Compounds and Compositions for Treating Conditions Associated with STING Activity

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of United States Provisional Application No. 62/769,327, filed on November 19, 2018 and United States Provisional Application No. 62/861,781, filed on June 14, 2019, each of which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

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.

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-KB 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 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:

In which A, B, W, and R ^N can be as defined anywhere 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 vasculopathywith 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 subj ect in need thereof are featured that include administering to the subj ect 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.

Embodiments can include one or more of the following features.

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 vasculopathywith 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 chemical entity can be administered in combination with one or more additional cancer therapies (e.g., surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof; e.g., chemotherapy that includes administering one or more (e.g., two, three, four, five, six, or more) additional chemotherapeutic agents. Non-limiting examples of additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g.,azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan;. amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Murom onab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti- angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1 - PD-L1, PD-

1 - PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-b (TGFP), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9 - TIM3, Phosphatidylserine - TIM3, lymphocyte activation gene 3 protein

(LAG3), MHC class II - LAG3, 4- 1 BB-4- 1 BB ligand, 0X40-0X40 ligand, GITR, GITR ligand - GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40- CD40 ligand, HVEM-LIGHT -LT A, HVEM, HVEM - BTLA, HVEM - CD 160, HVEM - LIGHT, HVEM-BTLA-CD 160, CD80, CD80 - PDL-1, PDL2 - CD80, CD244, CD48

- CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2,

HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86 - CD28, CD86 - CTLA, CD80 - CD28, CD39, CD73 Adenosine-CD39- CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine - TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

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

Non-limiting examples of cancer include melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma. In certain embodiments, the cancer can be a refractory cancer.

The chemical entity can be administered intratum orally.

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. As used herein, the term“STING” is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous STING molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

The term“acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

“API” refers to an active pharmaceutical ingredient.

The terms“effective amount” or“therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entity being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an“effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate“effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.

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 el 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, FL, 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, A-methyl -D-gl ucami ne, 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 "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

The term "alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci-io indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, No-propyl, /er/-butyl, «-hexyl.

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., -OCH ₃ ).

The term "alkylene" refers to a divalent alkyl (e.g., -CH2-). The term "alkenyl" refers to a 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, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it.

The term "alkynyl" refers to a 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, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it.

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 includes 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 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[TT0]butane, bicyclo[2.T0]pentane, bicyclo[l. Tl]pentane, bicyclo[3. T0]hexane, bicyclo[2. Tl]hexane, bicyclo[3.2.0]heptane, bicyclo[4. T0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.Tl]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 "cycloalkenyl" as used herein includes 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. Cycloalkenyl groups may have any degree of saturation provided that 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.

he term“heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl), and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S(0)o-2. Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3- _< i]pyrimidinyl, pyrrolo[2,3- />] pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-Z>]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-Z>]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[Z>][l,4]dioxine, benzo[<i][l,3]dioxole, 2,3- dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[Z>][l,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

The term "heterocyclyl" refers to a mon-, bi-, tri-, or polycyclic nonaromatic 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(0)o-2 if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2- azabicyclo[2.1.0]pentane, 2-azabicyclo[l . l . l]pentane, 3-azabicyclo[3.1.0]hexane, 5- azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3- azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7- azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2- oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[l . l . l]pentane, 3- oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3- oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7- oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1 azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2 azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1 , 7 -diazaspiro[4.5 ] decane, 7- azaspiro[4.5 ] decane 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2 oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1 -oxaspiro[3.5]nonane, 2 oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6 oxaspiro[2.6]nonane, l,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3 6]decane, 1 oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane and the like.

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 include ¹³ C and ¹⁴ C.

Non-limiting exemplified compounds of the formulae described herein include a stereogenic sulfur atom and optionally one or more stereogenic carbon atoms. This disclosure provides examples of stereoisomeric mixtures (e.g., racemic mixture of enantiomers; mixture of diastereomers). 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 cases of compounds containing only a stereogenic sulfur atom, resolved enantiomers are graphically depicted using one of the two following formats: formulas A/B (hashed and solid wedge three-dimensional representation); and formula C (“flat structures with * -labelled stereogenic sulfur).

In reaction schemes showing resolution of a racemic mixture, Formulas A/B and C are intended only to convey that the constituent enantiomers were resolved in enantiopure pure form (about 98% ee or greater). The schemes that show resolution products using the formula A/B format are not intended to disclose or imply any correlation between absolute configuration and order of elution. Some of the compounds shown in the tables below are graphically represented using the formula A/B format.

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

encompasses the tautomeric form containing the moiety: . y, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms. The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.

DETAILED DESCRIPTION

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.

Formula Compounds

In one aspect, provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof or a tautomer thereof,

wherein:

A is selected from the group consisting of:

(i) heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R ² ), O, S, and S(0) ₂ , and wherein from 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR ¹ , and CR ³ ; provided that at least one ring atom is substituted with R ¹ ; and (ii) heteroaryl including from 7-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R ² ), O, and S(0)o- ₂ , and wherein from 3-19 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH2, CR ¹ , CHR ¹ , C(R')2, CR ³ , CHR ³ , and C(R ³ ) ₂ ;

B and each occurrence of R ^N are defined according to (A) and (B) below:

(a) Ci- ₁₅ alkyl which is optionally substituted with from 1-6 R ^a ;

(b) C3-20 cycloalkyl, which is optionally substituted with from 1-4 R ^b ;

(c) phenyl substituted with from 1-4 R ^c ;

(d) C8-20 aryl optionally substituted with from 1-4 R ^c ;

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

(f) heterocyclyl including from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R ^b ; each R ^N is independently:

(i) H,

(ii) Ci- ₆ alkyl optionally substituted with from 1-3 R ^a ,

(iii) C3-6 cycloalkyl, optionally substituted with from 1-3 R ^a ,

(iv) -C(0)(Ci-4 alkyl), and

(v) -C(0)0(Ci-4 alkyl), i

B and one R ^N , taken together with the atoms to which each is attached form a ring including from 5-20 ring atoms, wherein the ring includes: (a) from 0-4 ring heteroatoms each independently selected from N, N(H), N(R ^d ), O, and S(0)o- ₂ (in addition to the heteroatoms

in the ^R moiety); and (b) from 2 to 17 ring carbon atoms, each of which is optionally substituted with 1-2 substituents independently selected from

(i) H;

(ii) oxo;

(iii) halo;

(iv) hydroxy;

(v) Ci- ₆ alkyl;

(vi) Ci- ₆ haloalkyl;

(vii) C6-io aryl optionally substituted with from 1-3 R ^c ;

(viii) heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected R ^c ;

(ix) heterocyclyl including from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R ^b ; and

(x) C _3-20 cycloalkyl, which is optionally substituted with from 1-4 R ^b ; and the remaining R ^N is H or Ci- ₆ alkyl;

W is O, NH, or N(R ^d );

R ¹ is: (i) -(U ¹ )q-U ² , wherein:

• q is O or l;

• U ¹ is Ci- ₆ alkylene, which is optionally substituted with from 1-6 R ^a ; and

• U ² is:

(a) C _3-12 cycloalkyl, which is optionally substituted with from 1-4 R ^b ,

(b) C6-10 aryl, which is optionally substituted with from 1-4 R ^c ;

(c) heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected R ^c , or

(d) heterocyclyl including from 3-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R ^b ,

OR

(ii) Ci-10 alkyl, which is optionally substituted with from 1-6 independently selected R ^a ; each occurrence of R ² is independently selected from the group consisting of:

(i) Ci- ₆ alkyl, which is optionally substituted with from 1-4 independently selected R ^a ;

(ii) C _3-6 cycloalkyl;

(iii) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2;

(iv) -C(0)(Ci-4 alkyl);

(v) -C(0)0(Ci-4 alkyl);

(vi) -CON(R’)(R”);

(vii) -S(0)I. ₂ (NR’R”);

(viii) - S(0)i- ₂ (Ci-4 alkyl); (ix) -OH; and

(x) Ci-4 alkoxy; each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1.4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NR ^e R ^f , -OH, oxo, -S(0)i- ₂ (NR’R”), -CI-4 thioalkoxy, -NO2, -C(=0)(Ci- ₄ alkyl), -C(=0)0(Ci- ₄ alkyl), - C(=0)OH, and -C(=0)N(R’)(R”); each occurrence of R ^a is independently selected from the group consisting of: -OH; -F; - Cl; -Br; -NR ^e R ^f ; C1-4 alkoxy; C1.4 haloalkoxy; -C(=0)0(Ci-4 alkyl); -C(=0)(Ci-4 alkyl); - C(=0)OH; -CON(R’)(R”); -S(0)i- ₂ (NR’R”); -S(0)I. ₂ (CM alkyl); cyano, and C3-6 cycloalkyl optionally substituted with from 1-4 independently selected C1-4 alkyl; each occurrence of R ^b is independently selected from the group consisting of: Ci-10 alkyl optionally substituted with from 1-6 independently selected R ^a ; C 1-4 haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR ^e R ^f ; CM alkoxy; CM haloalkoxy; -C(=0)(CM alkyl); -C(=0)0(CM alkyl); -C(=0)OH; -C(=0)N(R’)( ”); -S(0)i- ₂ (NR’R”); -S(0)I- ₂ (CM alkyl); cyano; and -L ¹ -L ² -R ^h ; each occurrence of R ^c is independently selected from the group consisting of:

(a) halo;

(b) cyano;

(c) Ci-io alkyl which is optionally substituted with from 1-6 independently selected R ^a ;

(d) C _2-6 alkenyl;

(e) C _2-6 alkynyl;

(g) Ci-4 alkoxy;

(h) Ci- ₄ haloalkoxy;

(i) -S(0)i- ₂ (Ci-4 alkyl);

G) -NR ^e R ^f ;

(k) -OH; (l) -S(0) _I-2 (NR ^, R”);

(m) -Ci- ₄ thioalkoxy;

(n) -N0 ₂ ;

(o) -C(=0)(Ci-4 alkyl);

(p) -C(=0)0(Ci-4 alkyl);

(q) -C(=0)0H;

(r) -C(=0)N(R’)(R”); and

(s) -L'-L ² -R ^h ; R ^d is selected from the group consisting of: Ci- ₆ alkyl; C _3-6 cycloalkyl; -C(0)(Ci- ₄ alkyl); -C(0)0(Ci-4 alkyl); -CON(R’)(R”); -S(0)i- ₂ (NR’R”); - S(0)I. ₂ (CM alkyl); -OH; and Ci- ₄ alkoxy; each occurrence of R ^e and R ^f is independently selected from the group consisting of: H; Ci- ₆ alkyl; Ci- ₆ haloalkyl; C _3-6 cycloalkyl; -C(0)(Ci- ₄ alkyl); -C(0)0(Ci- ₄ alkyl); - CON(R’)( ”); -S(0)i- ₂ (NR’R”); - S(0)I. ₂ (CM alkyl); -OH; and CM alkoxy; or R ^e and R ^f together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C _1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R ^e and R ^r ), which are each independently selected from the group consisting of N(R ^d ), NH, O, and S;

-L ¹ is a bond or C _1-3 alkyl ene;

-L ² is -O-, -N(H)-, -S-, or a bond;

R ^h is selected from:

• C _3-8 cycloalkyl optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, CM alkyl, and CM haloalkyl (in certain embodiments, it is provided that when R ^h is C _3-6 cycloalkyl optionally substituted with from 1-4 independently selected CM alkyl, -L ¹ is a bond, or -L ² is -O-, - N(H)-, or -S-); • heterocyclyl, wherein the heterocyclyl includes from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, and Ci-4 haloalkyl;

• heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ and wherein the heteroaryl ring is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci- 4 alkyl, and Ci-4 haloalkyl; and

• C ₆ -io aryl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, or Ci-4 haloalkyl; and each occurrence of R’ and R” is independently selected from the group consisting of: H, Ci-4 alkyl, and C _6-10 aryl optionally substituted with from 1-2 substituents selected from halo, Ci-4 alkyl, and Ci- ₄ haloalkyl; or R’ and R” together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from the group consisting of H and C _1-3 alkyl; and (b) from 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(R ^d ), O, and S; with the proviso that the compound is not:

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

Ring A

In some embodiments, A is: heteroaryl including from 7-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ² ), O, and S(0)o- ₂ , and wherein from 3-19 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CEE, CR ¹ , CHR ¹ , C(R') _2, OR ³ , CHR ³ , and C(R ³ ) _2.

In certain embodiments, A is: heteroaryl including from 8-16 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ² ), O, and S(0)o- ₂ , and wherein from 4-15 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH ₂ , CR ¹ , CHR ¹ , C(R ³ ) ₂ , CR ³ , CHR ³ , and C(R ³ ) _2.

In certain embodiments, A is: heteroaryl including from 8-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R ² ), O, and S(0)o- ₂ , and wherein from 4-9 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH ₂ , CR ¹ , CHR ¹ , CiR ¹ ) _! , CR ³ , CHR ³ , and C(R ³ ) _2.

In certain embodiments, A is: heteroaryl including from 8-9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R ² ), O, and S(0)o- ₂ , and wherein from 4-8 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH ₂ , CR ¹ , CHR ¹ , CiR ¹ ) _! , CR ³ , CHR ³ , and C(R ³ ) _2.

[C6] In certain embodiments, A has formula (A-l):

(A-l)

wherein

Z is selected from the group consisting of: a bond, CH, CR ¹ , CR ³ , N, NH, N(R ⁴ ) and N(R ² );

each of Y ¹ , Y ² , and Y ³ is independently selected from the group consisting of O, S, CH, CR ¹ , CR ³ , N, NH, N(R ⁴ ), and NR ² ;

Y ⁴ is C or N;

X ¹ is selected from the group consisting of O, S, N, NH, NR ¹ , NR ² , CH, CR ¹ , and CR ³ ;

X ² is selected from the group consisting of O, S, N, NH, NR ¹ , NR ² , CH,

CR ¹ , and CR ³ ; and

each— is independently a single bond or a double bond, provided that the five-membered ring comprising Y ⁴ , X ¹ , and X ² is heteroaryl; and the ring comprising Z, Y ¹ , Y ² , Y ³ , and Y ⁴ is aromatic (i.e., carbocyclic aromatic or heteroaromatic).

As used herein, when the ring comprising Z, Y ¹ , Y ² , Y ³ , and Y ⁴ is described as being aromatic, it means the 6- or 5-membered ring containing Z, Y ¹ , Y ² , Y ³ and

Y ⁴ (i.e., the moiety) has a continuous, delocalized p-electron system. Typically, the number of out of plane p-electrons corresponds to the Hiickel

rule (4n+2). Examples of such rings include:

, each of which of optionally substituted with one or more R ¹ and/or

R ³ as described anywhere herein.

[C7] In certain of these embodiments, Z is selected from the group consisting of: CH, CR ¹ , CR ³ , N, and N(R ² ).

[C8] For example, Z can be selected from the group consisting of: CH, CR ¹ , CR ³ , and N.

[C9] As another example, Z is selected from the group consisting of CH, CR ¹ , and CR ³ (e g., Z is CH).

[CIO] In certain of the foregoing embodiments, each of Y ¹ , Y ² , and Y ³ is independently selected from the group consisting of CH, CR ¹ , CR ³ , and N.

[Cll] In certain of these embodiments, each of Y ¹ , Y ² , and Y ³ is independently selected from the group consisting of CH, CR ¹ , and CR ³ .

[Cl 2] For example, the moiety can , wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2).

[C13] In other of the foregoing embodiments, from 1-2 of Y ¹ , Y ² , and Y ³ is independently N.

[C14] In certain embodiments, one of Y ¹ , Y ² , and Y ³ can be independently N. [C15] In certain of the foregoing embodiments, each of the remaining Y ¹ , Y ² , and

Y ³ is independently selected from the group consisting of CH, CR ¹ , and CR ³ , provided that one or more of Y ¹ , Y ² , and Y ³ independently CH. [C16] For example, the moiety can wherein the asterisk denotes point of attachment to Y ⁴ ; and m3 = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1 ; and m3 = 0 or 1).

[Cl 7] As another example, the moiety wherein the asterisk denotes point of attachment to Y ⁴ ; and m l = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1 ; and m3 = 0 or 1).

[C17a] As yet another example, the wherein the asterisk denotes point of attachment to Y ⁴ ; and m l = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).

[C18] In certain embodiments, two of Y ¹ , Y ² , and Y ³ are independently N.

[C19] In certain of the foregoing embodiments, the remaining of Y ¹ , Y ² , and Y ³ is independently CH or CR ¹ .

[C20] In certain embodiments, Z is N.

[C21] In certain of these embodiments, each of Y ¹ , Y ² , and Y ³ is independently selected from the group consisting of CH, CR ¹ , CR ³ , and N.

[C22] In certain embodiments, one of Y ¹ , Y ² , and Y ³ can be independently N; and each of the remaining Y ¹ , Y ² , and Y ³ can be independently CH, CR ¹ , CR ³ , and N; or

[C23] each of the remaining Y ¹ , Y ² , and Y ³ can be independently CH, CR ¹ , and

CR ³ 7 ml(R ¹ ) _M

f ^

^Y ¾. - ^N ₃ *^*

[C24] For example, the Y moiety can be ^m3 ^ ^R ) , wherein the asterisk denotes point of attachment to Y ⁴ ; and ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., m = 0 or 1; and m3 = 0 or 1).

[C25] In certain of the foregoing embodiments, Z is a bond.

[C26] In certain of these embodiments, each of Y ¹ , Y ² , and Y ³ is independently selected from the group consisting of O, S, CH, CR ¹ , CR ³ , N, NH, and NR ² .

[C27] In certain embodiments, from 1-2 of Y ¹ , Y ² , and Y ³ is independently selected from the group consisting of O, S, N, NH, and NR ² (e.g., S, N, and NR ² ).

*v t 1 h'*

[C28] For example, the moiety can be mi( ^R ) , wherein the asterisk denotes point of attachment to Y ⁴ ; and ml = 0 or 1; and m3 = 0, 1, or 2.

[C29] As another example, the moiety can be , or ), wherein the asterisk denotes point of attachment to Y ⁴ .

[C30] In certain of the foregoing embodiments, Y ⁴ is C.

[C31] In certain of the foregoing embodiments, X ¹ is selected from the group consisting of O, S, NH, NR ¹ , and NR ² .

[C32] In certain embodiments, X ¹ is selected from the group consisting of NH, NR ¹ , and NR ² (e.g., X ¹ can be NH).

[C33] In certain of the foregoing embodiments, X ² is selected from the group consisting of N, CH, CR ¹ , and CR ³ ; [C34] e.g., X ² is selected from the group consisting of N, C(Ci-3 alkyl), and CH;

[C35] e.g., X ² can be CH.

[C36] For example, X ¹ and X ² , taken together, can be ^H , wherein the asterisk denotes point of attachment to Y ⁴ .

[C37] Non-limiting examples of A include:

m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2).

[C38] Another non-limiting example of A includes: , wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 =

0 or 1).

[C39] A further non-limiting example of A includes: , wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 =

0 or 1).

[C40] A further non-limiting example of A includes: , wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2. further non-limiting example of A includes: , wherein ml = 0 or 1; and m3 = 0, 1, or 2.

[C42] Still other non-limiting examples of A include:

[C43] In some embodiments, A is: heteroaryl including from 8-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R ² ), O, and S(0)o- ₂ , and wherein from 4-19 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH ₂ , CR ¹ , CHR ¹ , C(R') _2, OR ³ , CHR ³ , and C(R ³ ) _2.

[C44] In certain embodiments, A is: heteroaryl (e.g., tricyclic heteroaryl) including from 10-16 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R ² ), O, and S(0)o- ₂ , and wherein from 6-15 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH ₂ , CR ¹ , CHR ¹ , C(R ¹ ) ₂ , CR ³ , CHR ³ , and C(R ³ ) _2.

[C45] In some embodiments, A is (A-2):

(A-2) wherein:

Z is selected from the group consisting of:

a bond, CH, CH ₂ , CR ¹ , CHR ¹ , C(R') ₂ , CR ³ , CHR ³ , C(R ³ ) ₂ , O, N, NH, N(R') and N(R ² ); each of Y ¹ and Y ² is independently selected from the group consisting of O, S,

CH, CH ₂ , CR ¹ , CHR ¹ , C(R ¹ ) ₂ , CR ³ , CHR ³ , C(R ³ ) ₂ , N, NH, N(R'), and NR ² ; one of Q ¹ and Q ² is absent, and the other one of Q ¹ and Q ² is a C _2-5 alkyl ene that is optionally interrupted with one heteroatom selected from -NH-, -N -, -N(R ² )-, and -O-; and

each— is independently a single bond or a double bond.

[C46] In certain embodiments (when A is (A-2)), Z is selected from CH, CR ¹ , CR ³ , and N.

[C47] In certain of the foregoing embodiments, Z is selected from CH and N (e.g., Z is CH).

[C48] In certain embodiments (when A is (A-2)), each of Y ¹ and Y ² is independently selected from the group consisting of CH, CR ¹ , CR ³ , and N.

[C49] In certain embodiments (when A is (A-2)), each of Y ¹ and Y ² is independently selected from the group consisting of CH, CR ¹ , and CR ³ .

[C50] In certain embodiments (when A is (A-2)), Q ¹ is a C _2-5 alkylene that is optionally interrupted with one heteroatom selected from -NH-, -N(R')-, -N(R ² )-, and -O- ; and Q ² is absent.

[C51] As a non-limiting example, Q ¹ can be a C _2-3 alkylene (e.g., C ₂ ).

[C52] In certain embodiments (when A is (A-2)), Q ² is a C _2-5 alkylene that is optionally interrupted with one heteroatom selected from -NH-, -N(R')-, -N(R ² )-, and -O- ; and Q ¹ is absent.

[C53] As a non-limiting example, Q ² is a C3-4 alkylene (e.g., C3).

[C54] In certain embodiments (when A is (A-2)), A is:

wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0; and m3 = 0).

[C55] In certain embodiments (when A is (A-2)), A is:

wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0; and m3 = 0).

[C56] In some embodiments, A is (A-3):

wherein

Ring A ^3A is a monocyclic or bicyclic ring including from 5-12 ring atoms, wherein from 0-2 ring atoms are heteroatoms cumulative with the value selected for Y ⁴ , wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R'), N(R ² ), O, and S(0)o- ₂ , and from 2-12 are ring carbon atoms each independently selected from C, CH, CH2, CR ¹ , CHR ¹ , C(R')2, OR ³ , CHR ³ , and C(R ³ )2, provided that Ring A ^3A is non-aromatic;

X ¹ is selected from the group consisting of O, S, N, NH, NR ¹ , NR ² , CH, CR ¹ , and

CR ³ ;

X ² is selected from the group consisting of O, S, N, NH, NR ¹ , NR ² , CH, CR ¹ , and CR ³ , provided that the ring including Y ⁴ , X ¹ , and X ² is heteroaromatic; and

Y ⁴ is selected from N or C.

[C57] In certain embodiments (when A is (A-3)), Y ⁴ is C [C58] In certain embodiments (when A is (A-3)), Ring A ^3A is a monocyclic ring including from 5-8 ring atoms, wherein from 0-2 ring atoms are heteroatoms cumulative with the value selected for Y ⁴ , wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R'), N(R ² ), O, and S(0)o- ₂ , and from 2-8 are ring carbon atoms each independently selected from C, CH, CH ₂ , CR ¹ , CHR ¹ , C(R')2, OR ³ , CHR ³ , and C(R ³ ) ₂ , provided that Ring A ^3A is non-aromatic;

[C59] In certain embodiments (when A is (A-3)), Ring A ^3A is a monocyclic ring including from 5-6 ring atoms, wherein from 0-2 ring (e.g., 0 or 1, e.g., 0) atoms are heteroatoms cumulative with the value selected for Y ⁴ , wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R ⁴ ), N(R ² ), O, and S(0)o- 2, and from 2-6 are ring carbon atoms each independently selected from C, CH2, CHR ¹ , C(R')2, CHR ³ , and C(R ³ ) ₂ , provided that Ring A ^3A is non-aromatic.

[C60] In certain embodiments (when A is (A-3)), A is:

, wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 =

0 or 1).

[C61] In certain embodiments (when A is (A-3)), Ring A ^3A is a bicyclic ring (e.g., spirobicyclic ring) including from 7-12 ring atoms, wherein from 0-2 ring (e.g., 0 or 1, e.g., 1) atoms are heteroatoms cumulative with the value selected for Y ⁴ , wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R ⁴ ), N(R ² ), O, and S(0)o- ₂ , and from 4-12 are ring carbon atoms each independently selected from C, CH, CH ₂ , CR ¹ , CHR ¹ , C(R') ₂ , CR ³ , CHR ³ , and C(R ³ ) ₂ , provided that Ring A ^3A is non aromatic.

[C62] In certain embodiments (when A is (A-3)), Ring A ^3A is a bicyclic ring (e.g., spirobicyclic ring) including from 7-9 (e.g., 8) ring atoms, wherein from 0-2 ring (e.g., 0 or 1, e.g., 1) atoms are heteroatoms cumulative with the value selected for Y ⁴ , wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R ⁴ ), N(R ² ), O, and S(0)o- ₂ , and from 4-9 are ring carbon atoms each independently selected from C, CH, CH2, CR ¹ , CHR ¹ , C(R ¹ )2, OR ³ , CHR ³ , and C(R ³ )2, provided that Ring A ^3A is non aromatic.

[C63] In certain embodiments (when A is (A-3)), Ring A ^3A is a bicyclic ring (e.g., spirobicyclic ring) including from 7-9 (e.g., 8) ring atoms, wherein from 0-2 ring (e.g., 0 or 1, e.g., 1) atoms are heteroatoms cumulative with the value selected for Y ⁴ , wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R ^d ) and O, and from 4-9 are ring carbon atoms each independently selected from C, CH2, CHR ¹ , C(R ³ ) ₂ , CHR ³ , and C(R ³ )2, provided that Ring A ^3A is non-aromatic.

[C64] In certain embodiments (when A is (A-3)), A is:

, wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).

[C65] In certain embodiments (when A is (A-3)), X ¹ is selected from NH, N(R ² ), O, and S.

[C66] As a non-limiting example of the foregoing embodiments, X ¹ can be NH. [C67] In certain embodiments (when A is (A-3)), X ² is selected from N, CH, and

CR ¹ .

[C68] As a non-limiting example of the foregoing embodiments, X ² is CH.

[C69] In certain embodiments (when A is (A-3)), A is:

, wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 =

0 or 1).

[C70] In certain embodiments (when A is (A-3)), A is:

, wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1). [C71] In some embodiments, A is: heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R ² ), O, S, and S(0) ₂ , and wherein from 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR ¹ , and CR ³ ; provided that at least one ring atom is substituted with R ¹ .

[C72] In certain of the foregoing embodiments, A is: heteroaryl including 5 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R ² ), O, and S, and wherein from 1-4 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR ¹ , and CR ³ ; provided that at least one ring atom is substituted with R ¹ .

[C73] In certain embodiments, A is: heteroaryl including 5 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R ² ), O, and S, and wherein from 1-4 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR ¹ , and CR ³ ; provided that one ring atom is substituted with from 1-2 R ¹ (e.g., 1).

[C74] In some embodiments,

wherein:

Z ² is selected from CH, CR ² , and N;

X ³ is selected from O, S, N, NH, NR ¹ , NR ² , CH, CR ¹ , and CR ³ ;

each of Y ⁵ and Y ⁶ is independently selected from O, S, CH, CR ¹ , CR ³ , NR ¹ , NR ² , NH, and N; and

each— is independently a single bond or a double bond, provided that the five- membered ring comprising Y ⁵ , Y ⁶ , X ³ , and Z ² is heteroaromatic.

[C75] In certain of the foregoing embodiments,

when X ³ is NR ¹ or CR ¹ , then each of Y ⁵ and Y ⁶ is independently selected from O, S, CH, CR ³ , NR ² , NH, and N; and when X ³ is selected from O, S, N, NH, NR ² , CH, and CR ³ , then one of Y ⁵ and Y ⁶ is CR ¹ or NR ¹ (in certain embodiments, the other of Y ⁵ and Y ⁶ is selected from O, S, CH, CR ³ , NR ² , NH, and N).

[C76] In certain embodiments (when A is (A-4)), Z ² is selected from CH and N.

[C77] As a non-limiting example, Z ² can be CH.

[C78] In certain embodiments (e.g., when A is (A-4); and/or Z ² is selected from CH and N), Y ⁶ is selected from N, CH, and CR ³ .

[C79] As a non-limiting example, Y ⁶ can be N.

[C80] In certain embodiments (e.g., when A is (A-4); Z ² is selected from CH and N; and/or Y ⁶ is selected from N, CH, and CR ³ ), Y ⁵ is CR ¹ .

[C81] In certain embodiments (e.g., when A is (A-4); Z ² is selected from CH and N; Y ⁶ is selected from N, CH, and CR ³ ; and/or Y ⁵ is CR ¹ ), X ³ is selected from S, O, NH, and N(R ² ).

[C83] As a non-limiting example, A can

[C84] As another non-limiting example, A can

[C85] In certain embodiments (when A is (A-4)), Z ² is N.

[C86] In certain embodiments (e.g., when A is (A-4); and/or Z ² is N), Y ⁶ is selected from N, CH, and CR ³ . [C87] As a non-limiting example, Y ⁶ can be CH.

[C88] In certain embodiments (e.g., when A is (A-4); Z ² is N; and/or Y ⁶ is selected from N, CH, and CR ³ ), Y ⁵ is CR ¹ .

[C89] In certain embodiments (e.g., when A is (A-4); Z ² is N; Y ⁶ is selected from N, CH, and CR ³ ; and/or Y ⁵ is CR ¹ ), X ³ is selected from O, S, NH, and NR ² .

[C91] As a non-limiting example, A can

Variable R ¹

[C92] In some embodiments, R ¹ is independently selected from: (i) -(U ¹ )q-U ² , wherein:

• q is O or l;

• U ¹ is Ci- ₆ alkylene, which is optionally substituted with from 1-6 R ^a ; and

• U ² is:

(a) C3-10 cycloalkyl, which is optionally substituted with from 1-4 R ^b ,

(b) C _6-10 aryl, which is optionally substituted with from 1-4 R ^c ;

(c) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected R ^c , or (d) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R ^b ,

AND

(ii) Ci- ₆ alkyl, which is optionally substituted with from 1-6 independently selected

R ^a .

[C93] In certain embodiments, R ¹ is -(U ¹ )q-U ² .

[C94] In certain embodiments, q is 0.

[C95] In some embodiments, U ² is C6-10 aryl, which is optionally substituted with from 1-4 R ^c .

[C96] In certain embodiments, U ² is C6-10 aryl, which is optionally substituted with from 1-2 R ^c .

[C97] As a non-limiting example, U ² can be phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c .

[C98] In some embodiments, U ² is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected R ^c .

[C99] In certain embodiments, U ² is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c .

[CIOO] In certain embodiments, U ² is heteroaryl including from 6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c . [C101] As a non-limiting example of the foregoing embodiments, U ² can be pyridinyl (e.g., 2-pyridinyl) or pyrimidinyl (2-pyrimidinyl), each of which optionally substituted with from 1-2 independently selected R ^c (e.g., unsubstituted).

[C102] In some embodiments, each occurrence of R ^c substituent on U ² is selected from:

(a) halo (e.g., Cl, F);

(b) cyano;

(c) Ci-io alkyl which is optionally substituted with from 1-6 independently selected R ^a ;

(f) Ci-4 haloalkyl;

(g) Ci-4 alkoxy;

(h) Ci- ₄ haloalkoxy; and

(m) -Ci- ₄ thioalkoxy. [C103] In certain embodiments, each occurrence of R ^c substituent on U ² is selected from: halo (e.g., Cl, F; e.g., F), cyano, Ci- ₆ alkyl, and Ci-4 haloalkyl.

[C104] As a non-limiting example, each occurrence of R ^c substituent on U ² can be selected from halo (e.g., Cl, F; e.g., F).

[C105] In some embodiments, U ² is heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R ^b .

[C106] In certain embodiments, U ² is heterocyclyl including from 3-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R ^b .

[C107] In certain embodiments, U ² is heterocyclyl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heterocyclyl ring is optionally substituted with from 1-2 independently selected R ^b . [C108] In certain embodiments, U ² is heterocyclyl including from 5 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heterocyclyl ring is optionally substituted with one independently selected R ^b (e.g., U ² is tetrahydrofuranyl).

[C109] In certain embodiments (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c .

[Cl 10] In certain of the foregoing embodiments, each R ^c is as defined in any one of paragraphs [Cl 02] -[Cl 04]

[Cl 10a] In certain of these embodiments, each occurrence of R ^c substituent on U ² is selected from:

(a) halo (e.g., Cl, F);

(b) cyano;

(c) Ci-io alkyl which is optionally substituted with from 1-6 independently selected

R ^a ;

(f) Ci- ₄ haloalkyl;

(g) Ci-4 alkoxy;

(h) Ci- ₄ haloalkoxy; and

(m) -Ci- ₄ thioalkoxy.

[Cl 10b] As a non-limiting example, each occurrence of R ^c substituent on U ² can be selected from: halo (e.g., Cl, F; e.g., F), cyano, Ci- ₆ alkyl, and Ci-4 haloalkyl.

[CllOc] For example, each occurrence of R ^c substituent on U ² can be selected from halo (e.g., Cl, F; e.g., F).

[Clll] In certain embodiments (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl).

[012] In certain of the foregoing embodiments, each R ^c is as defined in any one of paragraphs [Cl 02] -[Cl 04] [Cl 12a] In certain of these embodiments, each occurrence of R ^c substituent on U ² is selected from:

(a) halo (e.g., Cl, F);

(b) cyano;

(c) Ci-io alkyl which is optionally substituted with from 1-6 independently selected

R ^a ;

(f) Ci- ₄ haloalkyl;

(g) Ci-4 alkoxy;

(h) Ci- ₄ haloalkoxy; and

(m) -Ci- ₄ thioalkoxy.

[Cl 12b] As a non-limiting example, each occurrence of R ^c substituent on U ² can be selected from: halo (e.g., Cl, F; e.g., F), cyano, Ci- ₆ alkyl, and Ci-4 haloalkyl.

[C112c] For example, each occurrence of R ^c substituent on U ² can be selected from halo (e.g., Cl, F; e.g., F).

[C113]In some embodiments, R ¹ is Ci- ₆ alkyl, which is optionally substituted with from 1-6 independently selected R ^a .

[Cl 14] In certain embodiments, R ¹ is Ci- ₆ alkyl, which is optionally substituted with from 1-4 independently selected R ^a .

[Cl 15] In certain embodiments, R ¹ is C1-3 alkyl, which is optionally substituted with from 1-4 independently selected R ^a .

[Cl 16] As a non-limiting example, R ¹ can be C1-3 alkyl, which is optionally substituted with from 1-3 (e.g., 1, 2, or 3) independently selected R ^a .

[Cl 17] In some embodiments, each occurrence of R ^a substituent of R ¹ is independently selected from: -OH; -F; -Cl; -NR ^e R ^f ; C1-4 alkoxy; C1-4 haloalkoxy; - C(=0)0(Ci-4 alkyl); -C(=0)(Ci- ₄ alkyl); -C(=0)OH; -CON(R’)(R”); -S(0)i- ₂ (NR’R”); - S(0)i- ₂ (Ci- ₄ alkyl); cyano, and C3-6 cycloalkyl optionally substituted with from 1-4 independently selected C1-4 alkyl.

[Cl 18] In certain embodiments, each occurrence of R ^a substituent of R ¹ is independently selected from: -OH; -F; -Cl; C1-4 alkoxy; C1-4 haloalkoxy; -C(=0)0(Ci- ₄ alkyl); -C(=0)0H, and C3-6 cycloalkyl optionally substituted with from 1-4 independently selected C 1-4 alkyl.

[Cl 19] In certain embodiments, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)OH.

[C120] As non-limiting examples, R ¹ can be CF3 or CH2CO2H.

Variable R ³

In some embodiments, each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, C1-4 alkoxy, C1-4 haloalkoxy, -S(0)i- ₂ (Ci- ₄ alkyl), -NR ^e R ^f , -OH, -S(0)I. ₂ (NR’R”), -CM thioalkoxy, -C(=0)(CM alkyl), -C(=0)0(CM alkyl), - C(=0)OH, and -C(=0)N(R’)(R”)

In certain embodiments, each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, CM alkoxy, CM haloalkoxy, -S(0)I-2(CM alkyl), -S(0)i- ₂ (NR’R”), -C(=0)(CM alkyl), -C(=0)0(CM alkyl), -C(=0)OH, and -C(=0)N(R’)(R”).

In some embodiments (e.g., when ring A is a heteroaryl including 10 ring atoms), each occurrence of R ³ is independently selected from the group consisting of: fluoro, bromo, iodo, cyano, CM alkoxy, CM haloalkoxy, -S(0)I-2(CM alkyl), -NR ^e R ^f , -OH, - S(0)I. ₂ (NR’R”), -CM thioalkoxy, -C(=0)(CM alkyl), -C(=0)0(CM alkyl), -C(=0)OH, and -C(=0)N(R’)(R”).

As non-limiting examples, each occurrence of R ³ can be independently selected from the group consisting of: halo, cyano, C _M alkoxy, and C _M haloalkoxy.

Variable R ²

In some embodiments, each occurrence of R ² is independently selected from

(i) Ci- ₆ alkyl (e.g., methyl);

(ii) C _3-6 cycloalkyl;

(iv) -C(0)(CM alkyl) (e.g., C(O)Me);

(v) -C(0)0(CM alkyl);

(vi) -CON(R’)(R”); (vii) -S(0)I- ₂ (NR’R”); and

(viii) - S(0)i-2(Ci-4 alkyl) (e.g., S(0) ₂ Me).

In certain embodiments, each occurrence of R ² is independently Ci- ₆ alkyl (e.g., methyl).

In certain embodiments, each occurrence of R ² is independently -C(0)(Ci- ₄ alkyl) (e.g., C(O)Me).

In certain embodiments, each occurrence of R ² is independently - S(0)i- ₂ (Ci- ₄ alkyl) (e.g., S(0) ₂ Me).

Non-Limiting Combinations of R ¹ , R ³ , and Ring A

Non-Limiting Combinations when Ring A is (A-l ):

In some embodiments when Ring A is (A-l); and (A-l) is as defined in any one of paragraphs [C12], [C16], [C17], and [C24], ml = 1.

In certain of the foregoing embodiments, m3 = 0.

In some embodiments (when Ring A is (A-l); and (A-l) is as defined in any one of paragraphs [02], [06], [07], and [C24]), ml = 0; and m3 = 0.

In some embodiments (when Ring A is (A-l); and (A-l) is as defined in paragraph [C28]), ml = 1; and m3 = 0.

In certain embodiments (when Ring A is (A-l); and (A-l) is as defined in any one of paragraphs [02], [06], [07], [C24], and [C37]-[C42]), m3 = 1 or 2.

In certain of the foregoing embodiments, ml = 0.

In certain embodiments (when Ring A is (A-l); and (A-l) is as defined in any one of paragraphs [02], [06], [07], [C24], and [C37]-[C42]; m3 = 1 or 2; and/or ml = 0), each occurrence of R ³ is independently as defined in any one of paragraphs [021]-[023].

[A-la] ml (R ¹ )

In some embodiments, Ring A is (A-l); and the % Y° * moiety is ^m3 ^ ^R ) , wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1 or 2).

In certain of these embodiments, ml = 1.

In certain embodiments of [A- la], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-la], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-la], U ² is as defined in paragaph [C99]

In certain embodiments of [A-la], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of [A-la], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-la] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-la] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c] In certain embodiments of [A-la] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-la], R ¹ is as defined in paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph [016].

In certain embodiments of [A-la], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of [A-la], m3 = 0.

In certain other embodiments, m3 = 1 or 2.

In certain embodiments of [A-la], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i- ₂ (Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0) _{I -2} (NR’R”), -C _M thioalkoxy, -C(=0)(C _M alkyl), -C(=0)0(C _M alkyl), -C(=0)0H, and -C(=0)N(R’)(R”).

In certain embodiments of [A-la], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, CM alkoxy, CM haloalkoxy, -S(0)I- ₂ (CM alkyl), -S(0)I- ₂ (NR’R”), -C(=0)(CM alkyl), -C(=0)0(CM alkyl), -C(=0)0H, and - C(=0)N(R’)(R”).

In certain embodiments of [A-la], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, C _M alkoxy, and C _M haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F).

In certain of the foregoing embodiments, ml = 0.

In certain embodiments, ml = 0; and m3 = 0.

[A-lb] In some embodiments, Ring A is (A-l); the

wherein: the asterisk denotes point of attachment to Y ⁴ ; and m3 = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).

In certain of these embodiments, ml = 1.

In certain embodiments of [A-lb], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-lb], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-lb], U ² is as defined in paragaph [C99]

In certain embodiments of [A-lb], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of [A-lb], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-lb] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-lb] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-lb] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-lb], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph

[016].

In certain embodiments of [A-lb], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of [A-lb], m3 = 0.

In certain other embodiments, m3 = 1 or 2.

In certain embodiments of [A-lb], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i- ₂ (Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0) _{I -2} (NR’R”), -C _M thioalkoxy, -C(=0)(C _M alkyl), -C(=0)0(C _M alkyl), -C(=0)0H, and -C(=0)N(R’)(R”).

In certain embodiments of [A-lb], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, CM alkoxy, CM haloalkoxy, -S(0)I- ₂ (CM alkyl), -S(0)I- ₂ (NR’R”), -C(=0)(CM alkyl), -C(=0)0(CM alkyl), -C(=0)0H, and - C(=0)N(R’)(R”).

In certain embodiments of [A-lb], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, C _M alkoxy, and C _M haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F).

In certain of the foregoing embodiments, ml = 0.

In certain embodiments, ml = 0; and m3 = 0. [A-lc]

In some embodiments, Ring A is (A-l); the

wherein: the asterisk denotes point of attachment to Y ⁴ ; and m3 = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).

In certain of these embodiments, ml = 1.

In certain embodiments of [A-lc], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-lc], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-lc], U ² is as defined in paragaph [C99]

In certain embodiments of [A-lc], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of [A-lc], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-lc] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-lc] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-lc] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-lc], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph

[016].

In certain embodiments of [A-lc], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of [A-lc], m3 = 0.

In certain other embodiments, m3 = 1 or 2.

In certain embodiments of [A-lc], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i- ₂ (Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0)I- ₂ (NR’R”), -CM thioalkoxy, -C(=0)(CM alkyl), -C(=0)0(CM alkyl), -C(=0)0H, and -C(=0)N(R’)(R”).

In certain embodiments of [A-lc], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, CM alkoxy, CM haloalkoxy, -S(0)I- ₂ (CM alkyl), -S(0)I- ₂ (NR’R”), -C(=0)(CM alkyl), -C(=0)0(CM alkyl), -C(=0)0H, and - C(=0)N(R’)(R”).

In certain embodiments of [A-lc], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, C _M alkoxy, and C _M haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F). In certain of the foregoing embodiments, ml = 0.

In certain embodiments, ml = 0; and m3 = 0.

[A-ld]

In some embodiments, Ring A is (A-l); the moiety

wherein: the asterisk denotes point of attachment to Y ⁴ ; and ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., m = 0 or 1; and m3 = 0 or 1).

In certain of these embodiments, ml = 1.

In certain embodiments of [A-ld], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-ld], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-ld], U ² is as defined in paragaph [C99]

In certain embodiments of [A-ld], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of [A-ld], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-ld] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c] In certain embodiments of [A-ld] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-ld] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-ld], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph

[016].

In certain embodiments of [A-ld], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of [A-ld], m3 = 0.

In certain other embodiments, m3 = 1 or 2.

In certain embodiments of [A-ld], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i- ₂ (Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0) _{I -2} (NR’R”), -C _M thioalkoxy, -C(=0)(C _M alkyl), -C(=0)0(C _M alkyl), -C(=0)0H, and -C(=0)N(R’)(R”).

In certain embodiments of [A-ld], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, CM alkoxy, CM haloalkoxy, -S(0)I- ₂ (CM alkyl), -S(0)I. ₂ (NR’R”), -C(=0)(CI-4 alkyl), -C(=0)0(Ci- ₄ alkyl), -C(=0)OH, and - C(=0)N(R’)(R”).

In certain embodiments of [A-ld], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, C 1-4 alkoxy, and C 1-4 haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F).

In certain of the foregoing embodiments, ml = 0.

In certain embodiments, ml = 0; and m3 = 0.

[A-le]

In some embodiments, Ring A is (A-l); the

wherein: the asterisk denotes point of attachment to Y ⁴ ; and ml = 0 or 1; and m3 = 0, 1, or 2

In certain of these embodiments, ml = 1.

In certain embodiments of [A-le], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-le], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-le], U ² is as defined in paragaph [C99]

In certain embodiments of [A-le], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of [A-le], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04] In certain embodiments of [A-le] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-le] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-le] (when R ¹ is -(U ¹ ) _q -U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-le], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph

[016].

In certain embodiments of [A-le], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of [A-le], m3 = 0.

In certain other embodiments, m3 = 1 or 2.

In certain embodiments of [A-le], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i- ₂ (Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0) _{I -2} (NR’R”), -C _M thioalkoxy, -C(=0)(C _M alkyl), -C(=0)0(C _M alkyl), -C(=0)0H, and -C(=0)N(R ^, )(R”).

In certain embodiments of [A-le], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, CM alkoxy, CM haloalkoxy, -S(0)I-2(CM alkyl), -S(0)I. ₂ (NR’R”), -C(=0)(CM alkyl), -C(=0)0(CM alkyl), -C(=0)0H, and -

C(=0)N(R’)(R”).

In certain embodiments of [A-le], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, C _M alkoxy, and C _M haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F).

In certain of the foregoing embodiments, ml = 0.

In certain embodiments, ml = 0; and m3 = 0.

[A-lf]

In some embodiments, Ring A is (A-l); and the y

N-¾ N-¾ N-¾

,* ^

R ³ ^ S L. ^ _^ s

, or ^{H s} (e.g., ^{R s} ), wherein the asterisk denotes point of attachment to Y ⁴ .

In certain embodiments of [A-lf], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-lf], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-lf], U ² is as defined in paragaph [C99]

In certain embodiments of [A-lf], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl] In certain embodiments of [A-lf], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-lf] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-lf] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-lf] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-lf], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph

[016].

In certain embodiments of [A-lf], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H. In certain embodiments (when Ring A is as defined in any one of paragraphs [C37]-[C41]), ml =1. In certain of the foregoing embodiments, m3 = 0.

In certain other embodiments (when Ring A is as defined in any one of

paragraphs [C37]-[C41]), ml = 0; and m3 = 0.

[A-lg]

In some embodiments, A is:

wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2).

In certain of these embodiments, ml = 1.

In certain embodiments of [A-lg], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-lg], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-lg], U ² is as defined in paragaph [C99]

In certain embodiments of [A-lg], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of [A-lg], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04] In certain embodiments of [A-lg] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-lg] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-lg] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-lg], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph [016].

In certain embodiments of [A-lg], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of [A-lg], m3 = 0.

In certain other embodiments, m3 = 1 or 2.

In certain embodiments of [A-lg], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i- ₂ (Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0) I -2(NR’R”), -CM thioalkoxy, -C(=0)(CM alkyl), -C(=0)0(CM alkyl), -C(=0)OH, and -C(=0)N(R’)(R”).

In certain embodiments of [A-lg], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, CM alkoxy, CM haloalkoxy, -S(0)I-2(CM alkyl), -S(0)I- ₂ (NR’R”), -C(=0)(CM alkyl), -C(=0)0(CM alkyl), -C(=0)OH, and - C(=0)N(R’)(R”).

In certain embodiments of [A-lg], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, C 1-4 alkoxy, and C 1-4 haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F).

In certain of the foregoing embodiments, ml = 0.

In certain embodiments, ml = 0; and m3 = 0.

[A-lh]

In some embodiments, wherein ml = 0, 1, or 2; and m3 = 0,

1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).

In certain of these embodiments, ml = 1.

In certain embodiments of [A-lh], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-lh], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-lh], U ² is as defined in paragaph [C99]

In certain embodiments of [A-lh], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of [A-lh], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04] In certain embodiments of [A-lh] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-lh] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-lh] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-lh], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph

[016].

In certain embodiments of [A-lh], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of [A-lh], m3 = 0.

In certain other embodiments, m3 = 1 or 2.

In certain embodiments of [A-lh], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i- ₂ (Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0)I. ₂ (NR’R”), -CM thioalkoxy, -C(=0)(CM alkyl), -C(=0)0(CM alkyl), -C(=0)OH, and -C(=0)N(R’)(R”).

In certain embodiments of [A-lh], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, CM alkoxy, CM haloalkoxy, -S(0)I-2(CM alkyl), -S(0)I- ₂ (NR’R”), -C(=0)(CM alkyl), -C(=0)0(CM alkyl), -C(=0)OH, and - C(=0)N(R’)(R”).

In certain embodiments of [A-lh], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, C 1-4 alkoxy, and C 1-4 haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F).

In certain of the foregoing embodiments, ml = 0.

In certain embodiments, ml = 0; and m3 = 0.

[A-li]

In some embodiments, wherein ml = 0, 1, or 2; and m3 = 0,

1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).

In certain of these embodiments, ml = 1.

In certain embodiments of [A-li], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-li], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-li], U ² is as defined in paragaph [C99]

In certain embodiments of [A-li], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of [A-li], each R ^c substituent of U ² when present is as defined in paragraph [Cl 02] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-li] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-li] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-li] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-li], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph

[016].

In certain embodiments of [A-li], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of [A-li], m3 = 0.

In certain other embodiments, m3 = 1 or 2. In certain embodiments of [A-li], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0)I. ₂ (NR’R”), -CI-4 thioalkoxy, -C(=0)(Ci- ₄ alkyl), -C(=0)0(Ci- ₄ alkyl), -C(=0)OH, and -C(=0)N(R’)(R”).

In certain embodiments of [A-li], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci- ₄ alkoxy, Ci- ₄ haloalkoxy, -S(0)i- ₂ (Ci- ₄ alkyl), -S(0) _I-2 (NR’R”), -C(=0)(C _I-4 alkyl), -C(=0)0(Ci- ₄ alkyl), -C(=0)OH, and - C(=0)N(R’)(R”).

In certain embodiments of [A-li], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci- ₄ alkoxy, and Ci- ₄ haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F).

In certain of the foregoing embodiments, ml = 0.

In certain embodiments, ml = 0; and m3 = 0.

[A-lj]

In some embodiments, , wherein ml = 0, 1, or 2; and m3 = 0,

1, or 2.

In certain of these embodiments, ml = 1.

In certain embodiments of [A-lj], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-lj], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-lj], U ² is as defined in paragaph [C99]

In certain embodiments of [A-lj], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl] In certain embodiments of [A-lj], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-lj] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-le] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-lj] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-lj], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph

[016].

In certain embodiments of [A-lj], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H. In certain embodiments of [A-lj], m3 = 0.

In certain other embodiments, m3 = 1 or 2.

In certain embodiments of [A-lj], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0)I. ₂ (NR’R”), -CI-4 thioalkoxy, -C(=0)(Ci- ₄ alkyl), -C(=0)0(Ci- ₄ alkyl), -C(=0)OH, and -C(=0)N(R’)(R”).

In certain embodiments of [A-lj], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci- ₄ alkoxy, Ci- ₄ haloalkoxy, -S(0)i- ₂ (Ci- ₄ alkyl), -S(0) _I-2 (NR’R”), -C(=0)(C _I-4 alkyl), -C(=0)0(Ci- ₄ alkyl), -C(=0)OH, and - C(=0)N(R’)(R”).

In certain embodiments of [A-lj], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci- ₄ alkoxy, and Ci- ₄ haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F).

In certain of the foregoing embodiments, ml = 0.

In certain embodiments, ml = 0; and m3 = 0.

[A-lk]

In some embodiments, wherein ml = 0 or 1; and m3 = 0, 1, or 2.

In certain of these embodiments, ml = 1.

In certain embodiments of [A-lk], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-lk], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-lk], U ² is as defined in paragaph [C99]

In certain embodiments of [A-lk], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl] In certain embodiments of [A-lk], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-lk] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-lk] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-lk] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-lk], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph

[016].

In certain embodiments of [A-lk], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of [A-lk], m3 = 0. In certain other embodiments, m3 = 1 or 2.

In certain embodiments of [A-lk], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0)I. ₂ (NR’R”), -CI-4 thioalkoxy, -C(=0)(Ci- ₄ alkyl), -C(=0)0(Ci- ₄ alkyl), -C(=0)OH, and -C(=0)N(R’)(R”).

In certain embodiments of [A-lk], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci- ₄ alkoxy, Ci- ₄ haloalkoxy, -S(0)i- ₂ (Ci- ₄ alkyl), -S(0)I. ₂ (NR’R”), -C(=0)(CI- ₄ alkyl), -C(=0)0(Ci- ₄ alkyl), -C(=0)OH, and - C(=0)N(R’)(R”).

In certain embodiments of [A-lk], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci- ₄ alkoxy, and Ci- ₄ haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F).

In certain of the foregoing embodiments, ml = 0.

In certain embodiments, ml = 0; and m3 = 0.

In certain embodiments of [A-ll], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-ll], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-ll], U ² is as defined in paragaph [C99] In certain embodiments of [A-ll], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of [A-ll], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-ll] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-ll] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-ll] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-ll], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph

[016].

In certain embodiments of [A-ll], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

Non-Limiting Combinations when Ring A is (A-3):

In certain embodiments (when Ring A is as defined in any one of paragraphs [C60], [C64], and [C69]-[C70]), ml = 1.

In certain embodiments (when Ring A is as defined in any one of paragraphs [C60], [C64], and [C69]-[C70]), ml = 0; and m3 = 0.

[A-3a]

In some embodiments, , wherein ml = 0, 1, or 2; and m3 = 0,

1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).

In certain of these embodiments, ml = 1.

In certain embodiments of [A-3a], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-3a], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-3a], U ² is as defined in paragaph [C99]

In certain embodiments of [A-3a], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of [A-3a], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-3a] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-3a] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-3a] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-3a], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph

[016].

In certain embodiments of [A-3a], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of [A-3a], m3 = 0.

In certain other embodiments, m3 = 1 or 2.

In certain embodiments of [A-3a], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i- ₂ (Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0) _{I -2} (NR’R”), -CM thioalkoxy, -C(=0)(CM alkyl), -C(=0)0(CM alkyl), -C(=0)0H, and -C(=0)N(R’)(R”). In certain embodiments of [A-3a], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -S(0)I. ₂ (NR’R”), -C(=0)(CI-4 alkyl), -C(=0)0(Ci- ₄ alkyl), -C(=0)OH, and - C(=0)N(R’)(R”).

In certain embodiments of [A-3a], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F).

In certain of the foregoing embodiments, ml = 0.

In certain embodiments, ml = 0; and m3 = 0.

[A-3b]

In some embodiments, A is: , wherein ml = 0, 1, or 2; and m3 = 0,

1, or 2 (e.g., ml = 0 or 1 ; and m3 = 0 or 1).

In certain of these embodiments, ml = 1.

In certain embodiments of [A-3b], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-3b], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-3b], U ² is as defined in paragaph [C99]

In certain embodiments of [A-3b], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of [A-3b], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04] In certain embodiments of [A-3b] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-3b] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-3b] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-3b], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph [016].

In certain embodiments of [A-3b], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of [A-3b], m3 = 0.

In certain other embodiments, m3 = 1 or 2.

In certain embodiments of [A-3b], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i- ₂ (Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0) _{I -2} (NR’R”), -C _M thioalkoxy, -C(=0)(C _M alkyl), -C(=0)0(C _M alkyl), -C(=0)OH, and -C(=0)N(R’)(R”).

In certain embodiments of [A-3b], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, CM alkoxy, CM haloalkoxy, -S(0)I-2(CM alkyl), -S(0)I- ₂ (NR’R”), -C(=0)(CM alkyl), -C(=0)0(CM alkyl), -C(=0)OH, and - C(=0)N(R’)(R”).

In certain embodiments of [A-3b], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, C 1-4 alkoxy, and C 1-4 haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F).

In certain of the foregoing embodiments, ml = 0.

In certain embodiments, ml = 0; and m3 = 0.

[A-3c]

In some embodiments, wherein ml = 0, 1, or 2; and m3 = 0,

1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).

In certain of these embodiments, ml = 1.

In certain embodiments of [A-3c], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-3c], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-3c], U ² is as defined in paragaph [C99]

In certain embodiments of [A-3c], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of [A-3c], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-3c] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-3c] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-3c] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-3c], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph

[016].

In certain embodiments of [A-3c], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of [A-3c], m3 = 0.

In certain other embodiments, m3 = 1 or 2. In certain embodiments of [A-3c], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0)I. ₂ (NR’R”), -CI-4 thioalkoxy, -C(=0)(Ci- ₄ alkyl), -C(=0)0(Ci- ₄ alkyl), -C(=0)OH, and -C(=0)N(R’)(R”).

In certain embodiments of [A-3c], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci- ₄ alkoxy, Ci- ₄ haloalkoxy, -S(0)i- ₂ (Ci- ₄ alkyl), -S(0)I. ₂ (NR’R”), -C(=0)(CI- ₄ alkyl), -C(=0)0(Ci- ₄ alkyl), -C(=0)OH, and - C(=0)N(R’)(R”).

In certain embodiments of [A-3c], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci- ₄ alkoxy, and Ci- ₄ haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F).

In certain of the foregoing embodiments, ml = 0.

In certain embodiments, ml = 0; and m3 = 0.

[A-3d]

In some embodiments, , wherein ml = 0, 1, or 2; and m3 = 0,

1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).

In certain of these embodiments, ml = 1.

In certain embodiments of [A-3d], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-3d], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-3d], U ² is as defined in paragaph [C99]

In certain embodiments of [A-3d], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl] In certain embodiments of [A-3d], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-3d] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-3d] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-3d] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-3d], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph

[016].

In certain embodiments of [A-3d], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H. In certain embodiments of [A-3d], m3 = 0.

In certain other embodiments, m3 = 1 or 2.

In certain embodiments of [A-3d], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0)I. ₂ (NR’R”), -CI-4 thioalkoxy, -C(=0)(Ci- ₄ alkyl), -C(=0)0(Ci- ₄ alkyl), -C(=0)OH, and -C(=0)N(R’)(R”).

In certain embodiments of [A-3d], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci- ₄ alkoxy, Ci- ₄ haloalkoxy, -S(0)i- ₂ (Ci- ₄ alkyl), -S(0)I. ₂ (NR’R”), -C(=0)(CI- ₄ alkyl), -C(=0)0(Ci- ₄ alkyl), -C(=0)OH, and - C(=0)N(R’)(R”).

In certain embodiments of [A-3d], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci- ₄ alkoxy, and Ci- ₄ haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F).

In certain of the foregoing embodiments, ml = 0.

In certain embodiments, ml = 0; and m3 = 0.

Non-Limiting Combinations when Ring A is (A-2):

In certain embodiments (when Ring A is as defined in any one of paragraphs [C54]- [C55]), ml = 0. In certain of the foregoing embodiments, m3 = 0 or 1 (e.g., 0).

[A-2a]

wherein ml = 0, 1, 2, or 3; and m3

= 0, 1, 2, or 3 (e.g., ml = 0; and m3 = 0).

In certain of these embodiments, ml = 1.

In certain embodiments of [A-2a], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0. In certain embodiments of [A-2a], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-2a], U ² is as defined in paragaph [C99]

In certain embodiments of [A-2a], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of [A-2a], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-2a] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-2a] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-2a] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-2a], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph

[016]. In certain embodiments of [A-2a], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [C117] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [Cl 18] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)OH. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of [A-2a], m3 = 0.

In certain other embodiments, m3 = 1 or 2.

In certain embodiments of [A-2a], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i- ₂ (Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0)I. ₂ (NR’R”), -CI-4 thioalkoxy, -C(=0)(Ci- ₄ alkyl), -C(=0)0(Ci- ₄ alkyl), -C(=0)OH, and -C(=0)N(R’)(R”).

In certain embodiments of [A-2a], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci- ₄ alkoxy, Ci- ₄ haloalkoxy, -S(0)i- ₂ (Ci- ₄ alkyl), -S(0)I. ₂ (NR’R”), -C(=0)(CI- ₄ alkyl), -C(=0)0(Ci- ₄ alkyl), -C(=0)OH, and - C(=0)N(R’)(R”).

In certain embodiments of [A-2a], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci- ₄ alkoxy, and Ci- ₄ haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F).

In certain of the foregoing embodiments, ml = 0.

In certain embodiments, ml = 0; and m3 = 0.

[A-2b]

wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0; and m3 = 0).

In certain of these embodiments, ml = 1. In certain embodiments of [A-2b], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-2b], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-2b], U ² is as defined in paragaph [C99]

In certain embodiments of [A-2b], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of [A-2b], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] . As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-2b] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] . As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-2b] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-2b] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008] In certain embodiments of [A-2b], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph

[016].

In certain embodiments of [A-2b], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of [A-2b], m3 = 0.

In certain other embodiments, m3 = 1 or 2.

In certain embodiments of [A-2b], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i- ₂ (Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0)I- ₂ (NR’R”), -CM thioalkoxy, -C(=0)(CM alkyl), -C(=0)0(CM alkyl), -C(=0)0H, and -C(=0)N(R’)(R”).

In certain embodiments of [A-2b], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, CM alkoxy, CM haloalkoxy, -S(0)I- ₂ (CM alkyl), -S(0)I- ₂ (NR’R”), -C(=0)(CM alkyl), -C(=0)0(CM alkyl), -C(=0)0H, and - C(=0)N(R’)(R”).

In certain embodiments of [A-2b], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, C _M alkoxy, and C _M haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F).

In certain of the foregoing embodiments, ml = 0.

In certain embodiments, ml = 0; and m3 = 0. Non-Limiting Combinations when Ring A is (A-4 '):

In certain embodiments of [A-4a], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-4a], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-4a], U ² is as defined in paragaph [C99]

In certain embodiments of [A-4a], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of [A-4a], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-4a] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-4a] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently elected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-4a] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-4a], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph [016].

In certain embodiments of [A-4a], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of [A-4b], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-4b], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-4b], U ² is as defined in paragaph [C99]

In certain embodiments of [A-4b], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl] In certain embodiments of [A-4b], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-4b] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-4b] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-4b] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-4b], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph

[016].

In certain embodiments of [A-4b], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H. [A-4c]

In some embodiments,

In certain embodiments of [A-4c], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-4c], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-4c], U ² is as defined in paragaph [C99]

In certain embodiments of [A-4c], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of [A-4c], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-4c] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-4c] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c] In certain embodiments of [A-4c] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-4c], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph [016].

In certain embodiments of [A-4c], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of [A-4d], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-4d], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-4d], U ² is as defined in paragaph [C99]

In certain embodiments of [A-4d], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl] In certain embodiments of [A-4d], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-4d] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-4d] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of [A-4d] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-4d], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph

[016].

In certain embodiments of [A-4d], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H. In some embodiments,

In certain embodiments of [A-4e], R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of [A-4e], U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of [A-4e], U ² is as defined in paragaph [C99]

In certain embodiments of [A-4e], U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of [A-4e], each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of [A-4e] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of [A-4e] (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c] In certain embodiments of [A-4e] (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of [A-4e], R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph [016].

In certain embodiments of [A-4e], each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

[A-R'l Exemplary Embodiments of R ¹

In certain embodiments (when Ring A is (A-l); and (A-l) is as defined in any one of paragraphs [02], [06], [07], and [C24]; and/or ml = 1 (e.g., when m3 =0)), R ¹ is as defined in any one of paragraphs [C93]-[O04] and [O09]-[O12]

In certain embodiments (when Ring A is (A-l); and (A-l) is as defined in any one of paragraphs [02], [06], [07], and [C24]; and/or ml = 1 (e.g., when m3 =0)), R ¹ is as defined in any one of paragraphs [C93]-[C94] and [Cl 05] -[Cl 08].

In certain embodiments (when Ring A is (A-l); and (A-l) is as defined in any one of paragraphs [02], [06], [07], and [C24]; and/or ml = 1 (e.g., when m3 =0)), R ¹ is as defined in any one of paragraphs [C113]-[C120].

In certain embodiments (when Ring A is (A-l); and (A-l) is as defined in paragaphs [C28]-[C29]; ml = 1; and/or m3 = 0), R ¹ is as defined in any one of parapgrahs [C93]- [004] and [C109]-[C112]

In certain embodiments (when Ring A is (A-l); and (A-l) is as defined in any one of paragraphs [C28]-[C29]; ml = 1; and/or m3 = 0), R ¹ is as defined in any one of paragraphs [C93]-[C94] and [C105]-[C108]. In certain embodiments (when Ring A is (A-l); and (A-l) is as defined in paragaph [C28]; ml = 1; and/or m3 = O^R ¹ is as defined in any one of paragraphs [C113]-[C120].

In certain embdoiments (when Ring A is as defined in any one of paragraphs [C37]- [C41]; ml =1; and/or m3 = 0), R ¹ is as defined in any one of paragraphs [C93]-[C104] and [C109]-[C112]

In certain embdoiments (when Ring A is as defined in any one of paragraphs [C37]- [C41]; ml =1; and/or m3 = 0), R ¹ is as defined in any one of paragraphs [C93]-[C94] and [C105]-[C108].

In certain embdoiments (when Ring A is as defined in any one of paragraphs [C37]- [C41]; ml =1; and/or m3 = 0), R ¹ is as defined in any one of paragraphs [C113]-[C120].

In certain embodiments (when Ring A is as defined in paragraphs [C60], [C64], and [C69-70]; and/or ml = 1), R ¹ is as defined in any one of paragraphs [C93]-[C104] and [C109]-[C112]

In certain embodiments (when Ring A is as defined in any one of paragraphs [C60],

[C64], and [C 69-70]; and/or ml = 1), R ¹ is as defined in any one of paragraphs [C93]- [C94] and [C105]-[C108].

In certain embodiments (when Ring A is as defined in any one of paragraphs [C60], [C64], and [C 69-70]; and/or ml = 1), R ¹ is as defined in any one of paragraphs [013]- [020]

In certain embodiments (when Ring A is as defined in any one of paragraphs [C82]- [C84] and [C90]-[C91]), R ¹ is as defined in any one of paragraphs [C93]-[C104] and [C109]-[C112]

In certain embodiments (when Ring A is as defined in any one of paragraphs [C82]-

[C84] and paragraphs [C90]-[C91]), R ¹ is as defined in any one of paragraphs [C93]-[C94] and [ 05]- [ 08].

In certain embodiments (when Ring A is as defined in any one of paragraphs [C82]- [C84] and paragraphs [C90]-[C91]), R ¹ is as defined in any one of paragraphs [013]- [020] Ring B and Variable R ^N

Embodiments when Ring B and R ^N are as defined according to (A)

[C154] In some embodiments, B and each occurrence of R ^N are defined according to (A).

Ring B

[C155] In some embodiments, B is phenyl substituted with from 1-4 R ^c .

[C156] In certain embodiments, B is phenyl substituted with from 1-2 R ^c , wherein from 1-2 R ^c is at the ring carbons para or meta (e.g., one R ^c is at the ring carbon para ) to the point of attachment to the -S(0)(=N(R ^N ) ₂ )- moiety in Formula I.

[C156a] In certain embodiments, B is phenyl substituted with from 1-2 R ^c , wherein one R ^c is at the ring carbon para to the point of attachment to the -S(0)(=N(R ^N ) ₂ )- moiety in Formula I. In certain of the foregoing embodiments, B is not further substituted. In certain other embodiments, B is substituted with an additional R ^c at a carbon meta to the point of attachment to the -S(0)(=N(R ^N ) ₂ )- moiety in Formula I.

[C157] In some embodiments, B is heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected R ^c .

[C158] In certain of these embodiments, B is heteroaryl including from 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-3 independently selected R ^c .

[C159] In certain of the foregoing embodiments, B is heteroaryl including 5 ring atoms, wherein from 1-3 (e.g., 2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-3 independently selected R ^c . [C160] As a non-limiting example, B can be pyrazolyl or imidazolyl, each of which is optionally substituted with from 1-2 independently selected R ^c .

[061] In certain other embodiments, B is heteroaryl including from 6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c .

[062] As a non-limiting example, B can be pyridinyl (e.g., 2-pyridinyl, 3- pyridinyl, and 4-pyridinyl), which is optionally substituted with from 1-2 independently selected R ^c .

[063] In certain other embodiments, B is heteroaryl including from 9-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-3 independently selected R ^c .

[064] In certain of the foregoing embodiments, B is tricyclic heteroaryl including from 12-15 (e.g., 13) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-3 independently selected

[065] As a non-limiting example, B can be which is optionally substituted with from 1-2 independently selected R ^c .

[C166a] In some embodiments, each occurrence of R ^c substituent on B is selected from:

(a) halo;

(b) cyano;

(c) Ci-io alkyl which is optionally substituted with from 1-6 independently selected

R ^a ;

(d) C2-6 alkenyl; (e) C2-6 alkynyl;

(g) Ci-4 alkoxy;

(h) Ci- ₄ haloalkoxy;

(i) -S(0)i. ₂ (Ci-4 alkyl);

(j) -NR ^e R ^f , wherein one of R ^e and R ^f is other than H;

(k) -OH;

(l) -S(0) _I-2 (NR ^, R”);

(m) -Ci- ₄ thioalkoxy;

(n) -N0 ₂ ;

(o) -C(=0)(Ci-4 alkyl);

(p) -C(=0)0(Ci-4 alkyl);

(q) -C(=0)OH;

(r) -C(=0)N(R’)(R”); and

(s) -I^-lAR* ¹ ;

[C166] In some embodiments, each occurrence of R ^c substituent on B is selected from:

(a) halo;

(b) cyano;

(c) Ci-10 alkyl which is optionally substituted with from 1-6 independently selected R ^a ;

(g) Ci-4 alkoxy;

(h) Ci- ₄ haloalkoxy;

(i) -S(0)i- ₂ (Ci-4 alkyl);

(m) -Ci- ₄ thioalkoxy;

(o) -C(=0)(Ci-4 alkyl);

(p) -C(=0)0(Ci-4 alkyl);

(r) -C(=0)N(R’)(R”); and

(s) -iAlAR* ¹ [067] In certain embodiments, each occurrence of R ^c substituent on B is selected from:

(a) halo;

(b) cyano;

(c) Ci-10 alkyl which is optionally substituted with from 1-6 independently selected

(g) Ci-4 alkoxy;

(h) Ci- ₄ haloalkoxy; and

(s) -lA-lAR* ¹

[C168] In certain embodiments, each occurrence of R ^c substituent on B is selected from:

(a) halo;

(c) Ci-io alkyl which is optionally substituted with from 1-6 independently selected

R ^a ; and

(s) -L ¹ -L ² -R ^h .

[C169] In certain of these embodiments, one occurrence of R ^c is Ci-io alkyl which is optionally substituted with from 1-6 independently selected R ^a .

[C170] In certain embodiments, one occurrence of R ^c is C1-3 alkyl which is optionally substituted with from 1-6 independently selected R ^a .

[071] In certain of the foregoing embodiments, each occurrence of R ^a is independently selected from: -F; C1-4 alkoxy; and C1-4 haloalkoxy.

[072] As non-limiting examples,

[073] In certain embodiments (when one occurrence of R ^c is Ci-10 alkyl which is optionally substituted with from 1-6 independently selected R ^a ), R ^c is unsubstituted Ci-10 alkyl (e.g., unsubstituted Ci- ₆ (e.g., C1.3) alkyl.

[074] In certain embodiments, one occurrence of R ^c is -L ¹ -L ² -R ^h .

[075] In certain of these embodiments, -L ¹ is a bond.

[076] In certain other of these embodiments, -L ¹ is C1-3 alkylene. [C177] In certain embodiments (when one occurrence of R ^c is -L'-L ² -R ^h ), -L ² is a bond.

[C178] In certain other embodiments (when one occurrence of R ^c is -L'-L ² -R ^h ), - L ² is -0-.

[C179] In certain embodiments (when one occurrence of R ^c is -L ¹ -L ² -R ^h ), -L ¹ is a bond; and -L ² is a bond.

[C180] In certain embodiments (when one occurrence of R ^c is -L ¹ -L ² -R ^h ), -L ¹ is a bond; and -L ² is -0-.

[081] In certain embodiments (when one occurrence of R ^c is -L ¹ -L ² -R ^h ), -L ¹ is Ci- ₃ alkylene; and -L ² is -0-.

[082] In certain embodiments (when one occurrence of R ^c is -L'-L ² -R ^h ), R ^h is selected from:

• C3-8 cycloalkyl optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C1-4 haloalkyl, provided that when R ^h is C3-6 cycloalkyl optionally substituted with from 1-4 independently selected C 1-4 alkyl, -L ¹ is a bond, or -L ² is -0-, -N(H)-, or -S-; and

• C _6-10 aryl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, C _1-4 alkyl, or C _1-4 haloalkyl.

[C183] In certain embodiments (when one occurrence of R ^c is -L'-L ² -R ^h ), R ^h is selected from

• C _6-8 cycloalkyl optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C1-4 haloalkyl, provided that when R ^h is C3-6 cycloalkyl optionally substituted with from 1-4 independently selected C 1-4 alkyl, -L ¹ is a bond, or -L ² is -0-, -N(H)-, or -S-; and

• phenyl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, C 1-4 alkyl, or C 1-4 haloalkyl. [C184] As non-limiting examples (when one occurrence of R ^c is -JA-JA-R* ¹ ) one occurrence R ^c can be selected from: [C185] In certain embodiments, one occurrence of R ^c is unsubstituted C1-3 alkyl.

[C186] In certain embodiments, one occurrence of R ^c is halo (e.g., -F, or -Cl).

[C187] In certain of any of the foregoing embodiments, a second occurrence of R ^c when present is independently halo.

[C188] In some embodiments, B is C3-20 cycloalkyl, which is optionally substituted with from 1-4 R ^b .

[C189] In certain embodiments, B is C3-12 cycloalkyl, which is optionally substituted with from 1-2 R ^b .

[C190] In certain embodiments, B is C6-12 cycloalkyl, which is optionally substituted with from 1-2 R ^b .

[091] In certain of the foregoing embodiments, B is C6-12 cycloalkyl (e.g., B can

[092] In some embodiments, B is heterocyclyl including from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R ^b .

[093] In certain embodiments, B is heterocyclyl including from 3-12 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R ^b .

[094] In certain of these embodiments, B is heterocyclyl including from 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heterocyclyl ring is optionally substituted with from 1-2 independently selected R ^b (e.g., B can which is further optionally substituted with 1 R ^b ).

[C195] In certain other embodiments, B is heterocyclyl including from 7-12 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heterocyclyl ring is

optionally substituted with from 1-2 independently selected R ^b (e.g., B can

each of which is further optionally substituted with 1 R ^b ).

[C196] In certain of the foregoing embodiments (when B is heterocyclyl or cycloalkyl as defined in any of the embodiments above), each occurrence of R ^b is independently selected from the group consisting of: Ci-io alkyl; Ci-4 haloalkyl; -OH; oxo; -F; -Cl; -NR ^e R ^f ; CM alkoxy; CM haloalkoxy; -C(=0)(CM alkyl); -C(=0)0(CM alkyl); - S(0)I- ₂ (CM alkyl); cyano; and -IAI^-R* ¹ .

[C197] In certain embodiments, each occurrence of R ^b is independently selected from the group consisting of: Ci-io alkyl; C _M haloalkyl; -F; C _M alkoxy; C _M haloalkoxy; and -L ¹ -L ² -R ^h .

[C198] In certain embodiments, R ^b is independently selected from the group consisting of: Ci-io alkyl; C _M haloalkyl; -F; - and -L ¹ -L ² -R ^h .

[C199] In certain embodiments, one occurrence of R ^b is independently -L'-L ² -R ^h

[C200] In certain of these embodiments, -L ¹ is a bond; and -L ² is a bond. [C201] In certain of the foregoing embodiments, R ^h is C _6-10 aryl, which is optionally substituted with from 1-4 (e.g., 1-2, e.g., 1) substituents independently selected from the group consisting of halo, C _1-4 alkyl, or C _1-4 haloalkyl.

(R ^cA )ni

In some embodiments, wherein:

nl = 0 or 1; and

each of R ^cA and R ^cB is an independently selected R ^c .

In certain of these embodiments, R ^cB is Ci-io alkyl which is optionally substituted with from 1-6 independently selected R ^a .

In certain embodiments, R ^cB is C1-3 alkyl which is optionally substituted with from

1-6 independently selected R ^a . For example, R ^cB can be CF3 or (e.g., R ^cB can be CF ₃ ).

In certain of these embodiments, each occurrence of R ^a is independently selected from: -F; C1-4 alkoxy; and C1-4 haloalkoxy.

In certain embodiments (when one occurrence of R ^cB is Ci-io alkyl which is optionally substituted with from 1-6 independently selected R ^a ), R ^cB is unsubstituted Ci- ₁₀ alkyl (e.g., unsubstituted Ci-6 (e.g., C1-3) alkyl.

In certain embodiments, R ^cA is CF _3.

(R ^CA )ni

In certain embodiments (when B i is, F ^* -0 ^— V~ ^R ‘ ^B ), R ^cB is R ^c that is as defined in any one of paragraphs [Cl 74] -[Cl 84]

In certain embodiments, R ^cB is -L'-L ² -R ^h

In certain of these embodiments, -L ¹ is a bond. In certain other embodiments, -L ¹ is Ci-3 alkyl ene. In certain embodiments (when R ^cB is -L ¹ -L ² -R ^h ), -L ² is a bond. In certain other embodiments, -L ² is -O-.

In certain embodiments (when R ^cB is -L'-L ² -R ^h ), -L ¹ is a bond; and -L ² is a bond. In certain other embodiments, -L ¹ is a bond; and -L ² is -O-. In still certain other embodiments, -L ¹ is C 1-3 alkylene; and -L ² is -O-.

In certain embodiments (when R ^cB is -L'-L ² -R ^h ), R ^h is as defined in paragraph [C182] In certain embodiments, R ^h is as defined in paragraph [C183] For example, R ^h can be as defined in paragraph [Cl 84]

(R ^cA )ni

In certain embodiments (when B is R ^cB is unsubstituted Ci-10 alkyl (e.g., C 1-3 alkyl).

(R ^cA )ni

In certain embodiments (when B is R ^cB is halo.

(R ^cA )ni

In certain embodiments (when B is ), nl is 0.

(R ^cA )ni

In certain other embodiments (when B is ), nl is 1; and R ^cA is halo.

In some embodiments, B is heteroaryl including from 6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of

N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c ; and

R ^c is as defined in any one of paragraphs [C169]-[C173] (e.g., R ^c can be CF3). In certain of these embodiments, R ^c is Ci-io alkyl which is optionally substituted with from 1-6 independently selected R ^a .

In certain embodiments, R ^cB is C1-3 alkyl which is optionally substituted with from

1-6 independently selected R ^a . For example, R ^c can be CF3 or (e.g., R ^c can be CF ₃ ).

In certain of these embodiments, each occurrence of R ^a is independently selected from: -F; C1-4 alkoxy; and C1-4 haloalkoxy.

In certain embodiments (when one occurrence of R ^c is Ci-io alkyl which is optionally substituted with from 1-6 independently selected R ^a ), R ^c is unsubstituted Ci-10 alkyl (e.g., unsubstituted Ci- ₆ (e.g., C1-3) alkyl.

In some embodiments, B is heteroaryl including from 6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c ; and R ^c is as defined in any one of paragraphs [074]- [084]

In certain of these embodiments, R ^c is -L ¹ -L ² -R ^h .

In certain of these embodiments, -L ¹ is a bond. In certain other embodiments, -L ¹ is Ci- ₃ alkylene.

In certain embodiments (when R ^c is -L ¹ -L ² -R ^h ), -L ² is a bond. In certain other embodiments, -L ² is -0-.

In certain embodiments (when R ^c is -L ¹ -L ² -R ^h ), -L ¹ is a bond; and -L ² is a bond. In certain other embodiments, -L ¹ is a bond; and -L ² is -0-. In still certain other embodiments, -L ¹ is C1-3 alkylene; and -L ² is -0-.

In certain embodiments (when R ^c is -L ¹ -L ² -R ^h ), R ^h is as defined in paragraph [082] In certain embodiments, R ^h is as defined in paragraph [083] For example, R ^h can be as defined in paragraph [084] In some embodiments, B is heteroaryl including from 5 ring atoms, wherein from 1-3 (e.g., 2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c ; and R ^c is as defined in any one of paragaphs [C174]-[C184].

In certain of these embodiments, R ^c is -L ¹ -L ² -R ^h .

In certain of these embodiments, -L ¹ is a bond. In certain other embodiments, -L ¹ is Ci-3 alkyl ene.

In certain embodiments (when R ^c is -L ¹ -L ² -R ^h ), -L ² is a bond. In certain other embodiments, -L ² is -0-.

In certain embodiments (when R ^c is -L ¹ -L ² -R ^h ), -L ¹ is a bond; and -L ² is a bond. In certain other embodiments, -L ¹ is a bond; and -L ² is -0-. In still certain other embodiments, -L ¹ is C1-3 alkylene; and -L ² is -0-.

In certain embodiments (when R ^c is -L ¹ -L ² -R ^h ), R ^h is as defined in paragraph

[C182] In certain embodiments, R ^h is as defined in paragraph [C183] For example, R ^h can be as defined in paragraph [Cl 84]

As non-limiting examples, B can be imidazolyl or pyrazolyl, each of which is optionally substituted with from 1-2 independently selected R ^c .

In certain embodiments (when B is heteroaryl including from 5 ring atoms, wherein from 1-3 (e.g., 2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c ; and R ^c is as defined in any one of parargaphs [C174]-[C184]), one occurrence of R ^c is -L ¹ -L ² -R ^h , wherein -L ¹ is a bond; and/or -L ² is a bond. Variable R ^N

[C214] In some embodiments, each R ^N is independently selected from:

(i) H,

(ii) Ci- ₆ alkyl optionally substituted with from 1-3 R ^a ,

(iii) C3-6 cycloalkyl, optionally substituted with from 1-2 R ^a ,

(iv) -C(0)(Ci-4 alkyl), and

(v) -C(0)0(Ci-4 alkyl).

[C215] In some embodiments, one occurrence of R ^N is H.

[C216] In certain embodiments (when one occurrence of R ^N is H), the second occurrence of R ^N is H.

[C217] In certain other embodiments, the second occurrence of R ^N is selected from

(ii) Ci- ₆ alkyl optionally substituted with from 1-3 R ^a ,

(iii) C3-6 cycloalkyl, optionally substituted with from 1-2 R ^a ,

(iv) -C(0)(Ci-4 alkyl), and

(v) -C(0)0(Ci-4 alkyl).

[C218] In certain of these embodiments, the second occurrence of R ^N is Ci- ₆ alkyl optionally substituted with from 1-3 R ^a (e.g., 1-2, e.g., 1).

[C219] In certain of these embodiments, each occurrence of R ^a is selected from Ci- 4 alkoxy, C3-6 cycloalkyl, and hydroxy.

[C220] In certain embodiments (when one occurrence of R ^N is H), the second occurrence R ^N is -C(0)0(Ci- ₄ alkyl) (e.g., -C(O)Me).

[C221] In certain embodiments (when one occurrence of R ^N is H), the second occurrence R ^N is unsubstituted Ci- ₆ alkyl .

[C222] In some embodiments, one occurrence of R ^N is Ci- ₆ alkyl.

[C223] In certain of these embodiments, the second occurrence of R ^N is selected from the group consisting of:

(ii) Ci- ₆ alkyl optionally substituted with from 1-3 R ^a ,

(iii) C3-6 cycloalkyl, optionally substituted with from 1-2 R ^a , (iv) -C(0)(Ci-4 alkyl), and

(v) -C(0)0(Ci-4 alkyl).

[C224] In certain embodiments (when one occurrence of R ^N is Ci- ₆ alkyl), the second occurrence of R ^N is Ci- ₆ alkyl.

[C225] In certain embodiments (when one occurrence of R ^N is Ci- ₆ alkyl), the second occurrence of R ^N is C 1-3 alkyl.

Embodiments when Ring B and R ^N are as defined according to (B)

In some embodiments, B and each occurrence of R ^N are defined according to (B).

In some embodiments, B and one R ^N , taken together with the atoms to which each is attached form a ring including from 5-15 ring atoms, wherein the ring includes: (a) from 0-4 ring heteroatoms each independently selected from N, N(H), N(R ^d ), O, and S(0)o- ₂ (in

N.

addition to the heteroatoms in the ^R N 'R N'

moiety); and (b) from 2 to 12 ring carbon atoms, wherein each of which is optionally substituted with 1-2 substituents independently selected from

(i) H;

(ii) oxo;

(iii) halo;

(iv) hydroxy;

(v) Ci- ₆ alkyl;

(vi) Ci- ₆ haloalkyl;

(vii) C ₆ -io aryl optionally substituted with from 1-3 R ^c ;

(viii) heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected R ^c ;

(ix) heterocyclyl including from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R ^b ; and

(x) C _3-20 cycloalkyl, which is optionally substituted with from 1-4 R ^b .

In certain embodiments, B and one R ^N , taken together with the atoms to which each is attached form a ring including from 5-15 ring atoms, wherein the ring includes: (a) from 0-4 ring heteroatoms each independently selected from N, N(H), N(R ^d ), O, and S(0)o- ₂ (in

“V' _On

A o

V J

N ^N ~ ^rN

addition to the heteroatoms in the ^R moiety); and (b) from 2 to 12 ring carbon atoms, wherein each of which is optionally substituted with 1-2 substituents independently selected from

(i) H;

(ii) oxo;

(iii) halo;

(iv) hydroxy;

(v) Ci- ₆ alkyl;

(vi) Ci- ₆ haloalkyl;

(vii) C6-10 aryl optionally substituted with from 1-3 R ^c ; and

(viii) heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected R ^c .

In certain embodiments, B and one R ^N , taken together with the atoms to which each is attached form a ring including from 8-15 ring atoms, wherein the ring includes: (a) from 0-4 ring heteroatoms each independently selected from N, N(H), N(R ^d ), O, and S(0)o- ₂ (in

N R N'

addition to the heteroatoms in the ^R moiety); and (b) from 2 to 12 ring carbon atoms, wherein each of which is optionally substituted with 1-2 substituents independently selected from

(i) H;

(ii) oxo;

(iii) halo;

(iv) hydroxy;

(v) Ci- ₆ alkyl; and

(vi) Ci- ₆ haloalkyl.

In certain embodiments, B and one R ^N , taken together with the atoms to which each

is attached form: , which is optionally substituted with from 1-3 substituents independently selected from:

(ii) oxo;

(iii) halo;

(iv) hydroxy;

(v) Ci- ₆ alkyl; and

(vi) Ci- ₆ haloalkyl.

In certain of these embodiments, B and one R ^N , taken together with the atoms to

which each is attached form: , which is further optionally substituted with from 1-2 substituents independently selected from:

(ii) oxo;

(v) Ci- ₆ alkyl; and

(vi) Ci- ₆ haloalkyl. In certain embodiments, B and one R ^N , taken together with the atoms to which each is attached form a ring including from 5-7 ring atoms, wherein the ring includes: (a) from 0-4 ring heteroatoms each independently selected from N, N(H), N(R ^d ), O, and S(0)o-2 (in

"y.

o /

* s* ^N

V i

addition to the heteroatoms in the moiety); and (b) from 2 to 3 ring carbon atoms, wherein each of which is optionally substituted with 1-2 substituents independently selected from

(i) H;

(ii) oxo;

(iii) halo;

(iv) hydroxy;

(v) Ci- ₆ alkyl;

(vi) Ci- ₆ haloalkyl;

(vii) C6-io aryl optionally substituted with from 1-3 R ^c ; and

(viii) heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected R ^c .

In certain of these embodiments, B and one R ^N , taken together with the atoms to

Ar ^N which each is attached form: O , which is optionally substituted with from 1-3 substituents independently selected from: (ii) oxo; (iii) halo; (iv) hydroxy; and (v) Ci- ₆ alkyl;

wherein Ar ^N is selected from:

(vii) C6-io aryl optionally substituted with from 1-3 R ^c ; and

(viii) heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected R ^c (e.g., Ar ^N is C6-10 aryl optionally substituted with from 1-2 R ^c (e.g., R ^c can be haloalkyl such as CF ₃ )).

In some embodiments, R ^N is hydrogen. Variable W

In some embodiments, W is O.

In some embodiments, W is NH.

In some embodiments, W is NR ^d . Non-Limiting Combinations

[AA]

In some embodiments, the compound has Formula (1-1): wherein nl = 0 or 1; and

each of R ^cA and R ^cB is an independently selected R ^c .

In certain embodiments of Formula (1-1), A is (A-l):

wherein

Z is selected from the group consisting of:

a bond, CH, CR ¹ , CR ³ , N, NH, N(R') and N(R ² );

each of Y ¹ , Y ² , and Y ³ is independently selected from the group consisting of O, S, CH, CR ¹ , CR ³ , N, NH, N(R ⁴ ), and NR ² ;

Y ⁴ is C or N; X ¹ is selected from the group consisting of O, S, N, NH, NR ¹ , NR ² , CH, CR ¹ , and

CR ³ ;

X ² is selected from the group consisting of O, S, N, NH, NR ¹ , NR ² , CH, CR ¹ , and CR ³ ; and

each— is independently a single bond or a double bond, provided that the five- membered ring comprising Y ⁴ , X ¹ , and X ² is heteroaryl; and the ring comprising Z, Y ¹ , Y ² , Y ³ , and Y ⁴ is aromatic (i.e., carbocyclic aromatic or heteroaromatic).

In certain embodiments of Formula (1-1), A is:

m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1 ; and m3 = 0, 1, or 2).

In certain embodiments of Formula wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1 ; and m3 = 0 or 1).

In certain embodiments of Formula , wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., m l = 0 or 1 ; and m3 = 0 or 1).

In certain embodiments of Formula wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2. In certain embodiments of Formula (1-1), A is , wherein ml = 0 or 1; and m3 = 0, 1, or 2.

In certain embodiments of Formula (1-1), A is (A-2):

(A-2)

Z is selected from the group consisting of:

a bond, CH, CH ₂ , CR ¹ , CHR ¹ , C(R') ₂ , CR ³ , CHR ³ , C(R ³ ) ₂ , O, N, NH, N(R') and

N(R ² );

each of Y ¹ and Y ² is independently selected from the group consisting of O, S,

CH, CH ₂ , CR ¹ , CHR ¹ , C(R ¹ ) ₂ , CR ³ , CHR ³ , C(R ³ ) ₂ , N, NH, N(R'), and NR ² ;

one of Q ¹ and Q ² is absent, and the other one of Q ¹ and Q ² is a C _2-5 alkyl ene that is optionally interrupted with one heteroatom selected from -NH-, -N(R')-, -N(R ² )-, and -0-; and

each— is independently a single bond or a double bond. In certain embodiments of Formula (1-1), A is: , wherein ml = 0,

1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0; and m3 = 0).

In certain embodiments of Formula (1-1), A is: , wherein ml =

0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0; and m3 = 0).

In certain embodiments of Formula (1-1), A is (A-3):

wherein

Ring A ^3A is a monocyclic or bicyclic ring including from 5-12 ring atoms, wherein from 0-2 ring atoms are heteroatoms cumulative with the value selected for Y ⁴ , wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R'), N(R ² ), O, and S(0)o- ₂ , and from 2-12 are ring carbon atoms each independently selected from C, CH, CFh, CR ¹ , CHR ¹ , C(R')2, CR ³ , CHR ³ , and C(R ³ )2, provided that Ring A ^3A is non-aromatic;

X ¹ is selected from the group consisting of O, S, N, NH, NR ¹ , NR ² , CH, CR ¹ , and

CR ³ ;

X ² is selected from the group consisting of O, S, N, NH, NR ¹ , NR ² , CH, CR ¹ , and

CR ³ , provided that the ring including Y ⁴ , X ¹ , and X ² is heteroaromatic; and

Y ⁴ is selected from N or C.

In certain embodiments of Formula (1-1), A is: , wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).

In certain embodiments of Formula (1-1), A is: , wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).

In certain embodiments of Formula (1-1), A is: , wherein ml = 0,

1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).

In certain embodiments of Formula (1-1), A is: ^m3 w<R ⁾ , wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).

In certain embodiments of Formula (1-1), A is (A-4):

wherein:

Z ² is selected from CH, CR ² , and N;

X ³ is selected from O, S, N, NH, NR ¹ , NR ² , CH, CR ¹ , and CR ³ ; each of Y ⁵ and Y ⁶ is independently selected from O, S, CH, CR ¹ , CR ³ , NR ¹ , NR ² , NH, and N; and

each— is independently a single bond or a double bond, provided that the five-membered ring comprising Y ⁵ , Y ⁶ , X ³ , and Z ² is heteroaromatic.

In certain embodiments of Formula (1-1), A is selected from:

In certain embodiments of Formula

In certain embodiments of Formula

In certain embodiments of Formula (1-1), A is selected from: H

In certain embodiments of Formula (1-1), each R ¹ is as defined in any one of paragraphs [C92]-[C120].

In certain embodiments of Formula (1-1), R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of Formula (1-1), U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of Formula (1-1), U ² is as defined in paragaph [C99]

In certain embodiments of Formula (1-1), U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of Formula (1-1), each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [C104]

In certain embodiments of Formula (1-1) (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [CllOa] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of Formula (1-1) (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of Formula (1-1) (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008] In certain embodiments of Formula (1-1), R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph [016].

In certain embodiments of Formula (1-1), each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF ₃ or CH ₂ C0 ₂ H.

In certain embodiments of Formula (1-1), each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i- ₂ (Ci- ₄ alkyl), -NR ^e R ^f , -OH, -S(0)i. ₂ (NR’R”), -C _M thioalkoxy, -C(=0)(Ci- ₄ alkyl), - C(=0)0(Ci-4 alkyl), -C(=0)0H, and -C(=0)N(R’)(R”) _·

In certain embodiments of Formula (1-1), each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i- ₂ (Ci-4 alkyl), -S(0)i- ₂ (NR’R”), -C(=0)(Ci- ₄ alkyl), -C(=0)0(Ci- ₄ alkyl), -C(=0)0H, and - C(=0)N(R’)(R”).

In certain embodiments of Formula (1-1), each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F).

In certain of these embodiments, R ^cB is Ci-io alkyl which is optionally substituted with from 1-6 independently selected R ^a .

In certain embodiments, R ^cB is C _1-3 alkyl which is optionally substituted with from

1-6 independently selected R ^a . For example, R ^cB can be CF ₃ or (e.g., R ^cB can be CF ₃ ).

In certain of these embodiments, each occurrence of R ^a is independently selected from: -F; C _1-4 alkoxy; and C _1-4 haloalkoxy. In certain embodiments (when one occurrence of R ^cB is Ci-io alkyl which is optionally substituted with from 1-6 independently selected R ^a ), R ^cB is unsubstituted Ci-io alkyl (e.g., unsubstituted Ci-6 (e.g., C1.3) alkyl. In certain embodiments of Formula (1-1), R ^cB is R ^c as defined in any one of paragaphs [C174]-[C184]

In certain embodiments, R ^cB is -L'-L ² -R ^h

In certain of these embodiments, -L ¹ is a bond. In certain other embodiments, -L ¹ is Ci-3 alkyl ene.

In certain embodiments (when R ^cB is -L ¹ -L ² -R ^h ), -L ² is a bond. In certain other embodiments, -L ² is -0-.

In certain embodiments (when R ^cB is -L'-L ² -R ^h ), -L ¹ is a bond; and -L ² is a bond. In certain other embodiments, -L ¹ is a bond; and -L ² is -0-. In still certain other embodiments, -L ¹ is C1-3 alkylene; and -L ² is -0-.

In certain embodiments (when R ^cB is -L'-L ² -R ^h ), R ^h is as defined in paragraph

[C182] In certain embodiments, R ^h is as defined in paragraph [C183] For example, R ^h can be as defined in paragraph [Cl 84]

In certain embodiments of Formula (1-1), R ^cB is R ^c is unsubstituted Ci- ₆ alkyl (e.g., Ci- ₃ alkyl).

In certain embodiments of Formula (1-1), R ^cB is halo.

In certain embodiments of Formula (1-1), nl = 0.

In certain embodiments of Formula (1-1), nl = 1.

In certain of the foregoing embodiments, R ^cA is halo.

In certain embodiments of Formula (1-1), each R ^N is as defined in any one of paragraphs [C214]-[C225].

In certain embodiments of Formula (1-1), one occurrence of R ^N is H. In certain embodiments (when one occurrence of R ^N is H), the second occurrence of R ^N is H.

In certain other embodiments, the second occurrence of R ^N is selected from

(ii) Ci- ₆ alkyl optionally substituted with from 1-3 R ^a ,

(iii) C3-6 cycloalkyl, optionally substituted with from 1-2 R ^a ,

(iv) -C(0)(Ci-4 alkyl), and

(v) -C(0)0(Ci-4 alkyl).

In certain of these embodiments, the second occurrence of R ^N is Ci- ₆ alkyl optionally substituted with from 1-3 R ^a (e.g., 1-2, e.g., 1). For example, the second occurrence R ^N can be unsubstituted Ci- ₆ alkyl .

In certain of these embodiments, each occurrence of R ^a is selected from C _1-4 alkoxy, C _3-6 cycloalkyl, and hydroxy.

In certain embodiments (when one occurrence of R ^N is H), the second occurrence R ^N is -C(0)0(Ci- ₄ alkyl) (e.g., -C(O)Me).

In certain embodiments of Formula (1-1), each R ^N is H.

[BB]

In some embodiments, the compound has Formula (1-2):

wherein B ² is selected from:

a) heteroaryl including from 6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c ; and b) heteroaryl including from 5 ring atoms, wherein from 1-3 (e.g., 2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c .

In certain embodiments of Formula (1-2), B ² is heteroaryl including from 6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c ; and R ^c is as defined in any one of paragaphs [C169]-[C173] (e.g., R ^c can be CF3).

In certain of these embodiments, R ^c is Ci-10 alkyl which is optionally substituted with from 1-6 independently selected R ^a .

In certain embodiments, R ^c is C1-3 alkyl which is optionally substituted with from

E F

V _.0

1-6 independently selected R ^a . For example, R ^c can be CF3 or * ^ (e.g., R ^cB can be CF3).

In certain of these embodiments, each occurrence of R ^a is independently selected from: -F; C1-4 alkoxy; and C1-4 haloalkoxy.

In certain embodiments (when one occurrence of R ^c is Ci-10 alkyl which is optionally substituted with from 1-6 independently selected R ^a ), R ^c is unsubstituted Ci-10 alkyl (e.g., unsubstituted Ci- ₆ (e.g., C1.3) alkyl.

In certain embodiments of Formula (1-2), B ² is heteroaryl (e.g., imidazolyl or pyrazolyl) including from 5 ring atoms, wherein from 1-3 (e.g., 2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c ; and R ^c is as defined in any one of paragaphs [C174]-[C184]

In certain embodiments, R ^c is -L'-L ² -R ^h In certain of these embodiments, -L ¹ is a bond. In certain other embodiments, -L ¹ is Ci-3 alkyl ene.

In certain embodiments (when R ^c is -L'-L ² -R ^h ), -L ² is a bond. In certain other embodiments, -L ² is -0-.

In certain embodiments (when R ^c is -L ¹ -L ² -R ^h ), -L ¹ is a bond; and -L ² is a bond.

In certain other embodiments, -L ¹ is a bond; and -L ² is -0-. In still certain other embodiments, -L ¹ is C1-3 alkylene; and -L ² is -0-.

In certain embodiments (when R ^c is -L ¹ -L ² -R ^h ), R ^h is as defined in paragraph [C182] In certain embodiments, R ^h is as defined in paragraph [C183] For example, R ^h can be as defined in paragraph [Cl 84]

In certain embodiments of Formula (1-2), A is (A-l):

wherein

Z is selected from the group consisting of:

a bond, CH, CR ¹ , CR ³ , N, NH, N(R') and N(R ² );

each of Y ¹ , Y ² , and Y ³ is independently selected from the group consisting of O,

S, CH, CR ¹ , CR ³ , N, NH, N(R ⁴ ), and NR ² ;

Y ⁴ is C or N;

X ¹ is selected from the group consisting of O, S, N, NH, NR ¹ , NR ² , CH, CR ¹ , and

CR ³ ;

X ² is selected from the group consisting of O, S, N, NH, NR ¹ , NR ² , CH, CR ¹ , and CR ³ ; and

each— is independently a single bond or a double bond, provided that the five- membered ring comprising Y ⁴ , X ¹ , and X ² is heteroaryl; and the ring comprising Z, Y ¹ ,

Y ² , Y ³ , and Y ⁴ is aromatic (i.e., carbocyclic aromatic or heteroaromatic). In certain embodiments of Formula (1-2), A is:

wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2).

In certain embodiments of Formula wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).

In certain embodiments of Formula wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).

In certain embodiments of Formula wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2.

In certain embodiments of Formula (1-2), A is , wherein ml = 0 or 1; and m3 = 0, 1, or 2. In certain embodiments of Formula

In certain embodiments of Formula (1-2), each R ¹ is as defined in any one of paragraphs [C92]-[C120]

In certain embodiments of Formula (1-2), R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of Formula (1-2), U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of Formula (1-2), U ² is as defined in paragaph [C99]

In certain embodiments of Formula (1-2), U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of Formula (1-2), each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] . As another example, each R ^c substituent of U ² when present can be as defined in paragaph [C104]

In certain embodiments of Formula (1-2) (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [CllOa] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of Formula (1-2) (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of Formula (1-2) (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of Formula (1-2), R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph [016].

In certain embodiments of Formula (1-2), each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of Formula (1-2), each R ³ is as defined in any one of paragraphs [C121]-[C123].

In certain embodiments of Formula (1-2), each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i- ₂ (Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0)i. ₂ (NR’R”), -C _M thioalkoxy, -C(=0)(Ci- ₄ alkyl), - C(=0)0(Ci-4 alkyl), -C(=0)0H, and -C(=0)N(R’)(R”) _·

In certain embodiments of Formula (1-2), each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i- ₂ (Ci-4 alkyl), -S(0)i- ₂ (NR’R”), -C(=0)(CM alkyl), -C(=0)0(Ci- ₄ alkyl), -C(=0)0H, and - C(=0)N(R’)(R”).

In certain embodiments of Formula (1-2), each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F). In certain embodiments of Formula (1-2), each R ^N is as defined in any one of paragraphs [C214]-[C225].

In certain embodiments of Formula (1-2), one occurrence of R ^N is H.

In certain embodiments (when one occurrence of R ^N is H), the second occurrence of R ^N is H.

In certain other embodiments, the second occurrence of R ^N is selected from

(ii) Ci- ₆ alkyl optionally substituted with from 1-3 R ^a ,

(iii) C3-6 cycloalkyl, optionally substituted with from 1-2 R ^a ,

(iv) -C(0)(Ci-4 alkyl), and

(v) -C(0)0(Ci-4 alkyl).

In certain of these embodiments, the second occurrence of R ^N is Ci- ₆ alkyl optionally substituted with from 1-3 R ^a (e.g., 1-2, e.g., 1). For example, the second occurrence R ^N can be unsubstituted Ci- ₆ alkyl .

In certain of these embodiments, each occurrence of R ^a is selected from C _1-4 alkoxy, C _3-6 cycloalkyl, and hydroxy.

In certain embodiments (when one occurrence of R ^N is H), the second occurrence R ^N is -C(0)0(Ci- ₄ alkyl) (e.g., -C(O)Me).

In certain embodiments of Formula (1-2), each R ^N is H.

[CC]

In some embodiments, the compound has Formula (1-3):

wherein B ³ is selected from:

a) C _6-12 cycloalkyl, which is optionally substituted with from 1-2 R ^b ; b) heterocyclyl including from 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heterocyclyl ring is optionally substituted with from 1-2 independently selected R ^b ; and c) heterocyclyl including from 7-12 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heterocyclyl ring is optionally substituted with from 1-2 independently selected R ^b .

In certain embodiments of Formula (1-3), B ³ is C6-12 cycloalkyl, which is optionally substituted with one R ^b .

In certain embodiments of Formula (1-3), B ³ heterocyclyl including from 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heterocyclyl ring is optionally substituted with from 1-2 independently selected R ^b ; wherein one occurrence of R ^b is as defined in paragaphs [C196]-[C201]

In certain of the foregoing embodiments, one occurrence of R ^b is as defined in paragaphs [096]. In certain embodiments, one occurrence of R ^b is as defined in paragaphs [097]. In certain embodiments, one occurrence of R ^b is as defined in paragaphs [098]. In certain embodiments, one occurrence of R ^b is -L'-L ² -R ^h In certain of these embodiments, -L ¹ is a bond; and -L ² is a bond. In certain embodiments of Formula (1-2) (when one occurrence of R ^b is -L'-L ² -R ^h ), R ^h is C6-10 aryl, which is optionally substituted with from 1-4 (e.g., 1-2, e.g., 1) substituents independently selected from the group consisting of halo, C 1-4 alkyl, or C1-4 haloalkyl.

In certain embodiments of Formula (1-3), B ³ heterocyclyl including from 7-12 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heterocyclyl ring is optionally substituted with from 1-2 independently selected R ^b .

In certain of the foregoing embodiments, B ³ is unsubstituted. In certain embodiments of Formula (1-3), A is (A-l):

wherein

Z is selected from the group consisting of:

a bond, CH, CR ¹ , CR ³ , N, NH, N(R') and N(R ² );

each of Y ¹ , Y ² , and Y ³ is independently selected from the group consisting of O,

S, CH, CR ¹ , CR ³ , N, NH, N(R ⁴ ), and NR ² ;

Y ⁴ is C or N;

X ¹ is selected from the group consisting of O, S, N, NH, NR ¹ , NR ² , CH, CR ¹ , and

CR ³ ;

X ² is selected from the group consisting of O, S, N, NH, NR ¹ , NR ² , CH, CR ¹ , and CR ³ ; and

each— is independently a single bond or a double bond, provided that the five- membered ring comprising Y ⁴ , X ¹ , and X ² is heteroaryl; and the ring comprising Z, Y ¹ , Y ² , Y ³ , and Y ⁴ is aromatic (i.e., carbocyclic aromatic or heteroaromatic).

In certain embodiments of Formula (1-3), A is:

wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3

(e.g., ml = 0 or 1; and m3 = 0, 1, or 2). In certain embodiments of Formula wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).

In certain embodiments of Formula wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).

In certain embodiments of Formula wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2. ml(R. )

3> S

In certain embodiments of Formula (1-3), A is mslR") ^H , wherein ml = 0 or 1; and m3 = 0, 1, or 2.

In certain embodiments of Formula

In certain embodiments of Formula (1-3), A is (A-4):

wherein:

Z ² is selected from CH, CR ² , and N;

X ³ is selected from O, S, N, NH, NR ¹ , NR ² , CH, CR ¹ , and CR ³ ;

each of Y ⁵ and Y ⁶ is independently selected from O, S, CH, CR ¹ , CR ³ , NR ¹ , NR ² ,

NH, and N; and

each— is independently a single bond or a double bond, provided that the five- membered ring comprising Y ⁵ , Y ⁶ , X ³ , and Z ² is heteroaromatic.

In certain embodiments of Formula (1-3), A is selected from: H

In certain embodiments of Formula (1-3), A is selected from: H

In certain embodiments of Formula (1-3), each R ¹ is as defined in any one of paragraphs [C92]-[C120]

In certain embodiments of Formula (1-3), R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of Formula (1-3), U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of Formula (1-3), U ² is as defined in paragaph [C99]

In certain embodiments of Formula (1-3), U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of Formula (1-3), each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [C104]

In certain embodiments of Formula (1-3) (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [CllOa] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of Formula (1-3) (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c] In certain embodiments of Formula (1-3) (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of Formula (1-3), R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph [016].

In certain embodiments of Formula (1-3), each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of Formula (1-3), each R ³ is as defined in any one of paragraphs [021]-[023].

In certain embodiments of Formula (1-3), each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i- ₂ (Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0)i. ₂ (NR’R”), -C _M thioalkoxy, -C(=0)(Ci- ₄ alkyl), - C(=0)0(Ci-4 alkyl), -C(=0)0H, and -C(=0)N(R’)(R”) _·

In certain embodiments of Formula (1-3), each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i- ₂ (Ci-4 alkyl), -S(0)i- ₂ (NR’R”), -C(=0)(CM alkyl), -C(=0)0(Ci- ₄ alkyl), -C(=0)0H, and - C(=0)N(R’)(R”).

In certain embodiments of Formula (1-3), each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F).

In certain embodiments of Formula (1-3), each R ^N is as defined in any one of paragraphs [C214]-[C225].

In certain embodiments of Formula (1-3), one occurrence of R ^N is H. In certain embodiments (when one occurrence of R ^N is H), the second occurrence of R ^N is H.

In certain other embodiments, the second occurrence of R ^N is selected from

(ii) Ci- ₆ alkyl optionally substituted with from 1-3 R ^a ,

(iii) C3-6 cycloalkyl, optionally substituted with from 1-2 R ^a ,

(iv) -C(0)(Ci-4 alkyl), and

(v) -C(0)0(Ci-4 alkyl).

In certain of these embodiments, the second occurrence of R ^N is Ci- ₆ alkyl optionally substituted with from 1-3 R ^a (e.g., 1-2, e.g., 1). For example, the second occurrence R ^N can be unsubstituted Ci- ₆ alkyl .

In certain of these embodiments, each occurrence of R ^a is selected from C1-4 alkoxy, C3-6 cycloalkyl, and hydroxy.

In certain embodiments (when one occurrence of R ^N is H), the second occurrence R ^N is -C(0)0(Ci- ₄ alkyl) (e.g., -C(O)Me).

In certain embodiments of Formula (1-3), each R ^N is H.

[DD]

In some embodiments,

(A-l)

wherein

Z is selected from the group consisting of:

a bond, CH, CR ¹ , CR ³ , N, NH, N(R') and N(R ² );

each of Y ¹ , Y ² , and Y ³ is independently selected from the group consisting of O,

S, CH, CR ¹ , CR ³ , N, NH, N(R ⁴ ), and NR ² ;

Y ⁴ is C or N; X ¹ is selected from the group consisting of O, S, N, NH, NR ¹ , NR ² , CH, CR ¹ , and

CR ³ ;

X ² is selected from the group consisting of O, S, N, NH, NR ¹ , NR ² , CH, CR ¹ , and CR ³ ; and

each— is independently a single bond or a double bond, provided that the five- membered ring comprising Y ⁴ , X ¹ , and X ² is heteroaryl; and the ring comprising Z, Y ¹ , Y ² , Y ³ , and Y ⁴ is aromatic (i.e., carbocyclic aromatic or heteroaromatic);

B and one R ^N , taken together with the atoms to which each is attached form a ring including from 5-20 ring atoms, wherein the ring includes: (a) from 0-4 ring heteroatoms each independently selected from N, N(H), N(R ^d ), O, and S(0)o- ₂ (in addition to the

heteroatoms in the ^R N ^N ~ ^rN moiety); and (b) from 2 to 17 ring carbon atoms, each of which is optionally substituted with 1-2 substituents independently selected from

(i) H;

(ii) oxo;

(iii) halo;

(iv) hydroxy;

(v) Ci- ₆ alkyl;

(vi) Ci- ₆ haloalkyl;

(vii) C6-io aryl optionally substituted with from 1-3 R ^c ;

(viii) heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected R ^c ;

(ix) heterocyclyl including from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R ^b ; and (x) C3-20 cycloalkyl, which is optionally substituted with from 1-4 R ^b ; and the remaining R ^N is H or Ci- ₆ alkyl.

wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2).

In certain embodiments of [DD], A is

In certain embodiments of [DD], A is

and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 0 or 1).

In certain embodiments of [DD], A is , wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2. In certain embodiments of [DD], A is , wherein ml = 0 or 1; and m3 = 0, 1, or 2.

In certain embodiments of [DD], A is or

In certain embodiments of [DD], B and one R ^N , taken together with the atoms to

which each is attached form: PO , which is optionally substituted with from 1-3 substituents independently selected from:

(ii) oxo;

(iii) halo;

(iv) hydroxy;

(v) Ci- ₆ alkyl; and

(vi) Ci- ₆ haloalkyl.

In certain embodiments of [DD], B and one R ^N , taken together with the atoms to

which each is attached form: , which is optionally substituted with from 1-3 substituents independently selected from: (ii) oxo; (iii) halo; (iv) hydroxy; and (v) Ci- ₆ alkyl;

wherein Ar ^N is selected from: (vii) C6-io aryl optionally substituted with from 1-3 R ^c ; and

(viii) heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected R ^c .

In certain embodiments of [DD], each R ¹ is as defined in any one of paragraphs

[C92]-[C120]

In certain embodiments of (DD), R ¹ is -(U ¹ )q-U ² . In certain of these embodiments, q is 0.

In certain embodiments of (DD), U ² is as defined in paragraph [C96]. For example, U ² can be as defined in paragaph [C97].

In certain embodiments of (DD), U ² is as defined in paragaph [C99]

In certain embodiments of (DD), U ² is as defined in paragaph [CIOO] For example, U ² can be as defined in paragaph [ClOl]

In certain embodiments of (DD), each R ^c substituent of U ² when present is as defined in paragraph [C102] For example, each R ^c substituent of U ² when present can be as defined in paragaph [C103] As another example, each R ^c substituent of U ² when present can be as defined in paragaph [Cl 04]

In certain embodiments of (DD) (when R ¹ is -(U ¹ )q-U ² ), R ¹ is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R ^c . In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [Cl 10a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 10c]

In certain embodiments of (DD) (when R ¹ is -(U ¹ )q-U ² ), R ¹ is heteroaryl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R ^c (e.g., R ¹ is pyridinyl such as 2-pyridinyl or pyrimidinyl such as 2-pyrimidinyl). In certain of these embodiments, each R ^c substituent on U ² is as defined in paragraph [C112a] For example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12b] As another example, each R ^c substituent on U ² can be as defined in paragraph [Cl 12c]

In certain embodiments of (DD) (when R ¹ is -(U ¹ )q-U ² ; and q = 0), U ² is as defined in paragraph [006]. For example, U ² can be as defined in pargaph [007] As another example, U ² can be as defined in paragraph [008]

In certain embodiments of (DD), R ¹ is as defined I paragraph [014] (e.g., as defined in pargaph [015]). As a non-limiting example, R ¹ can be as defined in paragraph

[016].

In certain embodiments of (DD), each occurrence of R ^a substituent of R ¹ is as defined in paragraph [017] For example, each occurrence of R ^a substituent of R ¹ can be as defined in paragraph [018] As a non-limiting example, each occurrence of R ^a substituent of R ¹ is independently selected from: -F and -C(=0)0H. For example, R ¹ can be CF or CH ₂ C0 ₂ H.

In certain embodiments of [DD], each R ³ is as defined in any one of paragraphs

[C121]-[C123].

In certain embodiments of [DD], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i- ₂ (Ci-4 alkyl), -NR ^e R ^f , -OH, -S(0) _{I -2} (NR’R”), -C _M thioalkoxy, -C(=0)(C _M alkyl), -C(=0)0(C _M alkyl), -C(=0)0H, and -C(=0)N(R’)(R”).

In certain embodiments of [DD], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, CM alkoxy, CM haloalkoxy, -S(0)I- ₂ (CM alkyl), -S(0)I- ₂ (NR’R”), -C(=0)(CM alkyl), -C(=0)0(CM alkyl), -C(=0)0H, and - C(=0)N(R’)(R”).

In certain embodiments of [DD], each occurrence of R ³ is independently selected from the group consisting of: halo, cyano, C _M alkoxy, and C _M haloalkoxy. For example, each occurrence of R ³ can be halo (e.g., F). In some embodiments, the compound is selected from the following:

Table 1A

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is selected from the following:

Table IB

or a pharmaceutically acceptable salt thereof.

The (R ^N )2NS(0)(=N)- Moiety (when W is O)

In some embodiments, the sulfur atom in the (R ^N ) ₂ NS(0)(=N)- moiety has (S) stereochemistry.

In some embodiments, the sulfur atom in the (R ^N ) ₂ NS(0)(=N)- moiety has (R) stereochemistry.

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-a-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 a-, b, and g-cyclodextrin, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2- and 3- hydroxypropyl-P-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, see Remington: The Science and Practice of Pharmacy , 22 ^nd Edition (Pharmaceutical Press, London, UK. 2012).

Routes of Administration and Composition Components

In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracistemal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral). 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.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.

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.

Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p- oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabi sulfite, grapefruit seed extract, methyl sulfonyl methane (MSM) , lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.

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.). Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

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 ak, 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.

Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

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).

In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 1 1 weeks, 12 weeks, 4 months,

5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days,

6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 1 1 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

Methods of Treatment

In some embodiments, methods for treating a subject having condition, disease or disorder in which increased (e.g., excessivejSTING 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 cancer. Non-limiting examples of cancer include melanoma, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include breast cancer, colon cancer, rectal cancer, colorectal cancer, kidney or renal cancer, clear cell cancer lung cancer including small-cell lung cancer, non- small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, squamous cell cancer (e.g. epithelial squamous cell cancer), cervical cancer, ovarian cancer, prostate cancer, prostatic neoplasms, liver cancer, bladder cancer, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, gastrointestinal stromal tumor, pancreatic cancer, head and neck cancer, glioblastoma, retinoblastoma, astrocytoma, thecomas, arrhenoblastomas, hepatoma, hematologic malignancies including non-Hodgkins lymphoma (NHL), multiple myeloma, myelodysplasia disorders, myeloproliferative disorders, chronic myelogenous leukemia, and acute hematologic malignancies, endometrial or uterine carcinoma, endometriosis, endometrial stromal sarcoma, fibrosarcomas, choriocarcinoma, salivary gland carcinoma, vulval cancer, thyroid cancer, esophageal carcinomas, hepatic carcinoma, anal carcinoma, penile carcinoma, nasopharyngeal carcinoma, laryngeal carcinomas, Kaposi's sarcoma, mast cell sarcoma, ovarian sarcoma, uterine sarcoma, melanoma, malignant mesothelioma, skin carcinomas, Schwannoma, oligodendroglioma, neuroblastomas, neuroectodermal tumor, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcomas, Ewing Sarcoma, peripheral primitive neuroectodermal tumor, urinary tract carcinomas, thyroid carcinomas, Wilm's tumor, as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome. In some cases, the cancer is melanoma.

In some embodiments, the condition, disease or disorder is a neurological disorder, which includes disorders that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Non-limiting examples of cancer include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; age-related macular degeneration; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers' disease; alternating hemiplegia; Alzheimer's disease; Vascular dementia; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Anronl-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telegiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet's disease; Bell's palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger's disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome; causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy; chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorders; Cushing's syndrome; cytomegalic inclusion body disease; cyto egalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier's syndrome; Dejerine-Klumke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb's palsy; essential tremor; Fabry's disease; Fahr's syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich's ataxia; fronto-temporal dementia and other “tauopathies”; Gaucher's disease; Gerstmann's syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1- associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (also neurological manifestations of AIDS); holoprosencephaly; Huntington's disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile phytanic acid storage disease; infantile refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease Kinsboume syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau -Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh's disease; Lennox-Gustaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; Lissencephaly; locked-in syndrome; Lou Gehrig's disease (i.e., motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; Lyme disease— neurological sequelae; Machado- Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neuron disease; Moyamoya disease; mucopolysaccharidoses; milti-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; p muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O'Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson's disease; paramyotonia congenital; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick's disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; post-polio syndrome; postherpetic neuralgia; postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (types I and II); Rasmussen's encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus- associated myelopathy; Rett syndrome; Reye's syndrome; Saint Vitus dance; Sandhoff disease; Schilder's disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren's syndrome; sleep apnea; Soto's syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; Stiff-Person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subcortical arteriosclerotic encephalopathy; Sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; Tic Douloureux; Todd's paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau disease; Wallenberg's syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wildon's disease; amyotrophe lateral sclerosis and Zellweger syndrome.

In some embodiments, the condition, disease or disorder is STING-associated conditions, e.g., type I interferonopathies (e.g., STING-associated vasculopathywith 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 erythe atosus, 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 by E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella spp., Staphylococcus aureus, Streptococcus spp., or vancomycin-resistant enterococcus), 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, including Giardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, and Toxoplasma 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 embodiemnts, 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.

The one or more additional cancer therapies can include, without limitation, surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine, hepatitis B vaccine, Oncophage, Provenge) and gene therapy, as well as combinations thereof. Immunotherapy, including, without limitation, adoptive cell therapy, the derivation of stem cells and/or dendritic cells, blood transfusions, lavages, and/or other treatments, including, without limitation, freezing a tumor.

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 immunomodulatory moiety, e.g., an immune checkpoint inhibitor. In certain of these embodiments, the immune checkpoint inhibitor targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1 - PD-L1, PD-1 - PD-

L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-b (TGFP), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9 - TIM3, Phosphatidylserine - TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II - LAG3, 4- 1BB-4- IBB ligand, 0X40-0X40 ligand, GITR, GITR ligand - GITR,

CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM - BTLA, HVEM - CD 160, HVEM - LIGHT, HYEM-BTLA-CD 160, CD80, CD80 - PDL-1, PDL2 - CD80, CD244, CD48 - CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-

TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86 - CD28, CD86 - CTLA, CD80 - CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine - TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155; e.g., CTLA-4 orPDl or PD-L1). See, e.g., Postow, M. J Clin. Oncol. 2015, 33, 1.

In certain of these embodiments, the immune checkpoint inhibitor is selected from the group consisting of: Urelumab, PF-05082566, MED 16469, TRX518, Varlilumab, CP-870893, Pembrolizumab (PD1), Nivolumab (PD1), Atezolizumab (formerly

MPDL3280A) (PDL1), MEDI4736 (PD-L1), Avelumab (PD-L1), PDR001 (PD1), BMS-986016, MGA271, Lirilumab, IPH2201, Emactuzumab, INCB024360, Galunisertib,

Ulocuplumab, BKT140, Bavituximab, CC-90002, Bevacizumab, and MNRP1685A, and MGA271.

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 as Vinca 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. Topoisom erases 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 certain embodiments, the additional chemotherapeutic agent is a stilbenoid. In a further embodiment, a stilbenoid includes, but is not limited to, Resveratrol, Piceatannol, Pinosylvin, Pterostilbene, Alpha- Viniferin, Ampelopsin A, Ampelopsin E, Diptoindonesin C, Diptoindonesin F, Epsilon- Vinferin, Flexuosol A, Gnetin H, Hemsleyanol D, Hopeaphenol, Trans-Diptoindonesin B, Astringin, Piceid and Diptoindonesin A. In a further embodiment a stilbenoid is a synthetic, semisynthetic or derivative.

In certain embodiments, the additional chemotherapeutic agent is a cytotoxic antibiotic. In an embodiment, a cytotoxic antibiotic is, without limitation, an actinomycin, an anthracenedione, an anthracycline, thalidomide, dichloroacetic acid, nicotinic acid, 2- deoxyglucose and/or chlofazimine. In an embodiment, an actinomycin is, without limitation, actinomycin D, bacitracin, colistin (polymyxin E) and/or polymyxin B. In another embodiment, an antracenedione is, without limitation, mitoxantrone and/or pixantrone. In a further embodiment, an anthracycline is, without limitation, bleomycin, doxorubicin (Adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, mitomycin, plicamycin and/or valrubicin. In a further embodiment a cytotoxic antibiotic is a synthetic, semisynthetic or derivative.

n certain embodiments, the additional chemotherapeutic agent is selected from endostatin, angiogenin, angiostatin, chemokines, angioarrestin, angiostatin (plasminogen fragment), basement-membrane collagen-derived anti-angiogenic factors (tumstatin, canstatin, or arrestin), anti -angiogenic antithrombin III, signal transduction inhibitors, cartilage-derived inhibitor (CDI), CD59 complement fragment, fibronectin fragment, gro- beta, heparinases, heparin hexasaccharide fragment, human chorionic gonadotropin (hCG), interferon alpha/beta/gamma, interferon inducible protein (IP-10), interleukin- 12, kringle 5 (plasminogen fragment), metalloproteinase inhibitors (TIMPs), 2-methoxyestradiol, placental ribonuclease inhibitor, plasminogen activator inhibitor, platelet factor-4 (PF4), prolactin 16 kD fragment, proliferin-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin- 1 (TSP-1), transforming growth factor-beta (TGF- b), vasculostatin, vasostatin (calreticulin fragment) and the like. In certain embodiments, the additional chemotherapeutic agent is selected from abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-m ethyl -L-valyl-L-proly- 1 -Lproline-t- butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3',4'-didehydro-4'- deoxy-8'-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin (adriamycin), etoposide, 5- fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyureataxanes, ifosfamide, liarozole, lonidamine, lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxanes, nilutamide, onapristone, paclitaxel, prednimustine, procarbazine, RPR109881, stramustine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine.

In certain embodiments, the additional chemotherapeutic agent is platinum, cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, azathioprine, mercaptopurine, vincristine, vinblastine, vinorelbine, vindesine, etoposide and teniposide, paclitaxel, docetaxel, irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, teniposide, 5-fluorouracil, leucovorin, methotrexate, gemcitabine, taxane, leucovorin, mitomycin C, tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide and doxorubicin. Additional agents include inhibitors of mTOR (mammalian target of rapamycin), including but not limited to rapamycin, everolimus, temsirolimus and deforolimus.

In still other embodiments, the additional chemotherapeutic agent can be selected from those delineated in U.S. Patent 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 vasculopathywith 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 rheumatoid arthritis include non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g, prednisone), disease-modifying antirheumatic drugs (DMARDs; e.g., methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), leflunomide (Arava®), hydroxychloroquine (Plaquenil), PF-06650833, iguratimod, tofacitinib (Xeljanz®), ABBV-599, evobrutinib, and sulfasalazine (Azulfidine®)), and biologies (e.g., abatacept (Orencia®), adalimumab (Humira®), anakinra (Kineret®), certolizumab (Cimzia®), etanercept (Enbrel®), golimumab (Simponi®), infliximab (Remicade®), rituximab (Rituxan®), tocilizumab (Actemra®), vobarilizumab, sarilumab (Kevzara®), secukinumab, ABP 501, CHS-0214, ABC-3373, and tocilizumab (ACTEMRA®)).

Non-limiting examples of additional therapeutic agents and/or regimens for treating lupus include steroids, topical immunomodulators (e.g., tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel®)), thalidomide (Thalomid®), non-steroidal anti inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarial drugs (e.g., Hydroxychloroquine (Plaquenil)), corticosteroids (e.g, prednisone) and immunomodulators (e.g., evobrutinib, iberdomide, voclosporin, cenerimod, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®, Gengraf®), and mycophenolate mofetil) baricitinb, iguratimod, filogotinib, GS-9876, rapamycin, and PF-06650833), and biologies (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDI0700, obinutuzumab, vobarilizumab, lulizumab, atacicept, PF-06823859, and lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirolizumab, edratide, IFN-a-kinoid, OMS721, RC18, RSLV- 132, theralizumab, XmAb5871, and ustekinumab (Stelara®)). For example, non-limiting treatments for systemic lupus erythematosus include non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarial drugs (e.g., Hydroxychloroquine (Plaquenil)), corticosteroids (e.g, prednisone) and immunomodulators (e.g., iberdomide, voclosporin, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®, Gengraf®), and mycophenolate mofetil, baricitinb, filogotinib, and PF-06650833), and biologies (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDI0700, vobarilizumab, lulizumab, atacicept, PF-06823859, lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirolizumab, edratide, IFN-a-kinoid, RC18, RSLV-132, theralizumab, XmAb5871, and ustekinumab (Stelara®)). As another example, non-limiting examples of treatments for cutaneous lupus include steroids, immunomodulators (e.g., tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel®)), GS-9876, filogotinib, and thalidomide (Thalomid®). Agents and regimens for treating drug-induced and/or neonatal lupus can also be administered.

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 Aicardi-Goutieres Syndrome (AGS) include physiotherapy, treatment for respiratory complications, anticonvulsant therapies for seizures, tube-feeding, nucleoside reverse transcriptase inhibitors (e.g., emtricitabine (e.g., Emtriva®), tenofovir (e.g., Viread®), emtricitabine/tenofovir (e.g., Truvada®), zidovudine, lamivudine, and abacavir), and JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).

Non-limiting examples of additional therapeutic agents and/or regimens for treating IBDs include 6-mercaptopurine, AbGn-168H, ABX464, ABT-494, adalimumab, AJM300, alicaforsen, AMG139, anrukinzumab, apremilast, ATR-107 (PF0530900), autologous CD34-selected peripheral blood stem cells transplant, azathioprine, bertilimumab, BI 655066, BMS-936557, certolizumab pegol (Cimzia®), cobitolimod, corticosteroids (e.g., prednisone, Methylprednisolone, prednisone), CP-690,550, CT-P13, cyclosporine, DIMS0150, E6007, E6011, etrasimod, etrolizumab, fecal microbial transplantation, figlotinib, fmgolimod, firategrast (SB-683699) (formerly T-0047), GED0301, GLPG0634, GLPG0974, guselkumab, golimumab, GSK 1399686, HMPL-004 (. Andrographis paniculata extract), IMU-838, infliximab, Interleukin 2 (IL-2), Janus kinase (JAK) inhibitors, laquinimod, masitinib (AB1010), matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, mirikizumab (LY3074828), natalizumab, NNC 0142-0000-0002, NNC0114-0006, ozanimod, peficitinib (JNJ-54781532), PF-00547659, PF-04236921, PF-06687234, QAX576, RHB- 104, rifaximin, risankizumab, RPC1063, SB012, SHP647, sulfasalazine, TD-1473, thalidomide, tildrakizumab (MK 3222), TJ301, TNF-Kinoid®, tofacitinib, tralokinumab, TRK-170, upadacitinib, ustekinumab, UTTR1147A, V565, vatelizumab, VB-201, vedolizumab, and vidofludimus.

Non-limiting examples of additional therapeutic agents and/or regimens for treating irritable bowel syndrome include alosetron, bile acid sequesterants (e.g., cholestyramine, colestipol, colesevelam), chloride channel activators (e.g., lubiprostone), coated peppermint oil capsules, desipramine, dicyclomine, ebastine, eluxadoline, famesoid X receptor agonist (e.g., obeticholic acid), fecal microbiota transplantation, fluoxetine, gabapentin, guanylate cyclase-C agonists (e.g., linaclotide, plecanatide), ibodutant, imipramine, JCM-16021, loperamide, lubiprostone, nortriptyline, ondansetron, opioids, paroxetine, pinaverium, polyethylene glycol, pregabalin, probiotics, ramosetron, rifaximin, and tanpanor.

Non-limiting examples of additional therapeutic agents and/or regimens for treating scleroderma include non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g, prednisone), immunomodulators (e.g., azathioprine, methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), cyclophosphamide

(Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral®, Sandimmune®, Gengraf®), anti thymocyte globulin, mycophenolate mofetil, intravenous immunoglobulin, rituximab, sirolimus, and alefacept), calcium channel blockers (e.g., nifedipine), alpha blockers, serotonin receptor antagonists, angiotensin II receptor inhibitors, statins, local nitrates, iloprost, phosphodiesterase 5 inhibitors (e.g., sildenafil), bosentan, tetracycline antibiotics, endothelin receptor antagonists, prostanoids, and tyrosine kinase inhibitors (e.g., imatinib, nilotinib and dasatinib).

Non-limiting examples of additional therapeutic agents and/or regimens for treating Crohn’s Disease (CD) include adalimumab, autologous CD34-selected peripheral blood stem cells transplant, 6-mercaptopurine, azathioprine, certolizumab pegol (Cimzia®), corticosteroids (e.g., prednisone), etrolizumab, E6011, fecal microbial transplantation, figlotinib, guselkumab, infliximab, IL-2, JAK inhibitors, matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, natalizumab, ozanimod, RHB-104, rifaximin, risankizumab, SHP647, sulfasalazine, thalidomide, upadacitinib, V565, and vedolizumab.

Non-limiting examples of additional therapeutic agents and/or regimens for treating UC include AbGn-168H, ABT-494, ABX464, apremilast, PF-00547659, PF-06687234, 6- mercaptopurine, adalimumab, azathioprine, bertilimumab, brazikumab (MEDI2070), cobitolimod, certolizumab pegol (Cimzia®), CP-690,550, corticosteroids (e.g., multimax budesonide, Methylprednisolone), cyclosporine, E6007, etrasimod, etrolizumab, fecal microbial transplantation, figlotinib, guselkumab, golimumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitors (e.g., GS-5745), mesalamine, mesalamine, mirikizumab (LY3074828), RPC1063, risankizumab (BI 6555066), SHP647, sulfasalazine, TD-1473, TJ301, tildrakizumab (MK 3222), tofacitinib, tofacitinib, ustekinumab, UTTR1147A, and vedolizumab.

Non-limiting examples of additional therapeutic agents and/or regimens for treating autoimmune colitis include corticosteroids (e.g., budesonide, prednisone, prednisolone, Beclometasone dipropionate), diphenoxylate/atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No.

2012/0202848), and vedolizumab.

Non-limiting examples of additional therapeutic agents and/or regimens for treating iatrogenic autoimmune colitis include corticosteroids (e.g., budesonide, prednisone, prednisolone, Beclometasone dipropionate), diphenoxylate/atropine, infliximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No.

2012/0202848), and vedolizumab.

Non-limiting examples of additional therapeutic agents and/or regimens for treating colitis induced by one or more chemotherapeutics agents include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), diphenoxylate/atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012/0202848), and vedolizumab.

Non-limiting examples of additional therapeutic agents and/or regimens for treating colitis induced by treatment with adoptive cell therapy include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), diphenoxylate/atropine, infliximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012/0202848), and vedolizumab.

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.

Non-limiting examples of additional therapeutic agents and/or regimens for treating radaiation enteritis include teduglutide, amifostine, angiotensin-converting enzyme (ACE) inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril), probiotics, selenium supplementation, statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin), sucralfate, and vitamin E.

Non-limiting examples of additional therapeutic agents and/or regimens for treating collagenous colitis include 6-mercaptopurine, azathaioprine, bismuth subsalicate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.

Non-limiting examples of additional therapeutic agents and/or regimens for treating lyphocytic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), loperamide, mesalamine, methotrexate, and sulfasalazine.

Non-limiting examples of additional therapeutic agents and/or regimens for treating microscopic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), fecal microbial transplantation, loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.

Non-limiting examples of additional therapeutic agents and/or regimens for treating alloimmune disease include intrauterine platelet transfusions, intravenous immunoglobin, maternal steroids, abatacept, alemtuzumab, alphal -antitrypsin, AMG592, antithymocyte globulin, barcitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

Non-limiting examples of additional therapeutic agents and/or regimens for treating multiple sclerosis (MS) include alemtuzumab (Lemtrada®), ALKS 8700, amiloride, ATX- MS-1467, azathioprine, baclofen (Lioresal®), beta interferons (e.g., IFN-b- I a, IFN-b-I b), cladribine, corticosteroids (e.g., methylprednisolone), daclizumab, dimethyl fumarate (Tecfidera®), fmgolimod (Gilenya®), fluoxetine, glatiramer acetate (Copaxone®), hydroxychloroquine, ibudilast, idebenone, laquinimod, lipoic acid, losartan, masitinib, MD1003 (biotin), mitoxantrone, montelukast, natalizumab (Tysabri®), NeuroVax™, ocrelizumab, ofatumumab, pioglitazone, and RPC 1063.

Non-limiting examples of additional therapeutic agents and/or regimens for treating graft-vs-host disease include abatacept, alemtuzumab, alphal -antitrypsin, AMG592, antithymocyte globulin, barcitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

Non-limiting examples of additional therapeutic agents and/or regimens for treating acute graft-vs-host disease include alemtuzumab, alpha- 1 antitrypsin, antithymocyte globulin, basiliximab, brentuximab, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, ibrutinib, infliximab, itacitinib, LBH589, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, photopheresis, ruxolitinib, sirolimus, tacrolimus, and tocilizumab.

Non-limiting examples of additional therapeutic agents and/or regimens for treating chronic graft vs. host disease include abatacept, alemtuzumab, AMG592, antithymocyte globulin, basiliximab, bortezomib, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, mycophenolate mofetil, pentostatin, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

Non-limiting examples of additional therapeutic agents and/or regimens for treating celiac disease include AMG 714, AMY01, Aspergillus niger prolyl endoprotease, BL- 7010, CALY-002, GBR 830, Hu-Mik-Beta-1, IMGX003, KumaMax, Larazotide Acetate, Nexvan2®, pancrelipase, TIMP-GLIA, vedolizumab, and ZED1227.

Non-limiting examples of additional therapeutic agents and/or regimens for treating psoriasis include topical corticosteroids, topical crisaborole/AN2728, topical SNA-120, topical SAN021, topical tapinarof, topical tocafmib, topical IDP-118, topical M518101, topical calcipotriene and betamethasone dipropionate (e.g., MC2-01 cream and Taclonex®), topical P-3073, topical LEO 90100 (Enstilar®), topical betamethasone dipropriate (Sernivo®), halobetasol propionate (Ultravate®), vitamin D analogues (e.g., calcipotriene (Dovonex®) and calcitriol (Vectical®)), anthralin (e.g., Dritho-scalp® and Dritho-creme®), topical retinoids (e.g., tazarotene (e.g., Tazorac® and Avage®)), calcineurin inhibitors (e.g., tacrolimus (Prograf®) and pimecrolimus (Elidel®)), salicylic acid, coal tar, moisturizers, phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrow band UVB phototherapy, Goeckerman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), retinoids (e.g., acitretin (Soriatane®)), methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), Apo805Kl, baricitinib, FP187, KD025, prurisol, VTP-43742, XP23829, ZPL-389, CF101 (piclidenoson), LAS41008, VPD-737 (serlopitant), upadacitinib (ABT-494), aprmilast, tofacitibin, cyclosporine (Neoral®, Sandimmune®, Gengraf®), biologies (e.g., etanercept (Enbrel®), entanercept-szzs (Elrezi®), infliximab (Remicade®), adalimumab (Humira®), adalimumab-adbm (Cyltezo®), ustekinumab (Stelara®), golimumab (Simponi®), apremilast (Otezla®), secukinumab (Cosentyx®), certolixumab pegol, secukinumab, tildrakizumab-asmn, infliximab-dyyb, abatacept, ixekizumab (Taltz®), ABP 710, BCD-057, BI695501, bimekizumab (UCB4940), CHS-1420, GP2017, guselkumab (CNTO 1959), HD203, M923, MSB 11022, Mirikizumab (LY3074828), PF-06410293, PF-06438179, risankizumab (BI655066), SB2, SB4, SB5, siliq (brodalumab), namilumab (MT203, tildrakizumab (MK-3222), and ixekizumab (Taltz®)), thioguanine, and hydroxyurea (e.g., Droxia® and Hydrea®).

Non-limiting examples of additional therapeutic agents and/or regimens for treating cutaneous T-cell lymphoma include phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrow band UVB phototherapy, Goeckerman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), extracorporeal photopheresis, radiation therapy (e.g., spot radiation and total skin body electron beam therapy), stem cell transplant, corticosteroids, imiquimod, bexarotene gel, topical bis-chloroethyl-nitrourea, mechlorethamine gel, vorinostat (Zolinza®), romidepsin (Istodax®), pralatrexate

(Folotyn®) biologies (e.g., alemtuzumab (Campath®), brentuximab vedotin (SGN-35), mogamulizumab, and IPH4102).

Non-limiting examples of additional therapeutic agents and/or regimens for treating uveitis include corticosteroids (e.g., intravitreal triamcinolone acetonide injectable suspensions), antibiotics, antivirals (e.g., acyclovir), dexamethasone, immunomodulators (e.g., tacrolimus, leflunomide, cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral®, Sandimmune®, Gengraf®), chlorambucil, azathioprine, methotrexate, and mycophenolate mofetil), biologies (e.g., infliximab (Remicade®), adalimumab (Humira®), etanercept (Enbrel®), golimumab (Simponi®), certolizumab (Cimzia®), rituximab (Rituxan®), abatacept (Orencia®), basiliximab (Simulect®), anakinra (Kineret®), canakinumab (Haris®), gevokixumab (XOMA052), tocilizumab (Actemra®), alemtuzumab (Campath®), efalizumab (Raptiva®), LFG316, sirolimus (Santen®), abatacept, sarilumab (Kevzara®), and daclizumab (Zenapax®)), cytotoxic drugs, surgical implant (e.g., fluocinolone insert), and vitrectomy. Non-limiting examples of additional therapeutic agents and/or regimens for treating mucositis include AG013, SGX942 (dusquetide), amifostine (Ethyol®), cryotherapy, cepacol lonzenges, capsaicin lozenges, mucoadhesives (e.g., MuGard®) oral diphenhydramine (e.g., Benadry® elixir), oral bioadherents (e.g., polyvinylpyrrolidone- sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), caphosol, chamomilla recutita mouthwash, edible grape plant exosome, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., Peridex® or Periogard®), topical pain relievers (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and Ulcerease® (0.6% phenol)), corticosteroids (e.g., prednisone), pain killers (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor; Kepivance®), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble b-1,3/1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, granules comprising vaccinium myrtillus extract, macleaya cordata alkaloids and echinacea angustifolia extract (e.g., SAMITAL®), and gastrointestinal cocktail (an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid)). For example, non limiting examples of treatments for oral mucositis include AG013, amifostine (Ethyol®), cryotherapy, cepacol lonzenges, mucoadhesives (e.g., MuGard®) oral diphenhydramine (e.g., Benadry® elixir), oral bioadherents (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), caphosol, chamomilla recutita mouthwash, edible grape plant exosome, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., Peridex® or Periogard®), topical pain relievers (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and Ulcerease® (0.6% phenol)), corticosteroids (e.g., prednisone), pain killers (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor; Kepivance®), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble b- 1 ,3/1 ,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, and gastrointestinal cocktail (an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid)). As another example, non-limiting examples of treatments for esophageal mucositis include xylocaine (e.g., gel viscous Xylocaine 2%). As another example, treatments for intestinal mucositis, treatments to modify intestinal mucositis, and treatments for intestinal mucositis signs and symptoms include gastrointestinal cocktail (an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid)).

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. For example, the compounds described herein can be synthesized. 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, l,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, ¾ 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:

ACN = acetonitrile

AcOH = acetic acid

DCM = dichloromethane

DMF = N,N-dimethylformamide

DMSO = dimethyl sulfoxide

DIEA = N,N-diisopropylethylamine

TBS = tertbutylaimethylsilyl chloride

Py = pyridine

Et = ethyl

EtOH = ethanol

LC-MS = liquid chromatography - mass spectrometry

Me = methyl

MeOH = methanol

n-Bu = n-butyl

NMR = nuclear magnetic resonance

HPLC = high performance liquid chromatography

TEA = triethylamine TFA = trifluoroacetic acid

THF = tetrahydrofuran

RHS = right hand side

LHS = left hand side

IP A = iso-propyl alcohol

BTC = bis(trichloromethyl) carbonate

Scheme I illustrates a general method to prepare compounds of Formula I:

Scheme I

X ^L = leaving group (e.g., halo such as -Cl)

Compound of Formula I

Referring to Scheme I, amine 1-1 wherein Ring A is as defined for Formula I is reacted with a compound of Formula 1-2 wherein Ring B is as defined for Formula I, and X ^L is a leaving group such as -Cl to afford sulfonamide 1-3. Compound 1-3 is converted into a compound of Formula I via activation of one sulfonyl =0 group (e.g., with PPI1 ₃ CI ₂ and NFfe) followed by coupling of the intermediate with (R ^N ) ₂ NH wherein each R ^N is as defined for Formula I.

It is conceivable to a person of ordinary skill in the art that 1-1 and 1-2 may be prepared via approaches known in the art. For example, 1-1 can be obtained through sequential electrophilic aromatic nitration and reduction of the intermediary nitro compound. 1-2, for example, can be prepared from — via lithium-halogen exchange, trapping of the organolithium species with SO2, followed by the chlorination of the intermediary sulfmate (e.g., with NCS).

Examples

The following example is one method of preparing compound 1. Example 2, disclosed subsequently, discloses another method of preparing compound 1. Example 1

Preparation _ of _ N'-(lEl-indol-3-vO-4-(trifluoromethvObenzenesulfonimidamide

(Compound 1)

Sulfonamide (1 mmol) and TEA (1 mmol) were dissolved in DCM and cooled to 0 °C. To the solution, triphenylphosphinedihydrochloride (1 mmol) was added dropwise over 10 minutes. The resulting mixture was allowed to stir at -78 °C for 2 hours, after which liquid ammonia in THF (5 M solution, 30 mmol of NEE) was added and the reaction stirred overnight. The solution was concentrated in vacuo ; and the crude product was partitioned between water and DCM. The organic layer was dried over anhydrous MgSCE and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using hexane/EtOAc as an eluent. LCMS (Method A): 340.1 [M+H] ⁺ , retention time 1.77 min.

Method A: Shim-pack XR-ODS, CIS, 3x50 mm, 2.5 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 arau scan range, 190-400 am UV range, 5-100% (1.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA) and water (0.05% ^' IT A), 2 minute total ru time

The following compounds can also be synthesized by the method described above from the corresponding sulfonamide. Methods disclosed subsequently can also be used to prepare one or more of the following compounds.

The subsequent disclosure provides further methods of preparing compounds of Formula I.

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.

Method A: Titank Cl 8, 50x3 mm, 3 um column, 0.3 uL injection, 1.5 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: Water+5mMNH ₄ HC0 ₃ and Mobile Phase B: Acetonitrile. 10% MPB to 95.0% in 1.39 min, hold at 95% MPB for 0.8 min, 95% MPB to 10% in 0.03 min, then equilibration to 10% MPB for 0.27 min. Method B: EVO-C18, 50x3mm, 2.6 um column, 2.0 uL injection, 1.2 mL/min flow rate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: Water+5mMNH ₄ HC0 ₃ and Mobile Phase B: Acetonitrile. 10% MPB to 95.0% in 1.99 min, hold at 95% MPB for 0.6 min, 95% MPB to 10% in 0.20 min, then equilibration to 10% MPB for 0.25 min. Method C: Poroshell HPH-C18, 50 *3mm, 2.6 um column, 4.0 uL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile phase A: Water/5mmol NH4CO3 and Mobile Phase B: Acetonitrile. 5% MPB to 95% in 1.29 min, hold at 95% MPB for 0.9 min, 90% MPB to 10% in 0.05 min, then equilibration to 10% MPB for 0.25 min.

Method D: Poroshell HPH-C18, 50 *3mm, 2.6 um column, 2.7 pL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.04% NH4OH and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 1.99 min, hold at 95% MPB for 0.6 min, 95% MPB to 10% in 0.03 min, then equilibration to 10% MPB for 0.17 min.

Method E: XBridge Shield RP18, 50 *3.0 mm, 2.2 um column, 5.0 pL injection, 1.5 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.04% NH4OH and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2 min, hold at 95% MPB for 0.79 min, 95% MPB to 10% in 0.05 min, then equilibration to 10% MPB for 0.16 min.

Method F: CORTECS C18+ MVK, 50 *2.1 mm, 2.0 uL injection, 1.0 mL/min flowrate, 90-900 amu scan range, 210 nm UV detection. Mobile phase A:Water+0.1%FA; Mobile phase B:Acetonitrile+0.05%FA 10.0% MPB to 100.0% in 2.0 min, hold at 100.0% MPB for 0.75 min, 100.0% MPB to 10.0% in 0.02 min, then equilibration to 10.0% MPB for 0.23 min.

Method J: Kinetex@ 2.7 um XB-C18 100A, 50 *3.0 mm, 1.5 uL injection, 1.0 mL/min flowrate, 90-900 amu scan range, 210 nm UV detection. Mobile phase A: Water (0.05% TFA) and Mobile Phase B: MeCN. 5% MPB to 100% in 1.5 min, hold at 100% MPB for 0.8 min, 100% MPB to 5% in 0.03 min, then equilibration to 10% MPB for 0.17 min. Method K: Shim-pack XR-ODS, 50 *3.0 mm, 50 *3.0 mm, 2.2 um column, 2.2 pL injection, 1.2 mL/min flowraMethod Kte, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.05% TFA and Mobile Phase B (MPB): Acetonitrile. Elution 5% MPB to 95% in 2 min, hold at 95% MPB for 0.7 min, 95% MPB to 10% in 0.05 min, then equilibration to 5% MPB for 0.25 min. The final targets were purified by Prep-HPLC. The Prep-HPLC was carried out using the following method.

Method G: Pre-HPLC: Column: XBridge Prep C18 OBD Column 19*150mm, 5pm; Mobile Phase: Water (lOmMMLHCCL+O.U/oML HiO) and ACN, UV detection 254/210 nm.

Method H: Pre-HPLC: Column: XBridge Prep C18 OBD Column 19*150mm, 5pm; Mobile Phase: Water (lOmM NH4HCO3) and ACN, UV detection 254/210 nm.

Method I: Pre-HPLC: Column: YMC-Actus Triart C18 Column 30*250mm, 5pm; Mobile Phase: Water (10MMOL/L MLHCOs+O.U/oML.HiO) and ACN, UV detection 254/210 nm.

NMR was recorded on BRUKER NMR 300.03 Mz, DUL-C-H, ULTRASHIELD™ 300, AVANCE II 300 B-ACS™ 120 or BRUKER NMR 400.13 Mz, BBFO, ULTRASHIELD™ 400, AVANCE III 400, B-ACS™ 120.

Scheme for the preparation of Exemplary Intermediates: Schemes below illustrate the preparation of key intermediates of the remaining examples.

Scheme 1: Synthesis of intermediate 1 (N'-(tert-butyldimethylsilyl)-4- ethylbenzenesulfonimidamide)

Intermediate 1 Step 1: /V-(terf-butyldimethylsilyl)-4-ethylbenzenesulfonamide

4-Ethylbenzenesulfonamide (5.0 g, 26.9 mmol, 1.0 equiv.) was dissolved in THF (30.0 mL), then DIEA (13.97 mL, 81.0 mmol, 3.0 equiv.) and TBSC1 (8.1 g, 53.9 mmol, 2.0 equiv.) were added. Upon stirring 18 hours at ambient temperature, the resulting solution was concentrated under vacuum and. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1 :5) to give N-(tert- butyldimethylsilyl)-4-ethylbenzenesulfonamide (5.8 g, 71.8%) as a white solid. LCMS Method D, MS-ESI: 300.1 [M+H] ⁺ .

Step 2-3: A ^, -(tert-butyldimethylsilyl)-4-ethylbenzenesulfonimidami de

Intermediate 1

PPI13CI2 (5.0 g, 15.0 mmol, 1.5 equiv.) was dissolved in CHCb (50.0 mL), then DIEA (8.90 mL, 50.1 mmol, 5.0 equiv.) was added at 0 °C and the resulting mixture was stirred for 1 hour at 0 °C under N2. This was followed by the addition of N-(tert- butyldimethylsilyl)-4-ethylbenzenesulfonamide (3.0 g, 10.0 mmol, 1.0 equiv.) and the resulting mixture was stirred for additional 1 hour at 0 °C under N2. Then NH ₃ (g) was bubbled into above solution for 15 minutes at 0 °C. After stirred for 1 hour at ambient temperature, the solid was filtered out and the filtrate was concentrated in vacuo. The residue was purified by flash column on silica gel, eluting with EtOAc/petroleum ether (1/3) to give A _' ^f '-(/<3/7-butyl di ethyl si lyl)-4-ethylbenzenesulfoni ida ide (2.1 g, 71.7

%) as a white solid. LCMS Method D, MS-ESI: 299.2 [M+H] ⁺ . Scheme 2: Synthesis of intermediate 2 (4-hutyl-N-(tert- hutyldimethylsilyl)henzenesulfonimidoyl chloride)

Intermediate 2

Step 1: 4-butyl-/V-(fc/T-butyldimethylsilyl)benzenesulfonamide

P-butylbenzenesulfonamide (1.0 g, 4.7 mmol, 1.0 equiv) was dissolved in THF (30.0 mL), then DIEA (1.64 mL, 9.4 mmol, 2.0 equiv) and t-butyldimethylchlorosilane (850.0 mg, 5.6 mmol, 1.2 equiv) were added. The resulting solution was stirred for 4 hours at ambient temperature. The resulting mixture was concentrated. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1 :2) to give 4-butyl -A-(/er/-butyldimethylsilyl)benzenesulfonamide (1.2 g) as a white solid. LCMS Method B, MS-ESI: 328.2 [M+H] ⁺ .

Step 2: 4-butyl-/V-(ferf-butyldimethylsilyl)benzenesulfonimidoyl chloride

5' Intermediate 2

PPI13CI2 (1.6 g, 4.9 mmol, 1.6 equiv.) was dissolved in CHCh (50.0 mL), then DIEA (2.60 mL, 15.2 mmol, 5.0 equiv.) was added at 0 °C and the resulting mixture was stirred for 1 hour at 0 °C under N2. This was followed by the addition of 4-butyl -N-(tert- butyldimethylsilyl)benzenesulfonamide (1.0 g, 3.1 mmol, 1.0 equiv.) and the resulting mixture was stirred for additional 1 hour at 0 °C under N2. The resulting solution of 4- butyl-AX/ -butyl dimethyl si lyl)benzenesulfoni mi doyl chloride was used to next step directly.

The intermediates in Table 1 were prepared using the same method described for Intermediate 2.

Table 1

Scheme 2: Synthesis of intermediate 14 (N'-(lH-indol-3- yl)methanesulfonimidamide)

Step 1: /V-(terf-butyldimethylsilyl)methanesulfonamide

20 Step 1 21

Methanesulfonamide (20.0 g, 210.3 mmol, 1.0 equiv.) was dissolved in THF (200.0 ml), NaH (60% wt in mineral oil, 8.8 g, 220.8 mmol, 1.1 equiv.) was added. The reaction mixture was stirred for 30 min at ambient temperature. Then TBSC1 (34.9 g, 231.3 mmol, 1.1 equiv) was added in portions. The resulting solution was stirred for 2 hours at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give N-(tert- butyldimethylsilyl)methanesulfonamide (20 g, 45.43%) as a white solid. LCMS Method D, MS-ESI: 3210.1 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO-^e): d 7.05 (s, 1H), 2.92 (s, 3H), 0.92 (s, 9H), 0.18 (s, 6H).

Step 2-3: /V-(terf-butyldimethylsilyl)-/V ^, -(Li/-indol-3-yl)methanesulfonimidamide

PPI13CI2 (31.8 g, 95.4 mmol, 4.0 equiv.) was dissolved in CHCh (60.0 mL), then DIEA (33.70 mL, 141.7 mmol, 5.9 equiv.) was added at 0 °C and the resulting mixture was stirred for 1 hour at 0 °C under N2. This was followed by the addition of N-(tert- butyldimethylsilyl)methanesulfonamide (5.0 g, 23.9 mmol, 1.0 equiv.) and the resulting mixture was stirred for additional 1 hour at 0 °C under N2. Then to the mixture, a solution of liT-indol-3 -amine hydrochloride (14.2 g, 84.2 mmol, 1.2 equiv.) in CHCh (16.0 mL) was added dropwise. The reaction mixture was stirred for additional 2 hours at ambient temperature. The reaction was then quenched by the addition of water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1 :6) to give N-( /fH-butyl di ethyl si 1 yl )-N'-( 1 //-i ndol -3 - yl)methanesulfonimidamide (5 g, 22.0%). LCMS Method D, MS-ESI: 324.2 [M+H] ⁺ .

Step 4: A'-(l/ -indol-3-yl)methanesulfonimidamide

A-(/t77-butyldi methyl si lyl)-A ^f -( l //-indol -3 -yl)methanesulfonoi midamide (1.0 g, 3.0 mmol, 1.0 equiv) was dissolved in THF (20.0 mL). Then HF -Pyridine (70% wt., 0.1 mL) was added. The reaction solution was stirred for 30 min at ambient temperature and then quenched by the addition of NaiCCb (aq.) and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1 : 1) to give A-( l//-indol -3 -yl)methanesulfonoi midamide (500 mg ,77.3%) as a off-white solid. LCMS Method D, MS-ESI: 210.1 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO-i¾): 510.50-10.45 (m, 1H), 7.58 (d, 1H), 7.27 (d, 1H), 7.03-6.92 (m, 3H), 6.70-6.12 (m, 2H), 3.02 (s, 3H).

The intermediates in Table 2 were prepared using the same method described for Intermediate 14.

Table 2

Scheme 3: Synthesis of intermediate 16 (5,6-difluoro-lH-indol-3-amine)

Step 1: 5,6-difluoro-3-nitro-l//-indole

5,6-Difluoro-lH-indole (5.0 g, 32.7 mmol, 1.0 equiv) was dissolved in CH3CN (50.0 mL), and AgNCb (6.1 g, 36.0 mmol, 1.1 equiv) was added in portions at ambient temperature, the resulting solution was cooled to 0 °C and stirred for 5 minutes at 0 °C, then benzoyl chloride (4.1 mL, 36.0 mmol, 1.1 equiv) was added. The resulting solution was allowed to warm to ambient temperature for 2 hours, then the pH of the reaction mixture was adjusted to pH 8 by dropwise addition of 1 M aqueous NaiCCb solution. The mixture was extracted with EtOAc and the combined organic layers were concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (5/95) to give 5,6-difluoro-3-nitro-lH- indole (3.5 g, 17.7 mmol) as a yellow solid. LCMS Method D, MS-ESI: 199.1 [M+H] ⁺ .

Step 2: 5,6-difluoro-l//-indol-3-amine

5,6-Difluoro-3-nitro-liT-indole (3.5 g, 17.7 mmol, 1.0 equiv) was dissolved in 40%

HBr/H ₂ 0 (40 mL), then SnCL (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 ambient temperature and the pH was adjusted to pH 8 by dropwise addition of 1 M aqueous NaOH. The mixture was extracted with DCM and the combined organic layers were concentrated in vacuo. The residue was used in the next step directly without further purification. LCMS Method D, MS-ESI: 169.1 [M+H] ⁺ . The intermediates in Table 3 were prepared usins the same method described for Intermediate 16.

Table 3

Example 2: A '-(l/ -indol-3-yl)-4-(trifluoromethyl)benzenesulfonimidamide

(Compound 1)

Step 1: /V-(fe/7-butyldimethylsilyl)-/V'-(l//-indol-3-yl)-4- (trifluoromethyl)benzenesulfonimidamide

Intermediate 3 To the solution of N-{tert-b uty 1 di m eth y 1 si 1 y 1 )-4 -

(trifluoromethyl)benzenesulfonimidoyl chloride in CHCh (4 mL, 0.06M, 0.24 mmol, 1.0 equiv.) was added liT-indol-3 -amine (55.4 mg, 0.4 mmol, 1.5 equiv). The resulting solution was stirred for 30 min at room temperature and concentrated in vacuo. The crude product was purified by Prep-HPLC using Method G, to give N-(tert- butyl di ethyl si 1 yl )-A-( 1 //-i ndol -3 -yl )oromethyl ) benzene- 1-sulfonoimidamide (36 mg,

28.40%) as a white solid. LCMS: Method B, MS-ESI: 454.2 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO-r¾): d 10.84 (s, 1H), 9.07 (s, 1H), 7.87 (d, 2H), 7.81 (d, 2H), 7.25-7.22 (m, 2H), 6.99 (t, 1H), 6.90 (d, 1H), 6.83-6.79 (m, 1H), 0.90 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H). Step 2: A '-(l/ -indol-3-yl)-4-(trifluoromethyl)benzenesulfonimidamide

A ^f -(/<3/7-butyl dimethyl si lyl)-A-( l //-indol -3 -yl)-4-(trifluoromethyl)benzene- l - sulfonoimidamide (150.0 mg, 0.3 mmol, 1.0 equiv) was dissolved in THF (6.0 mL) and water (3.0 mL), HF -Pyridine (70% wt., 0.1 mL) was added. The resulting solution was stirred for 4 hours at ambient temperature. The pH value of the solution was adjusted to 7 with aqueous NH4CO3 solution. The resulting solution was extracted with DCM and the combined organic layer was concentrated in vacuo. The crude product was purified by Prep-HPLC, using Method H, to give A ^f -( 1 //-indol -3 -yl)-4-(trifluoromethyl (benzene -1 -sulfonoimidamide (26.3 mg, 23.44%) as a white solid. LCMS: Method B, MS-ESI: 340.1 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO-r¾): 5¾-NMR (400 MHz, DMSO) d 10.53 (brs, 1H), 8.09 (d, 2H), 7.88 (d, 2H), 7.48 (brs, 1H), 7.23 (d, 1H), 7.01-6.97 (m, 1H), 6.88-6.85 (m, 2H).

The analogs prepared in Table 5 were prepared using the same method described for Example 2.

Table 5

Example 3: (S or /?)-/V-(lH-indol-3-yl)-4-(trifluoromethyl)benzenesulfonimida mide [front peak, unconfirmed stereochemistry] (Compound la) and (R or -/V-(lH- indol-3-yl)-4-(trifluoromethyl)benzenesulfonimidamide [second peak, unconfirmed stereochemistry] (Compound lb)

The racemic compound was resolved by Prep chiral HPLC with the following conditions: Column: CHIRALPAK IC, 3*25cm,5um ; Mobile Phase A:Hex(8mmol/L NH3 MeOH)— HPLC, Mobile Phase B:IPA— HPLC; Flow rate:45 mL/min; Gradient:30 B to 30 B in 20 min; 254/220 nm; RT1 :7.5; RT2: 10.5. This resulted in (S)-JV-(lJ7-indol-3- yl)-4-(trifluoromethyl)benzenesulfonimidamide (25 mg, 33.53%) as a white solid and (R)- /V-( l//-indol -3 -yl)-4-(trifl uorom ethyl )benzenesulfoni midamide (24 mg, 32.93%) as a white solid.

Compound la: LCMS: Method F, MS-ESI: 340.1 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO- d ₆ ): d 10.51 (s, 1H), 8.09-8.01 (m, 2H), 7.97-7.93 (m, 2H), 7.49 (brs, 1H), 7.23-7.20 (m, 1H), 6.99-6.96 (m, 1H), 6.89-6.83 (m, 2H).

Compound lb: LCMS: Method F, MS-ESI: 340.1 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO- d ₆ ): d 10.51 (s, 1H), 8.09-8.01 (m, 2H), 7.97-7.93 (m, 2H), 7.49 (brs, 1H), 7.23-7.20 (m, 1H), 6.99-6.96 (m, 1H), 6.89-6.83 (m, 2H).

The analogs prepared in Table 6 were prepared using the same method from racemic mixture as described for Example 3.

Table 6

Example 4: methyl (/V-(l//-indol-3-yl)-4- (trifluoromethyl)phenylsulfonimidoyl)carbamate (Compound 107)

A ^f -( l //-indol -3 -yl)-4-(trifluorom ethyl )benzenesulfonoi midamide (100 mg, 0.3 mmol, 1.0 equiv) and TEA (59.6 mg, 0.6 mmol, 2.0 equiv) were dissolved in CEECN (10.0 mL), then methyl chloroformate (41.7 mg, 0.4 mmol, 1.5 equiv) was added and stirred for 2 hours at ambient temperature. The resulting mixture was concentrated in vacuo. The residue was purified by Prep-HPLC using Method H, to give methyl (N-(\H- indol-3-yl)-4-(trifluoromethyl)phenylsulfonimidoyl)carbamate (14 mg, 12.0%) as a white solid. LCMS: Method K, MS-ESI: 398.1 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO- d ₆ ): d 10.91 (s, 1H), 10.47-10.42 (m, 1H), 7.95 (d, 2H), 7.86 (d, 2H), 7.30-7.24 (m, 2H),

7.02-6.97 (m, 2H), 6.87-6.84 (m, 1H), 3.74(s, 3H).

The following compounds were prepared using the same method described for Example 4.

Example 5: /V ^, -(l//-indol-3-yl)-/V-methyl-4- (trifluoromethyl)benzenesulfonimidamide (Compound 112)

A ^f -( l //-i ndol -3 -yl)-4-(trifluoromethyl)benzenesulfonoi midamide (140.0 mg, 0.4 mmol, 1.0 equiv.) and CS2CO3 (134.4 mg, 0.4 mmol, 1.0 equiv.) were dissolved in THF (20.0 mL). This was followed by the addition of CH3I (0.1 mL, 1.2 mmol, 3.00 equiv) with stirring at 0 °C. The resulting solution was stirred for 2 hours at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with DCM and the organic layer was concentrated in vacuo. The residue was purified by Prep-HPLC using Method G, to give N-( 1 //-i ndol -3 -yl )-A ^f -m ethyl -4- (trifluoromethyl) benzenesulfonoimidamide (18 mg, 12.35%) as a off-white solid. LCMS: Method B, MS-ESI: 354.1 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO-^): d 11.04 (s, 1H), 7.87 (s, 4H), 7.31 (d, 1H), 7.09 (d, 1H), 7.02 (t, 1H), 6.88 (d, 1H), 6.79 (t, 1H), 4.80

(s, 1H), 3.22 (s, 3H).

Example 6: /V'-(Li/-indol-3-yl)-/V,/V-dimethyl-4- (trifluoromethyl)benzenesulfonimidamide (Compound 36) and /V-methyl-/V'-(l- methyl-lH-indol-3-yl)-4-(trifluoromethyl)benzenesulfonimidam ide (Compound 105)

A ^f -( l //-i ndol -3 -yl)-4-(trifluoromethyl)benzenesulfoni ida ide (200.0 mg, 0.6 mmol, 1.0 equiv.) and CS2CO3 (576.0 mg, 1.7 mmol, 3.0 equiv.) were dissolved in CH3CN (10.0 mL), then Mel (0.2 mL, 2.9 mmol, 5.0 equiv.) was added. The resulting solution was stirred for 3 hours at ambient temperature. The resulting mixture was concentrated. The residue was purified by Prep-HPLC using Method G to give N-(1H- indol -3 -yl)-A(A ^f -di methyl -4-(trifluoromethyl)benzenesulfonoi midamide (14 mg, 6.5%) and A-m ethyl -/V-(l-methylindol-3-yl)-4-(trifluorom ethyl )benzenesulfonoimidamide (40 mg, 18.5%) as a yellow solid.

Compound 36: LCMS Method E, MS-ESI: 368.1 [M+H] ⁺ . ¾ NMR (400 MHz, DMSO-i/e): d 10.60 (s, 1H), 8.22 (d, 2H), 8.05 (d, 2H), 7.68 (d, 1H), 7.29 (d, 1H), 7.05 (t, 1H), 7.00-6.94 (m, 2H), 2.66 (s, 6H).

Compound 105: LCMS Method B, MS-ESI: 366.0 [M-H] . ¾ NMR (300 MHz, DMSO-i/e): d 7.87 (s, 4H), 7.39 (d, 1H), 7.18 (s, 1H), 7.13-7.08 (m, 1H), 6.87-6.81 (m, 2H), 3.73 (s, 3H), 3.23 (s, 3H).

Biological Assays

STING pathway modulation by the compounds described herein was measured using THPl-Dual™ cells (KO-IFNAR2).

THPl-Dual™ KO-IFNAR2 Cells (obtained from invivogen) were maintained in RPMI, 10% FCS, 5 ml P/S, 2mM L-glut, lOmM 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 mM. Cells were plated into the TC plates at 40 pL 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 x384 plate:

o Solution A: 2 mL Optimem with one of the following stimuli:

60 uL of 10 mM 2'3 'cGAMP -> 150 pM stock o Solution B: 2 mL Optimem with 60 pL 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 pL of transfection solution (A+B) was added on top of the plated cells, with a final T 3’ cGAMP concentration of 15 pM. The plates were then centrifuged immediately at 340 g for 1 minute, after which they were incubated at 37 °C, 5% CO2 _, >98% humidity for 24h. Luciferase reporter activity was then measured. EC50 values were calculated by using standard methods known in the art.

Luciferase reporter assay: 10 pL 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 pL of QLC Stabilizer per 25 mL of QUANTI- Luc™ Plus solution was added. 50 pL 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. EC ₅₀ or IC ₅₀ values were calculated by using standard methods known in the art.

Table BA shows the activity of compounds in STING reporter assay: <0.008 pM = “++++++”; >0.008 and <0.04 pM =“+++++”; >0.04 and <0.2 pM =“++++”; >0.2 and <1 pM =“+++”; >1 and <5 pM =“++”; >5 and <100 pM =“+”.

Table BA.