HK1139058B

HK1139058B - Benzimidazole cannabinoid agonists bearing a substituted heterocyclic group

Info

Publication number: HK1139058B
Application number: HK10105112.0A
Authority: HK
Inventors: Henricus Jacobus Maria Gijsen; Michel Anna Jozef De Cleyn; Michel Surkyn; Bie Maria Pieter Verbist
Original assignee: Janssen Pharmaceutica N.V.
Priority date: 2006-07-04
Filing date: 2007-07-02
Publication date: 2014-07-11

Description

Benzimidazole cannabinoid agonists with substituted heterocyclic groups

The present invention relates to novel benzimidazole compounds of formula (I) having selective cannabinoid receptor 2 agonistic properties, pharmaceutical compositions comprising these compounds, chemical processes for preparing these compounds and their use in the treatment of diseases linked to the mediation of the cannabinoid receptors in animals, in particular humans.

Typical cannabinoids such as cannabinoids delta⁹-tetrahydro-cannabinol (Δ)⁹-THC) exerts its pharmacological effects by interacting with specific cannabinoid receptors in vivo. To date, two cannabinoid receptors have been characterized: CB1, which is a receptor found in mammalian brain and peripheral tissues; and CB2, which is a receptor found primarily in peripheral tissues. Compounds that are agonists or antagonists at one or both of these receptors have been shown to provide a variety of pharmacological effects. There is significant interest in developing cannabinoid analogs with selective CB2 agonistic activity, since it is believed that the high selectivity of the CB2 receptor may provide a way to exploit the beneficial effects of CB receptor agonists while avoiding central adverse events seen with cannabinoid structures (see, e.g., Expert Opinionon Investigational Drugs (2005), 14(6), 695-703).

WO-2006/048754 discloses sulfonyl benzimidazole derivatives having CB2 agonistic activity.

The structure of the compounds of the invention differs from the compounds known from the cited art by the presence of a heterocyclic moiety on the sulfonyl group, which is usually substituted.

It was unexpectedly found that the compounds of the invention have a higher ratio of CB2 agonism than CB1 agonism compared to the compounds known from the cited art. The compounds of the invention are therefore more selective CB2 agonists than the compounds known from the prior art of WO-2006/048754.

The invention relates to novel compounds of formula (I)

Pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, wherein

n is an integer 1 or 2;

R¹is C_2-6An alkyl group;

C_1-6alkyl substituted with 1, 2 or 3 substituents each independently selected from: halogen, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy, cyano, nitro, amino, and mono-or di (C)_1-4Alkyl) amino;

C_1-6an alkyl group substituted with a cyclic group selected from: c_3-8Cycloalkyl, oxo C_3-8Cycloalkyl radical, C_5-8Cycloalkenyl, bicyclo [2.2.1]Hept-2-enyl, bicyclo [2.2.2]Octyl and bicyclo [3.1.1]Heptylalkyl, wherein the cyclic group is optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy, cyano, nitro, NR⁵R⁶Or CONR⁵R⁶Wherein R is⁵And R⁶Independently selected from hydrogen or C_1-4An alkyl group; or

C_1-6Alkyl substituted with a heterocycle selected from: pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1-dioxo-tetrahydrothiopyranyl, [1, 3 ]]Dioxolanes, [1, 4 ] dioxolanes]Dioxolanes, [1, 3 ] dioxolanes]Dioxanyl, 5-oxo-pyrrolidin-2-yl, or 2-oxo-oxepanyl; wherein said heterocycle is optionally substituted with one or two substituents each independently selected from the group consisting of: c_1-4Alkyl, polyhalo C_1-4Alkyl, halogen, hydroxy, C_1-4Alkoxy, cyano, trifluoromethyl, COR⁵、COOR⁵、CONR⁵R⁶、SO₂R⁵Wherein R is⁵And R⁶Independently selected from hydrogen or C_1-4Alkyl or polyhalo C_1-4An alkyl group;

R²is C_2-6An alkyl group;

C_1-6alkyl substituted with 1, 2 or 3 substituents each independently selected from: halogen, hydroxy, C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C_1-4Alkoxy, polyhalo C_1-4Alkoxy, trifluoromethyl, cyano, nitro, NR⁷R⁸、CONR⁷R⁸Or NHCOR⁷Wherein R is⁷And R⁸Independently selected from hydrogen, C_1-4Alkyl or polyhalo C_1-4An alkyl group;

C_3-6an alkenyl group;

C_3-6an alkynyl group;

C_3-6a cycloalkyl group; or

The cyclic group is selected from pyrrolidinyl (pyrrolidinyl), piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, [1, 3 ]]Dioxolanes, [1, 3 ] dioxolanes]Dioxane alkyl group, [1, 4 ] dioxane alkyl group]Dioxanyl, 5-oxo-pyrrolidin-2-yl, bicyclo [2.2.1]Hept-2-enyl and bicyclo [3.1.1]A heptalkyl group; wherein said cyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of: c_1-4Alkyl, halogen, hydroxy, C_1-4Alkoxy or trifluoromethyl;

R³is hydrogen, halogen, C_1-4Alkyl radical, C_1-4Alkoxy, trifluoromethyl or cyano;

R⁴is a heteroaryl group;

heteroaryl is selected from N-oxy-pyridyl, N-oxy-pyridazinyl, N-oxy-pyrimidinyl or N-oxy-pyrazinyl; or

Selected from furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, isothiazolyl, thiadiazolyl, oxadiazole, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, N-oxy-pyridyl, N-oxy-pyridazinyl, N-oxy-pyrimidinyl, N-oxy-pyrazinyl or 2-oxo-1, 2-dihydro-pyridyl, each substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: halogen; a hydroxyl group; c_1-4An alkyl group; c_3-6A cycloalkyl group; c_2-6An alkenyl group; c_2-6Alkenyl substituted with 1 or 2 substituents selected from halogen; c_2-6An alkynyl group; c_2-6Alkynyl radical, which is substituted by C_1-4Alkoxy substitution; c_1-4An alkoxy group; c_1-4Alkoxy radical C_1-4An alkyl group; polyhalo C_1-4An alkyl group; polyhalo C_1-4An alkoxy group; a cyano group; a nitro group; NR (nitrogen to noise ratio)⁹R¹⁰；R¹¹-a carbonyl group; r¹¹-SO₂-；C_1-4Alkyl radicals substituted by hydroxy, NR⁹R¹⁰、R¹¹-carbonyl or R¹¹-SO₂-substitution; oxadiazolyl, optionally substituted by C_1-4Alkyl, polyhalo C_1-4Alkyl or C_3-6Cycloalkyl substitution; dioxolanes optionally substituted by 1 or 2C_1-4Alkyl substitution; c_1-4Alkoxy radicals substituted by hydroxy radicals, C_1-4Alkoxy radical C_1-4Alkylcarbonylamino, C_1-4Alkoxycarbonylamino, amino, di (C)_1-4Alkyl) amino or morpholinyl; c_1-4Alkylcarbonylamino group C_1-4An alkylamino group; c_1-4Alkoxy radical C_1-4An alkylamino group;

wherein R is⁹And R¹⁰Independently of one another, from hydrogen, C_1-4Alkyl, polyhalo C_1-4Alkyl, aminosulfonyl or C_1-8An alkylsulfonyl group; or R¹¹-a carbonyl group;

wherein R is⁹And R¹⁰And R⁹And R¹⁰Bound nitrogen atomTogether the atoms may form a pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl ring; and is

Wherein R is¹¹Is C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy, amino, mono-or di- (C)_1-4Alkyl) amino, (hydroxy C)_1-4Alkyl) amino, (C)_1-4Alkoxy radical C_1-4Alkyl) amino, di (C)_1-4Alkyl) amino C_1-4Alkyl, pyrrolidinyl, piperidinyl, morpholinyl, N-methyl-piperazinyl, or C substituted with_1-4Alkyl groups: hydroxy, C_1-4Alkoxy, trifluoromethyl, C_1-4Alkoxy radical C_1-4Alkyl, pyrrolidinyl, piperidinyl, morpholinyl, N-methyl-piperazinyl, or 2-oxo-imidazolidin-1-yl.

As used in the foregoing definitions:

halogen is typically fluorine, chlorine, bromine and iodine;

-C_1-4alkyl is defined as straight and branched chain saturated hydrocarbon groups having 1 to 4 carbon atoms, e.g., methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, and the like;

-C_1-6alkyl represents including C_1-4Alkyl groups and higher homologs thereof having 5 or 6 carbon atoms, e.g., 2-methylbutyl, pentyl, hexyl, and the like;

-C_2-6alkyl is defined as straight and branched chain saturated hydrocarbon groups having 2 to 6 carbon atoms, such as ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2-methylbutyl, pentyl, hexyl and the like;

-C_1-8alkyl represents including C_1-6Alkyl groups and their higher homologs having 7 or 8 carbon atoms, such as heptyl, ethylhexyl, octyl, and the like;

-polyhalo C_1-4Alkyl is defined as polyhalo-substituted C_1-4Alkyl, especially C, substituted by 2 to 6 halogen atoms_1-4Alkyl (as hereinbefore defined), e.g. difluoromethyl, trifluoromethylTrifluoroethyl, and the like;

-C_2-6alkenyl is defined as straight and branched chain hydrocarbon radicals containing one double bond and having 2 to 6 carbon atoms, such as vinyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 2-hexenyl and the like;

-C_3-6alkenylalkenyl is defined as straight and branched chain hydrocarbon radicals containing one double bond and having 3 to 6 carbon atoms, such as, for example, 2-propenyl, 3-butenyl, 2-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 2-hexenyl and the like;

-C_2-6alkynyl is defined as straight and branched chain hydrocarbon radicals containing one triple bond and having 2 to 6 carbon atoms, e.g., ethynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 3-methyl-2-butynyl, 3-hexynyl, 2-hexynyl, and the like;

-C_3-6alkynyl is defined as straight and branched chain hydrocarbon radicals containing one triple bond and having 3 to 6 carbon atoms, e.g., 2-propynyl, 3-butynyl, 2-pentynyl, 3-methyl-2-butynyl, 3-hexynyl, 2-hexynyl, and the like;

-C_3-6cycloalkyl groups are typically cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

-C_3-8cycloalkyl is typically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl;

-C_6-8cycloalkyl groups are typically cyclohexyl, cycloheptyl and cyclooctyl;

-C_5-8cycloalkenyl groups are typically cyclopentenyl, cyclohexenyl, cycloheptene and cyclooctene.

The pharmaceutically acceptable acid addition salts mentioned above are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. These pharmaceutically acceptable acid addition salts are conventionally obtained by treating the base form with such a suitable acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like; or organic acids such as acetic, propionic, glycolic, lactic, pyruvic, oxalic (i.e., oxalic), malonic, succinic (i.e., succinic), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

Conversely, the salt form can be converted to the free base form by treatment with a suitable base.

The compounds of formula (I) may exist in both non-solvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term 'hydrate' is used when the solvent is water.

The term "stereochemically isomeric forms" as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More particularly, the stereocenter may have the R-or S-configuration; the substituents on the divalent cyclic (partially) saturated groups may be in either the cis-or trans-configuration. Compounds containing a double bond may have E or Z-stereochemistry at the double bond. Stereochemically isomeric forms of the compounds of formula (I) are intended to be expressly included within the scope of the present invention.

The absolute stereochemical configuration of the compounds of formula (I) and the intermediates used in their preparation can be readily determined by those skilled in the art using well known procedures, such as X-ray diffraction.

Some of the compounds of formula (I) may also exist as tautomers thereof. Although such forms are not explicitly shown in the above formula, they are intended to be included within the scope of the present invention. For example, when an aromatic heterocycle is substituted with a hydroxyl group, the keto-formula may be the predominant occupied tautomer.

Within the framework of the present application, the expression "compounds of the invention" is also meant to include compounds according to formula (I) and prodrugs thereof, or isotopically labelled compounds thereof.

Also included within the scope of the present invention are so-called "prodrugs" of the compounds of formula (I). Prodrugs are certain derivatives of pharmaceutically active compounds which may themselves have little or no pharmacological activity, which when administered or administered into the body are capable of being converted to compounds of formula (I) having the desired pharmaceutical activity, for example by hydrolytic cleavage. Such derivatives are referred to as "prodrugs".

In one embodiment, the invention relates to compounds of formula (I), wherein

n is an integer 1 or 2;

R¹is C_2-6An alkyl group;

C_1-6an alkyl group substituted with a cyclic group selected from: c_3-8Cycloalkyl radical, C_5-8Cycloalkenyl, bicyclo [2.2.1]Hept-2-enyl, bicyclo [2.2.2]Octyl and bicyclo [3.1.1]Heptylalkyl, wherein the cyclic group is optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy, cyano, nitro, NR⁵R⁶Or CONR⁵R⁶Wherein R is⁵And R⁶Independently selected from hydrogen or C_1-4An alkyl group; or

C_1-6Alkyl substituted with a heterocycle selected from: pyrrolidinyl, piperidinyl, homoPiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1-dioxo-tetrahydrothiopyranyl, [1, 3 ]]Dioxolanes, [1, 4 ] dioxolanes]Dioxolanes, [1, 3 ] dioxolanes]Dioxanyl, 5-oxo-pyrrolidin-2-yl; wherein said heterocycle is optionally substituted with one or two substituents each independently selected from the group consisting of: c_1-4Alkyl, polyhalo C_1-4Alkyl, halogen, hydroxy, C_1-4Alkoxy, cyano, trifluoromethyl, COR⁵、COOR⁵、CONR⁵R⁶、SO₂R⁵Wherein R is⁵And R⁶Independently selected from hydrogen or C_1-4Alkyl or polyhalo C_1-4An alkyl group;

R²is C_2-6An alkyl group;

C_3-6an alkenyl group;

C_3-6an alkynyl group;

C_3-6a cycloalkyl group; or

The cyclic group is selected from pyrrolidinyl (pyrrolidinyl), piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, [1, 3 ]]Dioxolanes, [1, 3 ] dioxolanes]Dioxane alkyl group, [1, 4 ] dioxane alkyl group]Dioxanyl, 5-oxo-pyrrolidin-2-yl, bicyclo [2.2.1]Hept-2-enyl and bicyclo [3.1.1]A heptalkyl group; wherein said cyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of: c1-4 alkyl, halogen, hydroxy, C_1-4Alkoxy or trifluoromethyl;

R⁴is a heteroaryl group;

Selected from furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, isothiazolyl, thiadiazolyl, oxadiazole, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, N-oxy-pyridyl, N-oxy-pyridazinyl, N-oxy-pyrimidinyl or N-oxy-pyrazinyl, each substituted with 1, 2 or 3 substituents each independently selected from: halogen; a hydroxyl group; c_1-4An alkyl group; c_3-6A cycloalkyl group; c_2-6An alkenyl group; c_2-6An alkynyl group; c_1-4An alkoxy group; c_1-4Alkoxy radical C_1-4An alkyl group; polyhalo C_1-4An alkyl group; polyhalo C_1-4An alkoxy group; a cyano group; a nitro group; NR (nitrogen to noise ratio)⁹R¹⁰；R¹¹-a carbonyl group; r¹¹-SO₂-；C_1-4Alkyl radicals substituted by hydroxy, NR⁹R¹⁰、R¹¹-carbonyl or R¹¹-SO₂-substitution; oxadiazolyl, optionally substituted by C_1-4Alkyl, polyhalo C_1-4Alkyl or C_3-6Cycloalkyl substitution; or dioxolanes, optionally substituted by 1 or 2C_1-4Alkyl substitution;

wherein R is⁹And R¹⁰And load R⁹And R¹⁰The nitrogen atoms of (a) together may form a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring; and is

WhereinR¹¹Is C_1-4Alkyl, hydroxy, amino, mono-or di- (C)_1-4Alkyl) amino, (hydroxy C)_1-4Alkyl) amino, (C)_1-4Alkoxy radical C_1-4Alkyl) amino, di (C)_1-4Alkyl) amino C_1-4Alkyl, pyrrolidinyl, piperidinyl, morpholinyl, N-methyl-piperazinyl, or C substituted with_1-4Alkyl groups: hydroxy, C_1-4Alkoxy radical, C_1-4Alkoxy radical C_1-4Alkyl, trifluoromethyl, pyrrolidinyl, piperidinyl, morpholinyl, N-methyl-piperazinyl, or 2-oxo-imidazolidin-1-yl.

Compounds of formula (I) of interest are those of formula (I) wherein one or more of the following definitions are used:

a) n is the integer 1, or n is the integer 2; or

b)R¹Is C_1-6Alkyl, which is selected from C_3-8Cyclic group substitution of cycloalkyl; or

c)R¹Is C_1-6An alkyl group substituted with a heterocycle selected from tetrahydropyranyl; or

d)R²Is C_2-6Alkyl, especially R²Is tert-butyl or-CH₂-a tert-butyl group; or

e)R³Is hydrogen; or

f)R⁴Is N-oxy-pyridyl; or

g)R⁴Is furyl, thienyl, oxadiazolyl, pyridyl, or pyridazinyl; each substituted with 1, 2 or 3 substituents each independently selected from: halogen; a hydroxyl group; c_1-4An alkyl group; c_1-4An alkoxy group; polyhalo C_1-4An alkyl group; polyhalo C_1-4An alkoxy group; a cyano group; NR (nitrogen to noise ratio)⁹R¹⁰；R¹¹-a carbonyl group; r¹¹-SO₂-; or optionally is covered with C_1-4An alkyl substituted oxadiazolyl; wherein R is⁹And R¹⁰Independently of one another, from hydrogen or R¹¹-a carbonyl group; and wherein R¹¹Is C_1-4Alkyl, amino, or morpholinyl.

In one embodiment, the present invention relates to those compounds of formula (I), the N-oxides, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein N is the integer 1 or 2; r¹Is a quilt C_3-8Cycloalkyl or tetrahydropyranyl substituted C_1-6An alkyl group; r²Is C_2-6An alkyl group; r³Is hydrogen; r⁴Is N-oxy-pyridyl, or R⁴Is furyl, thienyl, oxadiazolyl, pyridyl, or pyridazinyl; each substituted with 1, 2 or 3 substituents each independently selected from: halogen; a hydroxyl group; c_1-4An alkyl group; c_1-4An alkoxy group; polyhalo C_1-4An alkyl group; polyhalo C_1-4An alkoxy group; a cyano group; NR (nitrogen to noise ratio)⁹R¹⁰；R¹¹-a carbonyl group; r¹¹-SO₂-; or optionally is covered with C_1-4An alkyl substituted oxadiazolyl; wherein R is⁹And R¹⁰Independently of one another, from hydrogen or R¹¹-a carbonyl group; and wherein R¹¹Is C_1-4Alkyl, amino, or morpholinyl.

The compounds of formula (I-a) defined by the compounds of formula (I) in which n represents 1 and the compounds of formula (I-b) defined by the compounds of formula (I) in which n represents 2 can be prepared by known techniques of S-oxidation of intermediate (A).

The S-oxidation reaction can be carried out using 30% aqueous hydrogen peroxide, or by other oxidizing agents such as NaIO₄T-butyloxy chloride, acyl nitrite, sodium perborate and peracids such as mCPBA (m-chloroperbenzoic acid). The sulfide can be oxidized to the sulfoxide by adding another equivalent of hydrogen peroxide, KMnO₄Sodium perborate, oxone, mCPBA or similar agents are further oxidized to sulfones.If sufficient oxidant is present, the sulfide can be converted directly to sulfone without isolation of the sulfoxide.

The compounds of formula (I-b) defined by the compounds of formula (I) wherein n represents 2 may be prepared as described in scheme 1.

Scheme 1

The condensation reaction to obtain the compound of formula (I-b) may be carried out under acidic or basic conditions. Under acidic conditions in solvents such as acetic acid, H₂In O, methanol, ethanol, dioxane, toluene, or dichloroethane, in an organic acid such as acetic acid or in an inorganic acid such as HCl or H₂SO₄Or a combination thereof. The condensation reaction is carried out under alkaline conditions in a reaction-inert solvent such as DMSO or alcoholic NaOH solution in an inorganic base such as K₂CO₃In the presence of oxygen. The reaction can be conveniently carried out at a temperature ranging from room temperature to the reflux temperature of the reaction mixture. The reaction rate and yield may be increased by microwave-assisted heating, such as at 190 ℃ in dichloroethane as a solvent, possibly eliminating the need for additional acid or base addition.

Intermediate (a) may be prepared as described in scheme 2 below.

Scheme 2

This condensation reaction to obtain the intermediate of formula (A) can be carried out under similar conditions as described in scheme 1 for obtaining the compound of formula (I-b).

Intermediate (A) may also be prepared by reacting in the presence of a suitable base such as Cs₂CO₃In the presence of a reaction inhibitorIntermediate (XVI) is reacted with intermediate (XV) in an acidic solvent such as 2-propanone or dioxane, wherein L is a leaving group such as halogen, methanesulfonyloxy, benzenesulfonyloxy, trifluoromethanesulfonyloxy and similarly reactive leaving groups. Depending on the type of substituents present in intermediate (XV), it may be desirable to introduce a protecting group in intermediate (XV), which can be removed after the coupling reaction. The reaction can also be carried out over a catalyst such as Pd₂(dba)₃And a suitable ligand such as Xantphos.

The compounds of formula (I) prepared as described above may be synthesized as racemic mixtures of enantiomers, which may be separated from each other according to resolution methods known in the art. Those compounds of formula (I) obtained in racemic form can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization, and the enantiomers are released therefrom by means of a base. An alternative way of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by stereospecific methods of preparation. These methods advantageously use enantiomerically pure starting materials.

The compounds of formula (I), pharmaceutically acceptable salts and stereoisomeric forms thereof have selective cannabinoid receptor 2(CB2) agonistic properties as demonstrated in the pharmacological examples. Pharmacological example c.1 describes a method for determining CB1 and CB2 agonism, and the ratio of CB2 agonism to CB1 agonism is listed in table c.1.

The compounds of formula (I) are therefore useful as pharmaceuticals, in particular for the treatment of conditions or diseases mediated by the agonist activity of the cannabinoid 2 receptor, in particular CB 2. The compounds are then useful in the preparation of medicaments for the treatment of conditions or diseases mediated by CB2 receptor activity, in particular CB2 agonist activity.

Preferably, the present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition or disease selected from the group consisting of CB2 conditions or diseases.

Further, the present invention provides a method of treating a condition mediated by CB2 receptor activity in a mammalian subject, the method comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Cannabinoid receptor 2 mediated conditions or disorders are for example cardiovascular diseases such as atherosclerosis, hypertension, myocardial ischemia; chronic pain disorders such as hyperalgesia, neuropathic pain, peripheral pain, visceral pain, inflammatory pain, thermal hyperalgesia, nociceptive pain, fibromyalgia, chronic low back pain, and dental pain; inflammation, edema, cystitis, neuroinflammatory disorders, immune system disorders, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, gastrointestinal disorders, intestinal motility disorders, Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), crohn's disease, chronic liver injury (cirrhosis), cancer, prostate cancer, cancer pain, glioma, allergy, nausea and vomiting, asthma, chronic obstructive pulmonary disease, psoriasis, epilepsy, and bone loss disorders such as osteoporosis (hereinafter referred to as ' CB2 disorder or disease ').

The terms "treatment" and "treat," as used herein, refer to curative, palliative, and prophylactic treatment, including reversing, alleviating, and inhibiting the progression of, or preventing the disease, disorder, or condition for which the term is used, or one or more symptoms of the disease, disorder, or condition.

The compounds of the invention may exhibit less toxicity, good absorption, distribution, good solubility, less protein binding affinity other than the CB2 receptor, and less drug-drug interaction reduced by interaction with CYP3a4 and (en)2D 6.

In addition, the present invention provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I).

To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is incorporated in intimate admixture with at least one pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in a single dosage form, which is preferably suitable for oral administration, rectal administration, transdermal administration, or parenteral injection.

For example, in preparing the oral dosage compositions, any of the usual liquid pharmaceutical carriers may be employed, such as water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid pharmaceutical carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously useful. For parenteral injection compositions, the pharmaceutical carrier will consist essentially of sterile water, although other ingredients may be included to improve the solubility of the active ingredient. Injectable solutions may be prepared, for example, by using a pharmaceutical carrier comprising saline solution, dextrose solution, or a mixture of the two. Injectable suspensions may also be prepared by using suitable liquid carriers, suspending agents and the like. In compositions suitable for transdermal administration, the pharmaceutical carrier may optionally include a penetration enhancer and/or a suitable wetting agent, optionally in combination with minor proportions of suitable additives that do not cause significant deleterious effects on the skin. The additives may be selected for ease of application of the active ingredient to the skin and/or to aid in the preparation of the desired composition. These typical compositions may be administered in a variety of ways, such as transdermal patches, spot-on patches, or ointments. The addition salts of the compounds of formula (I) are significantly more suitable for the preparation of aqueous compositions due to the increased aqueous solubility than the corresponding base forms.

For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the pharmaceutical compositions of the present invention in dosage unit form. As used herein, "dosage unit form" refers to physically discrete units, suitably single doses, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonful, tablespoonful and the like, and segregated multiples thereof.

For oral administration, the pharmaceutical compositions of the present invention may take the form of solid dosage forms, for example, tablets (swallowable or chewable forms), capsules or soft gelatin capsules prepared by conventional methods with pharmaceutically acceptable excipients and carriers such as: binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, etc.), fillers (e.g., lactose, microcrystalline cellulose, calcium phosphate, etc.), lubricants (e.g., magnesium stearate, talc, silicon dioxide, etc.), disintegrants (e.g., potato starch, sodium starch glycolate, etc.), wetting agents (e.g., sodium lauryl sulfate), and the like. Such tablets may also be coated by methods well known in the art.

Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be formulated as a dry product for admixture with water and/or another suitable liquid carrier before use. Such liquid preparations may be prepared by conventional means, optionally with other pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose, hydroxypropylmethyl cellulose or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (e.g. almond oil, oil esters or ethyl alcohol), sweetening agents, flavouring agents, taste-masking agents and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).

Pharmaceutically acceptable sweeteners useful in the pharmaceutical compositions of the present invention preferably include at least one potent sweetener such as aspartame, potassium acesulfame, sodium cyclamate, alitame, dihydrochalcone sweetener, monellin (monellin), stevioside sucralose (4, 1 ', 6' -trichloro-4, 1 ', 6' -trideoxylactosucrose) or, preferably, saccharin, sodium saccharin or calcium saccharin, and optionally at least one bulk sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt (isomalt), glucose, hydrogenated glucose syrup, xylitol, caramel or honey. Intense sweeteners are typically used at low concentrations. For example, in the case of sodium saccharin, the concentration may range from about 0.04% to 0.1% (weight/volume) of the final formulation. Bulk sweeteners are usefully employed in relatively large concentrations ranging from about 10% to about 35%, preferably from about 10% to 15% (weight/volume).

The pharmaceutically acceptable flavoring agent which may mask the bitter tasting ingredient in a low dosage formulation is preferably a fruity flavoring agent, such as cherry, raspberry, blackcurrant or strawberry flavoring. The possibility of combining two flavours gives very good results. In high dose formulations, a more concentrated pharmaceutically acceptable flavoring such as caramel chocolate, mint cooler, Fantasy, etc. may be required. Various flavoring agents may be present in the final composition in a concentration range of about 0.05% to 1% (weight/volume). Combinations of said potent flavourings are advantageously used. It is preferred to use flavouring agents which do not undergo any change or loss of taste and/or colour in the environment of the formulation.

The compounds of formula (I) may be formulated for parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, including an added preservative. They may be employed, for example, as suspensions, solutions or emulsions in oily or aqueous media, and may contain formulatory agents such as isotonic agents, suspending agents, stabilizing agents and/or dispersing agents. Alternatively, the active ingredient may be presented in powder form for admixture with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

The compounds of formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter and/or other glycerides.

A therapeutically effective amount of a compound of formula (I) will be readily determined by the skilled artisan in treating diseases associated with cannabinoid receptor modulation based on the test results provided below. It is generally contemplated that a therapeutically effective dose will be from about 0.001mg/kg to about 50mg/kg body weight, more preferably from about 0.01mg/kg to about 10mg/kg body weight of the patient being treated. It is suitable to administer the therapeutically effective dose in two or more sub-doses and at suitable intervals throughout the day. The sub-doses may be formulated in unit dosage forms, for example each containing from about 0.1mg to about 1000mg, more particularly from about 1 to about 500mg of active ingredient per unit dosage form.

As used herein, a "therapeutically effective amount" of a compound is the amount of the compound that, when administered to a subject or animal, produces a sufficiently high level of the compound in the subject or animal to cause significant increase or decrease in cannabinoid receptor stimulation.

The precise dose and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient, and other pharmaceutical treatments which the patient may take, as is well known to those skilled in the art. In addition, the "therapeutically effective amount" may be decreased or increased, depending on the response of the intended oral care agent, and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned above are therefore only instructive.

Test section

In the operations described below, the following terms are used: 'DCM' denotes dichloromethane; 'DMF' represents N, N-dimethyl-formamide; 'THF' represents tetrahydrofuran; ' DIPE ' represents diisopropyl ether, ' DMF ' represents N, N-dimethyl-formamide, ' DMSO ' represents dimethyl sulfoxide, ' NaBH₃(CN) 'denotes sodium cyanoborotrihydroborate,' mCPBA 'denotes 3-chlorophenylperoxyformic acid,' Cs₂CO₃'means Cesium carbonate,' MgSO 4 'means magnesium sulfate,' NaHCO 3 'means monosodium carbonate,' NaBH₄'represents sodium tetrahydroborate (-1)' Na₂SO₄'means sodium sulfate,' NH₄Cl 'represents ammonium chloride,' K₂CO₃'means potassium carbonate,' NH₄HCO₃'means monoammonium carbonate,' NaOH 'means sodium hydroxide,' NaCl 'means sodium chloride,' NaHCO 3 'means sodium bicarbonate,' Pd₂(dba)₃' represents tris [ mu- [ (1, 2-. eta.: 4, 5-. eta.) - (1E, 4E) -1, 5-diphenyl-1, 4-pentadien-3-one]]Dipalladium, 'Xantphos' denotes (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis [ diphenylphosphine]And ' TFA ' represents trifluoroacetic acid, ' Et₃N 'represents triethylamine,' EtOAc 'represents ethyl acetate,' CH₃OH ' represents methanol, ' PPTS ' represents pyridinium p-toluenesulfonate and ' PS ' represents polystyrene.

Isolute HM-N^TMThe filter is a product of Argonaut (Foster City, CA 94404, USA) and is a short column containing a modified form of diatomaceous earth that can remove water from a sample in combinatorial chemistry applications. Extrelt^TMIs a product of Merck KgaA (Darmstadt, Germany) and is a short column containing diatomaceous earth.

For some compounds purified by reverse phase High Performance Liquid Chromatography (HPLC), the methods used are described below (indicated by HPLC method A, HPLC, method B, HPLC, method C in compound handling). These methods may be modified slightly by those skilled in the art as necessary to achieve more desirable results for the separation.

HPLC method A

The product was obtained by reverse phase high performance liquid chromatography (Shandon Hyperprep)C18 BDS (basic deactivated silica gel) 8 μm, 250g, i.d.5 cm). Three mobile phases (phase A: 0.25% NH) were used₄HCO₃An aqueous solution; phase B: CH (CH)₃OH; and C phase: CH (CH)₃CN). First, 75% A and 25% B were maintained at a flow rate of 40ml/min for 0.5 min. Then a gradient was used to 50% B and 50% C over 41 minutes at a flow rate of 80 ml/min. Then a gradient was applied to 100% C for 20 minutes at a flow rate of 80ml/min for an additional 4 minutes.

HPLC method B

The product was obtained by reverse phase high performance liquid chromatography (Shandon Hyperprep)C18 BDS (basic deactivated silica gel) 8 μm, 250g, i.d.5 cm). Three mobile phases (phase A: 0.25% NH) were used₄HCO₃An aqueous solution; phase B: CH (CH)₃OH; and C phase: CH (CH)₃CN). First, 75% A and 25% B were maintained at a flow rate of 40ml/min for 0.5 min. A gradient was then applied to 100% B over 41 minutes at a flow rate of 80 ml/min. Then a gradient was applied to 100% C for 20 minutes at a flow rate of 80ml/min for an additional 4 minutes.

HPLC method C

The product was obtained by reverse phase high performance liquid chromatography (Shandon Hyperprep)C18 BDS (basic deactivated silica gel) 8 μm, 250g, ID.5 cm). Two mobile phases (phase A: 0.25% NH) were used₄HCO₃An aqueous solution; phase B: CH (CH)₃CN). First, 85% A and 15% B were maintained at a flow rate of 40ml/min for 0.5 min. Then a gradient was used to 10% A and 90% B over 41 minutes at a flow rate of 80 ml/min. Then a gradient was applied to 100% C for 20 minutes at a flow rate of 80ml/min for an additional 4 minutes.

A. Synthesis of intermediates

Example A.1

a) Preparation ofIntermediate (1)

A mixture of 5-chloro-2-nitroaniline (0.16mol), 4-methoxybenzenethiol (0.16mol) and potassium hydroxide (0.30mol) in ethanol (500ml) was stirred and refluxed for 2 hours. The reaction mixture was cooled. The reaction mixture was cooled. The precipitate was filtered off, washed with ethanol and dried to yield 48.5g of intermediate (1).

b) Preparation ofIntermediate (2)

2, 2-dimethylpropionyl chloride (0.14mol) was added dropwise to a mixture of intermediate (1) (0.125mol) and pyridine (500 ml). The reaction mixture was stirred and half refluxed for 2 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was taken up in DCM and washed with water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE containing 1 drop of hexane. The precipitate was filtered off, washed and dried to yield 28.9g of intermediate (2).

c) Preparation ofIntermediate (3)

A mixture of intermediate (2) (0.0748mol), Fe powder (56g) and acetic acid (10ml) in water (500ml) was stirred and refluxed for 4 hours. The mixture was cooled. The solvent was decanted. The residue was taken up in methanol and THF. The mixture was filtered through celite. The solvent was evaporated. The residue was taken up in DCM. The organic layer was separated and filtered through MgSO 4 and Celite. The solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried to yield 21g of intermediate (3).

d) Preparation ofIntermediate (4)

Nitrogen was bubbled through a mixture of intermediate (3) (0.03mol), DCM (600ml) and acetic acid (5ml) at room temperature. Cyclohexanecarboxaldehyde (4g) was added. After 5 minutes, add NaBH₃(CN) (1.8 g). The reaction mixture was stirred at room temperature for 1 hour. Water was added. The mixture is extracted. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried to yield 10.5g of intermediate (4).

Intermediate (81)

Intermediate (81) was prepared in a similar operation as intermediate (4) using 3, 3-dimethylbutyraldehyde.

Intermediate (96)

Intermediate (96) was prepared in a similar procedure as intermediate (4) using 2, 2-dimethylpropionaldehyde.

Intermediate (99)

Intermediate (99) was prepared in a similar procedure as intermediate (4) using tetrahydro-2H-pyran-4-acetaldehyde.

Intermediate (102)

Intermediate (102) was prepared in a similar procedure as intermediate (4) using tetrahydro-2H-thiopyran-4-carbaldehyde. In addition, for the synthesis of intermediate (102), titanium (IV) isopropoxide (4:1) was added.

Intermediate (102) was also run analogously to intermediate (4) using methyltetrahydro-2H-thiopyran-4-ylketone. And (4) preparation.

Intermediate (105)

Intermediate (105) was prepared in a similar procedure as intermediate (4) using 1, 4-dioxaspiro [4.5] decane-8-carbaldehyde. In addition, for the synthesis of intermediate (105), titanium (IV) isopropoxide (4:1) was added.

Intermediate (92)

Intermediate (92) was prepared in a similar procedure as intermediate (4) using cyclobutanecarboxaldehyde. In addition, for the synthesis of intermediate (92), titanium (IV) isopropoxide (4:1) was added.

Intermediate (119)

Intermediate (119) was prepared in a similar operation as intermediate (4) using 2-ethylbutanal.

Intermediate (122)

Intermediate (122) was prepared in a similar procedure as intermediate (4) using 2-methylpentanal.

Intermediate (125)

Intermediate (125) was prepared in a similar procedure as intermediate (4) using tetrahydro-2, 2-dimethyl-2H-pyran-4-carbaldehyde.

e) Preparation ofIntermediate (5)

A mixture of intermediate (4) (0.0045mol) and acetic acid (40ml) was stirred and refluxed for 6 hours. The mixture was cooled and the solvent was evaporated. The residue was taken up in DCM and water. The mixture was neutralized with NaHCO 3. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: DCM/methanol 100/0 to 98/2). The product fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off, washed and dried to yield 1g of intermediate (5).

Intermediate (82)

Intermediate (82) was prepared from intermediate (81) in a similar procedure as intermediate (5).

Intermediate (97)

Intermediate (97) was prepared from intermediate (96) in a similar procedure as intermediate (5).

Intermediate (100)

Intermediate (100) was prepared from intermediate (99) in a similar procedure as intermediate (5).

Intermediate (103)

Intermediate (103) was prepared from intermediate (102) in a similar operation as intermediate (5).

Intermediate (106)

Intermediate (106) was prepared from intermediate (105) in a similar operation as intermediate (5).

Intermediate (110)

Intermediate (110) was prepared from intermediate (92) in a similar operation as intermediate (5).

Intermediate (120)

Intermediate (120) was prepared from intermediate (119) in a similar procedure as intermediate (5).

Intermediates(123)

Intermediate (123) was prepared from intermediate (122) in a similar operation as intermediate (5). In addition, a few drops of HCl were added to the reaction mixture.

Intermediate (126)

Intermediate (126) was prepared from intermediate (125) in a similar operation as intermediate (5).

f) Preparation ofIntermediate (6)

A mixture of intermediate (5) (0.019mol) and trifluoroacetic acid (200ml) was stirred and refluxed for 5 hours. The mixture was cooled and the solvent was evaporated. The residue was taken up in ethyl acetate and water. The mixture was neutralized with NaHCO 3. The organic layer was separated, dried, filtered and the solvent was evaporated to give 8g of intermediate (6).

Intermediate (83)

Intermediate (83) was prepared from intermediate (82) in a similar procedure as intermediate (6).

Intermediate (98)

Intermediate (98) was prepared from intermediate (97) in a similar procedure as intermediate (6).

Intermediate (101)

Intermediate (101) was prepared from intermediate (100) in a similar operation as intermediate (6).

Intermediate (104)

Intermediate (104) was prepared from intermediate (103) in a similar procedure as intermediate (6).

Intermediate (118)

Intermediate (118) was prepared from intermediate (106) in a similar operation as intermediate (6).

Intermediate (111)

Intermediate (111) was prepared from intermediate (110) in a similar procedure as intermediate (6).

Intermediate (121)

Intermediate (121) was prepared from intermediate (120) in a similar procedure as intermediate (6).

Intermediate (124)

Intermediate (124) was prepared from intermediate (123) in a similar operation as intermediate (6).

Intermediate (127)

Intermediate (127) was prepared from intermediate (126) in a similar operation as intermediate (6).

Example A.2

a) Preparation ofIntermediate (7)

Nitrogen was bubbled through a mixture of intermediate (3) (0.032mol), DCM (650ml) and acetic acid (5ml) at room temperature. tetrahydro-2H-pyran-4-carbaldehyde (0.039mol) was added. After 5 minutes, add NaBH₃(CN) (2 g). The reaction mixture was stirred at room temperature for 1 hour. Water was added. The mixture is extracted. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried to yield 12g of intermediate (7).

b) Preparation ofIntermediate (8)

A mixture of intermediate (7) (0.027mol) and acetic acid (200ml) was stirred and refluxed for 6 hours. The mixture was cooled and the solvent was evaporated. The residue was taken up in DCM and water. The mixture was neutralized with NaHCO 3. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: DCM/CH)₃OH 100/0 to 96/4). The product fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off, washed and dried to yield 8g of intermediate (8).

c) Preparation ofIntermediate (9)

A mixture of intermediate (8) (0.019mol) in trifluoroacetic acid (200ml) was stirred and refluxed for 5 hours. The mixture was cooled and the solvent was evaporated. The residue was taken up in ethyl acetate and water. The mixture was neutralized with NaHCO 3. The organic layer was separated, dried, filtered and the solvent was evaporated to give 7g of intermediate (9).

Example A.3

a) Preparation of

Intermediate (10)

3, 3-dimethylbutyryl chloride (0.20mol) was added dropwise to a mixture of intermediate (1) (0.16mol) in pyridine (600ml) at room temperature, followed by stirring at room temperature for 1 hour. The solvent was evaporated. The residue was taken up in DCM. The mixture was washed with water, dilute aqueous HCl and then dilute aqueous NH 4 Cl. The separated organic layer was dried, filtered and the solvent was evaporated again to give 62g of intermediate (10).

b) Preparation ofIntermediate (11)

A mixture of intermediate (10) (0.12mol) in THF (500ml) was hydrogenated at a temperature below 30 ℃ with a mixture of platinum on activated carbon (5%) + vanadium pentoxide (0.5%) (5g) as catalyst. After absorption of hydrogen (3 equivalents), the catalyst is filtered off and the solvent of the filtrate is evaporated. The residue was suspended in DIPE. The precipitate was filtered off, washed and dried to yield 39g of intermediate (11).

c) Preparation ofIntermediate (12)

A mixture of intermediate (11) (0.07mol) in DCM (1300ml) and acetic acid (10ml) was sparged with nitrogen at room temperature. tetrahydro-2H-pyran-4-carbaldehyde (0.088mol) was added to the reaction mixture at room temperature, followed by stirring at room temperature for 30 minutes. Sodium cyanoborohydride (4.5g) was added in 10 parts at room temperature. The reaction mixture was stirred for 30 minutes. Water was added and after extraction, the separated organic layer was dried, filtered and the solvent was evaporated. The residue was suspended in DIPE. The precipitate was filtered off, washed and dried to yield 23.5g of intermediate (12).

Intermediate (76)

Intermediate (76) was prepared in a similar procedure as intermediate (12) using tetrahydro-2H-pyran-2-carbaldehyde.

d) Preparation ofIntermediate (13)

Intermediate (12) (0.051mol) was stirred in acetic acid (500ml) at reflux temperature for 2 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was taken up in DCM and water. The mixture was neutralized with NaHCO 3 to pH7. After extraction, the separated organic layer was dried, filtered and the solvent was evaporated again to give 23g of intermediate (13).

Intermediate (77)

Intermediate (77) was prepared from intermediate (76) in a similar procedure as intermediate (13).

e) Preparation ofIntermediates(14)

Intermediate (13) (0.0044mol) in trifluoroacetic acid (20ml) was heated in a microwave at 150 ℃ for 15 min. The reaction mixture was cooled and the solvent was evaporated. The residue was taken up in ethyl acetate and water. The mixture was neutralized with NaHCO 3 to pH7. After extraction, the separated organic layer was dried, filtered and the solvent was evaporated again to give 2.2g of intermediate (14).

Intermediate (78)

Intermediate (78) was prepared from intermediate (77) in a similar operation as intermediate (14).

Example A.4

a) Preparation of

Intermediate (15)

2, 2-dimethylbutyric acid chloride (0.2mol) was added to intermediate (1) (0.18mol) in pyridine (550 ml). The reaction mixture was stirred and half refluxed for 2 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was partitioned between water and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was suspended in DIPE. The resulting precipitate was filtered off and dried to yield 62g of intermediate (15).

b) Preparation ofIntermediate (16)

A mixture of intermediate (15) (0.16mol) in THF (500ml) was reacted at 25 ℃ with platinum on carbon (5%, 5g) as catalyst in a small amount of V₂O₅Hydrogenation in the presence. After absorption of hydrogen, the catalyst was filtered off and additional platinum on carbon (5%, 5g) and a small amount of V were added to the filtrate₂O₅. Hydrogenation was continued until absorption (3 equivalents). The catalyst is filtered off and the filtrate is evaporated again. The residue was suspended in DIPE, filtered off and dried to give intermediate (16).

c) Preparation ofIntermediate (17)

A mixture of intermediate (16) (0.056mol) in acetic acid (300ml) was stirred and refluxed for 3 hours, then cooled and the solvent was evaporated. The residue was partitioned between water and DCM. The mixture was neutralized with aqueous NaHCO 3. The organic layer was separated, dried, filtered and the solvent was evaporated. A portion of the residue (2.5g) was dissolved in ethanol (50 ml). Adding NaBH₄(0.160g), the reaction mixture was stirred and half refluxed for 2 hours. Adding additional NaBH₄(0.500g), the reaction mixture was stirred and half refluxed for 20 hours. The remaining residue was dissolved in ethanol. Adding NaBH₄(6g) The reaction mixture was then stirred and half refluxed for 20 hours. The reaction mixture was cooled. Water was added and the solvent was evaporated. The residue was partitioned between water and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was suspended in DIPE, filtered off and dried to yield 15g of intermediate (17).

d) Preparation ofIntermediate (18)

The reaction was carried out under nitrogen atmosphere. A solution of intermediate (17) (0.021mol) in THF (250ml) was stirred. Sodium hydride (0.025mol) was added and the reaction mixture was stirred at 40 ℃ for 30 minutes. Cyclobutylmethyl bromide (0.025mol) was added and the reaction mixture was stirred at 40 ℃ for 2 hours. More cyclobutyl-methyl bromide (1 eq) was added and the reaction mixture was stirred at 60 ℃ for 20 h. More sodium hydride (0.3g) was added. Adding additional cyclobutylmethyl(1g) and the reaction mixture was stirred at 60 ℃ for 20 hours. Additional sodium hydride (0.3g) was added followed by cyclobutylmethyl bromide (1 g). After completion of the reaction, the reaction mixture was cooled. The solvent was evaporated. The residue was partitioned between water and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH)₂Cl₂/CH₃OH 99/1). The product fractions were collected and the solvent was evaporated, yielding 1.2g of intermediate (18).

e) Preparation ofIntermediate (19)

The reaction is carried out in a microwave oven. Intermediate (18) (0.003mol) in trifluoroacetic acid (15ml) was heated at 110 ℃ for 15 min. The reaction mixture was cooled and the solvent was evaporated. The residue was partitioned between water and ethyl acetate. The mixture was neutralized with aqueous NaHCO 3. The organic layer was separated, dried, filtered and the solvent was evaporated to give intermediate (19).

Example A.5

Preparation ofIntermediate (20)

A mixture of morpholine (0.007mol) in THF (30ml) and triethylamine (0.800g) was stirred at room temperature. A solution of 5-bromo-2-thiophenesulfonyl chloride (0.005mol) in THF (10ml) was added slowly at room temperature. The reaction mixture was stirred overnight at room temperature in a closed reaction vessel. The reaction mixture was then taken up in ethyl acetate, washed with water, 1N HCl (20ml), saturated aqueous NaHCO 3, then dried, filtered and the solvent evaporated to yield 1.6g of intermediate (20).

Example A.6

Preparation ofIntermediate (21)

The ammonia was bubbled through a solution of THF (20ml) in excess. A solution of 2-bromo-5-furancarbonyl chloride (0.005mol) in THF (10ml) was added dropwise. The resulting reaction mixture was stirred at 50 ℃ for 3 hours. DCM (100ml) was added. Water (40ml) was added. The biphasic mixture was shaken for a moment. The layers were separated and the organic layer was dried, filtered and the solvent was evaporated again to give 0.970g of intermediate (21).

Example A.7

Preparation ofIntermediate (22)

The reaction was carried out under a stream of argon. Intermediate (8) (0.00235mol) was dissolved in degassed trifluoroacetic acid (20ml) and stirred at 80 ℃ overnight. The solvent was evaporated. The residue was taken up in dehydrotoluene. The mixture was then washed with degassed saturated aqueous NaHCO 3. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was dissolved in degassed dioxane (20 ml). 3-bromo-2, 4-pentanedione (0.00235mol) and Cs were added₂CO₃(1.15 g). The reaction mixture was stirred at 100 ℃ for 3 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was taken up in ethyl acetate. The organic layer was separated, washed with water, then brine, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: hexane/ethyl acetate 1/2). The product fractions were collected and the solvent was evaporated, yielding 0.090g of intermediate (22).

Example A.8

Preparation ofIntermediate (25)

A mixture of intermediate (9) (0.002mol) and 5-bromo-2-thiophenesulfonamide (0.0025mol) in dioxane (40ml) was degassed and a stream of nitrogen was introduced into the reaction mixture (3 times). Then adding Cs₂CO₃(0.004mol), the mixture is degassed again and a stream of nitrogen is introduced into the reaction mixture again (twice). Then Pd is added₂(dba)₃(0.0001mol) and Xantphos (0.0001mol), degassed and subjected to nitrogen (twice). A nitrogen balloon was placed over the reaction mixture and the reaction mixture was stirred at 100 ℃ overnight. The mixture was cooled, filtered and the filtrate was evaporated again to give intermediate (25).

The heterocyclic reagent 5-bromo-2-thiophenesulfonamide may be replaced by other heterocycles such as: 5-bromo-2 (1H) -pyridone, 4-chloro-pyridine hydrochloride, 1- (6-chloro-3-pyridinyl-1-ethanone, 5-bromo-2-thiophenesulfonamide, 3- (bromo-3-thienyl) -5-methyl-1, 2, 4-oxadiazole, 2- (ethylsulfonyl) -5-iodo-thiophene, 4-bromo-1H-pyridin-2) one, 4-bromo-2-ethoxy-pyridine, 2, 4, 6-trichloropyridine, 4-chloro-2-methyl-pyridine, 3-chloro-6-methoxy-pyridazine, 4-chloro-3- (trifluoromethyl) pyridine hydrochloride, n- (4-chloro-2-pyridyl) -acetamide, 4-bromo-2-methyl-pyridine, 4-bromo-2-fluoro-pyridine, 1- (5-bromopyridin-2-yl) ethanone, 2-methylsulfonyl-5-bromopyridine, intermediate (20), intermediate (21), 4-bromo-2-chloropyridine, 2-chloro-4-pyrimidinecarboxamide, 6-chloro-3-pyridinecarboxylic acid, methyl ester, 5-bromo-3-pyridinecarbonitrile, 5-bromo-2 (1H) -pyridone, 1- (5-bromo-2-thienyl)) ethanone, 5-bromo-2-thiophenecarbonitrile, 5-bromo-2-pyridinecarbonitrile ], 1- (4-iodophenyl) -ethanone, 5-bromo-2-methoxy-pyridine, 2- (4-bromo-2-furyl) -1, 3-dioxolane, 5-bromo-2- (methylsulfonyl) pyridine, 2-bromo-5- (methylsulfonyl) thiophene, 5-bromo-N-ethyl-2-thiophenesulfonamide, 5-bromo-2-furancarbonitrile, intermediate 34, 4- [ (4, 5-dibromo-2-thienyl) sulfonyl ] morpholine, 4- [ (6-chloro-3-pyridyl) sulfonyl ] -morpholine, 2-chloro-5- (methylsulfonyl) pyridine, intermediate 36, 5-bromo-2-thiophenecarboxamide, 1- [ (5-bromo-2-furyl) carbonyl ] pyrrolidine, 3-chlorobenzene-peroxycarboxylic acid, 4- [ (5-bromo-2-thienyl) carbonyl ] morpholine, 4- [ (5-bromo-2-furyl) carbonyl ] morpholine, 5-bromo-4-methyl-2-thiophenecarboxylic acid, methyl ester, 4- [ (4, 5-dibromo-2-thienyl) sulfonyl ] morpholine, 3-chloro-6-methoxypyridazine, 6-bromo-2-pyridinecarbonitrile, 4-bromo-2-methylpyridine, 4-chloro-2-methyl-pyrimidine, 4-bromo-2-fluoropyridine, 4-bromo-3-methoxypyridine, 3-iodo-2- (trifluoromethyl) pyridine, intermediate (84), intermediate (116), 4-chloropyridine hydrochloride (1:1), intermediate (129), intermediate (135), 2-chloro-5-thiazole-carbonitrile, 4-bromo-2 (1H) -pyridone, and 4-bromo-2-ethoxypyridine, to prepare further compounds of the invention.

The starting material intermediate (9) may be replaced by, for example, the following intermediates: intermediate (6), intermediate (14), intermediate (62), intermediate (66), intermediate (70), intermediate (78), intermediate (83), intermediate (98), intermediate (101), intermediate (104), intermediate (111), intermediate (118), intermediate (121), intermediate (124), intermediate (127) to prepare further compounds of the invention.

The following intermediates were prepared from intermediate (9) following a similar procedure as intermediate (25) (example a.8) and using the indicated variable heterocyclic reagent.

The following intermediates were prepared following a similar procedure as intermediate (25) (example a.8) but starting from intermediate (111) and 4-bromo-2-fluoropyridine (as the heterocyclic reagent).

Intermediate (112)

Example A.9

a) Preparation of

Mixing Cs₂CO₃(0.0061mol) to 4-bromo-2 (1H) -pyridinone (0.004mol) in dioxane (10 ml). The mixture was degassed three times with nitrogen. A degassed solution of intermediate (9) (0.0023mol) in dioxane (10ml) was added. The reaction mixture was degassed again. Adding Pd₂(dba)₃(0.047g) and Xantphos (0.060 g). The reaction mixture was degassed and then stirred at 100 ℃ overnight. The reaction mixture was cooled. DCM (150ml) was added. 5% NH 4 Cl aqueous solution (150ml) was added and mixed. The layers are separated. The aqueous phase was extracted with DCM (100 ml). The combined organic layers were dried, filtered and the solvent was evaporated. The residue was purified by Combiflash flash column chromatography (eluent: CH)₂Cl₂/CH₃OH from 100/0 to 94/6). The product fractions were collected and the solvent was evaporated, yielding 0.93g of intermediate (26).

b-1) preparationIntermediate (27)

Andintermediate (43)

Intermediate (26) (0.005mol), chlorodifluoroacetic acid sodium salt (0.01mol) and K₂CO₃(0.006ml) in DMF/H₂The mixture in O (5ml) was degassed for 15 minutes. The reaction mixture was stirred at 100 ℃ overnight. The reaction mixture was cooled and a mixture (4ml) of HCl 12N and water was added (ratio 1/1.5). The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by reverse phase HPLC (gradient elution using NH 4 HCO 3 buffer (0.25% in water)/CH₃OH/CH₃CN). Collecting two different productsFractions, work up, to give crude intermediate (43) (used as such in the next reaction) and 0.221g of intermediate (27).

b-2) preparationIntermediate (47)

Andintermediate (48)

1, 1, 1-trifluoro-2-iodoethane (0.0075mol) was added to a mixture of intermediate (26) (0.005mol) and sodium hydride (0.006mol) in DMF (5 ml). The reaction mixture was stirred at 0 ℃ for 4 hours. The reaction mixture was partitioned between DCM and water. The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by reverse phase HPLC (gradient elution using NH 4 HCO 3 buffer (0.25% in water)/CH₃OH/CH₃CN) purification. The desired product fractions were collected and reprocessed to yield 0.176g of intermediate (48) (E-isomer) and 0.367g of intermediate (47) (Z-isomer).

b-3) preparationIntermediate (55)

A mixture of intermediate (26) (0.000722mol), 2, 2, 2-trifluoro-ethanol, 1- (4-methyl-benzenesulfonate) (0.00144mol) and potassium carbonate (0.132g) in DMF (5ml) was heated to 60 ℃. The reaction mixture was extracted with DCM and water. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by reverse phase HPLC (gradient elution using NH 4 HCO 3 buffer (0.25% in water)/CH₃OH/CH₃CN). The desired product fractions were collected and the solvent was evaporated to yield 0.116g of intermediate (55).

Intermediate (58) was prepared in a similar operation as intermediate (55) from intermediate (23) and 1, 1, 2, 2, 3, 3, 4, 4, 4-nonafluoro-1-butanesulfonic acid, 2, 2, 2-trifluoroethyl ester.

Intermediate (58)

Example A.10

Preparation ofIntermediate (28)

Hydroxylamine hydrochloride (0.000211mol) and then water (0.5ml) were added to a solution of intermediate (22) (0.000211mol) dissolved in methanol (3.5ml), and stirred at 60 ℃ to 70 ℃ overnight. The reaction mixture was cooled and diluted with chloroform. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: ethyl acetate/hexane 50/50). The product fractions were collected and the solvent was evaporated, yielding 0.050g of intermediate (28).

Example A.11

a) Preparation ofIntermediate (29)

Mixing Cs₂CO₃(0.0032mol) was added to 4-chloro-2-pyridinecarboxamide (0.00318mol) in dioxane (10 ml). The mixture was degassed three times with nitrogen. A degassed solution of intermediate (9) (0.003mol) in dioxane (10ml) was added. The reaction mixture was degassed again. Adding Pd₂(dba)₃(0.100g) and Xantphos (0.130 g). The reaction mixture was degassed and then placed in a sealed reaction vessel under nitrogen atmosphere and then stirred at 100 ℃ overnight. The reaction mixture was cooled and water (2) was added00 ml). The mixture was extracted with DCM (2 × 150 ml). The combined organic layers were dried, filtered and the solvent was evaporated. The residue was purified by reverse phase HPLC. The product fractions were collected and the solvent was evaporated, yielding 0.6g of intermediate (29).

b) Preparation ofIntermediate (30)

Intermediate (29) (0.00075mol) in DMF (5ml) was cooled in an ice bath. Phosphorus trichloride (0.0016mol) was added dropwise. The reaction mixture was stirred for 4 hours with mixing at 0 ℃ to 5 ℃. The reaction mixture was poured into ice water (75 ml). The pH was neutralized by addition of NaHCO 3. The resulting precipitate was filtered off, washed with water and dried to yield 0.270g of intermediate (30).

Example A.12

Preparation ofIntermediate (31)

Intermediate (26) (0.000722mol), 2, 2, 2-trifluoroethanol, 4-methyl-benzenesulfonate (0.00144mol) and K₂CO₃A mixture of (0.132g) in DMF (3ml) was heated to 60 ℃. The reaction mixture was extracted with DCM and water. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by reverse phase HPLC (gradient elution using NH 4 HCO 3 buffer (0.25% in water)/CH₃OH/CH₃CN). The product fractions were collected and the solvent was evaporated. 0.085g of intermediate (31) was obtained.

Example A.13

Preparation ofIntermediate (32)

Intermediate (9) (up to 0.0016mol), methyl 6-chloro-3-picolinate (0.004mol) and Cs₂CO₃(0.003mol) A mixture in dioxane (10ml) was stirred at room temperature overnight. The solvent was evaporated under N2 flow. The residue was partitioned between DCM and water. The separated organic layer was dried through an Isolute filter and the solvent was evaporated. The residue was purified by reverse phase HPLC. The product fractions were collected and the solvent was evaporated, yielding 0.344g of intermediate (32).

The heterocyclic reagent methyl 6-chloro-3-picolinate may be replaced by a heterocycle such as: 2-chloro-5- (trifluoromethyl) pyridine, 2-chloro-3-pyridinecarbonitrile, 2-chloro-4- (trifluoromethyl) pyridine, 2-chloro-6- (trifluoromethyl) pyridine to prepare further intermediates.

Example A.14

Preparation ofIntermediate (34)

A mixture of sodium bicarbonate (0.570g) and sodium sulfite (0.800g) in water (15ml) was stirred. A solution of 4, 5-dibromo-2-thiophenesulfonyl chloride (0.005mol) in THF (10ml) was added. The resulting mixture was stirred at 75 ℃ for 2 hours. The mixture was then cooled to 30 ℃. Methyl iodide (1.4ml) was added to the reaction mixture, and the resulting reaction mixture was stirred at 50 ℃ overnight, then cooled, taken up in ethyl acetate, washed with water, and the layers were separated. The aqueous phase was re-extracted with ethyl acetate. The organic layers were combined, dried, filtered and the solvent was evaporated again to give 1.120g of intermediate (34).

Example A.15

a) Preparation ofIntermediate (35)

mCPBA (77%) (5.7g) was added to a mixture of 2-methyl-3- (methylthio) furan (1.4g, 0.011mol) in chloroform (50ml) at room temperature (slight exotherm). The reaction mixture was stirred for 2 hours and then washed with water and NaOH solution (30%). The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated to give 1.75g of intermediate (35).

b) Preparation ofIntermediate (36)

Intermediate (35) (0.004mol) was stirred in DMF (7 ml). 1-bromo-2, 5-pyrrolidinedione (0.0048mol) was carefully added over a period of 2 minutes. The reaction mixture was stirred for 1 hour. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated to give 1.00g of intermediate (36).

Example A.16

Preparation ofIntermediate (37)

Andintermediate (38)

A mixture of intermediate (26) (0.00116mol) and sodium hydride/mineral oil (60%) (0.0015mol) in DMF (10ml) was stirred at 60 ℃ for 30 min. The mixture was then allowed to cool to room temperature. Methyl iodide (0.0015mol) was added and the resulting reaction mixture was shaken at room temperature overnight. Ethyl acetate (100ml) was added. Water (100ml) was added and mixed thoroughly. The aqueous phase was extracted with ethyl acetate (100 ml). The combined organic layers were dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by reverse phase HPLC. Two product fractions were collected and their solvents were evaporated to yield 0.36g of intermediate (37) and 0.015g of intermediate (38).

Example A.17

Preparation ofIntermediate (39)

2, 4, 6-trichloropyridine (0.01034mol), Cs₂CO₃(3.3g)、Pd₂(dba)₃A mixture of (0.130g) and Xantphos (0.163g) in degassed dioxane was stirred. A solution of intermediate (9) (0.0047mol) in dioxane was added. The reaction mixture was heated at 100 ℃ for 20 hours, then cooled, filtered and the solvent of the filtrate was evaporated. The residue was partitioned between water and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated again to give intermediate (39) as a mixture of regioisomers.

Example A.18

Preparation ofIntermediate (40)

All equipment was purged with N2 and dried by heating. The reaction was carried out under Ar flow.

Intermediate (8) (0.00187mol) was dissolved in degassed TFA (15ml) and stirred at 85 ℃ for 4 h. The mixture was cooled. The solvent was evaporated under vacuum. The residue was taken up in degassed toluene. The organic layer was separated, washed with degassed aqueous NaHCO "3" (2X50ml), dried, filtered and the solvent evaporated in vacuo to give a yellow foam (R) ((R))^*). Under Ar, 4-bromo-5-Fluoro-2-methoxypyridine (1.3 equiv.; 0.500g) was dissolved in degassed dioxane (10 ml). Adding Cs₂CO₃(0.914g) to give a suspension (^**). The residual oil (C)^*) To this suspension was added a solution in degassed dioxane (10ml) ((^**). Then, Pd was added₂(dba)₃(0.029g) and Xantphos (0.032 g). The resulting brown reaction suspension was stirred at 100 ℃ overnight. The reaction mixture was cooled and the solvent was evaporated. The residue was dissolved in ethyl acetate and then washed with aqueous NaHCO 3 and again with brine. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel. The product fractions were collected and the solvent was evaporated, yielding 0.5113g of intermediate (40).

Example A.19

a) Preparation ofIntermediate (139)

A mixture of NaHCO 3 (0.570g) and sodium sulfite (0.800g) in water (15ml) was stirred. A solution of 5-bromo-6-chloro-3-pyridinesulfonyl chloride (0.005mol) in THF (10ml) was added. The resulting mixture was stirred at 75 ℃ for 2 hours. The mixture was then cooled to 30 ℃. Methyl iodide (1.4ml) was added to the reaction mixture, and the resulting reaction mixture was stirred at 50 ℃ overnight, then cooled, taken up in ethyl acetate, washed with water, and the layers were separated. The aqueous phase was extracted again with ethyl acetate. The combined organic layers were dried (MgSO 4), filtered and the solvent evaporated to give 1.400g of intermediate (139).

b) Preparation ofIntermediate (41)

Mixing Cs₂CO₃(0.00307mol) was added to intermediate (1) in dioxane (10ml)39) (0.003 mol). The mixture was degassed ((3X) vacuum, followed by N injection₂). A degassed solution of intermediate (9) (0.0023mol) in dioxane (10ml) was added. The reaction mixture was degassed again. Adding Pd₂(dba)₃(0.047g) and Xantphos (0.060 g). The reaction mixture was stirred at 100 ℃ overnight. The reaction mixture was cooled. DCM (150ml) was added. The organic layer was washed with water (150 ml). The aqueous layer was extracted again with DCM (150 ml). The combined organic layers were dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by reverse phase HPLC (gradient elution using NH 4 HCO 3 buffer (0.25% in water)/CH₃OH/CH₃CN). The product fractions were collected and the solvent was evaporated, yielding 0.83g of intermediate (41) as a mixture of two compounds.

Example A.20

Preparation ofIntermediate (42)

4-bromo-5-fluoro-2 (1H) -pyridone (0.0026mol) was dissolved in degassed dioxane (10 ml). Adding Cs₂CO₃(0.00325 mol). A solution of intermediate (9) (0.002167mol) in dioxane (10ml) was added and the mixture stirred. Xantphos (0.040g) and Pd were added₂(dba)₃(0.120g), and the resulting reaction mixture was stirred for 2 hours. The solvent was evaporated under vacuum. The residue was partitioned between chloroform (100ml) and water (2 × 75 ml). The organic layer was separated, washed with brine (75ml) and dried (Na)₂SO₄) Filtered and the solvent evaporated again (vacuum pump). The residue was purified by column chromatography over silica gel (eluent: ethyl acetate/CH)₃OH 9/1). The product fractions were collected and the solvent was evaporated, yielding 0.474g of intermediate (42).

Example A.21

a) Preparation ofIntermediate (49)

The reaction was carried out under a stream of nitrogen. Phosphorus trichloride (21ml) was added dropwise to a mixture of intermediate (1) (0.13mol) and 2-cyano-2-methyl-propionic acid (0.17mol) in pyridine (600ml) at 0 ℃ with vigorous stirring at 0 ℃. The reaction mixture was allowed to warm to room temperature. Water (1500ml) was added. The mixture was extracted with ethyl acetate. The separated organic layer was dried (MgSO 4), filtered and the solvent evaporated to give 44g of intermediate (49).

b) Preparation ofIntermediate (50)

A mixture of intermediate (49) (0.010mol) in THF (100ml) was hydrogenated at room temperature with a mixture of activated palladium on carbon (10%) and vanadium pentoxide (0.5%) (5g) as a catalyst in the presence of a thiophene/DIPE solution (4%) (1 ml). After uptake of hydrogen (3 equivalents), the catalyst was filtered off and the filtrate was diluted with methanol (300 ml). Acetic acid (2ml) and then tetrahydro-2H-pyran-4-carbaldehyde (0.015mol) were added to the mixture. Nitrogen was bubbled through the reaction mixture for 10 minutes. Sodium cyanoborohydride (400mg) was added to the reaction mixture. The solvent of the reaction mixture was evaporated to 1/3 of the original volume. DCM (700ml) and water (500ml) were added to the concentrate. After extraction, the separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated to give 4.5g of intermediate (50).

c) Preparation ofIntermediate (51)

Intermediate (50) (0.0066mol) in acetic acid (15ml) was heated in a microwave at 160 ℃ for 10 min. The solvent was evaporated. The reaction was carried out 8 times. All residues were combined and then taken up in DCM. Mixing the mixture withH₂O/NaHCO 3. After extraction, the separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by combiflash column chromatography over silica gel (eluent: DCM/CH)₃OH from 100/0 to 98/2). The product fractions were collected and the solvent was evaporated, yielding 10.5g of intermediate (51).

d) Preparation ofIntermediate (52)

Intermediate (51) (0.0023mol) in TFA (10ml) was heated in a microwave at 150 ℃ for 15 min. The reaction mixture was cooled and the solvent was evaporated. The residue was taken up in ethyl acetate and water and then neutralized with NaHCO 3. After extraction, the separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated. This operation was repeated 2 additional times to give a combined residue, yielding 3g of intermediate (52).

e) Preparation ofIntermediate (53)

Firstly, Pd is firstly added₂(dba)₃(200mg), then Xantphos (130mg) and finally Cs₂CO₃(0.003mol) to a mixture of 3-chloro-6-methoxypyridazine (0.007mol) in dioxane (10ml) which was degassed and in a sealed tube. Intermediate (52) (0.0023 mol; theoretically, crude) is added and the reaction mixture is degassed again with N2. The reaction mixture was stirred at 100 ℃ for 2 hours. The reaction mixture was cooled and then filtered. The solvent of the filtrate was evaporated. The residue was purified by combiflash column chromatography over silica gel (eluent: DCM/CH)₃OH from 100/0 to 99/1). The product fractions were collected and the solvent was evaporated, yielding 0.310g of intermediate (53).

Example A.22

Preparation ofIntermediate (57)

4-Chloropyridine N-oxide (0.010mol) and cesium carbonate (0.008) were added to a mixture of intermediate (14) (0.0042mol) in dioxane (50 ml). The reaction mixture was degassed with nitrogen and stirred under reflux for 4 hours. The reaction mixture was filtered through celite pad. The solvent of the filtrate was evaporated and the residue was dried to obtain 3g of intermediate (57).

Example A.23

a) Preparation of

The reaction was carried out under an inert argon atmosphere. Intermediate (8) (0.5g, 0.00117mol) was dissolved in TFA (98%) (10ml) and the mixture was heated at 80 ℃ overnight. The resulting brown solution was concentrated in vacuo and the residue was taken up in degassed toluene. The organic layer was dried with NaHCO 3 (sat.), Na₂SO₄) The solvent was then evaporated to give a viscous yellow oil. This oil was dissolved in THF (5ml), and the mixture was added dropwise to 1, 1, 1-trifluoro-5- [ (tetrahydro-2H-pyran-2-yl) oxy]-3-pentyn-2-one (0.333g, 1.2 eq) in THF (5 ml). The yellow mixture was then allowed to stir at room temperature for 2 hours, then PPTS (0.03g, 0.1 eq.) was added, followed by ethanol (10 ml). The reaction mixture was stirred at room temperature and an additional amount of PPTS (0.4 eq) was added. The mixture was heated at 60 ℃ for 3 hours. The solvent was then evaporated and the residue was taken up in chloroform. The organic layer was washed with NaHCO 3 (sat.), water and brine, dried (Na)₂SO₄) The solvent was then evaporated to give a brown foam. The crude product was purified by column chromatography over silica gel (eluent: ethyl acetate/hexane 3/2). The desired fractions were collected and the solvent was evaporated to give 0.16g of intermediate(72) As a mixture of the two products.

b) Preparation ofIntermediate (73)

Intermediate (72) (0.123 g; crude) was dissolved in DCM (4ml) and the solution was cooled to 0 ℃. A solution of hydrobromic acid (33%) in glacial acetic acid was added dropwise (this yellow mixture turned to a light brown). The reaction mixture was then kept at 0 ℃ for 2 hours, and the mixture was then quenched with NaHCO 3 (sat.). The crude product was extracted with DCM. The separated organic layer was washed with water and brine and dried (Na)₂SO₄) The solvent was then evaporated to give a brown foam. The crude product was purified by column chromatography over silica gel (eluent: hexane/ethyl acetate 1/1). The desired fractions were collected and the solvent was evaporated to yield 0.044g of intermediate (73).

Example A.24

a) Preparation ofIntermediate (59)

To a mixture of intermediate (3) (0.0290mol) in acetic acid (250ml) were added 4-formyl-1-piperidinecarboxylic acid, 1, 1-dimethylethyl ether (0.0468mol), acetic acid (2ml) and titanium (IV) isopropoxide (4:1) (3 g). The reaction mixture was stirred for 20 minutes. Sodium cyanoborohydride (0.03mol) was then added. The reaction mixture was stirred for 2 hours. Water was added to the reaction mixture. The organic layer was dried (MgSO 4), filtered and evaporated to give 120g of intermediate (59).

b) Preparation ofIntermediate (60)

A mixture of intermediate (59) (0.071mol), acetic acid (800ml) and hydrochloric acid (40ml) was stirred under reflux overnight. The reaction mixture was concentrated. The residue was taken up in DCM and water. The mixture was then neutralized with NaHCO 3. The organic layer was dried (MgSO 4), filtered and evaporated. The residue was used as such in the next reaction to give 35g of intermediate (60).

c-1) preparationIntermediate (61)

A mixture of intermediate (60) (0.071mol), acetic acid 1, 1' -anhydride (0.14mol) and DCM (700ml) was stirred at room temperature for 3 h. Aqueous NaHCO 3 was added and the mixture was stirred for an additional 1 hour to destroy excess acetic acid 1, 1' -anhydride. The organic layer was dried (MgSO 4), filtered and evaporated. The residue was used as such in the next reaction to give 35g of intermediate (61).

c-2) preparationIntermediate (65)

A mixture of intermediate (60) (0.026mol) in methyl formate (300ml) was stirred and refluxed overnight. The reaction mixture was cooled and the solvent was evaporated. Toluene was added and azeotroped on a rotary evaporator to afford 12g of intermediate (65).

d) Preparation ofIntermediate (62)

A mixture of intermediate (61) (0.01mol) and TFA (40ml) was stirred in a microwave at 100 ℃ for 25 min. The reaction mixture was cooled. The solvent was evaporated. The residue was taken up in ethyl acetate and washed with water/NaHCO 3 solution. The organic layer was dried (MgSO 4), filtered and evaporated. The crude residue was used in the next step to give 4.7g of intermediate (62).

e-1) preparationIntermediate (63)

N₂An atmosphere. Intermediate (62) (0.0021mol), 5-bromo-2-thiophene-carbonitrile (0.004mol), Xantphos (0.1g) and Pd₂(dba)₃(0.13g) A mixture in 1, 4-dioxane (20ml) was degassed. DIPE was added and the reaction mixture was degassed again. The reaction mixture was stirred at 80-90 ℃ for 2 hours. After cooling, the reaction mixture was filtered through celite pad. The filtrate was concentrated and the residue was purified on silica gel using DCM/CH₃OH(7N NH₃) (from 100% to 99/1) as eluent. The product fractions were collected and evaporated to dryness. The residue was used as such in the next reaction to obtain 0.45g of intermediate (63).

e-2) preparationIntermediate (64)

N2 atmosphere. Intermediate (62) (0.004mol), 4-iodo-1-methyl-1H-pyrazole (0.0035mol), 1, 4-dioxane (25ml) and Cs₂CO₃(1.6g) the mixture in Xantphos (0.1g) was degassed. Adding Pd₂(dba)₃(0.13g), and the reaction mixture was degassed again. The reaction mixture was stirred at 80-90 ℃ for 2 hours. After cooling, the reaction mixture was filtered through celite pad. The filtrate was concentrated and the residue was washed with silica gel using DCM/CH₃OH (from 100% to 96/4) was purified as eluent. The product fractions were collected and evaporated to dryness. The residue was used as such in the next reaction to obtain 0.14g of intermediate (64).

f) Preparation ofIntermediate (66)

A mixture of intermediate (65) (0.00155mol) in TFA (18ml) was stirred in a microwave oven at 100 ℃ for 25 min. The reaction mixture was concentrated. The residue was partitioned between aqueous NaHCO 3 and ethyl acetate. The organic layer was separated, dried (MgSO 4), filtered and the solvent evaporated to give. + -. 0.7g of intermediate (66).

g) Preparation ofIntermediate (67)

To 4-iodo-1-methyl-1H-pyrazole (0.003mol) and Cs₂CO₃(1g) To the mixture of (1) was added 10ml of dioxane. The mixture was degassed by alternating the use of an N2 atmosphere and vacuum. Intermediate (66) (0.0022mol) was added to 10ml of dioxane and degassed as above. Adding Pd₂(dba)₃(0.1g) and Xantphos (0.13g), degassed again and the reaction mixture stirred under N2 at 100 ℃ overnight. The reaction mixture was cooled, 150ml was added and extracted 2 times with 150ml of DCM. The combined organic layers were dried (MgSO 4), filtered and evaporated. The residue was purified by HPLC (HPLC method a). The residue was crystallized from DIPE to yield 0.195g of intermediate (67).

Example A.25

a) Preparation ofIntermediate (68)

A mixture of intermediate (3) (0.03mol) and acetic acid (5.2ml) in DCM (500ml) was stirred at room temperature with N₂Stirring under bubbling. 4, 4, 4-trifluorobutanal is added. After 15 minutes, add NaBH₃(CN), and the reaction mixture was stirred for another hour. Water was added and the reaction mixture was extracted again. The separated organic layer was collected, dried (MgSO 4), filtered and the filtrate evaporated. The residue was suspended in DIPE to give intermediate (68).

b) Preparation ofIntermediate (69)

Intermediate (68) (0.04mol) was dissolved in acetic acid (100 ml). The reaction mixture was stirred and refluxed overnight, and the solvent was evaporated again. The residue was extracted (DCM/NaHCO 3), dried, filtered and the solvent evaporated. The concentrate was suspended in DIPE and the precipitate was filtered off and dried to give intermediate (69).

c) Preparation ofIntermediate (70)

The reaction is carried out in a microwave. Intermediate (69) was dissolved in TFA. The reaction mixture was stirred at 100 ℃ for 30 minutes (10% of starting material remaining). The mixture was stirred again for 30 minutes at 100 ℃. The solvent was then evaporated and the residue was extracted (ethyl acetate/NaHCO 3), dried (MgSO 4), filtered and evaporated. The concentrate was used as crude to afford intermediate (70).

d) Preparation ofIntermediate (71)

4-chloropyridine, 1-oxide (0.0025mol) and Pd₂(dba)₃(catalytic amount), Xantphos (catalytic amount) and Cs₂CO₃(0.973g) A mixture in dioxane (5ml) was degassed by alternating use of N2 atmosphere and vacuum. Intermediate (70) (0.0023mol) in dioxane (15ml) was added under N2. The reaction mixture was stirred at 100 ℃ for 2 hours. The mixture was extracted (DCM/H)₂O), drying, filtering and evaporating. The residue was taken up in crude form to give intermediate (71).

Example A.26

a) Preparation ofIntermediate (74)

The reaction vessel was rendered inert with N2. A mixture of intermediate (8) (0.002355mol) in TFA (14ml) was heated at reflux overnight. The solvent was evaporated. To the residue were added degassed NaHCO 3 saturated aqueous solution (50ml) and degassed toluene (80 ml). The layers were separated into an organic layer OL1 and an aqueous layer AL 1. AL1 was re-extracted 3 times with toluene (40ml) to give 3 separate organic layers OL2, OL3 and OL 4. Combining OL1, OL2, OL3 and OL4 and drying (Na)₂SO₄) Filtration and re-evaporation of the solvent (vacuum, 1 hour) gave a residue a. The reaction vessel was rendered inert with N2. Mixing Cs₂CO₃(0.00471 mol; drying in vacuo) was added to a solution of 2-chloro-6-methylpyridine (0.003062mol) in DMSO (14ml) to obtain mixture A. The residue a in DMSO (14ml) was then added to mixture a. The reaction mixture was degassed for 15 minutes and then refluxed for 150 minutes. Ethyl acetate was added to the residue. The mixture was washed 4 times with water (125ml) and 1 time with NaCl (100 ml). The separated organic layer was dried (Na)₂SO₄) Filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: ethyl acetate/hexane 50/50 and 60/40). The product fractions were collected and the solvent was evaporated, yielding 0.097g of intermediate (74).

b) Preparation ofIntermediate (75)

The reaction vessel was rendered inert with N2. A mixture of intermediate (8) (0.002355mol) in TFA (14ml) was stirred under reflux overnight. The solvent was evaporated. The residue was taken up in degassed toluene (80ml) and then in degassed saturated aqueous NaHCO 3 (50 ml). The layers were separated into an organic layer OL1 and an aqueous layer AL 1. AL1 was re-extracted 3 times with toluene (40ml) to give 3 separate organic layers OL2, OL3 and OL 4. Combining OL1, OL2, OL3 and OL4 and drying (Na)₂SO₄) Filtering and evaporating the solvent(vacuum, 1 hour) to obtain residue a.

The reaction vessel was rendered inert with N2. Mixing Cs₂CO₃(0.002037 mol; dried in vacuo) was added to a suspension of 5-bromo-2-methoxypyrimidine (0.003062mol) in degassed dioxane (14ml) to give mixture A. The residue A in degassed dioxane (14ml) was then added to mixture A. Finally, Pd is added₂(dba)₃(0.036g), Xantphos (0.079g) and then potassium fluoride (0.000479mol) and the reaction mixture was degassed for a further 15 minutes. The reaction mixture was stirred at reflux for 19 hours. The solvent was evaporated. Chloroform was added to the residue. The mixture was washed 2 times with water and then 1 time with a saturated aqueous solution of NaCl. The separated organic layer was dried (Na)₂SO₄) Filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: ethyl acetate/hexane 50/50 and 60/40). The product fractions were collected and the solvent was evaporated, yielding 0.255g of intermediate (75).

Example A.27

a) Preparation ofIntermediate (79)

The reaction was carried out under dry conditions and an atmosphere of N2. A mixture of intermediate (8) (1.5g, 0.003553mol) in TFA (20ml) was refluxed overnight. The reaction mixture was evaporated and the extraction was performed with NaHCO 3 (degassed saturated solution) and toluene (4 ×, degassed). The separated organic layer was dried (Na)₂SO₄) Filtration and re-evaporation of the solvent gave a residue (1). The residue (1) was divided into 2 portions, each of which was further treated by a different route.

Reaction A：

The first portion of residue (1) was reacted with 3-bromo-4, 4-dimethoxy-2-butanone (0.450g) in DMF (8 ml; dry) at 0 ℃. Sodium hydride (60%) (0.051g) was added. The mixture was allowed to react at 0 ℃ for 30 minutes and then allowed to warm to room temperature.

Reaction B：

A second portion of the residue (1) was dissolved in DMF (3 ml; dry). A suspension of sodium hydride (60%) (0.051g) in DMF (2 ml; dry) was added to the solution at 0 ℃. The mixture was allowed to react at 0 ℃ for 30 minutes, followed by addition of a solution of 3-bromo-4, 4-dimethoxy-2-butanone (0.450g) in DMF (3 ml; dry). The reaction mixture was allowed to react at 0 ℃ for 15 minutes and then warmed to room temperature.

The two reaction mixtures A and B were extracted with ethyl acetate, NaHCO 3 (saturated solution) and water. The separated organic layer was dried (Na)₂SO₄) Filtration and re-evaporation of the solvent gave 0.76g of crude product from reaction A and 0.74g of crude product from reaction B. The two crude products from reaction A and reaction B were combined and purified by column chromatography over silica gel (eluent: ethyl acetate/hexane, first 1/1 and then 7/3). The desired fractions were collected and the solvent was evaporated to yield intermediate (79).

b) Preparation ofIntermediate (80)

Hydrazine dihydrochloride (0.181g, 0.001728mol) was added to a solution of intermediate (79) (0.075g, 0.000173mol) and ethanol (4.5ml) in a sealed tube and the reaction mixture was heated at 70-80 ℃. The mixture was then evaporated and extracted with chloroform, NaHCO 3 (saturated solution) and water. The separated organic layer was dried (MgSO 4), filtered and the solvent evaporated to give 0.075g of crude product. The crude product was purified by preparative HPLC to give 0.057g of intermediate (80).

Example A.28

Preparation ofIntermediate (84)

A mixture of N- (2-hydroxyethyl) acetamide (1g), dioxane (10ml) and sodium hydride (60%) (0.46g.) was stirred at 60 ℃ for 30 minutes. The reaction mixture was cooled. 4-bromo-2-fluoropyridine (1g) was added and the reaction mixture was stirred at 110 ℃ for 90 minutes. The reaction mixture was poured into 100ml of saturated NH₄In an aqueous Cl solution. The resulting precipitate was isolated by filtration, washed with water, and dried under vacuum to give 1.16g of intermediate (84).

Example A.29

a) Preparation ofIntermediate (85)

4-bromo-2-fluoropyridine (1.1 eq), Pd₂(dba)₃(1.7g), Xantphos (2.2g) and Cs₂CO₃(33g) The mixture in dioxane (q.s.) was degassed. A mixture of 4-chlorobenzenethiol (0.062mol) in dioxane (q.s.) was added. The reaction mixture was stirred at 100 ℃ overnight under an atmosphere of N2. The mixture was filtered and the solvent of the filtrate was evaporated. The residue was partitioned between DCM and water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent: hexane/DCM 60/40). The product fractions were collected and the solvent was evaporated to yield intermediate (85).

b) Preparation ofIntermediate (86)

3-Chlorobenzeneperoxyformic acid (20g) was added to a mixture of intermediate (85) (0.042mol) in chloroform. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between DCM and aqueous NaOH (2 ×). The organic layer was separated and then filtered through Extrelut. The solvent of the filtrate was evaporated. The residue was stirred in DIPE, filtered off and dried to give intermediate (86).

c) Preparation ofIntermediate (87)

A mixture of intermediate (86) (0.011mol) in sulfuric acid (concentrated) (35ml) was stirred and cooled to 0 ℃. Sulfuric (concentrated) and nitric (concentrated) (1/1) (5.6ml) were added dropwise at 0 ℃. The resulting reaction mixture was stirred at room temperature for 3 hours and then poured into ice water. The mixture was extracted with DCM. The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated. The residue was suspended in DIPE, filtered off and dried (vacuum, 40 ℃ C.) to yield 1.7g of intermediate (87).

d) Preparation ofIntermediate (88)

4, 4-difluoro-cyclohexanemethylamine trifluoroacetate (crude, 2 equivalents) in some DMSO was added to a mixture of intermediate (87) (0.0025mol, 0.800g) and N-ethyl-N- (1-methylethyl) -2-propylamine (0.834ml) in DMSO (50 ml). The mixture was stirred at 50 ℃ for 24 hours. Water was added. The mixture was extracted with ethyl acetate. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by reverse phase HPLC (gradient elution used (NH)₄OAc0.5% in water/CH₃In CN 90/10)/CH₃OH/CH₃CN). The pure fractions were collected. The organic solvent was evaporated. The aqueous concentrate is extracted. The separated organic layer was dried, filtered and the solvent was evaporated to give 0.129g of intermediate (88).

e) Preparation ofIntermediate (89)

A mixture of intermediate (88) (0.13g, 0.0003mol) in methanol (50ml) was hydrogenated using a mixture (0.1g) of platinum on activated carbon (5%) and vanadium pentoxide (0.5%) as a catalyst in the presence of a thiophene solution (0.1 ml). After uptake of hydrogen (3 equivalents), the catalyst was filtered off and the filtrate was evaporated again to give intermediate (89).

f) Preparation ofIntermediate (90)

Intermediate (89) (0.00024mol, crude) was dissolved in a mixture of DCM (5ml) and triethylamine (0.040 ml). 2, 2-dimethylpropionyl chloride (0.035ml) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted with DCM. The separated organic layer was washed with water, dried, filtered and the solvent was evaporated again to give intermediate (90).

g) Preparation ofIntermediate (91)

A mixture of intermediate (90) (0.00024mol, crude) in methanol (3ml) was treated with sodium hydroxide (50%) (7 drops). The reaction mixture was heated in a microwave oven at 70 ℃ for 20 minutes. Evaporation of the solvent afforded intermediate (91).

Example A.30

(a-1) preparationIntermediate (93)

2-bromo-4-chloropyridine (0.0025mol, 0.5g), dichlorobis (triphenylphosphine) -palladium (0.055g, 0.03 eq.) and copper iodide (0.015g, 0.03 eq.) were combined under N "2" flow. Triethylamine (6ml) and ethynyl trimethylsilyl (0.407ml, 1.1 equiv.) were added at 40 ℃. The mixture was stirred at 40 ℃ overnight. The reaction was quenched by the addition of water. The mixture was partitioned between DCM and water. The organic layer was separated, dried (MgSO 4), filtered and the solvent evaporated to give intermediate (93).

a-2) preparationIntermediate (94)

Intermediate (93) (0.0025mol) was added to a mixture of potassium hydroxide (0.005mol, 0.280g) and methanol (4.25ml) in DCM (2.25 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and then extracted with DCM. The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated to give intermediate (94).

b) Preparation ofIntermediate (95)

Intermediate (94) (0.0025mol, crude product), Pd₂(dba)₃(0.063g, 0.03 equiv.), Xantphos (0.079g, 0.06 equiv.), and Cs₂CO₃A mixture of (1.2g, 1.5 equivalents) in 1, 4-dioxane (20ml) was degassed. Intermediate (9) (0.0023mol) was added and the mixture was stirred at 100 ℃ overnight. The mixture was cooled and filtered. The filtrate was evaporated. The residue was dissolved in DCM and the mixture was extracted with water. The separated organic layer was dried, filtered and the solvent was evaporated again to give intermediate (95).

Example A.31

a) Preparation ofIntermediate (107)

Intermediate (106) (0.02mol), NaBH₄(0.28g) and methanol (100ml) were stirred at room temperatureFor 1 hour. The solvent was evaporated. The residue was taken up in DCM and washed with water. The organic layer was dried (MgSO 4), filtered and evaporated to give 0.6g of intermediate (107).

b) Preparation ofIntermediate (108)

Intermediate (107) (0.0013mol) and TFA (10ml) were stirred in a microwave at 100 ℃ for 25 min. The reaction mixture was cooled. The solvent was evaporated. The residue was taken up in ethyl acetate and washed with aqueous ethyl acetate/NaHCO 3 solution. The organic layer was dried (MgSO 4), filtered and evaporated. The crude residue was used in the next step to give 0.6g of intermediate (108).

c) Preparation of

N2 atmosphere. Intermediate (108) (0.007mol), 4-bromo-2-fluoropyridine (0.01mol), Xantphos (0.15g) and Pd₂(dba)₃(0.2g) the mixture in dioxane (50ml) was degassed. Adding Cs₂CO₃(3.3g), the reaction mixture was degassed again. The reaction mixture was stirred at 90 ℃ for 1 hour. The reaction mixture was filtered through celite pad. The filtrate was concentrated. The residue was taken up in DCM and washed with water. The organic layer was dried (MgSO 4), filtered and evaporated. The residue was taken up on a combiflash system (normal phase silica gel) using DCM/CH₃OH (100% to 96%/4%) was purified as eluent. The product fractions were collected and evaporated to give a residue (1.8g, mixture of cis/trans 13/80). A portion (0.35g) of this residue was purified by HPLC (HPLC method C) to isolate the cis/trans isomer. The desired product fractions (only the trans isomer was used for the next reaction step) were collected and evaporated until complete drying to yield 0.14g of intermediate (109) (1, 4-trans isomer (pure)).

Example A.32

a) Preparation ofIntermediate (113)

N2 atmosphere. Intermediate (9) (0.014mol), 4-bromo-2-chloropyridine (0.015mol), Xantphos (0.42g) and Pd₂(dba)₃(0.6g) the mixture in dioxane (100ml) was degassed. Adding Cs₂CO₃The reaction mixture is degassed again. The reaction mixture was stirred at 80-90 ℃ for 2 hours. The reaction mixture was cooled and filtered through celite pad. The filtrate was evaporated. The residue was crystallized from DIPE and a little 2-propanol. The solid was filtered off, washed and dried to yield 3.5g of intermediate (113).

b) Preparation ofIntermediate (114)

A mixture of intermediate (113) (0.0005mol) and N-methyl-1-butylamine (10ml) was stirred in a microwave at 150 ℃ for 12 hours. Excess N-methyl-1-butylamine was removed by evaporation. The residue was purified by column chromatography using DCM/MeOH: NH₃(100% to 98%/2%) was purified as eluent. The product fractions were collected and evaporated. The residue was used as such in the next reaction to give 0.125g of intermediate (114).

Example A.33

a) Preparation ofIntermediate (115)

The reaction was carried out under N2. Et at 40 ℃₃N (2.5ml) 2- (3-butyn-1-yl) -1H-isoindole-1, 3(2H) -dione (0.0011mol) was then added to 2-bromo-4-chloropyridine (0.001mol), dichloro-pyridineBis (triphenylphosphine) -palladium (0.022g) and copper iodide (0.006g) were mixed and stirred at 40 ℃ for 10 hours. The solvent was evaporated. The residue was partitioned between DCM and water. The mixture was filtered through Isolute and the solvent of the filtrate was evaporated. The residue was purified by column chromatography (eluent: DCM). The desired product fractions were collected and the solvent was evaporated. The residue was suspended in DIPE and the precipitate was filtered off to yield 0.200g of intermediate (115).

Intermediate (128)

Intermediate (128) was prepared in a similar procedure as intermediate (115) from 2, 4-dichloropyridine and 3-methoxy-1-propyne.

b) Preparation ofIntermediate (116)

A mixture of intermediate (115) (0.0026mol) in methanol (50ml) was hydrogenated with the catalyst platinum on activated carbon (5%) and thiophene (4%) in DIPE in the presence of triethylamine. After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the solvent was evaporated again to yield 0.5g of intermediate (116).

Intermediate (129)

Intermediate (129) was prepared from intermediate (128) in a similar operation as intermediate (116). Triethylamine was not used in the workup of intermediate (129).

Example A.34

a) Preparation ofIntermediate (130)

This reaction was carried out twice.

A mixture of 4-methoxycyclohexanecarboxaldehyde (0.0063mol) and intermediate (3) (0.0042mol) was dissolved in ethanol containing 1 equivalent of hydrogen. After absorption of hydrogen, the reaction mixture is evaporated.

The second time, the reaction was run with less intermediate (3) (1.23 g). The reaction mixture was extracted (DCM/water). The collected organic layer was dried, filtered and evaporated. The two residues were combined and purified by HPLC (HPLC method a). The desired fractions were collected and the solvent was evaporated to yield intermediate (30).

b) Preparation ofIntermediate (131)

A solution of intermediate (130) (0.042mol) in acetic acid (q.s.) and 1 drop of hydrochloric acid was heated in a microwave at 150 ℃ for 40 minutes. Some starting material still remained. The residue was heated at 150 ℃ for 25 minutes again. The solvent was then evaporated and the residue was extracted again (DCM/water). The organic layer was collected, dried (MgSO 4), filtered and evaporated. The crude residue was used as such in the next reaction to give intermediate (131).

c) Preparation ofIntermediate (132)

Intermediate (31) (0.0042mol) was dissolved in TFA (15 ml). The reaction mixture was stirred in a microwave at 100 ℃ for 30 minutes. The reaction mixture was evaporated. The residue was extracted twice (ethyl acetate/NaHCO 3.) the collected organic layers were dried (MgSO 4), filtered and evaporated. The crude residue was used as such in the next reaction to give intermediate (132).

4-bromo-2-fluoropyridine (0.635g) and Pd₂(dba)₃(catalytic amount), Xantphos (catalytic amount) and Cs₂CO₃(1.5g) A mixture in 1, 4-dioxane (5ml) was degassed by alternating use of N2 atmosphere and vacuum. Intermediate (132) in 1, 4-dioxane (15ml) was added under N2-atmosphere. The reaction mixture was stirred at 100 ℃ for 2 hours. The reaction mixture was filtered. After extraction (DCM/Water), the collected organic layers were dried (MgSO 4), filtered and the filtrate was evaporated. The residue was purified by HPLC (HPLC method a). The two product fractions were collected and their solvents were evaporated to yield intermediate (133) (trans; opposite; mixture) and intermediate (134) (cis; opposite; mixture).

Example A.35

Preparation ofIntermediate (135)

And reacting under an inert Ar atmosphere. Sodium hydride (60%) (1.81g, 1.1 eq) was suspended in DMF (60ml) and the suspension was cooled to 0 ℃. A solution of 4-iodo-1H-pyrazole (8g, 0.04124mol) in DMF (20ml) was slowly added to the cooled suspension, and the reaction mixture was stirred at 0 ℃ for 30 minutes and then at room temperature for 30 minutes. The mixture was cooled to 0 ℃ again, potassium iodide (6.8g, 1 eq) was added, followed by dropwise addition of 1-bromo-3-methoxypropane (9.47 g). The white suspension was stirred at 0 ℃ and then at room temperature for 3 hours. The mixture was cooled again to 0 ℃ and then quenched with water. The mixture was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with water and brine and dried (Na)₂SO₄) Filtered and the solvent evaporated under vacuum (pale yellow oil). The oily residue is purified by column chromatography over silica gel (eluent: hexane)Alkane/ethyl acetate 3/1). The desired fractions were collected and the solvent was evaporated to yield 9.064g of intermediate (135).

Example A.36

a) Preparation ofIntermediate (136)

A mixture of intermediate (3) (0.05mol) in acetic acid (400ml) was stirred and refluxed for 3 hours. The reaction mixture was cooled and then the solvent was evaporated. The residue was extracted in DCM/water. The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated to give 6.5g of intermediate (136).

b) Preparation ofIntermediate (137)

And reacting under an inert Ar atmosphere.

Intermediate (136) (1g, 0.00306mol) was dissolved in TFA (15 ml). The solution was stirred at 100 ℃ overnight. The mixture was cooled and the dark black mixture was concentrated in vacuo. The residue was taken up in ethyl acetate. The organic layer was washed with NaHCO 3 (sat.), water and brine, dried (Na)₂SO₄) Filtered and the solvent evaporated again (green residue). This green solid was dissolved in dioxane (15ml) under an inert Ar atmosphere. Adding 4-bromo-2-fluoropyridine (0.00306mol) and Cs₂CO₃(1.5g, 1.5 equiv.), Xantphos (0.09g) and Pd₂(dba)₃(0.08 g). The reaction was degassed for 15 minutes and then heated at 80 ℃ for 30 minutes. The cooled mixture was concentrated in vacuo and the resulting viscous brown oil was taken up in chloroform. The organic layer was washed with NaHCO 3 (sat.), water and brine, dried (Na)₂SO₄) Filtration and re-evaporation of the solvent gave a brown solid. Will be provided withThe solid was purified by column chromatography over silica gel (eluent: hexane/ethyl acetate 1/1). The desired fractions were collected and the solvent was evaporated to yield 0.642g of intermediate (137).

c) Preparation of

And reacting under an inert Ar atmosphere.

Intermediate (137) (0.645g, 0.00214mol) was dissolved in DMF. 2- (2-bromoethyl) -1, 3-dioxolane (0.002354mol) was added, followed by potassium iodide (0.002354 mol). The brown mixture was cooled to 0 ℃ and sodium hydride (60%) (0.129g, 1.5 eq.) was added dropwise. The brown reaction mixture was stirred at 0 ℃ for 30 minutes and then at room temperature overnight. The mixture was quenched with water and the crude product was extracted with ethyl acetate. The separated organic layer was washed with water and brine and dried (Na)₂SO₄) Filtered and the solvent evaporated to give a pale green solid. The solid was taken up in ethyl acetate and hexane was added. The precipitate (starting material) was filtered off and washed with hexane. The filtrate was concentrated in vacuo. The residue is worked up again and a second amount of precipitate (starting material) is filtered off. The filtrate was evaporated and the residue was purified by column chromatography over silica gel (eluent: hexane/ethyl acetate 1/1). The desired fractions were collected and the solvent was evaporated to yield 0.302g of intermediate (138) (mixture of isomers).

Example A.37

a) Preparation ofIntermediate (142)

Reacting 4-bromo-N¹- [2- (1-pyrrolidinyl) ethyl group]A mixture of-1, 2-phenylenediamine (0.0350mol) in DCM (200ml) was cooled to 0 ℃.2, 2-dimethylpropionyl chloride (0.0350mol) and then triethylamine (5.8ml) were added to the solutionThe reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water. The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated. The residue was suspended in DIPE and the precipitate was filtered off and dried (vacuum, 40 ℃) to yield 8g of intermediate (142).

b) Preparation ofIntermediate (143)

A mixture of intermediate (142) (0.0059mol) in acetic acid (30ml) was heated in a microwave at 150 ℃ for 20 minutes. The reaction mixture was cooled and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The mixture was neutralized with aqueous NaHCO 3. The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated to give 1.5g of intermediate (143).

c) Preparation ofIntermediate (144)

The intermediate (143) (0.0005mol), 4-methoxybenzenethiol (0.001mol), Pd₂(dba)₃A mixture of (0.040g) and Xantphos (0.040g) in dioxane (10ml) was degassed. N-Ethyl-N- (1-methylethyl) -2-propylamine (0.001mol) was added, and the reaction mixture was degassed again. The reaction mixture was stirred at 100 ℃ for 20 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was taken up in DCM and water. The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: DCM/methanol 99/1). The desired product fractions were collected and the solvent was evaporated to yield 1.2g of intermediate (144).

d) Preparation ofIntermediate (145)

A mixture of intermediate (144) (0.0028mol) in TFA (15ml) was heated in a microwave at 120 ℃ for 20 min. The solvent was evaporated. The residue was partitioned between ethyl acetate and water. The mixture was neutralized with aqueous NaHCO 3. The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated to give intermediate (145).

e) Preparation ofIntermediate (146)

A mixture of 4-bromo-2-fluoropyridine (0.0028mol) and cesium carbonate (1.7g) in dioxane (10ml) was degassed. Intermediate (145) (theoretical maximum, crude) in dioxane (10ml) was degassed and added to the reaction mixture. Then Pd₂(dba)₃(0.110g) and Xantphos (0.150g) were added to the reaction mixture and the reaction mixture was degassed. The reaction mixture was stirred at 100 ℃ for 1 hour. The reaction mixture was cooled and the solvent was evaporated. The residue was taken up in ethyl acetate and water. The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: DCM/methanol 99/1). The desired product fractions were collected and the solvent was evaporated to give 0.450g of residue. 0.100g of the residue is purified by high performance liquid chromatography (using NH)₄HCO₃Standard gradient elution of buffer). The desired product fractions were collected and the solvent was evaporated. The residue was suspended in DIPE and the precipitate was filtered off and dried (vacuum, 40 ℃ C.) to yield 0.029g of intermediate (146).

B. Synthesis of the final Compound

Example B.1

Preparation ofIntermediate (23)

Andcompound (1)

Cs₂CO₃(1g) To a mixture of 5-bromo-2 (1H) -pyridone (0.870g) and dioxane (6 ml). The resulting mixture was degassed by alternating vacuum and nitrogen atmosphere (3 cycles). A mixture of intermediate (9) (0.00157mol) in dioxane (4ml) was then added followed by Xantphos (0.056g) and Pd₂(dba)₃(0.044 g). The resulting reaction mixture was degassed again by alternating vacuum and nitrogen atmosphere (3 cycles). The reaction mixture was shaken overnight at 100 ℃ in a closed vessel. The mixture was then concentrated under a stream of nitrogen at 65 ℃. The residue was partitioned between DCM and water and reused with Isolute HM-N^TMThe filter filters to remove the aqueous phase. The organic layer was concentrated under a stream of nitrogen. The residue was subjected to reverse phase high performance liquid chromatography. The product fractions were collected and the solvent was evaporated to give intermediate (23). A portion (0.296g) of intermediate (23) was dissolved in chloroform (15ml) and mCPBA (0.405 g; 2.2 equiv) was added. The mixture was stirred at room temperature overnight. The organic layer was washed with NaOH (1N) and the product was in the aqueous layer. Acetic acid was added to the aqueous layer and extracted with DCM. Subjecting the organic layer to Isolute HM-N^TMFilter and evaporate the solvent. The residue was purified by high performance liquid chromatography. The desired fractions were collected and the solvent was evaporated to give compound (1) (mp.251 ℃).

Example B.2

Preparation ofIntermediate (24)

Andcompound (2)

Andcompound (3)

Mixing Cs₂CO₃(1g) To a mixture of 4-chloropyridine-N-oxide (0.650g) in dioxane (6 ml). A mixture of intermediate (9) (0.00156mol) in dioxane (4ml) was then added. The resulting reaction mixture was shaken overnight at 80 ℃. The mixture was cooled and then concentrated under a stream of nitrogen. The residue was partitioned between DCM and water and filtered through an IsoluteHM-NTM filter to remove the aqueous phase. The residue was purified by reverse phase high performance liquid chromatography. The product fractions were collected and the solvent was evaporated to give intermediate (24) (mp.: 186-. A portion (0.370g) of intermediate (24) was dissolved in chloroform (15ml) and mCPBA (0.430 g; max.2 eq) was added. The mixture was shaken at room temperature overnight. The organic layer was washed with NaOH (1N), water and Isolute HM-N^TMThe mixture was filtered through a filter and concentrated under a nitrogen stream. The residue was purified by reverse phase HPLC. Two different product fractions were collected and the solvent was evaporated to give 0.038g of compound (2) and 0.280g of compound (3) (mp.203 ℃).

The heterocyclic reagent 4-chloropyridine-N-oxide may be replaced by, for example, the following heterocycles: 3, 6-dichloropyridazine 1- (6-chloro-3-pyridinyl) ethanone, 6-chloro-3-pyridinecarboxamide, to prepare further compounds of the invention.

Example B.3

Preparation ofCompound (4)

Mixing Cs₂CO₃(0.0075mol) was added to a mixture of 5-acetyl-2-bromopyridine (0.0065mol) in dioxane (10 ml). The mixture was degassed with nitrogen. Intermediate (9) (0.005mol) dissolved in dioxane (10ml) was added to the reaction mixture, which was degassed again with nitrogen.Xantphos (0.115g) followed by Pd₂(dba)₃(0.090g) was added to the reaction mixture, which was again degassed with nitrogen. The reaction mixture was stirred at 100 ℃ overnight. Water (150ml) was added. The mixture was extracted twice with DCM (100 ml). The combined organic layers were dried, filtered and the solvent was evaporated. The residue was dissolved in chloroform (4g), and mCPBA (100ml) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed first twice with aqueous NaOH (1N, 100ml) and then with water (100 ml). The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH)₂Cl₂/(CH₃OH/NH₃) From 100/0 to 97/3). The product fractions were collected and the solvent was evaporated to give compound (4).

Example B.4

Preparation ofCompound (6)

A mixture of intermediate (25) (0.002mol) and mCPBA (0.005mol) in chloroform (50ml) was stirred at room temperature for 30 minutes. Then water was added. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by reverse phase chromatography. The desired fractions were collected and the solvent was evaporated to give 0.30g of compound (6).

Example B.5

Preparation ofCompound (19)

A stirred mixture of compound (18) (0.00021mol) and NH3 in ethanol (5ml) was stirred at 120 ℃ for 2 days. The reaction mixture was extracted with DCM. Removing the organic layer, evaporating, and recoveringThe residue was purified by column chromatography over silica gel (eluent: CH)₂Cl₂/CH₃OH gradient from 100/0 to 96/4). The product fractions were collected and the solvent was evaporated to give 0.051g of compound (19).

Example B.6

Preparation ofCompound (26)

3-chloro-6-methoxypyridazine (0.006mol) was dissolved in 1, 4-dioxane (10 ml). Adding Cs₂CO₃(2.1g), the mixture was degassed. A degassed solution of intermediate (19) (0.003mol) in 1, 4-dioxane (10ml) was added. Adding Pd₂(dba)₃(0.080g) was added and the mixture was degassed. Xantphos (0.095g) was added and the mixture was degassed. The reaction mixture was stirred at 100 ℃ for 20 hours, then cooled and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was stirred in chloroform (30 ml). The mixture was treated with mCPBA (2.1 g). The reaction mixture was stirred at room temperature for 1 hour, then it was washed with 1N NaOH (2 ×). The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH)₂Cl₂/CH₃OH 99/1). The product fractions were collected and the solvent was evaporated. The residue was purified by reverse phase HPLC (gradient elution using NH 4 HCO 3 buffer (0.25% in water)/CH₃OH/CH₃CN). The product fractions were collected and the solvent was evaporated. Methanol was added and evaporated again. The residue was dissolved in diethyl ether and converted to the hydrochloride salt (1:1) with HCl/diethyl ether. The resulting precipitate was filtered off and dried to obtain 0.034g of compound (26).

Example B.7

Preparation ofIntermediate (140)

Andcompound (34)

Mixing Cs₂CO₃(1g) To a mixture of 3-iodopyridine (1g) and dioxane (6 ml). The resulting mixture was degassed by alternating vacuum and N2 atmosphere (3 cycles). A mixture of intermediate (9) (up to 0.00157mol) in dioxane (4ml) was then added followed by Xantphos (0.056g) and Pd₂(dba)₃(0.044 g). The resulting reaction mixture was degassed again by alternating vacuum and N2 atmosphere (3 cycles). The reaction mixture was shaken overnight at 100 ℃ in a sealed vessel. The mixture was concentrated at 65 ℃ under N2 flow. The residue is in CH₂Cl₂And H₂Partition between O, filter with ISOLUTE HM-N filter, remove, and remove the aqueous phase. The organic layer was concentrated under N2 flow. The residue was purified by reverse phase high performance liquid chromatography. The product fractions were collected and the solvent was evaporated, yielding 0.240g of intermediate (140). A portion (0.215g) of intermediate (140) was dissolved in chloroform (15ml) and mCPBA (2.5 equiv) was added. The mixture was shaken at room temperature overnight. The organic layer was treated with NaOH (1N, 5ml), H₂O (5ml) was washed 2X and the organic layer was filtered through an ISOLUTE HM-N filter. The filtrate was concentrated under N2. The residue was purified by reverse phase HPLC. The desired product fractions were collected and the solvent was evaporated to give 0.028g of compound (34).

Example B.8

a) Preparation ofCompound (46)

A mixture of compound (35) (0.0021mol) and aqueous lithium hydroxide (1N) (10ml) in THF (40ml) was stirred at room temperature overnight. The reaction mixture was neutralized with 1N aqueous HCl to pH7. The solvent was evaporated. The residue was purified by reverse phase HPLC (gradient elution using NH 4 HCO 3 buffer (0.25% in water)/CH₃OH/CH₃CN). The product fractions were collected and worked up to give 0.7g of compound (46).

b) Preparation ofCompound (37)

Compound (46) (0.00044mol) was added to a mixture of triethylamine (0.00066mol) in chloroform (10 ml). 2-methoxy-ethylamine (0.0006mol) was added and shaken at room temperature overnight. DCM (100ml) was added. The mixture was washed 2 times with water (100 ml). The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by reverse phase HPLC (gradient elution using NH 4 HCO 3 buffer (0.25% in water)/CH₃OH/CH₃CN). The product fractions were collected and processed. The residue was triturated under acetonitrile. The precipitate was filtered off to give 0.105g of compound (37) (mp.206 ℃ C. to 207 ℃ C.).

The following compounds were prepared in an analogous manner using pyrrolidine instead of 2-methoxy-ethylamine as a reagent

Compound (38)

Example B.9

Preparation ofCompound (41)

Reacting NaBH₄(0.003mol) to a mixture of compound (40) (0.001mol) in methanol/ethanol mixture (50/50) (20ml) was stirred at room temperature under an N2 atmosphere. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated. DCM (100ml) was added. Water (50ml) was added. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue was crystallized from DIPE/2-propanol. The precipitate was filtered off, washed and dried to obtain 0.290g of compound (41).

Example B.10

a) Preparation ofCompound (42)

NaBH4(0.015mol) was added to a mixture of compound (4) (0.0011mol) in ethanol (30ml), and stirring was continued at room temperature. DCM (30ml) was added and stirring was continued at room temperature for 2 hours. The reaction mixture was quenched with aqueous HCl1N (10 ml). Mixing water (100ml) and NH₄Aqueous OH (20ml) and DCM (100ml) were added to the reaction mixture. The mixture was separated into an aqueous layer and an organic layer. The aqueous layer was re-extracted with DCM (100 ml). The organic layers were combined and washed with brine. The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/(CH)₃OH/NH₃) From 100/0 to 94/6). The product fractions were collected and the solvent was evaporated to give 0.36g of product. This product (0.36g) was placed in DIPE/CH₃And (5) grinding under CN. The precipitate was filtered off to give compound (42) (mp.177 ℃ to 179 ℃).

b) Preparation ofCompound (49)

Sodium hydride (60%) (0.00125mol) was added to compound (42) (0.000656mol) inThe mixture in THF (15ml) was stirred at room temperature for another 20 minutes. Methyl iodide (0.0014mol) was added and the mixture was stirred at room temperature overnight. Sodium hydride (60%) (0.00125mol) was again added and stirred at room temperature for 20 minutes. Methyl iodide (0.0014mol) was then added again and stirred at 40 ℃ over the weekend. Water (100ml) and DCM (100ml) were added. After extraction, the separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by reverse phase HPLC (gradient elution using NH 4 HCO 3 buffer (0.25% in water)/CH₃OH/CH₃CN). The product fractions were collected and the solvent was evaporated. The residue was separated from DIPE/few drops of CH₃CN, and the precipitate was filtered off to give 0.110g of Compound (49) (mp.140 ℃ C.).

Example B.11

Preparation ofIntermediate (141)

Andcompound (43)

Mixing Cs₂CO₃(0.015mol) to a mixture of 5-bromo-3-pyridinecarbonitrile (0.013mol) in dioxane (20 ml). The mixture was degassed with N2. Intermediate (9) (0.01mol) in dioxane (20ml) was added to the reaction mixture, degassed again with N2. Xantphos (0.230g) followed by Pd₂(dba)₃(0.180g) was added to the reaction mixture and degassed again with N2. The reaction mixture was stirred at 100 ℃ overnight. Water (150ml) was added. The mixture was extracted 2 times with DCM (100 ml). The combined organic layers were dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by combiflash column chromatography over silica gel (eluent: DCM/(CH)₃OH/NH₃) From 100/0 to 98/2). The product fractions were collected and the solvent was evaporatedTo yield 2g of intermediate (141). Intermediate (141) (2g) was dissolved in chloroform (3g), followed by addition of 3-chlorobenzene-peroxyformic acid (50 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed first 2 times with aqueous NaOH 1N (200ml) and then with brine (200 ml). The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by combiflash column chromatography over silica gel (eluent: DCM/(CH)₃OH/NH₃) From 100/0 to 98/2) the product fractions were collected and the solvent was evaporated. The residue was taken up in 2-propanol/CH₃CN, and the precipitate was filtered off to give 0.9g of Compound (43) (mp.240 ℃ C.).

Example B.12

Preparation ofCompound (44)

Compound (43) (0.0006mol) in sulfuric acid (4ml) was stirred at 30 ℃ -40 ℃ for 5 hours. The reaction mixture was poured into ice (100 ml). The mixture was washed with DCM/CH₃OH (100ml) was extracted 4 times. The combined organic layers were dried (MgSO 4), filtered and the solvent evaporated. The residue was recrystallized from DCM and the precipitate was filtered off to give 0.170g of compound (44) (mp.259 ℃ C.).

Example B.13

Preparation ofCompound (45)

A mixture of compound (4) (0.0032mol), 1, 2-ethanediol (1ml) and 4-methylbenzene-sulphonic acid (0.6g) in toluene (70ml) was stirred under reflux with a water separator. The reaction mixture was washed with saturated aqueous NaHCO 3. Drying the separated organic layer(MgSO 4), filtration and evaporation of the solvent. The residue was purified by reverse phase HPLC (gradient elution using NH 4 HCO 3 buffer (0.25% in water)/CH₃OH/CH₃CN). The product fractions were collected and the solvent was evaporated. The residue was taken up from DIPE/CH₃CN, and the precipitate was filtered off to obtain 0.606g of Compound (45) (mp.191 ℃ C.).

Example B.14

Preparation ofCompound (47)

A mixture of compound (6) (0.15g, 0.0003mol) and 2-propanol (10ml) was heated. A mixture of 2-propanol and HCl (6N) (1ml) was added. The mixture was then cooled. The precipitate was filtered off, washed and dried to obtain 0.060g of compound (47).

Example B.15a

Preparation ofCompound (170)

A mixture of intermediate (33) (0.013mol) and 3-chlorophenylperoxyformic acid (0.030mol) in chloroform (150ml) was stirred at room temperature for 30 minutes. Then water was added. The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/CH)₃OH from 100/0 to 98.5/1.5). The product fractions were collected and the solvent was evaporated. The residue was solidified in DIPE, then filtered off, washed and dried to yield 3.3g of compound (170).

Example B.15b

Preparation ofCompound (171)

A mixture of compound (170) (0.0045mol), hydroxylamine (0.009mol) and NaHCO 3 (0.009mol) in 2-propanol (40ml) was stirred at 60 ℃ for 5 hours, then cooled and the solvent evaporated. The residue was taken up in DCM. The organic solution was washed with water, dried (MgSO 4), filtered and the solvent evaporated to give 1.36g of compound (171).

Example B.15c

Preparation ofCompound (48)

A mixture of compound (171) (0.0011mol) and trifluoro [1, 1' -oxydi [ ethane ] ] boron (0.200ml) in trimethoxymethane (2ml) was stirred at 80 ℃ for 2 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was taken up in DCM and the organic solvent was washed with water and then dried (MgSO 4), filtered and the solvent was evaporated. The residue was crystallized from DIPE containing a small amount of 2-propanol. The precipitate was filtered off, washed and dried to obtain 0.325g of compound (48).

Example B.16

Preparation ofCompound (53)

A mixture of compound (40) (0.0011mol) in diethyl ether (10ml) and THF (5ml) was stirred at room temperature under an N2 atmosphere. A solution of bromomethyl-magnesium (3M) (0.0030mol) in diethyl ether was added dropwise. The reaction mixture was stirred overnight. SmallWater was added to the core. More diethyl ether was added. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by reverse phase HPLC (gradient elution using NH 4 HCO 3 buffer (0.25% in water)/CH₃OH/CH₃CN). The product fractions were collected and the solvent was evaporated. Methanol was added and the mixture was co-evaporated to give 0.445g of compound (53).

Example B.17

Preparation ofCompound (64)

Compound (62) (0.00021mol) in 2-propanol (5ml) was stirred at room temperature. Methanesulfonyl chloride (0.00031mol) was then added. The reaction mixture was warmed and then cooled. The precipitate was filtered off, washed and dried to obtain 0.077g of compound (64).

Example B.18

Preparation ofCompound (77)

Andcompound (78)

A mixture of compound (69) (0.00025mol) and a solution of sodium methoxide in methanol (30%) (0.5ml) in methanol (10ml) was stirred at room temperature overnight. The solvent was evaporated. The residue was purified by reverse phase HPLC. Two product fractions were collected and reprocessed to yield 0.015g of compound (77) and 0.022g of compound (78).

Example B.19

Preparation ofCompound (85)

Andcompound (84)

A mixture of intermediate (44) (0.00133mol) and 3-chlorobenzene-peroxyformic acid (0.0027mol) in chloroform (15ml) was shaken overnight at room temperature. The mixture was washed with 1N NaOH (2 × 15ml) and once with water (15 ml). The organic phase was filtered through an Isolute HM-N filter and the solvent of the filtrate was evaporated under N2 flow. The residue was purified by reverse phase HPLC. Fractions of both products were collected and their solvents were evaporated. Each fraction was crystallized from DIPE/2-propanol, filtered off and dried to yield 0.155g of compound (85) and 0.161g of compound (84).

Example B.20

Preparation ofCompound (86)

Andcompound (87)

Andcompound (88)

3-Chlorobenzeneperoxyformic acid (0.007mol) was added dropwise to intermediate (45) (0.00348mol) in chloroform (20 ml). The reaction mixture was shaken at room temperature overnight. The organic mixture was washed with 1N NaOH (2 × 20ml), once with water (20ml), then filtered through an Isolute HM-N filter and the solvent of the filtrate was evaporated under N "2" flow. The residue was purified by reverse phase HPLC. The different product fractions were collected and their solvents were evaporated. Each residue was crystallized from DIPE/2-propanol. The precipitates were filtered off and dried to obtain 0.242g of a compound (86); 0.213g of Compound (87) and 0.1g of Compound (88).

Example B.21

Preparation ofCompound (89)

A mixture of intermediate (46) (0.0043mol) and 3-chlorobenzene-peroxyformic acid (0.005mol) in chloroform (80ml) was stirred at room temperature for 1 hour. More 3-chlorophenylperoxyformic acid (0.005mol) was added and the reaction mixture was shaken overnight at room temperature. The mixture was washed with 1N NaOH (2 × 75ml) and once with water (75 ml). The organic phase was dried (MgSO 4), filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/(CH)₃OH/NH₃)97/3). The product fractions were collected and the solvent was evaporated. The residue (1.35g) was further purified by reverse phase HPLC. The desired fraction was collected and the solvent was evaporated. The residue of the desired product was crystallized from 2-propanol/DIPE to give 0.646g of compound (89).

Example B.22

Preparation ofCompound (93)

A mixture of intermediate (30) (0.77g, 0.0019mol), mCPBA (70%) (1.17g, 0.0047mol) and chloroform (40ml) was stirred at room temperature for 1 hour. Chloroform (100ml) was added and the mixture was further addedThe mixture was washed with NaOH solution (1N; 2X100 ml). The organic layer was dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/CH)₃OH(NH₃) From 100/0 up to 97/3. The desired fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol (ca. 50ml) and methanesulfonic acid (0.12 g added). The methanesulfonate salt crystallized from this solution. The product was filtered off, washed with 2-propanol/DIPE and dried (in vacuo) to yield 0.63g of compound (93).

Example B.23

a) Preparation ofCompound (94)

A mixture of compound (11) (0.0036mol, 1.6g) in hydrochloric acid was stirred and refluxed for 1 hour. The reaction mixture was cooled and DCM was added. The organic layer was separated, dried, filtered and the solvent was evaporated again to give 1.108g of compound (94).

b) Preparation ofCompound (100)

A mixture of compound (94) (0.0005mol, 0.200g, 1 eq) and 1, 1-dimethoxy-N, N-dimethylmethylamine (0.100ml, 1.5 eq) in DMF (1ml) was stirred and refluxed until the reaction was complete. Ice was added. Residue 1 precipitated from the mixture. The remaining mixture was extracted with DCM. Water was added. The organic layer was separated, dried, filtered and the solvent was evaporated again to give residue 2. The residues 1 and 2 were combined and the mixture was triturated under 2-propanol. The precipitate was filtered off and dried in vacuo to give 0.125g of compound (100).

Example B.24

Preparation ofCompound (95)

A mixture of intermediate (54) (0.00122mol) and 3-chlorophenylperoxyformic acid (0.0027mol) in chloroform (15ml) was shaken at room temperature for 3 hours. More 3-chlorophenylperoxyformic acid (0.32g) was added and the reaction mixture was shaken overnight at room temperature. The mixture was washed with 1N NaOH (2 × 15ml) and once with water (15 ml). The organic phase was then filtered through an Isolute HM-N filter and the solvent of the filtrate was evaporated under N2. The residue was purified by reverse phase HPLC. The product fractions were collected and worked up to give 0.100g of compound (95).

Example B.25

Preparation ofCompound (101)

A mixture of intermediate (56) (0.00121mol) and 3-chlorophenylperoxyformic acid (0.00242mol) in chloroform (18ml) was shaken at room temperature for 2 h. The mixture was washed with 1N NaOH (2X15ml), once with water (15ml) and then filtered through an Isolute HM-N filter and the solvent of the filtrate was evaporated under N2 flow. The residue was purified by Combiflash flash column chromatography over silica gel (eluent: DCM/(CH)₃OH/NH₃) From 100/0 to 96/4). The desired product fractions were collected and the solvent was evaporated to give 0.110g of compound (101).

Example B.26

Preparation ofCompound (159)

3-Chlorobenzeneperoxyformic acid (1g) was added in 2 portions at room temperature to a solution of intermediate (63) (0.001mol) in chloroform (40 ml). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with water/NaOH. The organic layer was dried (MgSO 4), filtered and evaporated. Using DCM/CH₃OH(7N NH₃) The residue was purified on a silica gel filter from 100/0 to 96/4 as eluent. The product fractions were collected and evaporated. The product was crystallized from DIPE and 2-propanol. The solid was filtered off, washed and dried to yield 0.24g of the compound ((159).

Example B.27

Preparation ofCompound (168)

3-Chlorobenzeneperoxyformic acid (0.2g) was added in 2 portions at room temperature to a solution of intermediate (64) (0.003mol) in chloroform (20 ml). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with water/NaOH. The organic layer was dried (MgSO 4), filtered and evaporated. Using DCM/CH₃OH(7N NH₃) The residue was purified on a silica gel column from 100/0 to 98/2 as eluent. The product fractions were collected and evaporated. The residue was crystallized from 2-propanol and some DIPE. The solid was filtered off, washed and dried to obtain 0.058g of compound (168).

Example B.28

Preparation ofCompound (156)

A mixture of intermediate (67) (0.0007mol), 3-chlorophenylperoxyformic acid (36g) and chloroform (20ml) was shaken at room temperature for 20 minutes. The reaction mixture was washed with 2x15 ml1N aqueous NaOH 1x15ml water and filtered through an HM-N filter. The solvent was removed at 50 ℃ under N2 flow and the residue was crystallized from DIPE to give 0.2g of compound ((156).

Example B.29

Preparation ofCompound (163)

Intermediate (71) (0.0023mol) was dissolved in chloroform (40ml) at room temperature. 3-Chlorobenzeneperoxyformic acid (0.567g) was added slowly (exothermic reaction) and the mixture was stirred for 30 minutes. The reaction mixture was extracted 2 times with saturated NaHCO 3 and 1 time with 1N NaOH. The organic layer was washed with water and dried (MgSO 4). The residue was purified by HPLC (HPLC method a). The desired fractions were collected and the solvent was evaporated to give compound (163).

Example B.30

a) Preparation ofCompound (116)

Compound (51) (0.0003mol), Raney nickel (0.02g) and NH₃The mixture in methanol (50ml) was catalytically hydrogenated under hydrogen atmosphere at 14 ℃. Absorption of H₂After (2 eq.) the reaction mixture was filtered through celite and concentrated. (during evaporation, the reaction mixture turned greenish black). The residue was purified by reverse phase HPLC (gradient elution using NH 4 HCO 3 buffer (0.25% in water)/CH₃OH/CH₃CN) to yield 115mg of compound ((116).

b) Preparation ofCompound (117)

A mixture of compound (116) (0.0002mol), acetic acid 1, 1' -anhydride (0.0003mol) and DCM (10ml) was shaken at room temperature for 2 hours. The organic layer was washed with 2 × 15ml saturated aqueous NaHCO 3, then with 15ml water for 1 ×. The mixture was filtered through an isolute HM-N filter. The filtrate was dried under a stream of nitrogen at 60 ℃. The residue was crystallized from DIPE/2-propanol to give 71mg of compound ((117).

Example B.31

Preparation ofCompound (137)

Andcompound (118)

A solution of intermediate (80) (0.07g, 0.000182mol) in chloroform (ethanol free) (3ml) was cooled to 0 ℃. mCPBA (70%) (0.135g, 0.000546mol) was added. The mixture was stirred at 0 ℃ for 30 minutes and then at room temperature for 2 hours. An additional amount of mCPBA (70%) (3 equivalents) was added and the mixture was stirred for another 90 minutes. The mixture was then diluted with chloroform and then NaOH (1N); water and NaCl were subjected to extraction operations. After extraction, two products (a and B) were obtained.

And (3) a product A: the separated organic layer was evaporated to give 0.040g of crude residue A. The crude product was purified by column chromatography on silica gel. The desired fractions were collected and the solvent was evaporated to give 0.028g of compound (137).

And (3) a product B: the aqueous layer obtained after extraction (NaOH) was also evaporated. The residue was triturated with chloroform in an ultrasonic bath for 15 minutes, filtered, and concentrated again to give 0.040g of compound (118).

Example B.32

Preparation ofCompound (122)

A mixture of intermediate (91) (0.00024mol, crude) in acetic acid (3ml) was heated in a microwave oven at 150 ℃ for 20 minutes. Hydrochloric acid (2 drops) was added and the reaction mixture was heated at 150 deg.C (microwave oven) for 2 hours. After cooling, the solvent was evaporated. The residue was partitioned between DCM and aqueous NaHCO 3. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was separated and subjected to reverse phase HPLC (gradient elution with (NH)₄OAc 0.5% in water/CH₃CN90/10 medium)/CH₃OH/CH₃CN) purification. The desired product fractions were collected and processed to yield 0.006g of compound (122).

Example B.33

a) Preparation ofCompound (123)

A reaction mixture of compound (25) (0.0007mol) and N- (2-aminoethyl) acetamide (0.0022mol) in dioxane (15ml) was stirred at 110 ℃ for 20 h. The reaction mixture was cooled and the solvent was evaporated. The residue was taken up in DCM and water. The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: DCM/CH)₃OH from 100/0 to 98/2). The product fractions were collected and the solvent was evaporated. The residue was suspended in DIPE/drop CH₃And (C) CN. The precipitate was filtered off and dried (vacuum, 50 ℃ C.) to give 0.100g of the compound ((123).

In a similar manner to compound (123), compound (126) can be prepared starting from compound (25) and using 3-methoxy-1-propylamine instead of N- (2-aminoethyl) -acetamide

Compound (126)

b) Preparation ofCompound (135)

The reaction was carried out under N2. Sodium hydride (60%) (0.001mol) was added to compound (25) (0.0007mol) in THF (5ml), and stirred at 40 ℃ for 15 minutes. 4-Morpholin-propanol (0.001mol) in THF (5ml) was then added. The reaction mixture was stirred at 50 ℃ for 20 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was taken up in DCM/water. The organic layer was separated, dried (MgSO 4), filtered and the solvent of the filtrate was evaporated. The residue was purified by reverse phase HPLC (gradient elution using NH 4 HCO 3 buffer (0.25% in water)/CH₃OH/CH₃CN). The product fractions were collected and the solvent was evaporated. The residue was stirred in ethyl acetate and HCl in 2-propanol at 0 ℃. The precipitate was filtered off and dried (vacuum, 60 ℃ C.) to yield 0.044g of compound (135).

c) Preparation ofCompound (152)

A mixture of compound (25) (0.0016mol), 1, 3-propanediol (0.005mol), 2-methyl-2-propanol, potassium salt in THF (1M) (2ml) and dioxane (10ml) was stirred at 80 ℃ for 2 hours. The reaction mixture was cooled. Water (100ml) was added and the mixture was extracted with 5x80ml DCM. The organic layer was dried (MgSO 4) and concentrated to give 0.7g of a residue. The residue was purified by reverse phase HPLC (HPLC method B) and worked up (crystallization from DIPE) to yield 0.170g of compound (152).

d) Preparation ofCompound (130)

A mixture of 1, 1-dimethylethyl ether (3-hydroxypropyl) carbamate (0.0033mol) and sodium hydride in mineral oil (60%) (0.0033mol) in dioxane (10ml) was stirred at 60 ℃ for 30 minutes. Compound (25) (0.00162mol) was added and the reaction mixture was stirred at 100 ℃ overnight. The reaction mixture was cooled. Water (100ml) was added. The mixture was extracted with DCM (2 × 100 ml). The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by reverse phase HPLC (gradient elution using NH 4 HCO 3 buffer (0.25% in water)/CH₃OH/CH₃CN). The product fractions were collected and the solvent was evaporated to give 0.225g of compound (130).

Other final compounds can be prepared in a similar manner to compound (130) by replacing (3-hydroxypropyl) carbamic acid 1, 1-dimethylethyl ether with 3- (dimethylamino) -1-propanol, 3-methoxy-1-propanol, or 2-methoxyethanol.

e) Preparation ofCompound (131)

A mixture of compound (130) (0.00036mol) and TFA (5ml) in DCM (5ml) was stirred at room temperature for 20 min. The solvent was removed under N2 flow. The residue was dissolved in DCM (12ml) and washed with 1N aqueous NaOH (10ml) and water (10 ml). The organic phase was filtered through an Isolute HM-N filter and the solvent was evaporated under N2 to give 0.176g of compound ((131).

f) Preparation ofCompound (132)

A mixture of compound (131) (0.003mol), acetic acid 1, 1' -anhydride (0.067g) and DCM (10ml) was shaken at room temperature for 3 hours. The reaction mixture was washed with 2x10ml of 1N aqueous NaOH, 1x10ml water and filtered through an Isolute HM-N filter. The filtrate was concentrated under N2 flow and crystallized from HCl salt in diethyl ether to give 14g of compound ((132).

Example B.34

Preparation ofCompound (124)

Andcompound (125)

Intermediate (95) (0.233g, 0.000528mol) was dissolved in chloroform. 3-chloro-benzoic acid peroxide (0.260g, 2 equivalents) was added. The mixture was partitioned between DCM and aqueous NaHCO 3. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (crude crystals, 0.0005mol) was dissolved in acetic acid (15 ml). Fe powder (0.215g) was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated. The residue was partitioned between DCM and aqueous NaHCO 3. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was separated and purified by HPLC. Two product fraction fractions were collected and reprocessed to yield 0.080g of compound (124) and 0.030g of compound (125).

Example B.35

a) Preparation ofCompound (146)

1, 4-trans

(comparative, mixture)

3-Chlorobenzeneperoxyformic acid (0.001mol) was added in 2 portions to a solution of intermediate (109) (0.003mol) in chloroform (20ml) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with water/NaOH. The organic layer was dried (MgSO 4), filtered and evaporated. The residue was filtered through a silica gel filter using DCM/CH₃OH(7N NH₃) Purified from 100/0 to 99/1 as eluents. The product fractions were collected and evaporated. The product was cured from DIPE. The solid was filtered off, washed and dried to obtain 0.12g of compound ((146) (1, 4-trans; relative; mixture).

b) Preparation ofCompound (134)

Under N "2", the directionMolecular sieves (0.2g) in a mixture of DCM (dry) (3ml) and pyridine, trichlorochromate (VI) was added compound (146) (0.0002mol) in DCM (1 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a celite pad filter. The filtrate was concentrated. The residue was taken up in crude to give compound (134).

c) Preparation ofCompound (153)

1, 4-cis form

(comparative, mixture)

Bromomethylmagnesium (3.0M) (0.2ml) in diethyl ether was added to diethyl ether (3 ml). The reaction mixture was cooled to-60 ℃. Compound (134) (0.0002mol) in THF (1ml) was added and the reaction mixture was allowed to reach room temperature. The solvent was evaporated and the residue was taken up in DCM/water. Separating the organic layer, filtering with Isolute filter, evaporating and filteringA solvent for the liquid. The residue was purified by reverse phase HPLC (gradient elution using NH 4 HCO 3 buffer (0.25% in water)/CH₃OH/CH₃CN) purification. The product fractions were collected and the solvent was evaporated. Adding CH₃OH and then evaporated. The residue was dried under vacuum at 50 ℃ to give 8mg of compound ((153) (1, 4-cis; relative; mixture).

Example B.36

Preparation ofCompound (136)

3-Chlorobenzeneperoxyformic acid (0.003mol) was added in 2 parts at room temperature to a solution of intermediate (112) (0.009mol) in chloroform (15 ml). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with water/NaOH. The organic layer was dried (MgSO 4), filtered and evaporated. The residue was purified by column chromatography using DCM/CH₃OH:NH₃(100% to 98%/2%) was purified as eluent. The product fractions were collected and evaporated. The residue was purified by reverse phase HPLC (gradient elution using NH 4 HCO 3 buffer (0.25% in water)/CH₃OH/CH₃CN) further purification. The product fractions were collected, evaporated and reacted with CH₃CN was co-evaporated. The residue was solidified in diethyl ether by addition of 1ml of HCl/ether solution (1M). The solid was filtered off, washed and dried to yield 0.15g of compound ((136).

Example B.37

Preparation ofCompound (138)

3-Chlorobenzeneperoxyformic acid (0.0009mol) was added in 2 parts at room temperature to the intermediate (A)114) (0.0003mol) in chloroform (10 ml). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with water/NaOH. The organic layer was dried (MgSO 4), filtered and evaporated. The residue was taken up in acetic acid (100%) (5ml) and Fe powder (0.1 g). The mixture was stirred at 60 ℃ for 1 hour. The residue was purified by column chromatography using DCM/CH₃OH:NH₃(100% to 98%/2%) was purified as eluent. The product fractions were collected and evaporated. The residue was purified by reverse phase HPLC (gradient elution using NH 4 HCO 3 buffer (0.25% in water)/CH₃OH/CH₃CN) further purification. The product fractions were collected, concentrated, and then extracted with DCM. The organic layer was dried (MgSO 4), filtered and evaporated. The residue was crystallized from DIPE, 2-propanol and HCl/ether 1M solution (0.5 ml). The solid was filtered off, washed and dried to obtain 0.04g of a compound ((138).

Example B.38

a) Preparation ofCompound (169)

A mixture of intermediate (117) (0.0005mol) in chloroform (20ml) was cooled to 0 ℃. 3-Chlorobenzeneperoxyformic acid (0.210g) was added and the reaction mixture was stirred for an additional 2 hours. The separated organic layer was washed with aqueous NaOH (1M), dried (MgSO 4), filtered and the solvent evaporated. The residue was added to acetic acid (6 ml). Then Fe powder (0.280g) was added. The mixture was stirred at 60 ℃ for 90 minutes. The mixture was cooled and the solvent was evaporated. The residue was partitioned between DCM and water. The mixture was basified with NaHCO 3. The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated to give 0.220g of compound (169).

b) Preparation ofCompound (139)

A mixture of compound (169) (0.0003mol) and hydrazine monohydrate (0.1ml) in ethanol (4ml) was stirred and refluxed for 1 hour. The reaction mixture was cooled and the solvent was evaporated. The residue was taken up in DCM and water. The separated organic layer was dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: DCM/CH)₃OH 90/10). The desired product fractions were collected and the solvent was evaporated to yield 0.105g of compound (139).

c) Preparation ofCompound (141)

Triethylamine (0.06ml) was added to a mixture of compound (139) (0.0002mol) in DCM (5ml) at 0 deg.C. Acetyl chloride (0.0002mol) was added to the reaction mixture, which was then stirred at room temperature for 10 minutes. The reaction mixture was washed with water and then filtered through Isolute. The solvent of the filtrate was evaporated under N2. The residue was taken up in ethyl acetate and HCl/diethyl ether solution. The precipitate was filtered and dried to obtain 0.032g of compound (141).

Example B.39

a) Preparation ofCompound (142)

Compound (18) (0.0045mol), tributylvinylstannane (0.0067mol), tetrakis (triphenylphosphine palladium (0.33g) and DMF (50ml) were degassed in a sealed vessel the reaction mixture was shaken at 80 ℃ for 24 h, 1, 4-dioxane (100ml) and potassium fluoride (2g) were added, the reaction mixture was packed with celite and filtered, the filtrate was concentrated, the residue was taken up in DCM and washed with water, the organic layer was dried (MgSO 4), filtered, evaporated and the residue was subjected to reverse phase HPLC (gradient elution with NH 4 HCO 3 buffer (0.25%)In water)/CH₃OH/CH₃CN) purification. The product fractions were collected, evaporated and co-evaporated with methanol until completely dried to yield 0.75g of compound ((142).

b) Preparation ofCompound (157)

A mixture of compound (142) (0.0005mol), 4-methoxybenzylamine (0.014mol) and N-ethyl-N- (1-methylethyl) -2-propylamine (0.003mol) in N, N-dimethyl-acetamide (5ml) was stirred at 110 ℃ for 3 days. After cooling, the reaction mixture was taken up in water (20ml) and ethyl acetate (50 ml). The organic layer was dried (MgSO 4), filtered and evaporated. The scavenger PS-benzaldehyde (8g) (capacity: 1.2mmol/g) in DCM (200ml) was used and the residue was shaken overnight. The scavenger is removed by filtration. The filtrate was concentrated and washed with DCM/CH on silica gel₃OH(7N NH₃) (from 100:0 to 96:4) as eluent. The product fractions were collected and evaporated to dryness. The residue was used as such in the next reaction to obtain 0.21g of a compound ((157).

c) Preparation ofCompound (172)

To a mixture of compound (157) (0.0003mol) and N-ethyl-N- (1-methylethyl) -2-propylamine (0.001mol) in THF (10ml) was added acetic acid 1, 1' -anhydride (0.0005mol) at room temperature. The reaction mixture was shaken in a sealed vessel at 35 ℃ for 1 hour. The reaction mixture was taken up in 100ml of DCM and then washed with 10ml of water. The organic layer was dried (MgSO 4), filtered and evaporated. The residue was used as such in the next reaction to obtain 0.2g of a compound ((172).

d) Preparation ofCompound (158)

TFA (10ml) was added to compound (172) (0.0003mol) in DCM (1ml) at room temperature. And (4) sealing the container. The reaction mixture was shaken for 1 week at 60 ℃. The reaction mixture was cooled and the solvent was evaporated. The residue was taken up in DCM and washed with water. The organic layer was dried (MgSO 4), filtered and evaporated. The residue was washed with DCM/CH on silica gel₃OH(7NNH₃) (from 100% to 96/4) as eluent. The product fractions were collected and evaporated to dryness. The residue was crystallized from DIPE and some 2-propanol. The solid was filtered off, washed and dried to obtain 0.095g of a compound ((158).

Example B.40

Preparation ofCompound (165)

A solution of intermediate (138) (0.3g, 0.000747mol) in chloroform (ethanol free) (10ml) was cooled to 0 ℃. mCPBA (70%) (0.4g, 3 eq.) was added and the mixture was stirred for 30 minutes at 0 ℃ and then for 3 hours at room temperature. The reaction was quenched with NaOH (1N) and the crude product was extracted with chloroform. The separated organic layer was washed with water and brine and dried (Na)₂SO₄) Then, the solvent was evaporated to give 0.286g of a white foam. The white foam was purified by reverse phase column chromatography. The desired product fractions were collected, processed and the solvent was evaporated again to give 0.097g of compound ((165).

Example B.41

Preparation ofCompound (144)

2-tert-butyl-5- (2-fluoro-pyridine-4-sulfonyl) -1- [2- (1-oxy-pyrrolidin-1-yl) -ethyl]A mixture of (E) -1H-benzimidazole (0.0003mol) in THF (150ml) was hydrogenated using activated carbon on palladium (10%) as catalyst. After absorption of hydrogen (3 equivalents), the catalyst is filtered off and the solvent is evaporated again. The residue was partitioned between DCM (10ml) and water (1 ml). The mixture was filtered through Isolute. The solvent of the filtrate was evaporated (in N)₂Down stream) to yield 0.135g of residue. 0.100g of the residue was purified by reverse phase HPLC (gradient elution using NH 4 HCO 3 buffer (0.25% in water)/CH₃OH/CH₃CN) the desired product fractions were collected and the solvent was evaporated. The residue was solidified in DIPE and the precipitate was filtered off and dried (vacuum, 40 ℃ C.) to yield 0.025g of compound (144).

Tables F-1 and F-2 list compounds prepared by analogy to one of the above examples.

TABLE F-1

TABLE F-2

Compound identification

LMCS general procedure A

HPLC measurements were performed using an Alliance HT 2790(Waters) system comprising a quaternary pump with degasser, an autosampler, a column oven (set at 40 ℃ C. unless otherwise indicated), a Diode Array Detector (DAD) and columns as described in the methods below. The flow from the column was split to the MS spectrometer. The MS detector is configured with an electrospray ion source. Mass spectra were acquired using a 0.1 second sampling time to scan from 100 to 1000 in 1 second. The capillary needle voltage was 3kV and the source temperature was maintained at 140 ℃. Nitrogen was used as the atomizing gas. Data were acquired using a Waters-MicromassMassLynx-Openlynx data System.

LCMS-general procedure B

LC assays were performed using an Acquisty UPLC (Waters) system comprising a binary pump, a sample organizer, a column heater (set at 55 ℃), a Diode Array Detector (DAD) and columns as described in the following methods. The flow from the column was split to the MS spectrometer. The MS detector is configured with an electrospray ion source. Mass spectra were acquired using a 0.02 second sampling time to scan from 100 to 1000 in 0.18 seconds. The capillary needle voltage was 3kV and the source temperature was maintained at 140 ℃. Nitrogen was used as the atomizing gas. Data were acquired using a Waters-Micromass MassLynx-Openlynx data System.

LCMS method 1

In addition to general procedure a: reverse phase HPLC was performed on a Xterra MS C18 column (3.5 μm, 4.6X100mm) with a flow rate of 1.6 ml/min. Three mobile phases (mobile phase a: 95% 25mM ammonium acetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to run gradient conditions: from 100% a to 1% a, 49% B and 50% C in 6.5 minutes and 1% a and 99% B in 1 minute, these conditions were maintained for an additional 1 minute and re-equilibrated with 100% a for an additional 1.5 minutes. An injection volume of 10 μ l was used. The cone voltage in the anodic ionization mode was 10V and the cone voltage in the cathodic ionization mode was 20V.

LCMS method 2

In addition to general procedure a: reverse phase HPLC was performed on an Atlantis C18 column (3.5 μm, 4.6X100mm) (3.5 μm, 4.6X100mm) with a flow rate of 1.6 ml/min. Two mobile phases (mobile phase A: 70% methanol + 30% H) were used₂O; mobile phase B: 0.1% formic acid in H₂O/methanol 95/5) to run gradient conditions: from 100% B to 5% B + 95% a in 12 minutes. An injection volume of 10 μ l was used. The cone voltage in the anodic ionization mode was 10V and the cone voltage in the cathodic ionization mode was 20V.

LCMS method 3

In addition to general procedure a: reverse phase HPLC was carried out on Chromolith (4.6X 25mm) with a flow rate of 3 ml/min. Three mobile phases (mobile phase a: 95% 25mM ammonium acetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to run gradient conditions: from 96% a, 2% B and 2% C to 49% B and 49% C in 0.9 min to 100% B in 0.3 min for a further 0.2 min. Injection volumes of 2 μ l were used. The cone voltage in the anodic ionization mode was 10V and the cone voltage in the cathodic ionization mode was 20V.

LCMS method 4

In addition to general procedure a: the column heater was set at 60 ℃. Reverse phase HPLC was performed on an XterraMS C18 column (3.5 μm, 4.6X100mm) with a flow rate of 1.6 ml/min. Three mobile phases (mobile phase a: 95% 25mM ammonium acetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to run gradient conditions: from 100% A to 50% B and 50% C in 6.5 minutes and to 100% B in 0.5 minutes, these conditions were maintained for an additional 1 minute and re-equilibrated with 100% A for an additional 1.5 minutes. An injection volume of 10 μ l was used. The cone voltage in the anodic ionization mode was 10V and the cone voltage in the cathodic ionization mode was 20V.

LCMS method 5

In addition to general procedure B: reverse phase UPLC (ultra performance liquid chromatography) was performed on a bridged ethyl siloxane/silica gel (BEH) C18 column (1.7 μm, 2.1 × 50mm) with a flow rate of 0.8 ml/min. Two mobile phases were used (mobile phase A: 0.1% formic acid in H)₂O/methanol 95/5; mobile phase B: methanol) to run gradient conditions: from 95% a and 5% B to 5% a and 95% B in 1.3 minutes, and for an additional 0.2 minutes. An injection volume of 0.5 μ l was used. The cone voltage in the anodic ionization mode was 10V and the cone voltage in the cathodic ionization mode was 20V.

LCMS method 6

In addition to general procedure a: reverse phase HPLC was performed on an Xbridge C18 column (3.5 μm, 4.6X100mm) (3.5 μm, 4.6X100mm) with a flow rate of 1.6 ml/min. Two mobile phases (mobile phase A: 70% methanol + 30% H) were used₂O; mobile phase B: 0.1% formic acid in H₂O/methanol 95/5) to run gradient conditions: from 100% B to 5% B + 95% a in 12 minutes. An injection volume of 10 μ l was used. The cone voltage in the anodic ionization mode was 10V and the cone voltage in the cathodic ionization mode was 20V.

Melting Point

For some compounds, melting points were determined by DSC823e (Mettler-Toledo). In this method, the melting point is determined with a temperature gradient of 30 ℃ per minute. The maximum temperature is 400 ℃.

For some compounds, the melting point was determined using a Buchi melting point apparatus (in an open capillary). The heating medium is a metal block. The melting point of the sample was visually observed by means of a magnifying glass and a high light contrast. Melting points were determined using a temperature gradient of 3 or 10 ℃ per minute. The maximum temperature is 300 ℃.

For some compounds, melting points were obtained with a Kofler hot bench (hot bench) consisting of a hot plate with a linear temperature gradient, a sliding indicator, and a temperature scale in degrees celsius.

The peak and melting range values are obtained using experimental uncertainties typically associated with this analytical method.

TABLE F-3: analytical data-retention time (R)_tMinute), (MH)⁺Peaks, LCMS methodology and physicochemical data (m.p. defined as melting point).

TABLE F-4: analytical data-retention time (R)_tMinutes), (MH) -peak, LCMS procedure and physicochemical data (m.p. is defined as melting point).

Compound numbering	R_t	(MH)^-	Method of operation	Physical and chemical data
					1	0.83	428	3
2	0.74	412	3
					8	4.10	428	4	m.p.：>300℃(Kofler)
97	4.89	510	4	m.p.：152.9℃(DSC)
					9	6.16	456	1	m.p.：174℃(Kofler)
25	5.05	430	4	m.p.：171.3℃(DSC)

C. Pharmacological examples

Inhibition of C.1 cAMP in response to activation of human CB1 and CB2 receptors

The functional activity of the test compounds was assessed by measuring their potency to inhibit forskolin-activated cAMP production after activation of human CB1(hCB1) or human CB2(hCB2) receptors by Homogeneous Time Resolved Fluorescence (HTRF) assay.

In a T175 Falcon flask, supplemented with 2% solution A (5.10)⁶IU/l penicillin G, 5G/l streptomycin sulfate, 5.5G/l pyruvate, 14.6G/l L-glutamine, 1M NaOH) and 10% fetal calf serum in DMEM/NUT MIX F-12 medium, to grow to 80-90% confluency CHO-K1 cells stably transfected with hCB1 or hCB 2. Prior to the assay, the medium was removed and the cells were treated with PBS/EDTA (140mM NaCl, 1mM Na)₂-EDTA、8mM Na₂HPO₄.2H₂O、8.5mM KH₂PO₄2.7mM KCl, 21mM glucose) and suspended in stimulating buffer solution (HBSS 1x, IBMX 1mM, Hepes 5mM, MgCl 210 mM, BSA 0.1%, ph 7.4). For the hCB1 assay, cells were diluted to 8.10⁵Cells/ml; for the hCB2 assay, cells were diluted to 10⁶Cells/ml. Analysis was performed using the cAMP Dynamic HTRF kit (CIS Biointemental, France) according to the manufacturer's instructions.

For CB1, wells of a 96 flat bottom black polystyrene assay plate (Costar) were filled with 25 μ l of stimulation buffer containing 6 μ M forskolin and test compound (in 2% DMSO), 2% DMSO, or 2 μ M CP55490 (in 2% DMSO). Then, 25. mu.l of diluted cells (20,000 cells/well) were added. After incubation in the dark at room temperature for 30 minutes, 25. mu.l cAMP-XL665 and 25. mu.l anti-cAMP cryptate (final dilution of both 1/80) were added to the cells.

For CB2, each well of a 384 flat bottom black polystyrene assay plate (Costar) was filled with 10. mu.l of stimulation buffer containing 15. mu.M forskolin and test compound (in 3% DMSO), 3% DMSO or 20. mu.M Win55212-2 (in 3% DMSO). Then, 20. mu.l of diluted hCB2-CHO-K1 cells (20,000 cells/well) were added. After incubation in the dark at room temperature for 30 minutes, 10. mu.l cAMP-XL665 and 10. mu.l anti-cAMP cryptate (both final dilutions of 1/100) were added to the cells.

After the reaction mixture was equilibrated in the dark at room temperature for 1 to 24 hours, the fluorescence was measured at 665nm and 620nm using a Discovery microplate fluorescence counter (Perkin Elmer), and the signal ratio of 665nm/620nm was calculated. The signal ratios of the test compounds were expressed relative to the signal ratios of the DMSO control (maximum signal ratio, no inhibition of cAMP) and CP55490 or WIN55212-2 (hCB1 and hCB2, respectively) (minimum signal ratio, maximum inhibition of cAMP). The dose at which 50% of the maximal inhibition of cAMP levels is measured (EC) is determined from the dose response curve generated for each test compound₅₀Expressed in the table as pEC₅₀＝-log(EC₅₀) Values) and the level of inhibition achieved with 10 μ M of test compound relative to CP55490 (for hCB1) or WIN55212-2 (for hCB2) was calculated.

TABLE C-1: DEC50 values for CB-1 and CB-2 agonism

Compound numbering	CB2 pEC50	CB1 pEC50	Ratio of CB2 agonism to CB1 agonism
				1	8.30	<5	>1995
2	7.42	<5	>263
				3	8.76	6.16	398
4	8.72	5.49	1679
				5	9.43	6.59	676
7	8.74	<5	>5495
				8	8.51	5.33	1514
9	9.48	5.85	4266
				10	9.13	5.02	12883
11	8.90	7.22	48
				12	8.81	6.33	302
13	8.90	5.69	1622
				14	9.11	5.42	4898
15	8.98	6.24	556
				16	8.63	6.07	359
17	8.80	5.03	5821
				18	9.17	6.20	933
19	8.95	6.14	638
				20	8.90	6.36	347
21	8.42	5.00	2630
				22	8.95	5.70	1758
23	8.99	6.39	398
				24	8.66	6.05	407
25	9.09	6.39	495
				26	9.10	6.27	676
27	9.15	<5	>14125
				28	8.54	<5	>3467
29	8.50	5.88	417

Compound numbering	CB2 pEC50	CB1 pEC50	Ratio of CB2 agonism to CB1 agonism
				30	8.77	5.28	3055
31	8.92	6.37	353
				32	8.59	5.12	2951
33	8.51	5.24	1884
				34	8.80	5.13	4732
35	9.39	7.49	79
				36	9.17	7.14	108
37	9.03	<5.00	>10839
				38	8.56	<5.00	>3631
39	8.77	5.69	1216
				40	8.97	6.68	193
42	9.20	6.97	168
				42	8.40	<5.00	>2512
43	9.00	5.79	1622
				44	8.70	6.90	64
45	8.52	<5.00	>3311
				46	8.98	5.41	3758
47	8.77	5.83	871
				48	9.24	6.70	347
49	8.33	<5.00	>2138
				50	9.16	5.35	6457
51	8.91	7.05	73
				52	9.16	6.64	331
53	8.43	5.65	607
				54	9.03	6.91	133
55	8.64	6.08	363
				56	8.58	<5.00	>3802
57	8.96	5.84	1328
				58	9.08	5.74	2188

Compound numbering	CB2 pEC50	CB1 pEC50	CB2 agonism on CB1 agonismRatio of action
				59	8.95	5.64	2018
60	8.98	6.18	638
				61	8.95	6.82	135
62	9.23	5.71	3299
				63	9.01	5.55	2818
64	9.32	5.73	3920
				65	8.53	<5.00	>3388
66	7.83	<5.00	>676
				67	8.37	<5.00	>2344
68	8.51	6.44	116
				69	8.76	6.16	398
70	9.26	5.85	2570
				71	9.13	<5.00	>13490
72	9.17	5.99	1525
				73	8.86	6.93	84
74	8.50	5.68	668
				75	8.38	5.02	2291
76	7.92	<5.00	>832
				77	8.71	5.59	1303
78	8.14	<5.00	>1380
				79	8.53	5.80	543
80	8.38	4.98	2483
				81	9.30	5.97	2138
82	8.41	5.80	407
				83	8.70	6.39	209
84	8.90	6.21	490
				85	9.03	6.08	891
86	7.92	<5.00	>832
				87	8.67	5.64	1072

Compound numbering	CB2 pEC50	CB1 pEC50	Ratio of CB2 agonism to CB1 agonism
				88	8.63	5.90	537
89	7.95	<5.00	>891
				90	8.57	<5.00	>3715
91	8.30	5.00	1995
				92	8.16	5.53	437
93	8.83	<5.00	>6761
				94	8.60	5.57	1059
95	8.24	<5.00	>1738
				96	8.70	<5.00	>5012
97	8.73	5.41	2065
				98	9.02	6.13	794
99	8.88	6.03	700
				100	8.80	6.00	631
101	8.60	6.83	58
				102	8.30	5.04	1820
103	8.15	5.68	295
				104	9.13	7.06	117
105	8.80	6.32	295
				106	9.14	6.50	432
107	8.62	5.81	646
				108	8.59	<5.00	>3890
109	9.09	6.58	324
				110	9.26	5.98	1905
111	8.94	6.37	372
				112	8.31	<5.00	>2030
113	8.58	6.10	302
				115	8.43	5.44	977
116	8.23	5.24	966
				117	8.35	6.01	219

Compound numbering	CB2 pEC50	CB1 pEC50	Ratio of CB2 agonism to CB1 agonism
				118	8.75	6.11	437
119	8.15	<5.00	>1413
				120	8.64	<5.00	>4365
121	8.51	5.55	912
				122	9.01	7.00	102
123	8.38	<5.00	>2399
				124	7.84	<5.00	>692
125	8.60	<5.00	>3981
				126	9.07	6.02	1129
127	8.78	<5.00	6026
				128	8.68	<5.00	>4786
129	7.81	5.02	617
				130	8.64	<5.00	>4315
131	7.80	<5.00	>631
				132	8.85	<5.00	>7079
133	8.40	<5.00	>2512
				134	8.86	5.42	2786
135	8.66	<5.00	>4571
				136	9.36	<5.00	>22734
137	8.95	6.11	687
				138	8.76	6.08	473
139	7.88	<5.00	>759
				141	8.25	<5.00	>1792
142	9.02	5.87	1413
				143	7.77	<5.00	>589
144	849	<5.00	>3090
				145	8.49	<5.00	>3090
146	8.60	<5.00	>3981
				147	9.02	<5.00	>10471

Compound numbering	CB2 pEC50	CB1 pEC50	Ratio of CB2 agonism to CB1 agonism
				148	9.59	<5.00	>38905
149	8.90	<5.00	>8035
				150	8.90	6.09	638
151	9.32	5.41	8035
				152	8.93	5.44	3090
153	9.07	<5.00	>11749
				154	8.95	<5.00	>9016
155	8.60	<5.00	>3951
				156	8.39	5.60	617
157	8.46	<5.00	>2884
				158	8.85	5.08	5888
159	8.67	<5.00	>4677
				160	8.37	<5.00	>2344
161	8.74	5.28	2951
				162	9.44	<5.00	>27542
165	7.97	<5.00	>923
				168	8.09	<5.00	>1230

C.2 comparison data

Table c.2 lists some sulfonyl benzimidazole derivatives that have an unsubstituted heterocyclic moiety on the sulfonyl group. These compounds are covered by reference WO-2006/048754.

TABLE C-2

The ratio of CB2 agonism to CB1 agonism for compounds a through E was determined using the same protocol as described in pharmacological example c.1. Table C-3 lists the ratio of CB2 to CB1, which differs from the ratio of CB2 to CB1 for compounds of formula (I) which differ in the substituents present on the heterocyclic moiety on the sulfonyl group of the structure.

TABLE C-3: comparison between the existing Compounds A to E and the Compounds of the invention

Compound numbering	Ratio of CB2 to CB1 agonism	Compound numbering	Ratio of CB2 to CB1 agonism
				A	215	3	398
	215	8	1514
					215	9	4266
	215215	1417	48985821
					215	19	638
	215	21	2630
					215215	2223	1758398
	215	25	495
				B	30	1	1995
	30	28	3467
				C	36	4	1679
	36	10	12883

Compound numbering	Ratio of CB2 to CB1 agonism	Compound numbering	Ratio of CB2 to CB1 agonism
				D	26	12	302
	26	20	346
				E	219	24	407

The compounds of the present invention are more selective CB2 agonists than the prior compounds a to E.

Claims

1. A compound of formula (I) and pharmaceutically acceptable acid addition salts thereof:

wherein

n is an integer 1 or 2;

R¹is C_2-6An alkyl group;

C_1-6alkyl, which is selected from 1, 2 or 3 each independentlyThe substituent (b): halogen, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy, cyano, nitro, amino, and mono-or di (C)_1-4Alkyl) amino;

C_1-6Alkyl substituted with a heterocycle selected from: pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1-dioxo-tetrahydro-thiopyranyl, [1, 3 ]]Dioxolanyl, [1, 4 ] or a salt thereof]Dioxolanyl, [1, 3 ] or a salt thereof]Dioxanyl, 5-oxo-pyrrolidin-2-yl, or 2-oxo-oxepanyl; wherein said heterocycle is optionally substituted with one or two substituents each independently selected from the group consisting of: c_1-4Alkyl, polyhalo C_1-4Alkyl, halogen, hydroxy, C_1-4Alkoxy, cyano, COR⁵、COOR⁵、CONR⁵R⁶、SO₂R⁵Wherein R is⁵And R⁶Independently selected from hydrogen or C_1-4Alkyl or polyhalo C_1-4An alkyl group;

R²is C_2-6An alkyl group;

C_1-6alkyl substituted with 1, 2 or 3 substituents each independently selected from: c_1-4Alkyl, cyano;

R³is hydrogen;

R⁴is a heteroaryl group;

Selected from the group consisting of furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl and isopropylOxazolyl, thiazolyl, triazolyl, tetrazolyl, isothiazolyl, thiadiazolyl, thiadiazol,Oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, N-oxy-pyridinyl, N-oxy-pyridazinyl, N-oxy-pyrimidinyl, N-oxy-pyrazinyl or 2-oxo-1, 2-dihydro-pyridinyl, each substituted with 1, 2 or 3 substituents each independently selected from: halogen; a hydroxyl group; c_1-4An alkyl group; c_3-6A cycloalkyl group; c_2-6An alkenyl group; c_2-6Alkenyl substituted with 1 or 2 substituents selected from halogen; c_2-6An alkynyl group; c_2-6Alkynyl radical, which is substituted by C_1-4Alkoxy substitution; c_1-4An alkoxy group; c_1-4Alkoxy radical C_1-4An alkyl group; polyhalo C_1-4An alkyl group; polyhalo C_1-4An alkoxy group; a cyano group; a nitro group; NR (nitrogen to noise ratio)⁹R¹⁰；R¹¹-a carbonyl group; r¹¹-SO₂-；C_1-4Alkyl radicals substituted by hydroxy, NR⁹R¹⁰、R¹¹-carbonyl or R¹¹-SO₂-substitution;oxadiazolyl, optionally substituted by C_1-4Alkyl, polyhalo C_1-4Alkyl or C_3-6Cycloalkyl substitution; or dioxolanyl optionally substituted by 1 or 2C_1-4Alkyl substitution; c_1-4Alkoxy radicals substituted by hydroxy radicals, C_1-4Alkoxy radical, C_1-4Alkylcarbonylamino, C_1-4Alkoxycarbonylamino, amino, di (C)_1-4Alkyl) amino or morpholinyl; c_1-4Alkylcarbonylamino group C_1-4An alkylamino group; c_1-4Alkoxy radical C_1-4An alkylamino group;

whereinR⁹And R¹⁰Independently of one another, from hydrogen, C_1-4Alkyl, polyhalo C_1-4Alkyl, aminosulfonyl or C_1-8An alkylsulfonyl group; or R¹¹-a carbonyl group;

wherein R is⁹And R¹⁰And R⁹And R¹⁰The nitrogen atoms to which they are attached may together form a pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl ring; and is

2. The compound of claim 1, wherein

R¹Is C_2-6An alkyl group;

C_1-6an alkyl group substituted with a cyclic group selected from: c_3-8Cycloalkyl, oxo C_3-8Cycloalkyl radical, C_5-8Cycloalkenyl, bicyclo [2.2.1]Hept-2-enyl, bicyclo [2.2.2]Octyl and bicyclo [3.1.1]Heptylalkyl, wherein the cyclic group is optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy, cyano, nitro, NR⁵R⁶Or CONR⁵R⁶Wherein R is⁵And R⁶Independently selected from hydrogenOr C_1-4An alkyl group; or

C_1-6Alkyl substituted with a heterocycle selected from: pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1-dioxo-tetrahydro-thiopyranyl, [1, 3 ]]Dioxolanyl, [1, 4 ] or a salt thereof]Dioxolanyl, [1, 3 ] or a salt thereof]Dioxanyl, 5-oxo-pyrrolidin-2-yl, or 2-oxo-oxepanyl; wherein said heterocycle is optionally substituted with one or two substituents each independently selected from the group consisting of: c_1-4Alkyl, halogen, hydroxy, C_1-4Alkoxy, cyano, trifluoromethyl, COR⁵、COOR⁵、CONR⁵R⁶、SO₂R⁵Wherein R is⁵And R⁶Independently selected from hydrogen or C_1-4Alkyl or polyhaloC 1-4 alkyl.

3. The compound of claim 1, wherein n is 2.

4. The compound of claim 1, wherein R¹Is C_1-6An alkyl group substituted with a cyclic group selected from: c_3-8Cycloalkyl or tetrahydropyranyl.

5. The compound of claim 1, wherein R²Is C_2-6An alkyl group.

6. The compound of claim 1, wherein R⁴Is an N-oxy-pyridyl group.

7. The compound of any one of claims 1 to 6, wherein R⁴Is furyl, thienyl,Oxadiazolyl, pyridinyl, or pyridazinyl; each of which is selected from 1, 2 or 3 each independentlySubstituent group substitution: halogen; a hydroxyl group; c_1-4An alkyl group; c_1-4An alkoxy group; polyhalo C_1-4An alkyl group; polyhalo C_1-4An alkoxy group; a cyano group; NR (nitrogen to noise ratio)⁹R¹⁰；R¹¹-a carbonyl group; r¹¹-SO₂-; or optionally is covered with C_1-4Alkyl substitutedA diazolyl group; wherein R is⁹And R¹⁰Independently of one another, from hydrogen or R¹¹-a carbonyl group; and wherein R¹¹Is C_1-4Alkyl, amino, or morpholinyl.

8. The compound of claim 1 which is

9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of claims 1 to 7.

10. A process for preparing a pharmaceutical composition according to claim 9, wherein a therapeutically effective amount of a compound according to any one of claims 1 to 7 is intimately mixed with a pharmaceutically acceptable carrier.

11. A process for the preparation of a compound of formula (I-a), defined as a compound of formula (I) according to claim 1 wherein n is 1, by S-oxidation of intermediate (A) with an oxidizing agent,

wherein R is¹、R²、R³And R⁴As in claimAs defined in claim 1.

12. The method according to claim 11, wherein the oxidizing agent is selected from NaIO₄T-butyloxy chloride, acyl nitrite, sodium perborate and peracids.

13. A process according to claim 12 wherein the peracid is m-chloroperbenzoic acid.

14. A process for the preparation of a compound of formula (I-b), defined as a compound of formula (I) according to claim 1 wherein n is 2, by S-oxidation of intermediate (A) with an oxidizing agent,

wherein R is¹、R²、R³And R⁴As defined in claim 1.

15. The method according to claim 14, wherein the oxidizing agent is selected from NaIO₄T-butyloxy chloride, acyl nitrite, sodium perborate and peracids.

16. The process according to claim 15, wherein the peracid is m-chloroperbenzoic acid.

17. A process for the preparation of a compound of formula (I-b), defined as a compound of formula (I) according to claim 1 wherein n is 2, by condensation of an intermediate of formula (XIII) under acidic or basic conditions,

wherein R is¹、R²、R³And R⁴As defined in claim 1.