Inhibitors of CGAS and uses thereof

Abstract

Compounds for inhibiting cGAS having the following structure (I) and methods of use thereof.

Description

Docket: 93597 / 7203 92154-A-PCT INHIBITORS OF cGAS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Provisional Application No. 63 / 601,333, filed November21, 2023, the contents of which are hereby incorporated by reference.

[0002] Throughout this application, various publications are referenced, including referenced inparenthesis. The disclosures of all publications mentioned in this application in their entireties are hereby incorporated by reference into this application in order to provide additional description of the art to which this invention pertains and of the features in the art which can be employed with this invention.

[0003] The entire content of U.S. Publication No. US 2021 / 01155625 and US 2022 / 0185812 are herebyincorporated by reference. BACKGROUND OF THE INVENTION

[0004] Tumors characterized by high levels of chromosomal instability (CIN) are associated with poorersurvival across diverse cancer types and are resistant to an array of cancer treatment modalities, particularly novel immunotherapies, however mechanisms of resistance remain to be elucidated.

[0005] A well-established consequence of CIN is the formation of micronuclei (MN) which harborexcessive dsDNA. These MN are highly rupture-prone, releasing dsDNA to the cytosol where it is sensed and activates cGAS, which converts dsDNA to cGAMP. cGAMP binds to STING which subsequently triggers a cascade resulting in production of type I interferons (IFNs) that are strong activators of adaptive anti-viral and anti-tumor immunity.

[0006] This represents a long-standing biological conundrum: if CINhigh tumors activate the cGAS-STING pathway, one would expect improved anti-tumor immunity, yet the opposite is true, and is exemplified by inherent resistance to ICB in CINhightumor types such as LKB1-deficient non-small cell lung cancer (NSCLC). Mechanistically, it has been previously shown that chromosomally unstable tumors re-wire downstream STING signaling to i) enact pro-metastatic signaling through activation of non- canonical NF-kB activation and ii) form an immunosuppressive microenvironment through the degradation of exported cGAMP to adenosine in the tumor microenvironment. BRIEF SUMMARY OF THE INVENTION

[0007] The present invention provides compound having the following structure:1 4861-1118-9745v.1wherein n is 1 or 2; R1 is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, CH2CH2OR3, or fluoro (C1-C6)alkyl; R3 is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; R5 is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, fluoro(C1- C6)alkyl, fluoro(C1-C6)alkoxy, or cyano; R6 is hydrogen, halogen, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or fluoro (C1- C6)alkyl; R7 is hydrogen, halogen, (C1-C6)alkoxy, fluoro(C1-C6)alkoxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or fluoro(C1-C6)alkyl; R8 and R9 are hydrogen, halogen, or (C1-C6)alkyl; R10 is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; wherein when n is 1: R2 is H, or a substituted or unsubstituted amino acid ester or α-hydroxy ester; R4 is a cyclic group substituted with one or more amines, or substituted with amino acids via the α-N wherein (i) when R2 is H, R4 is a cyclic group substituted with one or more amino acids viathe α-N; and (ii) when R2 is a substituted or unsubstituted amino acid ester or α-hydroxy ester, R4is a cyclic group substituted with one or more amines, or substituted with amino acids via the α-N; wherein when n is 2: R2is a substituted or unsubstituted amino acid ester or α-hydroxy ester, hydrogen, (C1- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or CH2CH2OR11, or a 4- to 6-membered aliphatic ring containing an O; R11is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; 2 4861-1118-9745v.1R4is hydrogen, halogen, (C1-C6)alkoxy, cyano, amino, an optionally substituted (C1- C6)alkyl, optionally substituted mono- or bicyclic heterocycle, optionally substituted phenyl,, optionally substituted benzyl, (C1-C6) acylamino, or (C1-C6)N-alkyl carboxamido, wherein the optionally substituted alkyl, mono- or bicylclic heterocyle, phenyl, or benzyl groups are optionally substituted with amino, (C1-C6)mono- or dialkylamino, (C1- C6)alkoxy, or heterocyclic groups or a pharmaceutically acceptable salt or a pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0008] The present invention provides a compound having the following structure:whereinY is -CH2- or -CH2-CH2-; preferably, Y is -CH2-; R1 is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, CH2CH2OR3, or fluoro (C1-C6)alkyl; wherein when Y is -CH2-; R2 is a substituted or unsubstituted amino acid; wherein when Y is -CH2-CH2-; R2 is a substituted or unsubstituted amino acid, hydrogen, (C1- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or CH2CH2 OR3, or, taken together along with the atoms to which they are attached, R2and R3may form a 4-to 6-membered aliphatic ring; R3is hydrogen, halogen, (C1-C6)alkyl; (C2-C6)alkenyl, or (C2-C6)alkynyl; R4is hydrogen, halogen, (C1-C6)alkoxy, optionally substituted monocyclic heterocyclyl, cyano, optionally substituted phenyl, optionally substituted bicyclic heterocyclyl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1- C6)alkyl, (C1-C6)dialkylamino (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)hydrocarbyl, heterocyclyl(C1-C6)alkyl, benzyl, heterocyclyl-substituted benzyl, (C1-C6) alkylaminocarbonyl, or (C1- C6)acylamino; R5is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl; (C1-C6)alkoxy, fluoro(C1-C6)alkyl, fluoro(C1-C6)alkoxy, or cyano; 3 4861-1118-9745v.1R6is hydrogen, halogen, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl; or fluoro (C1-C6)alkyl; R7is hydrogen, halogen, (C1-C6)alkoxy, fluoro(C1-C6)alkoxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl; or fluoro(C1-C6)alkyl; R8is hydrogen, halogen, or (C1-C6)alkyl, or, taken together with the carbon to which they are attached, R8and R9may form a 3- to 5-membered aliphatic carbocyclic ring; R9is hydrogen, halogen, or (C1-C6)alkyl, or, taken together with the carbon to which they are attached, R8and R9may form a 3- to 5-membered aliphatic carbocyclic ring; R10is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl, or, taken together along with the atoms to which they are attached, wherein (a) when R2 is (C1-C6)alkyl, not all of R4, R5, R6, and R7 can be hydrogen; (b) when R1 is hydrogen, R2 is methyl and R5 is halogen, R7 cannot be H or chloro; and (c) when R2 is (C1-C6)alkyl, and R5is methoxy or carboxy, R7cannot be H; or a pharmaceutically acceptable salt of the compound.

[0009] A prodrug or a pharmaceutically acceptable salt having the following:n is 1 or 2, preferably n is 1; R1 is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, CH2CH2OR3, or fluoro (C1-C6)alkyl; wherein when n is 1, R2 is a substituted or unsubstituted amino acid ester or α-hydroxy ester; wherein when n is 2, R2 is a substituted or unsubstituted amino acid ester or α-hydroxy ester, hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or CH2CH2OR3, or, a 4- to 6-membered aliphatic ring containing an O; R3 is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; R4is hydrogen, halogen, (C1-C6)alkoxy, cyano, amino, an optionally substituted mono- or bicyclic heterocycle, optionally substituted (C1-C6)alkyl, optionally substituted phenyl, optionally substituted benzyl, (C1-C6) acylamino, or (C1-C6)N-alkylcarboxamido, 4 4861-1118-9745v.1wherein the alkyl, mono- or bicyclic heterocycle, phenyl, or benzyl groups are optionally substituted with amino, (C1-C6)mono- or dialkylamino, (C1-C6)alkoxy, heterocyclic groups R5is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, fluoro(C1-C6)alkyl, fluoro(C1-C6)alkoxy, or cyano; R6is hydrogen, halogen, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or fluoro (C1-C6)alkyl; R7is hydrogen, halogen, (C1-C6)alkoxy, fluoro(C1-C6)alkoxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, or fluoro(C1-C6)alkyl; R8 and R9 are hydrogen, halogen, or (C1-C6)alkyl, or, taken together with the carbon to which they are attached, R8 and R9 may form a 3- to 5-membered aliphatic carbocycle; R10 is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl, or a pharmaceutically acceptable salt of the compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1A is a general structure of the compound disclosed in the present invention.

[0012] Figure 1B is a specific structure of the compound disclosed in the present invention in salt form.

[0013] Figure 1C is compound G150.DETAILED DESCRIPTION OF THE INVENTION

[0014] Through genetically-mediated knockout of cGAS in CINhigh models, present invention restoredsensitivity to ICB and restoration of pro-inflammatory signaling downstream of STING activation in chromosomally unstable tumor models, thus restoring protypical STING activation outputs even in CINhighmodels.

[0015] Thus, the present invention(s) are a set of chemically modified small-molecule inhibitorsof cGAS. These inhibitors will improve aqueous solubility, cell permeability, and / or oral bioavailability through the addition of polar groups at R’ and R’’ position (See Figure 1A). A prodrug coupling with alanine at the amino group at the 2-position of the pyridine ring permits the amide bond of the prodrug to be hydrolyzed by an aminopeptidase while having improved solubility.

[0016] The present invention provides compound having the following structure:5 4861-1118-9745v.1wherein n is 1 or 2; R1 is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, CH2CH2OR3, or fluoro (C1-C6)alkyl; R3 is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; R5 is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, fluoro(C1- C6)alkyl, fluoro(C1-C6)alkoxy, or cyano; R6 is hydrogen, halogen, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or fluoro (C1- C6)alkyl; R7 is hydrogen, halogen, (C1-C6)alkoxy, fluoro(C1-C6)alkoxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or fluoro(C1-C6)alkyl; R8 and R9 are hydrogen, halogen, or (C1-C6)alkyl; R10 is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; wherein when n is 1: R2 is H, or a substituted or unsubstituted amino acid ester or α-hydroxy ester; R4 is a cyclic group substituted with one or more amines, or substituted with amino acids via the α-N wherein (i) when R2 is H, R4 is a cyclic group substituted with one or more amino acids viathe α-N; and (ii) when R2 is a substituted or unsubstituted amino acid ester or α-hydroxy ester, R4is a cyclic group substituted with one or more amines, or substituted with amino acids via the α-N; wherein when n is 2: R2is a substituted or unsubstituted amino acid ester or α-hydroxy ester, hydrogen, (C1- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or CH2CH2OR11, or a 4- to 6-membered aliphatic ring containing an O; R11is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; 6 4861-1118-9745v.1R4is hydrogen, halogen, (C1-C6)alkoxy, cyano, amino, an optionally substituted (C1- C6)alkyl, optionally substituted mono- or bicyclic heterocycle, optionally substituted phenyl,, optionally substituted benzyl, (C1-C6) acylamino, or (C1-C6)N-alkyl carboxamido, wherein the optionally substituted alkyl, mono- or bicylclic heterocyle, phenyl, or benzyl groups are optionally substituted with amino, (C1-C6)mono- or dialkylamino, (C1- C6)alkoxy, or heterocyclic groups or a pharmaceutically acceptable salt or a pharmaceutically acceptable salt hydrate or deuterated analog thereof.

[0017] The present invention provides a compoundhaving the following structure: whereinY is -CH2- or -CH2-CH2-; preferably, Y is -CH2-; R1 is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, CH2CH2OR3, or fluoro (C1-C6)alkyl; wherein when Y is -CH2-; R2 is a substituted or unsubstituted amino acid; wherein when Y is -CH2-CH2-; R2 is a substituted or unsubstituted amino acid, hydrogen, (C1- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or CH2CH2 OR3, or, taken together along with the atoms to which they are attached, R2and R3may form a 4-to 6-membered aliphatic ring; R3is hydrogen, halogen, (C1-C6)alkyl; (C2-C6)alkenyl, or (C2-C6)alkynyl; R4is hydrogen, halogen, (C1-C6)alkoxy, optionally substituted monocyclic heterocyclyl, cyano, optionally substituted phenyl, optionally substituted bicyclic heterocyclyl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1- C6)alkyl, (C1-C6)dialkylamino (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)hydrocarbyl, heterocyclyl(C1-C6)alkyl, benzyl, heterocyclyl-substituted benzyl, (C1-C6) alkylaminocarbonyl, or (C1- C6)acylamino; R5is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl; (C1-C6)alkoxy, fluoro(C1-C6)alkyl, fluoro(C1-C6)alkoxy, or cyano; 7 4861-1118-9745v.1R6is hydrogen, halogen, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl; or fluoro (C1-C6)alkyl; R7is hydrogen, halogen, (C1-C6)alkoxy, fluoro(C1-C6)alkoxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl; or fluoro(C1-C6)alkyl; R8is hydrogen, halogen, or (C1-C6)alkyl, or, taken together with the carbon to which they are attached, R8and R9may form a 3- to 5-membered aliphatic carbocyclic ring; R9is hydrogen, halogen, or (C1-C6)alkyl, or, taken together with the carbon to which they are attached, R8and R9may form a 3- to 5-membered aliphatic carbocyclic ring; R10is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl, or, taken together along with the atoms to which they are attached, wherein (a) when R2 is (C1-C6)alkyl, not all of R4, R5, R6, and R7 can be hydrogen; (b) when R1 is hydrogen, R2 is methyl and R5 is halogen, R7 cannot be H or chloro; and (c) when R2 is (C1-C6)alkyl, and R5is methoxy or carboxy, R7cannot be H; or a pharmaceutically acceptable salt of the compound.

[0018] In some embodiments, R1 is hydrogen or (C1-C6)alkyl; preferably R1 is hydrogen.

[0019] In some embodiments, R2 is a substituted amino acid.

[0020] In some embodiments, the substituted amino acid is substituted with amino, (C1-C6)alkylamino,meta-( C1-C6)dialkylamino, (C1-C6) alkoxy, hydroxy, halogen, ortho-cyano, meta-cyano, aminocarbonyl, methylenedioxy, ethylenedioxy, (C1-C6)acylamino, fluoro(C1-C6)acylamino, and hydroxy (C1- C6)alkylaminosulfonyl.

[0021] In some embodiments, R2 is unsubstituted amino acid.

[0022] In some embodiments, R2 is alanine.

[0023] In some .

[0024] In someor (C1-C6)alkyl.

[0025] In some embodiments, R3 is hydrogen.

[0026] In some embodiments, R4 is optionally substituted monocyclic heterocyclyl, optionallysubstituted phenyl or optionally substituted bicyclic heterocyclyl. 8 4861-1118-9745v.1

[0027] In some embodiments, wherein when n is 1, R2 is an unsubstituted or α-substituted aminoacid ester or α-hydroxy ester, preferably the amino acid or α-hydroxy ester is substituted with amino, (C1-C6)alkylamino, (C1-C6)alkoxy, hydroxy, halogen, carboxyamido, methylenedioxy, ethylenedioxy, (C1-C6)acylamino, fluoro(C1-C6)acylamino, and hydroxy (C1- C6)alkylaminosulfonyl.

[0028] In some embodiments wherein when n is 1, R2 is an amino acid ester or α-hydroxy esteroptionally unsubstituted or substituted on the α-heteroatom with an amino acid residue, α-hydroxy ester, α-(C1-C6)alkoxy ester (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, amino(C1-C6)alkyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, phenyl, benzyl, preferably R2 is alanine.

[0029] In some embodiments, said optionally substituted monocyclic heterocyclyl may be substitutedwith one or more substituents chosen from: an amino acid, (C1-C6)alkyl, amino, cyano, (C1-C6)alkylamino, (C1-C6)alkoxy, oxo, fluoro (C1-C6)alkyl, halogen, hydroxy, and hydroxy(C1-C6)alkyl.

[0030] In some embodiments, said optionally substituted phenyl may be substituted with one or moresubstituents chosen from: an amino acid, amino, (C1-C6)alkylamino, meta-( C1-C6)dialkylamino, (C1-C6) alkoxy, hydroxy, halogen, ortho-cyano, meta-cyano, aminocarbonyl, methylenedioxy, ethylenedioxy, (C1- C6)acylamino, fluoro(C1-C6)acylamino, and hydroxy (C1-C6)alkylaminosulfonyl.

[0031] In some embodiments, said optionally substituted bicyclic heterocyclyl may be substituted withone or more substituents chosen from: an amino acid, (C1-C6)alkyl, hydroxy, and oxo; R5 is chosen from hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, fluoro(C1-C6)alkyl, fluoro(C1-C6)alkoxy, cyano.

[0032] In some embodiments, R4 is substituted monocyclic heterocyclyl substituted with an amino acid,(C1-C3)alkyl, or amino group.

[0033] In some embodiments, the said optionally substituted monocyclic heterocyclyl is substituted withan amino acid or amino group.

[0034] In some embodiments, the amino acid is alanine.

[0035] In some embodiments, R4 has the following structure:, wherein X is C or N, wherein R’ is an

[0036] In some embodiments, the amino acid is alanine.9 4861-1118-9745v.1

[0037] In some embodiments, X is C.

[0038] In some .

[0039] In some(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl.

[0040] In some embodiments, R5 is hydrogen, halogen, or (C1-C6)alkyl.

[0041] In some embodiments, R5 is hydrogen.

[0042] In some embodiments, R6 is hydrogen, halogen, cyano, or (C1-C6)alkyl.

[0043] In some embodiments, R6 is hydrogen, halogen, or (C1-C6)alkyl.

[0044] In some embodiments, R6 is halogen, methyl, or trifluoromethyl.

[0045] In some embodiments, R6 is halogen.

[0046] In some embodiments, R6 is Cl.

[0047] In some embodiments, R7 is hydrogen, halogen, cyano, or (C1-C6)alkyl.

[0048] In some embodiments, R7 is hydrogen, halogen, or (C1-C6)alkyl.

[0049] In some embodiments, R7 is halogen.

[0050] In some embodiments, R7 is Cl.

[0051] In some embodiments, R8 is hydrogen or (C1-C6)alkyl.

[0052] In some embodiments, R8 is hydrogen.

[0053] In some embodiments, R9 is hydrogen or (C1-C6)alkyl.

[0054] In some embodiments, R9 is hydrogen.

[0055] In some embodiments, R10 is hydrogen or halogen.

[0056] In some embodiments, R10 is hydrogen.

[0057] The present invention provides a compound having the following structure:10 4861-1118-9745v.1.

[0058] The present inventio eutically acceptable salt having thefollowing: whereinY is -CH2- or -CH2-CH2-; preferably, Y is -CH2-; R1is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, CH2CH2OR3, or fluoro (C1-C6)alkyl; wherein when Y is -CH2-; R2is a substituted or unsubstituted amino acid; wherein when Y is -CH2-CH2-; R2is a substituted or unsubstituted amino acid, hydrogen, (C1- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or CH2CH2OR3, or, taken together along with the atoms to which they are attached, R2and R3may form a 4-to 6-membered aliphatic ring; R3is hydrogen, halogen, (C1-C6)alkyl; (C2-C6)alkenyl, or (C2-C6)alkynyl; R4is hydrogen, halogen, (C1-C6)alkoxy, optionally substituted monocyclic heterocyclyl, cyano, optionally substituted phenyl, optionally substituted bicyclic heterocyclyl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1- C6)alkyl, (C1-C6)dialkylamino (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)hydrocarbyl, heterocyclyl(C1-C6)alkyl, benzyl, heterocyclyl-substituted benzyl, (C1-C6) alkylaminocarbonyl, or (C1- C6)acylamino; R5is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl; (C1-C6)alkoxy, fluoro(C1-C6)alkyl, fluoro(C1-C6)alkoxy, or cyano; R6is hydrogen, halogen, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl; or fluoro (C1-C6)alkyl; R7is hydrogen, halogen, (C1-C6)alkoxy, fluoro(C1-C6)alkoxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl; or fluoro(C1-C6)alkyl; R8 is hydrogen, halogen, or (C1-C6)alkyl, or, taken together with the carbon to which they are attached, R8 and R9 may form a 3- to 5-membered aliphatic carbocyclic ring; 11 4861-1118-9745v.1R9is hydrogen, halogen, or (C1-C6)alkyl, or, taken together with the carbon to which they are attached, R8and R9may form a 3- to 5-membered aliphatic carbocyclic ring; R10is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl, or, taken together along with the atoms to which they are attached, wherein (a) when R2is (C1-C6)alkyl, not all of R4, R5, R6, and R7can be hydrogen; (b) when R1is hydrogen, R2is methyl and R5is halogen, R7cannot be H or chloro; and (c) when R2 is (C1-C6)alkyl, and R5is methoxy or carboxy, R7cannot be Hwherein the .

[0059] In some embodiments, the present invention provides a compound having the structure:R' NH .

[0060] In someunsubstantiated or substituted aminoacids.

[0061] In some embodiments, R’ and R’’ are each independently unsubstantiated amino acids.

[0062] In some embodiments, R’ and R’’ are unsubstantiated amino acids.

[0063] In some embodiments, R’ and R’’ are alanine.

[0064] The present invention provides a pharmaceutical composition comprising the compounddescribed in the present invention and a pharmaceutically acceptable carrier. 12 4861-1118-9745v.1

[0065] The present invention provides a method of sensitizing tumors to immune checkpoint blockadeusing the compound described in the present invention or the pharmaceutical composition described in the present invention.

[0066] In some embodiments of the method, the tumors have chromosomal instability.

[0067] The present invention provides a method for inhibiting an inflammatory response in a patient,wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of the compound described in the present invention or the pharmaceutical composition described in the present invention.

[0068] The present invention provides a method for treating cancer metastasis in a patient, wherein themethod comprises administering to the patient in need thereof a therapeutically effective amount of the compound described in the present invention or the pharmaceutical composition described in the present invention.

[0069] In some embodiments of the method, the cancer is lung cancer, breast cancer, prostate cancer,cervical cancer, pancreatic cancer, colon cancer, ovarian cancer, stomach cancer, esophagus cancer, skin cancer, heart cancer, liver cancer, bronchial cancer, testicular cancer, kidney cancer, bladder cancer, spleen, cancer, thymus cancer, thyroid cancer, brain cancer, or gall bladder cancer.

[0070] The present invention provides a method of inhibiting inflammation, dsDNA–triggered interferonexpression, or CGAS in a patient comprising administering the compound described in the present invention or the pharmaceutical composition described in the present invention.

[0071] The present invention provides a method of treating Aicardi Goutières Syndrome, Parkinson'sdisease, Alzheimer's disease, Systemic lupus erythematosus, or cancer metastasis in a patient comprising administering the compound described in the present invention or the pharmaceutical composition described in the present invention.

[0072] The present invention provides a medicament comprising the compound described in the presentinvention or the pharmaceutical composition described in the present invention and optionally a therapeutic agent for Aicardi Goutières Syndrome, Parkinson's disease, Alzheimer's disease, Systemic lupus erythematosu , or cancer metastasis.

[0073] The compounds of the present invention include all hydrates, solvates, and complexes of thecompounds used by this invention. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Compounds containing a chiral center may be used as a 13 4861-1118-9745v.1racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. The compounds described in the present invention are in racemic form or as individual enantiomers. The enantiomers can be separated using known techniques, such as those described in Pure and Applied Chemistry 69, 1469–1474, (1997) IUPAC. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention.

[0074] The compounds of the subject invention may have spontaneous tautomeric forms. In caseswherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.

[0075] In the compound structures depicted herein, hydrogen atoms are not shown for carbon atomshaving less than four bonds to non-hydrogen atoms. However, it is understood that enough hydrogen atoms exist on said carbon atoms to satisfy the octet rule.

[0076] This invention also provides isotopic variants of the compounds disclosed herein, includingwherein the isotopic atom is2H and / or wherein the isotopic atom13C. Accordingly, in the compounds provided herein hydrogen can be enriched in the deuterium isotope. It is to be understood that the invention encompasses all such isotopic forms.

[0077] It is understood that the structures described in the embodiments of the methods hereinabove canbe the same as the structures of the compounds described hereinabove.

[0078] It is understood that where a numerical range is recited herein, the present invention contemplateseach integer between, and including, the upper and lower limits, unless otherwise stated.

[0079] Except where otherwise specified, if the structure of a compound of this invention includes anasymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, and isolated single enantiomer. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column. 14 4861-1118-9745v.1

[0080] The subject invention is also intended to include all isotopes of atoms occurring on thecompounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0081] It will be noted that any notation of a carbon in structures throughout this application, when usedwithout further notation, are intended to represent all isotopes of carbon, such as12C,13C, or14C. Furthermore, any compounds containing13C or14C may specifically have the structure of any of the compounds disclosed herein.

[0082] It will also be noted that any notation of a hydrogen in structures throughout this application,when used without further notation, are intended to represent all isotopes of hydrogen, such as1H,2H, or3H. Furthermore, any compounds containing2H or3H may specifically have the structure of any of the compounds disclosed herein.

[0083] Isotopically-labeled compounds can generally be prepared by conventional techniques known tothose skilled in the art using appropriate isotopically-labeled reagents in place of the non-labeled reagents employed.

[0084] In the compounds used in the method of the present invention, the substituents may be substitutedor unsubstituted, unless specifically defined otherwise.

[0085] In the compounds used in the method of the present invention, alkyl, heteroalkyl, monocycle,bicycle, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano, carbamoyl and aminocarbonyl and aminothiocarbonyl.

[0086] It is understood that substituents and substitution patterns on the compounds used in the methodof the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.

[0087] In choosing the compounds used in the method of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R1, R2, etc. are to be chosen in conformity with well- known principles of chemical structure connectivity.

[0088] As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatichydrocarbon groups having the specified number of carbon atoms. Thus, C1-Cnas in “C1–Cnalkyl" is 15 4861-1118-9745v.1defined to include groups having 1, 2......, n-1 or n carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl and so on. An embodiment can be C1-C12alkyl, C2-C12alkyl, C3-C12alkyl, C4-C12alkyl and so on. ”Alkoxy" represents an alkyl group as described above attached through an oxygen bridge.

[0089] The term "alkenyl" refers to a non-aromatic hydrocarbon radical, straight or branched, containingat least 1 carbon to carbon double bond, and up to the maximum possible number of non-aromatic carbon- carbon double bonds may be present. Thus, C2-Cnalkenyl is defined to include groups having 1, 2...., n-1 or n carbons. For example, "C2-C6alkenyl" means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and at least 1 carbon-carbon double bond, and up to, for example, 3 carbon-carbon double bonds in the case of a C6 alkenyl, respectively. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated. An embodiment can be C2-C12 alkenyl, C3-C12 alkenyl, C4-C12 alkenyl and so on.

[0090] The term "alkynyl" refers to a hydrocarbon radical straight or branched, containing at least 1carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present. Thus, C2-Cn alkynyl is defined to include groups having 1, 2...., n-1 or n carbons. For example, "C2-C6 alkynyl" means an alkynyl radical having 2 or 3 carbon atoms, and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms, and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms, and up to 3 carbon-carbon triple bonds. Alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight or branched portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated. An embodiment can be a C2- Cn alkynyl. An embodiment can be C2-C12 alkynyl, C3-C12 alkynyl, C4-C12 alkynyl and so on.

[0091] “Alkylene”, “alkenylene” and “alkynylene” shall mean, respectively, a divalent alkane, alkeneand alkyne radical, respectively. It is understood that an alkylene, alkenylene, and alkynylene may be straight or branched. An alkylene, alkenylene, and alkynylene may be unsubstituted or substituted.

[0092] As used herein, "heteroalkyl" includes both branched and straight-chain saturated aliphatichydrocarbon groups having the specified number of carbon atoms and at least 1 heteroatom within the chain or branch.

[0093] As used herein, "heterocycle" or "heterocyclyl" as used herein is intended to mean a 5- to 10-membered nonaromatic ring containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes bicyclic groups. "Heterocyclyl" therefore includes, but is not limited to the following: imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, 16 4861-1118-9745v.1dihydropiperidinyl, tetrahydrothiophenyl and the like. If the heterocycle contains a nitrogen, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.

[0094] As herein, "cycloalkyl" shall mean cyclic rings of alkanes of three to eight total carbon atoms, orany number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).

[0095] As used herein, "monocycle" includes any stable polyatomic carbon ring of up to 10 atoms andmay be unsubstituted or substituted. Examples of such non-aromatic monocycle elements include but are not limited to: cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of such aromatic monocycle elements include but are not limited to: phenyl.

[0096] As used herein, "bicycle" includes any stable polyatomic carbon ring of up to 10 atoms that isfused to a polyatomic carbon ring of up to 10 atoms with each ring being independently unsubstituted or substituted. Examples of such non-aromatic bicycle elements include but are not limited to: decahydronaphthalene. Examples of such aromatic bicycle elements include but are not limited to: naphthalene.

[0097] As used herein, "aryl" is intended to mean any stable monocyclic, bicyclic or polycyclic carbonring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted. Examples of such aryl elements include phenyl, p-toluenyl (4-methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.

[0098] As used herein, the term “polycyclic” refers to unsaturated or partially unsaturated multiple fusedring structures, which may be unsubstituted or substituted.

[0099] The term “arylalkyl” refers to alkyl groups as described above wherein one or more bonds tohydrogen contained therein are replaced by a bond to an aryl group as described above. It is understood that an “arylalkyl” group is connected to a core molecule through a bond from the alkyl group and that the aryl group acts as a substituent on the alkyl group. Examples of arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl), p-trifluoromethylbenzyl (4-trifluoromethylphenylmethyl), 1-phenylethyl, 2- phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.

[0100] The term "heteroaryl", as used herein, represents a stable monocyclic, bicyclic or polycyclic ringof up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridizine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) 17 4861-1118-9745v.1heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5- membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S. Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl, hexahydroazepinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra- hydroquinoline. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.

[0101] The term “alkylheteroaryl” refers to alkyl groups as described above wherein one or more bondsto hydrogen contained therein are replaced by a bond to an heteroaryl group as described above. It is understood that an “alkylheteroaryl” group is connected to a core molecule through a bond from the alkyl group and that the heteroaryl group acts as a substituent on the alkyl group. Examples of alkylheteroaryl moieties include, but are not limited to, -CH2-(C5H4N), -CH2-CH2-(C5H4N) and the like.

[0102] The term "heterocycle" or “heterocyclyl” refers to a mono- or poly-cyclic ring system which canbe saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms. Preferred heteroatoms include N, O, and / or S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation. The heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed. Such rings may be optionally fused to one or more of another "heterocyclic" ring(s), heteroaryl ring(s), aryl 18 4861-1118-9745v.1ring(s), or cycloalkyl ring(s). Examples of heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3-oxathiolane, and the like.

[0103] The alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl substituents may be substituted orunsubstituted, unless specifically defined otherwise. In the compounds of the present invention, alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.

[0104] As used herein, the term “halogen” refers to F, Cl, Br, and I.

[0105] The terms “substitution”, “substituted” and “substituent” refer to a functional group as describedabove in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non- hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Examples of substituent groups include the functional groups described above, and halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropryl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p- trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; mercapto; sulfanyl groups, such as methylsulfanyl, ethylsulfanyl and propylsulfanyl; cyano; amino groups, such as amino, methylamino, dimethylamino, ethylamino, and diethylamino; and carboxyl. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

[0106] It is understood that substituents and substitution patterns on the compounds of the instantinvention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. 19 4861-1118-9745v.1

[0107] In choosing the compounds of the present invention, one of ordinary skill in the art will recognizethat the various substituents, i.e. R1, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity.

[0108] The various R groups attached to the aromatic rings of the compounds disclosed herein may beadded to the rings by standard procedures, for example those set forth in Advanced Organic Chemistry: Part B: Reaction and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed. Edition. (2007), the content of which is hereby incorporated by reference.

[0109] The compounds used in the method of the present invention may be prepared by techniques wellknown in organic synthesis and familiar to a practitioner ordinarily skilled in the art. However, these may not be the only means by which to synthesize or obtain the desired compounds.

[0110] The compounds used in the method of the present invention may be prepared by techniquesdescribed in Vogel’s Textbook of Practical Organic Chemistry, A.I. Vogel, A.R. Tatchell, B.S. Furnis, A.J. Hannaford, P.W.G. Smith, (Prentice Hall) 5thEdition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley-Interscience) 5thEdition (2007), and references therein, which are incorporated by reference herein. However, these may not be the only means by which to synthesize or obtain the desired compounds.

[0111] Some compounds of the invention may be synthesized from those found in US11414422B2 byusing appropriate protecting reagents and conditions and standard peptide and ester coupling reagents and conditions. Some compounds of the invention may be synthesized from intermediates found in US11414422B2 by implementing commercially available reactants using standard reagents and conditions. Some compounds of the invention may be synthesized from similar intermediates and general reaction conditions found in US6583135B2 followed by the use of standard peptide and ester coupling reagents and conditions.

[0112] Another aspect of the invention comprises a compound used in the method of the presentinvention as a pharmaceutical composition.

[0113] In some embodiments, a pharmaceutical composition comprising the compound of the presentinvention and a pharmaceutically acceptable carrier.

[0114] As used herein, the term “pharmaceutically active agent” means any substance or compoundsuitable for administration to a subject and furnishes biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of disease, or affects the structure or any function of the subject. Pharmaceutically active agents include, but are not limited to, substances and compounds described in the Physicians’ Desk Reference (PDR Network, LLC; 64th edition; November 15, 2009) and 20 4861-1118-9745v.1“Approved Drug Products with Therapeutic Equivalence Evaluations” (U.S. Department Of Health And Human Services, 30thedition, 2010), which are hereby incorporated by reference. Pharmaceutically active agents which have pendant carboxylic acid groups may be modified in accordance with the present invention using standard esterification reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Where a pharmaceutically active agent does not possess a carboxylic acid group, the ordinarily skilled artisan will be able to design and incorporate a carboxylic acid group into the pharmaceutically active agent where esterification may subsequently be carried out so long as the modification does not interfere with the pharmaceutically active agent’s biological activity or effect.

[0115] The compounds used in the method of the present invention may be in a salt form. As used herein,a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used to treat an infection or disease caused by a pathogen, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.66:1-19).

[0116] The compounds of the present invention may also form salts with basic amino acids such a lysine,arginine, etc. and with basic sugars such as N-methylglucamine, 2-amino-2-deoxyglucose, etc. and any other physiologically non-toxic basic substance.

[0117] As used herein, “administering” an agent may be performed using any of the various methods ordelivery systems well known to those skilled in the art. The administering can be performed, for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, 21 4861-1118-9745v.1via local delivery, subcutaneously, intraadiposally, intraarticularly, intrathecally, into a cerebral ventricle, intraventicularly, intratumorally, into cerebral parenchyma or intraparenchchymally.

[0118] The compounds used in the method of the present invention may be administered in variousforms, including those detailed herein. The treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds. This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.

[0119] As used herein, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent,suspending agent or vehicle, for delivering the instant compounds to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutically acceptable carrier as are slow-release vehicles.

[0120] The dosage of the compounds administered in treatment will vary depending upon factors suchas the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.

[0121] A dosage unit of the compounds used in the method of the present invention may comprise asingle compound or mixtures thereof with additional antitumor agents. The compounds can be administeredin oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection, topical application, or other methods, into or topically onto a site of disease or lesion, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.

[0122] The compounds used in the method of the present invention can be administered in admixturewith suitable pharmaceutical diluents, extenders, excipients, or in carriers such as the novel programmable sustained-release multi-compartmental nanospheres (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, nasal, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone or mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier 22 4861-1118-9745v.1is generally chosen based on the type of administration being used. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.

[0123] Techniques and compositions for making dosage forms useful in the present invention aredescribed in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol. 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein.

[0124] Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoringagents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, 23 4861-1118-9745v.1polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0125] The compounds used in the method of the present invention may also be administered in the formof liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids such as lecithin, sphingomyelin, proteolipids, protein-encapsulated vesicles or from cholesterol, stearylamine, or phosphatidylcholines. The compounds may be administered as components of tissue-targeted emulsions.

[0126] The compounds used in the method of the present invention may also be coupled to solublepolymers as targetable drug carriers or as a prodrug. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

[0127] Gelatin capsules may contain the active ingredient compounds and powdered carriers, such aslactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

[0128] For oral administration in liquid dosage form, the oral drug components are combined with anyoral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. 24 4861-1118-9745v.1

[0129] Liquid dosage forms for oral administration can contain coloring and flavoring to increase patientacceptance. In general, water, asuitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

[0130] The compounds used in the method of the present invention may also be administered inintranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen.

[0131] Parenteral and intravenous forms may also include minerals and other materials such as solutoland / or ethanol to make them compatible with the type of injection or delivery system chosen.

[0132] The compounds and compositions of the present invention can be administered in oral dosageforms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by topical administration, injection or other methods, to the afflicted area, such as a wound, including ulcers of the skin, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.

[0133] Specific examples of pharmaceutically acceptable carriers and excipients that may be used toformulate oral dosage forms of the present invention are described in U.S. Pat. No. 3,903,297 to Robert, issued Sept.2, 1975. Techniques and compositions for making dosage forms useful in the present invention are described-in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: 25 4861-1118-9745v.1Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein.

[0134] The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets,powders, and chewing gum; or in liquid dosage forms, such as elixirs, syrups, and suspensions, including, but not limited to, mouthwash and toothpaste. It can also be administered parentally, in sterile liquid dosage forms.

[0135] Solid dosage forms, such as capsules and tablets, may be enteric-coated to prevent release of theactive ingredient compounds before they reach the small intestine. Materials that may be used as enteric coatings include, but are not limited to, sugars, fatty acids, proteinaceous substances such as gelatin, waxes, shellac, cellulose acetate phthalate (CAP), methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), and methyl methacrylate- methacrylic acid copolymers.

[0136] The compounds and compositions of the invention can be coated onto stents for temporary orpermanent implantation into the cardiovascular system of a subject.

[0137] Variations on those general synthetic methods will be readily apparent to those of ordinary skillin the art and are deemed to be within the scope of the present invention.

[0138] Each embodiment disclosed herein is contemplated as being applicable to each of the otherdisclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention.

[0139] Suppression of CIN or cGAS activity restores immunogenic potential of LKB1-deficientNSCLC. In experiments, relief of tonic STING activation via cGAMP could be removed by genetically deleting cGAS. Treatment of HCC44 with a commercially available human-selective cGAS inhibitor (G150) restored STING protein levels and enhanced pTBK1 and pIRF3 in response to cGAMP stimulation, thus, phenocopying genetic cGAS deletion experiments. Together, these results suggest that relief of tonic cGAS-STING activity through either suppression of CIN and genetic deletion or inhibition of cGAS restores productive immunogenic signaling in LKB1-deficient NSCLC.

[0140] Relief of CIN-induced signaling sensitizes NSCLC tumors to immune checkpoint blockade invivo:. Following subcutaneous (s.c.) implantation of KP or KL models in immunocompetent mice, tumors 26 4861-1118-9745v.1were treated with anti-PD1 (aPD1) therapy or isotype control. Animals with KP tumors had a significant response and delay in tumor growth following aPD1 treatment, while KL did not Up-modulation of CIN rates through expression of dnMCAK in KP cells rendered these tumors completely resistant to aPD1 therapy, while downmodulation of CIN in KL, through the overexpression of MCAK, was sufficient torestore partial sensitivity to aPD1 therapy. Deletion of Cgas in the KL model reduced tumor growth, andsubstantially sensitized tumors to aPD1, leading to improved tumor control and animal survival. Together, these results demonstrate that CIN and its downstream sensor cGAS are sufficient and necessary, respectively, to determine response to immunotherapies.

[0141] Loss of tumor Cgas restores sensitivity to Sting agonists

[0142] To test if loss of tumor cell cGAS activity would sensitize otherwise resistant chromosomally un-stable tumors to STING agonists, wild type or Cgas KO cells and treated tumors were transplanted biweekly with MSA-2. In four out of five models (KL, 4T1, CT26, and B16F10), treatment with MSA-2 significantly slowed the growth of Cgas KO tumors, extending the survival of treated animals. Importantly, these benefits were not observed in wildtype tumors, where MSA-2 treatment had a comparatively minimal effect Both cGAS proficient and deficient EO771.lmb tumors grew slightly slower in response to MSA-2, yet MSA-2 still prolonged survivalof animals harboring Cgas KO tumors.

[0143] Pre-treatment with cGAS inhibitors restores tumor sensitivity to STING agonists

[0144] We next asked whether pharmacological inhibition of cGAS prior to – and during – treatmentwith STING agonists might represent a viable therapeutic strategy to overcome the resistance of chromosomally unstable tumors to STING activation. To that end, we made use of the cGAS inhibitor, RU.521, known for its stronger selectivity towards mouse cGAS as compared with human cGAS61 .To confirm target inhibition, we incubated KL cells with RU.521 and measured expression of ISGs induction after stimulation with dsDNA. Unlike vehicle treated conditions, cells treated with RU.521 were unsuccessful in upregulating ISGs upon dsDNA stimulation. We next performed combination treatment of RU.521 and MSA-2 in all five previously described models and assessed for type I IFN induction. Indeed, pre-treatment with RU.521 significantly boosted ISG expression – except for Cxcl10 – in response to MSA- 2 exposure.

[0145] Given mounting evidence on reprograming of macrophages by STING agonists, macrophagepolarization assays were carried out. Inhibition of cGAS in cancer cells led to reductions of Arginase1 (an M2-like marker) in macrophages incubated with conditioned media from KL, 4T1, CT26 and B16F10 cells treated with MSA-2. Conversely, exposure of macrophages to conditioned media from MSA-2-treated Cgas KO cells led to a robust increase in iNOS (an M1-like marker) when compared to those exposed to media from wildtype MSA-2-treated cancer cells. Finally, KL, 4T1, and EO771.lmb were inoculated subcutaneously (KL) or orthotopically (4T1 and EO771.lmb) to evaluate the efficacy of RU.521 and MSA- 27 4861-1118-9745v.12 combination treatment. Animals were pre-treated with RU.521 to ensure sufficient drug exposure by the time the first MSA-2 dose was administrated and continued RU.521 throughout the treatment course. Animals were treated with MSA-2 when tumors reached ~100 mm3 . Expectedly, treatment with MSA-2 or RU.521 alone did not significantly hinder tumor growth in any of the models tested. On the other hand, combination treatment with MSA-2 and RU.521 led to a significant growth delay in KL, 4T1, and EO771.lmb tumors, thereby highlighting overcoming STING agonist resistance through cGAS inhibition. 28 4861-1118-9745v.1

Claims

CLAIMS 1. A compound having the following structure:whereinn is 1 or 2; R1is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, CH2CH2OR3, or fluoro (C1-C6)alkyl; R3is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; R5is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, fluoro(C1- C6)alkyl, fluoro(C1-C6)alkoxy, or cyano; R6is hydrogen, halogen, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or fluoro (C1- C6)alkyl; R7 is hydrogen, halogen, (C1-C6)alkoxy, fluoro(C1-C6)alkoxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or fluoro(C1-C6)alkyl; R8and R9are hydrogen, halogen, or (C1-C6)alkyl; R10 is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; wherein when n is 1: R2 is H, or a substituted or unsubstituted amino acid ester or α-hydroxy ester; R4 is a cyclic group substituted with one or more amines, or substituted with amino acids via the α-N wherein (i) when R2 is H, R4 is a cyclic group substituted with one or more amino acids viathe α-N; and (ii) when R2 is a substituted or unsubstituted amino acid ester or α-hydroxy ester, R4is a cyclic group substituted with one or more amines, or substituted with amino acids via the α-N; wherein when n is 2: 29 4861-1118-9745v.1R2is a substituted or unsubstituted amino acid ester or α-hydroxy ester, hydrogen, (C1- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or CH2CH2OR11, or a 4- to 6-membered aliphatic ring containing an O; R11is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; R4is hydrogen, halogen, (C1-C6)alkoxy, cyano, amino, an optionally substituted (C1- C6)alkyl, optionally substituted mono- or bicyclic heterocycle, optionally substituted phenyl,, optionally substituted benzyl, (C1-C6) acylamino, or (C1-C6)N-alkyl carboxamido, wherein the optionally substituted alkyl, mono- or bicylclic heterocyle, phenyl, or benzyl groups are optionally substituted with amino, (C1-C6)mono- or dialkylamino, (C1- C6)alkoxy, or heterocyclic groups or a pharmaceutically acceptable salt or a pharmaceutically acceptable salt hydrate or deuterated analog thereof.

2. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate ordeuterated analog thereof of claim 1, wherein (a) when R2 is (C1-C6)alkyl, up to three of R4, R5, R6, and R7 can be hydrogen; (b) when R1 is hydrogen, R2 is methyl, R5 is halogen, and R7 is a non-chloro halogen (C1- C6)alkoxy, fluoro(C1-C6)alkoxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or fluoro(C1-C6)alkyl; and (c) when R2 is (C1-C6)alkyl, R5is methoxy or carboxy, and R7is halogen, (C1-C6)alkoxy, fluoro(C1-C6)alkoxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or fluoro(C1- C6)alkyl.

3. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate ordeuterated analog thereof of any one of claims 1-2, wherein R1 is hydrogen or (C1-C6)alkyl, preferably R1 is hydrogen.

4. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate ordeuterated analog thereof of any one of claims 1-3, wherein when n is 1, R2is an unsubstituted or α- substituted amino acid ester or α-hydroxy ester, preferably the amino acid or α-hydroxy ester is substituted with amino, (C1-C6)alkylamino, (C1-C6)alkoxy, hydroxy, halogen, carboxyamido, methylenedioxy, ethylenedioxy, (C1-C6)acylamino, fluoro(C1-C6)acylamino, and hydroxy (C1-C6)alkylaminosulfonyl. 30 4861-1118-9745v.

15. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate ordeuterated analog thereof of any one of claims 1-4, wherein when n is 1, R2is an amino acid ester or α- hydroxy ester optionally unsubstituted or substituted on the α-heteroatom with an amino acid residue, α- hydroxy ester, α-(C1-C6)alkoxy ester (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, amino(C1-C6)alkyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, phenyl, benzyl, preferably R2is alanine.

6. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salt hydrate ordeuterated analog thereof of claim 5, wherein R2 is .

7. The compound of or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof claim 5, wherein when n is 1, R4is a substituted mono- or bicyclic heterocycle or substituted phenyl.

8. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of claim 7, wherein the substituted mono- or bicyclic heterocycle or substituted phenyl is substituted with one or more amino acids via the α-N.

9. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of claim 8, wherein R4is a mono-substituted heteroaromatic monocycle substituted with an amino acid via the α-N.

10. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of claim 8 or 9, wherein the amino acid is alanine.

11. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of claim 10, wherein R4 has the following structure: ,31 4861-1118-9745v.1wherein X is C or N, preferably X is C; wherein R’ is the amino acid.

12. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of any one of claims 1-3, wherein, when n is 2, R2is an unsubstituted or α-substituted amino acid ester, hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl, preferably R2is a substituted or unsubstituted amino acid, hydrogen, or (C1-C6)alkyl, more preferably R2is unsubstituted amino acid, more preferably R2is alanine.

13. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of claim 12, wherein, R2.

14. The compoundor pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of claim 13, wherein R3is hydrogen, or (C1-C6)alkyl, preferably R3is hydrogen.

15. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of claim 14, wherein R4is an optionally substituted cyclic group.

16. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of claim 15, wherein the optionally substituted cyclic group may be substituted with one or more substituents independently chosen from: (C1-C6)alkyl, amino, cyano, (C1- C6)mono- or dialkylamino, (C1-C6)alkoxy, oxo, fluoro (C1-C6)alkyl, halogen, hydroxy, hydroxy(C1- C6)alkyl, (C1-C6)N-alkylcarboxamido, methylenedioxy, ethylenedioxy, (C1-C6)acylamino, fluoro(C1- C6)acylamino, an amino acid via the α-N and hydroxy (C1-C6)alkylaminosulfonyl, preferably an amino acid via the α-N 17. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of claim 16, wherein the optionally substituted cyclic group is a phenyl or mono- or bicyclic heterocycle. 32 4861-1118-9745v.

118. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of claim 17, wherein the optionally substituted cyclic group is an optionally substituted heteroaromatic monocycle.

19. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of claim 18, wherein R4is an optionally substituted heteroaromatic monocycle substituted with an amino acid via the α-N, (C1-C3)alkyl, or amino group, preferably the said optionally substituted heteroaromatic monocycle is substituted with an amino acid via the α-N or amino group.

20. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of claim 19, wherein the amino acid is alanine.

21. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of claim 20, wherein R4 has the following structure: ,wherein X is C or N, preferably X is C; wherein R’ is an amino acid residue, preferably the amino acid is alanine.

22. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of claim 19, wherein R4 is .

23. The compound orsalt or pharmaceutically acceptable salthydrate or deuterated analog thereof of any one of claims 1-22, wherein R5is hydrogen, halogen, (C1- C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl, preferably R5is hydrogen, halogen, or (C1-C6)alkyl, more preferably R5is hydrogen.

24. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of any one of claims 1-23, wherein R6is hydrogen, halogen, cyano, or 33 4861-1118-9745v.1(C1-C6)alkyl, preferably R6is hydrogen, halogen, or (C1-C6)alkyl, more preferably R6is halogen, methyl, or trifluoromethyl, more preferably R6is halogen, more preferably the halogen is Cl.

25. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of any one of claims 1-24, wherein R7is hydrogen, halogen, cyano, or (C1-C6)alkyl, preferably R7is hydrogen, halogen, or (C1-C6)alkyl, more preferably R7is halogen, more preferably the halogen is Cl.

26. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of any one of claims 1-25, wherein R8 is hydrogen or (C1-C6)alkyl, preferably R8 is hydrogen.

27. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of any one of claims 1-26, wherein R9 is hydrogen or (C1-C6)alkyl, preferably R9 is hydrogen.

28. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of any one of claims 1-27, wherein R10 is hydrogen or halogen, preferably R10 is hydrogen.

29. The compound or pharmaceutically acceptable salt or pharmaceutically acceptable salthydrate or deuterated analog thereof of claim 1, having the structure: 34 4861-1118-9745v.1, , r 30. The pharmaceutically acceptable salt hydrate of claim 1, having the structure:35 4861-1118-9745v.

1.

31. A pharmaceutical composition comprising the compound of any one of claims 1-30 and apharmaceutically acceptable carrier.

32. A prodrug or a pharmaceutically acceptable salt having the following:O R2O whereinn is 1 or 2, preferably n is 1; R1 is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, CH2CH2OR3, or fluoro (C1-C6)alkyl; wherein when n is 1, R2 is a substituted or unsubstituted amino acid ester or α-hydroxy ester; wherein when n is 2, R2 is a substituted or unsubstituted amino acid ester or α-hydroxy ester, hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or CH2CH2OR3, or, a 4- to 6-membered aliphatic ring containing an O; R3is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; R4is hydrogen, halogen, (C1-C6)alkoxy, cyano, amino, an optionally substituted mono- or bicyclic heterocycle, optionally substituted (C1-C6)alkyl, optionally substituted phenyl, optionally substituted benzyl, (C1-C6) acylamino, or (C1-C6)N-alkylcarboxamido, wherein the alkyl, mono- or bicyclic heterocycle, phenyl, or benzyl groups are optionally substituted with amino, (C1-C6)mono- or dialkylamino, (C1-C6)alkoxy, heterocyclic groups R5is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, fluoro(C1-C6)alkyl, fluoro(C1-C6)alkoxy, or cyano; R6is hydrogen, halogen, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or fluoro (C1-C6)alkyl; 36 4861-1118-9745v.1R7is hydrogen, halogen, (C1-C6)alkoxy, fluoro(C1-C6)alkoxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, or fluoro(C1-C6)alkyl; R8and R9are hydrogen, halogen, or (C1-C6)alkyl, or, taken together with the carbon to which they are attached, R8and R9may form a 3- to 5-membered aliphatic carbocycle; R10is hydrogen, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl.

33. The compound of claim 32, whereinwhen R2is (C1-C6)alkyl, up to three of R4, R5, R6, and R7can be hydrogen; when R1 is hydrogen, R2 is methyl and R5 is halogen, R7 is a non-chloro halogen (C1-C6)alkoxy, fluoro(C1- C6)alkoxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or fluoro(C1-C6)alkyl; and when R2 is (C1-C6)alkyl, and R5is methoxy or carboxy, R7cannot be Hwherein the .

34. A method of sensitizing a tumor to immune checkpoint blockade therapy comprisingcontracting the tumor with the compound of any one of claims 1-30 or the pharmaceutical composition of claim 22.

35. The method of claim 34, wherein tumor has chromosomal instability.

36. A method for inhibiting an inflammatory response in a patient, wherein the methodcomprises administering to the patient in need thereof a therapeutically effective amount of the compound of any one of claims 1-30 or the pharmaceutical composition of claim 31.

37. A method for inhibiting cancer metastasis in a patient, wherein the method comprisesadministering to the patient in need thereof a therapeutically effective amount of the compound of any one of claims 1-30 or the pharmaceutical composition of claim 31. 37 4861-1118-9745v.

138. The method of claim 37, wherein the metastasis is of a lung cancer, breast cancer, prostatecancer, cervical cancer, pancreatic cancer, colon cancer, ovarian cancer, stomach cancer, esophagus cancer, skin cancer, heart cancer, liver cancer, bronchial cancer, testicular cancer, kidney cancer, bladder cancer, spleen, cancer, thymus cancer, thyroid cancer, brain cancer, or gall bladder cancer.

39. A method of inhibiting inflammation dsDNA–triggered interferon expression, or CGAS ina patient comprising administering the compound of any one of claims 1-30 or the pharmaceutical composition of claim 31.

40. A method of treating Aicardi Goutières Syndrome, Parkinson's disease, Alzheimer'sdisease, Systemic lupus erythematosus, or cancer metastasis in a patient comprising administering the compound of any one of claims 1-30 or the pharmaceutical composition of claim 31.

41. A medicament comprising the compound of any one of claims 1-30 or the pharmaceuticalcomposition of claim 31 and optionally a therapeutic agent for Aicardi Goutières Syndrome, Parkinson's disease, Alzheimer's disease, Systemic lupus erythematosus, or cancer metastasis.

42. The method of any of claims 33-38, further comprising identifying the tumor or cancer orhaving the subject identified as having a chromosomal instability.

43. The method of any of claims 34-38 or 42, wherein the tumor or cancer is a non-small celllung cancer.

44. The method of claim 43, wherein the non-small cell lung cancer is LKB1-deficientt.

45. The method of claim 34, 35, 42, 43 or 44, wherein the immune checkpoint blockade (ICB)therapy comprises an anti-PD1 therapy. 38 4861-1118-9745v.1

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