COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH STING ACTIVITY

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.

TECHNICAL FIELD

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or prodrug, and/or tautomer, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.

BACKGROUND

STING, also known as transmembrane protein 173 (TMEM173) and MPYS/MITA/ERIS, is a protein that in humans is encoded by the TMEM173 gene. STING has been shown to play a role in innate immunity. STING induces type I interferon production when cells are infected with intracellular pathogens, such as viruses, mycobacteria and intracellular parasites. Type I interferon, mediated by STING, protects infected cells and nearby cells from local infection in an autocrine and paracrine manner.

The STING pathway is pivotal in mediating the recognition of cytosolic DNA. In this context, STING, a transmembrane protein localized to the endoplasmic reticulum (ER), acts as a second messenger receptor for 2′, 3′ cyclic GMP-AMP (hereafter cGAMP), which is produced by cGAS after dsDNA binding. In addition, STING can also function as a primary pattern recognition receptor for bacterial cyclic dinucleotides (CDNs) and small molecule agonists. The recognition of endogenous or prokaryotic CDNs proceeds through the carboxy-terminal domain of STING, which faces into the cytosol and creates a V-shaped binding pocket formed by a STING homodimer. Ligand-induced activation of STING triggers its re-localization to the Golgi, a process essential to promote the interaction of STING with TBK1. This protein complex, in turn, signals through the transcription factors IRF-3 to induce type I interferons (IFNs) and other co-regulated antiviral factors. In addition, STING was shown to trigger NF-κB and MAP kinase activation. Following the initiation of signal transduction, STING is rapidly degraded, a step considered important in terminating the inflammatory response.

Excessive activation of STING is associated with a subset of monogenic autoinflammatory conditions, the so-called type I interferonopathies. Examples of these diseases include a clinical syndrome referred to as STING-associated vasculopathy with onset in infancy (SAVI), which is caused by gain-of-function mutations in TMEM173 (the gene name of STING). Moreover, STING is implicated in the pathogenesis of Aicardi-Goutieres Syndrome (AGS) and genetic forms of lupus. As opposed to SAVI, it is the dysregulation of nucleic acid metabolism that underlies continuous innate immune activation in AGS. Apart from these genetic disorders, emerging evidence points to a more general pathogenic role for STING in a range of inflammation-associated disorders such as systemic lupus erythematosus, rheumatoid arthritis and cancer. Thus, small molecule-based pharmacological interventions into the STING signaling pathway hold significant potential for the treatment of a wide spectrum of diseases

SUMMARY

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or prodrug, and/or tautomer, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.

An “antagonist” of STING includes compounds that, at the protein level, directly bind or modify STING such that an activity of STING is decreased, e.g., by inhibition, blocking or dampening agonist-mediated responses, altered distribution, or otherwise. STING antagonists include chemical entities, which interfere or inhibit STING signaling.

In one aspect, compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are featured:

eachis independently a single bond or a double bond, provided that the five-membered ring comprising X1and X2is heteroaryl (i.e., one or more of X1and X2is an independently selected heteroatom; and the 5-membered ring comprising X1, and X2is aromatic (as a non-limiting example, the ring comprising X1and X2can be pyrrole)).

In one aspect, compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a tautomer thereof, or any combination of the foregoing, are featured “Prodrug” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., compound of Formula (I)). Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some aspects, a prodrug is inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.

In one aspect, pharmaceutical compositions are featured that include a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same) and one or more pharmaceutically acceptable excipients.

In one aspect, methods for inhibiting (e.g., antagonizing) STING activity are featured that include contacting STING with a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same). Methods include in vitro methods, e.g., contacting a sample that includes one or more cells comprising STING (e.g., innate immune cells, e.g., mast cells, macrophages, dendritic cells (DCs), and natural killer cells) with the chemical entity. Methods can also include in vivo methods; e.g., administering the chemical entity to a subject (e.g., a human) having a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease.

In one aspect, methods of treating a condition, disease or disorder ameliorated by antagonizing STING are featured, e.g., treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). The methods include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).

In another aspect, methods of treating cancer are featured that include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).

In a further aspect, methods of treating other STING-associated conditions are featured, e.g., type I interferonopathies (e.g., STING-associated vasculopathy with onset in infancy (SAVI)), Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis. The methods include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).

In another aspect, methods of suppressing STING-dependent type I interferon production in a subject in need thereof are featured that include administering to the subject an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).

In a further aspect, methods of treating a disease in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the disease are featured. The methods include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).

In another aspect, methods of treatment are featured that include administering an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same) to a subject; wherein the subject has (or is predisposed to have) a disease in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the disease.

In a further aspect, methods of treatment that include administering to a subject a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same), wherein the chemical entity is administered in an amount effective to treat a disease in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the disease, thereby treating the disease.

The chemical entity can be administered in combination with one or more additional therapeutic agents and/or regimens. For examples, methods can further include administering one or more (e.g., two, three, four, five, six, or more) additional agents.

The chemical entity can be administered in combination with one or more additional therapeutic agents and/or regimens that are useful for treating other STING-associated conditions, e.g., type I interferonopathies (e.g., STING-associated vasculopathy with onset in infancy (SAVI)), Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis.

The subject can have cancer; e.g., the subject has undergone and/or is undergoing and/or will undergo one or more cancer therapies.

The chemical entity can be administered intratumorally.

The methods can further include identifying the subject.

Other embodiments include those described in the Detailed Description and/or in the claims.

Additional Definitions

To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.

“API” refers to an active pharmaceutical ingredient.

The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g.,Remington: The Science and Practice of Pharmacy,21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives,3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation,2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.

The terms “treat,” “treating,” and “treatment,” in the context of treating a disease or disorder, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof. The “treatment of cancer”, refers to one or more of the following effects: (1) inhibition, to some extent, of tumor growth, including, (i) slowing down and (ii) complete growth arrest; (2) reduction in the number of tumor cells; (3) maintaining tumor size; (4) reduction in tumor size; (5) inhibition, including (i) reduction, (ii) slowing down or (iii) complete prevention, of tumor cell infiltration into peripheral organs; (6) inhibition, including (i) reduction, (ii) slowing down or (iii) complete prevention, of metastasis; (7) enhancement of anti-tumor immune response, which may result in (i) maintaining tumor size, (ii) reducing tumor size, (iii) slowing the growth of a tumor, (iv) reducing, slowing or preventing invasion and/or (8) relief, to some extent, of the severity or number of one or more symptoms associated with the disorder.

The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-10indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.

The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo.

The term “alkoxy” refers to an —O-alkyl radical (e.g., —OCH3).

The term “alkylene” refers to a divalent alkyl (e.g., —CH2—).

The term “alkenyl” refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C2-6indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkenyl groups can either be unsubstituted or substituted with one or more substituents.

The term “alkynyl” refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C2-6indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups can either be unsubstituted or substituted with one or more substituents.

The term “aryl” refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

The term “cycloalkyl” as used herein refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl includes: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms.

The term “cycloalkenyl” as used herein means partially unsaturated cyclic hydrocarbon groups having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As partially unsaturated cyclic hydrocarbon groups, cycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the cycloalkenyl group is not fully saturated overall. Cycloalkenyl may include multiple fused and/or bridged and/or spirocyclic rings.

The term “heterocycloalkenyl” as used herein means partially unsaturated cyclic ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocycloalkenyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl. As partially unsaturated cyclic groups, heterocycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the heterocycloalkenyl group is not fully saturated overall. Heterocycloalkenyl may include multiple fused and/or bridged and/or spirocyclic rings.

As used herein, when a ring is described as being “aromatic”, it means said ring has a continuous, delocalized π-electron system. Typically, the number of out of plane π-electrons corresponds to the Hückel rule (4n+2). Examples of such rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself, e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.0] ring systems, in which 0 represents a zero atom bridge (e.g.,

(ii) a single ring atom (spiro-fused ring systems) (e.g.,

or (iii) a contiguous array of ring atoms (bridged ring
systems having all bridge lengths >0) (e.g.,

In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, 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, and isotopes of carbon include13C and14C.

In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety:

encompasses the tautomeric form containing the moiety:

Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

Some non-limiting exemplified compounds of the formulae described herein include one or more stereogenic carbon atoms. This disclosure provides examples of stereoisomer mixtures (e.g., racemic and non-racemic mixture of enantiomers; mixture of diastereomers, meso compounds). This disclosure also describes and exemplifies methods for separating individual components of said stereoisomer mixtures (e.g., resolving the enantiomers of a racemic mixture). In some instances, stereoisomers are graphically depicted using hashed and solid wedge three-dimensional representations. Unless otherwise indicated with “(R)” or “(S)” labels, the hashed and solid wedge three-dimensional representation are intended to convey relative stereochemistry only. Likewise, and unless otherwise indicated, reaction schemes showing resolution of a racemic mixture, the above-mentioned representations are intended only to convey that the constituent enantiomers were resolved in enantiopure pure form (about 98% ee or greater) and are not intended to disclose or imply any correlation between absolute configuration and order of elution.

The definitions of certain variables herein include -L1-L2-Rhand -L3-L4-Ri. For avoidance of doubt, when a variable is -L1-L2-Rh; -L1is a bond; and -L2is a bond, then said variable is —Rhthat is connected to the rest of the compound via a single bond. As a non-limiting example, when one occurrence of Rbis -L1-L2-Rh; -L1is a bond; and -L2is a bond, then said occurrence of Rbis —Rhthat is connected to the rest of the compound via a single bond. Similarly, when a variable is -L3-L4-Ri; -L3is a bond; and -L4is a bond, then said variable is —R that is connected to the rest of the compound via a single bond.

DETAILED DESCRIPTION

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or prodrug, and/or tautomer, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.

Formula I Compounds

In one aspect, compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are featured:

X1is selected from the group consisting of O, S, N, NR2, and CR5;

X2is selected from the group consisting of O, S, N, NR4, and CR5;

eachis independently a single bond or a double bond, provided that the five-membered ring comprising X1and X2is heteroaryl; and

the 6-membered ring

is aromatic;

Q-A is defined according to (A) or (B) below:(A)

Q is selected from the group consisting of: NH and N(C1-6alkyl) wherein the C1-6alkyl is optionally substituted with 1-2 independently selected Ra; and

A is:

(i) —(YA1)nYA2, wherein:n is 0 or 1;YA1is C1-6alkylene, which is optionally substituted with 1-6 substituents each independently selected from the group consisting of:oxo;Ra;C6-10aryl optionally substituted with 1-4 independently selected C1-4alkyl; andheteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected C1-4alkyl; orYA1is —YA3—YA4—YA5which is connected to Q via YA3wherein:YA3is a C1-3alkylene optionally substituted with 1-2 substituents each independently selected from the group consisting of oxo and Ra;YA4is —O—, —NH—, —N(C1-6alkyl)-, or —S—; andYA5is a bond or C1-3alkylene which is optionally substituted with 1-2 independently selected Ra; andYA2is:(a) C3-20cycloalkyl or C3-20cycloalkenyl, each of which is optionally substituted with 1-4 Rb,(b) C6-20aryl which is optionally substituted with 1-4 Rc;(c) heteroaryl of 5-20 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Rc; or(d) heterocyclyl or heterocycloalkenyl of 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl ring is optionally substituted with 1-4 independently selected Rb,

(iii) C1-20alkyl, which is optionally substituted with 1-6 independently selected Ra, or

E is a ring of 3-16 ring atoms, wherein 0-3 ring atoms are heteroatoms (in addition to the nitrogen atom this is already present), each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the ring is optionally substituted with 1-4 independently selected Rb,

R1aand R1b, R1band R1c, or R1cand R1d, taken together with the atoms connecting them, form a ring of 3-10 ring atoms, wherein 0-2 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2; and wherein the ring is optionally substituted with 1-4 substituents each independently selected from the group consisting of C1-6alkyl, halo, C1-6haloalkyl, —OH, NReRf, C1-6alkoxy, and C1-6haloalkoxy,

each occurrence of R2is independently selected from the group consisting of:

(i) C1-6alkyl, which is optionally substituted with 1-2 independently selected Ra;

(iii) heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2;

(v) heteroaryl of 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2;

R4is selected from the group consisting of H and C1-6alkyl optionally substituted with 1-3 independently selected Ra;

R6is selected from the group consisting of H; C1-6alkyl optionally substituted with 1-3 independently selected Ra; —OH; C1-4alkoxy; C(═O)H; C(═O)(C1-4alkyl); C6-10aryl optionally substituted with 1-4 independently selected C1-4alkyl; and heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected C1-4alkyl;

Rdis selected from the group consisting of: C1-6alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; C3-6cycloalkyl or C3-6cycloalkenyl, each optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; —C(O)(C1-4alkyl); —C(O)O(C1-4alkyl); —CON(R′)(R″); —S(O)1-2(NR′R″); —S(O)1-2(C1-4alkyl); —OH; and C1-4alkoxy;each occurrence of Reand Rfis independently selected from the group consisting of: H; C1-6alkyl; C1-6haloalkyl; C3-6 cycloalkyl or C3-6cycloalkenyl; —C(O)(C1-4alkyl); —C(O)O(C1-4alkyl); —CON(R′)(R″); —S(O)1-2(NR′R″); —S(O)1-2(C1-4alkyl); —OH; and C1-4alkoxy; or Reand Rftogether with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C1-3alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to Reand Rf), which are each independently selected from the group consisting of N(Rd), NH, 0, and S;

-L1is a bond or C1-3alkylene;

Rhis selected from the group consisting of:C3-8cycloalkyl or C3-8cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy;heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy;heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy; andC6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy;

-L3is a bond or C1-3alkylene;

Riis selected from the group consisting of:C3-8cycloalkyl or C3-8cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy;heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy;heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy; andC6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy; and

each occurrence of R′ and R″ is independently selected from the group consisting of: H, C1-4alkyl, C6-10aryl optionally substituted with 1-2 substituents selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl, and heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, —OH, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, C1-4alkyl, and C1-4haloalkyl; or R′ and R″ together with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C1-3alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R′ and R″), which are each independently selected from the group consisting of N(H), N(C1-6alkyl), O, and S.

In one aspect, compounds of Formula (I), a pharmaceutically acceptable salt thereof, or a tautomer thereof are featured:

X1is selected from the group consisting of O, S, N, NR2, and CR5;

X2is selected from the group consisting of O, S, N, NR4, and CR5;

eachis independently a single bond or a double bond, provided that the five-membered ring comprising X1and X2is heteroaryl; and the 6-membered ring is aromatic:

Q-A is defined according to (A) or (B) below:(A)

Q is selected from the group consisting of: NH and N(C1-6alkyl) wherein the C1-6alkyl is optionally substituted with 1-2 independently selected Ra; and

A is:

(i) —(YA1)n—YA2, wherein:n is 0 or 1;YA1is C1-6alkylene, which is optionally substituted with 1-6 substituents each independently selected from the group consisting of:Ra;C6-10aryl optionally substituted with 1-4 independently selected C1-4alkyl; andheteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected C1-4alkyl; andYA1is —YA3—YA4—YA5which is connected to Q via YA3wherein:YA3is a C1-3alkylene optionally substituted with 1-2 independently selected Ra;YA4is —O—, —NH—, or —S—; andYA5is a bond or C1-3alkylene which is optionally substituted with 1-2 independently selected Ra; andYA2is:(a) C3-20cycloalkyl or C3-20cycloalkenyl, each of which is optionally substituted with 1-4 Rb,(b) C6-20aryl, which is optionally substituted with 1-4 Rc;(c) heteroaryl of 5-20 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Rc; or(d) heterocyclyl or heterocycloalkenyl of 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl ring is optionally substituted with 1-4 independently selected Rb,

(iii) C1-20alkyl, which is optionally substituted with 1-6 independently selected Ra, or

E is a ring of 3-16 ring atoms, wherein 0-3 ring atoms are heteroatoms (in addition to the nitrogen atom this is already present), each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the ring is optionally substituted with 1-4 independently selected Rb,

R1aand R1b, R1band R1c, or R1cand R1d, taken together with the atoms connecting them, form a ring of 3-10 ring atoms, wherein 0-2 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2; and wherein the ring is optionally substituted with 1-4 substituents each independently selected from the group consisting of C1-6alkyl, halo, C1-6haloalkyl, —OH, NReRf, C1-6alkoxy, and C1-6haloalkoxy,

each occurrence of R2is independently selected from the group consisting of:

(i) C1-6alkyl, which is optionally substituted with 1-2 independently selected Ra;

(iii) heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2;

(v) heteroaryl of 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2; (vi) —C(O)(C1-4alkyl);

R4is selected from the group consisting of H and C1-6alkyl optionally substituted with 1-3 independently selected Ra;

R6is selected from the group consisting of H; C1-6alkyl optionally substituted with 1-3 independently selected Ra; —OH; C1-4alkoxy; C(═O)H; C(═O)(C1-4alkyl); C6-10aryl optionally substituted with 1-4 independently selected C1-4alkyl; and heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected C1-4alkyl;

each occurrence of Reis independently selected from the group consisting of:

Rdis selected from the group consisting of: C1-6alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; C3-6cycloalkyl or C3-6cycloalkenyl, each optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; —C(O)(C1-4alkyl); —C(O)O(C1-4alkyl); —CON(R′)(R″); —S(O)1-2(NR′R″); —S(O)1-2(C1-4alkyl); —OH; and C1-4alkoxy;

each occurrence of Reand Rfis independently selected from the group consisting of: H; C1-6alkyl; C1-6haloalkyl; C3-6cycloalkyl or C3-6cycloalkenyl; —C(O)(C1-4alkyl); —C(O)O(C1-4alkyl); —CON(R′)(R″); —S(O)1-2(NR′R″); —S(O)1-2(C1-4alkyl); —OH; and C1-4alkoxy; or Reand Rftogether with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C1-3alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to Reand Rf), which are each independently selected from the group consisting of N(Rd), NH, 0, and S;

-L1is a bond or C1-3alkylene;

Rhis selected from the group consisting of:C3-8cycloalkyl or C3-8cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy (in certain embodiments, it is provided that when Rhis C3-6 cycloalkyl or C3-6cycloalkenyl, each optionally substituted with 1-4 substituents independently selected C1-4alkyl, -L1is a bond, or -L2is —O—, —N(H)—, or —S—);heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy;heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy; andC6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy;

-L3is a bond or C1-3alkylene;

Riis selected from the group consisting of:C3-8cycloalkyl or C3-8cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy (in certain embodiments, it is provided that when Riis C3-6cycloalkyl or C3-6cycloalkenyl, each optionally substituted with 1-4 substituents independently selected C1-4alkyl, -L1is a bond, or -L2is —O—, —N(H)—, or —S—);heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy;heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy; andC6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy; and

each occurrence of R′ and R″ is independently selected from the group consisting of: H, C1-4alkyl, C6-10aryl optionally substituted with 1-2 substituents selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl, and heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, —OH, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, C1-4alkyl, and C1-4haloalkyl; or R′ and R″ together with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C1-3alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R′ and R″), which are each independently selected from the group consisting of N(H), N(C1-6alkyl), O, and S.

In one aspect, compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are featured:

or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

X1is selected from the group consisting of O, S, N, NR2, and CR5;

X2is selected from the group consisting of O, S, N, NR4, and CR5;

eachis independently a single bond or a double bond, provided that the five-membered ring comprising X1and X2is heteroaryl; and

the 6-membered ring is aromatic:

Q-A is defined according to (A) or (B) below:(A)

Q is selected from the group consisting of: NH and N(C1-6alkyl) wherein the C1-6alkyl is optionally substituted with 1-2 independently selected Ra; and

A is:

(i) —(YA1)n—YA2, wherein:n is 0 or 1;YA1is C1-6alkylene, which is optionally substituted with 1-6 substituents each independently selected from the group consisting of:Ra;C6-10aryl optionally substituted with 1-4 independently selected C1-4alkyl; andheteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected C1-4alkyl; andYA2is:

(a) C3-20cycloalkyl or C3-20 cycloalkenyl, each of which is optionally substituted with 1-4 Rb,

(b) C6-20aryl, which is optionally substituted with 1-4 Rc;

(c) heteroaryl of 5-20 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Rc; or

(d) heterocyclyl or heterocycloalkenyl of 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl ring is optionally substituted with 1-4 independently selected Rb,

(iii) C1-10alkyl, which is optionally substituted with 1-6 independently selected Ra, or(B)

E is a ring of 3-16 ring atoms, wherein 0-3 ring atoms are heteroatoms (in addition to the nitrogen atom that is present), each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the ring is optionally substituted with 1-4 independently selected Rb,

R1aand R1b, R1band R1c, or R1cand R1d, taken together with the atoms connecting them, form a ring of 3-10 ring atoms, wherein 0-2 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N(Rd), 0, and S(O)0-2; and wherein the ring is optionally substituted with 1-4 substituents each independently selected from the group consisting of C1-6alkyl, halo, C1-6haloalkyl, —OH, NReRf, C1-6alkoxy, and C1-6haloalkoxy,

each occurrence of R2is independently selected from the group consisting of:

(i) C1-6alkyl, which is optionally substituted with 1-2 independently selected Ra;

(iii) heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 0, and S(O)0-2;

(v) heteroaryl of 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2; (vi) —C(O)(C1-4alkyl);

R4is selected from the group consisting of H and C1-6alkyl optionally substituted with 1-3 independently selected Ra;

R6is selected from the group consisting of H; C1-6alkyl optionally substituted with 1-3 independently selected Ra; —OH; C1-4alkoxy; C(═O)H; C(═O)(C1-4alkyl); C6-10aryl optionally substituted with 1-4 independently selected C1-4alkyl; and heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected C1-4alkyl;

each occurrence of Reis independently selected from the group consisting of:

Rdis selected from the group consisting of: C1-6alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; C3-6cycloalkyl or C3-6cycloalkenyl, each optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; —C(O)(C1-4alkyl); —C(O)O(C1-4alkyl); —CON(R′)(R″); —S(O)1-2(NR′R″); —S(O)1-2(C1-4alkyl); —OH; and C1-4alkoxy;

each occurrence of Reand Rfis independently selected from the group consisting of: H; C1-6alkyl; C1-6haloalkyl; C3-6cycloalkyl or C3-6cycloalkenyl; —C(O)(C1-4alkyl); —C(O)O(C1-4alkyl); —CON(R′)(R″); —S(O)1-2(NR′R″); —S(O)1-2(C1-4alkyl); —OH; and C1-4alkoxy; or Reand Rftogether with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C1-3alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to Reand Rf), which are each independently selected from the group consisting of N(Rd), NH, O, and S;

-L1is a bond or C1-3alkylene;

Rhis selected from the group consisting of:C3-8cycloalkyl or C3-8cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl (in certain embodiments, it is provided that when Rhis C3-6cycloalkyl or C3-6cycloalkenyl, each optionally substituted with 1-4 substituents independently selected C1-4alkyl, -L1is a bond, or -L2is —O—, —N(H)—, or —S—);heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl;heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl; andC6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl;

-L3is a bond or C1-3alkylene;

Riis selected from the group consisting of:C3-8cycloalkyl or C3-8cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl (in certain embodiments, it is provided that when R is C3-6cycloalkyl or C3-6cycloalkenyl, each optionally substituted with 1-4 substituents independently selected C1-4alkyl, -L1is a bond, or -L2is —O—, —N(H)—, or —S—);heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl;heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl; andC6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, or C1-4haloalkyl; and

each occurrence of R′ and R″ is independently selected from the group consisting of: H, —OH; C1-4alkyl, C6-10aryl optionally substituted with 1-2 substituents selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl, and heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, —OH, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, C1-4alkyl, and C1-4haloalkyl; or R′ and R″ together with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C1-3alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R′ and R″), which are each independently selected from the group consisting of N(H), N(C1-6alkyl), O, and S.

Embodiments can include any one or more of the features delineated below and/or in the claims.

The Variables X1and X2

In some embodiments, X1is NR2. In certain of these embodiments, X1is NH.

In some embodiments, X2is CR5. In certain of these embodiments, X2is CH. In other embodiments, R5is other than H.

In some embodiments, the

In certain embodiments, the

moiety is

Non-Limiting Combinations of X1, X2, and the

In certain embodiments, the compound is a compound of Formula (I-a):

In certain of these embodiments, compound has formula (I-a1):

In certain embodiments of Formula (I-a), the compound has formula (I-a2):

In certain embodiments of Formula (I-a), the compound has formula (I-a3) or (I-a4):

In certain embodiments, the compound is a compound of Formula (I-a5):

In certain embodiments of Formula (I-a) (e.g., when the compound has Formula (I-a1), (I-a2), (I-a3), (I-a4), or (I-a5)), R2is H; and RIis H.

In certain embodiments, 0-3 (e.g., 0, 1, 2, or 3) of R1a, R1b, R1c, and R1dis other than H; and each of the remaining of R1a, R1b, R1c, and R1dis H.

In certain other embodiments, 1-2 occurrences of R1a, R1b, R1c, and R1dis other than H (e.g., R1band/or R1cis other than H). As a non-limiting example of the foregoing embodiments, two of R1a, R1b, R1c, and R1dare other than H (e.g., R1band R1care other than H).

In certain embodiments, one of R1a, R1b, R1c, and R1dis -L3-L4-Ri. In certain of these embodiments, L3is a bond; and/or L4is a bond. As a non-limiting example, one of R1a, R1b, R1c, and R1dis R (e.g., R is heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 0, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl; or Riis C6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, or C1-4haloalkyl).

In certain embodiments, one occurrence of R1a, R1b, R1c, and R1dis -L3-L4-Ri, such as R1bis -L3-L4-Ri; and each remaining occurrences of R1a, R1b, R1c, and R1dis H. In certain of these embodiments, -L3is a bond; and/or -L4is a bond.

In certain of the foregoing embodiments, —Riis selected from the group consisting of:heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy; andC6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy.

In certain of these embodiments, —Riis selected from the group consisting of:heteroaryl of 5-6 ring atoms (e.g., pyrazolyl), wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy; andphenyl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy.

In certain embodiments, one of R1a, R1b, R1c, and R1d(such as R1b) is selected from the group consisting of:heteroaryl of 5-6 ring atoms (such as pyrazolyl), wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy
(e.g.,

andphenyl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy (e.g.,

In certain of these embodiments, each remaining R1a, R1b, R1c, and R1dis H.
The Variables R2, R5, and R6

In some embodiments, R2is selected from the group consisting of:

heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2; and

heteroaryl of 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2.

In some embodiments, R5is H or halo. In certain embodiments, R5is H.

The Variables Q-A

In some embodiments, Q-A is defined according to (A).

In some embodiments, Q is NH. In some other embodiments, Q is N(C1-3alkyl) (e.g., NMe or NEt).

In some embodiments, A is —(YA1)n—YA2. In certain of these embodiments, n is 0.

In certain other embodiments (when A is —(YA1)—YA2), n is 1. In certain of these embodiments, YA1is C1-6alkylene, which is optionally substituted with 1-4 Ra.

(e.g., YA1is CH2). As a non-limiting example of the foregoing embodiments, YA1can be —CH2— or —CH2CH2—.

As a non-limiting example, YA1can be —CH2—. As another non-limiting example, YA1can be

or —CH2CH2—. As another non-limiting example, YA1can be

In certain embodiments, YA2is C6-10aryl, which is optionally substituted with 1-3 Rc.

In certain of these embodiments, YA2is C6aryl, which is optionally substituted with 1-3 Rc.

In certain embodiments, YA2is C6aryl, which is substituted with 1-3 Rc.

In certain embodiments, YA2is phenyl substituted with 1-3 Rc, wherein one Rcis at the ring carbon para to the point of attachment to YA1.

In certain embodiments, YA2is phenyl substituted with 1-3 Rc, wherein 1-2 Rcis at the ring carbons meta to the point of attachment to YA1.

In certain embodiments, YA2is phenyl substituted with 1-3 Rc, wherein 1-2 Rcis at the ring carbons ortho to the point of attachment to YA1.

or tetrahydronapthyl, each of which is optionally substituted with 1-3 Rc).

In certain embodiments, YA2is heteroaryl of 5-14 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Rc.

In certain of the foregoing embodiments, YA2is heteroaryl of 6 ring atoms (e.g., pyridyl or pyrimidinyl (e.g., pyridyl)), wherein 1-2 ring atoms are ring nitrogen atoms, and wherein the heteroaryl ring is optionally substituted with 1-3 independently selected Rc.

In certain of the foregoing embodiments, YA2is heteroaryl of 6 ring atoms (e.g., pyridyl or pyrimidinyl (e.g., pyridyl)), YA2is substituted with 1-3 independently selected Rc; and one occurrence of Rcis at the ring carbon atom para to the point of attachment to YA1(e.g.,

In certain of the foregoing embodiments, YA2is heteroaryl of 6 ring atoms (e.g., pyridyl or pyrimidinyl (e.g., pyridyl)), YA2is substituted with 1-3 independently selected Rc; and one occurrence of Rcis at the ring carbon atom meta to the point of attachment to YA1.

In certain embodiments, YA2is bicyclic or tricyclic heteroaryl of 7-14 (e.g., 9-12 (e.g., 9, 10, 11, or 12)) ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Rc.

In certain of these embodiments, YA2is bicyclic heteroaryl of 9-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Rc.

As a non-limiting example of the foregoing embodiments, YA2can be bicyclic heteroaryl of 10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2(e.g.,

and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Rc.

In certain of the foregoing embodiments (wherein YA2is aryl or heteroaryl as described supra), each occurrence of Rcis independently selected from the group consisting of: halo; cyano; C1-10alkyl which is optionally substituted with 1-6 independently selected Ra; C2-6alkenyl; C2-6alkynyl; C1-4alkoxy; C1-4haloalkoxy; —S(O)1-2(C1-4alkyl); —NReRf; —C1-4thioalkoxy; —C(═O)(C1-10alkyl); —C(═O)(OH); —C(═O)O(C1-4alkyl); and -L1-L2-Rh.

In certain embodiments, one occurrence of Reis halo (e.g., F or Cl (e.g., Cl)).

In certain embodiments, one occurrence of Rcis C2-6alkynyl (e.g.,

In certain embodiments, one occurrence of Rcis C1-4alkoxy or C1-4haloalkoxy (e.g., OCF3). In certain embodiments, one occurrence of Rcis SF5. In certain embodiments, one occurrence of Rcis S(O)2(C1-4haloalkyl) (e.g., S(O)2CF3). In certain embodiments, one occurrence of Rcis C1-4thiohaloalkoxy (e.g., SCF3).

In certain embodiments, one occurrence of Reis C1-10alkyl which is optionally substituted with 1-6 independently selected Ra.

In certain embodiments (when one occurrence of Rcis C1-10alkyl which is optionally substituted with 1-6 independently selected Ra), the occurrence of Reis C1-10alkyl which is substituted with 1-6 independently selected Ra. In certain of these embodiments, each occurrence of Rais independently selected from halo, OH, C1-4alkoxy, and C1-4haloalkoxy. As a non-limiting example, each occurrence of Rais halo (e.g., F). In certain embodiments (e.g., when one occurrence of Reis C1-10alkyl which is substituted with 1-6 independently selected Ra), the occurrence of Reis CF3.

In certain embodiments, one occurrence of Reis -L1-L2-Rh. In certain of these embodiments, L1is a bond and/or L2is a bond.

In certain embodiments (when one occurrence of Rcis -L1-L2-Rh), Rhis C6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, or C1-4haloalkyl.

In certain embodiments (when one occurrence of Rcis -L1-L2-Rh), Rhis C6aryl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo, C1-4alkyl, or C1-4haloalkyl (e.g.

In certain embodiments (when one occurrence of Rcis -L1-L2-Rh), Rhis heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-10 (e.g., 5-6) ring atoms, wherein 1-3 (e.g., 1-2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl. As a non-limiting example of the foregoing embodiments, Rhcan be

As another non-limiting example, Rhcan be

In certain embodiments (when one occurrence of Rcis -L1-L2-Rh), Rhis C3-8cycloalkyl or C3-8cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl. In certain of these embodiments, Rhis C3-6cycloalkyl or C3-6cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl. As non-limiting examples, Rhcan be selected from the group consisting of:

In any one of more of the foregoing embodiments of Rc, each of the remaining occurrences of Rcis C1-6alkyl or halo.

In certain embodiments, YA2is monocyclic C3-10cycloalkyl or C3310 cycloalkenyl, each of which is optionally substituted with 1-4 Rb.

In certain embodiments, YA2is cyclohexyl which is optionally substituted with 1-2 Rb.

In certain embodiments (when YA2is cyclohexyl which is optionally substituted with 1-2 Rb), one occurrence of Rbis at the ring carbon atom para to the point of attachment to YA1; or one occurrence of Rbis at the ring carbon atom meta to the point of attachment to YA1. For example, YA2can be

such as

In certain embodiments (when YA2is cyclohexyl which is optionally substituted with 1-2 Rb), two occurrences of Rbare at the ring carbon atom para to the point of attachment to YA1; or two occurrences of Rbare at the ring carbon atom meta to the point of attachment to YA1.

In certain embodiments, YA2is cyclobutyl which is substituted with 1-2 Rb, such as wherein YA2is

In certain embodiments, YA2is cyclopropyl which is substituted with 1-2 Rb. As a non-limiting example, YA2can be cyclopropyl substituted with -L1-L2-Rh(e.g.,

As another example, YA2can be

In certain of these embodiments, YA2is selected from the group consisting of: spiro[5.5]undecanyl (e.g.,

and adamantly (e.g.,

For example, YA2can be

In certain embodiments, YA2is heterocyclyl or heterocycloalkenyl of 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl ring is optionally substituted with 1-3 independently selected Rb.

In certain embodiments, YA2is heterocyclyl or heterocycloalkenyl of 4-10 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl ring is optionally substituted with 1-3 independently selected Rb.

In certain of these embodiments, one occurrence of Rbsubstituent of YA2is C1-10alkyl which is optionally substituted with 1-6 independently selected Ra.

In certain of these embodiments, one occurrence of Rbsubstituent of YA2is unsubstituted C1-10alkyl (e.g., C2, C3, C4, C5, C6, or C7-10). As a non-limiting example of the foregoing embodiments, one occurrence of Rbsubstituent of YA2can be ethyl, propyl (e.g., n-propyl), butyl (e.g., n-butyl; or sec-butyl; or tert-butyl; or iso-butyl), or octyl (e.g., n-octyl).

In certain embodiments, one occurrence of Rbsubstituent of YA2is C1-10alkyl which is substituted with 1-6 independently selected Ra. In certain of these embodiments, each occurrence of Rais independently selected from halo, OH, C1-4alkoxy, and C1-4haloalkoxy. For example, one or more occurrences of Racan be an independently selected halo (which can be the same or different halo); e.g., fluro, and Rbcan be CF3or —CF2CH3.

In certain embodiments, one occurrence of Rbsubstituent of YA2is -L1-L2-Rh(e.g., —Rhor —CH2—Rhsuch as benzyl).

In certain embodiments, one occurrence of Rbsubstituent of YA2is C1-4alkoxy or C1-4haloalkoxy (e.g.,

In certain embodiments, one occurrence of Rbis —F or —Cl (e.g., —F).

In certain embodiments, YA2is

n1 is 0, 1, or 2; and each of RcAand RcBis an independently selected Rc.

In certain embodiments, YA2is

n1 is 0, 1, or 2; and each of RcAand RcBis an independently selected Rc.

In certain embodiments, YA2is

one of Q1and Q2is N; the other one of Q1and Q2is CH; n1 is 0, 1, or 2; and each of RcAand RcBis an independently selected Rc.

In certain embodiments, YA2is

one of Q1, Q2, Q3, and Q4is N; each of the remaining of Q1, Q2, Q3, and Q4is CH; n1 is 0, 1, or 2; and each of RcAand RcBis an independently selected Rc.

In certain embodiments (when YA2is

In certain embodiments when YA2is

In certain embodiments (when YA2is

RcAis C1-10alkyl which is substituted with 1-6 independently selected Ra(e.g., each occurrence of Rais independently selected from halo, OH, C1-4alkoxy, and C1-4haloalkoxy). In certain of these embodiments, RcAis C1-10alkyl which is substituted with 1-6 independently selected halo (e.g., RcAis CF3).

In certain embodiments (when YA2is

In certain embodiments (when YA2is

In certain embodiments (when YA2is

In certain of these embodiments, -L1is a bond. In certain embodiments (when RcAis -L1-L2-Rh), -L2is a bond.

In certain embodiments (when RcAis -L1-L2-Rh), Rhis C6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1. 4 alkyl, or C1-4haloalkyl, such as C6aryl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo, C1-4alkyl, or C1-4haloalkyl (e.g.,

In certain embodiments (when RcAis -L1-L2-Rh), Rhis heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-10 (e.g., 5-6) ring atoms, wherein 1-3 (e.g., 1-2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl, such as

In certain embodiments (when YA2is

In certain embodiments (when YA2is

n1 is 1 or 2 (e.g., 1). In certain of these embodiments, each occurrence of RcBis independently halo or C1-3alkyl (e.g., halo).

In certain embodiments, YA2is

wherein Q5is N or CH; m1 and m2 are independently 0, 1, or 2; n2 is 0, 1, or 2; and each of RbAand RbBis an independently selected Rb.

In certain of these embodiments, Q5is CH.

In certain embodiments, YA2is

n2 is 0, 1, or 2; and each of RbAand RbBis an independently selected Rb.

In certain embodiments, YA2is

n2 is 0, 1, or 2; and each of RbAand RbBis an independently selected Rb.

In certain embodiments, YA2is

n2 is 0, 1, or 2; and each of RbAand RbBis an independently selected Rb.

In certain embodiments, YA2is

n2 is 0, 1, or 2; and each of RbAand RbBis an independently selected Rb.

In certain embodiments, YA2is

and Q5is N. In certain of these embodiments, YA2is

n2 is 0, 1, or 2; and each of RbAand RbBis an independently selected Rb.

In certain embodiments (when YA2is

RbAis C1-10alkyl which is optionally substituted with 1-6 independently selected Ra.

In certain embodiments (when YA2is

In certain embodiments (when YA2is

RbAis C1-10alkyl which is substituted with 1-6 independently selected Ra(e.g., each Rais selected from the group consisting of halo, OH, C1-4alkoxy, and C1-4haloalkoxy) (e.g., RbAis CF3or —CF2CH3).

In certain embodiments (when YA2is

In certain embodiments (when YA2is

RbAis -L1-L2-Rh(e.g., —Rhor —CH2—Rhsuch as benzyl). In certain of these embodiments, RbAis —Rh, —O—Rh, or —CH2—Rh. In certain of the foregoing embodiments, Rhis selected from the group consisting of:

Rhis heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are ring nitrogen atoms and wherein the heteroaryl ring is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy; and

C6aryl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy.

In certain embodiments (when YA2is

In certain embodiments (when YA2is

In certain embodiments (when YA2is

In certain other embodiments, n2 is 1 or 2. In certain of these embodiments, each occurrence RbBis selected from the group consisting of —F, —Cl, and C1-3alkyl.

Non-limiting examples of A include:

Further non-limiting examples of A include:

Further non-limiting examples of A include

In some embodiments, Q-A is as defined according to (B).

In certain embodiments, E is a saturated or partially unsaturated ring of 3-16 ring atoms, wherein 0-3 ring atoms are heteroatoms (in addition to the nitrogen atom that is present), each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the carbon portion of the ring is optionally substituted with 1-4 independently selected Rb.

In certain embodiments, E a ring of 5-8 ring atoms, wherein aside from the nitrogen atom present, 0-3 additional ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the ring is optionally substituted with 1-4 independently selected Rb(e.g., E is piperidinyl which is optionally substituted with 1-2 independently selected Rb(e.g., E is

As a non-limiting example, E can be

In certain embodiments, the compound has the following formula:

wherein n1 is 0, 1, or 2; each of RcAand RcBis an independently selected Rc; and R7is H or C1-4alkyl.

In certain embodiments, the compound has the following formula:

wherein n1 is 0, 1, or 2; each of RcAand RcBis an independently selected Rc; and R7is H or C1-4alkyl.

In certain embodiments, the compound has the following formula:

wherein one of Q1and Q2is N; the other one of Q1and Q2is CH; n1 is 0, 1, or 2; each of RcAand RcBis an independently selected Rc; and R7is H or C1-4alkyl.

In certain embodiments, the compound has the following formula:

wherein one of Q1, Q2, Q3, and Q4is N; each of the remaining of Qi, Q2, Q3, Q4is CH; n1 is 0, 1, or 2; and each of RcAand RcBis an independently selected Rc; and R7is H or C1-4alkyl.

In certain embodiments, the compound has the following formula:

wherein B1 is selected from the group consisting of:

(a) bicyclic or tricyclic heteroaryl of 7-14 (e.g., 9-12 (e.g., 9, 10, 11, or 12)) ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Rc; and

(b) C7-10bicyclic aryl, which is optionally substituted with 1-3 Rc; and R7is H or C1-4alkyl.

In certain embodiments of Formula (I-5), B1 is bicyclic or tricyclic heteroaryl of 9-10 (e.g., 10) ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Rc.

As a non-limiting example of the foregoing embodiments, B1 can be

In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), and (I-4), RcAis selected from the group consisting of: halo; cyano; C1-10alkyl which is optionally substituted with 1-6 independently selected Ra; C2-6alkenyl; C2-6alkynyl; C1-4alkoxy; C1-4haloalkoxy; —S(O)1-2(C1-4alkyl); —NReRf; —C1-4thioalkoxy; —C(═O)(C1-10alkyl); —C(═O)(OH); —C(═O)O(C1-4alkyl); and -L1-L2-Rh.

In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), and (I-4), RcAis C1-10alkyl which is substituted with 1-6 independently selected Ra(e.g., each occurrence of Rais independently selected from halo, OH, C1-4alkoxy, and C1-4haloalkoxy).

In certain of these embodiments, RcAis C1-10alkyl which is substituted with 1-6 independently selected halo (e.g., RcAis CF3).

In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), and (I-4), RcAis C2-6alkynyl (e.g.,

In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), and (I-4), RcA is C1-4alkoxy or C1-4haloalkoxy.

In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), and (I-4), RcAis -L1-L2-Rh. In certain of these embodiments, -L1is a bond. In certain embodiments (when RcAis -L1-L2-Rh), -L2is a bond.

In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), and (I-4) (when RcAis -L1-L2-Rh), Rhis C6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, or C1-4haloalkyl, such as C6aryl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo, C1-4alkyl, or C1-4haloalkyl (e.g.,

In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), and (I-4) (when RcAis -L1-L2-Rh), Rhis heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-10 (e.g., 5-6) ring atoms, wherein 1-3 (e.g., 1-2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl, such as

In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), and (I-4) (when RcAis -L1-L2-Rh), Rhis C3-8(e.g., C3-6) cycloalkyl or C3-8(e.g., C3-6) cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl (e.g., Rhis cyclohexyl).

In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), and (I-4), n1 is 0.

In certain other embodiments, n1 is 1 or 2 (e.g., 1). In certain of these embodiments, each occurrence of RcBis independently halo or C1-3alkyl (e.g., halo).

In certain embodiments, the compound has the following formula:

wherein n2 is 0, 1, or 2; each of RbAand RbBis an independently selected Rh; and R7is H or C1-4alkyl.

In certain embodiments, the compound has the following formula:

wherein n2 is 0, 1, or 2; each of RbAand RbBis an independently selected Rb; and R7is H or C1-4alkyl.

In certain embodiments, the compound has the following formula:

wherein n2 is 0, 1, or 2; each of RbAand RbBis an independently selected Rb; and R7is H or C1-4alkyl.

In certain embodiments, the compound has the following formula:

wherein n2 is 0, 1, or 2; each of RbAand RbBis an independently selected Rb; and R7is H or C1-4alkyl.

In certain embodiments, the compound has the following formula:

wherein B2is selected from the group consisting of:

bicyclic, tricyclic, or polycyclic heterocyclyl of 8-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl ring is optionally substituted with 1-4 independently selected Rb;

R7is H or C1-4alkyl.

In certain embodiments, the compound has the following formula:

R7is H or C1-4alkyl.

In certain of these embodiments, B2is: bicyclic, tricyclic, or polycyclic C7-12cycloalkyl or C7-12cycloalkenyl, each optionally substituted with 1-2 Rb.

In certain embodiments of Formula (I-8), B2is selected from the group consisting of: spiro[5.5]undecanyl (e.g.,

and adamantly (e.g.,

In certain embodiments of any one or more of Formulae (I-6) and (I-7), RbAis C1-10alkyl which is optionally substituted with 1-6 independently selected Ra.

In certain other embodiments, RbAis C1-10alkyl which is substituted with 1-6 independently selected Ra(e.g., each Rais selected from the group consisting of halo, OH, C1-4alkoxy, and C1-4haloalkoxy) (e.g., RbAis CF3).

In certain embodiments of any one or more of Formulae (I-6) and (I-7), RbAis —F or —Cl.

In certain embodiments of any one or more of Formulae (I-6) and (I-7), RbAis -L1-L2-Rh(e.g., —Rhor —CH2—Rhsuch as benzyl).

In certain embodiments of any one or more of Formulae (I-6) and (I-7), RbAis C1-4alkoxy or C1-4haloalkoxy (e.g.,

In certain embodiments of any one or more of Formulae (I-6) and (I-7), n2 is 0.

In certain other embodiments, n2 is 1 or 2. In certain of these embodiments, each occurrence RbBis selected from the group consisting of —F, —Cl, and C1-3alkyl.

In some embodiments, the compound has the following formula:

(a) C3-10cycloalkyl or C3-10cycloalkenyl, each of which is optionally substituted with 1-2 Rb,

(b) phenyl, which is optionally substituted with 1-2 Rc;

(c) heteroaryl of 5-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-2 independently selected Rc; and

R7is H or C1-4alkyl.

In certain embodiments of Formula (I-10), B2is C3-10cycloalkyl or C3-10cycloalkenyl, each of which is optionally substituted with 1-2 Rb. As a non-limiting example, B2can be C5. 7 cycloalkyl which is unsubstituted, such as unsubstituted cyclohexyl.

In certain embodiments of Formula (I-10), B2is phenyl, which is optionally substituted with 1-2 Re. As a non-limiting example, B2can be unsubstituted phenyl.

In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-11), and (I-12), n is 0.

In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-11), and (I-12),n is 1. In certain of these embodiments, YA1is C1-6alkylene, which is optionally substituted with 1-2 Ra.

As another non-limiting example, YA1can be

In certain embodiments, the compound has the following formula:

E is a ring of 3-16 ring atoms, wherein aside from the nitrogen atom present, 0-3 additional ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the ring is optionally substituted with 1-4 independently selected Rb.

In certain of these embodiments, E is a saturated or partially unsaturated ring of 3-16 ring atoms, wherein 0-3 ring atoms are heteroatoms (in addition to the nitrogen atom that is present), each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the carbon portion of the ring is optionally substituted with 1-4 independently selected Rb.

In certain embodiments of Formula (I-9), E is a ring of 5-8 ring atoms, wherein aside from the nitrogen atom present, 0-3 additional ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the ring is optionally substituted with 1-4 independently selected Rb(e.g., E is piperidinyl which is optionally substituted with 1-2 independently selected Rb(e.g., E is

In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), and (I-12), the

moiety is

In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), and (I-12), the

moiety is

In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), (I-4), (I-5), I-6), (I-7), (1-8), (I-9 (I-10), (I-11), and (I-12), the

moiety is

In certain of these embodiments, L3is a bond; and/or L4is a bond. As a non-limiting example, one of R1a, R1b, R1c, and R1dis R (e.g., R is heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl; or R is C6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, or C1-4haloalkyl).

In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), and (I-12), one of R1a, R1b, R1c, and R1d(such as R1b) is selected from the group consisting of:heteroaryl of 5-6 ring atoms (such as pyrazolyl), wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy (e.g.,

andphenyl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy (e.g.,).

In certain embodiments, the compound is a compound of Formula (I-13):

or a pharmaceutically acceptable salt thereof,

Q5is N or CH;

each of Rtand Rsis independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy.

In certain embodiments of Formula (I-13), R2is H; and R5is H. In certain embodiments of Formula (I-13), R6is H.

In certain embodiments of Formula (I-13), Q5is CH. In certain of these embodiments, L5is —O—. In certain embodiments of Formula (I-13), L5is —N(H)— or —N(C1-3alkyl), such as —N(H)—. In certain embodiments of Formula (I-13), L5is CH2or a bond.

In certain embodiments of Formula (I-13), Q5is N. In certain of these embodiments, L5is CH2. In certain embodiments, L5is a bond.

In certain embodiments of Formula (I-13), ml is 1; and m2 is 1. In certain embodiments of Formula (I-13), ml is 1; and m2 is 0. In certain embodiments of Formula (I-13), m1 is 2; and m2 is 1. In certain embodiments of Formula (I-13), ml is 0; and m2 is 0.

In certain embodiments of Formula (I-13), ml is 1; m2 is 1; Q5is CH; and L5is —O—.

In certain embodiments of Formula (I-13), ml is 0; m2 is 0; Q5is CH; and L5is —O—.

In certain embodiments of Formula (I-13), ml is 1; m2 is 0; Q5is N; and L5is a bond or CH2.

In certain embodiments of Formula (I-13), each of T1, T2, T3, and T4is independently CH or CRt, such as each of T1, T2, T3, and T4is CH. In certain embodiments of Formula (I-13), T1is N; and T2, T3, and T4are independently CH or CRt, such as wherein T1is N; and T2, T3, and T4are CH. In certain embodiments of Formula (I-13), T2is N; and T1, T3, and T4are independently CH or CRt, such as wherein T2is N; and T1, T3, and T4are CH.

In certain embodiments of Formula (I-13), Rsis C1-4alkyl, such as methyl. In certain embodiments of Formula (I-13), Rsis C1-4haloalkyl, such as CF3.

In certain embodiments of Formula (I-13), Rais H; and R1dis H or halo, such as: wherein R1ais H, and R1dis H; or wherein R1ais H, and R1dis halo such as —F or —Cl.

In certain embodiments of Formula (I-13), R1bis Ri; and R1cis H or halo, such as H; such as: wherein R1bis selected from the group consisting of:heteroaryl of 5-6 ring atoms (such as pyrazolyl), wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy (e.g.,

andphenyl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy (e.g.,

In certain embodiments of Formula (I-13), one of R1band R1cis selected from the group consisting of: cyano, C1-3alkyl optionally substituted with Ra, and C1-3haloalkyl; and the other of R1band R1cis H or halo, such as —H, —F, or —Cl.

In certain embodiments of Formula (I-13), R1a, R1b, R1c, and R1dare independently H or halo; R2, R5, and R6are H; and Rsis C1-4alkyl such as methyl or C1-4haloalkyl, such as CF3. In certain of these embodiments, each of T1, T2, T3, and T4is N or CH; and L5is a bond or —O—.

Compound Provisions

In some embodiments, the compound is other than

In some embodiments, when R1a, R1b, and R1dare each H; R1cis H, Me, or Cl; X1is NH; X2is CH or C—C(═O)Me; Q-A is as defined according to (A); A is —(YA1)n—YA2; and n is 0, then YA2is other than unsubstituted phenyl or unsubstituted 4-pyridyl.

In some embodiments, when X1is NH; X2is CH or C—C(═O)Me; Q-A is as defined according to (A); A is —(YA1)n—YA2; and n is 0, then YA2is other than unsubstituted phenyl or unsubstituted 4-pyridyl.

In some embodiments, when Q-A is as defined according to (A); A is —(YA1)n—YA2; and n is 0, then YA2is other than unsubstituted phenyl or unsubstituted 4-pyridyl.

In certain embodiments, the compound is selected from the group consisting of the compounds delineated in Table C1, or a pharmaceutically acceptable salt thereof.

Pharmaceutical Compositions and Administration

General

In some embodiments, a chemical entity (e.g., a compound that inhibits (e.g., antagonizes) STING, or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination thereof) is administered as a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

In some embodiments, the chemical entities can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-o-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%-100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, seeRemington: The Science and Practice of Pharmacy,22ndEdition (Pharmaceutical Press, London, U K. 2012).

Routes of Administration and Composition Components

Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.

Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia.2006, 10, 788-795.

In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.

In other embodiments, the compounds described herein or a pharmaceutical composition thereof are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).

In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP/NF standard is usually sufficient.

In certain embodiments, solid oral dosage forms can further include one or more components that chemically and/or structurally predispose the composition for delivery of the chemical entity to the stomach or the lower GI; e.g., the ascending colon and/or transverse colon and/or distal colon and/or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K. J., et al.,Current Topics in Medicinal Chemistry,2013, 13, 776-802, which is incorporated herein by reference in its entirety.

Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric/pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap.

Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non-sensitizing.

In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

Dosages

The dosages may be varied depending on the requirement of the patient, the severity of the condition being treating and the particular compound being employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.

In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about 0.001 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 150 mg/Kg; from about 0.01 mg/Kg to about 100 mg/Kg; from about 0.01 mg/Kg to about 50 mg/Kg; from about 0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg; from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about 0.5 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0.1 mg/Kg to about 200 mg/Kg; from about 0.1 mg/Kg to about 150 mg/Kg; from about 0.1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 50 mg/Kg; from about 0.1 mg/Kg to about 10 mg/Kg; from about 0.1 mg/Kg to about 5 mg/Kg; from about 0.1 mg/Kg to about 1 mg/Kg; from about 0.1 mg/Kg to about 0.5 mg/Kg).

Regimens

The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

Methods of Treatment

In some embodiments, methods for treating a subject having condition, disease or disorder in which increased (e.g., excessive)STING activity (e.g., e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., immune disorders, cancer) are provided.

Indications

In some embodiments, the condition, disease or disorder is STING-associated conditions, e.g., type I interferonopathies (e.g., STING-associated vasculopathy with onset in infancy (SAVI)), Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis. In certain embodiments, the condition, disease or disorder is an autoimmune disease (e.g., a cytosolic DNA-triggered autoinflammatory disease). Non-limiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel diseases (IBDs) comprising Crohn disease (CD) and ulcerative colitis (UC), which are chronic inflammatory conditions with polygenic susceptibility. In certain embodiments, the condition is an inflammatory bowel disease. In certain embodiments, the condition is Crohn's disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated by one or more alloimmune diseases (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In certain of these embodiments, the condition is alloimmune disease (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis or intestinal mucositis).

In some embodiments, modulation of the immune system by STING provides for the treatment of diseases, including diseases caused by foreign agents. Exemplary infections by foreign agents which may be treated and/or prevented by the method of the present invention include an infection by a bacterium (e.g., a Gram-positive or Gram-negative bacterium), an infection by a fungus, an infection by a parasite, and an infection by a virus. In one embodiment of the present invention, the infection is a bacterial infection (e.g., infection byE. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonellaspp.,Staphylococcus aureus, Streptococcusspp., or vancomycin-resistantenterococcus), or sepsis. In another embodiment, the infection is a fungal infection (e.g. infection by a mould, a yeast, or a higher fungus). In still another embodiment, the infection is a parasitic infection (e.g., infection by a single-celled or multicellular parasite, includingGiardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, andToxoplasma gondiz). In yet another embodiment, the infection is a viral infection (e.g., infection by a virus associated with AIDS, avian flu, chickenpox, cold sores, common cold, gastroenteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, and lower or upper respiratory tract infection (e.g., respiratory syncytial virus)).

In some embodiments, the condition, disease or disorder is hepatits B (see, e.g., WO 2015/061294).

In some embodiments, the condition, disease or disorder is selected from cardiovascular diseases (including e.g., myocardial infarction).

In some embodiments, the condition, disease or disorder is age-related macular degeneration.

In some embodiments, the condition, disease or disorder is mucositis, also known as stomatitits, which can occur as a result of chemotherapy or radiation therapy, either alone or in combination as well as damage caused by exposure to radiation outside of the context of radiation therapy.

In some embodiments, the condition, disease or disorder is uveitis, which is inflammation of the uvea (e.g., anterior uveitis, e.g., iridocyclitis or iritis; intermediate uveitis (also known as pars planitis); posterior uveitis; or chorioretinitis, e.g., pan-uveitis).

In some embodiments, the condition, disease or disorder is selected from the group consisting of a cancer, a neurological disorder, an autoimmune disease, hepatitis B, uvetitis, a cardiovascular disease, age-related macular degeneration, and mucositis.

Still other examples can include those indications discussed herein and below in contemplated combination therapy regimens.

Combination Therapy

This disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

In some embodiments, the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and/or one or more therapeutic regimens) in combination with administration of the compounds described herein.

In certain embodiments, the methods described herein can further include administering one or more additional cancer therapies.

In some embodiments, the one or more additional cancer therapies is chemotherapy, which can include administering one or more additional chemotherapeutic agents.

In certain embodiments, the additional chemotherapeutic agent is an alkylating agent. Alkylating agents are so named because of their ability to alkylate many nucleophilic functional groups under conditions present in cells, including, but not limited to cancer cells. In a further embodiment, an alkylating agent includes, but is not limited to, Cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin. In an embodiment, alkylating agents can function by impairing cell function by forming covalent bonds with the amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules or they can work by modifying a cell's DNA. In a further embodiment an alkylating agent is a synthetic, semisynthetic or derivative.

In certain embodiments, the additional chemotherapeutic agent is an anti-metabolite. Anti-metabolites masquerade as purines or pyrimidines, the building-blocks of DNA and in general, prevent these substances from becoming incorporated in to DNA during the “S” phase (of the cell cycle), stopping normal development and division. Anti-metabolites can also affect RNA synthesis. In an embodiment, an antimetabolite includes, but is not limited to azathioprine and/or mercaptopurine. In a further embodiment an anti-metabolite is a synthetic, semisynthetic or derivative.

In certain embodiments, the additional chemotherapeutic agent is a plant alkaloid and/or terpenoid. These alkaloids are derived from plants and block cell division by, in general, preventing microtubule function. In an embodiment, a plant alkaloid and/or terpenoid is a vinca alkaloid, a podophyllotoxin and/or a taxane. Vinca alkaloids, in general, bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules, generally during the M phase of the cell cycle. In an embodiment, a vinca alkaloid is derived, without limitation, from the Madagascar periwinkle,Catharanthus roseus(formerly known asVinca rosea). In an embodiment, a vinca alkaloid includes, without limitation, Vincristine, Vinblastine, Vinorelbine and/or Vindesine. In an embodiment, a taxane includes, but is not limited, to Taxol, Paclitaxel and/or Docetaxel. In a further embodiment a plant alkaloid or terpernoid is a synthetic, semisynthetic or derivative. In a further embodiment, a podophyllotoxin is, without limitation, an etoposide and/or teniposide. In an embodiment, a taxane is, without limitation, docetaxel and/or ortataxel. [021] In an embodiment, a cancer therapeutic is a topoisomerase. Topoisomerases are essential enzymes that maintain the topology of DNA. Inhibition of type I or type II topoisomerases interferes with both transcription and replication of DNA by upsetting proper DNA supercoiling. In a further embodiment, a topoisomerase is, without limitation, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In an embodiment a type I topoisomerase inhibitor is, without limitation, a camptothecin. In another embodiment, a camptothecin is, without limitation, exatecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67) and/or ST 1481. In an embodiment, a type II topoisomerase inhibitor is, without limitation, epipodophyllotoxin. In a further embodiment an epipodophyllotoxin is, without limitation, an amsacrine, etoposid, etoposide phosphate and/or teniposide. In a further embodiment a topoisomerase is a synthetic, semisynthetic or derivative, including those found in nature such as, without limitation, epipodophyllotoxins, substances naturally occurring in the root of American Mayapple (Podophyllum peltatum).

In still other embodiments, the additional chemotherapeutic agent can be selected from those delineated in U.S. Pat. No. 7,927,613, which is incorporated herein by reference in its entirety.

In some embodiments, the additional therapeutic agent and/or regimen are those that can be used for treating other STING-associated conditions, e.g., type I interferonopathies (e.g., STING-associated vasculopathy with onset in infancy (SAVI)), Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis and the like.

Non-limiting examples of additional therapeutic agents and/or regimens for treating STING-associated vasculopathy with onset in infancy (SAVI) include JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).

Non-limiting examples of additional therapeutic agents and/or regimens for treating colitis associated with one or more alloimmune diseases include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), sulfasalazine, and eicopentaenoic acid.

In certain embodiments, the second therapeutic agent or regimen is administered to the subject prior to contacting with or administering the chemical entity (e.g., about one hour prior, or about 6 hours prior, or about 12 hours prior, or about 24 hours prior, or about 48 hours prior, or about 1 week prior, or about 1 month prior).

In other embodiments, the second therapeutic agent or regimen is administered to the subject at about the same time as contacting with or administering the chemical entity. By way of example, the second therapeutic agent or regimen and the chemical entity are provided to the subject simultaneously in the same dosage form. As another example, the second therapeutic agent or regimen and the chemical entity are provided to the subject concurrently in separate dosage forms.

In still other embodiments, the second therapeutic agent or regimen is administered to the subject after contacting with or administering the chemical entity (e.g., about one hour after, or about 6 hours after, or about 12 hours after, or about 24 hours after, or about 48 hours after, or about 1 week after, or about 1 month after).

Patient Selection

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of such treatment (e.g., by way of biopsy, endoscopy, or other conventional method known in the art). In certain embodiments, the STING protein can serve as a biomarker for certain types of cancer, e.g., colon cancer and prostate cancer. In other embodiments, identifying a subject can include assaying the patient's tumor microenvironment for the absence of T-cells and/or presence of exhausted T-cells, e.g., patients having one or more cold tumors. Such patients can include those that are resistant to treatment with checkpoint inhibitors. In certain embodiments, such patients can be treated with a chemical entity herein, e.g., to recruit T-cells into the tumor, and in some cases, further treated with one or more checkpoint inhibitors, e.g., once the T-cells become exhausted.

In some embodiments, the chemical entities, methods, and compositions described herein can be administered to certain treatment-resistant patient populations (e.g., patients resistant to checkpoint inhibitors; e.g., patients having one or more cold tumors, e.g., tumors lacking T-cells or exhausted T-cells).

Compound Preparation

As can be appreciated by the skilled artisan, methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available. The skilled artisan will also recognize that conditions and reagents described herein that can be interchanged with alternative art-recognized equivalents. For example, in many reactions, triethylamine can be interchanged with other bases, such as non-nucleophilic bases (e.g. diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene).

The skilled artisan will recognize a variety of analytical methods that can be used to characterize the compounds described herein, including, for example,1H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy. The foregoing list is a subset of characterization methods available to a skilled artisan and is not intended to be limiting.

To further illustrate the foregoing, the following non-limiting, exemplary synthetic schemes are included. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the invention as described, and claimed herein. The reader will recognize that the skilled artisan, provided with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples.

The following abbreviations have the indicated meanings:

Materials and Methods

The progress of reactions was often monitored by TLC or LC-MS. The identity of the products was often confirmed by LC-MS. The LC-MS was recorded using one of the following methods.

Additional LCMS Analysis Conditions

Method AA

Instrument: Agilent LCMS system equipped with DAD and ELSD detector

Ion mode: Positive

Gradient: 4.5 min gradient method, actual method would depend on c log P of compound.

Method AB

Instrument: Agilent LCMS system equipped with DAD and ELSD detector

Ion mode: Positive

Gradient: 4.5 min gradient method; actual method would depend on the c log P of the compound.

Prep-HPLC was carried out using the following methods.

Column

Gradient: actual method would depend on clog P of compound

Detector: MS Trigger or UV

EXAMPLES

Intermediates

Step 1—Synthesis of 5,6-difluoro-3-nitrol-1H-indole: 5,6-Difluoro-1H-indole (5.0 g, 32.7 mmol, 1.0 equiv) was dissolved in CH3CN (50.0 mL), and AgNO3(6.1 g, 36.0 mmol, 1.1 equiv) was added in portions. The resulting solution was then cooled to 0° C., and after 5 minutes, benzoyl chloride (4.1 mL, 36.0 mmol, 1.1 equiv) was added. The resulting solution was allowed to warm to RT for 2 h, and then the pH of the reaction mixture was adjusted to pH 8 by dropwise addition of 1 M aqueous Na2CO3solution. The mixture was extracted with EtOAc (150 mL×3) and the organic layers were combined and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (5/95) to give 5,6-difluoro-3-nitro-1H-indole (3.5 g, 17.7 mmol) as a yellow solid. LC-MS Method B, MS-ESI: 199.1 [M+H+]. Alternatively, the residue can be purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0-100% EtOAc/Petroleum ether gradient @ 30 mL/min) to give 5,6-difluoro-3-nitro-1H-indole (2.9 g, 13.5 mmol) as a yellow solid. MS-ESI, 199.1 [M+H+].

Step 2—Synthesis of 5,6-difluoro-1H-indol-3-amine (Intermediate 1): 5,6-Difluoro-3-nitro-1H-indole (3.5 g, 17.7 mmol, 1.0 equiv) was dissolved in 40% HBr/H2O (40 mL), then SnCl2(16.8 g, 88.5 mmol, 5.0 equiv) was added and the reaction mixture was heated to 70° C. for 30 minutes. The reaction mixture was cooled to RT, and the pH was adjusted to pH 8 by dropwise addition of 1 M aqueous NaOH. The mixture was extracted with DCM (150 mL×5) and the combined organic layers were concentrated in vacuo. The residue was used in the next step directly without further purification. LCMS Method B, MS-ESI: 169.1 [M+H+].

Step 2—Synthesis of [[4-(trifluoromethyl)phenyl]carbamoyl]formic acid (Intermediate 2): Ethyl [[4-(trifluoro-methyl)phenyl]carbamoyl]formate (600.0 mg, 2.3 mmol, 1.0 equiv) was added to a mixture of THF (15.0 mL) and H2O (5.0 mL), then LiOH (275.1 mg, 11.5 mmol, 5.0 equiv) was added and the reaction mixture was stirred for 2 h at RT. The reaction mixture was adjusted to pH 5 with concentrated HCl. The aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give [[4-(trifluoromethyl)phenyl]carbamoyl]formic acid (500.0 mg, 2.2 mmol) as a yellow oil. LCMS: Method A, MS-ESI: 232.1 [M−H−].

Step 1—Synthesis of ethyl [[3-(trifluoromethyl)phenyl]carbamoyl]formate: The title compound was prepared using the same methods described in Intermediate 2, Step 1. LC-MS: Method A, MS-ESI: 262.1 [M+H+].

Step 2—Synthesis of [[3-(trifluoromethyl)phenyl]carbamoyl] formic acid (Intermediate 3): The title compound was prepared using the same methods described in Intermediate 2, Step 2. LC-MS: Method A, MS-ESI: 232.1 [M−H−].

Step 1—Synthesis of ethyl [(4-ethylcyclohexyl)carbamoyl]formate: The title compound was prepared using the same methods described in Intermediate 2, Step 1. LC-MS: Method A, MS-ESI: 228.1 [M+H+].

Step 2—Synthesis of [(4-ethylcyclohexyl)carbamoyl]formic acid (Intermediate 4): The title compound was prepared using the same methods described in Intermediate 2, Step 2. LC-MS: Method B, MS-ESI: 198.1 [M−H−].

Step 1—Synthesis of ethyl [methyl[4-(trifluoromethyl)phenyl]carbamoyl]formate: The title compound was prepared using the same methods described in Intermediate 2, Step 1. LC-MS: Method B, MS-ESI: 276.1 [M+H+].

Step 2—Synthesis of [methyl[4-(trifluoromethyl)phenyl]carbamoyl]formate (Intermediate 5): The title compound was prepared using the same methods described in Intermediate 2, Step 2. LC-MS: Method B, MS-ESI: 246.1 [M−H−].

Step 1—Synthesis of ethyl 2-(4-ethylpiperidin-1-yl)-2-oxoacetate: The title compound was prepared using the same methods described in Intermediate 2, Step 1. LC-MS: Method B, MS-ESI: 214.1 [M+H+].

Step 2—Synthesis of (4-ethylpiperidin-1-y)(oxo)acetic acid (Intermediate 6): The title compound was prepared using the same methods described in Intermediate 2, Step 2. LC-MS: Method B, MS-ESI: 184.1 [M−H−].

Step 2—Synthesis of 6-cyclohexylpyridin-3-amine (Intermediate 8): To a mixture of 6-(cyclohexen-1-yl)pyridin-3-amine (3.0 g, 17.2 mmol, 1.0 equiv.) in MeOH (40 mL) under an atmosphere of N2was added Pd/C (3.0 g, 10% wt/wt %, 0.28 mmol, 0.02 equiv.) in one portion. The suspension evacuated under vacuum and backfilled with H2(g) 3 times. The mixture was stirred at 25° C. for 16 hours under an atmosphere of hydrogen (balloon). The reaction mixture was filtered through a pad of Celite and concentrated in vacuo to give 6-cyclohexylpyridin-3-amine (2.1 g, 11.9 mmol) as a white solid. MS-ESI, 176.8 [M+H+].

Step 1—Synthesis of ethyl 2-((3-methyl-5-(trifluoromethyl)phenyl)amino)-2-oxoacetate: To a mixture of 3-methyl-5-(trifluoromethyl)aniline (2.0 g, 11.4 mmol, 1.0 equiv.) in THF (80 mL) was added a solution of ethyl 2-chloro-2-oxoacetate (1.7 g, 12.6 mmol, 1.1 equiv.) in THF (20 mL) over 5 minutes at 0° C. Then TEA (4.0 mL, 28.6 mmol, 2.5 equiv.) was added to the reaction mixture. The mixture was stirred at 30° C. for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to give ethyl 2-((3-methyl-5-(trifluoromethyl)phenyl)amino)-2-oxoacetate (2.7 g, 9.7 mmol) as a yellow oil that was used without additional purification.

Step 2—Synthesis of 2-((3-methyl-5-(trifluoromethyl)phenyl)amino)-2-oxoacetic acid (Intermediate 9): To a mixture of ethyl 2-((3-methyl-5-(trifluoromethyl)phenyl)amino)-2-oxoacetate (2.7 g, 9.7 mmol 1 equiv.) in MeOH (80 mL) was added aqueous NaOH (2 M, 7.3 mL, 14.6 mmol, 1.5 equiv.). The mixture was stirred at 30° C. for 2 hours. The reaction mixture concentrated under reduced pressure to give a residue. Then H2O (30 mL) was added and the mixture was adjusted to pH 4 by the dropwise addition of 2 M HCl. The resulting solid was collected by filtration and washed with water to give 2-((3-methyl-5-(trifluoromethyl)phenyl)amino)-2-oxoacetic acid (2.0 g, 8.1 mmol) as a white solid. MS-ESI, 248.1 [M+H+].

Synthesis of intermediate BI (5,6-difluoro-1H-indol-3-amine hydrochloride)

5,6-Difluoro-1H-indole (25.0 g, 163.3 mmol, 1.0 equiv.) was dissolved in in ACN (300 mL) and cooled to 0° C., then AgNO3(33.3 g, 195.9 mmol, 1.2 equiv.) was added. The resulting mixture was stirred for 15 min at 0° C., then benzoyl chloride (27.5 g, 195.9 mmol, 1.2 equiv.) was added batchwise, maintaining the reaction mixture at 0° C. After an additional 3 hours at 0° C. the reaction mixture was quenched by the addition of ice-water. The reaction mixture was adjusted to pH 8 with saturated aqueous NaHCO3, extracted with DCM, and the combined organic layers were concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (2:1) to give 5,6-difluoro-3-nitro-1H-indole (24.2 g) as a brown solid. LCMS Method CA: [M+H]+=199.

5,6-Difluoro-3-nitro-1H-indole (24.0 g, 121.1 mmol, 1.0 equiv.) was dissolved in MeOH (300 mL), then Pd/C (10% wt., 2.4 g) and (Boc)2O (39.7 g, 181.7 mmol, 1.5 equiv.) were added under nitrogen. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred overnight at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give tert-butyl N-(5,6-difluoro-1H-indol-3-yl)carbamate (22.4 g) as a yellow solid. LCMS Method CD: [M+H]+=269.

tert-Butyl N-(5,6-difluoro-H-indol-3-yl)carbamate (17.0 g, 63.4 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4N, 200 mL). The resulting mixture was stirred for 30 min at ambient temperature and then concentrated under vacuum to give 5,6-difluoro-1H-indol-3-amine hydrochloride (12.3 g) as a yellow solid that was used without any additional purification. LCMS Method CD: [M+H]+=169.

The following intermediates were prepared using the method described for Intermediate B1.

Synthesis of Intermediate B6 (3-(4-(trifluoromethyl)phenoxy)piperidine)

Piperidin-3-ol (369.8 mg, 3.6 mmol, 1.0 equiv.) was dissolved in DMF (10 mL) and cooled to 0° C., then NaH (60% wt in mineral oil, 292.0 mg, 7.3 mmol, 2.0 equiv.) was added at 0° C. After 20 min at 0° C., 1-fluoro-4-(trifluoromethyl)benzene (600.0 mg, 3.6 mmol, 1.0 equiv.) was added, maintaining the solution at 0° C. The reaction mixture was heated to 60° C. for 3 hours, then cooled to ambient temperature and quenched by the addition of ice water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 3-[4-(trifluoromethyl)phenoxy]piperidine (390.0 mg) as a brown oil. LCMS Method CC: [M+H]+=246.

The following intermediates were prepared using the method described for Intermediate B6.

tert-Butyl N-[cis-3-hydroxycyclobutyl]carbamate (2.2 g, 12.1 mmol, 2.0 equiv) was dissolved in DMF (10 mL) and cooled to 0° C., then NaH (60% wt in mineral oil, 363.4 mg, 15.1 mmol, 2.5 equiv.) was added in portions, maintaining the solution at 0° C. After 30 min at 0° C., 5-fluoro-2-(trifluoromethyl)pyridine (1.0 g, 6.1 mmol, 1.0 equiv.) was added. The reaction mixture was stirred for 1 hour at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give tert-butyl N-[cis-3-[[6-(trifluoromethyl)pyridin-3-yl]oxy]cyclobutyl]carbamate (1.5 g) as a white solid. LCMS Method CA: [M+H]+=333.

tert-Butyl N-[cis-3-[[6-(trifluoromethyl)pyridin-3-yl]oxy]cyclobutyl]carbamate (660.0 mg, 1.9 mmol, 1.0 equiv.) was dissolved in ethyl acetate (8 mL), then HCl/1,4-dioxane (4N, 10 mL) was added. The resulting mixture was stirred for 30 min at ambient temperature and then concentrated under vacuum to give cis-3-[[6-(trifluoromethyl)pyridin-3-yl]oxy]cyclobutan-1-amine hydrochloride (540.0 mg) as an off-white solid that was used without additional purification. LCMS Method CA: [M+H]+=233.

The following intermediates were prepared using the method described for Intermediate B12.

The title compound was prepared using the same methods described for Intermediate B12, Step 2. LCMS: Method CA, [M+H]+=246.

The title compound was prepared using the same methods described for Intermediate B12, Step 2. LCMS: Method CA, [M+H]+=232.

The following intermediates were prepared using the method described for Intermediate B25.

The title compound was prepared using the same methods described for Intermediate B12, Step 2. LCMS: Method CA, [M+H]+=197.

The title compound was prepared using the same methods described for Intermediate B12, Step 2. LCMS: Method CC, [M+H]+=245.

The following intermediate was prepared using the method described for Intermediate B31.

The title compound was prepared using the same methods described for Intermediate B12, Step 2. LCMS: Method CC, [M+H]+=178.

The following intermediate was prepared using the method described for Intermediate B33.

7-Bromo-2H,3H,4H-pyrido[3,2-b][1,4]oxazine (3.0 g, 14.0 mmol, 1.0 equiv.) was dissolved in THE (50 mL) and cooled to 0° C., then NaH (60% wt in mineral oil, 1.1 g, 28.0 mmol, 2.0 equiv.) was added, maintaining the solution at 0° C. After 30 min at 0° C., Mel (1.0 mL, 16.8 mmol, 1.2 equiv.) was added. The reaction mixture was stirred for additional 4 hours at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 7-bromo-4-methyl-2H,3H-pyrido[3,2-b][1,4]oxazine (2.3 g) as a pale yellow solid. LCMS Method CA: [M+H]+=230.

The title compound was prepared using the same methods described for Intermediate B12, Step 2. LCMS: Method CC, [M+H]+=166.

Synthesis of Intermediate B36 (5-amino-2-(pyrrolidin-1-yl)nicotinonitrile)

2-Chloro-5-nitropyridine-3-carbonitrile (500.0 mg, 2.7 mmol, 1.0 equiv.) was dissolved in DMF (10 mL), then pyrrolidine (193.7 mg, 2.7 mmol, 1.0 equiv.) and DIEA (0.2 mL, 5.4 mmol, 2.0 equiv.) were added. The resulting solution was heated to 80° C. for 3 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give crude 5-nitro-2-(pyrrolidin-1-yl)pyridine-3-carbonitrile (600.0 mg) as an off-white solid. LCMS Method CB: [M+H]+=219.

5-Nitro-2-(pyrrolidin-1-yl)pyridine-3-carbonitrile (580.0 mg, 2.6 mmol, 1.0 equiv.) was dissolved in MeOH (30 mL), then Pt/C (58.5 mg, wet) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 3 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18; mobile phase, ACN in water, 0% to 100% gradient in 15 min; detector, UV 254 nm. This gave 5-amino-2-(pyrrolidin-1-yl)pyridine-3-carbonitrile (412.5 mg) as an off-white solid. LCMS Method CB: [M+H]+=189.

6-Chloropyridine-2-carbonitrile (100.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in DMF (15 mL), then piperidine (61.4 mg, 0.7 mmol, 1.0 equiv.) and DBU (329.6 mg, 2.2 mmol, 3.0 equiv.) were added. The reaction mixture was heated to 110° C. for 16 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4and concentrated under vacuum to give 6-(piperidin-1-yl)pyridine-2-carbonitrile (105.3 mg) as a yellow oil. LCMS Method CD: [M+H]+=188.

The title compound was prepared using the same methods described for Intermediate B12, Step 2. LCMS: Method CC, [M+H]+=192.

The title compound was prepared using the same methods described for Intermediate B12, Step 2. LCMS: Method CA, [M+H]+=245.

6-Bromo-5-fluoropyridine-3-carboxylic acid (500.0 mg, 2.2 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (10 mL) and water (1 mL), then Cs2CO3(1.5 g, 4.5 mmol, 2.0 equiv.), Pd(dppf)Cl2(166.3 mg, 0.2 mmol, 0.1 equiv.) and 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (832.1 mg, 3.4 mmol, 1.5 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 90° C. for 8 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water and then washed with ethyl acetate. The aqueous layer was adjusted to pH 1 with aqueous HCl (2 M). The solids were collected by filtration and dried to give 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoronicotinic acid (452.4 mg) as a white solid. LCMS Method CB: [M−H]−=256.

6-(4,4-Difluorocyclohex-1-en-1-yl)-5-fluoronicotinic acid (450.0 mg, 1.7 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL), then Pd/C (45.5 mg, 10% wt.) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 5 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum to give 6-(4,4-difluorocyclohexyl)-5-fluoropyridine-3-carboxylic acid (422.5 mg) as a white solid. LCMS Method CB: [M−H]−=258.

6-(4,4-Difluorocyclohexyl)-5-fluoropyridine-3-carboxamide (210.0 mg, 0.8 mmol, 1.0 equiv.) and TEA (0.2 mL, 1.6 mmol, 2.0 equiv.) were dissolved in THE (10 mL), then TFAA (341.6 mg, 1.6 mmol, 2.0 equiv.) was added. The resulting solution was stirred for 2 hours at ambient temperature, then quenched by the addition of water. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4and concentrated under vacuum to give 6-(4,4-difluorocyclohexyl)-5-fluoropyridine-3-carbonitrile (181.2 mg) as a white solid. LCMS Method CH: [M+H]+=241.

6-(4,4-Difluorocyclohexyl)-5-fluoropyridine-3-carbonitrile (180.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL), then NiCl2.6H2O (356.2 mg, 1.5 mmol, 2.0 equiv.) and Boc2O (327.0 mg, 1.5 mmol, 2.0 equiv.) were added. This was followed by the addition of NaBH4(56.7 mg, 1.5 mmol, 2.0 equiv.). The reaction mixture was stirred for 3 hours at ambient temperature and then quenched by the addition of water. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give tert-butyl N-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]carbamate (121.3 mg) as a white solid. LCMS Method CA: [M+H]+=345.

The title compound was prepared using the same methods described for Intermediate B12, Step 2. LCMS: Method CA, [M+H]+=245.

5-Bromo-6-fluoro-1H-indole-3-carboxylic acid (1.0 g, 3.8 mmol, 1.0 equiv.) was dissolved in THE (20 mL), then TEA (1.1 mL, 7.7 mmol, 2.0 equiv.) and DPPA (1.6 g, 5.8 mmol, 1.5 equiv.) were added. The reaction mixture was stirred for 12 hours at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with of ethyl acetate, washed with brine, dried over anhydrous Na2SO4and concentrated under vacuum to give 5-bromo-6-fluoro-1H-indole-3-carbonyl azide (805.3 mg) of as a white solid. LCMS Method CC: [M+H]+=283.

5-Bromo-6-fluoro-1H-indole-3-carbonyl azide (800.0 mg, 2.8 mmol, 1.0 equiv.) was dissolved in t-BuOH (15 mL). The resulting solution was heated to 90° C. for 12 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give tert-butyl N-(5-bromo-6-fluoro-1H-indol-3-yl)carbamate (661.5 mg) as a white solid. LCMS Method CA: [M+H]+=329.

The title compound was prepared using the same methods described for Intermediate B12, Step 2. LCMS: Method CA, [M+H]+=229.

The following intermediates were prepared using the method described for Intermediate B40.

6-fluoropyridine-3-carbonitrile (1.0 g, 8.1 mmol, 1.0 equiv.) was dissolved in ACN (20 mL), then tert-butyl N-[trans-4-hydroxycyclohexyl]carbamate (1.7 g, 8.1 mmol, 1.0 equiv.) and Cs2CO3(5.3 g, 16.3 mmol, 2.0 equiv.) were added. The reaction mixture was heated to 60° C. overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl N-[trans-4-[(5-cyanopyridin-2-yl)oxy]cyclohexyl]carbamate (1.7 g) as an off-white solid. LCMS Method CA: [M+H]+=318.

The title compound was prepared using the same methods described for Intermediate B12, Step 2. LCMS: Method CA, [M+H]+=218.

Pyridin-3-ylboronic acid (2.0 g, 16.2 mmol, 1.0 equiv.) was dissolved in THE (50 mL), then tert-butyl N-[trans-3-hydroxycyclobutyl]carbamate (3.0 g, 16.2 mmol, 1.0 equiv.), Cu(AcO)2(591.0 mg, 3.2 mmol, 0.2 equiv.) and TEA (4.5 mL, 32.5 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred overnight at ambient temperature and then concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate, dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl N-[trans-3-(pyridin-3-yloxy)cyclobutyl]carbamate (1.5 g) as a brown oil. LCMS Method CA: [M+H]+=265.

The title compound was prepared using the same methods described for Intermediate B12, Step 2. LCMS: Method CA, [M+H]+=165.

Step 1—Synthesis of 2-((1H-indol-3-yl)amino)-2-oxoacetyl chloride: 1H-indol-3-amine (100.0 mg, 0.7 mmol, 1.0 equiv) was dissolved in THE (10.0 mL) and the reaction mixture was cooled to 0° C. Oxalyl chloride (0.07 mL, 0.7 mmol, 1.0 equiv) was added and the reaction mixture was stirred for 2 h at 0° C. The reaction mixture was concentrated in vacuo and the residue was used directly in the next step without additional purification.

5,6-difluoro-1H-indole (25.0 g, 163 mmol, 1.0 eq.) was dissolved in in ACN (300 mL) and cooled to 0° C. AgNO3(33.3 g, 196. mmol, 1.2 eq.) was then added. After 15 min, benzoyl chloride (27.5 g, 196. mmol, 1.2 eq.) was added. The resulting solution was stirred for 3 hours at 0° C. The pH of the solution was adjusted to 8 by the dropwise addition of saturated aqueous NaHCO3. The solids were removed by filtration, then filtrate was extracted with DCM, and the combined organic layers were concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (2:1) to give 5,6-difluoro-3-nitro-1H-indole (24 g) as a brown solid. MS-ESI: [M+H]+=199.

5,6-difluoro-3-nitro-1H-indole (24.0 g, 121 mmol, 1.0 eq.) was dissolved in MeOH (300 mL). Pd/C (2.4 g, 10% wt, 2 mmol, 0.02 eq.) and (Boc)2O (39.7 g, 182 mmol, 1.5 eq.) were then added. The reaction vessel was evacuated then back filled with hydrogen three times. The reaction mixture was then stirred for 16 h under an atmosphere of hydrogen. After filtration and concentration, the resulting residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give tert-butyl N-(5,6-difluoro-1H-indol-3-yl)carbamate (22 g) as a yellow solid. LCMS Method BA: [M+H]+=269.

Tert-butyl-N-(5,6-difluoro-1H-indol-3-yl)carbamate (17.0 g, 63 mmol, 1.0 eq.) was added to 4 N HCl in 1,4-dioxane (200.0 mL). The resulting mixture was stirred for 30 min and then concentrated to give 5,6-difluoro-1H-indol-3-amine hydrochloride (12 g) as a yellow solid that was used without additional purification. MS-ESI: [M+H]+=169.

Methyl [(5,6-difluoro-1H-indol-3-yl)carbamoyl]formate (5.0 g, 19.6 mmol, 1.0 eq) was dissolved in MeOH (60 mL)/H2O (12 mL). KOH (2.2 g, 39.4 mmol, 2.0 eq.) was then added. The resulting solution was stirred for 3 hr. The pH of the resulting solution was adjusted to 3 with 6 M HCl. The resulting solids were collected by filtration to give 2.5 g of [(5,6-difluoro-1H-indol-3-yl)carbamoyl]formic acid as a yellow solid. MS-ESI: [M−H]−=239.

Methyl [(5,6-difluoro-1H-indol-3-yl)carbamoyl]formate (5.0 g, 19.6 mmol, 1.0 equiv.) was dissolved in MeOH (60 mL) and water (12 mL), then KOH (2.2 g, 39.4 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 3 hours at ambient temperature and concentrated under vacuum. The residue was diluted with water, then adjusted to pH 3 with aqueous HCl (6M). The resulting solids were collected by filtration and dried to give [(5,6-difluoro-1H-indol-3-yl)carbamoyl]formic acid (2.5 g) as a yellow solid. LCMS Method CB: [M−H]−=239.

The following compounds were prepared using the method described for Example 94.

The following compounds were prepared using the method described for Example 112.

The following compounds were prepared using the method described for Example 120.

trans-4-[[5-(trifluoromethyl)pyridin-2-yl]oxy]cyclohexan-1-amine hydrochloride (550.0 mg, 2.1 mmol, 1.0 equiv.) and TEA (0.6 mL, 4.2 mmol, 2.0 equiv.) were dissolved in THE (20 mL) and cooled to 0° C., then methyl oxalyl chloride (0.2 mL, 2.1 mmol, 1.0 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for 2 hours at ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4and concentrated under vacuum to give methyl [[trans-4-[[5-(trifluoromethyl)pyridin-2-yl]oxy]cyclohexyl]carbamoyl]formate (650.0 mg) as a white solid. LCMS Method CA: [M+H]+=347.

Methyl [[trans-4-[[5-(trifluoromethyl)pyridin-2-yl]oxy]cyclohexyl]carbamoyl]formate (550.0 mg, 1.5 mmol, 1.0 equiv.) was dissolved in MeOH (15 mL) and water (5 mL), then LiGH (76.0 mg, 3.1 mmol, 2.00 equiv.) was added. The reaction mixture was stirred for 2 hours at ambient temperature and concentrated under vacuum. The residue was diluted with water, then adjusted to pH 3 with aqueous HCl (2N). The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4and concentrated under vacuum to give [[trans-4-[[5-(trifluoromethyl)pyridin-2-yl]oxy]cyclohexyl]carbamoyl]formic acid (312.5 mg) as a white solid. LCMS Method CB: [M+H]+=332.

5-Chloro-1H-indol-3-amine hydrochloride (9.0 g, 44.3 mmol, 1.0 equiv.) and TEA (7.2 mL, 53.1 mmol, 1.2 equiv.) were dissolved in THE (100 mL) and cooled to 0° C., then methyl oxalyl chloride (4.0 mL, 44.3 mmol, 1.0 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for 2 hours at ambient temperature and concentrated under vacuum. The residue was slurried in ethyl acetate (50 mL) for 1 hour at ambient temperature and the solids were collected by filtration to give methyl [(5-chloro-1H-indol-3-yl)carbamoyl]formate (6.5 g) as a light brown solid. LCMS Method CB: [M+H]+=253.

Methyl [(5-chloro-1H-indol-3-yl)carbamoyl]formate (6.5 g, 25.7 mmol, 1.0 equiv.) was dissolved in MeOH (50 mL) and water (10 mL), then KOH (2.1 g, 38.5 mmol, 1.5 equiv.) was added in portions. The resulting mixture was stirred for 2 hours at ambient temperature and concentrated under vacuum. The residue was diluted with of water, then adjusted to pH 3 with aqueous HCl (2M). The solids were collected by filtration and dried to give [(5-chloro-1H-indol-3-yl)carbamoyl]formic acid (5.1 g) as a light brown solid. LCMS Method CB: [M−H]−=237.

The following compound was prepared using the method described for Example 129.

The following compound was prepared using the method described for Example 131.

6-Fluoro-1H-indol-3-amine hydrochloride (434.2 mg, 2.3 mmol, 1.0 equiv.) and TEA (0.3 mL, 2.3 mmol, 1.0 equiv.) were dissolved in THF (20 mL) and cooled to 0° C., then methyl oxalyl chloride (0.2 mL, 2.3 mmol, 1.0 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for 2 hours at ambient temperature and then quenched by the addition of MeOH. The reaction mixture was concentrated under vacuum, diluted with water, extracted with ethyl acetate, dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give methyl [(6-fluoro-1H-indol-3-yl)carbamoyl]formate (361.5 mg) as a pale yellow solid. LCMS Method CD: [M+H]+=237.

Step 1: Isomer A and Isomer B

Step 2: Compound 220 and Compound 356

Step 3: Compound 228 and Compound 227

Compound 48 was prepared using the same method described for Example 94 with Intermediate B1 (5,6-difluoro-1H-indol-3-amine hydrochloride) and 2,2,2-trifluoro-1-phenylethan-1-amine.

The following compounds were obtained from Compound 195 (Example 95) using the method described for Examples 139-140, above.

Compound 49 was prepared using the same method for Example 94 with Intermediate B41 (5-bromo-1H-indol-3-amine hydrochloride) and (3-chloro-4-(trifluoromethyl)phenyl)methanamine.

N-[[3-chloro-4-(trifluoromethyl)phenyl]methyl]-N′-[5-[(E)-2-ethoxyethenyl]-1H-indol-3-yl]ethanediamide (270.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in THE (20 mL), then HCl/1,4-dioxane (4N, 2 mL) was added. The reaction mixture was stirred for 30 min at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na2SO4and concentrated under vacuum to give N-[[3-chloro-4-(trifluoromethyl)phenyl]methyl]-N′-[5-(2-oxoethyl)-1H-indol-3-yl]ethanediamide (230.1 mg) as a pale yellow solid. LCMS Method CA: [M+H]+=438.

Compound 53 was prepared using the method described for Example 112 with Intermediate B40 (5-bromo-6-fluoro-1H-indol-3-amine hydrochloride) and 4-(trifluoromethyl)aniline.

Step 1: Synthesis of 2-((5,6-difluoro-1H-indol-3-yl)amino)-2-oxoacetic acid

Methyl 2-((5,6-difluoro-1H-indol-3-yl)amino)-2-oxoacetate (4.0 g, 15.75 mmol, 1 equiv.) was dissolved in MeOH (100 mL) and then aqueous NaOH (2 M, 11.8 mL, 23.60 mmol, 1.5 equiv.) was added. The reaction mixture was heated at 30° C. for 2 hours, then concentrated in vacuo. Then H2O (30 mL) was added to the residue and the mixture was adjusted to pH 4 by the dropwise addition of 2 M HCl. The resulting solid was collected by filtration and washed with water to give 2-((5,6-difluoro-1H-indol-3-yl)amino)-2-oxoacetic acid (3.5 g, 14.58 mmol) as a light yellow solid. MS-ESI, 241.1 [M+H+].

The following examples were synthesized following the method above.

Example 173: Synthesis of N1-(5,6-difluoro-1H-indol-3-yl)-N2-(1-oxo-2,3-dihydro-1H-inden-4-yl)oxalamide

The following compounds were synthesized using the method described above for Example 173.

Step 1: Synthesis of ethyl 2-((6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)amino)-2-oxoacetate

6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (100.0 mg, 0.44 mmol, 1.0 equiv.) was dissolved in THF (3 mL) and cooled to 0° C. Then a solution of ethyl 2-chloro-2-oxoacetate (71.8 mg, 0.53 mmol, 1.2 equiv.) in THF (2 mL) was added over 5 minutes, maintaining the reaction mixture at 0° C. Then TEA (0.16 mL, 1.1 mmol, 2.5 equiv.) was added to the reaction mixture. The mixture was heated at 30° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give ethyl 2-((6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)amino)-2-oxoacetate (120 mg, 0.36 mmol) as a yellow oil that was used without additional purification.

Step 2: Synthesis of 2-((6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)amino)-2-oxoacetic acid

Ethyl 2-((6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)amino)-2-oxoacetate (120.0 mg, 0.36 mmol, 1 equiv.) was dissolved in MeOH (5 mL) and then aqueous NaOH (2 M, 0.27 mL, 0.54 mmol, 1.5 equiv.) was added. The mixture was heated at 30° C. for 2 hours, then concentrated in vacuo. Then H2O (30 mL) was added to the residue and the mixture was adjusted to pH 4 by the dropwise addition of 2 M HCl. The resulting solid was collected by filtration and washed with water to give 2-((6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)amino)-2-oxoacetic acid (80 mg, 0.27 mmol) as a light yellow solid.

Biological Assays

STING pathway activation by the compounds described herein was measured using THIP1-Dua1™ cells (KO-IFNAR2).

TTIP1-Dual™ KO-IFNAR2 Cells (obtained from invivogen) were maintained in RPMI, 10% FCS, 5 ml P/S, 2 mM L-glut, 10 mM Hepes, and 1 mM sodium pyruvate. Compounds were spotted in empty 384 well tissue culture plates (Greiner 781182) by Echo for a final concentration of 0.0017-100 μM. Cells were plated into the TC plates at 40 μL per well, 2×10E6 cells/mL. For activation with STING ligand, 2′3′cGAMP (MW 718.38, obtained from Invivogen), was prepared in Optimem media.

The following solutions were prepared for each 1×384 plate:Solution A: 2 mL Optimem with one of the following stimuli:60 uL of 10 mM 2′3′cGAMP->150 μM stockSolution B: 2 mL Optimem with 60 μL Lipofectamine 2000->Incubate 5 min at RT

2 mL of solution A and 2 ml Solution B was mixed and incubated for 20 min at room temperature (RT). 20 uL of transfection solution (A+B) was added on top of the plated cells, with a final 2′3′cGAMP concentration of 15 μM. The plates were then centrifuged immediately at 340 g for 1 minute, after which they were incubated at 37° C., 5% C02, >98% humidity for 24h. Luciferase reporter activity was then measured. EC50values were calculated by using standard methods known in the art.

Luciferase reporter assay: 10 μL of supernatant from the assay was transferred to white 384-plate with flat bottom and squared wells. One pouch of QUANTI-Luc™ Plus was dissolved in 25 mL of water. 100 μL of QLC Stabilizer per 25 mL of QUANTI-Luc™ Plus solution was added. 50 μL of QUANTI-Luc™ Plus/QLC solution per well was then added. Luminescence was measured on a Platereader (e.g., Spectramax I3X (Molecular Devices GF3637001)).

Luciferase reporter activity was then measured. EC50values were calculated by using standard methods known in the art.

Numbered Clauses

The compounds, compositions, methods, and other subject matter described herein are further described in the following numbered clauses:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

X1is selected from the group consisting of O, S, N, NR2, and CR5;

X2is selected from the group consisting of O, S, N, NR4, and CR5;

eachis independently a single bond or a double bond, provided that the five-membered ring comprising X1and X2is heteroaryl; and

the 6-membered ring

is aromatic;

Q-A is defined according to (A) or (B) below:(A)

Q is selected from the group consisting of: NH and N(C1-6alkyl) wherein the C1-6alkyl is optionally substituted with 1-2 independently selected Ra; and

A is:

(i) —(YA1)n—YA2, wherein:n is 0 or 1;YA1is C1-6alkylene, which is optionally substituted with 1-6 substituents each independently selected from the group consisting of:oxo;Ra;C6-10aryl optionally substituted with 1-4 independently selected C1-4alkyl; andheteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected C1-4alkyl; andYA1is —YA3—YA4—YA5which is connected to Q via YA3wherein:YA3is a C1-3alkylene optionally substituted with 1-2 substituents each independently selected from the group consisting of oxo and Ra;YA4is —O—, —NH—, —N(C1-6alkyl)-, or —S—; andYA5is a bond or C1-3alkylene which is optionally substituted with 1-2 independently selected Ra; orYA2is:(a) C3-20cycloalkyl or C3-20cycloalkenyl, each of which is optionally substituted with 1-4 Rb,(b) C6-20aryl, which is optionally substituted with 1-4 Rc;(c) heteroaryl of 5-20 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Rc; or(d) heterocyclyl or heterocycloalkenyl of 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl ring is optionally substituted with 1-4 independently selected Rb,

(iii) C1-20alkyl, which is optionally substituted with 1-6 independently selected Ra, or

E is a ring of 3-16 ring atoms, wherein 0-3 ring atoms are heteroatoms (in addition to the nitrogen atom this is already present), each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the ring is optionally substituted with 1-4 independently selected Rb, each of R1a, R1b, R1c, and R1dis independently selected from the group consisting of H; halo; cyano; C1-6alkyl optionally substituted with 1-2 Ra; C2-6alkenyl; C2-6alkynyl; C1-4haloalkyl; C1-4alkoxy; C1-4haloalkoxy; -L3-L4-Ri; —S(O)1-2(C1-4alkyl); —S(O)(═NH)(C1-4alkyl); SF5; —NReRf; —OH; oxo; —S(O)1-2(NR′R″); —C1-4thioalkoxy; —NO2; —C(═O)(C1-4alkyl); —C(═O)O(C1-4alkyl); —C(═O)OH; and —C(═O)N(R′)(R″); or

R1aand R1b, R1band R1c, or R1cand R1d, taken together with the atoms connecting them, form a ring of 3-10 ring atoms, wherein 0-2 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N(Rd), 0, and S(O)0-2; and wherein the ring is optionally substituted with 1-4 substituents each independently selected from the group consisting of C1-6alkyl, halo, C1-6haloalkyl, —OH, NReRf, C1-6alkoxy, and C1-6haloalkoxy,

each occurrence of R2is independently selected from the group consisting of:(i) C1-6alkyl, which is optionally substituted with 1-2 independently selected Ra;(ii) C3-6cycloalkyl or C3-6cycloalkenyl;(iii) heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2;(iv) C6-10aryl;(v) heteroaryl of 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 0, and S(O)0-2;(vi) —C(O)(C1-4alkyl);(vii) —C(O)O(C1-4alkyl);(viii) —CON(R′)(R″);(ix) —S(O)1-2(NR′R″);(x) —S(O)1-2(C1-4alkyl);(xi) —OH;(xii) C1-4alkoxy; and(xiii) H;

R4is selected from the group consisting of H and C1-6alkyl optionally substituted with 1-3 independently selected Ra;

R6is selected from the group consisting of H; C1-6alkyl optionally substituted with 1-3 independently selected Ra; —OH; C1-4alkoxy; C(═O)H; C(═O)(C1-4alkyl); C6-10aryl optionally substituted with 1-4 independently selected C1-4alkyl; and heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected C1-4alkyl;

each occurrence of Rcis independently selected from the group consisting of:

Rdis selected from the group consisting of: C1-6alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; C3-6cycloalkyl or C3-6cycloalkenyl, each optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; —C(O)(C1-4alkyl); —C(O)O(C1-4alkyl); —CON(R′)(R″); —S(O)1-2(NR′R″); —S(O)1-2(C1-4alkyl); —OH; and C1-4alkoxy;

each occurrence of Reand Rfis independently selected from the group consisting of: H; C1.6 alkyl; C1.6 haloalkyl; C3-6 cycloalkyl or C3-6 cycloalkenyl; —C(O)(C1-4alkyl); —C(O)O(C1-4alkyl); —CON(R′)(R″); —S(O)1-2(NR′R″); —S(O)1-2(C1-4alkyl); —OH; and C1-4alkoxy; or Reand Rftogether with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C1-3alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to Reand Rf), which are each independently selected from the group consisting of N(Rd), NH, 0, and S;

-L1is a bond or C1-3alkylene;

Rhis selected from the group consisting of:C3-8cycloalkyl or C3-8cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy (in certain embodiments, it is provided that when Rhis C3-6cycloalkyl or C3-6cycloalkenyl, each optionally substituted with 1-4 substituents independently selected C1-4alkyl, -L1is a bond, or -L2is —O—, —N(H)—, or —S—);heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy;heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy; andC6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy;

-L3is a bond or C1-3alkylene;

Riis selected from the group consisting of:C3-8cycloalkyl or C3-8cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy (in certain embodiments, it is provided that when R is C3-6cycloalkyl or C3-6cycloalkenyl, each optionally substituted with 1-4 substituents independently selected C1-4alkyl, -L1is a bond, or -L2is —O—, —N(H)—, or —S—);heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy;heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy; andC6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy; and

each occurrence of R′ and R″ is independently selected from the group consisting of: H, C1-4alkyl, C6-10aryl optionally substituted with 1-2 substituents selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl, and heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, —OH, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, C1-4alkyl, and C1-4haloalkyl; or R′ and R″ together with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C1-3alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R′ and R″), which are each independently selected from the group consisting of N(H), N(C1-6alkyl), O, and S.

2. The compound of clause 1, wherein X1is NR2.

3. The compound of any one of clauses 1-2, wherein X1is NH.

4. The compound of any one of clauses 1-3, wherein X2is CR5.

5. The compound of any one of clauses 1-4, wherein X2is CH.

6. The compound of any one of clauses 1-5, wherein X1is NH; and X2is CH.

7. The compound of any one of clauses 1-6, wherein the

moiety is

optionally wherein R1band R1care each independently selected substituents that are other than hydrogen, such as wherein R1band R1care independently selected halo, such as —F or —Cl.

8. The compound of any one of clauses 1-6, wherein the

moiety is

optionally wherein R1b, R1c, and R1dare each independently selected substituents that are other than hydrogen, such as wherein R1band R1care independently selected halo, such as —F or —Cl.

9. The compound of any one of clauses 1-2, wherein the compound is a compound of Formula (I-a):

10. The compound of clause 9, wherein the compound has formula (I-a1):

11. The compound of clause 9, wherein the compound has formula (I-a2):

12. The compound of clause 9, wherein the compound has formula (I-a3) or (I-a4):

13. The compound of any one of clauses 1-12, wherein R2is H; and R5is H.

15. The compound of any one of clauses 1-14, wherein 1-2 of R1a, R1b, R1c, and R1dis other than H; and each of the remaining of R1a, R1b, R1c, and R1dis H.

16. The compound of any one of clauses 1-15, wherein each of R1a, R1b, R1c, and R1dis H.

17. The compound of any one of clauses 1-15, wherein 1-2 occurrences of R1a, R1b, R1c, and R1dis other than H (e.g., R1band/or R1cis other than H)

18. The compound of clause 17, wherein two of R1a, R1b, R1c, and R1dare other than H (e.g., R1band R1care other than H).

20. The compound of any one of clauses 1-15 and 17-19, wherein 1-2 occurrence of R1a, R1b, R1c, and R1dis halo (e.g., F or Cl (e.g., F)).

21. The compound of any one of clauses 1-15 and 17-18, wherein one occurrence of R1a, R1b, R1c, and R1dis -L3-L4-Ri, such as R1bis -L3-L4-Ri; and each remaining occurrences of R1a, R1b, R1c, and R1dis H.

22. The compound of clause 21, wherein -L3is a bond.

23. The compound of any one of clauses 21-22, wherein -L4is a bond.

24. The compound of any one of clauses 21-23, wherein —Riis selected from the group consisting of:heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy; andC6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy.

25. The compound of clause 24, wherein —Riis selected from the group consisting of:heteroaryl of 5-6 ring atoms (e.g., pyrazolyl), wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy; andphenyl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy.

26. The compound of any one of clauses 21-25, wherein one of R1a, R1b, R1c, and R1d(such as R1b) is selected from the group consisting of:heteroaryl of 5-6 ring atoms (such as pyrazolyl), wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy (e.g.,

andphenyl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy (e.g.,

27. The compound of any one of clauses 1-13, wherein R1ais H; and R1dis H or halo, such as: wherein R1ais H, and R1dis H; or wherein R1ais H, and R1dis halo such as —F or —Cl.

31. The compound of any one of clauses 1-13 or 27, wherein R1bis Ri; and R1cis H or halo, such as H; such as: wherein R1bis selected from the group consisting of:heteroaryl of 5-6 ring atoms, such as pyrazolyl, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy (e.g.,

andphenyl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy (e.g.,

32. The compound of any one of clauses 1-13 or 27, wherein one of R1band R1cis selected from the group consisting of: cyano, C1-3alkyl optionally substituted with Ra, and C1-3haloalkyl; and the other of R1band R1cis H or halo, such as —H, —F, or —Cl.

33. The compound of any one of clauses 28-32, wherein R1ais H; and R1dis H.

34. The compound of any one of clauses 28-32, wherein R1ais H; and R1dis halo, such as —F or —Cl.

35. The compound of any one of claims1-34, wherein Q-A is defined according to (A).

36. The compound of any one of clauses 1-35, wherein Q is NH.

37. The compound of any one of clauses 1-35, wherein Q is N(C1-3alkyl) (e.g., NMe or NEt).

38. The compound of any one of clauses 1-37, wherein A is —(YA1)n—YA2

39. The compound of any one of clauses 1-38, wherein n is 0.

40. The compound of any one of clauses 1-38, wherein n is 1.

41. The compound of any one of clauses 1-38 or 40, wherein YA1is C1-6alkylene, which is optionally substituted with 1-4 Raand further optionally substituted with oxo.

42. The compound of clauses 1-38 or 40-41, wherein YA1is C1-6 alkylene which is optionally substituted with 1-4 Ra.

43. The compound of clause 42, wherein each Rais independently selected from the group consisting of: —F, —Cl, —Br, —C3-5cycloalkyl, and —OH.

45. The compound of clause 44, wherein YA1is —CH2—, —CH2CH2—, or

such as

46. The compound of clauses 1-38 or 40-41, wherein YA1is C1-6alkylene that is substituted with oxo, wherein YA1is further optionally substituted with 1-2 Ra.

47. The compound of clause 46, wherein YA1is C2-3alkylene substituted with oxo, such as wherein YA1is

wherein # represents point of attachment to YA2.

48. The compound of any one of clauses 1-38 or 40, wherein YA1is —YA3—YA4—YA5which is connected to Q via YA3.

49. The compound of clause 48, wherein YA5is a bond.

50. The compound of clauses 48 or 49, wherein YA4is —O—.

51. The compound of clauses 48 or 49, wherein YA4is —NH— or —N(C1-3alkyl)-, such as wherein YA4is -N(Me)-.

52. The compound of any one of clauses 48-51, wherein YA3is C2-3alkylene optionally substituted with 1-2 Ra, such as wherein YA3is

wherein # represents point of attachment to YA4.

53. The compound of any one of clauses 48-51, wherein YA3is C2-3alkylene substituted with oxo and further optionally substituted with Ra, such as wherein YA3is

wherein # represents point of attachment to YA4.

54. The compound of any one of clauses 1-38, 40, or 48-49, wherein YA1is —YA3—O—; and YA3is C2-3alkylene optionally substituted with 1-2 Ra, such as wherein YA3is

wherein # represents point of attachment to —O—.

55. The compound of any one of clauses 40 or 48-49, wherein YA1is —YA3—N(C1-3alkyl)-, such as —YA3—N(Me)-; and YA3is C2-3alkylene optionally substituted with 1-2 Ra, such as wherein YA3is

wherein # represents point of attachment to —N(C1-3alkyl)-.

56. The compound of any one of clauses 38-55, wherein YA2is C6-10aryl, which is optionally substituted with 1-3 Rc.

57. The compound of any one of clauses 38-56, wherein YA2is C6aryl, which is optionally substituted with 1-3 Rc.

58. The compound of any one of clauses 38-57, wherein YA2is C6aryl, which is substituted with 1-3 Rc.

59. The compound of any one of clauses 38-58, wherein YA2is phenyl substituted with 1-3 Rc, wherein one Rcis at the ring carbon para to the point of attachment to YA1.

60. The compound of any one of clauses 38-58, wherein YA2is phenyl substituted with 1-3 Rc, wherein 1-2 Rcis at the ring carbons meta to the point of attachment to YA1.

61. The compound of any one of clauses 38-58, wherein YA2is phenyl substituted with 1-3 Rc, wherein 1-2 Rcis at the ring carbons ortho to the point of attachment to YA1.

62. The compound of any one of clauses 38-57, wherein YA2is unsubstituted phenyl.

63. The compound of any one of clauses 38-56, wherein YA2is C7-10bicyclic aryl, which is optionally substituted with 1-3 Rc(e.g., YA2is naphthyl (e.g.,

each of which is optionally substituted with 1-3 Rc.

64. The compound of any one of clauses 38-55, wherein YA2is heteroaryl of 5-14 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Rc.

65. The compound of any one of clauses 38-55 and 64, wherein YA2is heteroaryl of 6 ring atoms (e.g., pyridyl or pyrimidinyl (e.g., pyridyl)), wherein 1-2 ring atoms are ring nitrogen atoms, and wherein the heteroaryl ring is optionally substituted with 1-3 independently selected Rc.

66. The compound of clause 65, wherein YA2is substituted with 1-3 independently selected Rc; and one occurrence of Rcis at the ring carbon atom para to the point of attachment to YA1, such as wherein YA2is

each of which is further optionally substituted with 1-2 independently selected Rc.

67. The compound of clause 65, wherein YA2is substituted with 1-3 independently selected Rc; and one occurrence of Rcis at the ring carbon atom meta to the point of attachment to YA1, such as wherein YA2is

each of which is further optionally substituted with 1-2 independently selected Rc.

68. The compound of any one of clauses 38-55 or 64, wherein YA2is bicyclic or tricyclic heteroaryl of 7-14 (e.g., 9-12 (e.g., 9, 10, 11, or 12)) ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Rc.

69. The compound of clause 68, wherein YA2is bicyclic heteroaryl of 9-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Rc.

70. The compound of clause 69, wherein YA2is bicyclic heteroaryl of 9-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-3 independently selected Rc.

71. The compound of clause 70, wherein YA2is selected from the group consisting of:

each of which is further optionally substituted with 1-2 independently selected Rc.

72. The compound of any one of clauses 56-71, wherein each occurrence of Rcis independently selected from the group consisting of: halo; cyano; C1-10alkyl which is optionally substituted with 1-6 independently selected Ra; C2-6alkenyl; C2-6alkynyl; C1-4alkoxy; C1-4haloalkoxy; —S(O)1-2(C1-4alkyl); —NReRf; —C1-4thioalkoxy; —C(═O)(C1-10alkyl); —C(═O)(OH); —C(═O)O(C1.4 alkyl); and -L1-L2-Rh.

73. The compound of any one of clauses 56-72, wherein one occurrence of Rcis halo (e.g., F or C1 (e.g., C1)); or wherein one occurrence of R is C2-6alkynyl (e.g.,

74. The compound of any one of clauses 56-72, wherein one occurrence of Rcis C1-10alkyl which is optionally substituted with 1-6 independently selected Ra.

75. The compound of any one of clauses 56-72 or 74, wherein one occurrence of Rcis unsubstituted C1-10alkyl (e.g., C2, C3, C4, C5, C6, or C7-10).

77. The compound of clause 74, wherein one occurrence of Rcis C1-10alkyl which is substituted with 1-6 independently selected Ra.

78. The compound of clause 77, wherein each occurrence of Rais independently selected from —F, —Cl, —Br, OH, C1-4alkoxy, and C1-4haloalkoxy.

79. The compound of clause 78, wherein each occurrence of Rais —F or —Cl, such as —F.

80. The compound of clause 77, wherein one occurrence of Rcis C1-3alkyl substituted with 1-6-F, such as wherein Rcis CF3.

81. The compound of any one of clauses 56-72, wherein one occurrence of Rcis -L1-L2-Rh.

82. The compound of clause 81, wherein L1is a bond.

83. The compound of clause 81, wherein L1is CH2.

84. The compound of any one of clauses 81-83, wherein L2is —O—.

85. The compound of any one of clauses 81-83, wherein L2is —N(H)— or —NH(C1-3alkyl)-, such as —N(H)—.

86. The compound of any one of clauses 81-83, wherein L2is a bond.

87. The compound of clause 81, wherein one occurrence of Rcis Rh.

88. The compound of clause 81, wherein one occurrence of Rcis —CH2—Rh.

89. The compound of clause 81, wherein one occurrence of Rcis —O—Rh, —N(H)—Rh, or —N(C1-3alkyl)-Rh.

90. The compound of any one of clauses 81-89, wherein Rhis C6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl.

91. The compound of any one of clauses 81-90, wherein Rhis C6aryl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl (e.g., Rhcan be

92. The compound of any one of clauses 81-89, wherein Rhis heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy.

93. The compound of any one of clauses 81-89 or 92, wherein Rhis heteroaryl of 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy.

94. The compound of any one of clauses 81-89, wherein Rhis heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-10 (e.g., 5-6) ring atoms, wherein 1-3 (e.g., 1-2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl.

95. The compound of clause 94, wherein Rhis

or wherein Rhis

or wherein Rhis

each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl.

96. The compound of any one of clauses 81-89, wherein Rhis C3-8cycloalkyl or C3-8cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl.

97. The compound of clause 96, wherein Rhis C3-6cycloalkyl or C3-6cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl.

98. The compound of clause 97, wherein Rhis selected from the group consisting of:

99. The compound of any one of clauses 73-98, wherein each of the remaining occurrences of Rcis C1.6 alkyl or halo.

100. The compound of any one of clauses 1-55, wherein YA2is monocyclic C3-10cycloalkyl or C3-10cycloalkenyl, each of which is optionally substituted with 1-4 Rb.

102. The compound of any one of clauses 1-55 or 100-101, wherein YA2is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1-2 Rb.

103. The compound of clause 102, wherein YA2is cyclohexyl which is optionally substituted with 1-2 Rb.

104. The compound of clause 103, wherein one occurrence of Rbis at the ring carbon atom para to the point of attachment to YA1; or one occurrence of Rbis at the ring carbon atom meta to the point of attachment to YA1, such as wherein YA2is

105. The compound of clause 103, wherein two occurrences of Rbare at the ring carbon atom para to the point of attachment to YA1; or two occurrences of Rbare at the ring carbon atom meta to the point of attachment to YA1.

107. The compound of clause 102, wherein YA2is cyclobutyl which is substituted with 1-2 Rb, such as wherein YA2is

108. The compound of clause 102, wherein YA2is cyclopentyl which is optionally substituted with 1-2 Rb, such as wherein YA2is unsubstituted cyclopentyl; or wherein YA2is

109. The compound of clause 102, wherein YA2is cyclopropyl which is substituted with 1-2 Rb, such as cyclopropyl substituted with -L1-L2-Rh(e.g.,

110. The compound of any one of clauses 1-55 or 100, wherein YA2is

112. The compound of any one of clauses 1-55 or 111, wherein YA2is a spirocyclic bicyclic C7-12cycloalkyl optionally substituted with 1-2 Rb, such as wherein YA2is: spiro[5.5]undecanyl (e.g.,

each of which is optionally substituted with Rb.

113. The compound of any one of clauses 1-55 or 111, wherein YA2is a bridged bicyclic C7-12cycloalkyl or C7-12cycloalkenyl optionally substituted with 1-2 Rb, such as wherein YA2is adamantly (e.g.,

each of which is optionally substituted with Rb.

114. The compound of any one of clauses 1-55, wherein YA2is heterocyclyl or heterocycloalkenyl of 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl ring is optionally substituted with 1-3 independently selected Rb, such as wherein YA2is heterocyclyl of 4-8 ring atoms, such as 4-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl ring is optionally substituted with 1-2 independently selected Rb, such as wherein YA2is

115. The compound of any one of clauses 1-55 or 114, wherein YA2is

116. The compound of any one of clauses 1-55 or 100-115, wherein each occurrence of Rbsubstituent of YA2is independently selected from the group consisting of: C1-10alkyl optionally substituted with 1-6 independently selected Ra; C1-4haloalkyl; —F; —Cl; —Br; cyano; C1-4alkoxy; C1-4haloalkoxy; —C(═O)(C1-10alkyl); —C(═O)O(C1-4alkyl); —S(O)1-2(C1-4alkyl); oxo; cyano; and -L1-L2-Rh.

117. The compound of any one of clauses 1-55 or 100-115, wherein one occurrence of Rbsubstituent of YA2is C1-10alkyl which is optionally substituted with 1-6 independently selected Ra.

120. The compound of clause 117, wherein one occurrence of Rbsubstituent of YA2is C1-10alkyl which is substituted with 1-6 independently selected Ra(e.g., Rbis CF3or —CF2CH3).

121. The compound of clause 120, wherein each occurrence of Rais independently selected from —F, —Cl, —Br, OH, C1-4alkoxy, and C1-4haloalkoxy.

122. The compound of any one of clauses 1-55 or 100-115, wherein one occurrence of Rbsubstituent of YA2is -L1-L2-Rh(e.g., —Rhor —CH2—Rhsuch as benzyl).

123. The compound of clause 122, wherein -L1is a bond.

124. The compound of clause 122, wherein -L1is CH2.

125. The compound of any one of clauses 122-124, wherein L2is —O—.

126. The compound of any one of clauses 122-124, wherein L2is —N(H)— or —NH(C1-3alkyl)-, such as —N(H)—.

127. The compound of any one of clauses 122-124, wherein L2is a bond.

128. The compound of any one of clauses 1-55, 100-115, or 122, wherein one occurrence of Rbis Rh.

129. The compound of any one of clauses 1-55, 100-115, or 122, wherein one occurrence of Rbis —CH2—Rh.

130. The compound of any one of clauses 1-55, 100-115, or 122, wherein one occurrence of Rbis —O—Rh, —N(H)—Rh, or —N(C1-3alkyl)-Rh.

131. The compound of any one of clauses 122-130, wherein Rhis C6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl.

132. The compound of any one of clauses 122-131, wherein Rhis C6aryl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl (e.g.,

133. The compound of any one of clauses 122-130, wherein Rhis heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy.

134. The compound of any one of clauses 122-130 or 133, wherein Rhis heteroaryl of 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy.

135. The compound of any one of clauses 122-130 or 133-134, wherein Rhis heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are ring nitrogen atoms and wherein the heteroaryl ring is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy.

136. The compound of clause 135, wherein Rhis pyridyl optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy, such as pyridyl substituted with C1-4haloalkyl, such as, wherein Rhis

137. The compound of any one of clauses 1-55, 100-115, or 122, wherein one occurrence of Rbis

138. The compound of any one of clauses 1-55, 100-115, or 122, wherein one occurrence of Rbis

139. The compound of clauses 137 or 138, wherein each of T1, T2, T3, and T4is independently CH or CRt, such as each of T1, T2, T3, and T4is CH.

140. The compound of clauses 137 or 138, wherein T1is N; and T2, T3, and T4are independently CH or CRt, such as wherein T1is N; and T2, T3, and T4are CH.

141. The compound of clauses 137 or 138, wherein T2is N; and T1, T3, and T4are independently CH or CRt, such as wherein T2is N; and T1, T3, and T4are CH.

142. The compound of any one of clauses 137-141, wherein Rsis C1-4alkyl, such as methyl.

143. The compound of any one of clauses 137-141, wherein Rsis C1-4haloalkyl, such as CF3.

144. The compound of any one of clauses 1-55, 100-115, 122, or 137, wherein Rbis

145. The compound of any one of clauses 1-55, 100-115, 122, or 137, wherein Rbis

146. The compound of any one of clauses 1-55 or 100-115, wherein one occurrence of Rbsubstituent of YA2is C1-4alkoxy or C1-4haloalkoxy (e.g.,

147. The compound of any one of clauses 1-55 or 100-115, wherein one occurrence of Rbis —F or —Cl (e.g., —F).

148. The compound of any one of clauses 117-147, wherein each remaining Rbsubstituent of YA2when present is —F, —Cl, or C1-3alkyl.

149. The compound of any one of clauses 1-55, wherein YA2is

n1 is 0, 1, or 2; and each of RcAand RcBis an independently selected Rc, such as wherein YA2is

150. The compound of any one of clauses 1-55, wherein YA2is

n1 is 0, 1, or 2; and each of RcAand RcBis an independently selected Rc, such as wherein YA2is

151. The compound of any one of clauses 1-55, wherein YA2is

one of Q1and Q2is N; the other one of Q1and Q2is CH; n1 is 0, 1, or 2; and each of RcAand RcBis an independently selected Rc, such as wherein YA2is

152. The compound of any one of clauses 1-55, wherein YA2is

one of Q1, Q2, Q3, and Q4is N; each of the remaining of Q1, Q2, Q3, and Q4is CH; n1 is 0, 1, or 2; and each of RcAand RcBis an independently selected Rc, such as wherein YA2is

153. The compound of any one of clauses 149-152, wherein RCA is selected from the group consisting of: halo; cyano; C1-10alkyl which is optionally substituted with 1-6 independently selected Ra; C2-6alkenyl; C2-6alkynyl; C1-4alkoxy; C1-4haloalkoxy; —S(O)1-2(C1-4alkyl); —NRIRf; —C1-4thioalkoxy; —C(═O)(C1-10alkyl); —C(═O)(OH); —C(═O)O(C1-4alkyl); and -L1-L2-Rh.

155. The compound of any one of clauses 149-153, wherein RcAis C1-10alkyl which is substituted with 1-6 independently selected Ra(e.g., each occurrence of Rais independently selected from —F, —Cl, —Br, OH, C1-4alkoxy, and C1-4haloalkoxy).

157. The compound of any one of clauses 149-153, wherein RcAis -L1-L2-Rh

158. The compound of clause 157, wherein -L1is a bond.

159. The compound of clauses 157 or 158, wherein -L2is a bond.

161. The compound of any one of clauses 157-160, wherein Rhis C6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl,

such as C6aryl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl (e.g.,

162. The compound of any one of clauses 157-160, wherein Rhis heteroaryl of 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy.

163. The compound of any one of clauses 157-160, wherein Rhis heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-10 (e.g., 5-6) ring atoms, wherein 1-3 (e.g., 1-2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl, such as

164. The compound of any one of clauses 157-160, wherein Rhis C3-8(e.g., C3-6) cycloalkyl or C3-8(e.g., C3-6) cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl (e.g., Rhis cyclohexyl).

165. The compound of any one of clauses 149-153, wherein RCA is C2-6alkynyl (e.g.,

166. The compound of any one of clauses 149-165, wherein n1 is 0.

167. The compound of any one of clauses 149-165, wherein n1 is 1 or 2 (e.g., 1).

168. The compound of clause 167, wherein each occurrence of RcBis independently halo or C1-3alkyl (e.g., halo).

169. The compound of any one of clauses 1-55, wherein YA2is wherein Q5is N or CH; m1 and m2 are independently 0, 1, or 2; n2 is 0, 1, or 2; and each of RbAand RbBis an independently selected Rb.

170. The compound of clause 169, wherein Q5is CH.

171. The compound of any one of clauses 1-55 or 169-170, wherein YA2is

n2 is 0, 1, or 2; and each of RbAand RbBis an independently selected Rb.

172. The compound of any one of clauses 1-55 or 169-170, wherein YA2is

n2 is 0, 1, or 2; and each of RbAand RbBis an independently selected Rb.

173. The compound of any one of clauses 1-55 or 169-170, wherein YA2is

n2 is 0, 1, or 2; and each of RbAand RbBis an independently selected Rb.

174. The compound of any one of clauses 1-55 or 169-170, wherein YA2is

n2 is 0, 1, or 2; and each of RbAand RbBis an independently selected Rb.

175. The compound of clause 169, wherein Q5is N.

176. The compound of any one of clauses 1-55, 169, or 175, wherein YA2is

n2 is 0, 1, or 2; and each of RbAand RbBis an independently selected Rb.

177. The compound of any one of clauses 169-176, wherein RbAis C1-10alkyl which is optionally substituted with 1-6 independently selected Ra

179. The compound of clause 177, wherein RbAis C1-10alkyl which is substituted with 1-6 independently selected Ra(e.g., each Rais selected from the group consisting of —F, —Cl, —Br, OH, C1-4alkoxy, and C1-4haloalkoxy) (e.g., RbAis CF3or —CF2CH3).

180. The compound of any one of clauses 169-176, wherein RbAis —F or —Cl.

181. The compound of any one of clauses 169-176, wherein RbAis -L1-L2-Rh(e.g., —Rhor —CH2—Rhsuch as benzyl).

182. The compound of clause any one of clauses 169-176 or 181, wherein RbAis Rhor —CH2—Rh.

183. The compound of any one of clauses 169-176 or 181, wherein RbAis —O—Rhor —N(H)—Rh.

184. The compound of any one of clauses 181-183, wherein Rhis selected from the group consisting of:

heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are ring nitrogen atoms and wherein the heteroaryl ring is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy; and

C6aryl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy.

185. The compound of any one of clauses 169-176, wherein RbAis

186. The compound of any one of clauses 169-174, wherein RbAis

187. The compound of any one of clauses 169-174, wherein RbAis C1-4alkoxy or C1-4haloalkoxy (e.g.,

188. The compound of any one of clauses 169-187, wherein n2 is 0.

189. The compound of any one of clauses 169-188, wherein n2 is 1 or 2; optionally wherein each occurrence RbBis selected from the group consisting of —F, —Cl, and C1-3alkyl.

190. The compound of any one of clauses 1-34, wherein Q-A is as defined according to (B).

191. The compound of clause 190, wherein E a ring of 5-8 ring atoms, wherein aside from the nitrogen atom present, 0-3 additional ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the ring is optionally substituted with 1-4 independently selected Rb, such as:

wherein E is piperidinyl or piperazinyl, each of which is optionally substituted with 1-2 independently selected Rb.

192. The compound of clause 191, wherein E is

193. The compound of clause 1, wherein the compound has the following formula:

wherein n1 is 0, 1, or 2; each of RcAand RcBis an independently selected Rc; and R7is H or C1-4alkyl,

optionally wherein the

moiety is

194. The compound of clause 1, wherein the compound has the following formula:

wherein n1 is 0, 1, or 2; each of RcAand RcBis an independently selected Rc; and R7is H or C1-4alkyl, optionally wherein the

195. The compound of clause 1, wherein the compound has the following formula:

wherein one of Q1and Q2is N; the other one of Q1and Q2is CH; n1 is 0, 1, or 2; each of RcAand RcBis an independently selected Rc; and R7is H or C1-4alkyl,

optionally wherein the

moiety is

196. The compound of clause 1, wherein the compound has the following formula:

wherein one of Q1, Q2, Q3, and Q4is N; each of the remaining of Q1, Q2, Q3, Q4is CH; n1 is 0, 1, or 2; and each of RcAand RcBis an independently selected Rc; and R7is H or C1-4alkyl,

optionally wherein the

moiety is

197. The compound of clause 1, wherein the compound has the following formula:

wherein B1is selected from the group consisting of:

(a) bicyclic or tricyclic heteroaryl of 7-14 (e.g., 9-12 (e.g., 9, 10, 11, or 12)) ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Rc; and

and R7is H or C1-4alkyl.

198. The compound of clause 197, wherein B1 is bicyclic or tricyclic heteroaryl of 9-10 (e.g., 10) ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Rc.

199. The compound of clause 198, wherein B1 is selected from the group consisting of:

each of which is further optionally substituted with 1-2 independently selected Rc.

202. The compound of any one of clauses 193-196 or 200, wherein RcAis C1-10alkyl which is substituted with 1-6 independently selected Ra(e.g., each occurrence of Rais independently selected from —F, —Br, —Cl, OH, C1-4alkoxy, and C1-4haloalkoxy).

203. The compound of clause 202, wherein RcAis C1-10alkyl which is substituted with 1-6 independently selected —F or —Cl (e.g., RcAis CF3).

204. The compound of any one of clauses 193-196 or 200, wherein RcAis -L1-L2-Rh.

205. The compound of clause 204, wherein -L1is a bond.

206. The compound of any one of clauses 204-205, wherein -L2is a bond.

207. The compound of any one of clauses 204-206, wherein Rhis C6-10aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl,

such as C6aryl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl (e.g.,

208. The compound of any one of clauses 204-206, wherein Rhis heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-10 (e.g., 5-6) ring atoms, wherein 1-3 (e.g., 1-2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl, such as

209. The compound of any one of clauses 204-206, wherein Rhis C3-8(e.g., C3-6) cycloalkyl or C3-8(e.g., C3-6) cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-4alkyl, and C1-4haloalkyl (e.g., Rhis cyclohexyl).

210. The compound of any one of clauses 193-196, wherein RCA is C2-6alkynyl (e.g.,

211. The compound of any one of clauses 193-210, wherein n1 is 0.

212. The compound of any one of clauses 193-210, wherein n1 is 1 or 2 (e.g., 1).

213. The compound of clause 212, wherein each occurrence of RcBis independently halo or C1-3alkyl (e.g., halo).

214. The compound of clause 1, wherein the compound has the following formula:

wherein n2 is 0, 1, or 2; each of RbAand RbBis an independently selected Rb; and R7is H or C1.4 alkyl.

215. The compound of clause 1, wherein the compound has the following formula:

wherein n2 is 0, 1, or 2; each of RbAand RbBis an independently selected Rb; and R7is H or C1-4alkyl.

216. The compound of clause 1, wherein the compound has the following formula:

wherein n2 is 0, 1, or 2; each of RbAand RbBis an independently selected Rb; and R7is H or C1-4alkyl.

217. The compound of clause 1, wherein the compound has the following formula:

wherein n2 is 0, 1, or 2; each of RbAand RbBis an independently selected Rb; and R7is H or C1-4alkyl.

218. The compound of clause 1, wherein the compound has the following formula:

wherein B2is selected from the group consisting of:

bicyclic, tricyclic, or polycyclic heterocyclyl of 8-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl ring is optionally substituted with 1-4 independently selected Rb; and

R7is H or C1-4alkyl.

219. The compound of clause 218, wherein B2is selected from the group consisting of:

each of which is optionally substituted with Rb.

each of which is optionally substituted with Rb.

220. The compound of clause 218, wherein B2is bicyclic, tricyclic, or polycyclic heterocyclyl of 8-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl ring is optionally substituted with 1-4 independently selected Rb, such as wherein B2is

221. The compound of any one of clauses 214-217, wherein RbAis C1-10alkyl which is optionally substituted with 1-6 independently selected Ra.

223. The compound of clause 221, wherein RbAis C1-10alkyl which is substituted with 1-6 independently selected Ra(e.g., each Rais selected from the group consisting of —F, —Cl, —Br, OH, C1-4alkoxy, and C1-4haloalkoxy) (e.g., RbAis CF3).

224. The compound of any one of clauses 214-217, wherein RbAis —F or —Cl.

225. The compound of any one of clauses 214-217, wherein RbAis -L1-L2-Rh(e.g., —Rhor —CH2—Rhsuch as benzyl).

226. The compound of any one of clauses 214-217 or 225, wherein RbAis Rhor —CH2—Rh.

227. The compound of any one of clauses 214-217 or 225, wherein RbAis —O—Rhor —N(H)—Rh

228. The compound of any one of clauses 225-227, wherein Rhis selected from the group consisting of:

Rhis heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are ring nitrogen atoms and wherein the heteroaryl ring is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy; and

C6aryl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy.

229. The compound of any one of clauses 214-217, wherein RbAis

230. The compound of any one of clauses 214-217, wherein RbAis

231. The compound of clauses 229 or 230, wherein each of T1, T2, T3, and T4is independently CH or CRt, such as each of Ti, T2, T3, and T4is CH.

232. The compound of clauses 229 or 230, wherein T1is N; and T2, T3, and T4are independently CH or CRt, such as wherein T1is N; and T2, T3, and T4are CH.

233. The compound of clauses 229 or 230, wherein T2is N; and T1, T3, and T4are independently CH or CRt, such as wherein T2is N; and T1, T3, and T4are CH.

234. The compound of any one of clauses 229-233, wherein R5is C1-4alkyl, such as methyl.

235. The compound of any one of clauses 229-233, wherein R5is C1-4haloalkyl, such as CF3.

236. The compound of any one of clauses 214-235, wherein n2 is 0.

237. The compound of any one of clauses 214-235, wherein n2 is 1 or 2.

238. The compound of clause 237, wherein each occurrence RbBis selected from the group consisting of —F, —Cl, and C1-3alkyl.

239. The compound of clause 1, wherein the compound has the following formula:

(a) C3-10cycloalkyl or C3-10cycloalkenyl, each of which is optionally substituted with 1-2 Rb,

(b) phenyl, which is optionally substituted with 1-2 Rc;

(c) heteroaryl of 5-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl ring is optionally substituted with 1-2 independently selected Rc; and

R7is H or C1-4alkyl.

240. The compound of clause 239, wherein B3is C3-10cycloalkyl or C3-10cycloalkenyl, each of which is optionally substituted with 1-2 Rb.

241. The compound of clause 240, wherein B3is C5-7cycloalkyl which is unsubstituted, such as unsubstituted cyclohexyl.

242. The compound of clause 239, wherein B3is phenyl, which is optionally substituted with 1-2 Rc.

244. The compound of any one of clauses 193-243, wherein n is 0.

245. The compound of any one of clauses 193-243, wherein n is 1.

246. The compound of any one of clauses 193-243 or 245, wherein YA1is C1-6 alkylene, which is optionally substituted with 1-4 Ra.

248. The compound of any one of clauses 193-243 or 245, wherein YA1is C2-3alkylene substituted with oxo, such as

wherein # represents point of attachment to YA2.

249. The compound of any one of clauses 193-243 or 245, wherein YA1is YA3—YA4—YA5.

250. The compound of clause 249, wherein YA3is C2-3alkylene.

251. The compound of clauses 249 or 250, wherein YA4is —O—; or wherein YA4is —NH— or —N(C1-3alkyl), such as —O— or —N(C1-3alkyl).

252. The compound of any one of clauses 249-251, wherein YA5is a bond.

253. The compound of any one of clauses 249-252, wherein YA1is

or wherein YA1is

254. The compound of clause 1, wherein the compound has the following formula:

E is a ring of 3-16 ring atoms, wherein aside from the nitrogen atom present, 0-3 additional ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the ring is optionally substituted with 1-4 independently selected Rb.

255. The compound of clause 254, wherein E is a ring of 5-8 ring atoms, wherein aside from the nitrogen atom present, 0-3 additional ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the ring is optionally substituted with 1-4 independently selected Rb(e.g., E is piperidinyl which is optionally substituted with 1-2 independently selected Rb(e.g., E is

256. The compound of any one of clauses 193-255, wherein the

moiety is

optionally wherein each of R1band R1cis an independently selected substituent that is other than H, such as wherein each of R1band R1cis an independently selected halo, such as —F or —Cl.

257. The compound of any one of clauses 193-255, wherein the

moiety is

258. The compound of any one of clauses 193-255, wherein the

moiety is

optionally wherein each of R1band R1cis an independently selected substituent that is other than H, such as wherein each of R1band R1cis an independently selected halo, such as —F or —Cl.

259. The compound of any one of clauses 193-258, wherein R2is H.

260. The compound of any one of clauses 193-259, wherein R5is H.

261. The compound of any one of clauses 193-253 and 256-260, wherein R7is H.

263. The compound of clause 262, wherein each of R1a, R1b, R1c, and R1dis H.

264. The compound of clause 262, wherein 1-2 of R1a, R1b, R1c, and R1dis other than H.

265. The compound of clauses 262 or 264, wherein 1-2 of R1a, R1b, R1c, and R1dis halo (e.g., F or Cl), such as wherein each of R1band R1cis independently F or Cl, such as F; or wherein R1cis H; and R1bis halo, such as —F or —Cl.

266. The compound of clauses 262 or 264, wherein one of R1a, R1b, R1c, and R1dis -L3-L4-Ri(e.g., R1bis -L3-L4-Ri); and each remaining R1a, R1b, R1c, and Rid is H.

267. The compound of clause 266, wherein one of R1a, R1b, R1c, and R1d(such as R1b) is selected from the group consisting of:heteroaryl of 5-6 ring atoms (such as pyrazolyl), wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy (e.g.,

andphenyl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy (e.g.,).

268. The compound of any one of clauses 1-267, wherein R6is H.

269. The compound of clause 1, wherein the compound is a compound of Formula (I-13):

Q5is N or CH;

each of Rtand Rsis independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy.

271. The compound of clauses 269 or 270, wherein R6is H.

272. The compound of any one of clauses 269-271, wherein Q5is CH.

273. The compound of clause 272, wherein L5is —O—.

274. The compound of clause 272, wherein L5is —N(H)— or -N(C1-3alkyl), such as —N(H)—.

275. The compound of clause 272, wherein L5is CH2or a bond.

276. The compound of any one of clauses 269-271, wherein Q5is N.

277. The compound of clause 276, wherein L5is CH2.

278. The compound of clause 276, wherein L5is a bond.

279. The compound of any one of clauses 269-278, wherein ml is 1; and m2 is 1.

280. The compound of any one of clauses 269-278, wherein ml is 1; and m2 is 0.

281. The compound of any one of clauses 269-278, wherein ml is 2; and m2 is 1.

282. The compound of any one of clauses 269-278, wherein ml is 0; and m2 is 0.

283. The compound of any one of clauses 269-271, wherein ml is 1; m2 is 1; Q5is CH; and L5is —O—.

284. The compound of any one of clauses 269-271, wherein ml is 0; m2 is 0; Q5is CH; and L5is —O—.

285. The compound of any one of clauses 269-271, wherein ml is 1; m2 is 0; Q5is N; and L5is a bond or CH2.

286. The compound of any one of clauses 269-285, wherein each of T1, T2, T3, and T4is independently CH or CRt, such as wherein each of T1, T2, T3, and T4is CH.

287. The compound of any one of clauses 269-285, wherein T1is N; and T2, T3, and T4are independently CH or CRt, such as wherein T1is N; and T2, T3, and T4are CH.

288. The compound of any one of clauses 269-285, wherein T2is N; and T1, T3, and T4are independently CH or CRt, such as wherein T2is N; and Ti, T3, and T4are CH.

289. The compound of any one of clauses 269-288, wherein R5is C1-4alkyl, such as methyl.

290. The compound of any one of clauses 269-288, wherein R5is C1-4haloalkyl, such as CF3.

291. The compound of any one of clauses 269-290, wherein R1ais H; and R1dis H or halo, such as: wherein R1ais H, and R1dis H; or wherein R1ais H, and R1dis halo such as —F or —Cl.

292. The compound of any one of clauses 269-291, wherein R1bis halo; and R1cis H, such as: wherein R1bis —Cl, and R1cis H; or wherein R1bis —F, and R1cis H; or

293. The compound of any one of clauses 269-291, wherein each of R1band R1cis an independently selected halo, such as wherein R1bis —Cl; and R1cis —F; or wherein R1bis —F; and R1cis —F.

294. The compound of any one of clauses 269-291, wherein R1bis R; and R1cis H or halo, such as H; such as: wherein R1bis selected from the group consisting of:heteroaryl of 5-6 ring atoms (such as pyrazolyl), wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2and wherein the heteroaryl ring is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy (e.g.,

andphenyl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo; C1-4alkyl optionally substituted with 1-2 independently selected Ra; C1-4haloalkyl; cyano; C1-4alkoxy; and C1-4haloalkoxy (e.g.,

295. The compound of any one of clauses 269-291, wherein one of R1band R1cis selected from the group consisting of: cyano, C1-3alkyl optionally substituted with Ra, and C1-3haloalkyl; and the other of R1band R1cis H or halo, such as —H, —F, or —Cl.

296. The compound of clause 1, wherein the compound is selected from the group consisting of the compounds delineated in Table C1 or a pharmaceutically acceptable salt thereof.

297. A pharmaceutical composition comprising a compound of clauses 1-296 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

298. A method for inhibiting STING activity, the method comprising contacting STING with a compound as defined in any one of clauses 1-296.

299. The method of clause 298, wherein the inhibiting comprises antagonizing STING.

300. The method of any one of clauses 298-299, which is carried out in vitro.

301. The method of clause 300, wherein the method comprises contacting a sample comprising one or more cells comprising STING with the compound.

302. The method of clause 300 or 301, wherein the one or more cells are one or more cancer cells.

304. The method of clause 302 or 303, which is carried out in vivo.

305. The method of clause 304, wherein the method comprises administering the compound to a subject having a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease.

306. The method of clause 305, wherein the subject is a human.

307. The method of clause 305, wherein the disease is cancer.

309. The method of clause 307 or 308, wherein the cancer is a refractory cancer.

310. The method of clause 305, wherein the compound is administered in combination with one or more additional cancer therapies.

311. The method of clause 310, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

312. The method of clause 311, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.

314. The method of any one of clauses 305-313, wherein the compound is administered intratumorally.

315. A method of treating cancer, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of clauses 1-296, or a pharmaceutical composition as defined in clause 297.

317. The method of clause 315 or 316, wherein the cancer is a refractory cancer.

318. The method of clause 315, wherein the compound is administered in combination with one or more additional cancer therapies.

319. The method of clause 318, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

320. The method of clause 319, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.

322. The method of any one of clauses 315-321, wherein the compound is administered intratumorally.

323. A method of inducing an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as defined in any one of clauses 1-296, or a pharmaceutical composition as defined in clause 297.

324. The method of clause 323, wherein the subject has cancer.

325. The method of clause 324, wherein the subject has undergone and/or is undergoing and/or will undergo one or more cancer therapies.

327. The method of clause 326, wherein the cancer is a refractory cancer.

328. The method of clause 323, wherein the immune response is an innate immune response.

329. The method of clause 328, wherein the at least one or more cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

330. The method of clause 329, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.

332. A method of treatment of a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of clauses 1-296, or a pharmaceutical composition as defined in clause 297.

333. A method of treatment comprising administering to a subject having a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease an effective amount of a compound as defined in any one of clauses 1-296, or a pharmaceutical composition as defined in clause 297.

334. A method of treatment comprising administering to a subject a compound as defined in any one of clauses 1-296, or a pharmaceutical composition as defined in clause 297, wherein the compound or composition is administered in an amount effective to treat a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease, thereby treating the disease.

335. The method of any one of clauses 332-334, wherein the disease is cancer.

337. The method of clause 335 or 336, wherein the cancer is a refractory cancer.

338. The method of any one of clauses 335-337, wherein the compound is administered in combination with one or more additional cancer therapies.

339. The method of clause 338, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

340. The method of clause 339, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.

342. The method of any one of clauses 332-341, wherein the compound is administered intratumorally.

343. A method of treatment of a disease, disorder, or condition associated with STING, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of clauses 1-296, or a pharmaceutical composition as defined in clause 297.

344. The method of clause 343, wherein the disease, disorder, or condition is selected from type I interferonopathies, Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, inflammation-associated disorders, and rheumatoid arthritis.

345. The method of clause 344, wherein the disease, disorder, or condition is a type I interferonopathy (e.g., STING-associated vasculopathy with onset in infancy (SAVI)).

346. The method of clause 345, wherein the type I interferonopathy is STING-associated vasculopathy with onset in infancy (SAVI)).

347. The method of clause 344, wherein the disease, disorder, or condition is Aicardi-Goutieres Syndrome (AGS).

348. The method of clause 344, wherein the disease, disorder, or condition is a genetic form of lupus.

349. The method of clause 344, wherein the disease, disorder, or condition is inflammation-associated disorder.

350. The method of clause 349, wherein the inflammation-associated disorder is systemic lupus erythematosus.

351. The method of any one of clauses 298-350, wherein the method further comprises identifying the subject.

352. A combination comprising a compounds defined in any one of clauses I to 296 or a pharmaceutically acceptable salt or tautomer thereof, and one or more therapeutically active agents.

353. A compound defined in any one of clauses 1 to 296 or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 297, for use as a medicament.

354. A compound defined in any one of clauses 1 to 296 or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 297, for use in the treatment of a disease, condition or disorder modulated by STING inhibition.

355. A compound defined in any one of clauses 1 to 296 or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition defined in clause 297, for use in the treatment of a disease mentioned in any one of clauses 298 to 350.

356. Use of a compound defined in any one of clauses 1 to 296 or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 297, in the manufacture of a medicament for the treatment of a disease mentioned in in any one of clauses 298 to 350.