The present invention is directed to compounds of the formula wherein all substituents are defined herein, as well as pharmaceutically acceptable compositions comprising compounds of the invention and methods of using said compositions in the treatment of various disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 62/846,830, filed May 13, 2019, the disclosure of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] The invention provides novel compounds, pharmaceutical compositions comprising the compounds, and methods of using them, for example, for the treatment or prophylaxis of certain cancers and to their use in therapy.

BACKGROUND OF THE INVENTION

[0003] RORgamma t (RORgt, RORyt) is a key lineage-defining transcription factor involved in the differentiation of naive T cells to Th17 and Tc17 cells. IL-17 is a signature cytokine of RORgt transactivation (Ivanov et al; Cell 2006, 126, 1121).

[0004] High IL-17 levels have been associated with various autoimmune diseases. Consequently, several groups have identified RORgt inverse agonists to decrease IL-17 production aimed at suppressing immunity to treat various autoimmune diseases, most notably psoriasis (Bronner et al. Expert Opin. Ther. Pat. 2017, 27, 1, 101)

[0005] More recently RORgt agonism has been reported to increase the production of antitumor cytokines and chemokines (such as IL-17A and GM-CSF), as well as augment the expression of co-stimulatory receptors (such as CD137 and CD226) and decrease the levels of co-inhibitory receptors (such as PD1 and TIGIT) (Hu et al. Oncoimmunology, 2016, 5, 12, e1254854). High levels of Th17 cells or IL-17 has been associated with patient survival in certain cancers (Kryczek et al. Blood 2009, 114, 1141; Sfanos et al. Clin. Can. Res. 2008, 14, 3254). Therefore RORgt agonism has the potential to boost immune response to tumors and thus confer durable antitumor response. A recent review (Qiu et al J. Med. Chem. 2018, 61, 5794) summarizes the progress by various research groups towards the identification of RORgt agonists.

[0006] The present invention, therefore, provides novel cyclic dinucleotides which may be useful for the treatment of cancer.

SUMMARY OF THE INVENTION

[0007] There is provided a compound of formula (I)

##STR00001##

wherein all substituents are defined herein.

[0008] In another aspect, there is provided a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0009] In another aspect, there is provided a method of treating cancer which comprises administering to a subject in need thereof a therapeutically effective amount of an agonist of RORγ.