HK1138262B - Novel phosphodiesterase inhibitors - Google Patents

Description

Novel phosphodiesterase inhibitors

Technical Field

The present invention relates to novel compounds having phosphodiesterase inhibitory activity and their use as therapeutic agents in the treatment of inflammatory diseases and disorders.

Background

Phosphodiesterases are enzymes that catalyze the hydrolysis of cyclic AMP and/or cyclic GMP to 5-AMP and 5-GMP, respectively, in cells, and as such, are critical for cellular regulation of cAMP or cGMP levels. Of the 11 phosphodiesterases identified to date, Phosphodiesterase (PDE)4, PDE7 and PDE8 are selective for cAMP. PDE4 is the most important cAMP modulator, expressed in immune and inflammatory cells such as neutrophils, macrophages and T-lymphocytes (z.huang and j.a.mannini, Current med.chem.13, 2006, 3253-. Since cAMP is a key second messenger in the regulation of inflammatory responses, PDE4 has been found to regulate the inflammatory response of inflammatory cells by modulating pro-inflammatory cytokines such as TNF α, IL-2, IFN- γ, GM-CSF and LTB 4. Therefore, inhibition of PDE4 has become an attractive target for the treatment of the following inflammatory diseases: asthma, Chronic Obstructive Pulmonary Disease (COPD), rheumatoid arthritis, atopic dermatitis, Crohn's disease, etc. (M.D. Houslay et al, Drug Discovery Today 10(22), 2005, page 1503) 1519). Since Atopic Dermatitis (AD) patients have enhanced PDE-activity, PDE 4-inhibition also appears to be a viable treatment for AD (Journal of Investigative Dermatology (1986), 87(3), 372-6).

The PDE4 gene family consists of at least four genes: A. b, C and D, which have a higher degree of homology (V.Boswell Smith and D.Spina, curr.Option investig. drugs6(11), 2006, 1136-. The 4 PDE4 isoforms are differentially expressed in different tissues and cell types. Thus, PDE4B is expressed predominantly in monocytes and neutrophils, but not in cortical and epithelial cells, whereas PDE4D is expressed in lung, cortical, cerebellum and T-cells (c.kroegel and m.foerster, exp. opinion investig. drugs 16(1), 2007, page 109-. It has been speculated that PDE4D inhibition in the brain is associated with the adverse effects found clinically when PDE4 inhibitors are administered, mainly nausea and vomiting, whereas PDE4B inhibition is associated with anti-inflammatory effects (b. lipworth, Lancet 365, 2005, page 167-). However, the PDE inhibitors developed to date are not believed to be specific for any of the four PDE4 subtypes.

The therapeutic effects of PDE4 inhibitors on inflammatory diseases have been studied, mainly asthma, inflammatory bowel disease and COPD. The first of these is theophylline, a weak non-selective phosphodiesterase inhibitor, used in the treatment of respiratory diseases such as asthma and COPD. However, treatment with theophylline can produce mild and severe adverse effects, such as arrhythmias and spasticity, limiting the clinical utility of theophylline (Kroegel and Foerster, supra). Since phosphodiesterases remain attractive targets for anti-inflammatory therapy, several other more selective PDE4 inhibitors have been developed and studied in the clinical setting. The development of many generation PDE4 inhibitors, such as rolipram, has been terminated by dose-limiting side effects, primarily nausea and vomiting. Second-generation PDE4 inhibitors with significantly fewer significant side effects are currently undergoing clinical trials (Houslay, supra).

Recently developed PDE-4 inhibitors are disclosed for example in EP 0771794 and EP 0943613. WO 96/31476 discloses structurally different 4-substituted-3, 5-dichloropyridines which are cyclic AMP phosphodiesterase inhibitors.

There is a continuing need to develop new PDE4 inhibitors that have a more favorable therapeutic window, i.e., fewer side effects, while retaining their anti-inflammatory therapeutic effects. An overview of preclinical and clinical trials of selective PDE4 inhibitors, including such inhibitors targeted for the treatment of atopic dermatitis and psoriasis, was recently reviewed in Inflammation & Allergy: drug Targets, 2007, 6(1), 17-26.

Summary of The Invention

The inventors have surprisingly found that: the novel compounds of the present invention exhibit PDE4 inhibitory activity and are useful as therapeutic agents for the following diseases: inflammatory allergic diseases such as bronchial asthma, allergic rhinitis and nephritis; autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, Crohn's disease and systemic lupus erythematosus; central nervous system diseases such as depression, amnesia, and dementia; organ pathology associated with ischemic reflux caused by heart failure, shock, cerebrovascular disease, and the like; insulin-resistant diabetes; trauma; AIDS, and the like.

The compounds of the present invention may also be useful in the prevention, treatment or amelioration of a variety of diseases, such as skin diseases or disorders, such as proliferative and inflammatory skin diseases, and in particular psoriasis, epidermal inflammation, alopecia, skin atrophy, steroid induced skin atrophy, skin aging, photo skin aging (photo skin aging), acne, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritis and eczema.

Accordingly, the present invention relates to compounds according to formula I,

wherein m and n independently represent 0, 1, 2, 3, 4, 5, 6 or 7;

wherein G and E independently represent sulfur, oxygen, -N ═ N (R)₅) -or-N (R)₅) C (O) -, and

R₁and R₂Together with the carbon atom to which they are attached form an unsaturated carbocyclic ring or contain one or two members selected from the group consisting of oxygen, sulfur, -S (O) -, -S (O)₂-、-N(R₅) -said unsaturated carbocyclic or heterocyclic ring optionally substituted by one or more identical or different heteroatoms selected from R₄Substituted with the substituent(s); or

Wherein G and E independently represent sulfur, oxygen, -N ═ N (R)₅) -or-N (R)₅) C (O) -, and

R₁and R₂Together with the carbon atom to which they are attached form a saturated carbocyclic ring in which one or more carbon atoms are optionally substituted by one or more, same or different, groups selected from R₄Provided that when G is oxygen, m and n are not both 0, and further provided that when G and E are both oxygen, the sum of m and n is 6 or greater than 6;

R₃is halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, formyl, alkoxycarbonyl, alkylcarbonyl or aminocarbonyl;

R₄is hydrogen, amino, thio (thioxo), alkyl, haloalkyl, hydroxyalkyl, alkoxy, halogen, oxo, thia or hydroxy;

R₅is hydrogen, alkyl, haloalkyl, alkylcarbonyl, hydroxyalkyl, alkoxycarbonyl, alkylsulfonyl, alkylaminosulfonyl or aminosulfonyl;

x is a bond, -CH₂-or-NH-;

a is aryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkenyl, optionally mono-or poly-substitutedA plurality of same or different substituents selected from R₄Substituted with the substituent(s); and pharmaceutically acceptable salts, hydrates, N-oxides or solvates thereof.

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of general formula I as defined above together with a pharmaceutically acceptable vehicle or excipient or one or more pharmaceutically acceptable carriers, and optionally one or more other therapeutically active compounds.

In yet another aspect, the present invention relates to a compound of formula I as defined above and pharmaceutically acceptable salts, hydrates, N-oxides or solvates thereof, for use in the prevention, treatment or amelioration of a skin disease or disorder, or an acute or chronic skin wound disorder.

In yet another aspect, the invention relates to a method of preventing, treating or ameliorating a skin disease or disorder or an acute or chronic cutaneous traumatic condition, said method comprising administering to a person suffering from at least one of said diseases an effective amount of one or more compounds of formula I as defined above and pharmaceutically acceptable salts, hydrates, N-oxides or solvates thereof; and optionally a pharmaceutically acceptable carrier or one or more excipients, optionally in combination with other therapeutically active compounds.

Detailed Description

The term "hydrocarbyl" refers to a group containing only hydrogen and carbon atoms, which may contain one or more carbon-carbon double and/or triple bonds, and which may contain a combination of cyclic moieties and branched or straight chain moieties. The hydrocarbon comprises from 1 to 20 carbon atoms, preferably from 1 to 12, such as from 1 to 6, such as from 1 to 4, such as from 1 to 3, such as from 1 to 2 carbon atoms. This term includes alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkynyl and aryl, arylalkyl groups as shown below.

The term "aryl" refers to an aromatic carbocyclic group comprising 6 to 20 carbon atoms, such as 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms, especially a 5-or 6-membered ring, a carbocyclic ring optionally fused to at least one aromatic ring, such as phenyl, naphthyl, indenyl and indanyl.

The term "heteroaryl" refers to a heterocyclic aromatic ring group comprising 1-6 heteroatoms (selected from O, S and N) and 1-20 carbon atoms, such as 1-5 heteroatoms and 1-10 carbon atoms, such as 1-5 heteroatoms and 1-6 carbon atoms, such as 1-5 heteroatoms and 1-3 carbon atoms, especially a 5-or 6-membered ring having 1-4 heteroatoms selected from O, S and N, or an optionally fused bicyclic ring having 1-4 heteroatoms, and wherein at least one ring is aromatic, for example pyridyl, quinolyl, isoquinolyl, indolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, pyrazinyl, isothiazolyl, benzimidazolyl and benzofuranyl.

In the context of the present invention, the term "alkyl" refers to a group that results when one hydrogen atom is removed from a hydrocarbon. The alkyl group contains 1 to 20, preferably 1 to 12, such as 1 to 6, such as 1 to 4 carbon atoms. This term includes the subclasses n-alkyl (n-alkyl), secondary alkyl and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl.

The term "cycloalkyl" refers to a saturated cycloalkyl group containing from 3 to 20 carbon atoms, preferably from 3 to 10 carbon atoms, especially from 3 to 8 carbon atoms, such as from 3 to 6 carbon atoms, including fused bicyclic rings, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term "heterocycloalkyl" refers to a cycloalkyl group as described above in which one or more carbon atoms are replaced by a heteroatom, containing 1 to 19 carbon atoms, such as 2 to 4 carbon atoms, further containing 1 to 6 heteroatoms, preferably 1, 2 or 3 heteroatoms selected from O, N or S, which may optionally be oxidized once or twice, such as [1, 3] dioxole, oxetane, [1, 3] dioxolane, [1, 3] dioxane, tetrahydrothiopyran-1, 1-dioxide, tetrahydrothiopyran-1-oxide, piperidine, tetrahydrothiophene, [1, 3] -dithiane, thietane, [1, 3] -dithiane-1, 3-dioxide or thietane-1-oxide, or including fused bicyclic rings having 1 to 4 heteroatoms, wherein at least one ring contains a heteroatom and wherein the other ring may be, for example, a carbocyclic ring, e.g., isoindolyl.

The term "alkenyl" refers to a mono-, di-, tri-, tetra-or pentaunsaturated hydrocarbon group comprising 2 to 10 carbon atoms, especially 2 to 6 carbon atoms, such as 2 to 4 carbon atoms, e.g. ethenyl, propenyl, butenyl, pentenyl or hexenyl.

The term "cycloalkenyl" refers to mono-, di-, tri-or tetraunsaturated non-aromatic cyclic hydrocarbon radicals containing from 3 to 20 carbon atoms, including fused bicyclic radicals, typically containing from 3 to 10 carbon atoms, such as 3, 4 or 6 carbon atoms, for example cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl.

The term "heterocycloalkenyl" refers to cycloalkenyl groups as described above wherein one or more carbon atoms are replaced with a heteroatom, containing 1 to 19 carbon atoms, for example 2 to 4 carbon atoms, further containing 1 to 6 heteroatoms, preferably 1, 2 or 3 heteroatoms selected from O, N or S, including fused bicyclic rings having 1 to 4 heteroatoms, wherein at least one ring contains a heteroatom, and wherein the other ring may be, for example, a carbocyclic ring, such as dihydrofuranyl or 2, 5-dihydro-1H-pyrrolyl.

The term "arylalkyl" refers to an aryl group as defined above covalently attached to an alkyl group, for example benzyl.

The term "heteroarylalkyl" refers to a heteroaryl group as defined above covalently attached to an alkyl group.

The term "alkynyl" refers to a hydrocarbon group containing 1 to 5C-C triple bonds and 2 to 20 carbon atoms, typically 2 to 10 carbon atoms, especially 2 to 6 carbon atoms, such as 2 to 4 carbon atoms, e.g. ethynyl, propynyl, butynyl, pentynyl or hexynyl.

The term "halogen" refers to substituents from the seventh main group of the periodic table, such as fluorine, chlorine, bromine and iodine.

The term "haloalkyl" refers to an alkyl group as defined above substituted with one or more halogen atoms as defined above, for example difluoromethyl.

The term "hydroxyalkyl" refers to an alkyl group as defined above substituted with one or more hydroxy groups, e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl.

The term "alkoxy" refers to a group of the formula-OR ', wherein R' is alkyl as shown above, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, and the like.

The term "alkoxycarbonyl" refers to a group of the formula-C (O) -O-R ', wherein R' is alkyl as shown above, e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, and the like.

The term "alkylcarbonyl" refers to a group of formula-c (o) -R ', wherein R' is alkyl as shown above, e.g., alkanoyl, acetyl.

The term "aminosulfonyl" refers to compounds of the formula-S (O)₂-NR ', wherein R' is as defined above, e.g. -SO₂Me。

The term "heterocycle" includes the definitions of heteroaryl, heterocycloalkyl and heterocycloalkenyl as defined above, further including ring systems that ring with each other or with a cyclic hydrocarbon, such as 2, 5-dihydrobenzo (b) dioxaoctatriene (diooxine), 2, 3, 5, 8-tetrahydro- [1, 4] dioxaoctatriene, 5, 8-dihydro- [1, 4] dioxaoctatriene.

The term "pharmaceutically acceptable salts" refers to salts of the compounds of formula I which are prepared by reaction with a suitable inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, 2-dichloroacetic acid, adipic acid, ascorbic acid, L-aspartic acid, L-glutamic acid, galactaric acid, lactic acid, maleic acid, L-malic acid, phthalic acid, citric acid, propionic acid, benzoic acid, glutaric acid, gluconic acid, D-glucuronic acid, methanesulfonic acid, salicylic acid, succinic acid, malonic acid, tartaric acid, benzenesulfonic acid, ethane-1, 2-disulfonic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, sulfamic acid or fumaric acid. Pharmaceutically acceptable salts of the compounds of formula I may also be prepared by reaction with a suitable base such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, silver hydroxide, aqueous ammonia and the like, or a suitable non-toxic amine such as lower alkylamines, for example triethylamine, hydroxy-lower alkylamines, for example 2-hydroxyethylamine, bis- (2-hydroxyethyl) -amine, cycloalkylamines, for example dicyclohexylamine, or benzylamines, for example N, N' -dibenzylethylenediamine and dibenzylamine, or L-arginine or L-lysine. Salts obtained by reaction with a suitable base include, but are not limited to, sodium, choline, 2- (dimethylamino) -ethanolate, 4- (2-hydroxyethyl) -morpholine, L-lysine, N- (2-hydroxyethyl) -pyrrolidine, ethanolamine, potassium, tetrabutylammonium, benzyltrimethylammonium, hexadecyltrimethylammonium, tetramethylammonium, tetrapropylammonium, tris (hydroxymethyl) aminomethane, N-methyl-D-glucamine, silver, benzethonium, and triethanolamine.

The term "solvate" refers to a substance formed by the interaction of a compound, e.g., a compound of formula I, and a solvent, e.g., an alcohol, glycerol, or water, wherein the substance is in solid form. When water is the solvent, the substance is referred to as a hydrate.

Embodiments of the invention

In one or more embodiments of the invention, E and G are both oxygen.

In one or more embodiments of the invention, m and n are both 1.

In one or more embodiments of the invention, m and n are both 0.

In one or more embodiments of the invention, R₁And R₂Together with the carbon atom to which they are attached form a composition comprising one or two members selected from-O-, -S (O)₂) -, -N ═ and-N (R)₅) -a heterocyclic ring of a heteroatom; one or more carbon atoms in the heterocycle are optionally substituted by one or more, same or different, substituents selected from R₄Is substituted with the substituent(s).

In one or more embodiments of the invention, R₁And R₂Together with the carbon atom to which they are attached form a group comprising one or twoSelected from-O-, -S (O)₂) -and-N (R)₅) -a heterocycloalkyl ring of the heteroatom (a); one or more carbon atoms in the heterocycloalkyl ring are optionally substituted by one or more, same or different, substituents selected from R₄Is substituted with the substituent(s).

In one or more embodiments of the invention, R₁And R₂Together with the carbon atom to which they are attached form a 4-, 5-or 6-membered heterocyclic ring, especially a 6-membered heterocyclic ring.

In one or more embodiments of the invention, the heterocycle is tetrahydropyran, oxetane, [1, 3] dioxolane, [1, 3] dioxane, tetrahydrothiopyran-1, 1-dioxide, tetrahydrothiopyran-1-oxide, piperidine, tetrahydrothiophene, [1, 3] -dithiane, thietane, [1, 3] -dithiane-1, 3-dioxide, thietane-1-oxide, or thietane-1, 1-dioxide.

In one or more embodiments of the invention, R is substituted with one or more substituents selected from the group consisting of₁And R₂The heterocyclic ring formed with the carbon atom to which it is attached contains one heteroatom or two heteroatoms in the ring.

In one or more embodiments of the invention, the heteroatom is located at the 4-position of the heterocycle. The heteroatom may be, for example, O.

In one or more embodiments of the invention, one or more heteroatoms are oxygen, sulfur, -S (O) -or-S (O)₂-。

In one or more embodiments of the present invention, a represents heteroaryl or heteroarylalkyl.

In one or more embodiments of the invention, a represents pyridyl, pyrazinyl or quinolinyl.

In other embodiments, a may represent phenyl.

In one or more embodiments of the invention, a is substituted with halogen, especially with chlorine, fluorine, bromine and iodine.

In one or more embodiments of the invention, R₃Is represented by C_1-6Alkoxy radical, C_1-6Haloalkyl or halogen.

In one or more embodiments of the invention, R₃Represents a methoxy group or an ethoxy group.

In one or more embodiments of the invention, X is-CH₂-or-NH-.

In one or more embodiments of the invention, a is 4- (3, 5-dichloropyridyl).

In one or more embodiments of the invention, the compound of formula I is represented by formula Ia or Ib

X, A, G, E, R therein₁、R₂、R₃、R₄、R₅M and n are as defined above.

In a particular embodiment of the invention, when R is₃Is represented by C_1-6When alkoxy, X is — NH-.

The present invention includes all embodiments wherein X, A, G, E, R₁、R₂、R₃、R₄、R₅In any combination described herein.

In particular, the compound of formula I may be selected from one of the following compounds:

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran ] -4-yl) ethanone (Compound 101),

n- (3, 5-dichloropyridin-4-yl) -7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran ] -4-carboxamide (Compound 102),

2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran ] -4-yl) ethanone (Compound 103),

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-4 ', 5 ' -dihydro-spiro [1, 3-benzodioxole-2, 3 ' - (2H) -thiophen ] -4-yl) ethanone (Compound 104),

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-spiro [1, 3-benzodioxol-2, 4' -piperidin ] -4-yl) ethanone (compound 105),

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-1 '- [ methoxycarbonyl ] -spiro [1, 3-benzodioxol-2, 4' -piperidin ] -4-yl) ethanone (Compound 106),

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-1 '- [ methanesulfonyl ] -spiro [1, 3-benzodioxol-2, 4' -piperidin ] -4-yl) ethanone (Compound 107),

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-1 '-acetyl-spiro [1, 3-benzodioxole-2, 4' -piperidin ] -4-yl) ethanone (Compound 108)

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-1 '-methyl-spiro [1, 5-benzodioxol-2, 4' -piperidin ] -4-yl) ethanone (Compound 109),

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 110),

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3', 5 ', 6' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 '- (4H) -thiopyran-1' -oxide ] -4-yl) ethanone (compound 111),

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxol-2, 4 ' - (4H) -thiopyran-1 ', 1 ' -dioxide ] -4-yl) ethanone (compound 112), or

2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran-1 ', 1 ' -dioxide ] -4-yl) ethanone (compound 113);

2- (3-bromopyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 114);

2- (3-bromo-pyrazin-2-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 115);

2- (-pyrazin-2-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole 2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 116);

2- (-pyridin-4-yl-) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 117);

2- (quinolin-4-yl-) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 118);

2- (2, 6-dichloro-phenyl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 119);

2- (2-chloro-phenyl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 120);

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 3' -oxetane]-6-yl } ethanone (compound 121);

2- (3, 5-dichloro-1-oxido-pyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 3' -oxetane]-6-yl } ethanone (compound 122);

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 3' -thietane]-6-yl } ethanone (compound 123);

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 3 ' -thietane-1 ', 1 ' -dioxide]-6-yl } ethanone (compound 124);

2- (3, 5-dichloropyridin-1-oxo-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 3 ' -thietane-1 ', 1 ' -dioxide]-6-yl } ethanone (compound 125);

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 2' - (1, 3-dioxolane)]-6-yl } ethanone (compound 126);

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 4' -tetrahydropyran]-6-yl } ethylKetones (compound 127);

2- (3, 5-dichloro-1-oxido-pyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 4' -tetrahydropyran]-6-yl) -ethanone (compound 128);

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-2 ', 2' -dimethyl-spiro [2H-1, 5-benzodioxan-3(4H)，5′-[1，3]Dioxane(s)]-6-yl } ethanone (compound 129);

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H)，5′-[1，3]Dioxane(s)]-6-yl } ethanone (compound 130);

2- (3, 5-dichloro-1-oxido-pyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H)，5′-[1，3]Dioxane(s)]-6-yl } ethanone (compound 131); and

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H)，5′-[1，3]Dithianes]-6-yl } ethanone (compound 132),

and pharmaceutically acceptable salts, hydrates, N-oxides or solvates thereof.

In one or more embodiments of the invention, the compounds of general formula I have a molecular weight of less than 800 daltons, such as less than 750 daltons, for example less than 700 daltons, or less than 650, 600, 550 or 500 daltons.

In one or more embodiments of the invention, the compounds of formula I as defined above are useful in therapy.

The compounds of formula I can be obtained in crystalline form directly by concentration from an organic solvent or by crystallization or recrystallization from an organic solvent or a mixture of said solvent and an organic or inorganic co-solvent, such as water. The crystals may be isolated in substantially solvent-free form or as solvates such as hydrates. The present invention covers all crystal modifications and forms and mixtures thereof.

The compounds of the formula I may or may not contain asymmetrically substituted (chiral) carbon atoms, which lead to the presence of isomeric forms, for example enantiomers and possibly diastereomers. The present invention relates to all these isomers, either in pure form or as mixtures thereof (e.g. racemates). Pure stereoisomeric forms of the compounds and intermediates of the invention may be obtained by employing procedures known in the art. The various isomeric forms can be separated by physical separation methods as follows: selective crystallization and chromatographic techniques, such as liquid chromatography using a chiral stationary phase. The enantiomers can be separated from each other by selective crystallization of their diastereomeric salts with optically active amines such as l-ephedrine. Alternatively, the enantiomers may be separated by chromatographic techniques using chiral stationary phases. Said pure stereoisomeric forms may also be obtained from the corresponding pure stereoisomeric forms of the appropriate starting materials, provided that the reaction occurs stereoselectively or stereospecifically. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by stereoselective or stereospecific methods of preparation. These methods will conveniently use chirally pure starting materials.

The compounds of the invention, optionally in combination with other active compounds, are useful for the treatment of skin diseases or disorders, or acute or chronic skin wound disorders, in particular for the treatment of proliferative and inflammatory skin diseases, psoriasis, cancer, epidermal inflammation, alopecia, skin atrophy, steroid induced skin atrophy, skin ageing, photo skin ageing, acne, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritis and eczema.

In addition to being useful for human therapy, the compounds of the present invention are also useful for veterinary therapy of animals, including mammals, such as horses, cattle, sheep, pigs, dogs, and cats.

For therapeutic use, the compounds of the present invention are generally in the form of pharmaceutical compositions. The present invention therefore relates to pharmaceutical compositions comprising a compound of formula I, and optionally one or more other therapeutically active compounds, and a pharmaceutically acceptable excipient or vehicle. The excipient must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

Conveniently, the active ingredient comprises 0.05 to 99.9% by weight of the formulation.

In dosage unit form, the compound may be administered one or more times daily at appropriate intervals, however this will generally depend on the condition of the patient and as prescribed by the medical practitioner. Conveniently, the dosage unit of the formulation comprises from 0.1mg to 1000mg, preferably from 1mg to 100mg, such as from 5 to 50mg, of a compound of formula I.

The appropriate dosage of the compounds of the invention will depend, inter alia, on the age and condition of the patient, the severity of the disease being treated and other factors well known to the practitioner. The compounds may be administered orally, parenterally or topically according to various dosing regimens, e.g., daily or weekly intervals. Generally, a single dose will be in the range of 0.01-400 mg/kg body weight. The compound may be administered once (i.e., once for the entire dose per day), or divided into two or more administrations per day.

For topical treatment, it is more appropriate to employ "use units", which represent a single dose capable of being administered to a patient and which can be readily handled and packaged, remaining in physically and chemically stable unit doses, containing such active substances or mixtures thereof with solid or liquid pharmaceutical diluents or carriers.

The term "unit of use" in connection with topical use denotes a unit, i.e. a single dose capable of topical administration to a patient of 0.1 to 10mg, preferably 0.2 to 1mg, of the active ingredient in question per square centimetre of affected area.

Also considered are: in certain treatment regimens, it may be beneficial to administer the drug at longer intervals, e.g., every other day, every week, or even longer intervals.

Useful dosages of The compounds are recommended for reference to Goodman & Gilman's The pharmaceutical Basis of Therapeutics, 9 th edition, j.g. hardman and l.e. limbirdd (ed), McGraw-Hill 1995, if treatment involves administration of another therapeutically active compound.

The compounds of the invention and one or more other active compounds may be administered simultaneously or sequentially.

Formulations include, for example, those suitable for oral (including sustained or timed release), rectal, parenteral (including subcutaneous, intraperitoneal, intramuscular, intraarticular and intravenous), transdermal, ocular, topical, dermal, nasal or buccal administration. Topical application of the claimed formulations is particularly suitable.

The formulations may conveniently be presented in dosage unit form and may be prepared by any of The methods well known in The art of Pharmacy, for example as disclosed in Remington, The Science and Practice of Pharmacy, 20 th edition, 2000. All methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; can be in the form of powder or granule; in the form of a solution or suspension in an aqueous liquid or a non-aqueous liquid such as ethanol or glycerol; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. Such oils may be edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums such as tragacanth, alginates, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomers and polyvinylpyrrolidone. The active ingredient may also be administered in the form of a bolus, electuary or paste.

Tablets may be prepared by compressing or molding the active ingredient and optionally one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with: binders such as lactose, glucose, starch, gelatin, gum arabic, tragacanth gum, sodium alginate, carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, wax, and the like; lubricants such as sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc.; disintegrating agents such as starch, methylcellulose, agar, bentonite, croscarmellose sodium, sodium starch glycolate, crospovidone, etc.; or a dispersant such as polysorbate 80. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent and a suitable carrier.

Formulations for rectal administration may be in the form of suppositories in which the compounds of the invention are combined with low melting water soluble or insoluble solids such as cocoa butter, hydrogenated vegetable oils, polyethylene glycols or polyethylene glycol fatty acid esters, while elixirs may be prepared using tetradecyl palmitate.

Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient, for example isotonic saline, isotonic glucose solution or buffer solutions. The formulation may conveniently be sterilized, for example, by the following methods: filtering with bacteria-retaining filter, adding sterilizing agent, irradiating preparation or heating preparation. Liposome formulations such as those disclosed in Encyclopedia of pharmaceutical technology, Vol.9, 1994 are also suitable for parenteral administration.

Alternatively, the compounds of formula I may be presented as sterile solid preparations, for example as a freeze-dried powder, which may be readily dissolved in a sterile solvent immediately prior to use.

Transdermal formulations may be in the form of plasters or patches.

Formulations suitable for ophthalmic administration may be in the form of sterile aqueous preparations of the active ingredient which may be in microcrystalline form, for example in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems, such as those disclosed in Encyclopedia of Pharmaceutical Technology, Vol.2, 1989, may also be used to present the active ingredient for ophthalmic administration.

Formulations suitable for topical or ocular administration include liquid or semi-liquid formulations such as liniments, lotions, gels, sprays, foams, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops. The composition for ocular treatment may preferably further comprise cyclodextrin.

For topical application, the compound of formula I may be present in an amount of 0.01 to 20% by weight of the composition, such as 0.1% to about 10%, but may also be present in an amount up to about 50% of the composition.

Formulations suitable for nasal or oral administration include powders, self-propelled and spray formulations such as aerosols and nebulizers. Such formulations are more thoroughly disclosed in, for example, the following documents: modern pharmaceuticals, 2 nd edition, g.s.banker and ct.rhodes (Eds.), page 427-432, Marcel Dekker, new york; modern pharmaceuticals, 3 rd edition, G.S.Bank and CT.Rhodes (Eds.), pages 619 and 718, 721, Marcel Dekker, New York and Encyclopedia of Pharmaceutical Technology, Vol.10, J.Swarbrich and J.C Boylan (Eds.), page 191, 221, Marcel Dekker, New York.

In addition to the above ingredients, the formulation of a compound of formula I may include one or more additional ingredients such as diluents, buffers, flavoring agents, colorants, surfactants, thickeners, preservatives, e.g., methyl hydroxybenzoate (including antioxidants), emulsifiers and the like.

When the active ingredient is administered in the form of a salt with a pharmaceutically acceptable non-toxic acid or base, preferred salts are, for example, readily soluble or sparingly soluble in water in order to obtain a specific and suitable absorption rate.

The pharmaceutical composition may additionally comprise one or more other active ingredients commonly used in the treatment of skin diseases or disorders, for example selected from glucocorticoids, vitamin D and vitamin D analogues, antihistamines, Platelet Activating Factor (PAF) antagonists, anticholinergic agents, methylxanthines, β -adrenergic agents, COX-2 inhibitors, salicylates, indomethacin, flufenamic acid (flufenamate), naproxen, timentin, gold salts (gold salt), penicillamine, serum cholesterol lowering agents, retinoids, zinc salts, azosulfapyridine salicylate and calcineurin inhibitors.

The invention is described in more detail in the following examples, which do not limit the scope of the invention as claimed in any way.

Preparation method

The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of synthesis. For example, the compounds of formula I may be prepared using the reactions and techniques outlined below, as well as methods known in the art of synthetic organic chemistry, or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, the methods described below. The reaction is carried out in a solvent suitable for the reagents and materials used and for the conversion carried out. Also, in the synthetic methods described below, it should be understood that: all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, experimental duration and work-up procedures, are chosen as standard conditions for the reaction, which are readily recognizable by the skilled person. Not all compounds in a given class are compatible with some of the reaction conditions required in some of the described processes. The limitations of substituents compatible with the reaction conditions will be apparent to those skilled in the art, and alternative methods may be used.

The starting materials are known compounds which are commercially available or they can be prepared by customary synthetic methods known to the person skilled in the art.

If desired, the compounds of the invention or any of the intermediates may be purified using standard procedures well known to synthetic organic chemists, for example as described in "Purification of Laboratory Chemicals", 5 th edition 2003. The starting materials are known compounds, are commercially available or they can be prepared by conventional synthetic methods well known to those skilled in the art.

General procedures, preparation and examples

¹H Nuclear Magnetic Resonance (NMR) spectra were recorded at 300MHz, and¹³c NMR spectra were recorded at 75.6 MHz. Relative to an internal standard tetramethylsilane (δ ═ 0.00) or chloroform (δ ═ 7.25) or tritiated chloroform (δ ═ 76.81,¹³c NMR), quote the chemical shift values (δ, in ppm) in the indicated solvents. Values for multiplets near the midpoint are given, definite (doublet (d), triplet (t), quartet (q)) or indeterminate (m), unless ranges are quoted. (bs) represents a broad singlet. The organic solvent used is generally anhydrous.

Chromatography was carried out on Merck silica gel 60(0.040-0-063 mm). Unless otherwise indicated, the solvent ratio refers to v: v.

The following abbreviations are used throughout:

DCM dichloromethane

DMF N, N' -dimethylformamide

DMSO dimethyl sulfoxide

Et Ethyl group

EtOAc ethyl acetate

h hours

L liter

LDA lithium diisopropylamide

LiHMDS lithium hexamethyldisilazide

m mm

Me methyl group

MeOH methanol

NMR nuclear magnetic resonance

Ppt precipitate

Rt Room temperature

TsCl tosyl chloride

THF hydrofuran

Volume V

Preparative HPLC/MS

Preparative HPLC/MS was performed in a Dionex APS-system equipped with two Shimadzu PP150 prep pumps and a ThermoMSQ Plus mass spectrometer. Column: waters XTerra C-18, 150mm × 19mm, 5 μm; solvent system: a ═ water (0.1% formic acid) and B ═ acetonitrile (0.1% formic acid); the flow rate is 18 mL/min; method (10 min): linear gradient method, from 10% B to 100% B in 6 min, with an additional 2min dwell at 100% B. Fractions were collected based on ion trace of the relevant ions and PDA signal (240-400 nm).

Analytical HPLC/MS

The method A comprises the following steps: analytical HPLC/MS was performed in a Dionex APS-system equipped with a P680A analytical pump and a Thermo MSQ Plus mass spectrometer. Column: waters XTerra C-18, 150mm × 4.6mm, 5 μm; solvent system: a ═ water (0.1% formic acid) and B ═ acetonitrile (0.1% formic acid); the flow rate is 1.0 mL/min; method (10 min): linear gradient method, from 10% B to 100% B in 6.6 min, with an additional 1.5 min at 100% B.

The method B comprises the following steps: analytical HPLC/MS was performed in a system consisting of Waters 2795HPLC, Micromass ZQ mass spectrometer, Waters 996 PDA. Column: waters XTerra C-18, 50mm x 3.0mm, 5 μm; solvent system: water acetonitrile 95: 5 (0.05% formic acid) and B acetonitrile (0.05% formic acid); the flow rate is 1.0 mL/min; method (8 min): linear gradient method, from 10% B to 100% B in 6.0 min, with a 1 min dwell at 100% B.

General procedure for preparation:

for example, the compounds of the present invention can be prepared by the following general method:

a compound of the formula Ia wherein R₁、R₂And R₃As defined above, can be prepared as follows:

the starting material of formula 1a is prepared according to standard procedures known to the skilled chemist in the art. Commun, (1986), 16, 645-48, using BCl, according to Kaisalo et al, Synth₃2, 3, 4-trimethoxybenzoic acid is selectively di-demethylated in the 2-and 3-positions.

Subsequent reaction of the deprotected compound in a clean ketone, enol ether, ketal or mixture thereof, with or without addition of an additional catalyst such as p-toluenesulfonic acid or a lewis acid, with microwave or conventional heating at a temperature of room temperature to 180 ℃, yields compound 2 a.

A compound of formula 2a is reacted with MeI (or dimethyl sulfate) in a suitable base such as K₂CO₃、KHCO₃Or Et₃Reaction in the presence of N in a suitable solvent such as DMF, acetone, THF or DCM at a temperature of from room temperature to 100 ℃ affords the compound of formula 3 a.

The esters 3a can also be prepared by classical esterification methods using alcohols and suitable acids such as H₂SO₄To prepare the compound.

Compounds of formula Ia (X ═ CH)₂) Obtained as follows: methyl esters formed by condensation of lithium carbanions (lithio carbanions) formed from a-methyl group wherein a is as hereinbefore defined and a suitable base such as LDA or LiHMDS in a suitable solvent such as THF at a temperature of-78 ℃ to room temperature. Grignard reagents can be used instead of lithium carbanions.

A compound of formula Ia (X ═ NH) is obtained as follows: compounds of formula 2a with (COCl)₂、SOCl₂Or PCl₅In a suitable solvent such as DCM or toluene, with or without the addition of a catalytic amount of DMF, at a temperature of 0 deg.C to 70 deg.C to provide the corresponding acid chloride. After evaporation of the solvent in vacuo, the condensation of the acid chloride formed with the nitrogen anion is subsequently carried out by adding a suitable base such as NaH, LDA or LiHMDS in A-NH in a suitable solvent such as THF at a temperature of-78 deg.C to room temperature₂Wherein a is as defined above.

A compound of the formula Ib wherein R₁、R₂And R₃As defined above, can be prepared as follows:

esterification of 1b using standard procedures, e.g. MeOH and H₂SO₄To obtain ester 2 b.

Using 3b (X ═ Br, I, OTs) in a suitable base such as K₂CO₃Alkylation of 2b in the presence of a suitable solvent such as DMSO at a temperature of from room temperature to 120 deg.C affords compounds of formula 4 b.

A compound of formula Ib (X ═ CH)₂) Obtained as follows: methyl esters formed by condensation of a-methyl groups, wherein a is as defined above, with a lithium carbanion formed from a suitable base, such as LDA or LiHMDS, in a suitable solvent, such as THF, at a temperature of-78 ℃ to room temperature. Grignard reagents can be used instead of lithium carbanions.

Standard conditions (acid) were usedBasic or alkaline) hydrolysis of the ester to give the carboxylic acid 7b, which can be converted into a formyl chloride and subsequently reacted with a nitrogen-anion (from a-NH) as described in the synthesis of Ia (X ═ NH)₂Generation) reaction.

Preparation 1:

7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran ] -4-carboxylic acid (Compound 501)

A suspension of 2, 3-dihydroxy-4-methoxybenzoic acid (6.04g, 32.8mmol) in 5, 6-dihydro-4-methoxy-2H-pyran (20mL, 152mmol) was maintained at 140 ℃ for three days. Ethyl acetate (200mL) was added at room temperature and the organic phase was saturated NaHCO₃Aqueous extraction (2X 50 mL). Et for aqueous phase₂Wash with O (2 × 40mL), acidify to pH 1 with concentrated HCl, and extract with dichloromethane (2 × 50 mL). The organic phase is over MgSO₄And (5) drying. Evaporating under reduced pressure to obtain trace amount of 2, 3-dihydroxy-4-methoxybenzoic acid and 7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran]4-Carboxylic acid (1.23g, 14%).

¹³C NMR(DMSO)δ164.9，148.2，146.6，134.5，123.7，117.0，107.1，106.8，64.4，56.0，35.3.

Preparation 2:

7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran ] -4-carboxylic acid methyl ester (Compound 502)

Will be coarsePino-7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran]-4-carboxylic acid (2.17g, 8.15mmol), KHCO₃A suspension of (2.58g, 26.0mmol) and dimethyl sulfate (1.58mL, 16.7mmol) in acetone (62mL) was stirred at room temperature for two days, after which it was evaporated to dryness under reduced pressure. Ethyl acetate (100mL) was added. The organic phase is washed with 0.5M aqueous NaOH (6X 30mL) and evaporated to dryness under reduced pressure. The crude product was redissolved in dichloromethane (75mL) over MgSO₄Dried and evaporated to dryness under reduced pressure. Standard silica gel column chromatography gave 7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran]-4-carboxylic acid methyl ester (1.87g, 79%).

¹³C NMR(CDCl₃)δ164.9，149.1，147.2，135.2，124.0，117.5，107.1，106.5，65.2，56.4，51.8，35.9.

Standard operation a:

example 1:

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran ] -4-yl) ethanone (Compound 101)

Reacting 7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran]A solution of methyl-4-carboxylate (1.80g, 6.42mmol) and 3, 5-dichloro-4-methylpyridine (1.46g, 8.99mmol) in tetrahydrofuran (33mL) was cooled to 0 ℃. A1.0M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (19.3mL, 19.3mmol) was added and the reaction mixture was allowed to reach room temperature overnight. Addition of saturated NH₄Aqueous Cl (70 mL). The aqueous phase was extracted with dichloromethane (3X 100 mL). The combined organic phases were washed with water (50mL) and MgSO₄Dried and evaporated to dryness under reduced pressure. Standard silica gel column chromatography followed by recrystallization from isopropanol gave 2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran]-4-yl) ethanone (1.90g, 71%).

¹³C NMR(DMSO)δ189.1，148.2，147.7，147.0，141.2，134.5，132.8，122.0，118.0，113.0，107.8，64.4，56.3，43.5，35.2.

Example 2:

n- (3, 5-dichloropyridin-4-yl) -7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran ] -4-carboxamide (Compound 102)

Oxalyl chloride (92 μ L, 1.1mmol) and a catalytic amount of N, N-dimethylformamide were added to 7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran]-4-carboxylic acid (48mg, 0.18mmol) in dichloromethane (2 mL). After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure and the crude acid chloride was redissolved in tetrahydrofuran (2 mL). A suspension of 3, 5-dichloropyridin-4-amine (67mg, 0.40mmol) and NaH (60% dispersed in mineral oil, 16mg, 0.40mmol) in tetrahydrofuran (1mL) was stirred at room temperature for 3 hours, then added dropwise to the tetrahydrofuran solution containing the crude acid chloride at room temperature. After stirring overnight at room temperature, the reaction mixture was diluted with ether (30mL) and the organic phase was washed with 0.5M aqueous NaOH (3X 10 mL). The organic phase is over MgSO₄Dried and evaporated to dryness under reduced pressure. Purification by standard HPLC to give N- (3, 5-dichloropyridin-4-yl) -7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran]-4-carboxamide (14mg, 19%).

¹³C NMR(DMSO)δ160.8，148.0，146.5，146.2，141.1，134.1，130.5，122.5，118.2，108.3，107.6，64.2，56.2，35.2.

Example 3:

2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran ] -4-yl) ethanone (Compound 103)

To 2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran]To a solution of (4-yl) ethanone (41mg, 0.99mmol) in dichloromethane (0.5mL) was added 30% H₂O₂(25. mu.L) and methyltrioxorhenium (VII) (3 mg). The mixture was stirred at room temperature overnight and MnO was added₂(3mg) and stirred for 1 hour. Water (10mL) was added and the aqueous phase was extracted with dichloromethane (3X 10 mL). The combined organic phases were over MgSO₄Dried and evaporated to dryness under reduced pressure. Purification by standard HPLC gave compound 103(8mg, 19%). LC/MS (method B): (m/z) 426.1; 428.1(MH +); RT is 2.98 min; purity (UV) ═ 100%.

Preparation 3:

tetrahydro-3, 3-dimethylthiophene (Compound 503)

A solution of tetrahydrothiophen-3-one (10.0g, 97.9mmol), methyl orthoformate (21.4mL, 196mmol) and p-toluenesulfonic acid monohydrate (50mg, 0.29mmol) in dry methanol (25mL) was refluxed for 1 hour. Then, 1.0M NaOMe in methanol (0.30mL, 0.30mmol) was added and the excess methanol and trimethyl orthoformate were removed by distillation (atmospheric pressure). Further distillation under reduced pressure gave a mixture of tetrahydro-thiophen-3-one (. about.0.67 g, 7%) and tetrahydro-3, 3-dimethoxythiophene (. about.9.8 g, 67%).

¹³C NMR(MeOH)δ113.01，50.11，36.90，36.11，27.72.

Preparation 4:

7-methoxy-4 ', 5 ' -dihydro-spiro [1, 3-benzodioxole-2, 3 ' - (2H) -thiophene ] -4-carboxylic acid (Compound 504)

P-toluenesulfonic acid (54mg, 0.28mmol) was added to a mixture of tetrahydro-3, 3-dimethylthiophene (. about.9.8 g, 66mmol) and tetrahydrothiophen-3-one (. about.0.67 g, 6.6 mmol). The oil bath was heated to 145 ℃ and approximately 1 equivalent of methanol (2.7mL, 67mmol) was distilled off. The temperature was lowered and distillation under reduced pressure was carried out to give 7.04g of an oil, to which was added 2, 3-dihydroxy-4-methoxybenzoic acid (1.00g, 5.43 mmol). The suspension was exposed to microwave heating (180 ℃, 1 hour) in a sealed reactor. Filtration followed by purification by standard HPLC gave compound 504(164mg, 11%). LC/MS (method B): (M/z)267.2 (M-1); RT 2.79 min; purity (UV) ═ 100%.

Preparation 5:

7-methoxy-4 ', 5 ' -dihydro-spiro [1, 3-benzodioxole-2, 3 ' - (2H) -thiophene ] -4-carboxylic acid methyl ester (Compound 505)

Reacting 7-methoxy-4 ', 5 ' -dihydro-spiro [1, 3-benzodioxole-2, 3 ' - (2H) -thiophene]-4-carboxylic acid (161mg, 0.600mmol), K₂CO₃A suspension of (166g, 1.20mmol) and dimethyl sulfate (74. mu.L, 0.78mmol) in acetone (1mL) was maintained at 50 ℃ overnight. Water (15mL) was added at room temperature and the aqueous phase was extracted with ethyl acetate (2X 20 mL). The organic phase is over MgSO₄Dried and evaporated to dryness under reduced pressure. Purification by standard HPLC gave compound 505(24mg, 14%).

¹H NMR(CDCl₃)δ7.44(d，1H)，6.56(d，1H)，3.94(s，3H)，3.88(s，3H)，3.32(d，1H)，3.24(d，1H)，3.05(t，2H)，2.49(td，2H).

Example 4:

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-4 ', 5 ' -dihydro-spiro [1, 3-benzodioxole-2, 3 ' - (2H) -thiophen ] -4-yl) ethanone (Compound 104)

Reacting 7-methoxy-4 ', 5 ' -dihydro-spiro [1, 3-benzodioxole-2, 3 ' - (2H) -thiophene]A solution of methyl-4-carboxylate (24mg, 85. mu. mol) and 3, 5-dichloro-4-methylpyridine (21mg, 0.13mmol) in tetrahydrofuran (1mL) was cooled to 0 ℃. A 1.0M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (0.26mL, 0.26mmol) was added and the reaction mixture was allowed to reach room temperature overnight. Addition of saturated NH₄Aqueous Cl (10 mL). The aqueous phase was extracted with dichloromethane (3X 10 mL). The combined organic phases were washed with water (20mL) and MgSO₄Dried and evaporated to dryness under reduced pressure. Purification by standard HPLC gave the title compound (12mg, 34%).

¹³C NMR(DMSO)δ189.02，148.09，147.51，147.05，140.98，134.48，132.69，127.57，122.31，112.81，107.81，56.35，43.26，37.54，36.54，25.70.

Preparation 6:

1-acetyl-4, 4-dimethoxy-piperidine (Compound 506)

A solution of 1-acetyl-4-piperidone (17.0g, 121mmol), trimethyl orthoformate (26.4mL, 241mmol) and p-toluenesulfonic acid monohydrate (80mg, 0.42mmol) in dry methanol (34mL) was refluxed for 1 hour. Then, 1.0M NaOMe in methanol (0.42mL, 0.42mmol) was added and the excess methanol and trimethyl orthoformate were removed by distillation (atmospheric pressure). Further distillation under reduced pressure gave 1-acetyl-4, 4-dimethoxy-piperidine (20.2g, 89%).

¹H NMR(DMSO)δ3.45-3.32(m，4H)，3.10(s，6H)，1.99(s，3H)，1.72-1.62(m，2H)，1.61-1.52(m，2H).

Preparation 7:

1-acetyl-1, 2, 3, 6-tetrahydro-4-methoxy-pyridine (Compound 507)

To 1-acetyl-4, 4-dimethoxy-piperidine (20.2g, 108mmol) was added p-toluenesulfonic acid monohydrate (80mg, 0.42 mmol). The mixture was heated to 160 ℃ and approximately 1 equivalent of methanol (4.38mL, 108mmol) was distilled off. The temperature was lowered and distillation under reduced pressure gave a mixture of 1-acetyl-4, 4-dimethoxy-piperidine (1.4g, 7%) and 1-acetyl-1, 2, 3, 6-tetrahydro-4-methoxy-pyridine (14.2g, 85%).

¹H NMR(DMSO)δ4.68-4.62(m，1H)，4.00-3.88(m，2H)，3.59-3.49(m，2H)，3.49-3.45(m，3H)，2.19-2.12(m，1H)，2.09-2.03(m，1H)，2.03-1.96(m，3H).

Preparation 8:

7-methoxy-1 '-acetyl-spiro [1, 3-benzodioxole-2, 4' -piperidine ] -4-carboxylic acid (Compound 508)

A mixture of 2, 3-dihydroxy-4-methoxybenzoic acid (1.23g, 6.67mmol), 1-acetyl-4, 4-dimethoxy-piperidine (1.4g, 7.6mmol) and 1-acetyl-1, 2, 3, 6-tetrahydro-4-methoxy-pyridine (14.2g, 91.5mmol) was exposed to microwave heating (180 ℃ C., 1 hour) in a sealed reactor. Filtration followed by purification by standard HPLC gave compound 508(0.54g, 26%). LC/MS (method B): (m/z)308.2(MH +); RT 2.27 min; purity (UV) ═ 95%.

Preparation 9:

7-methoxy-spiro [1, 3-benzodioxole-2, 4' -piperidine ] -4-carboxylic acid methyl ester (compound 509)

Mixing 7-methoxy-1 '-acetyl-spiro [1, 3-benzodioxole-2, 4' -piperidine]A solution of-4-carboxylic acid (143mg, 0.467mmol) and LiOH (224mg, 9.34mmol) in water (3mL) and MeOH (3mL) was heated to 75 ℃ for 5 hours. The mixture was neutralized with 2M HCl at room temperature and evaporated to dryness under reduced pressure. Crude 7-methoxy-spiro [1, 3-benzodioxole-2, 4' -piperidine]4-carboxylic acid [ LC/MS (method B): (m/z)266.2(MH +); RT ═ 1.57 min; pureDegree (UV) ═ 82%]Reflux overnight in 1.7M HCl in methanol (5 mL). Water (20mL) was added at room temperature. Et for aqueous phase₂O (10mL) and Na was added₂CO₃Made basic and extracted with dichloromethane (3X 10 mL). The organic phase is over MgSO₄Drying and evaporating under reduced pressure to obtain 7-methoxy-spiro [1, 3-benzodioxole-2, 4' -piperidine]-4-carboxylic acid methyl ester (75mg, 57%).

¹H NMR(DMSO)δ7.31(d，1H)，6.72(d，1H)，3.87(s，3H)，3.78(s，3H)，2.96-2.77(m，4H)，1.94-1.83(m，4H).

Example 5:

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-spiro [1, 3-benzodioxole-2, 4' -piperidin ] -4-yl) ethanone (Compound 105)

Mixing 7-methoxy-spiro [1, 3-benzodioxole-2, 4' -piperidine]A solution of methyl-4-carboxylate (75mg, 0.268mol) and 3, 5-dichloro-4-methylpyridine (65mg, 0.40mmol) in tetrahydrofuran (2.5mL) was cooled to 0 ℃. A1.0M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (0.80mL, 0.80mmol) was added and the reaction mixture was allowed to reach room temperature overnight. Addition of saturated NH₄Aqueous Cl (10 mL). The aqueous phase was extracted with dichloromethane (3X 10 mL). The combined organic phases were over MgSO₄Dried and evaporated to dryness under reduced pressure. Purification by standard HPLC gave compound 105(58mg, 53%).

¹H NMR(DMSO)δ8.66(s，2H)，7.38-7.36(m，1H)，6.83-6.80(m，1H)，4.62(s，2H)，3.91(s，3H)，3.02-2.91(m，4H)，2.12-1.93(m，4H).

Example 6:

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-1 '- [ methoxycarbonyl ] -spiro [1, 3-benzodioxol-2, 4' -piperidin ] -4-yl) ethanone (Compound 106)

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-spiro [1, 3-benzodioxole-2, 4' -piperidine]A solution of-4-yl) ethanone (10mg, 24. mu. mol), triethylamine (24. mu.L, 171. mu. mol) and methyl chloroformate (10. mu.L, 122. mu. mol) in dichloromethane (200. mu.L) was maintained at room temperature overnight. Water (500. mu.L) was added and the aqueous phase was extracted with dichloromethane (3X 500. mu.L). The organic phase is over MgSO₄Dried and evaporated to dryness under reduced pressure. Purification by standard HPLC gave compound 106(2.5mg, 22%).

¹H NMR(DMSO)δ8.65(s，2H)，7.39(d，1H)，6.84(d，1H)，4.62(s，2H)，3.91(s，3H)，3.80-3.66(m，2H)，3.62(s，3H)，3.58-3.46(m，2H)，2.18-1.97(m，4H).

Example 7:

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-1 '- [ methanesulfonyl ] -spiro [1, 3-benzodioxole-2, 4' -piperidin ] -4-yl) ethanone (Compound 107)

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-spiro [1, 3-benzodioxole-2, 4' -piperidine]A solution of-4-yl) ethanone (10mg, 24. mu. mol), triethylamine (24. mu.L, 171. mu. mol) and methanesulfonyl chloride (10. mu.L, 122. mu. mol) in dichloromethane (200. mu.L) was maintained at room temperature overnight. Water (500. mu.L) was added and the aqueous phase was extracted with dichloromethane (3X 500. mu.L). The organic phase is over MgSO₄Dried and evaporated to dryness under reduced pressure. Carry out the standardPurification by HPLC afforded compound 107(1.8mg, 15%).

¹H NMR(DMSO)δ8.66(s，2H)，7.45-7.38(m，1H)，6.88-6.81(m，1H)，4.62(s，2H)，3.92(s，3H)，3.50-3.36(m，4H)，2.98(s，3H)，2.29-2.11(m，4H).

Example 8:

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-1 '-acetyl-spiro [1, 3-benzodioxole-2, 4' -piperidin ] -4-yl) ethanone (Compound 108)

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-spiro [1, 3-benzodioxole-2, 4' -piperidine]A solution of-4-yl) ethanone (10mg, 24. mu. mol), triethylamine (24. mu.L, 171. mu. mol) and acetic anhydride (12. mu.L, 122. mu. mol) in dichloromethane (200. mu.L) was maintained at room temperature overnight. Water (500. mu.L) was added and the aqueous phase was extracted with dichloromethane (3X 500. mu.L). The organic phase is over MgSO₄Dried and evaporated to dryness under reduced pressure. Purification by standard HPLC gave compound 108(7.2mg, 65%).

¹H NMR(DMSO)δ8.66(s，2H)，7.40(d，1H)，6.84(d，1H)，4.63(s，2H)，3.92(s，3H)，3.90-3.84(m，1H)，3.75-3.68(m，1H)，3.64-3.58(m，1H)，3.55-3.49(m，1H)，2.21-2.15(m，1H)，2.15-2.05(m，5H)，2.01-1.94(m，1H).

Preparation 10:

4, 4-Dimethoxytetrahydro- (4H) -thiopyran (compound 510)

A mixture of tetrahydro- (4H) -thiopyran-4-one (15.0g, 129mmol), trimethyl orthoformate (28.3mL, 258mmol) and p-toluenesulfonic acid monohydrate (67mg, 0.35mmol) in methanol (40mL) was refluxed for 1 hour. The reaction mixture was cooled to room temperature, 1M NaOMe (0.35mL, 0.35mmol) was added, and excess methanol and trimethyl orthoformate were removed by distillation (atmospheric pressure). Further distillation under reduced pressure gave 4, 4-dimethoxytetrahydro- (4H) -thiopyran (20.7g, 99%).

¹H NMR(DMSO)δ3.07(s，6H)，2.56(m，4H)，1.84(m，4H).

Preparation 11:

7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-carboxylic acid (compound 511)

P-toluenesulfonic acid (97mg, 0.51mmol) was added to 4, 4-dimethoxytetrahydro- (4H) -thiopyran (20.7g, 128mmol) and the mixture was heated to 145 ℃ and maintained at this temperature until approximately 1 equivalent of methanol (5.17mL, 128mmol) distilled off. Then, the mixture was cooled to 130 ℃ and distilled under reduced pressure to give 10.1g of 5, 6-dihydro-4-methoxy- (2H) -thiopyran [2 ], [¹H NMR(DMSO)δ4.87(m，1H)，3.44(s，3H)，3.15(dt，2H)，2.72(t，2H)，2.22(m，2H)]And 4, 4-dimethoxytetrahydro- (4H) -thiopyran as a 5: 3 mixture. Without further purification, the mixture was added to 2, 3-dihydroxy-4-methoxybenzoic acid (2.00g, 10.9mmol) and the suspension was exposed to microwave heating (180 ℃, 1 hour) in a sealed reactor. Ethyl acetate (100mL) was added and the organic phase was washed first with 0.5M HCl (40mL) and then with saturated NaHCO₃Aqueous extraction (2X 30 mL). Et for aqueous phase₂Wash with O (2 × 40mL), acidify to pH 1 with concentrated HCl, and extract with dichloromethane (2 × 30 mL). The organic phase is over MgSO₄And (5) drying. Reduced pressureEvaporation to give 7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran]4-Carboxylic acid (1.86g, 61%).

¹³C NMR(DMSO)δ164.9，148.2，146.6，134.5，123.8，118.0，107.2，106.9，56.1，35.9，25.4.

Preparation 12:

7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-carboxylic acid methyl ester (compound 512)

Reacting 7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran]-4-Carboxylic acid (570mg, 2.02mmol), K₂CO₃A suspension of (558mg, 4.04mmol) and dimethyl sulfate (0.25mL, 2.62mmol) in acetone (14mL) was stirred at 50 deg.C overnight. Water (30mL) was added at room temperature. The aqueous phase was extracted with dichloromethane (3X 15 mL). The combined organic phases were over MgSO₄Dried and evaporated to dryness under reduced pressure. Standard silica gel column chromatography gave 7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran]-4-carboxylic acid methyl ester (407mg, 68%).

¹³C NMR(DMSO)δ163.8，148.1，146.9，134.6，123.4，118.3，107.1，105.9，56.1，51.6，35.9，25.4.

Example 9:

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (Compound 110)

Reacting 7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran]A solution of methyl-4-carboxylate (40mg, 0.14mmol) and 3, 5-dichloro-4-methylpyridine (33mg, 0.20mmol) in tetrahydrofuran (1.1mL) was cooled to 0 ℃. A1.0M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (0.41mL, 0.41mmol) was added and the reaction mixture was allowed to reach room temperature overnight. Addition of saturated NH₄Aqueous Cl (20 mL). The aqueous phase was extracted with dichloromethane (3X 15 mL). The combined organic phases were over MgSO₄Dried and evaporated to dryness under reduced pressure. Purification by standard HPLC afforded 2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran]-4-yl) ethanone (38mg, 67%).

¹³C NMR(DMSO)δ189.1，148.2，147.7，147.0，141.3，134.5，132.8，122.0，119.1，113.0，107.9，56.3，43.6，35.9，25.5.

Example 10:

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3', 5 ', 6' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 '- (4H) -thiopyran-1' -oxide ] -4-yl) ethanone (compound 111)

To 2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran]To a solution of (17mg, 40. mu. mol) of (4-yl) ethanone in dichloromethane (0.5mL) was added first 0.25M H₂O₂EtOH (128. mu.L, 32. mu. mol) and then methyltrioxorhenium (VII) (1mg, 4. mu. mol) were added.The mixture was stirred at room temperature for 2 days and evaporated to dryness under reduced pressure. Purification by standard HPLC afforded 2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3', 5 ', 6' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 '- (4H) -thiopyran-1' -oxide]-4-yl) ethanone (7mg, 40%).

¹H NMR(DMSO)δ8.66(s，2H)，7.42(d，1H)，6.85(d，1H)，4.63(s，2H)，3.93(s，3H)，3.17-2.94(m，4H)，2.69-2.55(m，2H)，2.36-2.24(m，2H).

Example 11:

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran-1 ', 1 ' -dioxide ] -4-yl) ethanone (compound 112)

To 2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran]To a solution of (11mg, 26. mu. mol) of (4-yl) ethanone in dichloromethane (0.25mL) was added m-chloroperbenzoic acid (10mg, 58. mu. mol), and the reaction was stirred at room temperature overnight. Addition of saturated NaHCO₃Aqueous (1mL) and the aqueous phase extracted with dichloromethane (2X 2 mL). The combined organic phases were over MgSO₄Dried and evaporated to dryness under reduced pressure. Purification by standard HPLC afforded 2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran-1 ', 1 ' -dioxide]-4-yl) ethanone (5mg, 42%).

¹H NMR(CDCl₃)δ8.52(s，2H)，7.55(d，1H)，6.68(d，1H)，4.55(s，2H)，3.99(s，3H)，3.45-3.37(m，2H)，3.33-3.25(m，2H)，2.79-2.66(m，4H).

Example 12:

2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran-1 ', 1 ' -dioxide ] -4-yl) ethanone (compound 113)

To 2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran]A solution of-4-yl) ethanone (10mg, 23. mu. mol) in absolute ethanol (2mL) was added H first₂O₂(100. mu.L, 0.97mmol) and then methyltrioxorhenium (VII) (2mg, 8. mu. mol) were added. The mixture was stirred at 40 ℃ overnight, followed by the addition of 5% W/V NaHSO₃Aqueous solution (10 mL).

The aqueous phase was extracted with dichloromethane (3X 20 mL). The combined organic phases were over MgSO₄Dried and evaporated to dryness under reduced pressure. Purification by standard HPLC afforded 2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran-1 ', 1 ' -dioxide]-4-yl) ethanone (2.5mg, 23%).

¹H NMR(DMSO)δ8.64(s，2H)，7.42(d，1H)，6.85(d，1H)，4.59(s，2H)，3.92(s，3H)，3.51(m，2H)，3.31(m，2H)，2.59(m，4H).

General procedure a:

LiHMDS (1M in THF, 3.0eq) was added dropwise to an ice-cold solution of ester 512(1eq) and a-methyl (1.3eq) in anhydrous THF. The reaction mixture was stirred at room temperature for 12 hours, H was added₂O (10mL) and saturated NH₄Aqueous Cl (20mL) and then extracted with EtOAc (3X 50 mL). The combined organic phases were dried (Na)₂SO₄) Filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to afford the ketone.

Example 13:

2- (3-Bromopyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (Compound 114)

Prepared according to general procedure A using 18mg of 4-bromo-3-methylpyridine (yield: 40%)

LC/MS (method B): (m/z)436.2(MH +); RT ═ 4.17 min; purity (UV) ═ 100%.

Example 14:

2- (3-bromo-pyrazin-2-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 115)

Prepared according to general procedure a using 17mg of 2-bromo-3-methylpyrazine (yield: 9%).

LC/MS (method B): (m/z) 437.2; 439.22(MH +); RT ═ 4.22 min; purity (UV) ═ 100%.

Example 15:

2- (-pyrazin-2-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 116)

Prepared according to general procedure A using 16mg of 2-methylpyrazine (yield: 52%).

LC/MS (method B): (m/z)359.3(MH +); RT ═ 3.33 min; purity (UV) ═ 100%.

Example 16:

2- (-pyridin-4-yl-) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (Compound 117)

Prepared according to general procedure a using 18mg 4-methyl-pyridine (yield: 13%).

LC/MS (method B): (m/z)358.3(MH +); RT is 2.50 min; purity (UV) ═ 100%.

Example 17:

2- (quinolin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 118)

Prepared according to general procedure A using 16mg 4-methylquinoline (yield: 12%).

LC/MS (method B): (m/z)408.3(MH +); RT ═ 3.33 min; purity (UV) ═ 100%.

Example 18:

2- (2, 6-dichloro-phenyl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 119)

Prepared according to general procedure A using 15mg of 2, 6-dichlorotoluene (yield: 8%).

LC/MS (method B): (m/z)425.24(MH +); RT ═ 5.28 min; purity (UV) ═ 100%.

Example 19:

2- (2-chloro-phenyl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 120)

Reacting 7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran]A solution of methyl-4-carboxylate (14mg) in dry THF (500mL) was cooled to 0 ℃ under Ar. A solution of 2-chlorobenzyl magnesium chloride in diethyl ether (0.25M solution, 189. mu.L) was added and the cooling was removed. After 2 hours at room temperature, another portion of 2-chlorobenzyl magnesium chloride in ether (0.25M solution, 189. mu.L) was added. The mixture was stirred for 18 hours, water was added, and extraction was performed with ethyl acetate. The combined organic phases were over MgSO₄Drying, and evaporating under reduced pressure toAnd (5) drying. Standard HPLC purification afforded compound 120 (9.2%). LC/MS (method B): (m/z)391.22(MH +); RT is 4.90 min; purity (UV) ═ 100%.

Preparation 13:

2, 3-dihydroxy-4-methoxybenzoic acid methyl ester (compound 513)

A solution of commercially available 2, 3-dihydroxy-4-methoxybenzoic acid (11.6g, 63mmol) in anhydrous MeOH (150mL) was cooled in an ice bath and concentrated H was added dropwise₂SO₄(8 mL). The reaction mixture was refluxed for 12 hours, then cooled to room temperature and the solvent was removed under reduced pressure. Addition of H₂O (100mL) and saturated NaHCO₃Aqueous (50mL) and extracted with EtOAc (3X 100 mL). The combined organic phases were dried (Na)₂SO₄) Filtration and concentration in vacuo gave compound 513 as a pale yellow solid, which was used in the next step without further purification.

LC-MS：R_T＝2.31min.；m/z 197.3(M-H)^-.¹H NMR(CDCl₃)：δ10.83(1H，s)，7.41(1H，d，J 9.0)，6.50(1H，d，J 8.9)，5.45(1H，s)，3.94(3H，s)，3.93(3H，s).

General procedure B:

to a stirred solution of compounds 513 and 3b (1.1eq) in anhydrous DMSO was added K₂CO₃(2.5eq) and the mixture is stirred at 100 ℃ for 4-12 hours under an inert atmosphere. After cooling to room temperature, a mixture of ice and water was added, stirred for 15 minutes, and then extracted with EtOAc (3X 50 mL). The combined organic phases were dried (Na)₂SO₄) Filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography.

Using general procedure B, the following compound was obtained:

preparation 14:

9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 3' -oxetane]-6-Carboxylic acid methyl ester (Compound 514)

According to the general procedure, commercial 3, 3-bis (iodomethyl) oxetane (372mg, 1.1mmol) in DMSO (5mL) in K₂CO₃Dialkylated 513(198mg, 1mmol) in the presence of (345mg, 2.5mmol) gave compound 514 as a white solid after purification by column chromatography (50-65% EtOAc/petroleum ether).

LC-MS：R_T＝2.40min.；m/z 281.26(M+H)⁺.¹H NMR(CDCl₃)：δ7.49(1H，d，J 8.8)，6.62(1H，d，J 8.8)，4.61(2H，d，J 6.8)，4.58(2H，d，J6.8)，4.48(4H，s)，3.90(3H，s)，3.87(3H，s).

Preparation 15:

9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 3' -thietane]-6-Carboxylic acid methyl ester (Compound 516)

Step A:

3, 3-bis (bromomethyl) thietane 515 was obtained from 1, 3-dibromo-2, 2-bis (bromomethyl) propane in a two-step procedure according to literature procedures (Petrukhina, M.A.; Henck, C; Li, B.; Block, E.; Jin, J.; Zhang, S-Z.; Clerac, R.Inorg. chem.2005, 44, 77-84). Thus, a mixture of 1, 3-dibromo-2, 2-bis (bromomethyl) propane (7.76g, 20mmol) and KSAc (2.28g, 20mmol) in dry THF (30mL) was refluxed for 30 hours. Ppt was filtered off, the filtrate was concentrated, and the resulting residue was purified by flash column chromatography (10-25% EtOAc/petroleum ether) to give thioacetic acid (2, 2- (bisbromomethyl) -3-bromopropyl) ester as a pale yellow solid. A mixture of thioacetic acid (2, 2- (dibromomethyl) -3-bromopropyl) ester (1.53g, 4mmol) and NaOMe (324mg, 6mmol) in anhydrous MeOH (10mL) was stirred at 0 deg.C for 2 h. MeOH was removed in vacuo, co-evaporated with toluene (2 × 2mL), and the resulting residue was filtered through a short pad of silica gel to give 3, 3-bis (bromomethyl) thietane 515 as a thick oil, which was used without further purification.

And B:

according to the general procedure, the reaction mixture was washed with 515(962mg, 3.7mmol), in DMSO (15mL), in K₂CO₃Dialkylated 513(665mg, 3.36mmol) in the presence of (1.16g, 8.4mmol) gave 516 after purification by column chromatography (40-60% EtOAc/petroleum ether) as a white solid.

LC-MS：R_T＝3.17min.；m/z 297.19(M+H)⁺.¹H NMR(CDCl₃)：δ7.49(1H，d，J 8.8)，6.63(1H，d，J 8.8)，4.30(2H，s)，4.28(2H，s)，3.90(3H，s)，3.87(3H，s)，3.11(4H，s).

Preparation 16:

9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 2' - (1, 3-dioxolane)]-6-Carboxylic acid methyl ester (Compound 518)

Step A:

2, 2-bis (bromomethyl) -1, 3-dioxolane 517 was obtained from dibromoacetone according to literature procedures (Valentin, M-L.; Bolte, J.Bull. Soc. Chim. Fr.1995, 132, 1167-71). Thus, a solution of dibromoacetone (4.04g, 18.7mmol), ethylene glycol (2.32g, 37.4mmol) and p-TsOH (25mg) in benzene (70mL) was refluxed for 12 hours with azeotropic removal of water. The reaction mixture was concentrated under reduced pressure and Et was added₂O (50mL), H for organic layer₂O (2X 50mL) and dried (Na)₂SO₄) Filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (7-10% EtOAc/petroleum ether) to give 2, 2-bis (bromomethyl) -1, 3-dioxolane (517) as a colorless liquid.

And B:

according to the general procedure, 517(572mg, 2.2mmol) in DMSO (10mL) in K₂CO₃Dialkylated 513(396mg, 2mmol) in the presence of (690mg, 5mmol) gave 518 as a white solid after purification by column chromatography (45-60% EtOAc/petroleum ether).

LC-MS：R_T＝2.70min.；m/z 297.18(M+H)⁺，319.16(M+Na)⁺.¹H NMR(DMSO-d₆)：δ7.34(1H，d，J 8.8)，6.76(1H，d，J 8.8)，4.11(2H，s)，4.09(2H，s)，3.94(4H，s)，3.80(3H，s)，3.75(3H，s).

Preparation 17:

9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 4' -tetrahydropyran]-6-Carboxylic acid methyl ester (Compound 520)

Step A:

4, 4-bis (p-toluenesulfonyloxymethyl) tetrahydropyran (519) was obtained from commercial dimethyl tetrahydropyran-4, 4-dicarboxylate in a two-step procedure. Thus, to an ice-cold solution of diester (3.03g, 15mmol) in anhydrous toluene (45mL) was added synhydide (70% in toluene, 19.5mL, 66mmol) dropwise and the mixture was stirred at 120 ℃ for 3 hours. The mixture was cooled to room temperature and H was added slowly₂O (50mL), concentrated over silica gel (35 g). With MeOH/CH₂Cl₂By flash column chromatography, 4- (dimethylol) tetrahydropyran was obtained as a white solid. A mixture of diol (1.46g, 10mmol) and TsCl (4.77g, 25mmol) in dry pyridine (25mL) was stirred at room temperature for 48 h. The solvent was removed in vacuo and co-evaporated with toluene (3X 10 mL). Addition of CH₂Cl₂(100mL) and saturated NaHCO₃Aqueous solution (100mL), separate the phases and dry the organic phase (Na)₂SO₄) Filtered and concentrated under reduced pressure. The resulting residue was subjected to flash chromatography (35-45% EtOAc/petroleum ether) to afford 4, 4-bis (p-toluenesulfonyloxymethyl) tetrahydropyran (519) as a white solid.

And B:

according to the general procedure compound 519(240mg, 0.53mmol), in DMSO (3mL) in K₂CO₃Dialkylated compound 513(95mg, 0.48mmol) in the presence of (166mg, 1.2mmol) gave compound 520 as a white solid after purification by column chromatography (45-65% EtOAc/petroleum ether).

LC-MS：RT＝2.40min.；¹H NMR(DMSO-d₆)：δ7.34(1H，d，J 8.8)，6.78(1H，d，J 8.8)，3.99(4H，s)，3.80(3H，s)，3.76(3H，s)，3.61(4H，t，J 5.5)，1.54(4H，t，J 5.5).

Preparation 18:

9-methoxy-2 ', 2' -dimethyl-spiro [2H-1, 5-benzodioxan-3(4H)，5′-[1，3]Dioxane(s)]-6-Carboxylic acid methyl ester (Compound 522)

Step A:

a solution of 2, 2-bis (bromomethyl) -1, 3-propanediol (5.0g, 19.1mmol), anhydrous acetone (20mL), and p-TsOH (100mg) in benzene (75mL) was refluxed for 12 hours with azeotropic removal of water. The reaction mixture was concentrated under reduced pressure, EtOAc (100mL) was added, and the organic layer was washed with H₂O (3X 30mL) and brine (30mL) were washed successively and dried (Na)₂SO₄) Filtered and concentrated under reduced pressure. The resulting white solid was ground with n-pentane (20mL)To obtain 5, 5-di (bromomethyl) -2, 2-dimethyl- [1, 3]Dioxane (521), as colorless crystals.

And B:

according to the general procedure, compound 521(2.0g, 6.62mmol) in DMSO (30mL) in K is used₂CO₃After purification of dialkylated compound 513(1.19g, 6mmol) by column chromatography (30-40% EtOAc/petroleum ether) in the presence of (2.07g, 15mmol) compound 522 was obtained as a white solid.

LC-MS：R_T＝2.99min.；m/z 339.31(M+H)⁺，361.25(M+Na)⁺.¹HNMR(CDCl₃)：δ7.45(1H，d，J 8.8)，6.59(1H，d，J 8.8)，4.22(2H，s)，4.18(2H，s)，3.89(3H，s)，3.86(7H，s)，1.43(6H，s).

Preparation 19:

9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H)，5′-[1，3]Dioxane(s)]-6-Carboxylic acid methyl ester (Compound 524)

Step A:

according to literature methods (Bitha, P.; Carvajal, S.G.; Citarella, R.V.; Delos Santos, E.F.; Durr, F.E.; Hlavka, J.J.; Lang, S.A.; Jr.; Lindsay, H.L.; Thomas, J.P.; Wallace, R.E.; Yang-I, L.J.Med.Chem.1989, 32(9), 2063-7 and Mitkin, O.D.; Wan Y).(ii) a Kurchan, a.n.; kutateladze, a.g. synthesis, 2001, (8), 1133-42), 5-bis (bromomethyl) - [1, 3] from 2, 2-bis (bromomethyl) -1, 3-propanediol]Dioxane (523). Thus, a solution of 2, 2-bis (bromomethyl) -1, 3-propanediol (2.5g, 9.55mmol), formaldehyde (37% in water, 3.5mL), and concentrated HCl (2.0mL) was refluxed for 12 hours. After cooling to room temperature, H was added to the reaction mixture₂O (25mL) with CH₂Cl₂(2X 25 mL). The combined organic layers were saturated with Na₂CO₃Aqueous solution (25mL) and H₂O (25mL) was washed successively and dried (Na)₂SO₄) Filtered and concentrated under reduced pressure. The obtained colorless liquid is passed through¹H NMR was found to be > 95% pure and used without further purification.

And B:

according to the general procedure, compound 523(301mg, 1.1mmol) in DMSO (5mL) in K₂CO₃Dialkylated compound 513(198mg, 1mmol) in the presence of (345mg, 2.5mmol) gave compound 524 as a white solid after purification by column chromatography (50-65% EtOAc/petroleum ether).

LC-MS：R_T＝2.65min.；m/z 311.23(M+H)⁺.¹H NMR(DMSO-d₆)：δ7.37(1H，d，J 8.8)，6.81(1H，d，J 8.8)，4.80(1H，d，J 6.4)，4.78(1H，d，J 6.4)，4.07(2H，s)，4.01(2H，s)，3.81(7H，s)，3.76(3H，s).

Preparation 20:

9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H)，5′-[1，3]Dithianes]-6-Carboxylic acid methyl ester (Compound 526)

Step A:

4, 4-bis (hydroxymethyl) - [1, 3] from compound 523 in two steps according to literature procedures (Mitkin, O.D.; Wan, Y.; Kurchan, A.N.; Kutateladze, A.G. Synthesis, 2001, (8), 1133-42) 4, 4-bis (hydroxymethyl) - [1, 3] is obtained]A dithiane. Thus, a mixture of compound 523(1.36g, 5mmol) and KSAc (1.71g, 15mmol) in anhydrous DMF (10mL) was stirred at room temperature for 30 h. The solvent was removed under reduced pressure and co-evaporated with toluene (3X 5 mL). A mixture of ice and water was added, followed by extraction with diisopropyl ether (2X 25 mL). The combined organic phases were dried (Na)₂SO₄) Filtered and concentrated to give 5, 5-bis (acetylthiomethyl) - [1, 3]Dioxane (1.32g, quantitative) as a pale yellow viscous oil. Which pass through¹H NMR was found to be > 95% pure and it was used without further purification.

Mixing 5, 5-di (acetyl sulfur methyl) - [1, 3]]A solution of dioxane (1.32g, 5mmol) in aqueous HCl (2N, 25mL) was refluxed for 16 hours and then cooled to room temperature. Dropwise addition of Na₂CO₃The mixture was basified with aqueous solution (2M) and then with CH₂Cl₂Extraction (3X 40 mL). The combined organic layers were dried (Na)₂SO₄) Filtered and concentrated under reduced pressure to give a white solid which was triturated with hot n-hexane-diisopropyl ether (2: 1, 15 mL). The white solid was filtered to give 4, 4-bis (hydroxymethyl) - [1, 3]]Dithiane, which is used without further purification.

Mixing 4, 4-bis (hydroxymethyl) - [1, 3]]A mixture of dithiane (405mg, 2.25mmol) and TsCI (1.29g, 6.75mmol) in dry pyridine (4mL) was stirred at room temperature for 48 h. The solvent was removed in vacuo and co-evaporated with toluene (3X 3 mL). Addition of CH₂Cl₂(40mL) and saturated NaHCO₃Aqueous solution (40mL), separate the phases and separate the organic phaseDrying (Na)₂SO₄) Filtered and concentrated under reduced pressure. The resulting residue was subjected to flash chromatography (35-55% EtOAc/petroleum ether) to afford 4, 4-bis (p-toluenesulfonyloxymethyl) - [1, 3]]Dithiane (525) as a white solid substance.

And B:

according to the general procedure, compound 525(806mg, 1.65mmol), in DMSO (7.5mL) in K₂CO₃Dialkylated compound 513(297mg, 1.5mmol) in the presence of (518mg, 3.75mmol) gave compound 526 as a white solid after purification by column chromatography (40-50% EtOAc/petroleum ether).

LC-MS：R_T＝3.53min.；m/z 343.14(M+H)⁺，365.12(M+Na)⁺，327.28(M-CH₃)^-.¹H NMR(DMSO-d₆)：δ7.36(1H，d，J 8.8)，6.81(1H，d，J 8.8)，4.20(2H，s)，4.14(2H，s)，3.83(2H，s)，3.81(3H，s)，3.77(3H，s)，2.85(4H，s).

General procedure C:

LiHMDS (1M in THF, 3.0eq) was added dropwise to an ice-cold solution of ester 4b and commercially available 3, 5-dichloro-4-methylpyridine (1.3eq) in anhydrous THF. The reaction mixture was stirred at room temperature for 12 hours, H was added₂O (10mL) and saturated NH₄Aqueous Cl (20mL) and the mixture extracted with EtOAc (3X 50 mL). The combined organic phases were dried (Na)₂SO₄) Filtered and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography to obtain ketoneIb。

Using general procedure C, the following compound was obtained:

example 20:

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 3' -oxetane]-6-yl } ethanone (Compound 121)

Following general procedure, 3, 5-dichloro-4-methylpyridine (169mg, 1.04mmol) and compound 514(224mg, 0.8mmol) were condensed in THF (4mL) in the presence of LiHMDS (2.4mL, 2.4mmol) and purified by column chromatography (65-80% EtOAc/petroleum ether) to give compound 121 as a white solid.

LC-MS：R_T＝3.24min.；m/z 410.07(M+H)⁺，408.19，410.22(M-H)^-.¹H NMR(DMSO-d₆)：δ8.66(2H，s)，7.45(1H，d，J 8.9)，6.91(1H，d，J9.0)，4.66(2H，s)，4.57(2H，s)，4.50(2H，d，J 6.5)，4.46(2H，d，J 6.5)，4.36(2H，s)，3.85(3H，s).

Example 21:

2- (3, 5-dichloro-1-oxido-pyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 3' -oxetane]-6-yl } ethanone (Compound 122)

To 2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 3' -oxetane]-6-yl } ethanone [121](20.5mg, 50. mu. mol) in CH₂Cl₂(1mL) to the solution was added 30% H₂O₂(15. mu.L) and methyltrioxorhenium (VII) (5 mg). The mixture was stirred for 18 hours and MnO was added₂(5mg) and stirred for 1 hour. Addition of CH₂Cl₂(1OmL), the organic phase is washed with water. The combined organic phases were over MgSO₄Dried and evaporated to dryness under reduced pressure. Standard HPLC purification afforded 14mg of product.

LC/MS (method B): (m/z) 426.18; 428.20(MH +); RT 2.42 min; purity (UV) ═ 100%.

Example 22:

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 3' -thietane]-6-yl } ethanone (Compound 123)

Following general procedure, 3, 5-dichloro-4-methylpyridine (366mg, 2.26mmol) and compound 516(516mg, 1.74mmol) were condensed in THF (10mL) in the presence of LiHMDS (5.2mL, 5.2mmol) and purified by column chromatography (55-65% EtOAc/petroleum ether) to give compound 123 as a white solid.

LC-MS：R_T＝4.23min.；m/z 426.24，428.25(M+H)⁺，424.23(M-H)^-.¹H NMR(CDCl₃)：δ8.51(2H，s)，7.57(1H，d，J 9.2)，6.71(1H，d，J 9.2)，4.64(2H，s)，4.46(2H，s)，4.33(2H，s)，3.93(3H，s)，3.20(2H，d，J 9.9)，3.12(2H，d，J 9.9).

Example 23:

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 3 ' -thietane-1 ', 1 ' -dioxide]-6-yl } ethanone (Compound 124)

To 2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 3' -thietane]-6-yl } ethanone [123 [ ]](42.6mg) in CH₂Cl₂(1mL) to the solution was added 30% H₂O₂(38. mu.L) and methyltrioxorhenium (VII) (5 mg). The mixture was stirred for 18 hours and then washed with water. The organic phase is over MgSO₄Dried and evaporated to dryness under reduced pressure. Standard HPLC purification afforded 6mg of product.

LC/MS (method B): (m/z)458.13, 460.10, 462.14(MH +); RT ═ 3.30 min; purity (UV) ═ 100%.

Example 24:

2- (3, 5-dichloropyridin-1-oxo-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan3(4H), 3 ' -thietane-1 ', 1 ' -dioxide]-6-yl } ethanone (Compound 125)

To 2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 3' -thietane]-6-yl } ethanone [123 [ ]](39.6mg) in CH₂Cl₂(1mL) to the solution was added 30% H₂O₂(76 μ L) and methyltrioxorhenium (VII) (5 mg). The mixture was stirred for 18 hours, followed by addition of water. The organic phase is over MgSO₄Dried and evaporated to dryness under reduced pressure. Purification by standard HPLC afforded 8.4mg of product.

LC/MS (method B): (m/z)474.17, 476.16, 478.18(MH +); RT 2.39 min; purity (UV) ═ 100%.

Example 25:

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan3(4H), 2' - (1, 3-dioxolane)]-6-yl } ethanone (Compound 126)

Following general procedure, 3, 5-dichloro-4-methylpyridine (53mg, 0.33mmol) and compound 518(74mg, 0.25mmol) were condensed in THF (1.5mL) in the presence of LiHMDS (0.75mL, 0.75mmol) and purified by column chromatography (60-80% EtOAc/petroleum ether) to give compound 126 as a white solid.

LC-MS：R_T＝3.63min.；m/z 426.18，428.16(M+H)⁺.¹HNMR(DMSO-d₆)：δ8.64(2H，s)，7.39(1H，d，J 8.8)，6.86(1H，d，J 8.9)，4.60(2H，s)，4.34(2H，s)，4.17(2H，s)，3.97(4H，s)，3.84(3H，s).

Example 26:

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 4' -tetrahydropyran]-6-yl } ethanone (Compound 127)

Following general procedure, 3, 5-dichloro-4-methylpyridine (59mg, 0.36mmol) and compound 520(85mg, 0.28mmol) were condensed in THF (1.5mL) in the presence of LiHMDS (0.85mL, 0.85mmol) and purified by column chromatography (60-70% EtOAc/petroleum ether) to give compound 127 as a white solid.

LC-MS：R_T＝3.70min.；m/z 438.21，440.21(M+H)⁺，436.30，438.27(M-H)^-.¹H NMR(DMSO-d₆)：δ8.65(2H，s)，7.42(1H，d，J 8.9)，6.87(1H，d，J 9.0)，4.63(2H，s)，4.25(2H，s)，4.07(2H，s)，3.84(3H，s)，3.64(4H，t，J 5.3)，1.60(4H，t，J 5.3).

Example 27:

2- (3, 5-dichloro-1-oxido-pyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 4' -tetrahydropyran]-6-yl) -ethanone (compound 128)

To 2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 4' -tetrahydropyran]-6-yl } ethanone [127](66mg, 150. mu. mol) in CH₂Cl₂(2mL) to the solution was added 30% H₂O₂(45. mu.L) and methyltrioxorhenium (VII) (10 mg). The mixture was stirred for 18 hours and MnO was added₂(10mg) and stirred for 1 hour. Addition of CH₂Cl₂(10mL), the organic phase was washed with water. The combined organic phases were over MgSO₄Dried and evaporated to dryness under reduced pressure. Purification by standard HPLC afforded 5.6mg of product.

LC/MS (method B): (m/z) 454.32; 456.32(MH +); RT 2.80 min; purity (UV) ═ 100%.

Example 28:

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-2 ', 2' -dimethyl-spiro [2H-1, 5-benzodioxan-3(4H)，5′-[1，3]Dioxane(s)]-6-yl } ethanone (Compound 129)

Following general procedure, 3, 5-dichloro-4-methylpyridine (93mg, 0.58mmol) and compound 522(150mg, 0.44mmol) were condensed in THF (2mL) in the presence of LiHMDS (1.3mL, 1.3mmol) and purified by column chromatography (55-60% EtOAc/petroleum ether) to give compound 129 as a white solid.

LC-MS：R_T＝3.95min.；m/z 468.19，470.23(M+H)⁺，466.36，468.33(M-H)^-.¹H NMR(DMSO-d₆)：δ8.65(2H，s)，7.42(1H，d，J 8.8)，6.89(1H，d，J 9.1)，4.63(2H，s)，4.33(2H，s)，4.08(2H，s)，3.84(3H，s)，3.82(4H，s)，1.39(3H，s)，1.37(3H，s).

Example 29:

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan3(4H)，5′-[1，3]Dioxane(s)]-6-yl } ethanone (Compound 130)

Following general procedure, 3, 5-dichloro-4-methylpyridine (211mg, 1.3mmol) and compound 524(310mg, 1.0mmol) were condensed in THF (6mL) in the presence of LiHMDS (3mL, 3.0mmol) and purified by column chromatography (60-80% EtOAc/petroleum ether) to give compound 130 as a white solid.

LC-MS：R_T＝3.64min.；m/z 440.16，442.17(M+H)⁺，438.27，440.29(M-H)^-.¹H NMR(DMSO-d₆)：δ8.65(2H，s)，7.43(1H，d，J 8.9)，6.89(1H，d，J 8.9)，4.84(1H，d，J 6.1)，4.79(1H，d，J 6.1)，4.64(2H，s)，4.34(2H，s)，4.08(2H，s)，3.90(2H，d，J 11.4)，3.85(3H，s)，3.82(2H，d，J 11.2).

Example 30:

2- (3, 5-dichloro-1-oxido-pyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H)，5′-[1，3]Dioxane(s)]-6-yl } ethanone (Compound 131)

To 2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H)，5′-[1，3]Dioxane(s)]-6-yl } ethanone [130](100mg) in CH₂Cl₂(2mL) to the solution was added 30% H₂O₂(120. mu.L) and methyltrioxorhenium (VII) (5 mg). The mixture was stirred for 18 hours and then washed with water. The organic phase is over MgSO₄Dried and evaporated to dryness under reduced pressure. Purification by standard HPLC afforded 85mg of product.

LC/MS (method B): (m/z)456.23(MH +); RT 2.55 min; purity (UV) ═ 95%.

Example 31:

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H)，5′-[1，3]Dithianes]-6-yl } ethanone (Compound 132)

Following general procedure, 3, 5-dichloro-4-methylpyridine (154mg, 0.95mmol) and compound 526(250mg, 0.73mmol) were condensed in THF (4mL) in the presence of LiHMDS (2.2mL, 2.2mmol) and purified by column chromatography (45-55% EtOAc/petroleum ether) to give compound 132 as a white solid.

LC-MS：R_T＝4.39min.；/m/z 472.15，474.14(M+H)⁺.¹HNMR(DMSO-d₆)：δ8.65(2H，s)，7.42(1H，d，J 8.9)，6.88(1H，d，J 8.9)，4.64(2H，s)，4.43(2H，s)，4.24(2H，s)，3.85(3H，s)，3.84(2H，s)，2.91(4H，s).

Example 32:

PDE4 assay

Human recombinant PDE4(Genbank database accession NM-006203) was incubated for 1 hour with test compound at a concentration of up to 10. mu.M, cAMP (1X 10-5M) and a small amount (0.021MBq) of radiolabeled cAMP. At the end of the incubation, substrate cleavage was assessed by binding of AMP product to SPA beads, which when bound to the radiotracer produced chemiluminescence. AMP products inhibit the binding of the radiotracer to the beads and compete for the luminescent signal. Results are calculated as the molar concentration that results in 50% inhibition of substrate cleavage compared to control samples and are given as IC₅₀And (M) represents.

The results are shown in table 1 below.

TABLE 1

Compound IC₅₀(PDE4)-

101 26nM

102 41nM

103 26nM

104 10nM

105 310nM

106 127nM

107 590nM

108 220nM

110 11nM

111 18nM

112 29nM

113 53nM

114 45nM

115 1410nM

116 1290nM

117 207nM

118 1800nM

119 71nM

120 310nM

121 52nM

122 50nM

123 17nM

124 104nM

125 200nM

126 67nM

127 22nM

128 11nM

129

130 40nM

131 43nM

132 26nM

Example 33:

TNF-alpha release

Human Peripheral Blood Mononuclear Cells (PBMC) were isolated from buffy coats (buffy coats). Blood was mixed with saline at a ratio of 1: 1 and PBMC were isolated using Lymphoprep tube TM (Nycomed, Norway). PBMC were suspended at a concentration of 5X 105c/ml in RPMI1640 containing 2% Fetal Calf Serum (FCS), penicillin/streptomycin and 2mm L-glutamine. Cells were preincubated with test compounds in 96-well tissue culture plates for 30min and stimulated with lipopolysaccharide 1mg/ml (Sigma) for 18 h. Levels of TNF-alpha in the culture supernatants use of TNF-alpha derived from R&Primary and secondary biotinylated antibodies for the D system were determined by enzyme immunoassay. Result in IC₅₀Values are expressed and calculated from the inhibition curve using secretion in LPS-stimulated wells as positive control and secretion in unstimulated cells as negative control.

The results are shown in table 2 below.

TABLE 2

Compound IC₅₀(PDE4)-

101 28nM

102 88nM

103 23nM

104 44nM

105 800nM

106 158nM

107 910nM

108 167nM

110 17nM

111 19nM

112 34nM

113 82nM

114 95nM

115 471nM

116 2940nM

117 286nM

118 5520nM

119 508nM

120 1250nM

121 64nM

122 20nM

123 35nM

124 135nM

125 135nM

126 111nM

127 27nM

128 9nM

130 50nM

131 16nM

132 29nM

Claims (26)

1. Compounds of the general formula I

Wherein m and n independently represent 0 or 1;

and wherein G and E independently represent oxygen, and

R₁and R₂Together with the carbon atom to which they are attached form a compound containing one or two members selected from the group consisting of oxygen, sulfur, -S (O) -, -S (O)₂-、-N＝、-N(R₅) -a hetero-atomic heterocycle selected from tetrahydropyran, oxetane, [1, 3]]Dioxolanes, [1, 3] dioxolanes]IIAlkane, tetrahydrothiopyran-1, 1-dioxide, tetrahydrothiopyran-1-oxide, piperidine, tetrahydrothiophene, [1, 3] or mixtures thereof]Dithianes, thietanes, [1, 3]]Dithiane-1, 3-dioxide, thietane-1-oxide or thietane-1, 1-dioxide, wherein one or more carbon atoms in the heterocycle are optionally substituted by one or more, same or different, groups selected from R₄Substituted with the substituent(s);

R₃is halogen, hydroxy, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6An alkylthio group;

R₄is hydrogen, amino, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_1-6Alkoxy, halogen or hydroxy;

R₅is hydrogen, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkylcarbonyl, hydroxy C_1-6Alkyl radical, C_1-6Alkoxycarbonyl, C_1-6Alkylsulfonyl radical, C_1-6An alkylaminosulfonyl or aminosulfonyl group;

x is a bond, -CH₂-or-NH-;

a is C_6-10Aryl radical, C_6-10Aryl radical C_1-6Alkyl, pyridyl, pyrazinyl or quinolyl, each optionally substituted by one or more, same or different, groups selected from R₄Substituted with the substituent(s);

wherein:

halogen or halo represents fluorine, chlorine, bromine or iodine;

and pharmaceutically acceptable salts or N-oxides thereof.

2. The compound of claim 1, wherein m and n are both 1.

3. The compound of claim 1, wherein m and n are both 0.

4. A compound according to any one of claims 1 to 3, wherein the heterocyclic ring contains one heteroatom.

5. A compound according to any one of claims 1 to 3, wherein the heterocyclic ring comprises two heteroatoms.

6. The compound of claim 4 or 5, wherein the one or more heteroatoms is oxygen.

7. The compound of claim 4 or 5, wherein the one or more heteroatoms are sulfur, -S (O) -or-S (O)₂-。

8. A compound according to any one of claims 1 to 3, wherein a is phenyl.

9. A compound according to any one of claims 1 to 3, wherein a is substituted by halogen.

10. A compound according to any one of claims 1 to 3, wherein R₃Is C_1-6Alkoxy radical, C_1-6Haloalkyl or halogen.

11. The compound of claim 10, wherein R₃Is methoxy or ethoxy.

12. A compound according to any one of claims 1 to 3, wherein X is-CH₂-。

13. A compound according to any one of claims 1 to 3, wherein X is-NH-.

14. The compound of claim 9, wherein a is 4- (3, 5-dichloropyridyl).

15. A compound according to any one of claims 1 to 3, wherein R₄Is hydrogen.

16. A compound selected from:

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran ] -4-yl) ethanone (Compound 101),

n- (3, 5-dichloropyridin-4-yl) -7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran ] -4-carboxamide (Compound 102),

2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -pyran ] -4-yl) ethanone (Compound 103),

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-4 ', 5 ' -dihydro-spiro [1, 3-benzodioxole-2, 3 ' - (2H) -thiophen ] -4-yl) ethanone (Compound 104),

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-spiro [1, 3-benzodioxole-2, 4' -piperadin ] -4-yl) ethanone (compound 105),

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-1 '- [ methoxycarbonyl ] -spiro [1, 3-benzodioxol-2, 4' -piperidin ] -4-yl) ethanone (Compound 106),

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-1 '- [ methanesulfonyl ] -spiro [1, 3-benzodioxol-2, 4' -piperidin ] -4-yl) ethanone (Compound 107),

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-1 '-acetyl-spiro [1, 3-benzodioxole-2, 4' -piperidin ] -4-yl) ethanone (Compound 108),

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 110),

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3', 5 ', 6' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 '- (4H) -thiopyran 1' -oxide ] -4-yl) ethanone (compound 111),

2- (3, 5-dichloropyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxol-2, 4 ' - (4H) -thiopyran-1 ', 1 ' -dioxide ] -4-yl) ethanone (compound 112),

2- (3, 5-dichloro-1-oxidopyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran-1 ', 1 ' -dioxide ] -4-yl) ethanone (compound 113),

2- (3-bromopyridin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (Compound 114),

2- (3-bromo-pyrazin-2-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 115),

2- (-pyrazin-2-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 116),

2- (-pyridin-4-yl-) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (Compound 117),

2- (quinolin-4-yl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 118),

2- (2, 6-dichloro-phenyl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 119),

2- (2-chloro-phenyl) -1- (7-methoxy-2 ', 3 ', 5 ', 6 ' -tetrahydro-spiro [1, 3-benzodioxole-2, 4 ' - (4H) -thiopyran ] -4-yl) ethanone (compound 120),

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 3' -oxetane]-6-yl } ethanone (compound 121),

2- (3, 5-dichloro-1-oxido-pyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 3' -oxetane]-6-yl } ethanone (compound 122),

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 3' -thietane]-6-yl } ethanone (compound 123),

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 3 ' -thietane-1 ', 1 ' -dioxide]-6-yl } ethanone (compound 124),

2- (3, 5-dichloropyridin-1-oxo-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan3(4H), 3 ' -thietane-1 ', 1 ' -dioxide]-6-yl } ethanone (compound 125),

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 2' - (1, 3-dioxolane)]-6-yl } ethanone (compound 126),

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methylOxy-spiro [2H-1, 5-benzodioxan-3(4H), 4' -tetrahydropyran]-6-yl } ethanone (compound 127),

2- (3, 5-dichloro-1-oxido-pyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H), 4' -tetrahydropyran]-6-yl } ethanone (compound 128),

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-2 ', 2' -dimethyl-spiro [2H-1, 5-benzodioxan-3(4H)，5′-[1，3]IIAlkane (I) and its preparation method]-6-yl } ethanone (compound 129),

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H)，5′-[1，3]IIAlkane (I) and its preparation method]-6-yl } ethanone (compound 130),

2- (3, 5-dichloro-1-oxido-pyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H)，5′-[1，3]IIAlkane (I) and its preparation method]-6-yl } ethanone (compound 131), and

2- (3, 5-dichloropyridin-4-yl) -1- { 9-methoxy-spiro [2H-1, 5-benzodioxan-3(4H)，5′-[1，3]Dithianes]-6-yl } ethanone (compound 132),

and pharmaceutically acceptable salts or N-oxides thereof.

17. A compound according to any one of claims 1 to 3 and 16 having a molecular weight of less than 800 daltons.

18. A pharmaceutical composition comprising a compound of any one of claims 1-16 and a pharmaceutically acceptable excipient or vehicle or one or more pharmaceutically acceptable carriers.

19. The pharmaceutical composition of claim 18, comprising one or more additional therapeutically active compounds.

20. Use of a compound according to any one of claims 1 to 16 in the manufacture of a medicament for the prevention, treatment or amelioration of a skin disease or disorder.

21. Use of a compound according to any one of claims 1 to 16 in the manufacture of a medicament for the prevention, treatment or amelioration of acute or chronic skin wound disorders.

22. The use according to claim 20 for the prevention, treatment or amelioration of proliferative and inflammatory skin diseases.

23. The use of claim 20 for the prevention, treatment or amelioration of psoriasis.

24. The use of claim 20, for preventing, treating or ameliorating dermatitis.

25. The use according to claim 20, for the prevention, treatment or amelioration of atopic dermatitis, seborrheic dermatitis, contact dermatitis.

26. The use according to claim 20 for the prevention, treatment or amelioration of pruritus.