FIELD OF THE INVENTION

The present invention relates to fused tricyclic heterocycles as agonists of the stimulator of interferon genes (STING), and preparation methods, pharmaceutical compositions, and medical uses thereof for the treatment of diseases in which modulation of STING is beneficial, for example, cancer, pre-cancerous disorders, hepatitis B virus (HBV), hepatitis C virus (HCV), influenza, human immunodeficiency virus infection, AIDS, inflammation, and infectious diseases, or use as immunogenic composition or vaccine adjuvants.

BACKGROUND OF THE INVENTION

Vertebrates defend against microorganisms or respond to signals from cellular or tissue damage by innate and adaptive immunity. Innate immunity has no antigen specificity and executes the defense mechanisms immediately after an antigen's appearance in the body. Adaptive immunity requires time to generate a full response, but is antigen-specific and long lasting. Once an antigen has been processed and recognized, the adaptive immune system utilizes a set of immune cells specifically designed to attack that antigen. During the course of an adaptive immune response, memory immune cells are generated which allow for a more rapid and effective response to re-exposure to antigens. The innate immune system is required to activate our adaptive immune system. Numerous molecules and cells involved in innate immunity and adaptive immunity function cooperatively (Shanker A. and Marincola F,Cancer Immunol. Immunother.,2011, 60: 1061-1074).

Innate immunity is initiated when the pathogen-associated molecular patterns (PAMPs) present in pathogens are recognized by pattern recognition receptors (PRRs) (Medzhitov, R.J. Immunol.2013, 191, 4473-4474). Some endogenous damage-associated molecular patterns (DAMPs), including various tumor-derived antigens can also be recognized by these PRRs as well (Matzinger, P.,Science2002, 296: 301-305). The free cytosolic DNA from pathogens and abnormal cells can be recognized by DNA sensors. cGAS (cyclic GMP-AMP Synthase) has been shown to be an important DNA sensor and catalyzes free cytosolic DNA into cyclic di-nucleotides (CDN) 2′3′-GAMP (Ng K W, et al,Trends in Immunology,2018, 39: 44-54).

Stimulator of interferon genes (STING; also known as MITA and MPYS, and encoded by TMEM173) is a signaling molecule associated with the endoplasmic reticulum (ER). Upon binding to the cyclic dinucleotides (CDNs) generated by cGAS as well as bacterial cyclic di-AMP (c-di-AMP) or c-di-GMP in the cytosol, STING undergoes a conformational change and forms a complex with TBK1. This complex translocates from the ER to the perinuclear golgi and then phosphorylates IRF3, which dimerizes and enters the nucleus to initiate the transcription of type I IFNs. TBK1 also phosphorylates residues on the protein IκB, leading to its degradation, which causes the activation and translocation of NF-κB to the nucleus and transcription of pro-inflammatory cytokines such as TNFα, IL-6 and IL-1β (Ahn J. and Barber G.,Current Opinion in Immunology2014, 31:121-126). Accumulating evidence indicates that STING-dependent signaling is critical in promoting antitumor immunity. STING deficient mice have decreased tumor rejection observed when compared with wild type mice (Woo S. et al,Immunity,2014, 41:830-842). Activation of STING significantly suppressed the growth of multiple types of mouse tumor (Corrales et al.,Cell Reports,2015, 11:1018-1030).

The antitumor activity mediated by STING is at least partially via type I IFNs (Corrales L. and Gajewski F,Clin. Cancer Res.,2015, 21: 4774-4779). The effect of type I IFNs (IFNα/β) on immune cells has been well established. Upon binding to IFNα/β, the IFNα/β receptor activates a cascade of events and induces the transcription of a wide variety of genes regulated by IFN-stimulated response elements (ISRE), thus modulating multiple types of immune cells. In particular, type I IFNs promote cross-priming, boost effector T cell function and expansion, mediate memory development, thereby coupling innate immunity with adaptive immunity (Zitvogel L. et al,Nature Reviews Immunology,2015, 15: 405-414). Type I IFNs contribute to antitumor immunity in various types of cancer (Parker B. et al.,Nat Rev Cancer,2016, 16:131-144). TNFα may be another important contributor to the therapeutic effect observed with the activation of STING (Francica B. et al.,Cancer Immunol Res.,2018, 6: 1-12).

The patent applications disclosing STING modulators include WO2010017248, WO2013166000, WO2017175147 and WO2017175156.

In summary, STING activation may have significant impact on innate and adaptive immune response and accordingly may have a beneficial impact on the treatment of cancer and other diseases such as viral infection.

SUMMARY OF THE INVENTION

The present invention provides a new class of fused tricyclic heterocycle compounds as represented by formula (I) below useful as STING agonists and as therapeutic agents for the treatment of diseases in which modulation of STING is beneficial, for example, cancer, pre-cancerous disorders, hepatitis B virus (HBV), hepatitis C virus (HCV), influenza, human immunodeficiency virus infection, AIDS, inflammation, and other infectious diseases. These compounds can also be used as immunogenic composition or vaccine adjuvants.

Thus, in one aspect, the present invention provides a compound of formula (I), or a tautomer, or a pharmaceutically acceptable salt, prodrug, or solvate thereof:


wherein:Rais selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, and hydroxyalkyl, wherein the alkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more, preferably one to five, and sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, carboxylic acid, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or Rais



ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

G is O or NRb;

Rbis selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl alkoxy, alkoxyalkyl and haloalkyl; wherein the alkyl, alkenyl, alkynyl, alkoxy or alkoxyalkyl is unsubstituted or substituted with one or more, preferably one to five, and sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, cyano, hydroxy, hydroxyalkyl, carboxylic acid, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Rcis selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl and alkynyl;

R1and R2are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more, preferably one to five, and sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R3and R4are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R5, R6and R7are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;

L1is selected from the group consisting of alkylene, alkenylene, NH, —(CH2)sNH—, —(CH2)sNH(CH2)r—, O, S(O)m, C(O), —C(O)NH—, —NHC(O)—, and —HNC(O)NH—, wherein the alkylene or alkenylene is unsubstituted or substituted with one or more, preferably one to five, and sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, oxo, —C(O)OR18, R19, cycloalkyl, heterocyclyl, aryl and heteroaryl; two substitutes on the same carbon can form a cycloalkyl or heterocyclyl ring; two substitutes on adjacent carbons can form a cycloalkyl, heterocyclyl, aryl and heteroaryl ring;

or L1is absent;

Z is selected from the group consisting of —C(O)O-benzyl, butyloxy carbonyl, hydrogen, halogen, alkyl, alkenyl, alkynyl alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more, preferably one to five, and sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, —NR9R10, oxo, —C(O)OR18, R19, cycloalkyl, heterocyclyl, aryl and heteroaryl;or Z is formula (Za) or a tautomer thereof:



wherein ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

R8at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more, preferably one to five, and sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R9and R10are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, —C(O)O-benzyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R11at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, —C(O)NR14R15, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl or alkoxy is unsubstituted or substituted with one or more, preferably one to five, and sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alkoxy, alkenyl, alkynyl haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, —O—P(O)(OH)2, cycloalkyl, heterocyclyl and NR16R17;

R12is selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl;

R13at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more, preferably one to five, and sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R14and R15are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more, preferably one to five, and sometimes more preferably one to three, substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R16and R17are identical or different, and each is independently selected from hydrogen or alkyl;

or, R16and R17together with the nitrogen atom to which they are attached form a heterocyclyl, wherein the heterocyclyl contains one or two identical or different heteroatoms selected from the group consisting of N, O and S, and the heterocyclyl is optionally substituted by one or more, preferably one to five, and sometimes more preferably one to three, substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy and hydroxyalkyl;

R18is hydrogen or alkyl;

R19is cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more, preferably one to five, and sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl and cyano;

n is 0, 1, 2, 3 or 4;

m is 0, 1 or 2;

s is integer of 1 to 6;

r is 1, 2, 3 or 4;

t is 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4; and

q is 0, 1, 2, 3 or 4.

In another aspect, the present invention provides a pharmaceutical composition, comprising a compound of formula (I), in any embodiment disclosed herein, or a tautomer, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents, or other excipients.

In another aspect, the present invention provides a method of treating a STING-mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), in any embodiment disclosed herein, or a tautomer, a pharmaceutically acceptable salt, solvate, prodrug, or composition thereof,

In another aspect, the present invention provides use of a compound of formula (I), in any embodiment disclosed herein, or a tautomer, a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a medicament for the treatment of a STING-mediated disease or disorder.

The STING-mediated disease or disorder includes, but is not limited to various cancers, a pre-cancerous syndromes, and viral infections, e.g., hepatitis B virus (HBV), hepatitis C virus (HCV), influenza, human immunodeficiency virus infection, AIDS, inflammation, infectious diseases or the like.

Other aspects and benefits of the present invention will be better understood through the detailed description, Examples, and claims.

