BACKGROUND OF THE INVENTION

Field of the Invention

The invention is directed to compounds useful as JAK inhibitors. The invention is also directed to pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat inflammatory and autoimmune diseases.

State of the Art

Inhibition of the family of JAK enzymes inhibits signaling of many key pro-inflammatory cytokines. Based on their mechanism of action, JAK inhibitors are expected to be useful in the treatment inflammatory skin diseases such as atopic dermatitis. Atopic dermatitis (AD) is a common chronic inflammatory skin disease that affects an estimated 14 million people in the United States alone. It is estimated that AD affects 10 to 20% of children and 1 to 3% of adults in developed countries (Bao et al.,JAK-STAT,2013, 2, e24137) and the prevalence is increasing. Elevation of proinflammatory cytokines that rely on the JAK-STAT pathway, in particular, IL-4, IL-5, IL-10, IL-12, IL-13, IFNγ, and TSLP has been associated with AD (Bao et al., Leung et al.,The Journal of Clinical Investigation,2004, 113, 651-657). In addition, upregulation of IL-31, another cytokine that signals through a JAK pairing, has been shown to have a role in the pruritus associated with the chronic state of AD (Sonkoly et al.,Journal of Allergy and Clinical Immunology,2006, 117, 411-417).

Due to the modulating effect of the JAK/STAT pathway on the immune system, systemic exposure to JAK inhibitors may have an adverse systemic immunosuppressive effect. Therefore, it would be desirable to provide a new JAK inhibitor which has its effect at the site of action without significant systemic effects. In particular, for the treatment of inflammatory skin diseases, such as atopic dermatitis, it would be desirable to provide a new JAK inhibitor which can be administered topically and achieve therapeutically relevant exposure in the skin which is rapidly cleared to minimize systemic exposure. There remains a need for JAK inhibitor compounds with the adequate solubility in aqueous and/or organic excipients allowing the development of formulations for topical application.

SUMMARY OF THE INVENTION

In one aspect, the invention provides compounds having activity as JAK inhibitors.

Accordingly, the invention provides a compound of formula (I):

wherein R1is F or H;L is selected from the group consisting of a bond, —CH2O—, —O—, and —OCH2—;R2is selected from the group consisting of oxetane, tetrahydrofuran, tetrahydropyran, and oxepane; each of which is optionally substituted with 1 to 3 Ra;each Rais independently selected from the group consisting of F, CN, OH, C1-4alkyl-OH, C1-4alkoxy and C1-4alkyl wherein the C1-4alkyl is optionally substituted with 1 to 3 fluoro groups;R3is selected from the group consisting of:(a) —S(O)2—C1-4alkyl, wherein C1-4alkyl is optionally substituted with CN or 1 to 3 fluoro groups;(b) —C1-4alkyl-CONRxRy, wherein each of Rxand Ryis independently selected from H and C1-4alkyl, wherein optionally Rxand Rymay be joined to form a 4 to 6 membered heterocyclic group;(c) —C(O)Rb, wherein Rbis C1-4alkyl optionally substituted with C3-6cycloalkyl, C1-4alkoxy or 1 to 3 fluoro groups; and(d) —CO2Rcwherein Rcis selected from(i) C1-4alkyl optionally substituted with C1-4alkoxy, and(ii) 4 to 7 membered heterocyclic group;

or a pharmaceutically-acceptable salt thereof.

The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable carrier.

The invention also provides a compound of formula (I) or a pharmaceutically-acceptable salt thereof for use as a medicament.

The invention also provides a compound of formula (I) or a pharmaceutically-acceptable salt thereof for use in treating a disease in a mammal for which a JAK inhibitor is indicated.

The invention also provides a compound of formula (I) or a pharmaceutically-acceptable salt thereof as described herein for use in treating inflammatory and autoimmune diseases or disorders.

The invention also provides a method of treating a disease in a mammal for which a JAK inhibitor is indicated, the method comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, to the mammal.

The invention also provides a method of treating inflammatory and autoimmune diseases of the skin, in particular atopic dermatitis and alopecia areata, in a mammal, the method comprising administering compound (I), or a pharmaceutically acceptable salt thereof, to the mammal.

