Patent Description:
Phosphodiesterases are enzymes that catalyse the hydrolysis of cyclic AMP and/or cyclic GMP in cells to <NUM>-AMP and <NUM>-GMP, respectively, and as such they are critical to cellular regulation of cAMP or cGMP levels. Of the <NUM> phosphodiesterases identified so far, phosphodiesterase (PDE) PDE4, PDE7 and PDE8 are selective for cAMP. PDE4 is the most important modulator of cAMP expressed in immune and inflammatory cells such as neutrophils, macrophages and T-lymphocytes. As cAMP is a key second messenger in the modulation of inflammatory responses, PDE4 has been found to regulate inflammatory responses of inflammatory cells by modulating proinflammatory cytokines such as TNF-o, IL-<NUM>, IFN-γ, GM-CSF and LTB4. Inhibition of PDE4 has therefore become an attractive target for the therapy of inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, atopic dermatitis, psoriasis, inflammatory bowel disease such as Crohn's disease etc. (<NPL>). As atopic dermatitis (AD) patients have increased PDE-activity, PDE4-inhibition would also appear to be a viable treatment of AD (<NPL>).

The PDE4 gene family consists at least of four genes, A, B, C and D, which have a high degree of homology (<NPL>). The four PDE4 isoforms are differentially expressed in different tissues and cell types. Thus, PDE4B is predominantly expressed in monocytes and neutrophils, but not in cortex and epithelial cells, while PDE4D is expressed in lung, cortex, cerebellum and T-cells (<NPL>). It has been speculated that inhibition of PDE4D in the brain is associated with the adverse effects found when administering PDE4 inhibitors clinically, primarily nausea and emesis, whereas inhibition of PDE4B is associated with anti-inflammatory effects (<NPL>).

Numerous PDE4 inhibitors have been studied for their therapeutic effect on inflammatory diseases, primarily asthma and COPD.

<CIT>, <CIT>, <CIT>, <CIT>, and <CIT>, (all Boehringer Ingelheim International) each disclose dihydrothieno-pyrimidines which are substituted with piperazine for the treatment of respiratory or inflammatory diseases. The compounds are stated to inhibit the PDE4B enzyme.

<CIT>, <CIT>, and <CIT> each disclose dihydrothieno-pyrimidines which are substituted with piperidine for the treatment of respiratory or inflammatory diseases. The compounds are stated to inhibit the PDE4B enzyme.

There is a continuous need for developing novel PDE4 inhibitors which have a more favourable therapeutic window, i.e. fewer adverse effects, while retaining their therapeutic effect.

It is an object of the present invention to provide novel dihydrothieno-pyrimidines substituted with azetidine. In one aspect the present invention relates to PDE4 inhibitors that could have a stability profile in biological tissue that implies that a low systemic exposure of the compounds to be observed upon e.g. topical administration, indicating that the compounds of the present invention could have high clearance in human liver microsomes, that they could hydrolyse in human whole blood and could display stability towards enzymatic hydrolyses in human keratinocytes.

In one aspect the invention provides a compound of general formula (I)
<CHM>
wherein.

In another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention as defined above together with a pharmaceutically acceptable vehicle or excipient or pharmaceutically acceptable carrier(s), optionally together with one or more other therapeutically active compound(s).

In another aspect, the invention provides the use of a compound of the invention, for the manufacture of pharmaceutical compositions.

Also provided, is a compound as defined in the claims, for use as a medicament.

In yet another aspect the invention provides a method for treatment, prevention or alleviation of diseases, disorders or conditions responsive to PDE4 inhibitory activity, and which method comprises the step of administering to a living animal body a therapeutically effective amount of the compound of the invention.

Other objects of the invention will be apparent to the person skilled in the art from the following detailed description and examples.

As used throughout the present specification and appended claims, the following terms have the indicated meaning:
The term "alkyl" is intended to indicate a radical obtained when one hydrogen atom is removed from a branched or linear hydrocarbon. Said alkyl comprises <NUM>-<NUM>, such as <NUM>-<NUM>, such as <NUM>-<NUM>, such as <NUM>-<NUM> or such as <NUM>-<NUM> carbon atoms. The term includes the subclasses normal alkyl (n-alkyl), secondary and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and isohexyl.

The terms "alkyloxy" and "alkoxy" are intended to indicate a radical of the formula -OR', wherein R' is alkyl as indicated herein, wherein the alkyl group is appended to the parent molecular moiety through an oxygen atom, e.g. methoxy (-OCH<NUM>), ethoxy (-OCH<NUM>CH<NUM>), n-propoxy, isopropoxy, butoxy, tert-butoxy, and the like.

The term alkoxyalkyl is intended to indicate an alkyl group as defined above substituted with one or more alkoxy groups as defined above, e.g. methoxymethyl, ethoxymethyl, <NUM>-methoxyethyl, <NUM>-ethoxyethyl, <NUM>-methoxyprop-<NUM>-yl, and the like The term "haloalkyl" is intended to indicate an alkyl group as defined herein substituted with one or more halogen atoms as defined herein, e.g. fluoro or chloro, such as fluoromethyl, difluoromethyl or trifluoromethyl.

The terms "haloalkyloxy" and "haloalkoxy" are intended to indicate a haloalkyl group as defined herein which is appended to the parent molecular moiety through an oxygen atom, such as difluoromethoxy or trifluoromethoxy.

The term "halogen" is intended to indicate a substituent from the <NUM>th main group of the periodic table, such as fluoro, chloro and bromo.

The term "cyano" is intended to indicate a -CN group attached to the parent molecular moiety through the carbon atom.

The term "cycloalkyl" is intended to indicate a saturated cycloalkane hydrocarbon radical, comprising <NUM>-<NUM> carbon atoms, <NUM>-<NUM> carbon atoms, <NUM>-<NUM> carbon atoms, <NUM>-<NUM> carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "aryl" is intended to indicate a radical of aromatic carbocyclic rings comprising <NUM>-<NUM> carbon atoms, <NUM>-<NUM> carbon atoms, such as <NUM> carbon atoms, including fused carbocyclic rings with at least one aromatic ring. If the aryl group is a fused carbocyclic ring, the point of attachment of the aryl group to the parent molecular moiety may be through an aromatic or through an aliphatic carbon atom within the aryl group. Representative examples of aryl include, but are not limited to phenyl, naphthyl, indenyl, indanyl, dihydronaphtyl, tetrahydronaphtyl and fluorenyl.

The term "heteroaryl" is intended to indicate radicals of monocyclic heteroaromatic rings comprising <NUM>- or <NUM>-membered ring which contains from <NUM>-<NUM> carbon atoms and from <NUM>-<NUM> heteroatoms selected from oxygen, sulphur and nitrogen. The heteroaryl radical may be connected to the parent molecular moiety through a carbon atom or a nitrogen atom contained anywhere within the heteroaryl group. Representative examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, and triazolyl.

The term "heterocycloalkyl" is intended to indicate a cycloalkane radical as described herein, wherein one or more carbon atoms are replaced by heteroatoms, comprising <NUM>-<NUM> carbon atoms, e.g. <NUM>-<NUM> or <NUM>-<NUM> carbon atoms, further comprising <NUM>-<NUM> heteroatoms, preferably <NUM> to <NUM> heteroatoms, selected from O, N, S, S(=O) or S(=O)<NUM>. The heterocycloalkyl radical may be connected to the parent molecular moiety through a carbon atom or a nitrogen atom contained anywhere within the heterocycloalkyl group. Representative examples of heterocycloalkyl groups include, but are not limited to azepanyl, azetidinyl, aziridinyl, dioxolanyl, dioxolyl, imidazolidinyl, morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.

The term "(<NUM>-<NUM>) membered heterocycloalkyl" is intended to indicate a heterocycloalkyl as defined herein, comprising <NUM>-<NUM> ring-atoms, and comprising <NUM>-<NUM> carbon atoms, e.g. <NUM>-<NUM> or <NUM>-<NUM> carbon atoms, further comprising <NUM>-<NUM> heteroatoms, preferably <NUM> to <NUM> heteroatoms, selected from O, N, S, S(=O) or S(=O)<NUM>. Representative examples of (<NUM>-<NUM>) membered heterocycloalkyl groups include azetidinyl, dioxanyl, dioxolanyl, imidazolidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-<NUM>-oxide, thiomorpholinyl-<NUM>,<NUM>-dioxide, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiophenyl, thietanyl, and dioxothianyl.

The term "(<NUM>-<NUM>) membered heteroaryl" is intended to indicate radicals of monocyclic heteroaromatic rings comprising <NUM>- or <NUM>-membered ring which contains from <NUM>-<NUM> carbon atoms e.g. <NUM>-<NUM> or <NUM>-<NUM> carbon atoms, and from <NUM>-<NUM> heteroatoms, preferably <NUM> to <NUM> heteroatoms, e.g. <NUM>-<NUM> heteroatoms selected from oxygen, sulphur and nitrogen. The heteroaryl radical may be connected to the parent molecular moiety through a carbon atom or a nitrogen atom contained anywhere within the heteroaryl group. Representative examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, and triazolyl.

The term "hydrocarbon radical" is intended to indicate a radical containing only hydrogen and carbon atoms, it may contain one or more double and/or triple carbon-carbon bonds, and it may comprise cyclic moieties in combination with branched or linear moieties. Said hydrocarbon comprises <NUM>-<NUM> carbon atoms, and preferably comprises <NUM>-<NUM>, e.g. <NUM>-<NUM>, e.g. <NUM>-<NUM>, e.g. <NUM>-<NUM> carbon atoms. The term includes alkyl, cycloalkyl and aryl, as indicated herein.

In some instances, the number of carbon atoms in a hydrocarbon radical (e.g. alkyl, cycloalkyl and aryl) is indicated by the prefix "(Ca-Cb)", wherein a is the minimum number and b is the maximum number of carbons in the hydrocarbon radical. Thus, for example (C<NUM>-C<NUM>)alkyl is intended to indicate an alkyl radical comprising from <NUM> to <NUM> carbon atoms, and (C<NUM>-C<NUM>)cycloalkyl is intended to indicate a cycloalkyl radical comprising from <NUM> to <NUM> carbon ring atoms.

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

The term "hydroxyl" is intended to indicate an -OH group.

The term "oxo" is intended to indicate an oxygen atom which is connected to the parent molecular moiety via a double bond (=O).

The group C(O) is intended to represent a carbonyl group (C=O).

The term "pharmaceutically acceptable salt" is intended to indicate salts prepared by reacting a compound of formula (I), which comprise a basic moiety, with a suitable inorganic or organic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, formic, acetic, <NUM>,<NUM>-dichloroacetic, adipic, ascorbic, L-aspartic, L-glutamic, galactaric, lactic, maleic, L-malic, phthalic, citric, propionic, benzoic, glutaric, gluconic, D-glucuronic, methanesulfonic, salicylic, succinic, malonic, tartaric, benzenesulfonic, ethane-<NUM>,<NUM>-disulfonic, <NUM>-hydroxy ethanesulfonic acid, toluenesulfonic, sulfamic or fumaric acid. Further examples of pharmaceutical acceptable salts are listed in <NPL>, which is incorporated herein by reference.

The term "solvate" is intended to indicate a species formed by interaction between a compound, e.g. a compound of formula (I), and a solvent, e.g. alcohol, glycerol or water, wherein said species are in a crystalline form. When water is the solvent, said species is referred to as a hydrate.

The term "treatment" as used herein means the management and care of a patient for the purpose of combating a disease, disorder or condition. The term is intended to include the delaying of the progression of the disease, disorder or condition, the amelioration, alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condition. The term may also include prevention of the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. Nonetheless, prophylactic (preventive) and therapeutic (curative) treatments are two separate aspects.

The terms "disease", "condition" and "disorder" as used herein are used interchangeably to specify a state of a patient which is not the normal physiological state of man.

The term "medicament" as used herein means a pharmaceutical composition suitable for administration of the pharmaceutically active compound to a patient.

The term "pharmaceutically acceptable" as used herein means suited for normal pharmaceutical applications, i.e. giving rise to no adverse events in patients etc..

In another embodiment of the present invention in formula (I).

In another embodiment of the present invention in formula (I), R<NUM> is hydrogen or (C<NUM>-C<NUM>)alkyl; and R<NUM> is selected from the group consisting of tetrahydropyranyl, oxaspiroheptanyl, pyrrolidinyl and piperidinyl; wherein said pyrrolidinyl and piperidinyl are optionally substituted -C(O)(C<NUM>-C<NUM>)alkyl; and R<NUM> is selected from the group consisting of (C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)cycloalkyl, (C<NUM>-C<NUM>)alkyl(C<NUM>-C<NUM>)cycloalkyl, halo(C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkoxy, (C<NUM>-C<NUM>)alkyl(C<NUM>-C<NUM>)alkoxy, halo(C<NUM>-C<NUM>)alkyloxy, (<NUM>-<NUM>)membered heterocycloalkyl, (C<NUM>-C<NUM>)alkyl(<NUM>-<NUM>)membered heterocycloalkyl, (<NUM>-<NUM>)membered heteroaryl, (C<NUM>-C<NUM>)alkyl(<NUM>-<NUM>)membered heteroaryl, aryl and (C<NUM>-C<NUM>)alkylaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted with one or more substituents independently selected from R<NUM>; and R<NUM> is selected from the group consisting of halogen, hydroxyl, (C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyloxy, ORx, SRx, -S(O)<NUM>Rx, -S(O)<NUM>NRaRb, -C(O)(C<NUM>-C<NUM>)alkyl, -C(O)(ORx), and -C(O)NRaRb; and Rx consists of (C<NUM>-C<NUM>)alkyl, or (C<NUM>-C<NUM>)cycloalkyl; and Ra and Rb are independently selected from the group consisting of hydrogen, (C<NUM>-C<NUM>)alkyl and halo(C<NUM>-C<NUM>)alkyl, or Ra and Rb may together with the nitrogen atom to which they are attached form a (<NUM>-<NUM>)membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more (C<NUM>-C<NUM>)alkyl.

In another embodiment of the present invention in formula (I), R<NUM> is hydrogen or (C<NUM>-C<NUM>)alkyl; and R<NUM> is selected from the group consisting of tetrahydropyranyl, oxaspiroheptanyl, pyrrolidinyl and piperidinyl, wherein said pyrrolidinyl and piperidinyl are optionally substituted with R<NUM>; and R<NUM> is selected from the group consisting of - C(O)(C<NUM>-C<NUM>)alkyl, and -C(O)O(C<NUM>-C<NUM>)alkyl; and R<NUM> is selected from the group consisting of (C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)cycloalkyl, (C<NUM>-C<NUM>)alkyl(C<NUM>-C<NUM>)cycloalkyl, halo(C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkoxy, (C<NUM>-C<NUM>)alkyl(C<NUM>-C<NUM>)alkoxy, halo(C<NUM>-C<NUM>)alkyloxy, (<NUM>-<NUM>)membered heterocycloalkyl, (C<NUM>-C<NUM>)alkyl(<NUM>-<NUM>)membered heterocycloalkyl, (<NUM>-<NUM>)membered heteroaryl, (C<NUM>-C<NUM>)alkyl(<NUM>-<NUM>)membered heteroaryl, aryl and (C<NUM>-C<NUM>)alkylaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted with one or more substituents independently selected from R<NUM>; and R<NUM> is selected from the group consisting of halogen, cyano, hydroxyl, (C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyloxy, ORx, SRx, -S(O)<NUM>Rx, -S(O)<NUM>NRaRb, -C(O)(C<NUM>-C<NUM>)alkyl, -C(O)(ORx), and -C(O)NRaRb; and Rx consists of (C<NUM>-C<NUM>)alkyl, or (C<NUM>-C<NUM>)cycloalkyl; and Ra and Rb are independently selected from the group consisting of hydrogen, (C<NUM>-C<NUM>)alkyl and halo(C<NUM>-C<NUM>)alkyl, or Ra and Rb may together with the nitrogen atom to which they are attached form a (<NUM>-<NUM>)membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more (C<NUM>-C<NUM>)alkyl.

In another embodiment of the present invention in formula (I), R<NUM> is hydrogen or (C<NUM>-C<NUM>)alkyl; and R<NUM> is selected from the group consisting of tetrahydropyranyl, oxaspiroheptanyl, pyrrolidinyl and piperidinyl, wherein said pyrrolidinyl and piperidinyl are optionally substituted with R<NUM>; and R<NUM> is selected from the group consisting of - C(O)(C<NUM>-C<NUM>)alkyl, and -C(O)O(C<NUM>-C<NUM>)alkyl; and R<NUM> is selected from the group consisting of (C<NUM>-C<NUM>)cycloalkyl, (<NUM>-<NUM>)membered heterocycloalkyl, and (<NUM>-<NUM>)membered heteroaryl, all of which are optionally substituted with one or more substituents independently selected from R<NUM>; and R<NUM> is selected from the group consisting of halogen, cyano, hydroxyl, (C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyloxy, ORx, SRx, -S(O)<NUM>Rx, - S(O)<NUM>NRaRb, -C(O)(C<NUM>-C<NUM>)alkyl, -C(O)(ORx), and -C(O)NRaRb; and Rx consists of (C<NUM>-C<NUM>)alkyl, or (C<NUM>-C<NUM>)cycloalkyl; and Ra and Rb are independently selected from the group consisting of hydrogen, (C<NUM>-C<NUM>)alkyl and halo(C<NUM>-C<NUM>)alkyl, or Ra and Rb may together with the nitrogen atom to which they are attached form a (<NUM>-<NUM>)membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more (C<NUM>-C<NUM>)alkyl.

In another embodiment of the present invention in formula (I), R<NUM> is hydrogen or (C<NUM>-C<NUM>)alkyl; and R<NUM> is selected from the group consisting of tetrahydropyranyl, oxaspiroheptanyl, pyrrolidinyl and piperidinyl, wherein said pyrrolidinyl and piperidinyl are optionally substituted with -C(O)(C<NUM>-C<NUM>)alkyl; and R<NUM> is selected from the group consisting of (C<NUM>-C<NUM>)cycloalkyl, (<NUM>-<NUM>)membered heterocycloalkyl, and (<NUM>-<NUM>)membered heteroaryl.

In another embodiment of the present invention in formula (I), R<NUM> is hydrogen or (C<NUM>-C<NUM>)alkyl; and R<NUM> is oxaspiroheptanyl; and R<NUM> is selected from the group consisting of (C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)cycloalkyl, (C<NUM>-C<NUM>)alkyl(C<NUM>-C<NUM>)cycloalkyl, halo(C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkoxy, (C<NUM>-C<NUM>)alkyl(C<NUM>-C<NUM>)alkoxy, halo(C<NUM>-C<NUM>)alkyloxy, (<NUM>-<NUM>)membered heterocycloalkyl, (C<NUM>-C<NUM>)alkyl(<NUM>-<NUM>)membered heterocycloalkyl, (<NUM>-<NUM>)membered heteroaryl, (C<NUM>-C<NUM>)alkyl(<NUM>-<NUM>)membered heteroaryl, aryl and (C<NUM>-C<NUM>)alkylaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted with one or more substituents independently selected from R<NUM>; and R<NUM> is selected from the group consisting of halogen, cyano, hydroxyl, (C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)-alkyloxy, ORx, SRx, -S(O)<NUM>Rx, -S(O)<NUM>NRaRb, -C(O)(C<NUM>-C<NUM>)alkyl, -C(O)(ORx), and - C(O)NRaRb; and Rx consists of (C<NUM>-C<NUM>)alkyl, or (C<NUM>-C<NUM>)cycloalkyl; and Ra and Rb are independently selected from the group consisting of hydrogen, (C<NUM>-C<NUM>)alkyl and halo(C<NUM>-C<NUM>)alkyl, or Ra and Rb may together with the nitrogen atom to which they are attached form a (<NUM>-<NUM>)membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more (C<NUM>-C<NUM>)alkyl.

In another embodiment of the present invention in formula (I), R<NUM> is hydrogen or (C<NUM>-C<NUM>)alkyl; and R<NUM> is oxaspiroheptanyl; and R<NUM> is selected from the group consisting of (C<NUM>-C<NUM>)cycloalkyl, (<NUM>-<NUM>)membered heterocycloalkyl, and (<NUM>-<NUM>)membered heteroaryl, all of which are optionally substituted with one or more substituents independently selected from R<NUM>; and R<NUM> is selected from the group consisting of halogen, cyano, hydroxyl, (C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyloxy, ORx, -SRx, -S(O)<NUM>Rx, - S(O)<NUM>NRaRb, -C(O)(C<NUM>-C<NUM>)alkyl, -C(O)(ORx), and -C(O)NRaRb; and Rx consists of (C<NUM>-C<NUM>)alkyl, or (C<NUM>-C<NUM>)cycloalkyl; and Ra and Rb are independently selected from the group consisting of hydrogen, (C<NUM>-C<NUM>)alkyl and halo(C<NUM>-C<NUM>)alkyl, or Ra and Rb may together with the nitrogen atom to which they are attached form a (<NUM>-<NUM>)membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more (C<NUM>-C<NUM>)alkyl.

In another embodiment of the present invention in formula (I), R<NUM> is hydrogen or (C<NUM>-C<NUM>)alkyl; and R<NUM> is oxaspiroheptanyl; and R<NUM> is selected from the group consisting of (C<NUM>-C<NUM>)cycloalkyl, (<NUM>-<NUM>)membered heterocycloalkyl, and (<NUM>-<NUM>)membered heteroaryl.

In another embodiment of the present invention in formula (I), R<NUM> is hydrogen; and R<NUM> is oxaspiroheptanyl; and R<NUM> is selected from the group consisting of (<NUM>-<NUM>)membered heterocycloalkyl, and (<NUM>-<NUM>)membered heteroaryl.

In another embodiment of the present invention in formula (I), R<NUM> is hydrogen or (C<NUM>-C<NUM>)alkyl; and R<NUM> is pyrrolidinyl, which is optionally substituted with R<NUM>; R<NUM> is selected from the group consisting of -C(O)(C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkyl, -C(O)O(C<NUM>-C<NUM>)alkyl, - C(O)NRaRb and -(C<NUM>-C<NUM>)alkyl-C(O)NRaRb; R<NUM> is selected from the group consisting of (C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)cycloalkyl, (C<NUM>-C<NUM>)alkyl(C<NUM>-C<NUM>)cycloalkyl, halo(C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkoxy, (C<NUM>-C<NUM>)alkyl(C<NUM>-C<NUM>)alkoxy, halo(C<NUM>-C<NUM>)alkyloxy, (<NUM>-<NUM>)membered heterocycloalkyl, (C<NUM>-C<NUM>)alkyl(<NUM>-<NUM>)membered heterocycloalkyl, (<NUM>-<NUM>)membered heteroaryl, (C<NUM>-C<NUM>)alkyl(<NUM>-<NUM>)membered heteroaryl, aryl and (C<NUM>-C<NUM>)alkylaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted with one or more substituents independently selected from R<NUM>; and R<NUM> is selected from the group consisting of halogen, cyano, hydroxyl, (C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyloxy, ORx, SRx, -S(O)<NUM>Rx, -S(O)<NUM>NRaRb, -C(O)(C<NUM>-C<NUM>)alkyl, -C(O)(ORx), and -C(O)NRaRb; and Rx consists of (C<NUM>-C<NUM>)alkyl, or (C<NUM>-C<NUM>)cycloalkyl; and Ra and Rb are independently selected from the group consisting of hydrogen, (C<NUM>-C<NUM>)alkyl and halo(C<NUM>-C<NUM>)alkyl, or Ra and Rb may together with the nitrogen atom to which they are attached form a (<NUM>-<NUM>)membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more (C<NUM>-C<NUM>)alkyl.

In another embodiment of the present invention in formula (I), R<NUM> is hydrogen or (C<NUM>-C<NUM>)alkyl; and R<NUM> is pyrrolidinyl, which is optionally substituted with R<NUM>; and R<NUM> is selected from the group consisting of -C(O)(C<NUM>-C<NUM>)alkyl, and -C(O)O(C<NUM>-C<NUM>)alkyl; and R<NUM> is selected from the group consisting of (C<NUM>-C<NUM>)cycloalkyl, (<NUM>-<NUM>)membered heterocycloalkyl, and (<NUM>-<NUM>)membered heteroaryl, all of which are optionally substituted with one or more substituents independently selected from R<NUM>; and R<NUM> is selected from the group consisting of halogen, cyano, hydroxyl, (C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyloxy, ORx, -SRx, -S(O)<NUM>Rx, -S(O)<NUM>NRaRb, -C(O)(C<NUM>-C<NUM>)alkyl, - C(O)(ORx), and -C(O)NRaRb; and Rx consists of (C<NUM>-C<NUM>)alkyl, or (C<NUM>-C<NUM>)cycloalkyl; and Ra and Rb are independently selected from the group consisting of hydrogen, (C<NUM>-C<NUM>)alkyl and halo(C<NUM>-C<NUM>)alkyl, or Ra and Rb may together with the nitrogen atom to which they are attached form a (<NUM>-<NUM>)membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more (C<NUM>-C<NUM>)alkyl.

In another embodiment of the present invention in formula (I), R<NUM> is hydrogen or (C<NUM>-C<NUM>)alkyl; and R<NUM> is pyrrolidinyl which is optionally substituted with -C(O)(C<NUM>-C<NUM>)alkyl; and R<NUM> is selected from the group consisting of (C<NUM>-C<NUM>)cycloalkyl, (<NUM>-<NUM>)membered heterocycloalkyl, and (<NUM>-<NUM>)membered heteroaryl.

In another embodiment of the present invention in formula (I), R<NUM> is hydrogen; and R<NUM> is pyrrolidinyl substituted with -C(O)(C<NUM>-C<NUM>)alkyl; and R<NUM> is selected from the group consisting of (<NUM>-<NUM>)membered heterocycloalkyl, and (<NUM>-<NUM>)membered heteroaryl.

In another embodiment of the present invention in formula (I), R<NUM> is hydrogen or (C<NUM>-C<NUM>)alkyl; and R<NUM> is piperidinyl, which is optionally substituted with R<NUM>; R<NUM> is selected from the group consisting of -C(O)(C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkyl, -C(O)O(C<NUM>-C<NUM>)alkyl, - C(O)NRaRb and -(C<NUM>-C<NUM>)alkyl-C(O)NRaRb; R<NUM> is selected from the group consisting of (C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)cycloalkyl, (C<NUM>-C<NUM>)alkyl(C<NUM>-C<NUM>)cycloalkyl, halo(C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkoxy, (C<NUM>-C<NUM>)alkyl(C<NUM>-C<NUM>)alkoxy, halo(C<NUM>-C<NUM>)alkyloxy, (<NUM>-<NUM>)membered heterocycloalkyl, (C<NUM>-C<NUM>)alkyl(<NUM>-<NUM>)membered heterocycloalkyl, (<NUM>-<NUM>)membered heteroaryl, (C<NUM>-C<NUM>)alkyl(<NUM>-<NUM>)membered heteroaryl, aryl and (C<NUM>-C<NUM>)alkylaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted with one or more substituents independently selected from R<NUM>; and R<NUM> is selected from the group consisting of halogen, cyano, hydroxyl, (C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyloxy, ORx, SRx, -S(O)<NUM>Rx, -S(O)<NUM>NRaRb, -C(O)(C<NUM>-C<NUM>)alkyl, -C(O)(ORx), and -C(O)NRaRb; and Rx consists of (C<NUM>-C<NUM>)alkyl, or (C<NUM>-C<NUM>)cycloalkyl; and Ra and Rb are independently selected from the group consisting of hydrogen, (C<NUM>-C<NUM>)alkyl and halo(C<NUM>-C<NUM>)alkyl, or Ra and Rb may together with the nitrogen atom to which they are attached form a (<NUM>-<NUM>)membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more (C<NUM>-C<NUM>)alkyl.

In another embodiment of the present invention in formula (I), R<NUM> is hydrogen or (C<NUM>-C<NUM>)alkyl; and R<NUM> is piperidinyl, which is optionally substituted with R<NUM>; and R<NUM> is selected from the group consisting of -C(O)(C<NUM>-C<NUM>)alkyl, and -C(O)O(C<NUM>-C<NUM>)alkyl; and R<NUM> is selected from the group consisting of (C<NUM>-C<NUM>)cycloalkyl, (<NUM>-<NUM>)membered heterocycloalkyl, and (<NUM>-<NUM>)membered heteroaryl, all of which are optionally substituted with one or more substituents independently selected from R<NUM>; and R<NUM> is selected from the group consisting of halogen, cyano, hydroxyl, (C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyloxy, ORx, -SRx, -S(O)<NUM>Rx, -S(O)<NUM>NRaRb, -C(O)(C<NUM>-C<NUM>)alkyl, - C(O)(ORx), and -C(O)NRaRb; and Rx consists of (C<NUM>-C<NUM>)alkyl, or (C<NUM>-C<NUM>)cycloalkyl; and Ra and Rb are independently selected from the group consisting of hydrogen, (C<NUM>-C<NUM>)alkyl and halo(C<NUM>-C<NUM>)alkyl, or Ra and Rb may together with the nitrogen atom to which they are attached form a (<NUM>-<NUM>)membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more (C<NUM>-C<NUM>)alkyl.

In another embodiment of the present invention in formula (I), R<NUM> is hydrogen or (C<NUM>-C<NUM>)alkyl; and R<NUM> is piperidinyl which is optionally substituted with -C(O)(C<NUM>-C<NUM>)alkyl; and R<NUM> is selected from the group consisting of (C<NUM>-C<NUM>)cycloalkyl, (<NUM>-<NUM>)membered heterocycloalkyl, and (<NUM>-<NUM>)membered heteroaryl.

In another embodiment of the present invention in formula (I), R<NUM> is hydrogen; and R<NUM> is piperidinyl substituted with -C(O)(C<NUM>-C<NUM>)alkyl; and R<NUM> is selected from the group consisting of (<NUM>-<NUM>)membered heterocycloalkyl, and (<NUM>-<NUM>)membered heteroaryl.

In another embodiment the invention provides a compound of general formula (II)
<CHM>
wherein.

In another embodiment of the present invention in formula (II), R<NUM> is hydrogen or (C<NUM>-C<NUM>)alkyl; and R<NUM> is selected from the group consisting of (C<NUM>-C<NUM>)cycloalkyl, (<NUM>-<NUM>)-membered heterocycloalkyl, (<NUM>-<NUM>)membered heteroaryl and aryl, all of which are optionally substituted with one or more substituents independently selected from R<NUM>; and R<NUM> is selected from the group consisting of halogen, cyano, hydroxyl, (C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyloxy, ORx, -SRx, -S(O)<NUM>Rx, -S(O)<NUM>NRaRb, -C(O)(C<NUM>-C<NUM>)alkyl, -C(O)(ORx), and -C(O)NRaRb; and Rx consists of (C<NUM>-C<NUM>)alkyl, or (C<NUM>-C<NUM>)cycloalkyl; and Ra and Rb are independently selected from the group consisting of hydrogen, (C<NUM>-C<NUM>)alkyl and halo(C<NUM>-C<NUM>)alkyl, or Ra and Rb may together with the nitrogen atom to which they are attached form a (<NUM>-<NUM>)membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more (C<NUM>-C<NUM>)alkyl.

In another embodiment of the present invention in formula (II), R<NUM> is hydrogen or methyl; and R<NUM> is selected from the group consisting of (C<NUM>-C<NUM>)cycloalkyl, (<NUM>-<NUM>)-membered heterocycloalkyl and (<NUM>-<NUM>)membered heteroaryl.

In another embodiment of the present invention in formula (II), R<NUM> is hydrogen or methyl; and R<NUM> is (<NUM>-<NUM>)membered heteroaryl.

In another embodiment of the present invention in formula (II), R<NUM> is hydrogen; and R<NUM> is selected from the group consisting of cyclopentyl, tetrahydropyranyl, isothiazolyl and thiazolyl.

In another embodiment of the present invention in formula (II), R<NUM> is hydrogen; and R<NUM> is selected from the group consisting of isothiazolyl and thiazolyl.

In another embodiment of the present invention in formula (II), R<NUM> is methyl; and R<NUM> is selected from the group consisting of tetrahydropyranyl, isothiazolyl and thiazolyl.

In another embodiment of the present invention in formula (II), R<NUM> is methyl; and R<NUM> is selected from the group consisting of isothiazolyl and thiazolyl.

In another embodiment of the present invention, S* represents a chiral sulphur atom being in the R-configuration.

In another embodiment of the present invention, S* represents a chiral sulphur atom being in the S-configuration.

In another embodiment the invention provides a compound of general formula (IIa)
<CHM>.

In another embodiment of the present invention in formula (IIa), R<NUM> is hydrogen or (C<NUM>-C<NUM>)alkyl; and R<NUM> is selected from the group consisting of (C<NUM>-C<NUM>)cycloalkyl, (<NUM>-<NUM>)-membered heterocycloalkyl, (<NUM>-<NUM>)membered heteroaryl and aryl, all of which are optionally substituted with one or more substituents independently selected from R<NUM>; and R<NUM> is selected from the group consisting of halogen, cyano, hydroxyl, (C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyloxy, ORx, -SRx, -S(O)<NUM>Rx, -S(O)<NUM>NRaRb, -C(O)(C<NUM>-C<NUM>)alkyl, -C(O)(ORx), and -C(O)NRaRb; and Rx consists of (C<NUM>-C<NUM>)alkyl, or (C<NUM>-C<NUM>)cycloalkyl; and Ra and Rb are independently selected from the group consisting of hydrogen, (C<NUM>-C<NUM>)alkyl and halo(C<NUM>-C<NUM>)alkyl, or Ra and Rb may together with the nitrogen atom to which they are attached form a (<NUM>-<NUM>)membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more (C<NUM>-C<NUM>)alkyl.

In another embodiment of the present invention in formula (IIa), R<NUM> is hydrogen or methyl; and R<NUM> is selected from the group consisting of (C<NUM>-C<NUM>)cycloalkyl, (<NUM>-<NUM>)-membered heterocycloalkyl and (<NUM>-<NUM>)membered heteroaryl.

In another embodiment of the present invention in formula (IIa), R<NUM> is hydrogen or methyl; and R<NUM> is (<NUM>-<NUM>)membered heteroaryl.

In another embodiment of the present invention in formula (IIa), R<NUM> is hydrogen; and R<NUM> is selected from the group consisting of cyclopentyl, tetrahydropyranyl, isothiazolyl and thiazolyl.

In another embodiment of the present invention in formula (IIa), R<NUM> is hydrogen; and R<NUM> is selected from the group consisting of isothiazolyl and thiazolyl.

In another embodiment of the present invention in formula (IIa), R<NUM> is hydrogen; and R<NUM> is selected from the group consisting of <NUM>-isothiazolyl and <NUM>-thiazolyl.

In another embodiment of the present invention in formula (IIa), R<NUM> is methyl; and R<NUM> is selected from the group consisting of tetrahydropyranyl, isothiazolyl and thiazolyl.

In another embodiment of the present invention in formula (IIa), R<NUM> is methyl; and R<NUM> is selected from the group consisting of isothiazolyl and thiazolyl.

In another embodiment of the present invention in formula (IIa), R<NUM> is methyl; and R<NUM> is selected from the group consisting of <NUM>-isothiazolyl and <NUM>-thiazolyl.

In another embodiment the invention provides a compound selected from the following:.

In another embodiment the invention provides an intermediate compound of general formula (III)
<CHM>.

In another embodiment of the present invention in formula (III), R<NUM> is hydrogen or (C<NUM>-C<NUM>)alkyl; and R<NUM> is tetrahydropyranyl.

In another embodiment of the present invention in formula (III), R<NUM> is hydrogen or methyl; and R<NUM> is tetrahydropyranyl.

In another embodiment of the present invention in formula (III), R<NUM> is hydrogen; and R<NUM> is tetrahydropyranyl.

In another embodiment of the present invention in formula (III), R<NUM> is methyl; and R<NUM> is tetrahydropyranyl.

In another embodiment the invention provides an intermediate compound of general formula (III) selected from the following:.

The compounds of the invention could be obtained in crystalline form either directly by concentration from an organic solvent or by crystallisation or re-crystallisation from an organic solvent or mixture of said solvent and a co-solvent that could be organic or inorganic, such as water. The crystals could be isolated in essentially solvent-free form or as a solvate, such as a hydrate. The invention covers all crystalline modifications and forms and also mixtures thereof.

The compounds of the invention comprise asymmetrically substituted (chiral) atoms which give rise to the existence of isomeric forms, e.g. enantiomers and possibly diastereomers. The present invention relates to all such isomers, either in optically pure form or as mixtures thereof (e.g. racemic mixtures or partially purified optical mixtures). Pure stereoisomeric forms of the compounds and the intermediates of this invention may be obtained by the application of procedures known in the art. The various isomeric forms may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. high pressure liquid chromatography using chiral stationary phases. Enantiomers may be separated from each other by selective crystallization of their diastereomeric salts which may be formed with optically active amines, such as l-ephedrine, or with optically active acids. Optically purified compounds may subsequently be liberated from said purified diastereomeric salts. Enantiomers may also be resolved by the formation of diastereomeric derivatives. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric forms of the appropriate starting materials, provided that the reaction occurs stereoselectively or stereospecifically. If a specific stereoisomer is desired, said compound will be synthesized by stereoselective or stereospecific methods of preparation. These methods will advantageously employ chiral pure starting materials.

Furthermore, when a double bond or a fully or partially saturated ring system is present in the molecule geometric isomers may be formed. It is intended that any geometric isomer, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention.

The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include <NUM>C and <NUM>C. Isotopically-labelled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labelled reagent in place of the non-labelled reagent otherwise employed.

Compounds of the invention, optionally in combination with other active compounds, could be useful for the treatment of dermal diseases or conditions, in particular for the treatment of proliferative and inflammatory skin disorders, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, psoriasis, cancer, epidermal inflammation, alopecia, alopecia areata, skin atrophy, steroid induced skin atrophy, skin ageing, photo skin ageing, acne, urticaria, pruritis, and eczema.

Besides being useful for human treatment, the compounds of the present invention could also be useful for veterinary treatment of animals including mammals such as horses, cattle, sheep, pigs, dogs, and cats.

For use in therapy, compounds of the present invention are typically in the form of a pharmaceutical composition. The invention therefore relates to a pharmaceutical composition comprising a compound of the invention, optionally together with one or more other therapeutically active compound(s), together with 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.

In the form of a dosage unit, the compound could be administered one or more times a day at appropriate intervals, always depending, however, on the condition of the patient, and in accordance with the prescription made by the medical practitioner. Conveniently, a dosage unit of a topical formulation contains between <NUM> and <NUM>, preferably between <NUM> and <NUM>, such as <NUM>-<NUM> of a compound of the invention. Also, conveniently, a dosage unit of a topical formulation contains between <NUM> and <NUM> mg, preferably between <NUM> and <NUM>, such as <NUM>-<NUM> of a compound of formula (I).

A suitable dosage of the compound of the invention will depend, inter alia, on the age and condition of the patient, the severity of the disease to be treated and other factors well known to the practising physician. The compound could be administered either orally, parenterally or topically according to different dosing schedules, e.g. daily or with weekly intervals. In general a single dose will be in the range from <NUM> to <NUM>/kg body weight, e.g. in the range from <NUM> to <NUM>/kg body weight. Also, in general a single dose will be in the range from <NUM> to <NUM>/kg body weight, e.g. in the range from <NUM> to <NUM>/kg body weight. The compound could be administered as a bolus (i.e. the entire daily dose is administered at once) or in divided doses two or more times a day.

In the context of topical treatment it could be more appropriate to refer to a "usage unit", which denotes unitary, i.e. a single dose which is capable of being administered to a patient, and which could be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers. A "usage unit" is capable of being administered topically to a patient in an application per square centimetre of the skin of from <NUM> to <NUM> and preferably from <NUM> to <NUM> of the final formulation in question.

It is also envisaged that in certain treatment regimes, administration with longer intervals, e.g. every other day, every week, or even with longer intervals could be beneficial.

If the treatment involves administration of another therapeutically active compound it is recommended to consult <NPL>, for useful dosages of said compounds.

The administration of a compound of the present invention with one or more other active compounds could be either concomitantly or sequentially.

The formulations include e.g. those in a form suitable for oral (including sustained or timed release), rectal, parenteral (including subcutaneous, intraperitoneal, intramuscular, intraarticular and intravenous), transdermal, ophthalmic, topical, dermal, nasal or buccal administration. Topical administration of the claimed formulation is particularly suitable.

The formulations could conveniently be presented in dosage unit form and could be prepared by but not restricted to any of the methods well known in the art of pharmacy, e.g. as disclosed in <NPL>. All methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier, semisolid carrier or a finely divided solid carrier or combinations of these, and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral and buccal administration could be in the form of discrete units as capsules, sachets, tablets, chewing gum or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder, granules or pellets; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid, such as ethanol or glycerol; or in the form of a gel, a nano- or microemulsion, an oil-in-water emulsion, a water-in-oil emulsion or other dispensing systems. The oils could be edible oils, such as but not restricted to e.g. cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural surfactants and viscosifying agents such as but not restricted to tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomers, polyvinylpyrrolidone, polysorbates, sorbitan fatty acid esters. The active ingredients could also be administered in the form of a bolus, electuary or paste.

A tablet could be made by compressing, moulding or freeze drying the active ingredient optionally with one or more accessory ingredients. Compressed tablets could be prepared by compressing, in a suitable machine, the active ingredient(s) in a free-flowing form such as a powder or granules, optionally mixed by a binder and/or filler, such as e.g. lactose, glucose, mannitol starch, gelatine, acacia gum, tragacanth gum, sodium alginate, calcium phosphates, microcrystalline cellulose, carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol, waxes or the like; a lubricant such as e.g. sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or the like; a disintegrating agent such as e.g. starch, methylcellulose, agar, bentonite, croscarmellose sodium, sodium starch glycollate, crospovidone or the like or a dispersing agent, such as polysorbate <NUM>. Moulded tablets could be made by moulding, in a suitable machine, a mixture of the powdered active ingredient and suitable carrier moistened with an inert liquid diluent. Freeze dried tablets could be formed in a freeze-dryer from a solution of the drug substance. A suitable filler can be included.

Formulations for rectal administration could be in the form of suppositories in which the compound of the present invention is admixed with low melting point, water soluble or insoluble solids such as cocoa butter, hydrogenated vegetable oils, polyethylene glycol or fatty acids esters of polyethylene glycols, while elixirs could be prepared using myristyl palmitate.

Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredients, which is preferably isotonic with the blood of the recipient, e.g. isotonic saline, isotonic glucose solution or buffer solution. Furthermore, the formulation could contain a cosolvent, solubilising agent and/or complexation agents. The formulation could be conveniently sterilised by for instance filtration through a bacteria retaining filter, addition of sterilising agent to the formulation, irradiation of the formulation or heating of the formulation. Liposomal formulations as disclosed in e.g. <NPL>, are also suitable for parenteral administration.

Alternatively, the compounds of the invention could be presented as a sterile, solid preparation, e.g. a freeze-dried powder, which is readily dissolved in a sterile solvent immediately prior to use.

Transdermal formulations could be in the form of a plaster, patch, microneedles, liposomal or nanoparticulate delivery systems or other cutaneous formulations applied to the skin.

Formulations suitable for ophthalmic administration could be in the form of a sterile aqueous preparation of the active ingredients, which could be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems e.g. as disclosed in <NPL>, could also be used to present the active ingredient for ophthalmic administration.

Formulations suitable for topical, such as dermal, intradermal or ophthalmic administration include liquid or semi-solid preparations such as liniments, lotions, gels, applicants, sprays, foams, filmforming systems, microneedles, micro- or nano-emulsions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops. Compositions for ophthalmic treatment could additionally contain cyclodextrin.

For topical administration, the compound of the invention could typically be present in an amount of from <NUM> to <NUM>% by weight of the composition, such as <NUM>% to about <NUM> %, but could also be present in an amount of up to about <NUM>% of the composition.

Formulations suitable for nasal or buccal administration include powder, self-propelling and spray formulations, such as aerosols and atomisers. Such formulations are disclosed in greater detail in e.g. <NPL>; <NPL> and <NPL>.

In addition to the aforementioned ingredients, the formulations of a compound of the invention could include one or more additional ingredients such as diluents, buffers, flavouring agents, colourant, surface active agents, thickeners, penetration enhancing agents, solubility enhancing agents, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.

When the active ingredient is administered in the form of salts with pharmaceutically acceptable non-toxic acids or bases, preferred salts are for instance easily watersoluble or slightly soluble in water, in order to obtain a particular and appropriate rate of absorption.

The pharmaceutical composition could additionally comprise one or more other active components conventionally used in the treatment of dermal disease or conditions, e.g. selected from the group consisting of glucocorticoids, vitamin D and vitamin D analogues, antihistamines, platelet activating factor (PAF) antagonists, anticholinergic agents, methylxanthines, β-adrenergic agents, COX-<NUM> inhibitors, JAK inhibitors, other PDEs, salicylates, indomethacin, flufenamate, naproxen, timegadine, gold salts, penicillamine, serum cholesterol lowering agents, retinoids, zinc salts, salicylazosulfa-pyridine and calcineurin inhibitors.

Deuterated analogues. Any formula given herein is also intended to represent unlabelled forms as well as isotopically labelled forms of the compounds. For example, any hydrogen represented by "H" in any of the formulae herein is intended to represent all isotopic forms of hydrogen, e.g. <NUM>H, <NUM>H or D, <NUM>H. Enrichment with heavier isotopes, particularly deuterium (i.e. <NUM>H or D) could afford certain therapeutic advantages due to for example an increased metabolic skin stability or an increased, systemic, in vivo clearance. Changes that would result in reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the formula (I).

Isotopically-enriched compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Preparations and Examples using any appropriate isotopically enriched reagent in place of the non-enriched reagent previously employed.

As the compounds of the invention could exhibit PDE4 inhibitory activity, the compounds could be useful as therapeutic agents for inflammatory allergic diseases such as bronchial asthma, COPD, allergic rhinitis, and nephritis; autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, Crohn's disease, and systemic lupus erythematosus; acute or chronic cutaneous wound disorders; diseases of the central nervous system such as depression, amnesia, and dementia; organopathy associated with ischemic reflux caused by cardiac failure, shock, and cerebrovascular diseases, and the like; insulin-resistant diabetes; wounds; AIDS, and the like.

In one embodiment, the compounds of the present invention are considered useful for the treatment, prevention or alleviation of dermal diseases or conditions.

In another embodiment, the compounds of the present invention are considered useful for the treatment, prevention or alleviation of dermal diseases or conditions selected from the group consisting of proliferative and inflammatory skin disorders, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, psoriasis, cancer, epidermal inflammation, alopecia, alopecia areata, skin atrophy, steroid induced skin atrophy, skin ageing, photo skin ageing, acne, urticaria, pruritis, and eczema.

In another embodiment, the compounds of the present invention are considered useful for the treatment or alleviation of atopic dermatitis.

In another embodiment, the compounds of the present invention are considered useful for the treatment or alleviation of psoriasis.

In another embodiment, the compounds of the present invention are considered useful for the treatment or alleviation of alopecia areata.

In another embodiment, the compounds of the present invention are considered useful for the treatment or alleviation of acne.

In another embodiment, the compounds of the present invention are considered useful for the treatment or alleviation of pruritis.

In another embodiment, the compounds of the present invention are considered useful for the treatment or alleviation of eczema.

The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of synthesis. The compounds of the invention could for example be prepared using the reactions and techniques outlined below together with methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are carried out in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected. Also, in the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedures, are chosen to be conditions of standard for that reaction, which should be readily recognized by one skilled in the art. Not all compounds falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods can be used.

The compounds of the present invention or any intermediate could be purified if required using standard methods well known to a synthetic organist chemist, e.g. methods described in "<NPL>.

Starting materials are either known or commercially available compounds or can be prepared by routine synthetic methods well known to a person skilled in the art.

<NUM>H nuclear magnetic resonance (NMR) spectra were recorded at <NUM> or <NUM> unless otherwise specified. Chemical shift values (δ, in ppm) are quoted relative to internal tetramethylsilane (δ = <NUM>) standards. The value of a multiplet, either defined doublet (d), triplet (t), quartet (q) or (m) at the approximate midpoint is given unless a range is quoted. (s) indicates a singlet. The organic solvents used were usually anhydrous. Chromatography was performed on Merck silica gel <NUM> (<NUM> - <NUM>-<NUM>). The solvent ratios indicated refer to v:v unless otherwise noted. All NMR spectra are recorded in DMSO-d<NUM> unless another solvent is stated.

Analytical UPLC/MS is performed on a Waters Acquity UPLC-system and SQD-MS. Column: Waters Acquity HSS T3 <NUM>, <NUM> × <NUM>; solvent system: A = <NUM> Ammonium acetate in water + <NUM>% HCOOH and B = acetonitrile + <NUM>% HCOOH; flow rate = <NUM>/min; method (<NUM>): Linear gradient method from <NUM> % B to <NUM> % B over <NUM> minutes then <NUM> % B for <NUM> minutes. Column temperature is <NUM>.

Preparative HPLC/MS was performed on a Waters AutoPurification system with a Waters SQD2 mass spectrometer. This includes three steps, pre-analysis, preparative purification and re-analysis on the purified compound.

Solvent: A = <NUM>% formic acid and solvent B = acetonitrile with <NUM>% formic acid.

Method: Linear gradient method going from <NUM> % B to <NUM> % B in <NUM> minutes and staying at <NUM> % B for another <NUM> minutes to obtain the retention time of the compounds provides the following four different preparative gradient methods:.

<NUM>-<NUM>: <NUM>% B for <NUM> minutes followed by a linear gradient method going from <NUM>% B to <NUM> % B in <NUM> minutes and going to <NUM>% B and staying at <NUM> % B for another <NUM> minutes.

<NUM>-<NUM> min: <NUM>% B for <NUM> minutes followed by a linear gradient method going from <NUM>% B to <NUM>% B in <NUM> minutes and going to <NUM>% B and staying at <NUM>% B for another <NUM> minutes.

<NUM>-<NUM> min: <NUM>% B for <NUM> minutes followed by a linear gradient method going from <NUM>% B to <NUM>% B in <NUM> minutes and going to <NUM>% B and staying at <NUM> % B for another <NUM> minutes.

<NUM>-<NUM> min: <NUM>% B for <NUM> minutes followed by a linear gradient method going from <NUM>% B to <NUM>% B in <NUM> minutes and staying at <NUM>% B for another <NUM> minutes.

The fractions were collected based on ion traces of relevant ions and PDA signal (<NUM>-<NUM>).

Method: Linear gradient method going from <NUM> % B to <NUM> % B in <NUM> minutes and staying at <NUM> % B for another <NUM>.

Solvent: A = <NUM> Ammonium hydrogen carbonate and solvent B = acetonitrile.

A quality check was performed on a Waters LCT Premier MS instrument and a Waters Aquity UPLC.

Column: Waters Aquity UPLC HSS T3 <NUM>, <NUM> × <NUM>, at <NUM>. Solvents: A = <NUM> ammonium acetate + <NUM>% HCOOH, B = MeCN + <NUM>% HCOOH. Flow: <NUM>/min. Injection volume <NUM>µl. UV detection range <NUM> - <NUM>.

The MW confirmation and purity was extracted and checked with OpenLynx.

The following abbreviations have been used throughout:.

Compounds of the invention may be prepared according to the following non-limiting general methods and examples:.

Synthesis of a compound of general formula (I), wherein R<NUM>, R<NUM> and R<NUM> are as previously defined:
<CHM>.

Synthesis of a compound of general formula (II), wherein R<NUM> and R<NUM> are as previously defined:
<CHM>.

Synthesis of a compound of general formula (IIa), wherein R<NUM> and R<NUM> are as previously defined:
<CHM>.

Synthesis of a compound of general formula (II), wherein R<NUM> is hydrogen or methyl and R<NUM> is as previously defined:
<CHM>.

Synthesis of a compound of general formula (IIa) wherein R<NUM> is hydrogen or methyl and R<NUM> is as previously defined:
<CHM>.

DIPEA (<NUM>, <NUM> mmol) and tetrahydropyran-<NUM>-amine (<NUM>, <NUM> mmol) was added to a suspension of <NUM>,<NUM>-dichloro-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidine (<NUM>, <NUM> mmol) in DMF (<NUM>). The mixture was stirred at <NUM> for <NUM> hour before it cooled to room temperature and poured into water (<NUM>). The suspension was then stirred at room temperature for <NUM> minutes. The precipitate was filtered off, washed twice with water (<NUM> × <NUM>) and tert-butyl methyl ether (<NUM> × <NUM>). The solid material was dried under reduced pressure, before it was re-dissolved in a warm toluene:DCM (<NUM>:<NUM>) solution (<NUM>). The mixture was concentrated to approximately <NUM> and left to stand for <NUM> hour at room temperature. The formed precipitate was filtered off, washed with toluene (<NUM>) and dried under reduced pressure. The title compound was obtained as off-white solid material.

<NUM>H NMR (DMSO-d6) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

<NUM>-Chloro-N-tetrahydropyran-<NUM>-yl-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-amine (<NUM>, <NUM> mmol) was dissolved in acetic acid (<NUM>). Hydrogen peroxide (<NUM>% aqueous solution, <NUM>, <NUM> mmol) was added and the solution was stirred at room temperature for <NUM> hour before it was diluted with water (<NUM>) and extracted four times with DCM (<NUM> × <NUM>). The combined organic phases were dried over MgSO<NUM>, filtered and evaporated to dryness under reduced pressure. The obtained solid material was suspended in diethyl ether (<NUM>) and the mixture was stirred at room temperature for <NUM> minutes. The solid material was then filtered off, washed with diethyl ether (<NUM>) and dried. The title compound was obtained as off-white solid material.

<NUM>H NMR (DMSO-d6) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

A tube containing a suspension of <NUM>-chloro-N-tetrahydropyran-<NUM>-yl-<NUM>,<NUM>-dihydrothieno-[<NUM>,<NUM>-d]pyrimidin-<NUM>-amine (<NUM>, <NUM> mmol), (S) (-)-<NUM>,<NUM>'-binaphtol (<NUM>, <NUM> mmol), titanium tetraisopropoxide (<NUM>, <NUM> mmol) and water (<NUM>, <NUM> mmol) in DCM (<NUM>) was flushed with argon and sealed. The mixture was stirred at room temperature for <NUM> hour and then cooled in a water bath before tert-butyl hydroperoxide (<NUM>% aqueous solution, <NUM>, <NUM> mmol) was added. After <NUM> minutes at room temperature the mixture was concentrated in vacuo, dissolved in hot (<NUM>) MeOH (<NUM>), filtered twice through a pad of celite, concentrated to approximately <NUM>. Precipitation was observed. EtOH (<NUM>) was added. The mixture was concentrated in vacuo to approximately <NUM> and left for <NUM> hour. The formed crystals were filtered off, washed twice with EtOH (<NUM> × <NUM>) and dried under reduced pressure. The title compound was obtained as pale yellowish solid.

<NUM>H NMR (DMSO-d6) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). Chiral HPLC analysis: ee > <NUM>%.

The absolute configuration was assigned on the basis of X-ray structure analysis.

A tube containing a suspension of <NUM>-chloro-N-tetrahydropyran-<NUM>-yl-<NUM>,<NUM>-dihydrothieno-[<NUM>,<NUM>-d]pyrimidin-<NUM>-amine (<NUM>, <NUM> mmol), (R) (+)-<NUM>,<NUM>'-binaphtol (<NUM>, <NUM> mmol), titanium tetraisopropoxide (<NUM>, <NUM> mmol) and water (<NUM>, <NUM> mmol) in DCM (<NUM>) was flushed with argon and sealed. The mixture was stirred at room temperature for <NUM> hour and then cooled in a water bath before tert-butyl hydroperoxide (<NUM>% aqueous solution, <NUM>, <NUM> mmol) was added. After <NUM> minutes at room temperature additional tert-butyl hydroperoxide (<NUM>% aqueous solution, <NUM>, <NUM> mmol) was added and the mixture was stirred at room temperature for <NUM> hour before it was concentrated in vacuo, suspended in EtOH (<NUM>), stirred at room temperature for <NUM> minutes. The solid was filtered off, washed twice with EtOH (<NUM> × <NUM>) and dried under reduced pressure. The title compound was obtained as pale yellowish solid.

<NUM>H NMR (DMSO-d6) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

A mixture of (5R)-<NUM>-chloro-<NUM>-oxido-N-tetrahydropyran-<NUM>-yl-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-amine (<NUM>, <NUM> mmol), azetidin-<NUM>-ol hydrochloride (<NUM>, <NUM> mmol) and DIPEA (<NUM>, <NUM> mmol) in DMF (<NUM>) was stirred at room temperature overnight. The formed precipitate was filtered off and washed with MeCN (<NUM>). Freeze drying afforded the title compound as off-white solid material.

<NUM>H NMR (DMSO-d6) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). HPLC-Retention time (XE Metode <NUM>): <NUM> minutes.

A mixture of <NUM>-[(5R)-<NUM>-oxido-<NUM>-(tetrahydropyran-<NUM>-ylamino)-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-yl]azetidin-<NUM>-ol (<NUM>, <NUM> mmol), <NUM>-isothiazolecarboxylic acid (<NUM>, <NUM> mmol), DMAP (<NUM>, <NUM> mmol) and EDAC (<NUM>, <NUM> mmol) in DCM (<NUM>) was shaken in a sealed vial at <NUM> for <NUM> hour. Prep-HPLC purification (acidic) afforded the title compound as off-white solid.

<NUM>H NMR (Chloroform-d) δ: <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (tt, J = <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dtd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (dtd, J = <NUM>, <NUM>, <NUM>, <NUM>).

HPLC-Retention time (XE Metode <NUM>): <NUM> minutes.

A suspension of <NUM>-[(5R)-<NUM>-oxido-<NUM>-(tetrahydropyran-<NUM>-ylamino)-<NUM>,<NUM>-dihydrothieno-[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-yl]azetidin-<NUM>-ol (<NUM>, <NUM> mmol), <NUM>-thiazolecarboxylic acid (<NUM>, <NUM> mmol), DMAP (<NUM>, <NUM> mmol) and EDAC (<NUM>, <NUM> mmol) in DCM (<NUM>) and DMF (<NUM>) was stirred in a sealed vial at room temperature for <NUM> minutes and then for <NUM> minutes at <NUM>. Prep-HPLC purification (acidic) afforded the title compound.

<NUM>H NMR (DMSO-d6) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (tt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

To a suspension of <NUM>,<NUM>-dichloro-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidine (<NUM>, <NUM> mmol) in ethanol (<NUM>) was added DIPEA (<NUM>, <NUM> mmol) and N-methyltetrahydropyran-<NUM>-amine (<NUM>, <NUM> mmol). The pale yellow suspension was stirred at room temperature for <NUM> hours before it was heated to <NUM> for 1½ hour and then left to stir at room temperature overnight. The mixture was concentrated in vacuo. Aqueous sodium chloride solution (<NUM>) was added and mixture was extracted twice with EtOAc (<NUM> × <NUM>). The organic phases was washing with brine (<NUM>), dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. Freeze drying afforded the title compound as pale yellow solid.

<NUM>H NMR (Chloroform-d) δ: <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

<NUM>-Chloro-N-methyl-N-tetrahydropyran-<NUM>-yl-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-amine (<NUM>, <NUM> mmol) was dissolved in acetic acid (<NUM>). Hydrogen peroxide (<NUM>% aqueous solution, <NUM>, <NUM> mmol) was added and the mixture was stirred at room temperature for <NUM> hour. NaI (<NUM>, <NUM> mmol) was added in order to destroy excess hydrogen peroxide before the reaction mixture was evaporated to dryness. Prep-HPLC purification afforded the title compound.

<NUM>H NMR (DMSO-d6) δ: <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

A suspension of (5R)-<NUM>-chloro-<NUM>-oxido-N-tetrahydropyran-<NUM>-yl-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-amine (<NUM>, <NUM> mmol) in MeCN (<NUM>) was under an argon atmosphere cooled in an ice bath. Water (<NUM>, <NUM> mmol), Cs<NUM>CO<NUM> (<NUM>, <NUM> mmol) and methyl iodide (<NUM>, <NUM> mmol) was added. The ice bath was removed and the mixture was stirred over night at room temperature. The crude was poured into a sat. ammonium chloride solution (<NUM>) and extracted with EtOAc (<NUM> x <NUM>). The combined organic phases were washed with brine (<NUM>) and dried over sodium sulfate. Column chromatography (ethyl acetate/heptane <NUM>:<NUM>, Rf = <NUM>) afforded a solid to which an <NUM>:<NUM> mixture of EtOAc/diisopropyl ether (<NUM>) was added. The suspension was stirred for <NUM>. before filtration and washings with <NUM>:<NUM> mixtures of EtOAc/diisopropyl ether gave the title compound.

<NUM>H NMR (CD<NUM>OD) δ: <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

DIPEA (<NUM>, <NUM> mmol) and azetidin-<NUM>-ol hydrochloride (<NUM>, <NUM> mmol) was added to a solution of <NUM>-chloro-N-methyl-<NUM>-oxido-N-tetrahydropyran-<NUM>-yl-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-amine (<NUM>, <NUM> mmol) in DMF (<NUM>). The mixture was stirred at room temperature over night before it was concentrated in vacuo. Prep HPLC purification (basic) afforded the title compound.

<NUM>H NMR (DMSO-d6) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

A mixture of (5R)-<NUM>-chloro-N-methyl-<NUM>-oxido-N-tetrahydropyran-<NUM>-yl-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-amine (<NUM>, <NUM> mmol), azetidin-<NUM>-ol hydrochloride (<NUM>, <NUM> mmol) and Cs<NUM>CO<NUM> (<NUM>, <NUM> mmol) in MeCN (<NUM>) was stirred at room temperature for <NUM> hours. The mixture was filtered and subsequently concentrated in vacuo. The residue was taken up in DCM (<NUM>). The precipitate was filtered off and the filtrate was concentrated in vacuo, giving the crude product. Column chromatography (MeOH/ethyl acetate <NUM>:<NUM>, Rf = <NUM>) afforded the title compound.

<NUM>H NMR (DMSO-d6) δ: <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

To a solution of <NUM>-[<NUM>-[methyl(tetrahydropyran-<NUM>-yl)amino]-<NUM>-oxido-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-yl]azetidin-<NUM>-ol (<NUM>, <NUM>µmol) in DCE (<NUM>) was added solutions of <NUM>-isothiazolecarboxylic acid (<NUM> in <NUM> DCE, <NUM>µmol), DMAP (<NUM> in <NUM> DCE, <NUM>µmol) and EDAC (<NUM> in <NUM> DCE, <NUM>µmol).

The mixture was shaken at <NUM> for <NUM> hour before it was concentrated in vacuo. Prep HPLC purification (acidic) afforded the title compound.

<NUM>H NMR (DMSO-d6) δ: <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). HPLC-Retention time (XE Metode <NUM>): <NUM> minutes.

To a solution of <NUM>-[(5R)-<NUM>-[methyl(tetrahydropyran-<NUM>-yl)amino]-<NUM>-oxido-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-yl]azetidin-<NUM>-ol (<NUM>, <NUM> mmol) in DCM (<NUM>) was added <NUM>-isothiazolecarboxylic acid (<NUM>, <NUM> mmol), DMAP (<NUM>, <NUM> mmol) and EDAC (<NUM>, <NUM> mmol). The mixture was stirred at room temperature overnight before it was concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH gradient <NUM>:<NUM> to <NUM>:<NUM>(Rf = <NUM> (MeOH/DCM <NUM>:<NUM>))) and subsequently crystallized twice from n-butyl acetate. The title compound was obtained as colorless crystalline material.

<NUM>H NMR (DMSO-d6) δ: <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

To a solution of <NUM>-[<NUM>-[methyl(tetrahydropyran-<NUM>-yl)amino]-<NUM>-oxido-<NUM>,<NUM>-dihydrothieno-[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-yl]azetidin-<NUM>-ol (<NUM>, <NUM>µmol) in DCE (<NUM>) was added solutions of <NUM>-thiazolecarboxylic acid (<NUM> in <NUM> DCE, <NUM>µmol), DMAP (<NUM> in <NUM> DCE, <NUM>µmol) and EDAC (<NUM> in <NUM> DCE, <NUM>µmol). The mixture was shaken at <NUM> for <NUM> hour before it was concentrated in vacuo. Prep HPLC purification (acidic) afforded the title compound.

<NUM>H NMR (DMSO-d6) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (tt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

To a solution of <NUM>-[(5R)-<NUM>-[methyl(tetrahydropyran-<NUM>-yl)amino]-<NUM>-oxido-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-yl]azetidin-<NUM>-ol (<NUM>, <NUM>µmol) in DCM (<NUM>) was added <NUM>-thiazolecarboxylic acid (<NUM>, <NUM>µmol), DMAP (<NUM>, <NUM>µmol) and EDAC (<NUM>, <NUM>µmol). The mixture was stirred at room temperature for <NUM> hour before it was concentrated in vacuo. Prep HPLC purification (basic) afforded the title compound.

<NUM>H NMR (DMSO-d6) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (tt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). HPLC-Retention time (XE Metode <NUM>): <NUM> minutes.

A mixture of tetrahydropyran-<NUM>-one (<NUM>, <NUM> mmol), ethylammonium chloride (<NUM>, <NUM> mmol), sodium triacetoxyborohydride (<NUM>, <NUM> mmol) and acetic acid (<NUM>, <NUM> mmol) in DCE (<NUM>) was stirred at room temperature overnight. Saturated aqueous Na<NUM>CO<NUM> (<NUM>) was subsequently added and the aqueous phase was extracted <NUM> times with DCM (<NUM> × <NUM>). The combined organic phases were dried over MgSO<NUM> and filtered. Evaporation to dryness afforded brown oil. <NUM>H NMR (DMSO-d6) δ: <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

A mixture of <NUM>,<NUM>-dichloro-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidine (<NUM>, <NUM> mmol), DIPEA (<NUM>, <NUM> mmol) and N-ethyltetrahydropyran-<NUM>-amine (<NUM>, <NUM> mmol) in DMSO (<NUM>) was shaken in a sealed vial at <NUM> for <NUM> days. Aqueous <NUM> HCl (<NUM>) was added and the mixture was extracted three times with EtOAc (<NUM> × <NUM>). The organic phases was dried over MgSO<NUM> and filtered. Evaporation to dryness afforded brown oil, which was used without further purification in the next step.

<NUM>-Chloro-N-ethyl-N-tetrahydropyran-<NUM>-yl-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-amine (<NUM>, <NUM> mmol) was dissolved in acetic acid (<NUM>). Hydrogen peroxide (<NUM>% aqueous solution, <NUM>, <NUM> mmol) was added and the mixture was stirred at room temperature for <NUM> minutes before it was evaporated to dryness. Water (<NUM>) was added to crude mixture and the aqueous phase was extracted five times with DCM (<NUM> × <NUM>). The organic phases were dried over MgSO<NUM> and filtered. Evaporation to dryness afforded yellow oil, which was used without further purification in the next step.

DIPEA (<NUM>, <NUM> mmol) and azetidin-<NUM>-ol hydrochloride (<NUM>, <NUM> mmol) was added to a solution of <NUM>-chloro-N-ethyl-<NUM>-oxido-N-tetrahydropyran-<NUM>-yl-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-amine (<NUM>, <NUM> mmol) in DMF (<NUM>). The mixture was stirred <NUM> hours at room temperature before it was concentrated in vacuo. Prep HPLC purification (acetic) afforded the title compound as colorless oil.

<NUM>H NMR (DMSO-d6) δ: <NUM> (br. s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br. d, <NUM>), <NUM> (br. d, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

To a solution of <NUM>-[<NUM>-[ethyl(tetrahydropyran-<NUM>-yl)amino]-<NUM>-oxido-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-yl]azetidin-<NUM>-ol (<NUM>, <NUM>µmol) in DCE (<NUM>) was added solutions of <NUM>-isothiazolecarboxylic acid (<NUM> in <NUM> DCE, <NUM>µmol), DMAP (<NUM> in <NUM> DCE, <NUM>µmol) and EDAC (<NUM> in <NUM> DCE, <NUM>µmol). The mixture was shaken at <NUM> for <NUM> minutes before it was concentrated in vacuo. Prep HPLC purification (basic) afforded the title compound as colorless oil.

<NUM>H NMR (DMSO-d6) δ: <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

To a solution of <NUM>-[<NUM>-[ethyl(tetrahydropyran-<NUM>-yl)amino]-<NUM>-oxido-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-yl]azetidin-<NUM>-ol (<NUM>, <NUM>µmol) in DCE (<NUM>) was added solutions of <NUM>-thiazolecarboxylic acid (<NUM> in <NUM> DCE, <NUM>µmol), DMAP (<NUM> in <NUM> DCE, <NUM>µmol) and EDAC (<NUM> in <NUM> DCE, <NUM>µmol). The mixture was shaken at <NUM> for <NUM> minutes before it was concentrated in vacuo. Prep HPLC purification (basic) afforded the title compound as colorless oil.

<NUM>H NMR (DMSO-d6) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

A mixture of tetrahydropyran-<NUM>-one (<NUM>, <NUM> mmol), n-propylammonium chloride (<NUM>, <NUM> mmol), sodium triacetoxyborohydride (<NUM>, <NUM> mmol) and acetic acid (<NUM>, <NUM> mmol) in DCE (<NUM>) was stirred at room temperature overnight. Saturated aqueous Na<NUM>CO<NUM> (<NUM>) was subsequently added and the aqueous phase was extracted <NUM> times with DCM (<NUM> x <NUM>). The combined organic phases were dried over MgSO<NUM> and filtered. Evaporation to dryness afforded brown oil. <NUM>H NMR (DMSO-d6) δ: <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (h, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

To a suspension of <NUM>,<NUM>-dichloro-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidine (<NUM>, <NUM> mmol) in DMSO (<NUM>) was added DIPEA (<NUM>, <NUM> mmol) and N-propyltetra-hydropyran-<NUM>-amine (<NUM>, <NUM> mmol). The pale yellow suspension was shaken for <NUM> hours at <NUM> and then at <NUM> for <NUM> days. Aqueous HCl (<NUM>, <NUM>) was added and mixture was extracted three times with EtOAc (<NUM> × <NUM>). The organic phases was washing with brine (<NUM>), dried over MgSO<NUM>, filtered and evaporated to dryness under reduced pressure. Freeze drying afforded the title compound as brown oil, which was used without further purification in the next step.

<NUM>-Chloro-N-propyl-N-tetrahydropyran-<NUM>-yl-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-amine (<NUM>, <NUM> mmol) was dissolved in acetic acid (<NUM>). Hydrogen peroxide (<NUM>% aqueous solution, <NUM>, <NUM> mmol) was added and the mixture was stirred at room temperature for <NUM> minutes before it was evaporated to dryness. Aqueous NaHCOs (<NUM>) was added to crude mixture and the aqueous phase was extracted three times with DCM (<NUM> × <NUM>). The organic phases were washed with brine (<NUM>), dried over MgSO<NUM> and filtered. Evaporation to dryness afforded clear yellow oil, which was used without further purification in the next step.

DIPEA (<NUM>, <NUM> mmol) and azetidin-<NUM>-ol hydrochloride (<NUM>, <NUM> mmol) was added to a solution of <NUM>-chloro-N-propyl-<NUM>-oxido-N-tetrahydropyran-<NUM>-yl-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-amine (<NUM>, <NUM> mmol) in DMF (<NUM>). The mixture was stirred at room temperature for <NUM> hours before it was concentrated in vacuo. Prep HPLC purification (basic) afforded the title compound.

<NUM>H NMR (DMSO-d6) δ: <NUM> - <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

To a solution of <NUM>-[<NUM>-[propyl(tetrahydropyran-<NUM>-yl)amino]-<NUM>-oxido-<NUM>,<NUM>-dihydro-thieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-yl]azetidin-<NUM>-ol (<NUM>, <NUM>µmol) in DCE (<NUM>) was added solutions of <NUM>-isothiazolecarboxylic acid (<NUM> in <NUM> DCE, <NUM>µmol), DMAP (<NUM> in <NUM> DCE, <NUM>µmol) and EDAC (<NUM> in <NUM> DCE, <NUM>µmol). The mixture was shaken at room temperature overnight before it was concentrated in vacuo. Prep HPLC purification (basic) afforded the title compound as colorless oil.

<NUM>H NMR (DMSO-d6) δ: <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (tt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

To a solution of <NUM>-[<NUM>-[propyl(tetrahydropyran-<NUM>-yl)amino]-<NUM>-oxido-<NUM>,<NUM>-dihydrothieno-[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-yl]azetidin-<NUM>-ol (<NUM>, <NUM>µmol) in DCE (<NUM>) was added solutions of <NUM>-thiazolecarboxylic acid (<NUM> in <NUM> DCE, <NUM>µmol), DMAP (<NUM> in <NUM> DCE, <NUM>µmol) and EDAC (<NUM> in <NUM> DCE, <NUM>µmol). The mixture was shaken at room temperature overnight before it was concentrated in vacuo. Prep HPLC purification (basic) afforded the title compound as colorless oil.

<NUM>H NMR (DMSO-d6) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>). HPLC-Retention time (XE Metode <NUM>): <NUM> minutes.

The human PDE4D catalytic domain (UniProt no. Q08499 [S380-L740]) was incubated with a mixture of non-labelled cAMP (cyclic adenosine monophosphate) and fluorescein amidite (FAM) conjugated cAMP and titrated test or reference compound. Following brief incubation the enzymatic reaction was stopped by addition of binding buffer containing nanoparticles with immobilized trivalent metal ions capable of binding <NUM>) AMP phospho groups and <NUM>) terbium (Tb) donor fluorophores. Subsequent excitation of the Tb donor triggered time-resolved FRET to adjacent FAM acceptor molecules resulting in light emission. In the presence of a PDE4 inhibitor, AMP generation was reduced resulting in a lower fluorescence signal. The cAMP phosphodiester is not bound by the detection system.

Results were expressed as IC<NUM> values (nM) calculated from inhibition curves where the TR-FRET signal was normalized to Tb fluorescence intensity and the negative (DMSO vehicle) and positive (10microM a PDE4 inhibitor reference compound) controls.

Human peripheral blood mononuclear cells (PBMC) were isolated from fresh buffy coats by density centrifugation using lymphoprep tubes (Medinor). Frozen PBMC's were washed in serum free assay buffer (RPMI1640 with <NUM> HEPES, <NUM> % pen/strep, <NUM> L glutamine, <NUM>% human serum albumin) and living cells counted. Lipopolysaccharide (1microg/ml; SIGMA) was added to the cells which were then transferred to <NUM> well tissue culture plates (<NUM> × <NUM><NUM> c/ml) containing titrated test compounds. The cells were incubated for <NUM> hours at <NUM> in serum free assay buffer and the level of TNFalpha in the supernatant was quantitated by AlphaLISA (PerkinElmer) by measuring fluorescence intensity at <NUM>.

Results were expressed as IC<NUM> values calculated from inhibition curves using as controls the secretion in LPS stimulated wells and the secretion in cells incubated with 10microM of a PDE4 inhibitor reference compound.

An alcohol (<NUM>µmol) was dissolved in DCE (<NUM>). A solution of an acid (<NUM> equiv) in DCE (<NUM>) and a solution of DMAP (<NUM> equiv) in DCE (<NUM>) were added. To the resulting mixture was added EDAC (<NUM> equiv). The mixture was shaken at <NUM> for <NUM> hour before it was concentrated in vacuo. The residue was dissolved in DMF (<NUM>) and subjected to preparative LCMS purification, giving an ester.

The Examples <NUM> and <NUM> shown in Table <NUM> were prepared by reacting Compound 003a as described in the General Procedure with the appropriate acid:.

The Examples <NUM> - <NUM> shown in Table <NUM> were prepared by reacting Compound <NUM> as described in the General Procedure (with the exception that the mixture was shaken at <NUM> overnight instead of at <NUM> for <NUM> hour) with the appropriate acid:.

The Examples <NUM> and <NUM> shown in Table <NUM> were prepared by reacting Compound 008a as described in Example <NUM> with the appropriate acid replacing <NUM>-isothiazolecarboxylic acid:.

To a solution of <NUM>,<NUM>-dichloro-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidine (<NUM>, <NUM> mmol) in DMSO (<NUM>) was added DIPEA (<NUM>, <NUM> mmol) and <NUM>-oxaspiro[<NUM>]heptan-<NUM>-amine hydrochloride (<NUM>, <NUM> mmol) was added. The reaction mixture was stirred at rt overnight. Water (<NUM>) was added and the obtained slurry was stirred for <NUM> before filtration and subsequent washings with water afforded the title compound as solid material.

<NUM>H NMR (DMSO-d6) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (h, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

To a suspension of <NUM>-chloro-N-(<NUM>-oxaspiro[<NUM>]heptan-<NUM>-yl)-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-amine (<NUM>, <NUM> mmol) in acetic acid (<NUM>) was added hydrogen peroxide (<NUM>%) (<NUM>, <NUM> mmol). The mixture was stirred at room temperature. Additional hydrogen peroxide (<NUM>%) (<NUM>, <NUM> mmol) was added after <NUM> hours and the mixture was stirred for another hour before it was diluted with water (<NUM>) and extracted twice with DCM (<NUM> × <NUM>). The combined organic phases were concentrated in vacuo and the obtained yellow oil was crystallized from MTBE. Filtration and washings with TBME afforded the title compound as solid material.

<NUM>H NMR (DMSO-d6) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

To a solution of <NUM>-chloro-<NUM>-oxido-N-(<NUM>-oxaspiro[<NUM>]heptan-<NUM>-yl)-<NUM>,<NUM>-dihydrothieno-[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-amine (<NUM>, <NUM> mmol) in DMF (<NUM>) was added azetidin-<NUM>-ol hydrochloride (<NUM>, <NUM> mmol) and DIPEA (<NUM>, <NUM> mmol). The mixture was stirred at room temperature overnight. Water (<NUM>) was added and the pH of the solution was adjusted to <NUM> with acetic acid. Prep-HPLC purification afforded the title compound.

<NUM>H NMR (DMSO-d6) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

The Examples <NUM> - <NUM> shown in Table <NUM> were prepared by reacting Compound <NUM> as described in the General Procedure with the appropriate acid:.

The Examples <NUM> and <NUM> in Table <NUM> were obtained by separating the two enantiomers of the [<NUM>-[<NUM>-(<NUM>-oxaspiro[<NUM>]heptan-<NUM>-ylamino)-<NUM>-oxido-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]-pyrimidin-<NUM>-ium-<NUM>-yl]azetidin-<NUM>-yl] isothiazole-<NUM>-carboxylate racemate using chiral SFC.

The Examples <NUM> and <NUM> in Table <NUM> were obtained by separating the two enantiomers of the [<NUM>-[<NUM>-(<NUM>-oxaspiro[<NUM>]heptan-<NUM>-ylamino)-<NUM>-oxido-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]-pyrimidin-<NUM>-ium-<NUM>-yl]azetidin-<NUM>-yl] thiazole-<NUM>-carboxylate racemate using chiral SFC.

To a solution of <NUM>-[(<NUM>)-<NUM>-aminopyrrolidin-<NUM>-yl]ethanone trifluoroacetic acid (<NUM>, <NUM> mmol) in DMF (<NUM>) was added DIPEA (<NUM>, <NUM> mmol) and <NUM>,<NUM>-dichloro-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidine (<NUM>, <NUM> mmol). The reaction mixture was heated to <NUM> overnight, before it was cooled to room temperature, diluted with water (<NUM>) and extracted three times with DCM (<NUM> × <NUM>). The combined organic phases were washed with water (<NUM>), dried over MgSO<NUM> and filtered. Evaporation to dryness afforded the title compound.

<NUM>H NMR (CDCl<NUM>) δ: <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Hydrogen peroxide (<NUM>%) (<NUM>, <NUM> mmol) was added to a mixture of <NUM>-[(<NUM>)-<NUM>-[(<NUM>-chloro-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-yl)amino]pyrrolidin-<NUM>-yl]ethanone (<NUM>, <NUM> mmol) in acetic acid (<NUM>). The reaction mixture was stirred at room temperature for <NUM> hour before it was diluted with water (<NUM>) and extracted twice with DCM (<NUM> × <NUM>). Evaporation of the combined organic phases afforded the title compound as beige foam.

<NUM>H NMR (DMSO-d6) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

To a solution of <NUM>-[(<NUM>)-<NUM>-[(<NUM>-chloro-<NUM>-oxido-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-yl)amino]pyrrolidin-<NUM>-yl]ethanone (<NUM>, <NUM>µmol) in DMF (<NUM>) was added a solution of azetidin-<NUM>-ol hydrochloride (<NUM>, <NUM>µmol) in DMF (<NUM>) and DIPEA (<NUM>µL, <NUM> mmol). The mixture was shaken at <NUM> overnight. LCMS purification afforded the title compound.

To a solution of <NUM>-[(3R)-<NUM>-aminopyrrolidin-<NUM>-yl]ethanone trifluoroacetic acid (<NUM>, <NUM> mmol) in DMF (<NUM>) was added DIPEA (<NUM>, <NUM> mmol) and <NUM>,<NUM>-dichloro-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidine (<NUM>, <NUM> mmol). The reaction mixture was heated to <NUM> overnight, before it was cooled to room temperature, diluted with water (<NUM>) and extracted three times with DCM (<NUM> × <NUM>). The combined organic phases were washed with water (<NUM>), dried over MgSO<NUM> and filtered. Evaporation to dryness afforded the title compound.

<NUM>H NMR (CDCl<NUM>) δ: <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Hydrogen peroxide (<NUM>%) (<NUM>, <NUM> mmol) was added to a mixture of <NUM>-[(3R)-<NUM>-[(<NUM>-chloro-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-yl)amino]pyrrolidin-<NUM>-yl]ethanone (<NUM>, <NUM> mmol) in acetic acid (<NUM>). The reaction mixture was stirred at room temperature for <NUM> hour before it was diluted with water (<NUM>) and extracted twice with DCM (<NUM> × <NUM>). Evaporation of the combined organic phases afforded the title compound as beige foam.

<NUM>H NMR (DMSO-d6) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

To a solution of <NUM>-[(3R)-<NUM>-[(<NUM>-chloro-<NUM>-oxido-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-yl)amino]pyrrolidin-<NUM>-yl]ethanone (<NUM>, <NUM>µmol) in DMF (<NUM>) was added a solution of azetidin-<NUM>-ol hydrochloride (<NUM>, <NUM>µmol) in DMF (<NUM>) and DIPEA (<NUM>µL, <NUM> mmol). The mixture was shaken at <NUM> overnight. LCMS purification afforded the title compound.

Example <NUM> shown in Table <NUM> was prepared by reacting Compound <NUM> as described in the General Procedure with tetrahydropyran-<NUM>-carboxylic acid:.

To a solution of <NUM>-(<NUM>-amino-<NUM>-piperidyl)ethanone (<NUM>, <NUM> mmol) in DMF (<NUM>) was added DIPEA (<NUM>, <NUM> mmol) and <NUM>,<NUM>-dichloro-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidine (<NUM>, <NUM> mmol). The reaction mixture was heated to <NUM> overnight. The obtained suspension was cooled to room temperature, diluted with water (<NUM>). Filtration and subsequent washings with water (<NUM> × <NUM>) and TBME:heptane (<NUM>:<NUM>) (<NUM> × <NUM>) afforded the title compound as solid material.

<NUM>H NMR (CDCl<NUM>) δ: <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Hydrogen peroxide (<NUM>%) (<NUM>, <NUM> mmol) was added to a mixture of <NUM>-[<NUM>-[(<NUM>-chloro-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-yl)amino]-<NUM>-piperidyl]ethanone (<NUM>, <NUM> mmol) in acetic acid (<NUM>). The reaction mixture was stirred at room temperature for <NUM> hour before it was diluted with water (<NUM>), extracted twice with DCM (<NUM> × <NUM>) and evaporated to dryness. Crystallization from TBME afforded the title compound as crystalline powder.

<NUM>H NMR (DMSO-d6) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dt, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

To a solution of <NUM>-[<NUM>-[(<NUM>-chloro-<NUM>-oxido-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-d]pyrimidin-<NUM>-ium-<NUM>-yl)amino]-<NUM>-piperidyl]ethanone (<NUM>, <NUM>µmol) in DMF (<NUM>) was added a solution of azetidin-<NUM>-ol hydrochloride (<NUM>, <NUM>µmol) in DMF (<NUM>) and DIPEA (<NUM>µL, <NUM> mmol). The mixture was shaken at <NUM> overnight. LCMS purification afforded the title compound.

The Examples <NUM> and <NUM> shown in Table <NUM> were prepared by reacting Compound <NUM> as described in the General Procedure with the appropriate acid:.

Claim 1:
A compound of general formula (I)
<CHM>
wherein R<NUM> is hydrogen or (C<NUM>-C<NUM>)alkyl; and
wherein R<NUM> is selected from the group consisting of tetrahydropyranyl, oxaspiroheptanyl, pyrrolidinyl and piperidinyl; wherein said pyrrolidinyl and piperidinyl are optionally substituted with one or more substituents independently selected from R<NUM>; and
wherein R<NUM> is selected from the group consisting of -C(O)(C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkyl, - S(O)<NUM>RX, -S(O)<NUM>NRaRb, -C(O)O(C<NUM>-C<NUM>)alkyl, -C(O)NRaRb and -(C<NUM>-C<NUM>)alkyl-C(O)NRaRb; and
wherein Ra and Rb are independently selected from the group consisting of hydrogen, (C<NUM>-C<NUM>)alkyl and halo(C<NUM>-C<NUM>)alkyl, or
Ra and Rb may together with the nitrogen atom to which they are attached form a (<NUM>-<NUM>)-membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more (C<NUM>-C<NUM>)alkyl; and
wherein R<NUM> is selected from the group consisting of (C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)cycloalkyl, (C<NUM>-C<NUM>)alkyl(C<NUM>-C<NUM>)cycloalkyl, halo(C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkoxy, (C<NUM>-C<NUM>)alkyl(C<NUM>-C<NUM>)alkoxy, halo(C<NUM>-C<NUM>)alkyloxy, (<NUM>-<NUM>)membered heterocycloalkyl, (C<NUM>-C<NUM>)alkyl(<NUM>-<NUM>)membered heterocycloalkyl, (<NUM>-<NUM>)membered heteroaryl, (C<NUM>-C<NUM>)alkyl(<NUM>-<NUM>)membered heteroaryl, aryl and (C<NUM>-C<NUM>)alkylaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted with one or more substituents independently selected from R<NUM>; and
wherein R<NUM> is selected from the group consisting of halogen, cyano, hydroxyl, (C<NUM>-C<NUM>)-alkyl, halo(C<NUM>-C<NUM>)alkyl, halo(C<NUM>-C<NUM>)alkyloxy, ORx, -SRx, -S(O)<NUM>RX, -S(O)<NUM>NRaRb, -C(O)Rx, - C(O)(ORx), and -C(O)NRaRb; and
wherein Rx is selected from the group consisting of (C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)cycloalkyl, and heterocycloalkyl; and
wherein S* represent a chiral sulphur atom; and
pharmaceutically acceptable salts, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, hydrates and solvates thereof.