Substituted azetidine dihydrothienopyrimidines and their use as phosphodiesterase inhibitors

1. A compound of general formula (I)

wherein:

R 1 is selected from the group consisting of phenyl, 6-membered heteroaryl, phenoxy, and 6: membered heteroaryloxy; wherein the phenyl, 6-membered heteroaryl, phenoxy, or 6-membered heteroaryloxy is optionally substituted with one or more substituents independently selected from R 3 ;

R 2 is selected from the group consisting of (C 3 -C 7 )cycloalkyl, bridged (C 3 -C 7 )cycloalkyl, and (4-7 membered) heterocycloalkyl; wherein the (C 3 -C 7 )cycloalkyl, bridged (C 3 -C 7 )cycloalkyl, or (4-7 membered) heterocycloalkyl is optionally substituted with one or more substituents independently selected from R 4 ;

R 3 is selected from the group consisting of fluoro, —CN, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, and (C 3 -C 6 )cycloalkyl;

R 4 is selected from the group consisting of fluoro, —CN, —OH, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, —OR x , —S(O) 2 R x , —S(O) 2 NR a R b , —C(O)R x , —C(O)(OR x ), and —C(O)NR a R b ;

R x is selected from the group consisting of (C 1 -C 4 )alkyl and (C 3 -C 6 )cycloalkyl;

R a and R b are each independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl and (C 3 -C 6 )cycloalkyl; and

S* is a chiral sulfur atom with (R) stereochemistry;

or a pharmaceutically acceptable salt, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, hydrate or solvate thereof.

2. A compound according to claim 1 wherein R 1 is selected from the group consisting of phenyl, pyridinyl, pyridyloxy, and phenoxy; wherein the phenyl, pyridinyl, pyridyloxy, or phenoxy is optionally substituted with one or more substituents independently selected from R 3 .

3. A compound according to claim 1 , wherein R 2 is selected from the group consisting of tetrahydropyranyl, piperidinyl, pyrrolidinyl, dioxothietanyl, dioxothianyl, cyclobutyl, and bicyclo[1.1.1]-pentyl; wherein tetrahydropyranyl, piperidinyl, pyrrolidinyl, dioxothietanyl, dioxothianyl, cyclobutyl, or bicyclo[1.1.1]-pentyl is optionally substituted with one or more substituents independently selected from R 4 .

4. A compound according to claim 1 , wherein R 3 is fluoro or (C 1 -C 4 )alkyl.

5. A compound according to claim 1 , wherein R 4 is (C 1 -C 4 )alkyl or —C(O)(OR x ); and R x is (C 1 -C 4 )alkyl.

6. A compound according to any one of the preceding claim 1 selected from the group consisting of:

(i) (R)-2-(3-Phenylazetidin-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide,

(ii) (R)-2-(3-Phenoxyazetidin-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide,

(iii) (R)-2-(3-(4-Fluorophenoxy)azetidin-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide,

(iv) (R)-3-((5-Oxido-2-(3-phenylazetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)thietane 1,1-dioxide,

(v) Methyl (3S)-3-(((5R)-5-oxido-2-(3-phenylazetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)pyrrolidine-1-carboxylate,

(vi) Methyl (3R)-3-(((5R)-5-Oxido-2-(3-phenylazetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)pyrrolidine-1-carboxylate,

(vii) Methyl (3R)-3-(((5R)-2-(3-(4-Fluorophenoxy)azetidin-1-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate,

(viii) Methyl (3S)-3-(((5R)-2-(3-(4-Fluorophenoxy)azetidin-1-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate,

(ix) (R)-4-(Bicyclo[1.1.1]pentan-1-ylamino)-2-(3-(4-fluorophenyl)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide,

(x) (R)-4-(Bicyclo[1.1.1]pentan-1-ylamino)-2-(3-(4-fluorophenoxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide,

(xi) (R)-4-(Bicyclo[1.1.1]pentan-1-ylamino)-2-(3-phenylazetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide,

(xii) (R)-4-(Bicyclo[1.1.1]pentan-1-ylamino)-2-(3-(pyridin-2-yl)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide,

(xiii) (R)-4-(Bicyclo[1.1.1]pentan-1-ylamino)-2-(3-(3-fluorophenyl)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide,

(xiv) (R)-4-(Bicyclo[1.1.1]pentan-1-ylamino)-2-(3-(pyridin-3-yloxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide,

(xv) (R)-4-((1-Methylcyclobutyl)amino)-2-(3-(pyridin-2-yl)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide,

(xvi) (R)-4-((1-Methylcyclobutyl)amino)-2-(3-(pyridin-3-yl)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide, and

(xvii)(5R)—N-(1,1-Dioxothian-4-yl)-5-oxido-2-(3-phenylazetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl-amine,

or a pharmaceutically acceptable salt, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, hydrate and solvate thereof.

7. A pharmaceutical composition comprising a compound according to 1 and one or more pharmaceutically acceptable vehicles, excipients, or carriers.

8. A method for treatment or alleviation of a disease or a disorder or a condition responsive to PDE4 inhibitory activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 .

9. A method of treating or ameliorating one or more dermal diseases, disorders, or conditions, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 .

10. The method according to claim 9 , wherein the dermal disease, disorder, or condition is selected from the group consisting of proliferative and inflammatory skin disorders, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, hand dermatitis, psoriasis, psoriasis vulgaris, inverse psoriasis, psoriatic arthritis, spondyloarthritis, epidermal inflammation, alopecia, alopecia areata, rosacea, skin atrophy, steroid induced skin atrophy, photo skin ageing, SAPHO syndrome, acne vulgaris, hidradenitis suppurativa, urticaria, pruritis, and eczema.

11. A method of treating or ameliorating one or more dermal diseases, disorders, or conditions, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 7 .

12. The method according to claim 11 , wherein the dermal disease, disorder, or condition is selected from the group consisting of proliferative and inflammatory skin disorders, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, hand dermatitis, psoriasis, psoriasis vulgaris, inverse psoriasis, psoriatic arthritis, spondyloarthritis, epidermal inflammation, alopecia, alopecia areata, rosacea, skin atrophy, steroid induced skin atrophy, photo skin ageing, SAPHO syndrome, acne vulgaris, hidradenitis suppurativa, urticaria, pruritis, and eczema.