 3.76 min.

2- (Chloromethyl) -4-ethyl-1,3-benzothiazole.

5 (Procedure J) A solution of 4-ethyl-1,3-benzothiazol-2-amine (1.0 g, 5.6 mmol, 1 equiv.) And KOH (7.4 g, 112.2 mmol, 20 equiv.) In 2-methoxy- Ethanol (9 ml) and H2O (9 ml) was stirred under N2 and refluxed for 20 h. After cooling to room temperature, the mixture was poured into water (150 ml) and extracted with CH2Cl2 (2x40 ml). The aqueous phase was neutralized with concentrated HCl and extracted again with CH2Cl2 (3x70 ml). The combined neutral extracts were washed with water (2x60 ml), dried (Na2SO4) and evaporated to dryness under pressure.

10 reduced. The yellow-green semi-solid residue (790 mg) was mixed with 2-chloro-1,1,1-trimethoxy ethane (1.62 g,

10.4 mmol) and the mixture was stirred, under N2, at 60 ° C, for 4 h. The volatiles were removed by evaporation under reduced pressure and the brown liquid residue was purified by column chromatography on silica, eluted with CH2Cl2 / hexane (10% and 50%), to obtain a yellow liquid (406 mg, 34% of production over two steps). HPLC-MS (procedure 1): m / z 212 [M + H] +, Reaction time = 5.00 min

Example 223: 3 - [(4-Ethyl-1,3-benzothiazol-2-yl) methoxy] -2,6-difluorobenzenecarboxamide.

Synthesized from 2,6-difluoro-3-hydroxybenzenecarboxamide and 2- (chloromethyl) 4-ethyl-1,3-benzothiazole according to Procedure B, scheme 2. Production 17%, mp 184-186 ° C, HPLC -MS (production 1): m / z 349 [M + H] +, Reaction time = 4.16 min.

20 2- (Chloromethyl) -6-methoxy-1,3-benzothiazole

Synthesized from 6-methoxy-1,3-benzothiazol-2-amine commercially available, according to Procedure J, scheme 25. It was used raw in the next step.

Example 224: 2,6-Difluor-3 - [(6-methoxy-1,3-benzothiazol-2-yl) methoxy] benzenecarboxamide.

Synthesized from 2,6-difluoro-3-hydroxybenzenecarboxamide and 2- (chloromethyl) -6-methoxy-1,3-benzothiazole according to Procedure B, scheme 2. Production 19%, mp 190-192 ° C, HPLC -MS (production 1): m / z 351 [M + H] +, Reaction time = 3.50 min.

Scheme 26: (a) BrCH2CN, K2CO3, Nal, DMF, 60 ° C; (b) KOH, 2-methoxy-ethanol: H2O (1: 1), reflux.

Example 225: 3- (Cyanomethoxy) -2,6-difluorobenzenecarboxamide.

10 Synthesized from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Procedure B, scheme 2. Production 86%, mp 122-123 ° C, HPLC-MS (method 1): m / z 213 [M + H ] +, Reaction time = 1.97 min.

Example 226: 3 - [(4-Chloro-1,3-benzothiazol-2-yl) methoxy] -2,6-difluorobenzenecarboxamide.

 (Procedure K) A solution of KOH (15.15 g, 270 mmol, 20 equiv.) In H2O (25 ml) was added to a solution

15 of 4-chloro-1,3-benzothiazol-2-amine (2.5 g, 13.5 mmol, 1 equiv.) In 2-methoxy-ethanol (25 ml) and the reaction mixture was heated to reflux overnight. After cooling to room temperature, the mixture was diluted with H2O (200 ml), acidified with 5N HCl solution until reaching pH 4 and extracted with CH2Cl2 (3x150 ml). The combined organic extracts were washed with brine (100 ml), dried (Na2SO4) and concentrated under reduced pressure to dryness, to obtain 1.5 g (70% production). From this crude residue, 167 mg (assuming 1.05 mmol) were mixed with 3- (cyanomethoxy) -2,6-difluorobenzenecarboxamide (150 mg, 0.7 mmol) and the mixture was stirred at 120 ° C, in a Pre-heated oil bath, under N2, for 2 h. EtOH (2 ml) was added and the reaction mixture was heated for an additional 2 hours. After cooling to room temperature, the solid was filtered, washed with EtOH and re-crystallized from EtOAc / pentane, to obtain the desired product as a pale yellow solid, 62 mg (25% yield in the second stage). HPLC-MS (procedure 1): m / z 355 [M + H] +, Reaction time = 3.75 min.

Example 227: 3 - [(6-Chloro-1,3-benzothiazol-2-yl) methoxy] -2,6-difluorobenzenecarboxamide.

Synthesized from 6-chloro-1,3-benzothiazol-2-amine and 3- (cyanomethoxy) -2,6-difluorobenzene carboxamide, according to Procedure K, scheme 26. Production 38% (second phase), mp 190-191 ° C, HPLC-MS (procedure 1): m / z 355 [M + H] +, Reaction time = 3.85 min.

Example 228: 2,6-Difluor-3 - [(4-methyl-1,3-benzothiazol-2-yl) methoxy] benzenecarboxamide.

Synthesized from 4-methyl-1,3-benzothiazol-2-amine and 3- (cyanomethoxy) -2,6-difluorobenzene carboxamide, according to procedure K, scheme 26. Production 36% (second stage), mp 201-202 ° C, HPLC-MS (method 1): m / z 335 [M + H] +, Reaction time = 3.79 min.

Example 229: 2,6-Difluor-3 - [(6-methyl-1,3-benzothiazol-2-yl) methoxy] benzenecarboxamide.

Synthesized from 6-methyl-1,3-benzothiazol-2-amine and 3- (cyanomethoxy) -2,6-difluorobenzene carboxamide, according to Procedure K, scheme 26. Production 17% (second stage), HPLC -MS (procedure 1): m / z 335 [M + H] +, Reaction time = 3.70 min.

Example 230: 2,6-Difluor-3- [6- (trifluoromethoxy) -1,3-benzothiazol-2-yl] methoxybenzenecarboxamide.

Synthesized from 6- (trifluoromethoxy) -1,3-benzothiazol-2-amine and 3- (cyanomethoxy) -2,6-difluorbenzenecarboxamide, according to Procedure K, scheme 26. Production 34% (second phase), mp 174- 175Â ° C, HPLC-MS (procedure 1): m / z 405 [M + H] +, Reaction time = 4.14 min.

6-Propyl-1,3-benzothiazol-2-amine.

A solution of Br2 (3.8 ml, 74 mmol, 2 equiv.) In glacial AcOH (18.5 ml) was added, dropwise, at <25 ° C, to a stirred solution of 4-propylamine (5.0 g, 37 mmol, 1 equiv.) and ammonium thiocyanate (5.63 g, 74 mmol, 2 equiv.) in 10 glacial AcOH (110 ml). The resulting mixture was stirred at room temperature for 2 h, diluted with H2O (700 ml) and extracted with EtOAc (2x250 ml). The aqueous layer was alkalized with aqueous ammonia solution to pH 10 and extracted with EtOAc (3x300 ml). The combined alkaline extracts were washed with H2O (2x200 ml), dried and evaporated to dryness under reduced pressure, to obtain the desired product as a white solid, 2.34 g (33% production), mp 120-122 ° C. HPLC-MS (procedure 1): m / z 193 [M + H] +, Time of

15 reaction = 3.92 min.

Example 231: 2,6-Difluor-3 - [(6-propyl-1,3-benzothiazol-2-yl) methoxy] benzenecarboxamide.

Synthesized from 6-propyl-1,3-benzothiazol-2-amine and 3- (cyanomethoxy) -2,6-difluorobenzenecarboxamide, according to procedure K, scheme 26. Production 18% (second stage), mp 173- 175 ° C. HPLC-MS 20 (procedure 1): m / z 363 [M + H] +, Reaction time = 4.35 min.

Scheme 27. (a) NBS, α, αâ € “azoisobutyronitrile, CCl4, (b) K2CO3, DMF, 60 ° C; (c) Boronic acid 4-pyridine, Na2CO3, Pd (PPh3) 4, dioxane.

5-Bromo-2- (bromomethyl) -1,3-benzothiazole.

N-Bromosuccinimide (4.45 g, 25 mmol, 1.4 equiv.) Was added and then α, αâ € ™ -azoisobutyronitrile (110 mg,

0.7 mmol, 0.04 equiv.) To a solution of 5-bromo-2-methyl-benzothiazole (4.07 g, 17.85 mmol, 1 equiv.) In CCl4 (110 ml). The reaction mixture was stirred at reflux for 24 hrs. After cooling, the succinimide was removed by filtration and rinsed with CCl4 (100 ml). The filtrate was evaporated to dryness under reduced pressure and

The orange solid residue was purified by column chromatography on silica, eluted with CH2Cl2 / hexane (20% 70% gradient), to obtain the desired product as a white solid, 2.15 g (39% yield). Mp 116-117, HPLC-MS (procedure 1): m / z 308 [M + H] +, Reaction time = 4.84 min. The reaction also gave 1.40 g (20% production) of the by-product 5-bromo-2-dibromomethyl-benzothiazole, in addition to 0.89 g (22%) of unreacted raw material.

15 3 - [(5-Bromo-1,3-benzothiazol-2-yl) methoxy] -2,6-difluorobenzenecarboxamide. Synthesized from 2,6-difluoro-3-hydroxybenzenecarboxamide and 5-bromo-2- (bromomethyl) -1,3-benzothiazole,

according to Procedure B, scheme 2. Production 81%, mp 244-246 ° C, HPLC-MS (procedure 1): m / z 399, 401 [M + H] +, Reaction time = 3.98 min.

Example 232: 2,6-Difluor-3- [5- (4-pyridinyl) -1,3-benzothiazol-2-yl] methoxybenzenecarboxamide.

A mixture of 3 - [(5-bromo-1,3-benzothiazol-2-yl) methoxy] -2,6-difluorobenzenecarboxamide (168 mg, 0.42 mmol, 1 equiv.), Acidic was suspended in dioxane (3.5 ml) Boronic 4-pyridine (98 mg, 0.63 mmol, 1.5

equiv.) and aqueous Na2CO3 solution (0.42 ml, 0.82 mmol, 2 equiv.) and the mixture was degassed and washed with N2. Tetrakis (triphenylphosphine) palladium (0) (37 mg, 0.031 mmol, 0.075 equiv.) Catalyst was added and the reaction mixture was heated at reflux for 12 h. After cooling to room temperature, the mixture was diluted with H2O and the solid precipitant was filtered and rinsed with H2O, IMS, IMS / Et2O and Et2O. Re-crystallized from CH3CN,

5 to obtain the desired product as an off-white solid, 47 mg (28% production), mp 255-258 ° C. HPLC-MS: m / z 398 [M + H] +, Reaction time = 3.28 min.

Examples 233-241 were synthesized from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Procedure B, scheme 2.

Examples 233-241 (Table K)

Example

233 2. 3. 4 235

Structure

Performance (%)

58 25 63

Mp (ºC)

207-209 198-199 208-210

HPLC-MS: procedure no., M / z, ion

Reaction time (min)

3.96 3.89 3.84

236

237 238

54

6 (only -75% pure) 17

222-224

- 188-189

4.13

3.75 3.17

239

240 241

60

44 77

177-178

164-165 172-173

3.62

3.65 3.76

Table of product compound names; Examples 233-241:

Example

Compound name

233

2,6-Difluor-3 - [(2-phenyl-1,3-thiazol-4-yl) methoxy] benzenecarboxamide

2. 3. 4

3- [5- (4-Chlorophenyl) -1,3,4-thiadiazol-2-yl] methoxy-2,6-difluorobenzenecarboxamide

235

2,6-Difluor-3 - [(4-phenyl-1,3-thiazol-2-yl) methoxy] benzenecarboxamide

236

2,6-Difluor-3- [2- (4-methylphenyl) -1,3-thiazol-4-yl] methoxybenzenecarboxamide

237

3 - [(2-Amino-1,3-thiazol-4-yl) methoxy] -2,6-difluorobenzenecarboxamide

238

2,6-Difluor-3 - [(5-phenyl-1,3,4-oxadiazol-2-yl) methoxy] benzenocarboxamide

239

2,6-Difluor-3 - [(5-phenyl-1,2,4-oxadiazol-3-yl) methoxy] benzenecarboxamide

240

2,6-Difluor-3 - [(3-phenyl-1,2,4-oxadiazol-5-yl) methoxy] benzenocarboxamide

241

2,6-Difluor-3- [3- (4-methoxyphenyl) -1,2,4-oxadiazol-5-yl] methoxybenzenecarboxamide

Example 242: 2,6-Difluor-3- [3- (4-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] methoxybenzenecarboxamide.

(Procedure L) Boron tribromide solution (1.0 M in CH2Cl2, 1.5 ml, 1.5 mmol, 2 equiv.) Was slowly added dropwise to agitated suspension of 2,6-difluoro-3- [3- (4-methoxyphene) -1-2-4-oxadiazol-5

10 il] methoxybenzenecarboxamide (272 mg, 0.75 mmol, 1 equiv.) In CH2Cl2 (5 ml), at room temperature, under N2. The reaction mixture was stirred at room temperature for 4 h and poured into water (20 ml). CH2Cl2 (10 ml) was added and the biphasic mixture was stirred for 30 min. at room temperature. The undissolved white solid was filtered, washed with water and Et2O, to obtain 170 mg (65% yield), mp 209-210 ° C, HPLC-MS (method 1): m / z 348 [M + H] + , Reaction time = 3.00 min.

Examples 234-250 (Table L)

Examples 243-250 were synthesized from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Procedure B, scheme 2

Example

243 244 245

Structure

No example

Performance (%)

38 81

Mp (ºC)

168-169 173-174

HPLC-MS: procedure no., M / z, ion

Reaction time (min)

4.27 3.81

Table of product compound names: Examples 243-250:

Example

Compound name

243

2,6-Difluor-3- (3- [4- (trifluoromethyl) phenyl] -1,2,4-oxadiazol-5-ylmethoxy) benzenecarboxamide

245

2,6-Difluor-3- [3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl] methoxybenzenecarboxamide

246

3- [3- (4-Chlorophenyl) -1,2,4-oxadiazol-5-yl] methoxy-2,6-difluorobenzenecarboxamide

247

2,6-Difluor-3- [3- (4-methylphenyl) -1,2,4-oxadiazol-5-yl] methoxybenzenecarboxamide

248

2,6-Difluor-3- [3- (4-isopropylphenyl) -1,2,4-oxadiazol-5-yl] methoxybenzenecarboxamide

249

3- (3- [4- (tert-Butyl) phenyl] -1,2,4-oxadiazol-5-ylmethoxy) -2,6-difluorobenzenecarboxamide

250

3- [3- (4-Ethylphenyl) -1,2,4-oxadiazol-5-yl] methoxy-2,6-difluorobenzenecarboxamide

Scheme 28: (a) (Boc) 2O, Et3N, DMAP, THF; (b) K2CO3, Nal, DMF, room temperature; (c) 4H HCl, dioxane, room temperature.

tert-Butyl N-4- [5- (chloromethyl) -1,2,4-oxadiazol-3-yl] phenylcarbamate.

Di-tert-butyl dicarbonate (1.04 g, 4.75 mmol, 1.05 equiv.) Was added, part by part, to a solution of 4- [5

10 (chloromethyl) -1,2,4-oxadiazol-3-yl] aniline (950 mg, 4.53 mmol, 1 equiv.), Et3N (0.20 ml, 5.44 mmol, 1.2 equiv.) And dimethylaminopyridine (catalyst), and the Reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated under reduced pressure, the residue was triturated with Et2O and the solid was filtered off. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica, eluted with EtOAc / hexane (20%), to obtain a creamy solid, 780 mg (55% of

15 production). About 70% pure by HPLC-MS (procedure 1): m / z 308 [M-H] -, Reaction time = 4.72 min. It was used without further purification in the next phase.

Tert-Butyl N- [4- (5- [3- (aminocarbonyl) -2,4-difluorophenoxy] methyl-1,2,4-oxadiazol-3-yl) phenyl] carbamate.

Synthesized from 2,6-difluoro-3-hydroxybenzenecarboxamide and N-4- [5- (chloromethyl) -1,2,4-oxadiazol-3-yl] phenylcarbamate of tert-butyl, according to Procedure B, scheme 2, at room temperature. Production 42%, mp 165-166 ° C, HPLC-MS (procedure 1): m / z 447 [M + H] +, Reaction time = 4.10 min.

Example 251: 3- [3- (4-Aminophenyl) -1,2,4-oxadiazol-5-yl] methoxy-2,6-difluorobenzenecarboxamide hydrochloride salt

Tert N- [4- (5- [3- (aminocarbonyl) -2,4-difluorophenoxy] methyl-1,2,4-oxadiazol-3-yl) phenyl] tert carbamate was dissolved

10 Butyl (300 mg, 0.67 mmol, 1 equiv.) In 4N HCl in dioxane (7 ml, 28 mmol, 42 equiv.) And the reaction mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure, the residue was triturated with dry Et2O and the solid formed was filtered and rinsed with dry Et2O. The crude product (200 mg) was absorbed in EtOH (2 ml) and triturated with 2N HCl in Et2O solution (0.3 ml) and dry Et2O. The white solid was filtered and washed with dry Et2O, to obtain 110 mg of the desired product (43% production).

HPLC-MS (method 1): m / z 347 [M + H-HCl] +, Reaction time = 2.98 min.

Examples 252-266 (Table M)

Examples 252, 254-256 and 258-266 were synthesized from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Procedure B, scheme 2. Examples 253 and 257 were synthesized from carboxamide 2,6

20 difluor-3- [3- (2-methoxyphenyl) -1,2,4-oxadiazol-5-yl] methoxybenzene according to procedure L.

Example

252 252a 253

Structure

Performance (%)

60 73 54

Mp (ºC)

148-149 263-264 164-165

HPLC-MS: procedure no., M / z, ion

Reaction time (min)

3.95 3.45 3.52

Table of product compound names; Examples 252-266:

Example

Compound name

252

2,6-Difluor-3- [3- (2-methylphenyl) -1,2,4-oxadiazol-5-yl] methoxybenzenecarboxamide

252a

2,6-Difluor-3- [3- (2-methoxyphenyl) -1,2,4-oxadiazol-5-yl] methoxybenzenecarboxamide

253

2,6-Difluor-3- [3- (2-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] methoxybenzenecarboxamide

254

3- [3- (2-Chlorophenyl) -1,2,4-oxadiazol-5-yl] methoxy-2,6-difluorobenzenecarboxamide

255

3- [3- (3-Chlorophenyl) -1,2,4-oxadiazol-5-yl] methoxy-2,6-difluorobenzenecarboxamide

256

2,6-Difluor-3- [3- (3-methoxyphenyl) -1,2,4-oxadiazol-5-yl] methoxybenzenecarboxamide

257

2,6-Difluor-3- [3- (3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] methoxybenzenecarboxamide

258

2,6-Difluor-3- (3- [3- (trifluoromethyl) phenyl] -1,2,4-oxadiazol-5-ylmethoxy) benzenecarboxamide

259

2,6-Difluor-3- [3- (3-nitrophenyl) -1,2,4-oxadiazol-5-yl] methoxybenzenecarboxamide

260

3- [3- (2,6-Dichlorophenyl) -1,2,4-oxadiazol-5-yl] methoxy-2,6-difluorobenzenecarboxamide

261

3- [3- (2,4-Dimethoxyphenyl) -1,2,4-oxadiazol-5-yl] methoxy-2,6-difluorobenzenecarboxamide

262

3- [3- (2,4-Dimethoxyphenyl) -1,2,4-oxadiazol-5-yl] methoxy-2,6-difluorobenzenecarboxamide

263

2,6-Difluor-3- (3 - [(4-methylphenoxy) methyl] -1,2,4-oxadiazol-5-ylmethoxy) benzenecarboxamide

264

3- (3 - [(2,6-Dichlorophenoxy) methyl] -1,2,4-oxadiazol-5-ylmethoxy) -2,6-difluorobenzenecarboxamide

265

3- [3- (4-Chlorobenzyl) -1,2,4-oxadiazol-5-yl] methoxy-2,6-difluorobenzenecarboxamide

266

3 - [(3-Benzyl-1,2,4-oxadiazol-5-yl) methoxy] -2,6-difluorobenzenecarboxamide

4- Chloro-N-hydroxy-benzamide

5 Hydroxylamine hydrochloride (5.03 g, 73.0 mmol) and NaOH (2.90 g, 73.0 mmol) were added to a solution of 4-chlorobenzonitrile (10.0 g, 73.0 mmol) in EtOH (250 ml). The resulting reaction mixture was refluxed for 15h. After the reaction was completed (TLC monitoring), the mixture was concentrated, EtOH was added and filtered. The filtrate was evaporated in vacuo and used as such for the next step (crude production 12.0 g, 66%).

10 5-Bromomethyl-3- (4-chloro-phenyl) - [1,2,4] oxadiazole

Bromoacetyl bromide (1.50 mL, 17.58 mmol) was added to 4-Chloro-N-hydroxy-benzamide (1.0 g, 5.86 mmol) and K2CO3 (3.18 g, 23.44 mmol). The reaction mixture was heated at 100 ° C for 15 min. After completion of the reaction mixture (TLC monitoring), water (100 ml) was added and extracted with ethyl acetate (3 x 50 ml). He

The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on silica gel (60-120 M, 1% EtOAc-Hexane) to obtain the desired product (0.44 g, 28%) as a white solid.

Examples 267-270 (Table N)

The compounds of examples 267-270 were synthesized according to the following general procedure:

20 added reactant (B) and potassium carbonate (C) to a solution of 5-bromomethyl-3- (4-chloro-phenyl) - [1,2,4] oxadiazole (A) in 2 ml of anhydrous DMF . The reaction mixture was stirred at 25 ° C for 24 hours under a nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400 M) using ethyl acetate / hexane (45:55) as eluent to obtain the product compound.

Table N

Example

267 268

Product

3- [3- (4-Chloro-phenyl) - [1,2,4] oxadiazol-5-ylmethoxy] 2-fluoro-benzamide 5- [3- (4-Chloro-phenyl) - [1,2,4] oxadiazol-5ylmethoxy] -2-fluoro-benzamide

Reaction scheme

Reagent (B)

2-fluorine-3-hydroxy-benzamide 2-fluorine-5-hydroxy-benzamide

Quantities of A; B; C

Production

0.3 g, 43% off-white solid 0.025 g, 27% white solid

1H NMR (DMSO-d6, 400 MHz)

δ 5.72 (s, 2H), 7.17-7.25 (m, 2H), 7.39-7.43 (m, 1H), 7.80 (m, 3H), 7.80 (br s, 1H) and 8.03 (d, J = 8.80 Hz, 2H) δ 5.63 (s, 2H), 7.23-7.33 (m, 3H), 7,657.73 (m, 4H) and 8.03 (d, J = 8.40 Hz, 2H)

HPLC Procedure Number, reaction time (minutes)

269

270

6-Chloro-3- [3- (4-chloro-phenyl) - [1,2,4] oxadiazol-5-methoxy] -2-fluoro-benzamide

6-Chloro-3- [3- (4-chloro-phenyl) - [1,2,4] oxadiazol-5-ylmethoxy] -6-fluorobenzamide

6-Chloro-2-fluorine-3-hydroxy-benzamide

2-Chloro-6-fluorine-3-hydroxy-benzamide

0.070 g, 71% white solid

0.013 g, 13% white solid

δ 5.74 (s, 2H), 7.30-7.39 (m, 2H), 7.67 (d, J = 8.80 Hz, 2H), 7.88 (br s, 1H), 8.03 (d, J = 8.80 Hz, 2H) and 8.16 (br s, 1H)

δ 5.73 (s, 2H), 7.27-7.37 (m, 2H), 7.65 (d, J = 8.40 Hz, 2H), 7.87 (br s, 1H), 8.03 (d, J = 8.40 Hz, 2H) and 8.14 (br s, 1H)

Scheme 30: (a) 2-Benzyloxy-thioacetamide, DMF; (b) BBr3, DCM, (c) PBr3, Toluene (d) Corresponding phenols

2-Benzyloxymethyl-4- (4-chloro-phenyl) -thiazole

5 2-Bromo-1- (4-chloro-phenyl) -ethanone (3.0 g, 12.87 mmol) was added to the solution of 2-Benzyloxy-thioacetamide (3.0g,

16.57 mmol) in 3 ml of DMF. The reaction mixture was heated at 130 ° C for 24 hours under a nitrogen atmosphere. After completing the reaction mixture (TLC monitoring), water (25 ml) was added and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on silica gel (230-400 M, 2% EtOAc-Hexane) to obtain the

10 desired product (2.0 g, 49%). The corresponding cyano derivative was also prepared by the same general method.

[4- (4-Chloro-phenyl) -thiazol-2-yl] -methanol

A solution of 2-Benzyloxymethyl-4- (4-chloro-phenyl) -thiazole (2.0g, 6.34 mmol) in 25 ml of DCM was cooled to -78 °

15 C followed by the addition of BBr3 (2.38 ml, 25.3 mmol). The reaction mixture was stirred at 25 ° C for 2 h. After completion of the reaction mixture (TLC monitoring), a solution of NaHCO3 (20 ml) was added at 0 ° C and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on silica gel (60-120 M, 40% EtOAc-Hexane) to obtain the desired product (0.8g, 57%). The corresponding cyano derivative was also prepared

20 for the same general method.

2-Bromomethyl-4- (4-chloro-phenyl) -thiazole

PBr3 (0.51 ml, 5.33 mmol) was added to the solution of [4- (4-Chloro-phenyl) -thiazol-2-yl] -methanol (0.80g, 3.55 mmol) in 10 ml of toluene and the mixture The reaction was heated at 120 ° C for 20 min under a nitrogen atmosphere. After

After completion of the reaction mixture (TLC monitoring), water (25 ml) was added and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated to obtain the desired product (0.17 g, 17%). The corresponding cyano derivative was also prepared by the same general method.

30 Examples 271-276 (Table O)

The compounds of examples 271-276 were synthesized according to the following general procedure: reagent (B) and potassium carbonate (C) were added to a reagent solution (A) in anhydrous DMF. The reaction mixture was stirred at 25 ° C for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M)

Using ethyl acetate / hexane as the eluent to obtain the product compound.

Table O

Example

271 272

Product

3- [4- (4-Chloro-phenyl) -thiazol-2-ylmethoxy] -2-fluorbenzamide 3- [4- (4-Chloro-phenyl) -thiazol-2-ylmethoxy] -2-fluorbenzamide

Reaction scheme

Ethyl acetate ratio: hexane

Reagent (A)

2-bromomethyl-4- (4-chloro-phenyl) -thiazole 2-bromomethyl-4- (4-chloro-phenyl) -thiazole

Reagent (B)

2-fluorine-3-hydroxy-benzamide 2-fluorine-5-hydroxy-benzamide

Quantities of A; B; C; DMF volume

Production

0.035 g, 40% white solid 0.020 g, 23% white solid

1H NMR (DMSO-d6, 400 MHz)

δ 5.60 (s, 2H), 7.20 (m, 2H), 7.44 (m, 1H), 7.53 (d, J = 8.40 Hz, 2H), 7.66 (br s, 1H), 7.79 (br s, 1H), 8.0 (d, J = 8.40 Hz, 2H) and 8.25 (s, 1H) δ 5.52 (s, 2H), 7.24 (m, 2H), 7.33 (m, 1H), 7.53 (d, J = 8.40 Hz, 2H), 7.72 (m, 2H), 8.01 (d, J = 8.40 Hz, 2H) and 8.25 (s, 1H)

HPLC Procedure Number, reaction time (minutes)

273

274

6-Chloro-3- [4- (4-chloro-phenyl) -thiazol-2-ylmethoxy] -2-fluorobenzamide

6-Chloro-3- [4- (4-chloro-phenyl) -thiazol-2-ylmethoxy] -6-fluorobenzamide

2-bromomethyl-4- (4-chloro-phenyl) -thiazole

2-bromomethyl-4- (4-chloro-phenyl) -thiazole

6-chloro-2-fluorine-3-hydroxy-benzamide

2-Chloro-6-fluorine-3-hydroxy-benzamide

0.017 g, 17% white solid

0.042 g, 43% white solid

δ 5.62 (s, 2H), 7.29-7.32 (m, 1H), 7.37-7.41 (m, 1H), 7.53 (d, J = 8.80 Hz, 2H), 7.86 (br s, 1H), 8.0 (d, J = 8.80 Hz, 2H), 8.14 (br s, 1H) and 8.26 (s, 1H)

δ 5.60 (s, 2H), 7.30 (m, 1H), 7.38 (m, 1H), 7.53 (d, J = 8.40 Hz, 2H), 7.86 (br s, 1H), 8.0 (d, J = 8.40 Hz , 2H), 8.13 (br s, 1H) and 8.24 (s, 1H)

275

276

2- [4- (4-Chloro-phenyl) -thiazol-2-ylmethoxy] -isonicotinamide

3- [4- (4-Cyano-phenyl) -thiazol-2-ylmethoxy] -2,6-fluoro-benzamide

2-bromomethyl-4- (4-chloro-phenyl) -thiazole

4- (2-Bromomethyl-thiazol-4-yl) -benzonitrile

2-hydroxy-isonicotinamide

2,6-difluor-3-hydroxy-benzamide

0.027 g, 12% white solid

0.41 g, 56% white solid

δ 5.46 (s, 2H), 6.63 (m, 1H), 6.90 (s, 1H), 7.51 (d, J = 8.40 Hz, 2H), 7.70 (br s, 1H), 7.98 (m, 3H) and 8.15 (m, 2H)

δ 5.60 (s, 2H), 7.12 (t, J = 8.80 Hz, 1H), 7.40 (m, 1H), 7.89 (br s, 1H), 7.94 (d, J = 8.40 Hz, 2H), 8.17 (m , 3H) and 8.48 (s, 1H)

4- (4-Methoxy-phenyl) -2-methyl-thiazole

The mixture of thioacetamide (16.0 g, 213 mmol) and 2-bromo-1- (4-methoxy-phenyl) -ethanone (4.0 g, 17.5 mmol) was heated at 140 ° C for 24 h under nitrogen atmosphere. After completing the reaction mixture (TLC monitoring), water (100 ml) was added and extracted with ethyl acetate (3 x 100 ml). The combined organic was washed with water,

10 brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on silica gel (230-400 M, 1% EtOAc-Hexane) to obtain the desired product (2.5 g, 69%).

5-Bromo-2-bromomethyl-4- (4-methoxy-phenyl) -thiazole

NBS (7.43 g, 41.74 mmol) was added to the solution 4- (4-Methoxy-phenyl) -2-methyl-thiazole (5.0, 24.3 mmol) in CCl4 (20 ml)

15 and the reaction mixture was heated at 100 ° C for 2 h under nitrogen atmosphere. After completing the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400 M) using 1% ethyl acetate / hexane to obtain the desired product (3.0 g, 34%).

3- [5-Bromo-4- (4-methoxy-phenyl) -thiazol-2-ylmethoxy] -2,6-difluoro-benzamide

2,6-Difluor-3-hydroxy-benzamide (0.23 g, 1.37 mmol) and potassium carbonate (0.75 g, 5.43 mmol) were added to a solution of 5-Bromo-2-bromomethyl-4- (4- Methoxy-phenyl) -thiazole (0.50 g, 1.37 mmol) in 5 ml of anhydrous DMF. The

The reaction mixture was stirred at 25 ° C for 24 hours under a nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethylacetate / hexane (30:70) as the eluent to provide the title compound (0.30 g , 48%).

Examples 277-287 (Table P).

The compounds of examples 277-287 were synthesized according to the following general procedure: reagent (B) and potassium phosphate (C) were added to a solution of 3- [5-bromo-4- (4- methoxy-phenyl) -thiazol-2-ylmethoxy] -2,6-difluor-benzamide (A) in 5 ml of anhydrous DMF and water. The reaction mixture was degassed for 10 minutes followed by the addition of palladium dichlorobis (triphenyl phosphine) (II) (D). The reaction mixture was heated at 120 [deg.] C. for 12 h under the nitrogen atmosphere. After completion of the reaction mixture (monitoring

15 with TLC), water (25 ml) was added and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on silica gel (45% EtOAc-Hexane) to obtain the desired product compound.

P table

Example

277 278

Product

2,6-Difluoro-3- [5- (2-hydroxy-phenyl) -4- (4-methoxyphenyl) -thiazol-2-ylmethoxy] -benzamide 2,6-Difluoro-3- [5- (3-hydroxy-phenyl) -4- (4-methoxyphenyl) -thiazol-2-ylmethoxy] -benzamide

Reaction scheme

Reagent (B)

Boronic acid 2-hydroxyphenyl Boronic acid 2-hydroxyphenyl

Quantities of A; B; C; D

Silica gel

60-120 M 60-120 M

Production

0.005 g, 3% white solid 0.02 g, 10% white solid

1H NMR (DMSOd6, 400 MHz)

δ 3.72 (s, 3H), 5.54 (s, 2H), 6.80 (m, 3H) 7,087.23 (m, 2H), 7.39-7.46 (m, 3H), 7.88 (br s, 1H), 8.17 (br s, 1H) and 9.90 (br s, 1H) δ 3.75 (s, 3H), 5.54 (s, 2H), 6.77 (m, 3H), 7.16 (m, 2H), 7.45 (m, 3H), 7.89 (br s, 1H), 8.17 (br s, 1H ) and 9.64 (br s, 1H)

HPLC Procedure Number, reaction time (minutes)

279

280

2,6-Difluoro-3- [5- (4-hydroxy-phenyl) -4- (4-methoxy-phenyl) -thiazol-2-methoxy] -benzamide

2,6-Difluoro-3- [5- (2-methoxy-phenyl) -4- (4-methoxy-phenyl) -thiazol2-ylmethoxy] -benzamide

Boronic acid 4-hydroxyphenyl

Boronic acid 2-methoxyphenyl

60-120 M

60-120 M

0.02 g, 10% white solid

0.019 g, 18% white solid

δ 3.74 (s, 3H), 5.52 (s, 2H), 6.78 (d, J = 8.40 Hz, 2H), 6.89 (d, J = 8.40 Hz, 2H), 7.13 (m, 3H), 7.37-7.45 ( m, 3H), 7.89 (br s, 1H), 8.17 (br s, 1H) and 9.79 (br s, 1H)

δ 3.70 (s, 3H), 3.72 (s, 3H), 5.54 (s, 2H), 6.85 (d, J = 8.80 Hz, 2H), 6.95 (m, 1H), 7.14-7.19 (m, 3H), 7.36 (d, J = 8.80 Hz, 2H), 7.44 (m, 2H), 7.87 (br s, 1H) and 8.16 (br s, 1H)

281

282

2,6-Difluoro-3- [5- (3-methoxy-phenyl) -4- (4-methoxy-phenyl) -thiazol2-ylmethoxy] -benzamide

2,6-Difluoro-3- [5- (4-methoxy-phenyl) -4- (4-methoxy-phenyl) -thiazol-2-methoxy] -benzamide

Boronic acid 4-methoxyphenyl

Boronic acid 4-methoxyphenyl

60-120 M

60-120 M

0.025 g, 24% white solid

0.018 g, 17% yellow solid

δ 3.69 (s, 3H), 3.75 (s, 3H), 5.55 (s, 2H), 6.89-6.96 (m,

δ 3.74 (s, 3H), 3.77 (s, 3H), 5.53 (s, 2H), 6.90 (d, J = 8.80

5H), 7.14 (m, 1H), 7.31 (m, 1H), 7.38-7.46 (m, 3H), 7.89 (br s, 1H) and 8.17 (br s, 1H)

Hz, 2H), 6.97 (d, J = 8.80 Hz, 2H), 7.13 (m, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.44 ( m, 1H), 7.89 (br s, 1H) and 8.16 (br s, 1H)

283

284

2,6-Difluoro-3- [5- (2-amino-phenyl) -4- (4-methoxy-phenyl) -thiazol-2-methoxy] -benzamide

2,6-Difluoro-3- [5- (3-amino-phenyl) -4- (4-methoxy-phenyl) thiazol-2-ylmethoxy] -benzamide

Boronic acid 4-aminophenyl

Boronic acid 4-aminophenyl

60-120 M

60-120 M

0.042 g, 41% light yellow solid

0.015 g, 14% light yellow solid

δ 3.72 (s, 3H), 4.94 (br s, 1H), 5.54 (s, 2H), 6.57 (t, J = 7.20 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.84 (m , 2H), 7.14 (m, 1H), 7.0 (m, 1H), 7.14 (m, 2H), 7.51 (m, 3H), 7.89 (br s, 1H) and 8.18 (br s, 1H)

δ 3.74 (s, 3H), 5.25 (br s, 1H), 5.53 (s, 2H), 6.44 (m, 1H), 6.56 (m, 2H), 6.89 (m, 2H), 7.03 (m, 1H) , 7.13 (m, 1H), 7.42 (m, 3H), 7.88 (br s, 1H) and 8.17 (br s, 1H)

285

286

2,6-Difluoro-3- [5- (4-amino-phenyl) -4- (4-methoxy-phenyl) -thiazol-2-methoxy] -benzamide

-3- [5-cyclopropyl-4- (4-methoxy-phenyl) -thiazol-2-ylmethoxy] - 2,6-difluor-benzamide

Boronic acid 4-aminophenyl

Boronic Cyclopropyl Acid

60-120 M

60-120 M

0.01 g, 9% brown solid

0.01 g, 10% white solid

287

2,6-Difluor-3 - [- 4- (4-methoxy-phenyl) -5-phenyl-thiazol-2-ylmethoxy] -benzamide

Boronic acid phenyl

230-400 M

0.02 g, 22%

Example 288: 2,6-Difluor-3- [4â € ™ - (4-methoxy-phenyl) - [4,5â € ™] bitiazolyl-2â € -ylmethoxy] -benzamide

4-tributylstanyl thiazole (0.16 g, 0.43 mmol) was added to a solution of 3- [5-bromo-4- (4-methoxy-phenyl) -thiazol-2-methylmethoxy] -2,6-difluoro-benzamide ( 0.20 g, 0.043 mmol) in 5 ml of anhydrous DMF and the reaction mixture was degassed for 10 minutes. Tetrakis palladium (triphenylphosphine) (0) (0.05 g, 0.043 mmol) was then added and the reaction mixture was heated at 120 ° C for 12 h under a nitrogen atmosphere. Then, the reaction mixture was cooled to room temperature, water (25 ml) was added and the compound was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400 M) using 10 ethyl acetate / hexane (40:60) as the eluent to obtain the title compound as a white solid (0.072g, 36%). 1H NMR (DMSO-d6, 400 MHz): δ3.80 (s, 3H), 5.56 (s, 2H), 7.01 (d, J = 8.80 Hz, 2H), 7.13 (m, 1H), 7.41-7.50 ( m, 4H), 7.90 (br s, 1H), 8.18 (br s, 1H) and 9.18 (s, 1H). MS ES + (460.32), HPLC (procedure II) Reaction time =

16.37 min.

Example 289: 3- [5-Cyano-4- (4-methoxy-phenyl) -thiazol-2-ylmethoxy] -2,6-difluoro-benzamide

CuCN (0.19 g, 2.19 mmol) was added to a solution of 3- [5-bromo-4- (4-methoxy-phenyl) -thiazol-2-ylmethoxy] -2,6-difluorobenzamide (0.20 g, 0.43 mmol) in pyridine (4.0 ml). The reaction mixture was heated at 150 ° C in microwave for 2 h. After completion of the reaction, the pH was adjusted to 3-4 with 1 N HCl solution and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on silica gel (60-120 M, 45% EtOAc-Hexane) to obtain the desired product (0.02 g, 11%) as a brown solid. 1HNMR (DMSO-d6, 400 MHz): δ 3.79 (s, 3H), 5.67 (s, 2H),

7.16 (m, 3H), 7.42 (m, 1H), 7.88 (br s, 1H), 8.03 (d, J = 8.80 Hz, 2H) and 8.19 (br s, 1H). MS ES + (402.07), HPLC (procedure I) Reaction time = 16.60 min.

Scheme 32: (a) Zn / acetic acid; (b) BBr3 / DCM

2,6-Difluor-3- [4- (4-methoxy-phenyl) -thiazol-2-ylmethoxy] -benzamide

Zn powder (2.0 g) was added to a solution of 3- [5-bromo-4- (4-methoxy-phenyl) -thiazol-2-ylmethoxy] -2,6-difluoro-benzamide

(2.0 g, 4.37 mmol) in 50 ml of acetic acid. The reaction mixture was heated at 120 ° C for 1 h. After

The reaction mixture was completed (TLC monitoring), water (100 ml) was added and the pH was adjusted to 8-9 with NaOH solution and extracted with ethyl acetate (3 x 150 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated to obtain the desired product (0.8 g, 50%) as a white solid.

Example 290: 2,6-Difluor-3- [4- (4-hydroxy-phenyl) -thiazol-2-ylmethoxy] -benzamide

A solution of 2,6-Difluoro-3- [4- (4-methoxy-phenyl) -thiazol-2-ylmethoxy] -benzamide (0.20 g, 0.53 mmol) in 15 ml of DCM was cooled to -78 ° C followed by the addition of BBr3 (0.2ml, 2.14 mmol). The reaction mixture was stirred at 25 ° C for 2 h. After completion of the reaction mixture (TLC monitoring), NaHCO3 solution (20 ml) was added at 0 ° C and extracted with ethyl acetate (3 x 150 ml). The combined organic was washed with water,

10 brine, dried (Na2SO4), filtered and concentrated, the residue was purified by column chromatography on silica gel (60-120 M) using ethylacetate / hexane (50:50) as eluent to obtain the title compound as a solid. light yellow (0.06 g, 31%). 1H NMR (DMSO-d6, 400 MHz): δ 5.55 (s, 2H), 6.83 (d, J = 8.40 Hz, 2H), 7.13 (m, 1H), 7.40 (m, 1H), 7.78 (d, J = 8.80 Hz, 2H), 7.88 (br s, 1H), 7.91 (s, 1H), 8.17 (br s, 1H) and 9.64 (br s, 1H). MS ES + (363.25), HPLC (procedure I) Reaction time = 14.57 min.

15 Scheme 33: (a) Thioacetamide; (b) NBS; (c) 2,6-Difluoro-3-hydroxybenzamide, K2CO3, DMF.

4- (2-Methyl-thiazol-4-yl) -benzonitrile

The compound was prepared following the general procedure as described in the preparation of 4- (420 Methoxyphenyl) -2-methyl-thiazole (Scheme 31).

4- (5-Bromo-2-bromomethyl-thiazol-4-yl) -benzonitrile

The compound was prepared following the general procedure as described in the preparation of 5-Bromo-2-bromomethyl-4- (4-methoxy-phenyl) -thiazole (Scheme 31).

Example 291: 3- [5-Bromo-4- (4-cyano-phenyl) -thiazol-2-ylmethoxy] -2,6-difluoro-benzamide

2,6-Difluoro-3-hydroxy-benzamide (0.20 g, 1.20 mmol) and potassium carbonate (0.58 g, 4.20 mmol) were added to a solution of 4- (5-Bromo-2-bromomethyl-thiazole-) 4-yl) -benzonitrile (0.43 g, 1.20 mmol) in 5 ml of anhydrous DMF. The reaction mixture was stirred at 25 ° C for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethylacetate / hexane (30:70) as eluent to obtain the title compound as a white solid. (0.35 g, 66%). 1H NMR (DMSO-d6, 400 MHz): δ 5.57 (s, 2H), 7.13 (m, 1H), 7.44 (m, 1H), 7.89 (br s, 1H), 8.0 (d, J = 8.40 Hz, 2H), 8.10 (d, J = 8.40 Hz, 2H) and 8.17 (br s, 1H). MS ES + (450.09), HPLC (procedure I) Reaction time = 16,127 min.

Scheme 34: (a) NH2OH.HCl, NaOH, EtOH; (b) Bromoacetyl bromide, (c) K2CO3, DMF.

Trifluoromethoxyphenyl -N-hydroxy-benzamide

Hydroxylamine hydrochloride (0.365 g, 5.0 mmol) and NaOH (0.212 g, 5.0 mmol) were added to a solution of 4-Trifluoromethoxybenzonitrile (1.0 g, 5.0 mmol) in EtOH (20 ml). The resulting reaction mixture was refluxed.

15 for 15h. After completion of the reaction (TLC monitoring), the mixture was concentrated, EtOH was added and filtered. The filtrate was evaporated in vacuo and used as such for the next step (crude production 12.0 g, 66%).

5-Bromomethyl-3- (Tri Fluoro Methoxy Phenyl) - [1,2,4] oxadiazole

Bromoacetyl bromide (2.0 ml, 23.12 mmol) was added to trifluoromethoxy-N-hydroxybenzamide (0.40 g, 5.86 mmol) and K2CO3 (0.87 g, 6.0 mmol). The reaction mixture was heated at 100 ° C for 15 min. After completion of the reaction mixture (TLC monitoring), water (100 ml) was added and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on silica gel (60-120 M, 3% EtOAc-Hexane) to obtain the desired product (0.25 g, 43%)

25 as a white solid.

Example 292: 3- [3- (4-Trifluoromethoxy-phenyl) - [1,2,4] oxadiazol-5-ylmethoxy] -2-fluoro-benzamide

2,6-Difluoro-3-hydroxybenzamide (0.18 g, 1.0 mmol) and potassium carbonate (0.516 g, 3.7 mmol) were added to a solution of 5-Bromomethyl-3- (Trifluoromethoxyphenyl) - [1,2, 4] oxadiazole (0.24 g, 1.0 mmol) in 2.5 ml of anhydrous DMF. The reaction mixture was stirred at 25 ° C for 24 h under nitrogen atmosphere. The reaction mixture was

evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate / hexane (50:50) as eluent to obtain the title compound as a white solid (0.090 g, 20 %). 1H NMR (DMSO-d6,400 MHz): δ 5.71 (s, 2H), 7.15 (t, J = 7.60 Hz, 1H), 7.40 (m, 1H),

7.60 (d, J = 8.0 Hz, 2H), 7.91 (br s, 1H), 8.15 (d, J = 8.40 Hz, 2H) and 8.18 (brs, 1H). MS ES + (41628), HPLC (procedure I), Reaction time = 16.79 min

Scheme 35:

4-Chloromethyl-2- (4-methoxy-phenyl) -oxazola (general procedure)

10 4-Methoxybenzamide (0.30 g, 1.90 mmol) was added to a solution of 1.3 dichloroacetone (0.504 g, 3.90 mmol) in toluene (5 ml). The reaction mixture was heated at 120 ° C for 1 h. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified on silica gel (230-400 M, 15% EtOAc-Hexane) to obtain the desired product

(0.37 g, 83%).

Example 293: 2,6-Difluor-3- [2- (4-methoxy-phenyl) -oxazol-4-ylmethoxy] -benzamide

2,6-Difluor-3-hydroxy-benzamide (0.077 g, 0.40 mmol) and potassium carbonate (0.216 g, 1.50 mmol) were added to a solution of 4-Chloromethyl-2- (4-methoxy-phenyl) -oxazola (0.100 g, 0.4mmol) in 2 ml of anhydrous DMF. The reaction mixture was stirred at 25 ° C for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethylacetate / hexane (50:50) as eluent to obtain the title of the compound as a solid. white (0.044 g, 27%). 1H NMR (DMSO-d6, 400 MHz): δ 4.01 (s, 3H), 5.12 (s, 2H), 7.10 (m, 3H), 7.40 (m, 1H), 7.85 (br s, 1H), 7.93 ( d, J = 8.80 Hz, 2H), 8.13 (br s, 1H) and 8.25 (s, 1H). MS ES + (361.16), HPLC (procedure I) Reaction time =

15.47 min.

Example 294: 3- [2- (4-Chloro-phenyl) -oxazol-4-ylmethoxy] -2; 6-difluoro-benzamide

2,6-Difluor-3-hydroxy-benzamide (0.15 g, 0.78 mmol) and potassium carbonate (0.363 g, 2.60 mmol) were added to a solution of 4-Chloromethyl-2- (4-chloro-phenyl) -oxazola (0.20 g, 0.87 mmol) in 2 ml of anhydrous DMF. The reaction mixture was stirred at 25 ° C for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M)

using ethyl acetate / hexane (50:50) as eluent to obtain the title compound as a white solid (0.10 g, 31%). 1H NMR (DMSO-d6, 400 MHz): δ 5.14 9s, 2H), 7.12 (t, J = 9.20 Hz, 1H), 7.40 (m, 1H), 7.63 (d, J = 8.40, 2H),

7.85 (br s, 1H), 8.0 (d, J = 8.40 Hz, 2H), 8.13 (br s, 1H) and 8.36 (s, 1H). MS ES + (365.13), HPLC (procedure I) Reaction time = 16.36 min.

Example 295: 2,6-Difluor-3- (2-p-tolyl-oxazol-4-ylmethoxy) -benzamide

2,6-Difluoro 3-hydroxy-benzamide (0.08 g, 0.50 mmol) and potassium carbonate (0.233g, 1.50 mmol) were added to a solution of 4-Chloromethyl-2-p-tolyl-oxazola (0.10 g , 0.50 mmol) in 2 ml of anhydrous DMF. The reaction mixture was stirred at 25 ° C for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness.

10 under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate / hexane (50:50) as eluent to obtain the title compound as a white solid (0.03 g, 18%). 1H NMR (DMSO-d6, 400 MHz): δ 2.37 (s, 3H), 5.13 (s, 2H), 7.11 (m, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.41 (m, 1H ), 7.88 (m, 3H), 8.12 (br s, 1H) and 8.29 (s, 1H). MS ES + (345.24), HPLC (procedure I) Reaction time = 16.07 min.

Scheme 36: 2- (4-Methoxy-phenyl) -4,5-dimethyl-oxazola (general procedure)

A mixture of 3-Chloro-2-butanone (2.1g, 10.0 mmol) and 4-methoxybenzamide (0.30 g, 1.0 mmol) was heated at 115 ° C for 15 h under a nitrogen atmosphere. After completion of the reaction mixture (monitoring with

20 TLC), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified on silica gel (230-400 M, 20% EtOAc-Hexane) to obtain the desired product (0.17 g, 42%) as a solid white. The corresponding chlorine derivative was also prepared by the same general procedure.

4-Bromomethyl-2- (4-methoxy-phenyl) -5-methyl-oxazola

NBS (7.43 g, 41.74 mmol) was added to the solution of 4-Bromomethyl-2- (4-methoxy-phenyl) -5-methyl-oxazola (0.17 g, 0.80 mmol) in acetonitrile (4.0 ml). The reaction mixture was stirred at 25 ° C for 1 h under nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), the reaction mixture was cooled to 0 ° C and 2 ml of water was added. The resulting precipitate was filtered and dried to obtain the desired product (0.11 g, 46%). The corresponding chlorine derivative was also prepared by the same general procedure.

Example 296: 2,6-Difluor-3- [2- (4-methoxy-phenyl) -5-methyl-oxazol-4-ylmethoxy] -benzamide

2,6-Difluoro-3-hydroxy-benzamide (0.061 g, 0.35 mmol) and potassium carbonate (0.171 g, 1.05 mmol) were added to a solution of 4-Bromomethyl-2- (4-methoxy-phenyl) -5-methyl-oxazola (0.10 g, 0.35 mmol) in 2 ml of anhydrous DMF. The reaction mixture was stirred at 25 ° C for 24 h under a nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethylacetate / hexane (50:50) as eluent to obtain the title compound as a white solid. (0.117 g, 87%). 1H NMR (DMSO-d6, 400 MHz): δ 2.42 (s, 3H), 3.82 (s, 3H), 5.06 (s, 2H), 7.10 (m, 3H),

7.37 (m, 1H), 7.86 (m, 3H) and 8.13 (br s, 1H). MS ES + (375.12), HPLC (procedure I) Reaction time = 15.78 10 min.

Example 297: 3- [2- (4-Chloro-phenyl) -5-methyl-oxazol-4-ylmethoxy] -2,6-difluoro-benzamide

2,6-Difluor-3-hydroxy-benzamide (0.072 g, 0.42 mmol) and potassium carbonate (0.203 g, 1.20 mmol) were added to a solution of 4-Bromomethyl-2- (4-chloro-phenyl) -5-methyl-oxazola (0.12 g, 0.42 mmol) in 2 ml of anhydrous DMF. The reaction mixture 15 was heated at 25 ° C for 24 h under a nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60120 M) using ethylacetate / hexane (50:50) as eluent to obtain the title compound as a white solid.

(0.01 g, 6%). 1H NMR (DMSO-d6, 400 MHz): δ 2.49 (s, 3H), 5.09 (s, 2H), 7.11 (m, 1H), 7.38 (m, 1H), 7.60 (d, J = 8.40

Hz, 2H), 7.85 (br s, 1H), 7.95 (d, J = 8.40 Hz, 2H) and 8.13 (br s, 1H). MS ES + (379.25), HPLC (procedure I) Reaction time 20 = 16.71 min.

Scheme 37: (a) PBr3; (b) SnCl2.2H2O; (c) 2-benzoyloxyacetyl chloride; (d) Lawesson's reagent; (e) BBr3; (f) 2,6-difluor-3-hydroxy benzamide, K2CO3, DMF; (g) Suzuki or Stannilo conditions.

2,5-Dibromo-3-nitro-pyridine

PBr3 (6.60 ml, 68.49 mmol) was added to a solution of 5-Bromo-3-nitro-pyridin-2-ol (10.0 g, 45.66 mmol) in 70 ml of toluene and 7 ml of DMF and the mixture of Reaction was heated at 120 ° C for 20 min under nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), water (100 ml) was added and extracted with ethyl acetate (3 x 200 ml). The organic combined was washed with water, brine, dried (Na2SO4), filtered and concentrated to obtain the desired product (10.30 g, 80.03%).

2,5-Dibromo-pyridin-3-ilamine

10 SnCl2 (24.0 g, 106.42 mmol) was added slowly to the solution of 2,5-Dibromo-3-nitro-pyridine (10.30 g, 35.47 mmol) in 100 ml of ethanol. The reaction mixture was heated at 80 ° C for 2 h. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. Water (250 ml) was added, the white solid was separated, the reaction mixture was basified with NaOH solution. To this the 250 ml of ethyl acetate were added. It was filtered and the residue was washed with ethyl acetate, the layers are separated,

15 dried (Na2SO4), filtered, concentrated to obtain the desired product (6.20g, 67.39%).

2-Benzyloxy-N- (2,5-dibromo-pyridin-3-yl) -acetamide

Triethylamine (5.3 ml, 37.53 mmol) was added to the solution of 2,5-Dibromo-pyridin-3-ylamine (8.6 g, 34.12 mmol) in 50 ml of DCM. The reaction mixture was cooled to 0 ° C. To this was added the solution of 2-benzyloxyacetyl chloride (7.45 g, 20 40.95 mmol) in 35 ml of DCM. The reaction mixture was stirred at 25 ° C for 12 hr. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate / hexane

(10:90) as eluent to obtain the title compound (3.2 g, 24.17%).

2-Benzyloxymethyl-5-bromo-thiazolo [5,4-b] pyridine

Lawesson's reagent (1.51g, 3.74 mmol) was added to the solution of 2-Benzyloxy-N- (2,5-dibromo-pyridin-3-yl) acetamide (2.5 g, 6,248 mmol) in 30 ml of toluene . The reaction mixture was heated at 120 ° C for 2 h. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60

30 120 M) using ethyl acetate / hexane (5:95) as eluent to obtain the title compound (1.60 g, 76.5%).

5-Bromo-2-bromomethyl-thiazolo [5,4-b] pyridine

A solution of 2-Benzyloxymethyl-5-bromo-thiazolo [5,4-b] pyridine (1.60 g, 4.77 mmol) DCM (15 ml) was cooled to -78 ° C followed by the addition of BBr3 (2.27 ml, 23.86 mmol). The reaction mixture was stirred at 25 ° C for 2 h. After completion of the reaction mixture (TLC monitoring), NaHCO3 solution (20 ml) was added to

0 ° C and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated to obtain the desired product (2.0 g, crude production).

Example 298: 3- (5-Bromo-thiazolo [5,4-b] pyridin-2-ylmethoxy) -2,6-difluoro-benzamide

5 2,6-Difluor-3-hydroxy-benzamide (1.01 g, 5.84 mmol) and potassium carbonate (3.09 g, 22.72 mmol) were added to a solution of 5-bromo-2-bromomethyl-thiazolo [5, 4-b] pyridine (2.0 g, 6.493mmol) in 10 ml of anhydrous DMF. The reaction mixture was stirred at 25 ° C for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60120 M) using ethylacetate / hexane (50:50) as eluent to obtain the title compound (1.80 g, 69% ). 1 HOUR

10 NMR (DMSO-d6, 400 MHz): δ 5.72 (s, 2H), 7.12 (t, J = 7.60 Hz, 1H), 7.39 (m, 1H), 7.90 (br s, 1H), 8.18 (br s , 1H) and

8.80 (m, 2H). MS ES + (402.08), HPLC (procedure I) Reaction time = 15.50 min.

3- (5-Allyl-thiazolo [5,4-b] pyridin-2-ylmethoxy) -2,6-difluoro-benzamide

Alil tributiltin (0.26 ml, 0.86 mmol) was added to a solution of 3- (5-bromo-thiazolo [5,4-b] pyridin-2-ylmethoxy) -2,6-difluoro

15 benzamide (0.15 g, 0.37 mmol) in 5 ml of anhydrous DMF and the reaction mixture was degassed for 10 minutes. Tetrakis palladium (triphenylphosphine) (0) (0.007 g, 0.0056 mmol) was then added and the reaction mixture was heated at 120 ° C for 1 h under the nitrogen atmosphere. Then the reaction mixture was cooled to room temperature, water (25 ml) was added and the compound was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. He

The compound was purified by column chromatography on silica (100-200 M) using ethyl acetate / Hexane (60:40) as eluent to obtain the title compound (0.10 g, 75%).

Example 299: 2,6-Difluor-3- (5-propyl-thiazolo [5,4-b] pyridin-2-ylmethoxy) -benzamide

Pd-C (10%, 5 mg) was added to a solution of 3- (5-Allyl-thiazolo [5,4-b] pyridin-2-ylmethoxy) -2,6-difluoro-benzamide (0.018

25 g, 0.049 mmol) in 5 ml of anhydrous methanol and the reaction mixture was stirred at 25 ° C for 12 h under nitrogen atmosphere. The reaction mixture was filtered on the celite bed and the filtrate was evaporated to dryness under reduced pressure to obtain the title compound as a white solid (0.0078 g, 43%). 1H NMR (DMSO-d6, 400 MHz); δ 0.91 (m, 3H), 1.65 (m, 2H), 2.74 (m, 2H), 5.69 (s, 2H), 7.12 (m, 1H), 7.39 (m, 1H), 7.90 (br s, 1H) , 8.18 (br s, 1H), 8.27 (br s, 1H) and 8.52 (br s, 1H). MS ES + (364.11), HPLC (procedure I) Time of

30 reaction = 15.85 min.

Example 300: 2,6-Difluoro-3- [5- (1-methyl-1H-imidazol-2-yl) -thiazolo [5,4-b] pyridin-2-ylmethoxy] -benzamide

1-Methyl-2-tributylstannanyl-1 H -imidazole (0.120 g, 0.32 mmol) was added to a solution of 3- (5-bromo-thiazolo [5,4b] pyridin-2-ylmethoxy) -2,6- difluor-benzamide (0.10 g, 0.24 mmol) in 5 ml of anhydrous DMF and the reaction mixture was degassed for 10 minutes. Tetrakis palladium (triphenylphosphine) (0) (0.004 g, 0.0037 mmol) was then added and the reaction mixture was heated at 120 ° C for 12 h under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature, water (25 ml) was added and the compound was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400 M) using ethyl acetate / hexane (40:60) as eluent to obtain the title compound as a solid brick red (0.020 g, 20%). 1H NMR (DMSO-d6, 400 MHz): δ 3.14 (s, 3H), 5.67 (s, 2H), 7.07 (m, 1H), 7.28-7.37 (m, 2H), 7.87 (m, 2H), 8.28

10 (s, 1H), 8.53 (s, 1H) and 8.75 (br s, 1H). MS ES + (402.22), HPLC (procedure I) Reaction time = 12.05 min.

Example 301: 2,6-Difluor-3- [5- (1-methyl-1H-pyrrol-2-yl) -thiazolo [5,4-b] pyridin-2-ylmethoxy] -benzamide

1-Methyl-2-tributilestannanyl-1H-pyrrola (0.120 g, 0.32 mmol) was added to a solution of 3- (5-bromo-thiazolo [5,4b] pyridin-2-ylmethoxy) -2,6- difluor-benzamide (0.10 g, 0.24 mmol) in 5 ml of anhydrous DMF and the reaction mixture was degassed for 10 minutes. Tetrakis palladium (triphenylphosphine) (0) (0.004 g, 0.0037 mmol) was then added and the reaction mixture was heated at 120 ° C for 12 h under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature, water (25 ml) was added and the compound was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400 M) using

Ethyl acetate / Hexane (40:60) as eluent to obtain the title compound as a yellow solid (0.032 g, 32%). 1H NMR (DMSO-d6, 400 MHz): δ 3.73 (s, 3H), 5.72 (s, 2H), 6.13 (br s, 1H), 6.40 (br s, 1H), 6.97 (s, 1H), 7.12 (m, 1H), 7.42 (m, 1H), 7.90 (br s, 1H), 8.18 (br s, 1H), 8.48 (s, 1H) and 8.75 (s, 1H). MS ES + (401.26), HPLC (procedure I) Reaction time = 15.61 min.

Example 302: 2,6-Difluor-3- (5-phenyl-thiazolo [5,4-b] pyridin-2-ylmethoxy) -benzamide

Boronic acid phenyl (0.12 g, 0.99 mmol) and potassium phosphate (0.13 g, 0.59 mmol) were added to a solution of 3- (5-bromo-thiazolo [5,4-b] pyridin-2-ylmethoxy) -2,6-difluor-benzamide (0.20 g, 0.49 mmol) in 4 ml of DMF and water (2.0 ml). The reaction mixture was degassed for 10 minutes followed by the addition of palladium dichlorobis (tri phenyl phosphine)

(II) (0.070 g, 0.099 mmol). The reaction mixture was heated at 120 [deg.] C. for 2 hours under a nitrogen atmosphere.

After completion of the reaction mixture (TLC monitoring), water (25 ml) was added and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on silica gel (100-200 M, 60% EtOAc-Hexane) to obtain the desired product (0.080 g, 41%) as a light brown solid. 1H NMR (DMSO-d6, 400 MHz): δ 5.74 (s, 2H), 7.10 (m, 1H), 7.41-7.56 (m, 4H), 7.85 (m, 3H), 8.19 (m, 1H), 8.71 (br s, 1H) and 8.98 (br s, 1H). MS ES + (398.09), HPLC

35 (procedure I) Reaction time = 16.07 min.

Scheme 38:

4-Chloromethyl-2-p-tolyl-thiazole (Representative example)

5 4-Methylthiobenzamide (0.50 g, 3.31 mmol) was added to a solution of 1.3 dichloroacetone (0.84 g, 6.62 mmol) in toluene (5 ml) and the reaction mixture was heated at 120 ° C for 1 h . After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified on silica gel (230-400 M, 15% EtOAc-Hexane) to obtain the desired product

(0.49 g, 67%). The other derivatives were also prepared by the same general procedure.

10 3- (4-Chloromethyl-thiazol-2-yl) -phenol

3-Hydroxythiobenzamide (0.25 g, 1.63 mmol) was added to a solution of 1.3 dichloroacetone (0.42 g, 3.26 mmol) in toluene (5 ml) and the reaction mixture was heated at 120 ° C for 1 h. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness, water was added and

15 extracted with EtOAc (x 3). The combined organic was dried with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on silica gel (230-400 M, 10% EtOAc-Hexane) to obtain the desired product (0.14 g, 38%).

Scheme 39: (a) acetamide 2-benzyloxy, DMF; (b) BBr3, DCM; (c) 2,6-Difluor-3-hydroxybenzamide, K2CO3, DMF.

2-Benzyloxymethyl-4- (4-chloro-phenyl) -oxazola (representative procedure)

2-Bromo-1- (4-chlorophenyl) -ethanone (2.0 g, 8.56 mmol) was added to a solution of 2-Benzyloxy-acetamide (1.40 g,

8.56 mmol) in 4 ml of DMF and the reaction mixture was heated at 130 ° C for 6 h under nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), water (25 ml) was added and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on silica gel (230-400 M, 10% EtOAc-Hexane) to obtain the desired product (1: 1 g, 44%).

2-Bromomethyl-4- (4-chloro-phenyl) -oxazola (representative procedure)

A solution of 2-Benzyloxymethyl-4- (4-chloro-phenyl) -oxazola (1.10 g, 3.6 mmol) in 10 ml of DCM was cooled to -78 ° C followed by the addition of BBr3 (1.76 ml, 18.0 mmol) . The reaction mixture was stirred at 25 ° C for 2 h. After completion of the reaction mixture (TLC monitoring), NaHCO3 solution (20 ml) was added at 0 ° C and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and

15 concentrate to obtain the desired product (0.5g, 49%, raw).

Examples 303-310 (Table Q)

The compounds of examples 303-310 were synthesized according to the following general procedure: 2,6-Difluor-3-hydroxy-benzamide (B) and potassium carbonate (C) were added to a reagent solution (A ) in 2 ml of anhydrous DMF. The reaction mixture was stirred at 25 ° C for 24 h under nitrogen atmosphere. The mixture of

The reaction was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate / hexane (50:50) as eluent to obtain the product compound.

Table Q

Example

303 304

Product

2,6-Difluor-3- [2-p-tolyl-thiazol-4-ylmethoxy] - benzamide 2,6-Difluor-3- [2- (4-hydroxy-phenyl) -thiazol-4-methoxy] -benzamide

Reaction scheme

Reagent (A)

4-Chloromethyl-2-p-tolyl-thiazole 4- (4-Chloromethyl-thiazol-2-yl) -phenol

Quantities of A; B; C

Production

0.022 g, 13% white solid 0.012 g, 3% white solid

1H NMR (DMSO-d6, 400 MHz)

HPLC Procedure Number, reaction time (minutes)

305

306

2,6-Difluor-3- [2- (fluorine-phenyl) -thiazol-4-ylmethoxy] - benzamide

-3- [2- (4-Chloro-phenyl) -thiazol-4-ylmethoxy] - 2,6-Difluorobenzamide

4-Chloromethyl-2- (4-fluorine-phenyl) -thiazole

4-Chloromethyl-2- (4-chloro-phenyl) -thiazole

0.06 g, 25% white solid

0.035 g, 34% white solid

307

308

2,6-Difluor-3- [2- (4-trifluoromethoxy-phenyl) -thiazol-4-ylmethoxy] - benzamide

2,6-Difluor-3- [2- (3-hydroxy-phenyl) -thiazol-4-ylmethoxy] - benzamide

4-Chloromethyl-2- (4-trifluoromethoxy-phenyl) -thiazole

3- (4-Chloromethyl-thiazol-2-yl) -phenol

0.008 g, 16% white solid

0.014 g, 7% white solid

309

310

3- [4- (4-Chloro-phenyl) -oxazol-2-ylmethoxy] -2,6-Difluorobenzamide

2,6-Difluor-3- (4-phenyl-oxazol-2-ylmethoxy] - benzamide

2-Bromomethyl-4- (4-chloro-phenyl) -oxazola

2-Bromomethyl-4-phenyl-oxazola

0.02 g, 22% white solid

0.04 g, 14% light yellow solid

Scheme 40: (a) Acetamide; (b) NBS, AIBN, CCl4; (c) 2,6-Difluoro-3-hydroxybenzamide, K2CO3, DMF; (d) Zn / Acetic acid; (e) BBr3, DCM.

4- (4-Methoxy-phenyl) -2-methyl-oxazola

Prepared as per the procedure mentioned in Scheme 31.

5-Bromo-2-bromomethyl-4- (4-methoxy-phenyl) -oxazola

Prepared as per the procedure mentioned in Scheme 31.

3- [5-Bromo-4- (4-methoxy-phenyl) -oxazol-2-ylmethoxy] -2,6-difluoro-benzamide

Prepared as per the procedure mentioned in Scheme 31.

Example 311: 2,6-Difluor-3- [4- (4-methoxy-phenyl) -oxazol-2-ylmethoxy] -benzamide

50 mg of Zn powder was added to a solution of 3- [5-Bromo-4- (4-methoxy-phenyl) -oxazol-2-ylmethoxy] -2,6-difluoro

10 benzamide (0.06g, 0.13 mmol) in 5 ml of acetic acid. The reaction mixture was heated at 120 ° C for 1 h. After completion of the reaction mixture (TLC monitoring), water (25 ml) was added and the pH was adjusted to 8-9 with NaOH solution and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated to obtain the desired product (0.02 g, 40%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 3.77 (s, 3H), 5.36 (s, 2H), 6.99 (d, J = 8.40 Hz, 2H), 7.12 (m, 1H),

15 7.37 (m, 1H), 7.71 (d, J = 8.40 Hz, 2H), 7.87 (br s, 1H), 8.15 (br s, 1H) and 8.56 (s, 1H). MS ES + (361.24), HPLC (procedure I) Reaction time = 15.41 min.

Example 312: 2,6-Difluor-3- [4- (4-methoxy-phenyl) -oxazol-2-ylmethoxy] -benzamide

A solution of 2,6-Difluor-3- [4- (4-methoxy-phenyl) -oxazol-2-ylmethoxy] -benzamide (0.20 g, 0.55 mmol) in 10 ml of DCM

20 was cooled to -78 ° C followed by the addition of BBr3 (0.10 ml, 2.20 mmol). The reaction mixture was stirred at 25 ° C for 2 h. After completion of the reaction mixture (TLC monitoring), NaHCO3 solution (20 ml) was added at 0 ° C and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate / hexane (50:50) as eluent to obtain the title compound as a

25 white solid (0.012 g, 6%). 1H NMR (DMSO-d6, 400 MHz): δ 5.35 (s, 2H), 6.82 (d, J = 8.40 Hz, 2H), 7.14 (m, 1H),

7.38 (m, 1H), 7.58 (d, J = 8.40 Hz, H), 7.87 (br s, 1H), 8.15 (br s, 1H), 8.47 (s, 1H) and 9.63 (s, 1H). MS ES + (347.22), HPLC (procedure 1) Reaction time = 14.00 min.

(f) 2,6-Difluoro-3-hydroxybenzamide, K2CO3, DMF.

4- (4-Methoxy-phenyl) -2-methyl-thiazole

A mixture of thioacetamide (16.0 g, 213 mmol) and 2-Bromo-1- (4-methoxy-phenyl) -ethanone (4.0 g, 17.5 mmol) was heated at 140 ° C for 24 h under nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), water (25 ml) was added and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on gel

10 silica (230-400 M, 1% EtOAc-Hexane) to obtain the desired product (2.5 g, 69%).

5-Bromo-4- (4-methoxy-phenyl) -2-methyl-thiazole

NBS (4.32 g, 24.3 mmol) and AIBN (0.4 g, 2.43 mmol) were added to the solution of 5-Bromo-2-bromomethyl-4- (4-methoxyphenyl) thiazole (5.0 g, 24.3 mmol) in 20 ml of CCl4. The reaction mixture was heated at 100 ° C for 2 h under

15 atmosphere of nitrogen. After completion of the reaction mixture (TLC monitoring), it was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400 M) using 1% ethyl acetate / hexane as eluent to obtain the desired product (4.0 g, 58%).

4- (4-Methoxy-phenyl) -2-methyl-thiazola-5-carbonitrile

20 CuCN (3.10 g, 35.2 mmol) was added to a solution of 5-Bromo-4- (4-methoxy-phenyl) -2-methyl-thiazole (2.0 g, 7.0 mmol) in 15 ml of pyridine and the reaction mixture was heated at 150 ° C in microwave for 2 h. After completion of the reaction, the pH was adjusted to 3-4 with 1 N HCl solution and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on silica gel (60-120 M, 12% EtOAc-Hexane) to obtain the desired product (1.5 g, 92%) as

25 a white solid.

 Methyl esters of carboxylic acid-4- (4-Methoxy-phenyl) -2-methyl-thiazole-5

Dry HCl gas was passed to a solution of 4- (4-Methoxy-phenyl) -2-methyl-thiazola-5-carbonitrile (0.50 g, 2.1 mmol) in 15 ml of methanol for 1 h at 0 ° C. The mixture of reaction was stirred at 25 ° C for 24 h. After completion of the reaction mixture (TLC monitoring), it was evaporated to dryness under reduced pressure. Water (50 ml) was added and the pH was adjusted to 7-8 with NaHCO3 solution and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated to obtain the desired product (0.25g, 44%) as a white solid.

Methyl esters of carboxylic acid-2-Bromomethyl-4- (4-methoxy-phenyl) -thiazole-5

NBS (0.16 g, 0.94 mmol) and AIBN (0.015 g, 0.094 mmol) were added to the solution of methyl esters of carboxylic acid 4- (4-Methoxy-phenyl) -2-methyl-thiazole-5 ( 0.25 g, 0.94 mmol) in 20 ml of CCl4. The reaction mixture was stirred at 100 ° C for 2 h. After completion of the reaction mixture (TLC monitoring), it was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on 15 silica (230-400 M) using 10% ethyl acetate / hexane as eluent to obtain the desired product (0.078 g, 24%).

Example 313: Methyl esters of carboxylic acid 2- (3-Carbamoyl-2,4-difluoro-phenoxymethyl) -4- (4-methoxy-phenyl)

tiazole-5

20 2,6-Difluoro-3-hydroxy-benzamide (0.025 g, 0.14 mmol) and potassium carbonate (0.07 g, 0.50 mmol) were added to a solution of methyl esters of carboxylic acid-2-Bromomethyl -4- (4-methoxy-phenyl) -thiazole-5 (0.05 g, 0.14 mmol) in 2 ml of anhydrous DMF. The reaction mixture was stirred at 25 ° C for 24 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60120 M) using ethylacetate / hexane (50:50) as eluent to obtain the title product as a white solid.

25 (0.025g, 40%). 1H NMR (DMSO-d6, 400 MHz): δ 3.76 (s, 3H), 3.81 (s, 3H), 5.60 (s, 2H), 7.01 (d, J = 8.40 Hz, 2H), 7.12 (m, 1H ), 7.41 (m, 1H), 7.74 (d, J = 8.40 Hz, 2H), 7.90 (br s, 1H) and 8.18 (br s, 1H). MS ES + (435.06), HPLC (procedure I) Reaction time = 15.86 min.

Scheme 42: (a) triflic anhydride, pyridine, DCM; (b) 2,6-Difluoro-3- [5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1Hinden-2-ylmethoxy] -benzamide, Pd catalyst , Potassium Phosphate; (c) H2, Pd-C

Trifluoromethanesulfonic acid cyclohex-1-enyl estero

 Pyridine (4.48 ml, 56.0 mmol) was added to a solution of cyclohexanone (5.0 g, 51 mmol) in 80 ml of DCM and the

The resulting reaction mixture was cooled to -78 ° C. It was added over a period of 1 h. the solution of triflic anhydride (7.40 ml, 56.0 mmol) in 30 ml of DCM to the reaction mixture. The reaction mixture was stirred at 25 ° C for 24 h. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was triturated with n-pentane and the decanted organic layer, dried (Na2SO4), filtered and concentrated to obtain the desired product (5.0 g, 42%).

Example 314: 3- (5-Cyclohex-1-enyl-1H-inden-2-ylmethoxy) -2,6-difluoro-benzamide

Cyclohex-1-enyl esters of trifluoromethanesulfonic acid (0.15 g, 0.60 mmol) and potassium phosphate (0.057 g, were added

0.20 mmol) to a solution of 2,6-Difluoro-3- [5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-inden-2-ylmethoxy ] benzamide (0.10 g, 0.20 mmol) in 3 ml of anhydrous DMF and water (1.5 ml). The reaction mixture was degassed for 10 minutes followed by the addition of palladium dichlorobis (triphenyl phosphine) (II) (0.02 g, 0.03 mmol). The reaction mixture was heated at 80 ° C for 1 h under nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), water (25 ml) was added and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on silica gel (230-400 M, 45% EtOAc-Hexane) to obtain the desired product (0.017g, 19%)

20 as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 1.63 (m, 4H), 2.20 (m, 2H), 2.45 (m, 2H), 5.67 (s, 2H), 6.29 (m, 1H), 7.12 (m , 1H), 7.37 (m, 1H), 7.57 (m, 2H), 7.90 (br s, 1H), 8.03 (d, J = 8.40 Hz, 1H) and 8.18 (br s, 1H). MS ES + (401.16), HPLC (procedure II) Reaction time = 14.13 min.

Example 315: 3- (5-Cyclohexyl-1H-inden-2-ylmethoxy) -2,6-difluoro-benzamide

25 Pd-C (10%, 100 mg) was added to a solution of 3- (5-Cyclohex-1-enyl-1H-inden-2-ylmethoxy) -2,6-difluoro-benzamide

(0.01 g, 0.25 mmol) in 5 ml of anhydrous methanol. The reaction mixture was stirred at 25 ° C for 48 h under hydrogen atmosphere. The reaction mixture was filtered on a bed of celite and evaporated to dryness under reduced pressure to obtain the title compound as a white solid (0.01 g, 10%). 1H NMR (DMSO-d6, 400 MHz); δ 1.40 (m, 6H), 1.72 (m, 4H), 2.63 (m, 1H), 5.66 (s, 2H), 7.09 (m, 1H), 7.35 (m, 2H), 7.83 (br s, 1H) , 7.89 (d, J =

30 8.40 Hz, 1H), 7.99 (d, J = 8.40 Hz, 1H) and 8.18 (br s, 1H). MS ES + (403.33), HPLC (procedure II) Reaction time = 18.76 min.

Cyclopentpent-1-enyl ester of trifluoromethanesulfonic acid

Pyridine (5.2 ml, 65.0 mmol) was added to a solution of cyclopentanone (5.0 g, 59 mmol) in 80 ml of DCM and the resulting reaction mixture was cooled to -78 ° C. Triflic anhydride solution (9.2 ml, 65.0 mmol) was added to the reaction mixture in 30 ml of DCM over a period of 1 h. The reaction mixture was stirred at 25 ° C for 24 h. After completion of the reaction mixture (TLC monitoring), the reaction mixture was

10 evaporated to dryness under reduced pressure. The residue was triturated with n-pentane and decanted, the dried organic layer (Na2SO4), filtered and concentrated to obtain the desired product (2.4 g, 22%).

Example 316: 3- (5-Cyclopent-2-enyl-1 H-inden-2-ylmethoxy) -2,6-difluoro-benzamide

Trichlorpent-1-enyl esters of trifluoromethanesulfonic acid (0.37g, 1.70 mmol) and potassium phosphate (0.14 g, were added

0.60 mmol) to a solution of 2,6-Difluoro-3- [5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-inden-2- ilmethoxy] benzamide (0.25 g, 0.56 mmol) in 7 ml of anhydrous DMF and water (3.5 ml). The reaction mixture was degassed for 10 minutes followed by the addition of palladium dichlorobis (triphenyl phosphine) (II) (0.05 g, 0.08 mmol). The reaction mixture was heated at 80 ° C for 1 h under nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), water (25 ml) was added and extracted with ethyl acetate (3 x 50 ml). The organic

The combined was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on silica gel (230-400 M, 45% EtOAc-Hexane) to obtain the desired product (0.14 g, 65%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 1.22 (m, 2H), 2.01 (m, 2H), 2.88 (m, 2H), 5.68 (s, 2H), 6.43 (s, 1H), 7.01 (t , J = 9.20 Hz, 1H), 7.37 (m, 1H), 7.67 (d, J = 8.40 Hz, 1H), 7.89 (br s, 1H), 7.94 (s, 1H), 8.07 (d, J = 8.40 Hz, 1H) and 8.18 (br s, 1H). MS ES + (387.15), HPLC (procedure II) Reaction time = 13.74 min.

25 Example 317: 3- (5-Cyclopentyl-1H-inden-2-ylmethoxy) -2,6-difluoro-benzamide

Pd-C (10%, 100 mg) was added to a solution of 3- (5-Cyclopent-1-enyl-1H-inden-2-ylmethoxy) -2,6-difluoro-benzamide

(0.05 g, 0.10 mmol) in 5 ml of anhydrous methanol. The reaction mixture was stirred at 25 ° C for 48 h under

hydrogen atmosphere. The reaction mixture was filtered on a bed of celite and evaporated to dryness under reduced pressure to obtain the compound as a white solid (0.005 g, 10%). 1H NMR (DMSO-d6, 400 MHz); δ

1.22 (m, 2H), 1.67 (m, 4H), 1.80 (m, 2H), 2.07 (m, 2H), 3.20 (m, 1H), 5.67 (s, 2H), 7.09 (m, 1H), 7.37 (m, 2H), 7.87 (m, 2H), 8.0 (m, 1H) and 8.18 (br s, 1H). MS ES + (389.12), HPLC (procedure II) Reaction time = 18.19 min.

Scheme 44 (Examples 318-320): (a) Lawesson's reagent; (b) substituted bromoacetophenones (c) LAH, THF; (d) PBr3, Toluene; (e) 2,6-Difluoro-3-hydroxybenzamide, K2CO3, DMF.

Ethylthio oxamate

Lawesson's reagent (24.15 g, 59.7 mmol) was added to the ethyloxamate solution (10.0 g, 85.30 mmol) in 120 ml of toluene and the reaction mixture was heated at 120 ° C for 12 h. After completion of the reaction mixture (TLC monitoring), it was evaporated to dryness under reduced pressure. The residue was

10 purified by column chromatography on silica (230-400 M) using ethyl acetate / hexane (5:95) as the eluent to obtain the title compound (1.8 g, 16%).

Ethyl ester of 4- (4-Trifluoromethyl-phenyl) -thiazole-2-carboxylic acid (Representative example)

Ethyl thio-oxamate (0.15 g, 1.14 mmol) was added to the solution of 2-Bromo-1- (4-trifluoromethyl-phenyl) -ethanone (0.50 g, 0.80

15 mmol) in 7 ml of ethanol. The reaction mixture was heated at 80 ° C for 2 h under nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), it was concentrated under reduced pressure, water (25 ml) was added and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on silica gel (230 400 M, 2% EtOAc-Hexane) to obtain the desired product (0.21 g, 76%). The other derivatives were also

20 prepared by the same general procedure.

[4- (4-Trifluoromethyl-phenyl) -thiazol-2-yl] -methanol

A solution of 4- (4-Trifluoromethyl-phenyl) -thiazole-2-carboxylic acid ethyl ester (0.21 g, was added dropwise

0.71 mmol) in 5 ml of THF to a frozen suspension of LAH (0.056 g, 1.40 mmol) in 8 ml of anhydrous THF. The

The reaction mixture was stirred at 25 ° C for 1 h. After completion of the reaction mixture (TLC monitoring), the reaction mixture was cooled to 0 ° C and lowered with 2.5 ml of water followed by the addition of 15% NaOH solution (2 ml) and finally 4 ml of water The resulting solution was filtered through celite bed and the filtrate was concentrated under reduced pressure. Water (50 ml) was added and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated to obtain the desired product (0.13 g, 70%). The other derivatives were also prepared by the same general method.

2-Bromomethyl-4- (4-trifluoromethyl-phenyl) -thiazole

PBr3 (0.072 ml, 0.752 mmol) was added to the solution of [4- (4-Trifluoromethyl-phenyl) -thiazol-2-yl] -methanol (0.13g, 0.50 mmol) in 2 ml of toluene and the mixture Reaction was heated at 120 ° C for 20 min under nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), water (25 ml) was added and

10 extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on silica gel (230-400 M, 1% EtOAc-Hexane) to obtain the desired product (0.04 g, 25%). The other derivatives were also prepared by the same general procedure.

Scheme 45 (Example 321): (a) MeOH, H2SO4; (b) SnCl2.2H2O, EtOH; (c) 2-benzyloxyacetyl chloride; (d) Lawesson's Reagent 15; (e) BBr3, DCM; (f) PBr3, toluene-DMF; (g) 2,6-Difluoro-3-hydroxybenzamide, K2CO3, DMF.

4-Chloro-3-nitro-benzoic acid methyl ester

H2SO4 (2ml, 37.02 mmol) was added to a solution of 4-chloro-3-nitrobenzoic acid (5.0 g, 24.81 mmol) in 50 ml of

20 methanol and the reaction mixture was heated at 70 ° C for 5 h. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. Water (50 ml) was added and extracted with ethyl acetate (3 x 50 ml). The combined organic was dried (Na2SO4), filtered and concentrated to obtain the desired product (5.04 g, 94%).

3-Amino-4-chloro-benzoic acid methyl ester

SnCl2.2H2O (26.0 g, 115.96 mmol) was added to a solution of 4-Chloro-3-nitro-benzoic acid methyl ester (5.0 g, 23.19 mmol) in 100 ml of ethanol and the reaction mixture It was heated at 80 ° C for 2 h. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. Water (100 ml) was added, the reaction mixture was basified with NaOH solution and extracted with hot EtOAc (3 x 250 ml). The combined organic was dried over Na2SO4, filtered and concentrated to obtain the desired product (3.0 g, 69%).

3- (2-Benzyloxy-acetylamino) -4-chloro-benzoic acid methyl ester

A solution of monobenzyl esters of carbonic acid (3.50 g, 21.0 mmol) in 50 ml of DCM and 0.50 ml of DMF was

10 cooled to -78 ° C followed by the addition of oxalyl chloride (11.79 ml, 105 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. After completion of the reaction mixture (TLC monitoring), it was concentrated to obtain 2-benzyloxyacetyl chloride (3.0 g, 96%). Triethylamine (2.47 ml, 17.78 mmol) was added to an ice-cold solution of methyl esters of 3-amino-4-chloro-benzoic acid in 10 ml of DCM followed by the addition of 2-benzyloxyacetyl chloride (3.0 g , 17.78 mmol) in 10 ml of DCM. The reaction mixture was stirred at

15-25 ° C for 12 hr. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The resiudo was purified by column chromatography on silica (60-120 M) using ethyl acetate / hexane (5:95) as eluent to obtain the title compound (1.70 g, 31%).

3- (2-Benzyloxy-thioacetylamino) -4-chloro-benzoic acid methyl ester

Lawesson's reagent (1.03 g, 2.50 mmol) was added to the solution of methyl esters of 3- (2-Benzyloxyacetylamino) -4-chloro-benzoic acid (1.70 g, 5.10 mmol) in 20 ml of toluene and The reaction mixture was heated at 120 ° C for 2 h. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on

25 silica (60-120 M) using ethyl acetate / hexane (5:95) as the eluent to obtain the title compound (1.20 g, 67%).

2-Benzyloxymethyl-benzothiazola-6-carboxylic acid methyl ester

 (0.12 g, 5.10 mmol) was added, part by part, to a methyl ester solution of 3- (2-Benzyloxy-thioacetylamino acid)

30 4-Chloro-benzoic acid (1.20 g, 3.40 mmol) in 8 ml of NMP. The reaction mixture was heated at 160 ° C for 3 h. After completion of the reaction mixture (TLC monitoring), it was poured into 150 ml of ice water and extracted with ethyl acetate (3 x 150 ml). The combined organic was dried (Na2SO4), filtered and concentrated to obtain the desired product. (1.07 g, 56%).

2-Hydroxymethyl-benzothiazola-6-carboxylic acid methyl ester

A 2-Benzyloxymethyl-benzothiazola-6-carboxylic acid methyl ester solution (0.10 g, 0.32 mmol) in 2 ml of DCM was cooled to -78 ° C followed by the addition of BBr3 (0.06 ml, 0.64 mmol ). The reaction mixture was stirred at 25 ° C for 2 h. After completion of the reaction mixture (TLC monitoring), NaHCO3 solution (20 ml) was added at 0 ° C and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with

Water, brine, dried (Na2SO4), filtered and concentrated to obtain the desired product (0.08 g, crude production).

2-Bromomethyl-benzothiazola-6-carboxylic acid methyl ester

PBr3 (0.06 ml, 0.60 mmol) was added to a solution of methyl esters of 2-Hydroxymethyl-benzothiazole-6-carboxylic acid (0.08 g, 0.40 mmol) in 5 ml of toluene and 1 ml of DMF. The reaction mixture was heated at 120 [deg.] C. for 20 min under a nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), water (25 ml) was added and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated to obtain the desired product (0.044 g, 36%).

10 Benzo [1,3] dioxola-5-carbonitrile

Dibromomethane (19.25 g, 110.0 mmol) and potassium carbonate (25.50 g, 184.90 mmol) were added to a solution of 3.4 Dihydroxybenzonitrile (5.0 g, 37.0 mmol) in 20 ml of DMF. The reaction mixture was heated at 120 [deg.] C. for 2 h under nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), the mixture

The reaction was cooled to room temperature. Water (50 ml) was added to the reaction mixture and the compound was extracted with ethyl acetate (3 x 100 ml). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure to obtain the title compound as a yellow solid.

(5.16 g, 94.8%).

N-Hydroxy-benzo [1,3] dioxola-5-carboxamidine

Hydroxylamine hydrochloride (4.68 g, 67.90 mmol) and NaOH (2.71 g, 67.9 mmol) were added to a solution of Benzo [1,3] dioxola-5-carbonitrile (5.0 g, 33.9 mmol) in EtOH (100 ml ). The resulting reaction was refluxed for 12 h. After completion of the reaction (TLC monitoring), the mixture was concentrated, EtOH was added and filtered. The filtrate was evaporated under reduced pressure and used as such for the next step.

25 (gross production 4.8 g, 78.68%).

3-Benzo [1,3] dioxol-5-yl-5-bromomethyl- [1,2,4] oxadiazole

Bromoacetyl bromide (0.22 g, 1.10 mmol) was added to N-Hydroxy-benzo [1,3] dioxola-5-carboxamidine (0.40 g,

0.55 mmol) and K2CO3 (0.38 g, 0.78 mmol). The reaction mixture was heated at 100 ° C for 15 min. After

The reaction mixture was completed (TLC monitoring), water (25 ml) was added and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on silica gel (60-120 M, 5% EtOAc-Hexane) to obtain the desired product (0.05 g, 31%).

Scheme 47 (Example 323): (a) Ethyl bromopyruvate, EtOH; (b) LAH, THF; (c) PBr3, toluene; (d) 2,6-Difluoro-3-hydroxybenzamide, K2CO3, DMF.

2- (4-Methoxy-phenyl) -thiazola-4-carboxylic acid ethyl ester

Triethylamine (0.41 ml, 2.98 mmol) was added followed by dropwise addition of ethyl bromopyruvate (0.56 ml, 4.40 mmol) to an ice cold solution of 4-methoxy-thiobenzamide (0.50 g, 2.98 mmol) in ethanol (25 ml) The reaction mixture was heated at 65 ° C for 12 h. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure, water (25 ml) was added and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and

15 concentrated. The crude residue was purified on silica gel (60-120 M, 10% EtOAc-Hexane) to obtain the desired product (0.38 g, 48%).

[2- (4-Methoxy-phenyl) -thiazol-4-yl] -methanol

A solution of 2- (4-Methoxy-phenyl) -thiazole-4-carboxylic acid ethyl ester (0.26 g, 0.98 mmol) in 5 ml of

THF 20 to an icy suspension of LAH (0.08 g, 2.07 mmol) in 10 ml of anhydrous THF. The reaction mixture was heated to 60 ° C for 1 h. After completion of the reaction mixture (TLC monitoring), the reaction mixture was cooled to 0 ° C, water (2.0 ml) was added followed by the addition of 15% NaOH solution (2 ml) and Finally, 4 ml of water. The resulting solution was filtered through celite bed and concentrated under reduced pressure; Water (25 mL) was added and extracted with ethyl acetate (3 x 50 mL). The combined organic was washed

25 with water, brine, dried (Na2SO4), filtered and concentrated to obtain the desired product (0.14 g, 64%).

4-Bromomethyl-2- (4-methoxy-phenyl) -thiazole

PBr3 (0.078 ml, 0.813 mmol) was added to a solution of [2- (4-Methoxy-phenyl) -thiazol-4-yl] -methanol (0.12 g, 0.50 mmol) in 3 ml of toluene and the mixture The reaction was heated at 120 ° C for 20 min under a nitrogen atmosphere. 30 After completion of the reaction mixture (TLC monitoring), water (25 ml) was added and extracted with

ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated to obtain the desired product (0.13 g, 84%).

Scheme 48 (Example 324): (a) propionic anhydride, K2CO3; (b) NBS, AIBN, CCl4; (c) 2,6-Difluoro-3-hydroxybenzamide, K2CO3, DMF.

3- (4-Chloro-phenyl) -S-ethyl- [1,2,4] oxadiazole

Propionic anhydride (0.75 mL, 5.79 mmol) was added to 4-Chloro-N-hydroxy-benzamide (0.50 g, 2.89 mmol) and K2CO3

(2.0 g, 14.48 mmol). The reaction mixture was heated at 100 ° C for 30 min. After completing the

10 reaction mixture (TLC monitoring), the reaction mixture was cooled to 0 ° C, water (25 ml) was added and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on silica gel (60-120 M, 5% EtOAc-Hexane) to obtain the desired product (0.29 g, 48%).

5- (1-Bromo-ethyl) -3- (4-chloro-phenyl) - [1,2,4] oxadiazole

NBS (0.24 g, 1.38 mmol) and AIBN (0.02 g, 0.0001 mmol) were added to a solution of 3- (4-Chloro-phenyl) -5-ethyl [1,2,4] oxadiazole (0.29 g, 1.38 mmol) in CCl4 (10 ml). The reaction mixture was heated at 100 ° C for 2 h under nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by chromatography of

20 column on silica (230-400 M) using 1% ethyl acetate / hexane as eluent to obtain the desired product (0.12 g, 30%).

Scheme 49 (Example 325): (a) PBr3, toluene (b) 2,6-difluoro-3-hydroxybenzamide, K2CO3, DMF.

4-Bromomethyl-5-methyl-2-phenyl-2H- [1,2,3] triazole

PBr3 (0.53 g, 1.90 mmol) was added to a solution of (5-Methyl-2-phenyl-2H- [1,2,3] triazol-4-yl) -methanol (0.25 g, 1.30 mmol) in 10 ml of toluene and the reaction mixture was heated at 120 ° C for 20 min under a nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), water (25 ml) was added and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated to obtain the desired product (0.30 g, 90%) as a yellow solid.

Scheme 50 (Example 326): (a) CuCN, Pyridine; (b) Hydroxylamine hydrochloride, ethanol; (c) chloroacetyl chloride, K2CO3; (d) 2,6-Difluoro-3-hydroxybenzamide, K2CO3, DMF.

Thiazola-2-carbonitrile

CuCN (1.09 g, 12.19 mmol) is added to a solution of 2-bromothiazole (1.0 g, 6.09 mmol) in 4 ml of pyridine. The reaction mixture was heated at 150 ° C for 3 h. After completion of the reaction, the pH was adjusted to 34 with 1 N HCl solution and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated to obtain the desired product (0.42 g, 63%).

N-Hydroxy-thiazola-2-carboxamidine

 Hydroxylamine hydrochloride (0.53 g, 7.60 mmol) and pyridine (0.27 g, 3.40 mmol) were added to a solution of thiazole 2-carbonitrile (0.42 g, 3.80 mmol) in EtOH (20 ml). The resulting reaction mixture was refluxed for 15h. After completion of the reaction (TLC monitoring), the mixture was concentrated, EtOH was added and filtered. The filtrate was evaporated under reduced pressure and used as such for the next step (crude production 0.50 g, 91% crude production).

5-Chloromethyl-3-thiazol-2-yl- [1,2,4] oxadiazole

Chloroacetyl Chloride (5.0 ml, 44.5 mmol) was added to N-Hydroxy-thiazola-2-carboxamidine (0.50 g, 3.49 mmol) and K2O3 (1.0 g 7.20 mmol). The reaction mixture was heated at 100 ° C for 15 min. After completion of the reaction mixture (TLC monitoring), water (25 ml) was added and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The raw residue was

30 purified on silica gel (230-400 M, 10% EtOAc-Hexane) to obtain the desired product (0.18 g, 25%) as a white solid.

N- (4-Phenoxy-phenyl) -acetamide

Triethylamine (0.90 ml, 5.93 mmol) was added followed by acetyl chloride (0.50 g, 6.47mmol) to an ice cold solution of 4-phenoxy-phenylamine (1.0 g, 5.39 mmol) in 10 ml of DCM. The reaction mixture was stirred at 25 ° C for 2 h. After completion of the reaction mixture (TLC monitoring), water was added, extracted with DCM (3 x 50 ml). The combined organic was dried (Na2SO4), filtered and concentrated to obtain the desired product (1.20

10 g, raw production).

N- (4-Phenoxy-phenyl) -thioacetamide

Lawesson's reagent (1.50 g, 3.70 mmol) was added to a solution of N- (4-phenoxy-phenyl) -acetamide (1.20 g, 5.28 mmol) in 10 ml of toluene. The reaction mixture was heated at 120 ° C for 2 h. After completing the

After reaction (monitoring with TLC), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120M) using ethylacetate / hexane (5:95) as eluent to yield the title compound (0.78 g, 60.7%).

2-Methyl-6-phenoxy-benzothiazole

Br2 (0.32 ml, 6.40 mmol) was added dropwise to an ice cold solution of N- (4-phenoxy-phenyl) -thioacetamide (0.78 g, 3.20 mmol) in 10 ml of DCM. The reaction mixture was heated at 45 ° C for 2 h. After completion of the reaction (TLC monitoring), the reaction mixture was evaporated under reduced pressure. The residue was basified with anhydrous NH4OH solution and extracted with ethyl acetate. The combined organic was dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (230-400 M) using

Ethyl acetate / hexane (3:97) as eluent to obtain the title compound (0.08 g, 10.3%).

2-Bromomethyl-6-phenoxy-benzothiazole

NBS (0.039 g, 0.22 mmol) and AIBN (0.004 g, 0.024 mmol) were added to a solution of 2-methyl-6-phenoxy-benzothiazole 30 (0.06 g, 0.24 mmol) in 5 ml of CCl4. The reaction mixture was heated at 100 ° C for 2 h under nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400M) using 1% ethyl acetate / hexane as eluent to obtain the desired product (0.005g, 6.3%).

Scheme 52 (Example 330): (a) NBS, AIBN, CCl4; (b) 2,6-Difluoro-3-hydroxybenzamide, K2CO3, DMF.

7-Bromomethyl-quinoline

NBS (0.14 g, 0.77 mmol) and AIBN (0.025 g, 0.15 mmol) were added to a solution of 7-methylquinoline (0.10 g, 0.70

10 mmol) in 5 ml of CCl4. The reaction mixture was heated at 100 ° C for 2 h under nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230400M) using 1% ethyl acetate / hexane as eluent for obtain the desired product (0.090g, 58%).

Examples 318-333 (Table R)

The compounds of Examples 318-333 were synthesized according to the following general procedure: 2,6-Difluoro-3-hydroxy-benzamide (B) and potassium carbonate (C) were added to a reagent solution ( A) in anhydrous DMF. The reaction mixture was stirred at 25 ° C for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica using ethylacetate / hexane as eluent to obtain the product compound.

20 Table R

Example

318 319

Product

2,6-Difluor-3- [4- (4-fluorine-phenyl) -thiazol-2-methoxy] -benzamide 2,6-Difluor-3- [4- (4-trifluoromethyl-phenyl) thiazol-2-ylmethoxy] -benzamide

Reaction scheme

Reagent (A)

2-Bromomethyl-4- (4-fluorine-phenyl) -thiazole 2-Bromomethyl-4- (4-trifluoromethyl-phenyl) thiazole

Quantities of A; B; C; DMF volume

Ethyl Acetate Ratio: Hexane

Silica

Production

0.035 g, 8% white solid 0.017 g, 33% white solid

1H NMR (DMSO-d6, 400 MHz)

HPLC Procedure Number, reaction time (minutes)

320

321

2,6-Difluor-3- [4- (4-trifluoromethyl-phenyl) -thiazol-2-ylmethoxy] benzamide

2- (3-Carbamoyl-2,4-difluorophenoxymethyl) -benzothiazola-6-carboxylic acid methyl ester

2-Bromomethyl-4- (4-trifluoromethyl-phenyl) -thiazole

2-Bromomethyl-benzothiazole-6 carboxylic acid methyl ester

0.005 g, 2% white solid

1.20 g, 64.8% white solid

322

323

3- (3-Benzo [1,3] dioxol-5-yl- [1,2,4] oxadiazol-5-ylmethoxy) - 2,6-difluor-benzamide

2,6-Difluor-3- [2- (4-methoxy-phenyl) -thiazol-4-ylmethoxy] benzamide

3-Benzo [1,3] dioxol-5-yl-5-bromomethyl- [1,2,4] oxadiazole

4-Bromomethyl-2- (4-methoxy-phenyl) -thiazole

0.13 g, 32.67% white solid

0.035 g, 23% white solid

324

325

3- (1- [4-Chloro-phenyl) - [1,2,4] oxadiazol-5-yl] -ethoxy) -2,6-difluor-benzamide

2,6-Difluor-3- (5-methyl-2-phenyl-2H- [1,2,3] triazol-4-ylmethoxy) benzamide

5- (1-Bromo-ethyl) -3- (4-chloro-phenyl) - [1,2,4] oxadiazole

4-Bromomethyl-5-methyl-2-phenyl-2H- [1,2,3] triazole

0.06 g, 41% white solid

0.03 g, 9.5% white solid

326

327

2,6-Difluor-3- (3-thiazol-2-yl- [1,2,4] oxadiazol-5-ylmethoxy) benzamide

2,6-Difluor-3- (5-phenoxy-benzothiazol-2-ylmethoxy) benzamide

5-Chloromethyl-3-thiazol-2-yl- [1,2,4] oxadiazole

2-Bromomethyl-5-phenoxy-benzothiazole

0.10 g, 33% lemon yellow solid

0.001 g, 16% white solid

328

329

3- [3- (4-Difluoromethoxy-3-methoxy-phenyl) - [1,2,4] oxadiazol-5-methoxy) -2,6-Difluoro-benzamide

3- [3- (4-Chloro-3-nitro-phenyl) - [1,2,4] oxadiazol-5-methoxy) -2,6-Difluoro-benzamide

(a) 2,6-Difluoro-3-hydroxybenzamide, K2CO3, DMF

(a) 2,6-Difluoro-3-hydroxybenzamide, K2CO3, DMF

5-Chloromethyl-3- (4-Difluoromethoxy-3-methoxy-phenyl) [1,2,4] oxadiazole

5-chloromethyl-3- (4-Chloro-3-nitro-phenyl) - [1,2,4] oxadiazole

0.035 g, 23% white solid

0.06 g, 26% white solid

330

331

2,6-Difluor-3- (quinolin-7-ylmethoxy] -benzamide

3- (3-Chloro-benzyloxy) -2,6-Difluor-benzamide

(to) 2,6-difluor-3-hydroxybenzamide, K2CO3, DMF

7-Bromomethylquinoline

1-bromometi-3-chlorobenzene

0.012 g, 10% white solid

0.14 g, 48% white solid

332

333

2,6-Difluor-3- (3-nitro-benzyloxy) -benzamide

2,6-Difluor-3- [2- (5-methyl-2-p-tolyl-oxazol-4-yl) -ethoxy] -benzamide

(to)

2,6-difluor-3-hydroxybenzamide, K2CO3, DMF (a) 2,6-Difluoro-3-hydroxybenzamide, K2CO3, DMF

1-Bromomethyl-3-nitro-benzeno

4- (2-Bromo-ethyl) -5-methyl-2-p-tolyl-oxazol

0.11 g, 35% white solid

0.022 g, 16% white solid

4- (3-Methoxy-phenyl) -2-methyl-thiazole

A mixture of thioacetamide (8.0 g, 106.0 mmol) and 2-bromo-1- (3-methoxy-phenyl) -ethanone (2.0 g, 8.81 mmol) was heated at 140 ° C for 6 h under nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), water (50 ml) was added and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on gel

10 silica (230-400 M, 2% EtOAc-Hexane) to obtain the desired product (1.5g, 83%).

5-Bromo-2-bromomethyl-4- (3-methoxy-phenyl) -thiazole

 NBS (2.60 g, 14.60 mmol) and AIBN (0.12 g, 0.73 mmol) were added to a solution of 4- (3-methoxy-phenyl) -2-methyl-thiazole (1.50, 7.30 mmol) in 20 ml of CCl4. The reaction mixture was heated at 100 ° C for 2 h under the atmosphere of

15 nitrogen. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400 M) using 2% ethyl acetate / hexane as eluent to obtain the desired product (1.20 g, 45%).

3- [5-Bromo-4- (3-methoxy-phenyl) -thiazol-2-ylmethoxy] -2,6-difluoro-benzamide

20 2,6-Difluor-3-hydroxy-benzamide (0.38 g, 2.20 mmol) and potassium carbonate (1.06 g, 7.70 mmol) were added to a solution of 5-Bromo-2-bromomethyl-4- (3 -methoxy-phenyl) -thiazole (0.80 g, 2.20 mmol) in 5 ml of anhydrous DMF. The reaction mixture was stirred at 25 ° C for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120M) using ethylacetate / hexane (50:50) as eluent to obtain the title compound as a white solid ( 0.50 g, 49%).

2,6-Difluor-3- [4- (3-methoxy-phenyl) -thiazol-2-ylmethoxy] -benzamide

Zinc powder (0.50 g, w / w) was added to the solution of 3- [5-bromo-4- (3-methoxy-phenyl) -thiazol-2-ylmethoxy] -2,6-difluorobenzamide (0.50 g, 1.10 mmol) in 10 ml of acetic acid. The reaction mixture was heated at 120 ° C for 1 h. After completion of the reaction mixture (TLC monitoring), water (50 ml) was added and the pH was adjusted to 8-9 with NaOH solution and extracted with ethyl acetate (3 x 100 ml). The combined organic was washed with

10 water, brine, dried (Na2SO4), filtered and concentrated to obtain the desired product (0.22 g, 53%).

Example 334: 2,6-Difluor-3- [4- (3-hydroxy-phenyl) -thiazol-2-ylmethoxy] -benzamide

A solution of 2,6-Difluoro-3- [4- (3-methoxy-phenyl) -thiazol-2-ylmethoxy] -benzamide (0.20 g, 0.53 mmol) in 15 ml of DCM was cooled to -78 ° C followed by the addition of BBr3 (0.20 ml, 2.14 mmol). The reaction mixture was stirred at 25 ° C for 2 h. After completion of the reaction mixture (TLC monitoring), NaHCO3 solution (20 ml) was added at 0 ° C and extracted with ethyl acetate (3 x 50 ml). The combined organic was washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate / hexane (50:50) as eluent to obtain the title compound as a white solid (0.065 g, 33%). 1H NMR (DMSO-d6, 400 MHz): δ 5.60 (s, 2H), 6.74 (m, 1H), 7.10 (m, 1H), 7.24 (m, 1H).

20 7.37-7.45 (m, 3H), 7.90 (br s, 1H), 8.10 (s, 1H), 8.17 (br s, 1H) and 9.55 (s, 1H). MS ES + (362.99), HPLC (procedure II) Reaction time = 14.95 min.

Minimum Inhibitory Concentration Analysis (MIC)

The antimicrobial activity of the compounds of this invention was analyzed by susceptibility analysis in

25 liquid media. The MICs for compounds against each strain were determined by a broth microdilution procedure according to the guidelines of the Committee for Clinical Laboratory Standards (known by NCCLS, its acronym in English). (NCCLS 2000. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically-fifth edition. Approved standard M7-A5. NCCLS, Wayne, Pa.).

Briefly, analysis compounds are prepared in 100 Pl of 1.6% DMSO solution in multiwell plates.

30 Various bacterial colonies of a newly scratched plate are transferred to a rich and appropriate broth, such as that of Mueller Hinton. The cell suspension is adjusted to an optical density of 0.09 and subsequently diluted 1: 100 with 2x hot broth. This cell suspension is dispensed in wells containing solution of the compound such that the final volume is 200 Ql. The plates are incubated overnight (16-20 hours) at 37 ° C and turbidity is measured by eye and quantified epectrophotometrically. The CIM is defined as the lowest concentration

35 that inhibits visible growth.

The compounds of the present invention were found to have antimicrobial activity in the MIC analysis described above.

Results

Table 1 shows the Minimum Inhibitory Concentration (MIC) of the examples against Bacillus subtilis 168CA. The activities were rated as â € ™ Aâ € ™ if the MIC was ≤8 micrograms / ml, â € ™ Bâ € ™ if the MIC was 16 to 64 micrograms / ml and â € ™ Câ € ™ if the MIC was greater than 64 micrograms / ml.

Table 1 Bacillus subtilis CIMs

Example

Activity  Example Activity  Example Activity

one

TO 33 C 65 TO

2

C 3. 4 B 66 TO

3

C 35 B 67 TO

4

C 36 TO 68 TO

5

B 37 C 69 TO

6

C 38 TO 70 TO

7

C 39 B 71 TO

8

B 40 TO 72 B

9

C 41 B 73 TO

10

TO 42 B 74 TO

eleven

C 43 B 75 TO

12

B 44 TO 76 TO

13

B Four. Five TO 77 B

14

B 46 TO 78 TO

fifteen

B 47 TO 79 B

16

C 48 TO 80 B

17

B 49 TO 81 TO

18

C fifty TO 82 TO

19

TO 51 TO 83 TO

twenty

TO 52 TO 84 TO

twenty-one

B 53 C 85 TO

22

B 54 B 86 TO

2. 3

B 55 TO 87 TO

24

TO 56 TO 88 TO

25

C 57 TO 89 TO

26

C 58 TO 90 TO

27

C 59 TO 91 TO

28

TO 60 B 92 TO

29

B 61 TO 93 TO

30

C 62 TO 94 TO

31

B 63 TO 95 B

32

TO 64 TO

Example

Activity  Example Activity  Example Activity

96

B 153 TO 210 TO

97

TO 154 TO 211 TO

98

TO 155 TO 212 TO

99

TO 156 TO 213 TO

100

TO 157 TO 214 B

101

B 158 TO 215 TO

102

TO 159 TO 216 TO

103

TO 160 TO 217 TO

104

TO 161 TO 218 TO

105

TO 162 TO 219 TO

106

TO 163 TO 220 TO

107

TO 164 TO 221 TO

108

B 165 TO 222 TO

109

TO 166 C 223 TO

110

TO 167 B 224 B

111

TO 168 C 225 C

112

TO 169 C 226 B

113

TO 170 C 227 TO

114

TO 171 B 228 TO

115

B 172 C 229 TO

116

B 173 C 230 TO

117

TO 174 B 231 TO

118

TO 175 TO 232 B

119

TO 176 TO 233 TO

120

TO 177 TO 2. 3. 4 TO

121

TO 178 B 235 TO

122

TO 179 C 236 TO

123

TO 180 TO 237 B

124

TO 181 TO 238 B

125

TO 182 C 239 B

126

TO 183 B 240 TO

127

TO 184 B 241 TO

128

TO 185 C 242 TO

129

C 186 TO 243 TO

130

TO 187 B 244

131

B 188 B 245 TO

132

TO 189 C 246 TO

133

TO 190 B 247 TO

134

B 191 B 248 TO

135

TO 192 C 249 TO

136

TO 193 B 250 TO

Example

Activity  Example Activity  Example Activity

137

B 194 C 251 B

138

C 195 TO 252 TO

139

TO 196 TO 253 B

140

C 197 B 254 TO

141

TO 198 B 255 TO

142

TO 199 C 256 TO

143

C 200 TO 257 TO

144

C 201 TO 258 TO

145

B 202 TO 259 TO

146

TO 203 C 260 TO

147

B 204 B 261 B

148

TO 205 TO 262 B

149

TO 206 TO 263 TO

150

TO 207 TO 264 B

151

TO 208 TO 265 TO

152

B 209 B 266 B

267

TO 290 TO 314 TO

268

TO 291 TO 315 TO

269

TO 292 TO 316 TO

270

TO 293 TO 317 TO

271

TO 294 TO 318 TO

272

TO 295 TO 319 TO

273

TO 296 TO 320 TO

274

TO 297 TO 321 TO

275

B 298 TO 322 TO

276

TO 299 TO 323 TO

277

TO 301 TO 324 TO

278

TO 302 TO 325 TO

279

TO 303 TO 326 B

280

TO 304 TO 327 TO

281

TO 305 TO 328 TO

282

TO 306 TO 329 TO

283

TO 307 TO 330 B

284

TO 308 TO 331 TO

285

TO 309 TO 332 B

286

TO 310 TO 333 TO

287

TO 311 TO 334 B

288

TO 312 B

289

TO 313 TO

Some of the examples were also analyzed for their activity against the pathogenic organism Staphylococcus aureus ATCC29213. Table 2 shows the MICs of the examples against Staphylococcus aureus. The activities were again classified as â € œAâ €? if the MIC was ≤8 micrograms / ml, â € ™ Bâ € ™ if the MIC was 16 to 64 micrograms / ml and â € ™ Câ € ™ if the MIC was greater than 64 micrograms / ml.

Table 2 Staphylococcus aureus CIMs

Example

Activity  Example Activity  Example Activity

one

TO 46 TO 72 B

5

B 47 B 73 TO

8

B 49 TO 74 TO

12

TO 51 B 75 TO

fifteen

B 52 TO 76 TO

17

B 53 C 77 B

18

C 54 B 78 TO

19

TO 55 TO 79 B

24

TO 56 TO 80 B

26

C 57 B 81 TO

27

C 58 TO 82 TO

28

C 59 B 83 B

29

B 60 B 84 TO

30

C 61 TO 85 TO

31

B 62 TO 86 TO

32

B 64 TO 87 TO

36

C 65 TO 88 TO

39

B 66 TO 89 TO

40

TO 67 TO 90 TO

41

B 68 TO 91 TO

42

B 69 TO 93 B

43

B 70 TO 94 TO

Four. Five

TO 71 TO 95 C

TO

98

TO 153 TO 208 TO

99

TO 155 TO 209 C

100

TO 156 TO 210 TO

101

B 157 TO 211 B

102

TO 158 TO 212 B

103

TO 159 TO 213 B

104

TO 161 TO 214 B

105

TO 162 TO 215 TO

106

TO 163 TO 216 TO

107

TO 164 TO 217 TO

108

B 165 TO 218 TO

109

B 166 C 219 TO

111

TO 167 B 220 TO

Example

Activity  Example Activity  Example Activity

114

TO 168 C 221 TO

115

TO 169 C 222 TO

116

B 170 C 223 TO

117

TO 171 B 224 C

118

TO 172 C 225 C

119

TO 173 C 226 B

120

TO 174 B 227 TO

121

TO 175 TO 228 B

122

TO 176 B 229 TO

123

TO 177 TO 230 TO

124

TO 178 B 231 TO

125

TO 179 C 232 TO

126

TO 180 B 233 TO

127

TO 181 B 235 TO

128

B 182 C 236 TO

129

B 183 B 237 B

130

TO 184 B 239 B

132

TO 185 C 240 TO

133

TO 186 B 241 TO

134

B 187 B 242 TO

135

TO 188 B 243 TO

136

TO 189 C 245 TO

137

B 190 B 246 TO

138

C 191 B 247 TO

139

TO 192 C 248 TO

140

TO 193 B 249 TO

141

TO 194 C 250 TO

143

TO 195 B 251 B

144

C 196 B 252 TO

145

C 197 B 256 B

146

B 200 B 257 TO

147

B 201 B 260 TO

148

TO 202 B 262 B

149

B 204 B 263 B

150

B 205 TO 265 B

151

B 206 C 266 B

152

B 207 B

267

TO 289 TO 311 TO

268

B 290 TO 312 TO

269

TO 291 TO 313 TO

Example

Activity  Example Activity  Example Activity

270

TO 292 TO 314 B

271

TO 293 TO 315 TO

272

TO 294 TO 316 TO

273

TO 295 TO 317 TO

274

TO 296 TO 318 TO

275

B 297 TO 319 TO

276

TO 298 TO 320 TO

277

TO 299 TO 321 TO

278

TO 300 B 322 TO

279

TO 301 B 323 TO

280

TO 302 TO 324 TO

281

TO 303 TO 325 B

282

TO 304 TO 326 B

283

TO 305 TO 327 TO

284

TO 306 TO 331 B

285

TO 307 TO 333 TO

286

TO 308 B 334 TO

287

TO 309 TO

288

TO 310 B

Some of the examples were also analyzed for their activity against other bacterial species. Table 3 shows the MICs of the examples against various bacterial species. The activities were again classified as â € œAâ €? if the MIC was ≤8 micrograms / ml, â € ™ Bâ € ™ if the MIC was 16 to 64 micrograms / ml and â € ™ Câ € ™ if the MIC was greater than 64 micrograms / ml.

Table 3 MICs against various bacteria

Activity

Example

Bacillus cereus ATCC 14579 Staphylococcus Epidermidis ATCC 12228 Staphylococcus haemolyticus ATCC 29970 Staphylococcus saprophyticus ATCC 15305

46

TO

84

TO

87

TO

88

TO

175

TO

215

TO

177

TO

217

TO TO TO

218

TO TO TO TO

236

TO TO

111

TO

208

TO TO

114

TO TO

106

TO TO TO TO

Example

Bacillus cereus ATCC 14579 Staphylococcus Epidermidis ATCC 12228 Staphylococcus haemolyticus ATCC 29970 Staphylococcus saprophyticus ATCC 15305

246

TO TO TO TO

242

TO TO

135

TO

139

TO TO

287

TO

271

TO

282

TO

311

TO

Some of the examples were also analyzed for their activity against staphylococcal clinical isolates. Table 4 shows the MICs of the examples against various clinical isolates. The activities were again classified as â € œAâ €? if the MIC was ≤8 micrograms / ml, â € ™ Bâ € ™ if the MIC was 16 to 64 micrograms / ml and â € ™ Câ € ™ if the MIC was greater than 64 micrograms / ml.

Table 3 MICs against various bacteria

 Activity Example

Organism

Do not. Oxacillin (S / R1) Antibiotic Susceptibility2 Other information 217 236 218

S. aureus

0100 S ATCC 29213 TO TO TO

1134

S Hospital TO TO TO

753

S Hospital TO TO TO

1662

S Hospital TO TO TO

1015

R Van-S, LZD-S Hospital TO TO TO

1135

R Van-S, LZD-S Hospital TO TO TO

2012

R Van-I, LZD-S Hospital TO TO TO

2018

R Van-I, LZD-S Hospital TO TO TO

1651

R Van-S, LZD-S Hospital TO TO TO

1652

R Van-S, LZD-S Hospital (G2576T, G) TO TO TO

1725

R Van-S, LZD-S Hospital (T2500T, A) TO TO TO

2011

R Tet-R, MI-S Hospital (G2576T) TO TO TO

1 S, susceptible; I, intermediate; R, resistant

Go, vancomycin; LZD, linezolid; Tet, tetracycline; MI, minocycline; CC, clindamycin; SXT, trimetroprim / sulfamethoxazola; Doxi, doxycycline; ELMI, inducible streptogramin-lincosamide-macrolide resistance B; TMP, trimethoprim; Rif, rifampin

757

R Tet-R, MI-S Hospital (tetK) TO TO TO

1729

R Tet-R, MI-S Hospital (tetM) TO TO TO

2147

R CC-S, SXT-S Community TO TO TO

2142

R CC-S, SXT-S Community TO TO TO

2158

R CC-R, Doxi-I Community TO TO TO

2150

R CC-S, SXT-S Community TO TO TO

2149

R CC-R (ELMI), SXT-S Community TO TO TO

2175

R TMP-R Community TO TO TO

Organism

Do not. Oxacillin (S / R3) Antibiotic Susceptibility4 Other information 217 236 218

2143

R Rif-R Community TO TO TO

S. epidermidis

835 S TO TO TO

1139

S TO TO TO

831

TO TO TO

1142

TO TO TO

1144

TO TO TO

The activity of some of the examples was also tested in a Staphylococcus aureus septicemia infection model in one mouse. Table 5 shows the day 7 survival of infected mice treated with a single intraperitoneal dose of 100 mg / kg of each Example within one hour after intraperitoneal inoculation with a lethal dose of Staphylococcus aureus.

Table 5 Murine Survival

Example

Survival percentage

Vehicle Control

0

218

100

106

100

241

100

247

100

246

100

3 S, susceptible; I, intermediate; R, resistant

Go, vancomycin; LZD, linezolid; Tet, tetracycline; MI, minocycline; CC, clindamycin; SXT, trimetroprim / sulfamethoxazola; Doxi, doxycycline; ELMI, inducible streptogramin-lincosamide-macrolide resistance B; TMP, trimethoprim; Rif, rifampin

Claims (18)

COORA, -CORA, -OCORA, -SO2RA, -CONRARB, -SO2NRARB, -NRARB, -OCONRARB, -NRBCORA, -NRBCOORA, NRBSO2ORA Ó -NRACONRARB where RA and RB are independently hydrogen or a group (C1-C6 ) Alkyl or, in the case where RA and RB are linked to the same atom N, RA and RB taken together with said nitrogen 15 can form a cyclic amino ring, and where the substitute is phenyl, phenoxide or heteroaryl or heroaryloxide monocyclic with 5 or 6 atoms, being its phenyl or heteroaryl anyl, itself, substituted by any of the preceding substituents except phenyl, phenoxide, heteroaryl or heteroaryloxide; W is = C (R1) -Ó = N-: R1 is hydrogen and R2 is methyl, hydrogen or fluorine; or R1 and R2 taken together are â € “CH2-, -CH2CH2-, -O-, or, in any orientation, -O-CH2-, OCH2CH2-; R3 is a radical of the formula â € “(Alk1) m- (Z) p- (Alk2) n-Q where m, p and n, are, independently, 0 or 1, provided that at least one of m, p and n is 1, Z is â € “O-, -S-, -S (O) -. â € “S (O2) -. â € “NH-, -N (CH3) -. â € “N (CH2CH3) -, -C (= O) -, -O-, - (C = O) -, -C (= O) -O-, an optionally substituted divalent monocyclic, carbocyclic or heterocyclic radical that have atoms of 3 to 6 rings; or a Optionally substituted divalent bicyclic heterocyclic radical having atoms of 5 to 10 rings; Alq1 and Alq2 are optionally substituted C1-C6alkylene, C2-C6alkenylene or C2-C6alkylene radicals, which may optionally end with or be interrupted by â € “O-, -S-, -S (O) -. â € “S (O2) -. â € “NH-, -N (CH3) -. â € “N (CH2CH3); Y Q is hydrogen, halogen, nitrile (-CN), or hydroxyl or a monocyclic, carbocyclic or heterocyclic radical 30 optionally substituted having atoms of 3 to 7 rings; or an optionally substituted bicyclic heterocyclic radical having atoms of 5 to 10 rings; and in the definitions of 2 Alq1, Alq2 and Q the term â € œreplacedâ €? means substituted with up to four compatible substitutes, each of which is independently selected from (C1-C6) alkyl, (C2-C6) alkenyl, (C2-Ce) alkynyl, (C1-C6) alkoxide, hydroxide, hydroxide (C1C6) alkyl, mercapto, mercapto (C1-C6) alkyl, (C1-C6) alkylthio, halo, (C1-C3) fully or partially fluorinated alkyl, 35 (C1-C3) alkoxide or (C1-C3) alkylthio, nitro, nitrile, (-CN), oxo (= O), phenyl, phenoxide, monocyclic heteroaryl or heteroaryloxide with 5 or 6 ring atoms, -COORA , -CORA, -OCORA, -SO2R, -CONRARB, -SO2NRARB, -NRARB, OCONRARB, -NRBCORA, -NRBCOORA, -NRBSO2ORA or -NRACONRARB where RA and RB are independently hydrogen or a group (C1-C6) alkyl or, in the case where RA and RB are linked to the same atom N, RA and RB taken together with said nitrogen can form a cyclic amino ring, and where the substitute is phenyl, Phenoxide or heteroaryl or heterocyclyl monocyclic with 5 or 6 atoms, being its phenyl or heteroaryl, itself, substituted by any of the preceding substituents except phenyl, phenoxide, heteroaryl or heteroaryloxide. 2. The method according to claim 1, wherein the compound formula (IA) Where R4 and R5 are, independently, fluorine or chlorine, or one of R4 and R5 is hydrogen while the other is fluorine or chlorine and R1, R2 and R3 are as defined in claim 1. 3. The use claimed in claim 1 wherein the compound has formula (IB) Where R2 is hydrogen, methyl or fluorine; and R3 are as defined in claim 1

Four.

The use claimed in any one of claims 1 to 3 wherein R1 and R2 are hydrogen.

5.

The use claimed in any one of claims 1 to 4 wherein p is 1, and Z is a radical

Optionally substituted carbocyclic or non-aromatic monocyclic heterocyclic having atoms of 3 to 6 rings; or an optionally substituted bicyclic non-aromatic carbocyclic or heterocyclic having atoms of 5 to 10 rings, which is linked to the â € “(Alk1) m-of R3 part and to the - (Alk2) nQ part of R3 it is via ring carbon or nitrogen atoms. 6. The use claimed in claim 2 wherein R2 is hydrogen and R3 is quinolin-2-yl, benzothiazol-2-yl, 15 thiazolopyridin-2-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxadiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxadiazol-3-yl or oxazol -5-yl optionally substituted.

7.

The use claimed in claim 6 wherein R3 is substituted by optionally substituted phenyl.

8.

The use claimed in claim 6 wherein any optional substitutes in R3 are

selected from methyl, -OCH3, -CF3, -OCF3, ethyl, cyclopropyl, oxo, hydroxyl, -F, -Cl, -Br, cyano, acetyl, amino, methylamino, acetylamino, carbamate, -CONH2, nitro, - COOH and â € “CH2OH. 9. A compound that is a substituted benzamide or pyridylamide of the formula (I) or a salt, hydrate, or solvate thereof Where W is = C (R1) - Ó = N-; R1 is hydrogen and R2 is methyl, hydrogen or fluorine; or R1 and R2 taken together are â € “CH2-, -CH2CH2-, -O-, or, in any orientation, -O-CH2-, or OCH2CH2-; R4 and R5 are, independently, fluorine or chlorine, or one of R4 and R5 is hydrogen while the other is fluorine or chlorine;  R3 is a radical selected from those of the following A-H formulas, in which any vacant position in the ring is optionally substituted: Where Q is hydrogen, halogen, nitrile or hydroxyl or an optionally substituted monocyclic, carbocyclic or heterocyclic radical having atoms of 3 to 6 rings; or an optionally bicyclic heterocyclic radical 15 substituted with atoms of 5 to 10 rings; and in the definitions of R3 and Q the term â € œoptionally substitutedâ €? It has the same meaning as in the definitions of Z, Alq1, Alq2 and Q in claim 1.

10.

A compound as claimed in claim 9 wherein W is = CH- and R2 is hydrogen.

eleven.

A compound as claimed in claim 9 or in claim 10 wherein Q in the radical R3 is optionally substituted hydrogen or phenyl.

12. A compound as claimed in claim 9 or claim 10 wherein R3 is quinolin-2-yl, benzothiazol-2-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxadiazol- 3-yl, oxadiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl or optionally substituted thiazolopyridin-2-yl.

13.

A compound as claimed in claim 12 wherein R3 is substituted by optionally substituted phenyl.

14.

A compound as claimed in claims 9 to 13 wherein any optional substitutes in R3 are selected from methyl, -OCH3, -CF3, -OCF3, ethyl, cyclopropyl, oxo, hydroxyl, -F, -Cl, -Br, cyano, acetyl, amino, methylamino, acetylamino, carbamate, -CONH2, nitro, -COOH and â € “CH2OH.

fifteen.

A compound that is a pyridylamide of the formula (ID) or a salt, hydrate, or solvate thereof

Where R2 is hydrogen, methyl, or fluorine; and R3 is as defined in claim 9.

16.

A compound as claimed in claim 15 wherein R2 is hydrogen.

17.

A compound as claimed in claim 15 or in claim 16 wherein Q in the radical R3 is optionally substituted hydrogen or phenyl.

18. A compound as claimed in claim 15 or claim 16 wherein R3 is quinolin-2-yl, benzothiazol-2-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxadiazol- 3-yl, oxadiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl or optionally substituted thiazolopyridin-2-yl. 19. A compound as claimed in claim 18 wherein R3 is substituted by optionally substituted phenyl. A compound as claimed in claim 15 to 19 wherein any optional substitutes in R3 are selected from methyl, -OCH3, -CF3, -OCF3, ethyl, cyclopropyl, oxo, hydroxyl, -F, -Cl, -Br, cyano, acetyl, amino, methylamino, acetylamino, carbamate, -CONH2, nitro, -COOH and â € “CH2OH. 21. A pharmaceutical composition comprising a compound as claimed in any one of claims 9 to 20, together with a pharmaceutically acceptable carrier.