# US 11,299,497 B2 · Substituted tetrahydropyran dihydrothienopyrimidines and their use as phosphodiesterase inhibitors

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- Number: US 11,299,497 B2
- Document ID: US11299497B2
- Status: Granted
- Kind: B2
- Application number: 16/772,536
- Filed: 2018-12-14
- Published: 2020-12-10
- Granted: 2022-04-12
- Earliest claimed: 2017-12-15
- Assignees: UNION therapeutics A/S
- Applicants: UNION therapeutics A/S
- Inventors: Jens Larsen; Simon Feldbaek Nielsen; Peter Andersen
- Web page: https://patentgrep.com/patent/US11299497B2

## CPC

- C07D 495/04: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 17/00: Drugs for dermatological disorders
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to novel substituted tetrahydropyran dihydrothienopyrimidines with phosphodiesterase inhibitory activity, and to their use in therapy, and to pharmaceutical compositions comprising the compounds and to methods of treating diseases with the compounds (I).

## Claims

### Claim 1

A compound of general formula (I)
wherein:
R1 is (C1-C4)alkyl; and
R2 is selected from the group consisting of (C1-C4)alkyl, (C3-C6)cycloalkyl, bridged (C3-C6)cycloalkyl, (4-8 membered) heterocycloalkyl, bridged (4-8 membered) heterocycloalkyl, and phenyl; wherein the (C1-C4)alkyl, (C3-C6)cycloalkyl, bridged (C3-C6)cycloalkyl, (4-8 membered) heterocycloalkyl, bridged (4-8 membered) heterocycloalkyl, or phenyl is optionally substituted with one or more substituents independently selected from R3;
R3 is selected from the group consisting of halogen, —CN, —OH, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C6)alkoxy, and halo(C1-C4)alkyloxy; 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.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein R1 is methyl.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein R2 is (C1-C4)alkyl.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein R2 is (C3-C6)cycloalkyl, optionally substituted with one or more substituents independently selected from R3.

### Claim 5 (depends on 1)

A compound according to claim 1 wherein R2 is a (4-6 membered) heterocycloalkyl.

### Claim 6 (depends on 1)

A compound according to claim 1 selected from the group consisting of:
(i) (5R)—N2-methyl-5-oxido-N4-tetrahydropyran-4-yl-N2-(2-tetrahydropyran-4-ylethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-2,4-diamine;
(ii) (5R)—N2-ethyl-5-oxido-N4-tetrahydropyran-4-yl-N2-(2-tetrahydropyran-4-ylethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-2,4-diamine;
(iii) N4-tert-butyl-N2-methyl-5-oxido-N2-(2-tetrahydropyran-4-ylethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-2,4-diamine;
(iv) N2-methyl-5-oxido-N4-propyl-N2-(2-tetrahydropyran-4-ylethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-2,4-diamine;
(v) N4-isopropyl-N2-methyl-5-oxido-N2-(2-tetrahydropyran-4-ylethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-2,4-diamine;
(vi) N4-butyl-N2-methyl-5-oxido-N2-(2-tetrahydropyran-4-ylethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-2,4-diamine;
(vii) N4-isobutyl-N2-methyl-5-oxido-N2-(2-tetrahydropyran-4-ylethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-2,4-diamine;
(viii) N2-methyl-N4-(1-methylcyclobutyl)-5-oxido-N2-(2-tetrahydropyran-4-ylethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-2,4-diamine;
(ix) N4-cyclobutyl-N2-methyl-5-oxido-N2-(2-tetrahydropyran-4-ylethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-2,4-diamine;
(x) 1-[[2-[methyl(2-tetrahydropyran-4-ylethyl)amino]-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-4-yl]amino]cyclobutanecarbonitrile;
(xi) 1-[[2-[methyl(2-tetrahydropyran-4-ylethyl)amino]-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-4-yl]amino]cyclopropanecarbonitrile;
(xii) N2-methyl-N4-[(1S)-1-methylpropyl]-5-oxido-N2-(2-tetrahydropyran-4-ylethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-2,4-diamine;
(xiii) N2-methyl-N4-[(1R)-1-methylpropyl]-5-oxido-N2-(2-tetrahydropyran-4-ylethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-2,4-diamine;
(xiv) N2-methyl-N4-(1-methylcyclopropyl)-5-oxido-N2-(2-tetrahydropyran-4-ylethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-2,4-diamine;
(xv) N2-methyl-N4-(6-oxaspiro[3.3]heptan-2-yl)-5-oxido-N2-(2-tetrahydropyran-4-ylethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-2,4-diamine;
(xvi) N4-(3-methoxyphenyl)-N2-methyl-5-oxido-N2-(2-tetrahydropyran-4-ylethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-2,4-diamine;
(xvii) N4-cyclohexyl-N2-methyl-5-oxido-N2-(2-tetrahydropyran-4-ylethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-2,4-diamine;
(xviii) 2-methyl-2-[[2-[methyl(2-tetrahydropyran-4-ylethyl)amino]-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-4-yl]amino]propan-1-ol;
(xix) N4-ethyl-N2-methyl-5-oxido-N2-(2-tetrahydropyran-4-ylethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-2,4-diamine;
(xx) N4-cyclopentyl-N2-methyl-5-oxido-N2-(2-tetrahydropyran-4-ylethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-2,4-diamine;
(xxi) N2-methyl-N4-(oxetan-3-yl)-5-oxido-N2-(2-tetrahydropyran-4-ylethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-2,4-diamine;
(xxii) [1-[[2-[methyl(2-tetrahydropyran-4-ylethyl)amino]-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-4-yl]amino]cyclopentyl]methanol;
(xxiii) [1-[[2-[methyl(2-tetrahydropyran-4-ylethyl)amino]-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-4-yl]amino]cyclobutyl]methanol;
(xxiv) [1-[[2-[methyl(2-tetrahydropyran-4-ylethyl)amino]-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-4-yl]amino]cyclopropyl]methanol;
or a pharmaceutically acceptable salt, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, hydrate or solvate thereof.

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

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.

### Claim 9 (depends on 1)

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.

### Claim 10 (depends on 9)

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.

### Claim 11 (depends on 7)

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.

### Claim 12 (depends on 11)

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.