Compounds and Compositions for Treating Conditions Associated with STING Activity

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Serial No. 63/052,080, filed on July 15, 2020 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 Z, Y ¹ , Y ² , Y ³ , X ¹ , X ² , R ⁶ , Ring B, L ^A , al, and Ring C can be as defined anywhere herein.

In one aspect, compounds of Formula (II), or a pharmaceutically acceptable salt thereof, are featured: in which X ¹ , X ² , R ⁶ , Ring B, L ^A , al, and Ring C can be as defined anywhere herein.

In one aspect, compounds of Formula (III), or a pharmaceutically acceptable salt thereof, are featured: in which R ^1a , R ^1b , R ^1c , X ¹ , X ² , R ⁶ , Ring B, L ^A , al, and Ring C 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 subject in need thereof are featured that include administering to the subject an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).

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

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

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

In another aspect, there is provided is a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein, for use in the treatment of a disease, condition or disorder modulated by STING inhibition. In another aspect, there is provided a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for use in the treatment of a condition, disease or disorder associated with increased (e.g., excessive) STING activation.

In another aspect, there is provided a compound, or a pharmaceutically acceptable salt or tautomer thereof, described herein for use in the treatment of cancer.

In another aspect, there is provided a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for use in the treatment of cancer selected from the group consisting of 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 another aspect, there is provided a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for use in the treatment of type I interferonopathies.

In another aspect, there is provided a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for use in the treatment of type I interferonopathies selected from 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 another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein in the manufacture of a medicament for the treatment of a condition, disease or disorder associated with increased (e.g., excessive) STING activation.

In another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein in the manufacture of a medicament for the treatment of cancer.

In another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein in the manufacture of a medicament for the treatment of cancer selected from the group consisting of 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 another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein in the manufacture of a medicament for the treatment of type I interferonopathies.

In another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for use in the manufacture of a medicament for the treatment of type I interferonopathies selected from 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 another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein, for the treatment of a disease, condition or disorder modulated by STING inhibition.

In another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for the treatment of a condition, disease or disorder associated with increased (e.g., excessive) STING activation.

In another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for the treatment of cancer.

In another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for the treatment of cancer selected from the group consisting of 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 another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for the treatment of type I interferonopathies.

In another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for the treatment of type I interferonopathies selected from STING-associated vasculopathy with onset in infancy (SAVI)), Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, and inflammation- associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis.

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 topoisom erase; 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 antihelminthic 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, 4-1BB-4-1BB 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, HVEM-BTL A-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 et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed !; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed !; Gibson Ed.; CRC Press LLC: Boca Raton, 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, N-m ethyl -D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acichorganic 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 saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C _1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, Ao-propyl, tert-butyl, «-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.

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

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

The term "alkylene" refers to a divalent alkyl (e.g., -CH2-).

The term "alkenyl" refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C _2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkenyl groups can either be unsubstituted or substituted with one or more substituents.

The term "alkynyl" refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C _2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups can either be unsubstituted or substituted with one or more substituents.

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

The term "cycloalkyl" as used herein refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl includes: bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[l.l.l]pentanyl, bicyclo[3.1.Ojhexanyl, bicyclo[2.1.1 jhexanyl, bicyclo[3 2.0]heptanyl, bicyclo[4.1.Ojheptanyl, bicyclo[2.2. ljheptanyl, bicyclo[3.1.ljheptanyl, bicyclo[4.2.0]octanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, 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]pentanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[2.6]nonanyl, spiro[4.5]decanyl, spiro[3.6]decanyl, spiro[5.5]undecanyl, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms.

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

The term “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, and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). 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-d]pyrimidinyl, pyrrolo[2,3- 6]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-6]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-/>]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[7>][l,4]dioxinyl, benzo[d][l,3]dioxolyl, 2,3- dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[Z>][l,4]oxathiinyl, isoindolinyl, 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 saturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of 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]butanyl, 2-azabicyclo[2.1.0]pentanyl, 2- azabicyclo[l.l.l]pentanyl, 3-azabicyclo[3.1.0]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3- azabicyclo[3.2.0]heptanyl, octahydrocyclopenta[c]pyrrolyl, 3-azabicyclo[4.1.0]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 7-azabicyclo[4.2.0]octanyl, 2- azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl, 2-oxabicyclo[1.1.0]butanyl, 2- oxabicyclo[2.1.0]pentanyl, 2-oxabicyclo[l.l.l]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, 5- oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.2.0]heptanyl, 3-oxabicyclo[4.1.0]heptanyl, 7- oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 7-oxabicyclo[4.2.0]octanyl, 2- oxabicyclo[2.2.2]octanyl, 3-oxabicyclo[3.2.1]octanyl, 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]pentanyl, 4-azaspiro[2.5]octanyl, l-azaspiro[3.5]nonanyl, 2- azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[4.4]nonanyl, 6- azaspiro[2.6]nonanyl, l,7-diazaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl, 2,5- diazaspiro[3.6]decanyl, 3-azaspiro[5.5]undecanyl, 2-oxaspiro[2.2]pentanyl, 4- oxaspiro[2.5]octanyl, l-oxaspiro[3.5]nonanyl, 2-oxaspiro[3.5]nonanyl, 7- oxaspiro[3.5]nonanyl, 2-oxaspiro[4.4]nonanyl, 6-oxaspiro[2.6]nonanyl, 1,7- dioxaspiro[4.5]decanyl, 2,5-dioxaspiro[3.6]decanyl, l-oxaspiro[5.5]undecanyl, 3- oxaspiro[5.5]undecanyl, 3-oxa-9-azaspiro[5.5]undecanyl and the like. The term “saturated” as used in this context means only single bonds present between constituent ring atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.

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

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

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

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

In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ¹³ C and ¹⁴ C.

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

. Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms. 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, the disclosure features compounds of Formula I:

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

Z, Y ¹ , Y ² , and Y ³ are independently selected from the group consisting of CR ¹ , C(=O), N, and NR ² ;

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

X ² is selected from the group consisting of O, S, N, NR ⁴ , and CR ⁵ ; provided that when each one of Z, Y ¹ , and Y ² is CR ¹ , then Y ³ cannot be N, or when each one of Z, Y ¹ , Y ² , and Y ³ is CR ¹ , then at least one R ¹ is other than H; each — is independently a single bond or a double bond, provided that the five- membered ring comprising X ¹ and X ² is heteroaryl, and that the six-membered ring comprising Z, Y ¹ , Y ² , and Y ³ is aryl or heteroaryl; each R ¹ is independently selected from the group consisting of: H; R ^c ; R ^g ; and -

(L ¹ ) _b1 -R ^g ; each R ² is independently selected from the group consisting of: H; R ^d ; R ^g ; and -

(L ² ) _b2 -R ^g ;

R ⁴ is selected from the group consisting of: H and R ^d ;

R ⁵ is selected from the group consisting of: H; R ^c ; and R ^h ;

R ⁶ is selected from the group consisting of: H; R ^d ; and R ^h ;

Ring B is a heteroarylene of 5 ring atoms, wherein 1-4 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(R ^d ), O, and S, wherein the heteroarylene of Ring B is optionally substituted with 1-2 substituents independently selected from the group consisting of: oxo and R ^c , provided that Ring B is attached to the C(=O)NR ⁶ group via a ring carbon atom; each L ^A is independently selected from the group consisting of: C _1-3 alkylene optionally substituted with 1-4 R ^a1 ; -O-; -NH-; -NR ^d _; -S(O) _0-2 ; and C(O); al is 0, 1, 2, or 3;

Ring C is selected from the group consisting of:

• C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R ^c ;

• heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R ^c ; • heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R ^c ; and

• C _6-10 aryl optionally substituted with 1-4 R ^c ; each occurrence of R ^a and R ^a1 is independently selected from the group consisting of: -OH; -halo; -NR ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)O(C _1-4 alkyl); -C(=O)(C _1-4 alkyl); -C(=O)OH; -CONR’R”; -S(O) _1-2 NR’R”; -S(O) _1-2 (C _1-4 alkyl); and cyano; each occurrence of R ^c is independently selected from the group consisting of: halo; cyano; C _1-10 alkyl which is optionally substituted with 1-6 independently selected R ^a ; C _2-6 alkenyl; C _2-6 alkynyl; C _1-4 alkoxy; C _1-4 haloalkoxy; -S(O) _1-2 (C _1-4 alkyl); -S(O)(=NH)(C _1-4 alkyl); -NR ^e R ^f ; -OH; -S(O) _1-2 NR’R”; -C _1-4 thioalkoxy; -NO ₂ ; -C(=O)(C _1-10 alkyl); - C(=O)O(C _1-4 alkyl); -C(=O)OH; -C(=O)NR’R”; and -SF ₅ ; each occurrence of R ^d is independently selected from the group consisting of: C _1-6 alkyl optionally substituted with 1-3 independently selected R ^a ; -C(O)(C _1-4 alkyl); - C(O)O(C _1-4 alkyl); -CONR’R”; -S(O) _1-2 NR’R”; - S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; each occurrence of R ^e and R ^f is independently selected from the group consisting of: H; C _1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR’R”, -OH, and R ⁱ ; -C(O)(C _1-4 alkyl); -C(O)O(C _1-4 alkyl); -CONR’R”; -S(O) _1-2 NR’R”; - S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; each occurrence of R ^g is independently selected from the group consisting of:

• C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R ^c , R ^h , and -(L ^g ) _bg ,-R ^h ;

• heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R ^c , R ^h , and -(L ^g ) _bg -R ^h ;

• heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h ; and

• C _6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h ; each occurrence of R ^h is independently selected from the group consisting of:

• C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each of which is optionally substituted with 1-4 R ⁱ ;

• heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 R ⁱ ;

• heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R ⁱ ; and

• C _6-10 aryl optionally substituted with 1-4 R ⁱ ; each occurrence of R ⁱ is independently selected from the group consisting of: C _1-6 alkyl; C _1-4 haloalkyl; C _1-4 alkoxy; C _1-4 haloalkoxy; C _1-6 alkyl-O-C _1-6 alkyl-; C _1-4 haloalkyl- O-C _1-6 alkyl-; halo; cyano; -OH; -NR’R”; and C3-6 cycloalkyl; each occurrence of L ¹ , L ² , and L ^g is independently selected from the group consisting of: -O-, -NH-, -NR ^d , -S(O) _0-2 , C(O), and C _1-3 alkylene optionally substituted with 1-3 R ^a ; bl, b2, and bg are each independently 1, 2, or 3; and each occurrence of R’ and R” is independently selected from the group consisting of: H; -OH; and C _1-4 alkyl.

In some embodiments of Formula (I), it is provided that one or more of the compound provisions herein apply.

In another aspect, provided herein is a compound of Formula II:

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

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

X ² is selected from the group consisting of O, S, N, NR ⁴ , and CR ⁵ ; each — is independently a single bond or a double bond, provided that the five- membered ring comprising X ¹ and X ² is heteroaryl;

R ¹ is selected from the group consisting of: H; R ^c ; R ^g ; and -(L ¹ ) _b1 -R ^g ;

R ² is selected from the group consisting of: H; R ^d ; R ^g ; and -(L ² ) _b2 -R ^g ;

R ⁴ is selected from the group consisting of: H and R ^d ;

R ⁵ is selected from the group consisting of: H; R ^c ; and R ^h ;

R ⁶ is selected from the group consisting of: H; R ^d ; and R ^h ;

Ring B is a heteroarylene of 5 ring atoms, wherein 1-4 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(R ^d ), O, and S, wherein the heteroarylene of Ring B is optionally substituted with 1-2 substituents independently selected from the group consisting of: oxo and R ^c , provided that Ring B is attached to the C(=O)NR ⁶ group via a ring carbon atom; each L ^A is independently selected from the group consisting of: C _1-3 alkylene optionally substituted with 1-4 R ^a1 ; -O-; -NH-; -NR ^d _; -S(O) _0-2 ; and C(O); al is 0, 1, 2, or 3;

Ring C is selected from the group consisting of:

• C _3-12 cycloalkylene or C _3-12 cycloalkenylene, each optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R ^c ,

• heterocyclylene or heterocycloalkenylene of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R ^c ,

• heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroarylene is optionally substituted with 1-4 R ^c ; and

• C _6-10 aryl optionally substituted with 1-4 R ^c ; each occurrence of R ^a and R ^a1 is independently selected from the group consisting of: -halo; -NR ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)O(C _1-4 alkyl); -C(=O)(C _1-4 alkyl); -C(=O)OH; -CONR’R”; -S(O) _1-2 NR’R”; -S(O) _1-2 (C _1-4 alkyl); and cyano; each occurrence of R ^c is independently selected from the group consisting of: halo; cyano; C _1-10 alkyl which is optionally substituted with 1-6 independently selected R ^a ; C _2-6 alkenyl; C _2-6 alkynyl; C _1-4 alkoxy; C _1-4 haloalkoxy; -S(O) _1-2 (C _1-4 alkyl); -S(O)(=NH)(C _1-4 alkyl); -NR ^e R ^f ; -OH; -S(O) _1-2 NR’R”; -C _1-4 thioalkoxy; -NO ₂ ; -C(=O)(C _1-10 alkyl); - C(=O)O(C _1-4 alkyl); -C(=O)OH; -C(=O)NR’R”; and -SF ₅ ; each occurrence of R ^d is independently selected from the group consisting of: C _1-6 alkyl optionally substituted with 1-3 independently selected R ^a ; -C(O)(C _1-4 alkyl); - C(O)O(C _1-4 alkyl); -CONR’R”; -S(O) _1-2 NR’R”; - S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; each occurrence of R ^e and R ^f is independently selected from the group consisting of: H; C _1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR’R”, -OH, and R ⁱ ; -C(O)(C _1-4 alkyl); -C(O)O(C _1-4 alkyl); -CONR’R”; -S(O) _1-2 NR’R”; -S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; each occurrence of R ^g is independently selected from the group consisting of:

• C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R ^c , R ^h , and -(L ^g ) _bg -R ^h ;

• heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R ^c , R ^h , and -(L ^g ) _bg -R ^h ;

• heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h ; and

• C _6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h ; each occurrence of R ^h is independently selected from the group consisting of:

• C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each of which is optionally substituted with 1-4 R ⁱ ;

• heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 R ⁱ ;

• heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R ⁱ ; and

• C _6-10 aryl optionally substituted with 1-4 R ⁱ ; each occurrence of R' is independently selected from the group consisting of: C _1-6 alkyl; C _1-4 haloalkyl; C _1-4 alkoxy; C _1-4 haloalkoxy; C _1-6 alkyl-O-C _1-6 alkyl-; C _1-4 haloalkyl- O-C _1-6 alkyl-; halo; cyano; -OH; -NR’R”; and C3-6 cycloalkyl; each occurrence of L ¹ , L ² , and L ^g is independently selected from the group consisting of: -O-, -NH-, -NR ^d , -S(O) _0-2 , C(O), and C _1-3 alkylene optionally substituted with 1-3 R ^a ; bl, b2, and bg are each independently 1, 2, or 3; and each occurrence of R’ and R” is independently selected from the group consisting of: H; -OH; and C _1-4 alkyl.

In some embodiments of Formula (II), it is provided that:

1) Ring C is other than: unsubstituted morpholinyl, unsubstituted pyrrolidinyl, unsubstituted tetrahydrofuranyl, unsubstituted cyclopentyl, monosub stituted oxetanyl, methylfuranyl, unsubstituted thiophenyl, or methylpyrrolyl; or

2) -(L ^A ) _a1 -Ring C is other than: unsubstituted benzyl or phenyl that is optionally substituted with one substituent selected from the group consisting of: -F, -OMe, and -OEt.

In some embodiments of Formula (II), it is provided that one or more of the compound provisions herein apply.

In another aspect, provided herein is a compound of Formula III

Formula III or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein: X ¹ is selected from the group consisting of O, S, N, NR ² , and CR ¹ ;

X ² is selected from the group consisting of O, S, N, NR ⁴ , and CR ⁵ ; each — is independently a single bond or a double bond, provided that the five- membered ring comprising X ¹ and X ² is heteroaryl;

R ¹ , R ^1a , R ^1b , and R ^1c are each independently selected from the group consisting of: H;R ^c ; R ^g ; and -(L ¹ ) _b1 -R ^g ;

R ² is independently selected from the group consisting of: H; R ^d ; R ^g ; and -(L ² ) _b2 -

R ^g ;

R ⁴ is selected from the group consisting of: H and R ^d ;

R ⁵ is selected from the group consisting of: H; R ^c ; and R ^h ;

R ⁶ is selected from the group consisting of: H; R ^d ; and R ^h ;

Ring B is a heteroarylene of 5 ring atoms, wherein 1-4 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(R ^d ), O, and S, wherein the heteroarylene of Ring B is optionally substituted with 1-2 substituents independently selected from the group consisting of: oxo and R ^c , provided that Ring B is attached to the C(=O)NR ⁶ group via a ring carbon atom; each L ^A is independently selected from the group consisting of: C _1-3 alkylene optionally substituted with 1-4 R ^a1 ; -O-; -NH-; -NR ^d _; -S(O) _0-2 ; and C(O); al is 0, 1, 2, or 3;

Ring C is selected from the group consisting of:

• C _3-12 cycloalkylene or C _3-12 cycloalkenylene, each optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R ^c ,

• heterocyclylene or heterocycloalkenylene of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R ^c , • heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroarylene is optionally substituted with 1-4 R ^c ; and

• C _6-10 arylene optionally substituted with 1-4 R ^c ; each occurrence of R ^a and R ^a1 is independently selected from the group consisting of: -halo; -NR ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)O(C _1-4 alkyl); -C(=O)(C _1-4 alkyl); -C(=O)OH; -CONR’R”; -S(O) _1-2 NR’R”; -S(O) _1-2 (C _1-4 alkyl); and cyano; each occurrence of R ^c is independently selected from the group consisting of: halo; cyano; C _1-10 alkyl which is optionally substituted with 1-6 independently selected R ^a ; C _2-6 alkenyl; C _2-6 alkynyl; C _1-4 alkoxy; C _1-4 haloalkoxy; -S(O) _1-2 (C _1-4 alkyl); -S(O)(=NH)(C _1-4 alkyl); -NR ^e R ^f ; -OH; -S(O) _1-2 NR’R”; -C _1-4 thioalkoxy; -NO ₂ ; -C(=O)(C _1-10 alkyl); - C(=O)O(C _1-4 alkyl); -C(=O)OH; -C(=O)NR’R”; and -SF ₅ ; each occurrence of R ^d is independently selected from the group consisting of: C _1-6 alkyl optionally substituted with 1-3 independently selected R ^a ; -C(O)(C _1-4 alkyl); - C(O)O(C _1-4 alkyl); -CONR’R”; -S(O) _1-2 NR’R”; - S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; each occurrence of R ^e and R ^f is independently selected from the group consisting of: H; C _1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR’R”, -OH, and R ⁱ ; -C(O)(C _1-4 alkyl); -C(O)O(C _1-4 alkyl); -CONR’R”; -S(O) _1-2 NR’R”; - S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; each occurrence of R ^g is independently selected from the group consisting of:

• C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R ^c , R ^h , and -(L ^g ) _bg ,-R ^h ;

• heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R ^c , R ^h , and -(L ^g ) _bg -R ^h ;

• heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h ; and

• C _6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h ; each occurrence of R ^h is independently selected from the group consisting of:

• C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each of which is optionally substituted with 1-4 R ⁱ ;

• heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 R ⁱ ;

• heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R ⁱ ; and

• C _6-10 aryl optionally substituted with 1-4 R ⁱ ; each occurrence of R ⁱ is independently selected from the group consisting of: C _1-6 alkyl; C _1-4 haloalkyl; C _1-4 alkoxy; C _1-4 haloalkoxy; C _1-6 alkyl-O-C _1-6 alkyl-; C _1-4 haloalkyl- O-C _1-6 alkyl-; halo; cyano; -OH; -NR’R”; and C3-6 cycloalkyl; each occurrence of L ¹ , L ² , and L ^g is independently selected from the group consisting of: -O-, -NH-, -NR ^d , -S(O) _0-2 , C(O), and C _1-3 alkylene optionally substituted with 1-3 R ^a ; bl, b2, and bg are each independently 1, 2, or 3; and each occurrence of R’ and R” is independently selected from the group consisting of: H; -OH; and C _1-4 alkyl.

In some embodiments of Formula (III), it is provided that when Ring B is unsubstituted wherein aa is the point of connection to (L ^A ) _a1 ; and (L ^A ) _a1 is unsubstituted CH2, then Ring C is other than unsubstituted pyridyl, unsubstituted pyrrolyl, or phenyl which is optionally substituted with one substituent selected from the group consisting of: -F, -Cl, -Me, -OMe, or -CN.

In some embodiments of Formula (III), it is provided that one or more of the compound provisions herein apply.

The Variables Z, Y ¹ , Y ² , Y ³ , X ¹ , and X ²

In some embodiments of Formula (I), each of Z, Y ¹ , Y ² , and Y ³ is independently N or CR ¹ .

In some embodiments, the compound of Formula (I) is a compound of Formula

(la):

Formula (la) or a pharmaceutically acceptable salt thereof, wherein: R ^1a , R ^1b , R ^1c , and R ^1d are each an independently selected R ¹ .

In some embodiments of Formula (I), one of Z, Y ¹ , and Y ² is N; and each remaining one of Z, Y ¹ , Y ² , and Y ³ is an independently selected CR ¹ . In some embodiments, the compound of Formula (I) is selected from the group consisting of a compound of the following formulae: or a pharmaceutically acceptable salt thereof, wherein: R ^1a , R ^1b , R ^1c , and R ^1d are each an independently selected R ¹ .

In certain of these embodiments, the compound of Formula (I) is a compound of Formula (lb) or a pharmaceutically acceptable thereof.

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

(Ic) or a pharmaceutically acceptable thereof.

In certain embodiments, the compound of Formula (I) is a compound of Formula (Id) or a pharmaceutically acceptable thereof.

In some embodiments of Formulae (I), (II), or (III), X ¹ is NR ² . In certain of these embodiments, X ¹ is NH.

In some embodiments of Formulae (I), (II), or (III), X ² is CR ⁵ . In certain of these embodiments, X ² is CH.

In some embodiments of Formulae (I), (II), or (III), X ¹ is NR ² ; and X ² is CR ⁵ . In certain of these embodiments, X ¹ is NH; and X ² is CH.

In some embodiments, the compound of Formula (I) is a compound of Formula

(la-1):

Formula (la-1) or a pharmaceutically acceptable salt thereof, wherein: R ^1a , R ^1b , R ^1c , and R ^1d are each an independently selected R ¹ .

In some embodiments, the compound of Formula (I) is selected from the group consisting of a compound of the following formulae: or a pharmaceutically acceptable salt thereof, wherein: R ^1a , R ^1b , R ^1c , and R ^1d are each an independently selected R ¹ .

In certain of these embodiments, the compound of Formula (I) is a compound of Formula (Ib-1), or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is a compound of Formula (Ic-1), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is a compound of Formula

(Id-1), or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II) is a compound of Formula

(II-l)

Formula (II- 1) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III) is compound of a compound of Formula (III-l):

Formula (PI-1) or a pharmaceutically acceptable salt thereof.

In some embodiments of Formulae (la-1), (Ib-1), (Ic-1), (I-dl), (P-l), or (III-l), R ² is H. In some embodiments of Formulae (la-1), (Ib-1), (Ic-1), (I-dl), (P-l), or (III-l), R ⁵ is H. In certain of these embodiments, R ² is H; and R ⁵ is H.

The Variables R ¹ , R ^1a , R ^1b , R ^1c , and R ¹⁽¹

In some embodiments of Formula (I), from 1-2 R ¹ is independently selected from the group consisting of: R ^c1 and R ^g1 ; and each remaining R ¹ is H, wherein R ^c1 is an independently selected R ^c ; and R ^g1 is an independently selected R ^g .

In certain of these embodiments, two occurrences of R ¹ are independently selected from the group consisting of: R ^c1 and R ^g1 ; and each remaining R ¹ is H. In certain embodiments, two occurrences of R ¹ are independently selected R ^c1 ; and each remaining R ¹ is H. In certain embodiments, one occurrence of R ¹ is selected from the group consisting of: R ^c1 and R ^g1 ; and each remaining R ¹ is H. In certain embodiments, one occurrence of R ¹ is R ^c1 ; and each remaining R ¹ is H. In certain embodiments, one occurrence of R ¹ is R ^g1 ; and each remaining R ¹ is H. In certain embodiments, one occurrence of R ¹ is R ^c1 ; one occurrence of R ¹ is R ^g1 ; and each remaining R ¹ is H.

In certain embodiments, each R ^c1 is an independently selected halo, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, or C _1-3 alkyl substituted with from 1-6 independently selected halo, such as wherein R ^c1 is -F, -Cl, or -CN. As non-limiting examples of the foregoing embodiments, each R ^c1 is independently -F or -Cl, such as -F.

In certain embodiments, each R ^g1 is independently selected from the group consisting of:

• heteroaryl of 5- 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, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h ; and

• C _6-10 aryl optionally substituted with from 1-4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h

In certain embodiments, each R ^g1 is independently selected from the group consisting of:

• heteroaryl of 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 is optionally substituted with from 1-4 R ^c ; and

• C ₆ aryl optionally substituted with from 1-4 R ^c .

In certain embodiments, each R ^g1 is independently heteroaryl of 5 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 is optionally substituted with from 1-4 R ^c .

In certain embodiments, each R ^g1 is pyrazolyl that is optionally substituted with from 1-2 R ^c , such from 1-2 independently selected C _1-6 (e.g., C _1-3 ) alkyl which is optionally substituted with from 1-6 independently selected R ^a (e.g., unsubstituted C _1-6 (e.g., C _1-3 ) alkyl). As a non-limiting example of the foregoing embodiments, R ^g1 can be and optionally R ^c is C _1-6 (e.g., C _1-3 ) alkyl which is optionally substituted with from 1-6 independently selected R ^a .

In certain embodiments, R ^g1 is phenyl optionally substituted with from 1-4 R ^c , such as phenyl optionally substituted with from 1-2 substituents each independently selected from the group consisting of: C _1-6 alkyl optionally substituted with from 1-6 R ^a ; -halo; - cyano; C _1-4 alkoxy; and C _1-4 haloalkoxy.

In certain embodiments, each R ^g1 is independently selected from the group consisting of:

• heteroaryl of 5- 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, and wherein the heteroaryl is substituted with one occurrence of R ^h1 or -(L ^g ) _bg -R ^h1 and further optionally substituted with from 1-2 R ^c ; and

• C _6-10 aryl that is substituted with one occurrence of R ^h1 or -(L ^g ) _bg -R ^h1 and further optionally substituted with from 1-2 R ^c , wherein R ^h1 is an independently selected R ^h .

In certain of these embodiments, each R ^g1 is heteroaryl of 5-6 (such as 5) 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 is substituted with one occurrence of R ^h1 or -(L ^g ) _bg -R ^h1 and further optionally substituted with from 1- 2 R ^c , wherein R ^h1 is an independently selected R ^h . As non-limiting examples of the foregoing embodiments, each R ^g1 can be pyrazolyl that is substituted with R ^h1 or -(L ^g ) _bg - R ^h1 (such as R ^h1 or -CFhR* ¹¹ ) and further optionally substituted with from 1-2 R ^c . For example, each R ^g1 can be , each of which is optionally substituted with R ^c . In certain embodiments, R ^h1 is selected from the group consisting of:

• heteroaryl of 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(O) _0-2 , and wherein the heteroaryl is optionally substituted with from 1-4 R ⁱ ; and

• Ce aryl optionally substituted with from 1-4 R ⁱ , such as wherein R ^g1 is phenyl optionally substituted with from 1-4 R ⁱ .

In certain embodiments, R ^h1 is selected from the group consisting of:

• heteroaryl of 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(O) _0-2 , and wherein the heteroaryl is optionally substituted with from 1-2 R ⁱ ; and

• Ce aryl optionally substituted with from 1-2 R ⁱ , such as wherein R ^g1 is phenyl optionally substituted with from 1-4 R ⁱ .

In some embodiments of Formulae (I), (lb), (Ib-1), (Ic), (Ic-1), (Id), (Id-1), (III), and (IP-1), each R ¹ is H.

In some embodiments of Formulae (la), (lb), (Ic), (la-1), (Ib-1), (Ic-1), (III), or, (III-l), R ^1a H

In some embodiments of Formulae (la), (lb), (Id), (la-1), (Ib-1), (Id-1), (III), or, (III-l), R ^1b is H

In some embodiments of Formulae (la), (lb), (Id), (la-1), (Ib-1), (Id-1), (III), or, (III-l), is halo, such as -F or -Cl (e.g., -F).

In some embodiments of Formulae (la), (lb), (Id), (la-1), (Ib-1), (Id-1), (III), or, (III-l), R ^1b is heteroaryl of 5 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 is optionally substituted with from 1-2 R ^c .

In some embodiments of Formulae (la), (lb), (Id), (la-1), (Ib-1), (Id-1), (III), or, (III-l), R ^1b is pyrazolyl that is optionally substituted with from 1-2 R ^c , such as each R ^c is an independently selected C _1-6 (e.g., C _1-3 ) alkyl which is optionally substituted with from 1-6 independently selected R ^a (e.g., unsubstituted). In some embodiments of Formulae (la), (lb), (Id), (la-1), (Ib-1), (Id-1), (III), or, (III-l), R ^1b is phenyl optionally substituted with from 1-4 R ^c , such as phenyl optionally substituted with from 1-2 substituents each independently selected from the group consisting of: C _1-6 alkyl optionally substituted with from 1-6 R ^a ; -halo; -cyano; C _1-4 alkoxy; and C _1-4 haloalkoxy.

In some embodiments of Formulae (la), (lb), (Id), (la-1), (Ib-1), (Id-1), (III), or, (III-l), R ^1b is heteroaryl of 5-6 (such as 5) 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 is substituted with one occurrence of R ^h1 or -(L ^g ) _bg -R ^h1 and further optionally substituted with from 1-2 R ^c , wherein R ^h1 is an independently selected R ^h . As non-limiting examples of the foregoing embodiments, R ^1b can be pyrazolyl that is substituted with R ^h1 or -(L ^g ) _bg -R ^h1 (such as R ^h1 or -CFhR* ¹¹ ) and further optionally substituted with from 1-2 R ^c , such as wherein R ^1b is , each of which is optionally substituted with R ^c .

In some embodiments of Formulae (la), (Ic), (Id), (la-1), (Ic-1), (Id-1), (III), or, (III-l), R ^1c is H. In some embodiments of Formulae (la), (Ic), (Id), (la-1), (Ic-1), (Id-1), (III), or, (III-l), R ^1c is halo, such as -F or -Cl.

In some embodiments of Formulae (la), (lb), (Ic), (Id), (la-1), (Ib-1), (Ic-1), or (Id-1), R ^1d is H. In some embodiments of Formulae (la), (lb), (Ic), (Id), (la-1), (Ib-1), (Ic-1), or (Id-1), R ^1d is halo, such as -F or -Cl (e.g., -F).

In some embodiments of Formulae (la), (lb), (Ic), (Id), (la-1), (Ib-1), (Ic-1), (Id- 1), (III), or (III-l), R ^1a and R ^1d when present are H; and R ^1b and R ^1c when present are independently selected halo, such as -F or -Cl, such as -F; such as: wherein R ^1b and R ^1c when present are -F; or wherein R ^1b when present is -F, and R ^1c when present is -Cl; or wherein R ^1b when present is -Cl, and R ^1c when present is -F. In some embodiments of Formulae (la), (lb), (Ic), (Id), (la-1), (Ib-1), (Ic-1), (Id- 1), (III), or (III-l), R ^1a and R ^1d when present are H; one of R ^1b and R ^1c when present is H; and the other one of R ^1b and R ^1c when present is halo, such as -F or -Cl, such as -F; such as: wherein R ^1b when present is H, and R ^1c when present is -F; or wherein R ^1b when present is H, and R ^1c when present is -Cl; or wherein R ^1b when present is -F, and R ^1c when present is H; or wherein R ^1b when present is -Cl, and R ^1c when present is H.

In some embodiments of Formulae (la), (lb), (Ic), (Id), (la-1), (Ib-1), (Ic-1), (Id- 1), (III), or (III-l), R ^1a and R ^1d when present are H; R ^1c when present is halo or H, such as -F, -Cl, or H; and R ^1b when present is heteroaryl of 5 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 is optionally substituted with from 1-4 R ^c .

In some embodiments of Formulae (la), (lb), (Ic), (Id), (la-1), (Ib-1), (Ic-1), (Id- 1), (III), or (III-l), R ^1a and R ^1d when present are H; R ^1c when present is halo or H, such as -F, -Cl, or H; and R ^1b when present is heteroaryl of 5-6 (such as 5) 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 is substituted with one occurrence of R ^h1 or -(L ^g ) _bg -R ^h1 (such as R ^h1 or -CFh-R* ¹¹ ) and further optionally substituted with from 1-2 R ^c , wherein R ^h1 is an independently selected R ^h .

In some embodiments of Formulae (la), (lb), (Ic), (Id), (la-1), (Ib-1), (Ic-1), (Id- 1), (III), or (III-l), R ^1a and R ^1d when present are H; R ^1c when present is halo or H, such as -F, -Cl, or H; and R ^1b when present is phenyl optionally substituted with from 1-4 R ^c , such as phenyl optionally substituted with from 1-2 substituents each independently selected from the group consisting of: C _1-6 alkyl optionally substituted with from 1-6 R ^a ; - halo; -cyano; C _1-4 alkoxy; and C _1-4 haloalkoxy.

In some embodiments of Formulae (la), (lb), (Ic), (Id), (la-1), (Ib-1), (Ic-1), (Id- 1), (III), or (III-l), R ^1a when present is H; R ^1d when present is halo, such as -F or -Cl; R ^1c when present is H; and R ^1b when present is R ^g .

In some embodiments of Formulae (la) or (la-1), R ^1a and R ^1d are H; and R ^1b and R ^1c are independently selected halo, such as -F or -Cl, such as -F; such as: wherein R ^1b and R ^1c are -F; or wherein R ^1b is -F, and R ^1c is -Cl; or wherein R ^1b is -Cl, and R ^1c is -F.

In some embodiments of Formulae (la) or (la-1), R ^1a and R ^1tl are H; one of R ^1b and R ^1c is H; and the other one of R ^1b and R ^1c is halo, such as -F or -Cl, such as -F; such as: wherein R ^1b is H, and R ^1c is -F; or wherein R ^1b is H, and R ^1c is -Cl; or wherein R ^1b is -F, and R ^1c is H; or wherein R ^1b is -Cl, and R ^1c is H.

In some embodiments of Formulae (la) or (la-1), R ^1a and R ^1d are H; R ^1c is halo or H, such as -F, -Cl, or H; and R ^1b is heteroaryl of 5 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 is optionally substituted with from 1-4 R ^c .

In some embodiments of Formulae (la) or (la-1), R ^1a and R ^1d are H; R ^1c is halo or H, such as -F, -Cl, or H; and R ^1b is heteroaryl of 5-6 (such as 5) 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 is substituted with one occurrence of R ^h1 or -(L ^g ) _bg -R ^h1 (such as R ^h1 or -CFh-R* ¹¹ ) and further optionally substituted with from 1-2 R ^c , wherein R ^h1 is an independently selected R ^h .

In some embodiments of Formulae (la) or (la-1), R ^1a and R ^1d are H; R ^1c is halo or H, such as -F, -Cl, or H; and R ^1b is phenyl optionally substituted with from 1-4 R ^c , such as phenyl optionally substituted with from 1-2 substituents each independently selected from the group consisting of: C _1-6 alkyl optionally substituted with from 1-6 R ^a ; -halo; - cyano; C _1-4 alkoxy; and C _1-4 haloalkoxy.

In some embodiments of Formulae (la), (lb), (Ic), (Id), (la-1), (Ib-1), (Ic-1), (Id- 1), (III), or (III-l), R ^1a is H; R ^1d is halo, such as -F or -Cl; R ^1c is H; and R ^1b is R ^g

The Variable R ⁶

In some embodiments, R ⁶ is H. The Variable Ring B

In some embodiments, Ring B is a heteroarylene of 5 ring atoms, wherein from 2- 3 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(R ^d ), O, and S, wherein the heteroarylene of Ring B is optionally substituted with from 1-2 R ^c , provided that Ring B is attached to the C(=O)NR ⁶ group via a ring carbon atom;

In certain of these embodiments, Ring B is selected from the group consisting of: pyrazolylene; imidazolylene; thiazolylene; oxazolylene; triazolylene such as 1,2,3- triazolylene or 1,2,4-triazolylene; isoxazolylene; and isothiazolylene, each of which is optionally substituted with R ^c ; and a ring nitrogen is optionally substituted with R ^d .

As non-limiting examples of the foregoing embodiments, Ring B can be pyrazolylene; imidazolylene; 1,2, 3 -triazolylene; 1,2,4-triazolylene, each of which is optionally substituted with R ^c ; and a ring nitrogen is optionally substituted with R ^d .

In some embodiments, Ring B has Formula B1 or B2:

B ⁴ is C or N;

B ¹ , B ² , and B ³ are each independently CH, CR ^C , NH, N(R ^d ), N, O, or S; provided that from 0-2 of B ¹ , B ² , and B ³ is CR ^C ; aa is the point of attachment to (L ^A ) _a1 ; and each ==is independently a single bond or a double bond provided that the ring including B'-B ⁴ is a heteroaryl.

In certain embodiments, Ring B has Formula Bl.

In certain embodiments of (Bl), B ⁴ is N. In certain embodiments, Ring B is: or example, Ring B can be

In certain embodiments, Ring wherein B ¹ and B ² are independently CH, CR ^C , NH, N(R ^d ), N, O, or S.

In certain of these embodiemnts, Ring B is or

In certain embodiments, Ring B is , wherein B ² and B ³ are independently CH, CR ^C , or N.

In certain of these embodiments, Ring B is or . As a non- limiting example of the foregoing embodiments, Ring B can be . As further a a non-limiting examples, Ring B can be or (e g _· , ). For example, Ring B can be . As further non-limiting examples, Ring B can be or . For example, Ring B can be

In certain embodiments of (Bl), B ⁴ is C.

In certain embodiments, Ring B is , wherein one of B ¹ and B ² is NH, NR ^d , O, or S; and the other one of B ¹ and B ² is N. In certain of these embodiments, B ³ is CH or CR ^C , such as CH. As non-limiting examples of these embodiments, Ring B each of which is further optionally substituted with R ^c (such as not further optionally substituted). In certain embodiments, Ring wherein one of B ¹ and B ³ is

NH, NR ^d , O, or S; and the other one of B ¹ and B ³ is N, wherein Ring B is further optionally substituted with R ^c . In certain embodiments, Ring wherein one of B ² and B ³ is

NH, NR ^d , O, or S; and the other one of B ² or B ³ is N, wherein Ring B is further optionally substituted with R ^c .

As non-limiting examples, Ring B can each of which is optionally substituted with R ^c (such as unsubstituted).

In certain embodiments, Ring B has Formula (B2). In certain embodiments of (B2),

B ⁴ is N. As non-limiting examples of the foregoing embodiments, Ring each of which is optionally substituted with R ^c (such as unsubstituted).

In certain embodiments, each R ^c substituent of Ring B is independently -OH; C _1-3 alkyl; C _1-3 alkyl optionally substituted with from 1-6 independently selected halo; halo; cyano; C _1-4 alkoxy; or C _1-4 haloalkoxy. The Variables L ^A and al

In some embodiments, al is 0. In some embodiments, al is 1.

In some embodiments, L ^A is C _1-3 alkylene optionally substituted with from 1-4 R ^a1 . In certain of these embodiments, L ^A is CH2 optionally substituted with from 1-2 R ^a1 . In certain embodiments, L ^A is C(H)Me optionally substituted with from 1-4 R ^a1 , such as wherein L ^A is C(H)Me. In certain embodiments, L ^A is CH2CH2.

In certain embodiments, al is 1; and L ^A is C _1-3 alkylene optionally substituted with from 1-4 R ^a1 . In certain of these embodiments, L ^A is CH2 optionally substituted with from 1-2 R ^a1 . In certain embodiments, L ^A is C(H)Me optionally substituted with from 1-4 R ^a1 , such as wherein L ^A is C(H)Me. In certain embodiments, L ^A is CH2CH2.

In certain embodiments, al is 2; and (L ^A ) _a1 is -L ^A1 -L ^A2 , wherein L ^A1 and L ^A2 are independently selected L ^A , and L ^A2 is the point of attachment to Ring C. In certain of these embodiments, L ^A1 is C _1-3 alkylene optionally substituted with from 1-4 R ^a1 , such as CH2, C(H)Me, or CH2CH2. In certain of the foregoing embodiments, L ^A2 is -O-.

The Variable Ring C

In some embodiments, Ring C is selected from the group consisting of:

• heteroaryl of 5-12 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(O) _0-2 , and wherein the heteroaryl is optionally substituted with from 1-4 R ^c ; and

• C _6-10 aryl optionally substituted with from 1-4 R ^c .

In some embodiments, Ring C is selected from the group consisting of:

• heteroaryl of 5-6 ring atoms, wherein from 1-3 (such as 1-2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroaryl is optionally substituted with from 1-4 R ^c ; and

• phenyl optionally substituted with from 1-4 R ^c . In certain embodiments, Ring C is , wherein Q ¹ , Q ² , Q ³ , Q ⁴ , and Q ⁵ are independently CH, CR ^C , or N, provided that at least two of Q'-Q ⁵ are CH

In certain of these embodiments, Q ³ is CR ^C . In certain embodiments, each one of Q ¹ , Q ² , Q ⁴ , and Q ⁵ is independently CH or CR ^C . As non-limiting examples of the foregoing embodiments, Ring C can be: , , or , such as . In certain embodiments, R ^c is C1-C4 haloalkyl (e.g., fluoroalkyl or perfluoroalkyl), e.g., C1-C2 haloalkyl (e.g., fluoroalkyl or perfluoroalkyl), e.g., C1 haloalkyl (e.g., fluoroalkyl or perfluoroalkyl), e.g., CF ₃ . In certain embodiments, one of Q ¹ and Q ² is N; and each remaining one of Q ¹ , Q ² ,

Q ⁴ , and Q ⁵ is independently CH or CR ^C . As non-limiting examples of the foregoing embodiments, Ring C is or

In certain embodiments, Q ² is CR ^C . In certain of these embodiments, each one of Q ¹ , Q ³ , Q ⁴ , and Q ⁵ is independently CH or CR ^C . As non-limiting examples of the foregoing embodiments, Ring C can be , or , such as

In certain embodiments, Q ² is CR ^C ; one of Q ¹ and Q ³ (such as Q ¹ ) is N; and each remaining one of Q ¹ , Q ³ , Q ⁴ , and Q ⁵ is independently CH or CR ^C . In certain of these embodiments, each one of Q ¹ , Q ² , Q ³ , Q ⁴ , and Q ⁵ is CH (i.e., Ring C is unsubstituted phenyl). In certain embodiments, one of Q ¹ and Q ² is N; and each remaining one of Q ¹ , Q ² ,

Q ³ , Q ⁴ , and Q ⁵ is CH, such as wherein Ring C is , or wherein Ring C is

In some embodiments, Ring C is selected from the group consisting of:

• C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R ^c , and

• heterocyclyl or heterocycloalkenyl of 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(O) _0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R ^c .

In certain of these embodiments, Ring C is selected from the group consisting of:

• C3-6 cycloalkyl optionally substituted with from 1-4 R ^c , and

• heterocyclyl of 4-6 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(O) _0-2 , and wherein the heterocyclyl is optionally substituted with from 1-4 R ^c .

In certain embodiments, Ring C is C3-6 cycloalkyl optionally substituted with from 1-2 R ^c , such as wherein Ring C is cyclohexyl; or wherein R ⁶ is cyclohexyl substituted with from 1-2 R ^c (e.g., halo).

In certain embodiments, each R ^c substituent of Ring C is selected from the group consisting of: halo; cyano; C _1-6 alkyl; C _1-6 alkyl substituted with from 1-6 R ^a ; C _1-4 alkoxy; and C _1-4 haloalkoxy. In certain of these embodiments, one occurrence of R ^c substituent of Ring C is C _1-6 alkyl or C _1-6 alkyl substituted with from 1-6 R ^a , such as C _1-6 alkyl substituted with from 1-6 independently selected halo, such as -F.

Non-Limiting Combinations

In some embodiments, the compound of Formula (I) is a compound of Formula

(Ia-1-1):

Formula (Ia-1-1) or a pharmaceutically acceptable salt thereof, wherein:

B ⁴ is C or N;

B ¹ , B ² , and B ³ are each independently CH, CR ^C , NH, N(R ^d ), N, O, or S; provided that from 0-2 of B ¹ , B ² , and B ³ is CR ^C ; each ==is independently a single bond or a double bond provided that the ring including B'-B ⁴ is a heteroaryl; and

Q ¹ , Q ² , Q ³ , Q ⁴ , and Q ⁵ are independently CH, CR ^C , or N, provided that from 2-5 of Q ⁴ -Q ⁵ are CH.

In some embodiments of Formula (Ia-1-1), R ² is H; and R ⁵ is H. In some embodiments of Formula (Ia-1-1), R ⁶ is H.

In some embodiments of Formula (Ia-1-1), R ^1a and R ^1tl are H; and R ^1b and R ^1c are independently selected halo, such as -F or -Cl, such as -F, such as: wherein R ^1b and R ^1c are -F; or wherein R ^1b is -F; and R ^1c is -Cl; or wherein R ^1b is -Cl; and R ^1c is -F.

In some embodiments of Formula (Ia-1-1), R ^1a and R ^1d are H; one of R ^1b and R ^1c is H; and the other one of R ^1b and R ^1c is halo, such as -F or -Cl, such as -F, such as wherein R ^1c is H, and R ^1b is -F; or wherein R ^1c is H, and R ^1b is -Cl; or wherein R ^1c is -Cl, and R ^1b is H; or wherein R ^1c is -F; and R ^1b is H.

In some embodiments of Formula (Ia-1-1), R ^1a and R ^1d are H; R ^1c is halo or H, such as -F, -Cl, or H; and R ^1b is heteroaryl of 5 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 is optionally substituted with from 1-4 R ^c , such as wherein R ^1b is pyrazolyl optionally substituted with R ^c .

In some embodiments of Formula (Ia-1-1), R ^1a and R ^1tl are H; R ^1c is halo or H, such as -F, -Cl, or H; and R ^1b is heteroaryl of 5-6 (such as 5) 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 is substituted with one occurrence of R ^h1 or -(L ^g ) _bg -R ^h1 and further optionally substituted with from 1-2 R ^c , wherein R ^h1 is an independently selected R ^h , such as wherein R ^1b is pyrazolyl substituted with R ^h1 .

In some embodiments of Formula (Ia-1-1), R ^1a and R ^1tl are H; R ^1c is halo or H, such as -F, -Cl, or H; and R ^1b is phenyl optionally substituted with from 1-4 R ^c , such as phenyl optionally substituted with from 1-2 substituents each independently selected from the group consisting of: C _1-6 alkyl optionally substituted with from 1-6 R ^a ; -halo; -cyano; C _1-4 alkoxy; and C _1-4 haloalkoxy.

In some embodiments of Formula (Ia-1-1), R ^1a is H; R ^1d is halo, such as -F or -Cl; R ^1c is H; and R ^1b is R ^g

In some embodiments of Formula (Ia-1-1), Ring B is:

In some embodiments of Formula (Ia-1-1), Ring , such as

In some embodiments of Formula (Ia-1-1), Ring such In some embodiments of Formula (Ia-1-1), Ring

In some embodiments of Formula (Ia-1-1), Ring such

In some embodiments of Formula (Ia-1-1), Ring each of which is further optionally substituted with R ^c (such as not further optionally substituted).

In some embodiments of Formula (Ia-1-1), al is 0. In some embodiments of Formula (Ia-1-1), al is 1; and L ^A is C _1-3 alkylene optionally substituted with from 1-4 R ^a1 . In certain of these embodiments, L ^A is CFh. In certain embodiments, L ^A is C(H)Me. In some embodiments of Formula (Ia-1-1), the moiety is . In certain embodiments, R ^c is C1-C4 haloalkyl (e.g., fluoroalkyl or perfluoroalkyl), e.g., C1-C2 haloalkyl (e.g., fluoroalkyl or perfluoroalkyl), e.g., Cl haloalkyl (e.g., fluoroalkyl or perfluoroalkyl), e.g., CF ₃ .

In some embodiments of Formula (Ia-1-1), the moiety

In some embodiments, the compound is a compound of Formula (Ia-1-1) wherein: R ^1a and R ^1d are each independently a H; R ^1b and R ^1c are each independently selected from: H; and R ^c ;

R ² , R ⁵ , R ⁶ are each independently H;

B ¹ is selected from CH and N;

B ² and B ⁴ are each independently N; B ³ is CH;

L ^A is CH2, when present; al is 0 or 1;

Q\ Q ² , Q ³ , Q ⁴ , and Q ⁵ are independently CH, CR ^C , or N, provided that from 3-5 of Q ⁴ -Q ⁵ are CH; each ==is independently a single bond or a double bond provided that the ring including B ⁴ -B ⁴ is a heteroaryl; wherein each occurrence of R ^c is independently selected from the group consisting of: halo; C _1-10 alkyl which is optionally substituted with 1-6 independently selected R ^a ; wherein each occurrence of R ^a is independently selected from the group consisting of: halo.

Compound Provisions

In some embodiments of one or more formulae herein, the compound is other than the compounds disclosed in PCT/US2020/013786 (e.g., in Table Cl), filed on Jan 16, 2020, which is incorporated herein by reference in its entirety.

In some embodiments, the compound of Formula (I) is other than a compound selected from the group consisting of compounds 124, 125, 126, 144, 145, 146, 147, 148, 149, 158, 159, 160, 164, 165, 166, and 167 as delineated in Table Cl of PCT/US2020/013786, filed on Jan 16, 2020, which is incorporated herein by reference in its entirety.

In some embodiments of the compound of Formula (I), it is provided that when Z is CH, Y ¹ is C-F, Y ² is C-F, and Y ³ is CH, then -(Ring B)-(L ^A ) _a1 -(Ring C) is other than:

In some embodiments, the compound of Formula (II) is other than a compound selected from the group consisting of compounds 156, 157, 161, 162, 163, and 168 as delineated in Table Cl of PCT/US2020/013786, filed on Jan 16, 2020, which is incorporated herein by reference in its entirety.

In some embodiments of the compound of Formula (II), it is provided that: when - (L ^A ) _a1 -Ring C is 4-trifluoromethyl -benzyl, then Ring B is other than: , wherein aa is the point of connection to (L ^A ) _a1.

In some embodiments of the compound of Formula (II), it is provided that: when wherein aa is the point of connection to (L ^A ) _a1 , then -(L ^A ) _a1 -Ring C is other than

In some embodiments of the compound of Formula (II), it is provided that the compound is other than:

In some embodiments of the compound of Formula (II), the compound is other than:

In some embodiments of the compound of Formula (II), it is provided that:

1) Ring C is other than: unsubstituted morpholinyl, unsubstituted pyrrolidinyl, unsubstituted tetrahydrofuranyl, unsubstituted cyclopentyl, monosub stituted oxetanyl, methylfuranyl, unsubstituted thiophenyl, or methylpyrrolyl; or

2) -(L ^A ) _a1 -Ring C is other than: unsubstituted benzyl or phenyl that is optionally substituted with one substituent selected from the group consisting of: -F, -OMe, and -OEt.

In some embodiments of the compound of Formula (III), it is provided that the compound is other than:

In some embodiments of the compound of Formula (III), the compound is other than compounds disclosed in WO 2013/114113 or U.S. Patent No. 10,000,481, each of which is incorporated herein by reference in its entirety.

In some embodiments of the compound of Formula (III), the compound is other than compounds disclosed in WO 2009/140320 or U.S. Patent No. 8,981,085, each of which is incorporated herein by reference in its entirety. In some embodiments of Formula (III), it is provided that when Ring B is wherein aa is the point of connection to (L ^A ) _a1 ; (L ^A ) _a1 is unsubstituted CFh, then Ring C is other than unsubstituted pyridyl, unsubstituted pyrrolyl, or phenyl which is optionally substituted with one substituent selected from the group consisting of: -F, -Cl, - Me, -OMe, or -CN.

Non-Limiting Exemplary Compounds

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

Table Cl

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, intraci sternal, 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 ah, “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, methyl oxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthangum, 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 0.01 mg/Kg to about 100 mg/Kg; from about 0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 1 mg/Kg; from from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0. 1 mg/Kg to about 100 mg/Kg; from about 0. 1 mg/Kg to about 10 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, 11 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 neurological disorders 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 tel egi ectasia; 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; cytomegalovirus 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 erythematosus, multiple sclerosis, inflammatory bowel diseases (IBDs) comprising Crohn disease (CD) and ulcerative colitis (UC), which are chronic inflammatory conditions with polygenic susceptibility. In certain embodiments, the condition is an inflammatory bowel disease. In certain embodiments, the condition is Crohn’s disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated by one or more alloimmune diseases (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In certain of these embodiments, the condition is alloimmune disease (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis or intestinal mucositis).

In some embodiments, modulation of the immune system by STING provides for the treatment of diseases, including diseases caused by foreign agents. Exemplary infections by foreign agents which may be treated and/or prevented by the method of the present invention include an infection by a bacterium (e.g., a Gram-positive or Gram negative bacterium), an infection by a fungus, an infection by a parasite, and an infection by a virus. In one embodiment of the present invention, the infection is a bacterial infection (e.g., infection 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 -di oxygenase (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, HVEM-BTL A-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-CXCL 12, 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, MEDI6469, 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. Topoisomerases are essential enzymes that maintain the topology of DNA. Inhibition of type I or type II topoisomerases interferes with both transcription and replication of DNA by upsetting proper DNA supercoiling. In a further embodiment, a topoisomerase is, without limitation, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In an embodiment a type I topoisomerase inhibitor is, without limitation, a camptothecin. In another embodiment, a camptothecin is, without limitation, exatecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67) and/or ST 1481. In an embodiment, a type II topoisomerase inhibitor is, without limitation, epipodophyllotoxin. In a further embodiment an epipodophyllotoxin is, without limitation, an amsacrine, etoposid, etoposide phosphate and/or teniposide. In a further embodiment a topoisomerase is a synthetic, semisynthetic or derivative, including those found in nature such as, without limitation, epipodophyllotoxins, substances naturally occurring in the root of American Mayapple (Podophyllum peltatum).

In 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, semi synthetic or derivative. In 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, auri statin, 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-methyl-L-valyl-L-proly-l-Lpro line-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®), antithymocyte 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- 1 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 (Ilaris®), 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. on-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. 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, ¹ H 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.

Examples The following abbreviations have the indicated meanings:

Abbreviations

Materials and Methods

The LC-MS was recorded using one of the following methods.

LCMS Method A: Kinetex EVO C18 100A, 30 *3mm, 0.5 gL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5mM NH4HCO3 and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.30 min, 95% MPB to 10% in 0.10 min.

LCMS Method B: Xselect CSH C18, 50 *3mm, 1.0 gL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.1% FA and Mobile Phase B (MPB): Acetonitrile/0.1% FA. Elution 5% MPB to 100% in 2.00 min, hold at 100% MPB for 0.70 min, 100% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.15 min.

LCMS Method C: Shim-pack XR-ODS, 50 *3mm, 0.3 gL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.05 TFA and Mobile Phase B (MPB): Acetonitrile/0.05% TFA. Elution 5% MPB to 100% in 1.10 min, hold at 100% MPB for 0.60 min, 100% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.25 min.

LCMS Method D: Kinetex 2.6gm EVO C18 100A, 50 *3mm, 0.6 gL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH4HCO3 and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 1.20 min, hold at 95% MPB for 0.50 min, 95% MPB to 10% in 0.05 min, then equilibration to 10% MPB for 0.10 min.

LCMS Method E: Kinetex 2.6gm EVO C18 100A, 50 *3mm, 0.6 gL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH4HCO3 and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 1.20 min, hold at 95% MPB for 0.50 min, 95% MPB to 10% in 0.05 min, then equilibration to 10% MPB for 0.10 min.

LCMS Method F: EVO C18, 50 *3mm, 0.1 gL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH4HCO3 and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.60 min, 95% MPB to 10% in 0.15 min, then equilibration to 10% MPB for 0.25 min. LCMS Method G: Titank C18, 50 *3mm, 0.5 gL injection, 1.5 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH4HCO3 and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 1.80 min, hold at 95% MPB for 0.80 min, 95% MPB to 10% in 0.15 min, then equilibration to 10% MPB for 0.25 min.

LCMS Method H: XB ridge BEH Cl 8, 50 *3mm, 4.0 gL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH4HCO3 and Mobile Phase B (MPB): Acetonitrile. Elution 5% MPB to 95% in 2.00 min, hold at 95% MPB for 0.70 min, 95% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.25 min.

LCMS Method A-l: Kinetex EVO C18 100A, 30*3mm, 0.5 gL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5mM NH4HCO3 and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.30 min, 95% MPB to 10% in 0.10 min.

LCMS Method B-l: Xselect CSH C18, 50*3mm, 1.0 gL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.1% FA and Mobile Phase B (MPB): Acetonitrile/0.1% FA. Elution 5% MPB to 100% in 2.00 min, hold at 100% MPB for 0.70 min, 100% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.15 min.

LCMS Method C-l: Shim-pack XR-ODS, 50*3mm, 0.3 gL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.05 TFA and Mobile Phase B (MPB): Acetonitrile/0.05% TFA. Elution 5% MPB to 100% in 1.10 min, hold at 100% MPB for 0.60 min, 100% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.25 min.

LCMS Method D-l: Shim-pack Scepter 08-120, 33*3mm, 0.5 gL injection, 1.5 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH4HCO3 and Mobile Phase B (MPB): Acetonitrile. Elution 50% MPB to 95% in 2.00 min, hold at 95% MPB for 0.60 min, 95% MPB to 10% in 0.05 min, then equilibration to 10% MPB for 0.25 min.

LCMS Method E-l: kinetex 2.6gm EVO, 50*3mm, 0.5 gL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH4HCO3 and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.70 min, 95% MPB to 10% in 0.05 min, then equilibration to 10% MPB for 0.25 min.

LCMS Method F-l: HALOC18, 30*3mm, 0.5 pL injection, 1.5 mL/min flowrate, 30- 2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.05% TFA and Mobile Phase B (MPB): Acetonitrile/0.05% TFA. Elution 5% MPB to 100% in 1.20 min, hold at 100% MPB for 0.60 min, 100% MPB to 5% in 0.02 min, then equilibration to 5% MPB for 0.18 min.

LCMS Method G-l: HALOC18, 30*3mm, 0.5 pL injection, 1.5 mL/min flowrate, 30- 2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.1% FA and

Mobile Phase B (MPB): Acetonitrile/0.1% FA. Elution 5% MPB to 100% in 1.20 min, hold at 100% MPB for 0.60 min, 100% MPB to 5% in 0.02 min, then equilibration to 5%

MPB for 0.18 min.

LCMS Method BA

Instrument: Agilent LCMS system equipped with DAD and ELSD detector Ion mode: Positive

Column: Waters X-Bridge Cl 8, 50*2.1 mm*5 μm or equivalent Mobile Phase: A: H2O (0.04% TFA); B: CFECN (0.02% TFA)

Gradient: 4.5 min gradient method, actual method would depend on clogP of compound.

Flow Rate: 0.6 mL/min or 0.8 mL/min Column Temp: 40 °C or 50 °C UV: 220 nm

LCMS Method BB

Instrument: Agilent LCMS system equipped with DAD and ELSD detector Ion mode: Positive

Column: Waters X-Bridge ShieldRP18, 50*2.1 mm*5 μm or equivalent Mobile Phase:A: H2O (0.05% NH3Ή2O) or 10 mM ammonia bicarbonate; B: CFLCN Gradient: 4.5 min gradient method; actual method would depend on the clogP of the compound. Flow Rate: 0.6 mL/min or 0.8 mL/min Column Temp: 40 °C UV: 220 nm

Prep. HPLC condition

Instrument:

1. GILSON 281 and Shimadzu LCMS 2010A

2. GILSON 215 and Shimadzu LC-20AP

3. GILSON 215 Mobile phase: A: NH4OH/H2O = 0.05% v/v; B: ACN A: FA/H2O = 0.225% v/v; B: ACN Column

Xtimate C18 150*25mm*5μm; Flow rate: 25 mL/min or 30 mL/min; Monitor wavelength: 220&254 nm; Gradient: actual method would depend on clog P of compound; Detector: MS Trigger or UV

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.

Preparative examples

Synthesis of intermediate 1 (l-(4-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid) Step 1: ethyl l-(4-(trifluoromethyl)benzyl)-1H -pyrazole-4-carboxylate 1H -pyrazole-4-carboxylate (5.0 g, 35.7 mmol, 1.0 equiv.) was dissolved in ACN (100.0 mL), then K2CO3 (1.5 g, 107.0 mmol, 3.0 equiv.) and l-(bromomethyl)-4- (trifluoromethyl)benzene (9.4 g, 39.2 mmol, 1.1 equiv.) were added. The resulting solution was stirred for 16 hours at ambient temperature. After filtration and washing the solids with MeOH, the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give ethyl l-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-4-carboxylate (5.1 g) as a white solid. LCMS Method E: [M+H] ⁺ = 299. Step 2: l-(4-(trifluoromethyl)benzyl)-lH-pyrazole-4-carboxylic acid

Ethyl l-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-4-carboxylate (200.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in MeOH (2.0 mL) and water (2.0 mL), then NaOH (80.5 mg, 2.0 mmol, 3.0 equiv.) was added. The reaction mixture was heated to 90 °C for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water and adjusted to pH 5 with aqueous HC1 (6M). The resulting solid was collected by filtration and washed with water, then dried to give l-[[4- (trifluoromethyl)phenyl]methyl]pyrazole-4-carboxylic acid (200 mg) as a white solid. LCMS Method G: [M-H]- = 269.

The intermediates in the following table were prepared using the same method described for Intermediate 1.

Synthesis of intermediates 7 and 38 (l-(2-(pyridin-3-yloxy)ethyl)-lH-pyrazole-5- carboxylic acid and l-(2-(pyridin-3-yloxy)eihyl)-lH-pyrazole-3-carboxylic acid)

Step 1: methyl l-(2-(pyridin-3-yloxy)ethyl)-1H -pyrazole-5-carboxylate and methyl l-(2-(pyridin-3-yloxy)ethyl)-1H -pyrazole-3-carboxylate

3-(2-Bromoethoxy)pyridine (300.0 mg, 1.5 mmol, 1.0 equiv.) and methyl 1 H- imidazole-4-carboxylate (187.3 mg, 1.5 mmol, 1.0 equiv.) were dissolved in ACN (10 mL), then K2CO3 (413.4 mg, 3.0 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 90 °C for 2 hours, then cooled to ambient temperature. The solid was removed by filtration and the filter cake was washed with MeOH, then the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10 to 1:1) to give methyl l-(2-(pyridin-3- yloxy)ethyl)- 1H-pyrazole-5-carboxylate (compound 4A, 150 mg) as a white solid and methyl l-(2-(pyri din-3 -yloxy)ethyl)-17/-pyrazole-3-carboxylate (compound 4B, 140 mg) as a white solid. LCMS of compound 4 A, Method B : [M+H] ⁺ = 248. ¹ H NMR of compound 4A (400 MHz, DMSO-de): δ 8.21-8.16 (m, 2H), 7.64-7.63 (m, 1H), 7.37-7.29 (m, 2H), 6.92-6.91 (m, 1H), 4.92 (t, 2H), 4.45 (t, 2H), 3.84 (s, 3H). LCMS of compound 4B, Method B: [M+H] ⁺ = 248. ¹ H NMR of compound 4B (400 MHz, DMSO-d ₆ ): δ 8.27 (d, 1H), 8.21- 8.18 (m, 1H), 7.99-7.96 (m, 1H), 7.49-7.30 (m, 2H), 6.79-6.76 (m, 2H), 4.63 (t, 2H), 4.48 (t, 2H), 3.80 (s, 3H).

Step 2: l-(2-(pyridin-3-yloxy)ethyl)-1H -pyrazole-5-carboxylic acid

Methyl l-(2-(pyridin-3-yloxy)ethyl)-lH-pyrazole-5-carboxylate (150.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in MeOH (3 mL) and water (3 mL), then NaOH (48.5 mg, 1.2 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80 °C for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, then the solution was adjusted to pH 5 with aqueous HC1 (6 M). The solids were collected by filtration and dried to give 1 -(2-(pyri din-3 -yloxy)ethyl)-1H - pyrazole-5-carboxylic acid (110 mg) as a white solid. LCMS Method A: [M-H]- = 232. Step 3: l-(2-(pyridin-3-yloxy)ethyl)-1H -pyrazole-3-carboxylic acid

The same method described for step 2 was used to give l-(2-(pyridin-3-yloxy)ethyl)- 1H -pyrazole-3 -carboxylic acid (120 mg) as a white solid. LCMS Method A: [M-H]- = 232. The intermediates in the following table were prepared using the same method described for Intermediates 7 and 38.

Synthesis of intermediate 11 ( l-((5-(trifluoromethyl)pyridin-2-yl)methyl)-lH - imidazole-4-carboxylic acid)

Intermediate 11 Step 1: ethyl l-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H -imidazole-4- carboxylate l-[5-(trifluoromethyl)pyridin-2-yl]methanamine (200.0 mg, 1.1 mmol, 1.0 equiv.) was dissolved in /-BuOH (5.0 mL), then ethyl (2Z)-3-(dimethylamino)-2-formonitrileprop- 2-enoate (230.6 mg, 1.4 mmol, 1.2 equiv.) was added. The reaction mixture was heated to 130 °C for 3 days and then cooled to ambient temperature and concentrated under vacuum.

The residue was purified by Flash-Prep-HPLC with the following conditions: Column, Cl 8 silica gel; mobile phase, ACN/Water (0.1% NH4HCO3) increased from 0 to 100% within 40 min; Detector, UV 254 nm. This resulted in ethyl l-((5-(trifluoromethyl)pyri din-2 - yl)methyl)-1H -imidazole-4-carboxylate (120 mg) as a pale yellow solid. LCMS Method A: [M+H] ⁺ =300. ¹ H NMR (400 MHz, CDCb): δ 8.84 (s, 1H), 7.92-7.89 (m, 1H), 7.83- 7.75 (m, 2H), 7.23 (d, 1H), 5.71 (s, 2H), 4.29 (q, 2H), 1.32 (t, 3H). Step 2: l-((5-(trifluoromethyl)pyridin-2-yl)methyl)-lH-imidazole-4-c arboxylic acid Ethyl l-[[5-(trifluoromethyl)pyridin-2-yl]methyl]imidazole-4-carbo xylate (100.0 mg, 0.3 mmol, 1.0 equiv.) was dissolved in MeOH (5.0 mL) and water (5.0 mL), then NaOH (26.7 mg, 0.7 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80 °C for 4 hours and then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water and adjusted to pH 3 with aqueous HC1 (1M). The resulting solid was collected by filtration and further purified by Flash-Prep-HPLC with the following conditions: Column, C18 silica gel; mobile phase, ACN/Water (0.1% TFA) increasing from 0 to 100% within 40 min; Detector, UV 254 nm. This resulted in l-((5- (trifluoromethyl)pyridin-2-yl)methyl)-lH-imidazole-4-carboxy lic acid (70 mg) as a white solid. LCMS Method A: [M+H] ⁺ = 272.

The following intermediate was prepared using the same method described for Intermediate 11.

Synthesis of intermediate 13 (5-oxo-l-(4-(trifluoromethyl)benzyl)-4,5-dihydro-lH- 1, 2, 4-triazole-3-carboxylic acid)

Step 1: ethyl (Z)-2-amino-2-(2-(4-(trifluoromethyl)benzyl)hydrazineylidene )acetate

(4-(Trifluoromethyl)benzyl)hydrazine dihydrogen chloride (1.0 g, 5.3 mmol, 1.0 equiv.) was dissolved in EtOH (30.0 mL), then K2CO3 (1.5 g, 10.5 mmol, 2.0 equiv.) and ethyl 2-amino-2-thioxoacetate (0.7 g, 5.3 mmol, 1.0 equiv.) were added. The reaction mixture was stirred for 16 hours at ambient temperature and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give ethyl (Z)-2-amino-2-(2-(4- (trifluoromethyl)benzyl)hydrazineylidene)acetate (590 mg) as a pale yellow solid. LCMS Method A: [M+H] ⁺ = 290.

Step 2: ethyl 5-oxo-l-(4-(trifluoromethyl)benzyl)-4,5-dihydro-1H -l,2,4-triazole-3- carboxylate

Ethyl (Z)-2-amino-2-(2-(4-(trifluoromethyl)benzyl)hydrazineylidene )acetate (550.0 mg, 1.9 mmol, 1.0 equiv.) was dissolved in DCM (20.0 mL), then CDI (1.2 g, 7.6 mmol, 4.0 equiv.) was added. The resulting solution was stirred for 16 hours at ambient temperature and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give ethyl 5-oxo-l-(4-(trifluoromethyl)benzyl)-4, 5-dihydro- 1/7-1, 2, 4-triazole-3- carboxylate (500 mg) as a pale yellow solid. LCMS Method A: [M+H] ⁺ = 316. Step 3: 5-oxo-l-(4-(trifluoromethyl)benzyl)-4,5-dihydro-1H -l,2,4-triazole-3- carboxylic acid

Ethyl 5-oxo- 1 -(4-(trifluoromethyl)benzyl)-4, 5-dihydro- 1H- 1 ,2,4-triazole-3- carboxylate (500.0 mg, 1.6 mmol, 1.0 equiv.) was dissolved in MeOH (20.0 mL) and water (5.0 mL), then LiOH (76.0 mg, 3.2 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 1 hour at ambient temperature and concentrated under vacuum. The residue was diluted with water and adjusted to pH 5 with aqueous HC1 (6M). The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 5-oxo-l-(4-(trifluoromethyl)benzyl)-4,5-dihydro- lH-l,2,4-triazole-3-carboxylic acid (400 mg) as a white solid. LCMS Method A: [M+H] ⁺ = 288.

Synthesis of intermediate 14 ( 5-methyl-l-(4-(trifluoromethyl)benzyl)-lH-pyrazole-3 - carboxylic acid)

Intermediate 14

Step 1: methyl 5-methyl-l-(4-(trifluoromethyl)benzyl)-Li/-pyrazole-3-carbox ylate

(4-(Trifluoromethyl)benzyl)hydrazine (1.0 g, 5.7 mmol, 1.0 equiv.) was dissolved in acetic acid (10.0 mL), then methyl 2,4-dioxopentanoate (0.9 g, 6.2 mmol, 1.1 equiv.) was added. The reaction mixture was heated to 90 °C for 4 hours and then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give methyl 5-methyl -1 -(4-(trifluoromethyl)benzyl)-1H -pyrazole-3 -carboxyl ate (810 mg) as a white solid. LCMS Method A: [M+H] ⁺ = 299. ¹ H NMR (400 MHz, DMSO-rfc): 7 δ.74 (d, 2H), 7.33 (d, 2H), 6.63 (s, 1H), 5.52 (s, 2H), 3.79 (s, 3H), 2.26 (s, 3H). Step 2: 5-methyl-l-(4-(trifluoromethyl)benzyl)-1H -pyrazole-3-carboxylic acid

Methyl 5-methyl- 1 -(4-(trifluoromethyl)benzyl)- 1H-py razol e-3 -carboxyl ate (500.0 mg, 1.7 mmol, 1.0 equiv.) was dissolved in MeOH (5.0 mL) and water (5.0 mL), then NaOH (134.1 mg, 3.4 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80 °C for 2 hours and concentrated under vacuum. The residue was diluted with water and adjusted to pH 5 with aqueous HC1 (6M). The resulting solid was collected by filtration and washed with water, then dried to give 5-methyl- l-(4-(trifluoromethyl)benzyl)-1H - pyrazole-3-carboxylic acid (250 mg) as a white solid. LCMS Method A: [M+H] ⁺ = 285.

The following intermediate was prepared using the same method described for Intermediate 14.

Synthesis of intermediate 16 (5-(4-(trifluoromethyl)benzyl)-lH-pyrazole-3-carboxylic acid)

Step 1: ethyl 2,4-dioxo-5-(4-(trifluoromethyl)phenyl)pentanoate l-(4-(Trifluoromethyl)phenyl)propan-2-one (200.0 mg, 1.0 mmol, 1.0 equiv.) was dissolved in EtOH (5.0 mL) and cooled to 0 °C, then ethyl oxalate (144.6 mg, 1.0 mmol, 1.0 equiv.) and EtONa (74.1 mg, 1.1 mmol, 1.1 equiv.) were added. The resulting mixture was stirred overnight at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum to give crude ethyl 2,4-dioxo-5-(4- (trifluoromethyl)phenyl)pentanoate, which was used in the next step directly without further purification. LCMS Method B: [M-H]-= 301.

Step 2: ethyl 5-(4-(trifluoromethyl)benzyl)-1H -pyrazole-3-carboxylate

Ethyl 2,4-dioxo-5-(4-(trifluoromethyl)phenyl)pentanoate (200.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in acetic acid (5.0 mL), then hydrazine hydrogen chloride (32.5 mg, 0.7 mmol, 1.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature and quenched by the addition of water. The resulting solution was adjusted to pH 7 with aqueous NaOH (4 M), then extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; ACN/water increasing from 0 to 100% within 30 min; detector, UV 254 nm. This resulted in ethyl 5 -[[4-(trifluoromethyl)phenyl]methyl]- 1H-pyrazole-3 -carboxyl ate (150 mg) as a yellow solid. LCMS Method B: [M+H] ⁺ = 299. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.92 (brs, 1H), 7.58 (d, 2H), 7.37 (d, 2H), 6.61 (s, 1H), 4.38 (q, 2H), 4.14 (s, 2H), 1.38 (t, 3H). Step 3: 5-(4-(trifluoromethyl)benzyl)-1H -pyrazole-3-carboxylic acid

Ethyl 5-[[4-(trifluoromethyl)phenyl]methyl]-1H-pyrazole-3 -carboxyl ate (150.0 mg, 0.5 mmol, 1.0 equiv.) was dissolved in MeOH (5.0 mL) and water (5.0 mL), then NaOH (40.2 mg, 1.0 mmol, 2.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature and then concentrated under vacuum. The residue was diluted with water then adjusted to pH 6 with aqueous HC1 (1M). The resulting solids were collected by filtration and dried to give crude 5-(4-(trifluoromethyl)benzyl)-1H -pyrazole-3- carboxylic acid (110 mg) as a yellow solid, which was used in the next step directly without further purification. LCMS Method A: [M+H] ⁺ = 271.

Synthesis of intermediate 17 (5-(4-(trifluoromethyl)phenyl)-lH-imidazole-2-carboxylic acid)

Step 1: ethyl 5-(4-(trifluoromethyl)phenyl)-1H -imidazole-2-carboxylate

2-Amino-l-[4-(trifluoromethyl)phenyl]ethanone (1.0 g, 4.9 mmol, 1.0 equiv.) was dissolved in acetic acid (10.0 mL), then ethyl 2-amino-2-thioxoacetate (0.7 g, 5.0 mmol, 1.0 equiv.) and NaOAc (1.2 g, 14.8 mmol, 3.0 equiv.) were added. The reaction mixture was heated to 100 °C for 3 hours and cooled to ambient temperature. The mixture was adjusted to pH 7 with aqueous NaOH (4M), then extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give ethyl 5-(4-(trifluoromethyl)phenyl)-1H-imidazole-2-carboxylate (350 mg) as a yellow solid. LCMS Method B: [M+H] ⁺ = 285. ¹ H NMR (400 MHz, MeOD-d ₄ ): d 8.02 (d, 2H), 7.83 (s, 1H), 7.70 (d, 2H), 4.45 (q, 2H), 1.45 (t, 3H).

Step 2: 5-(4-(trifluoromethyl)phenyl)-1H -imidazole-2-carboxylic acid

Ethyl 5-(4-(trifluoromethyl)phenyl)-1H-imidazole-2-carboxylate (35.0 mg, 0.1 mmol, 1.0 equiv.) was dissolved in MeOH (1.0 mL) and water (1.0 mL), then NaOH (10.0 mg, 0.2 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80 °C for 2 hours and then cooled to ambient temperature. The residue was diluted with water then adjusted to pH 5 with aqueous HC1 (1M). The resulting mixture was extracted with ethyl acetate, dried over anhydrous Na2S04 and concentrated under vacuum to give 5-(4- (trifluoromethyl)phenyl)-1H -imidazole-2-carboxylic acid (30 mg) as a yellow solid. LCMS Method B: [M+H] ⁺ = 257. Synthesis of intermediate 18 ( l-methyl-5-(4-(trifluoromethyl)benzyl)-lH-pyrazole-3 - carboxylic acid)

Step 1: ethyl l-methyl-5-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-3-car boxylate Ethyl 5-[[4-(trifluoromethyl)phenyl]methyl]-1H-pyrazole-3 -carboxyl ate (500.0 mg,

1.7 mmol, 1.0 equiv.) was dissolved in THF (5.0 mL) and cooled to 0 °C, then NaH (60% wt in mineral oil, 134.2 mg, 3.4 mmol, 2.0 equiv.) was added at 0 °C under an atmosphere of nitrogen. The resulting mixture was stirred for 15 min, then Mel (356.9 mg, 2.5 mmol, 1.5 equiv.) was added dropwise, maintaining the reaction mixture at 0 °C. The reaction mixture was stirred overnight at ambient temperature and then quenched by the addition of aqueous HC1 (4M). The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give ethyl l-methyl-5-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-3- carboxylate (280 mg) as a off-white solid. LCMS Method F: [M+H] ⁺ =313.

Step 2: l-methyl-5-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-3-car boxylic acid Ethyl 1 -methyl-5-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-3-carb oxylate (280.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in MeOH (5.0 mL) and water (5.0 mL), then NaOH (71.7 mg, 1.8 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80 °C for 2 hours and then cooled to ambient temperature and concentrated under vacuum.

The residue was diluted with water, then adjusted to pH 5 with aqueous HC1 (6M). The resulting solid was collected by filtration and washed with water, then dried to give 1- methyl-5-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-3-carbo xylic acid (150 mg) as a white solid. LCMS Method A: [M+H] ⁺ =285.

Synthesis of intermediate 19 (5,6-difluoro-lH-indol-3-amine hydrogen chloride) Step 1: 5,6-difluoro-3-nitro-1H -indole

5.6-Difluoro-1H -indole (25.0 g, 163.3 mmol, 1.0 equiv.) was dissolved in in ACN (300 mL) and cooled to 0 °C, then AgNCb (33.3 g, 195.9 mmol, 1.2 equiv.) was added. The resulting mixture was stirred for 15 min, then benzoyl chloride (27.5 g, 195.9 mmol, 1.2 equiv.) was added batchwise, maintaining the reaction mixture at 0 °C. After an additional 3 hours at 0 °C the reaction mixture was quenched by the addition of ice-water. The reaction mixture was adjusted to pH 8 with saturated aqueous NaHCCb, then extracted with DCM and the organic layers concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petr oleum ether (2: 1) to give 5,6-difluoro-3-nitro-1H -indole (24 g) as a brown solid. LCMS Method A: [M+H] ⁺ = 199.

Step 2: tert- butyl A-(5,6-difluoro-1H -indol-3-yl)carbamate

5.6-Difluoro-3-nitro-1H -indole (24.0 g, 121.1 mmol, 1.0 equiv.) was dissolved in MeOH (300 mL), then Pd/C (2.4 g, wt 10%) and (BofO (39.7 g, 181.7 mmol, 1.5 equiv.) were added under nitrogen. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred overnight at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give tert-butyl N-(5,6-difluoro-l H -indol -3 -yl (carbamate (22 g) as a yellow solid. LCMS Method C: [M+H] ⁺ = 269.

Step 3: 5,6-difluoro-1H -indol-3-amine hydrochloride tert-Butyl N-(5,6-difluoro-1H -indol-3-yl)carbamate (17.0 g, 63.4 mmol, 1.0 equiv.) was dissolved in HC1 in 1,4-dioxane (4N, 200 mL). The resulting mixture was stirred for 30 min at ambient temperature and then concentrated under vacuum to give 5,6-difluoro- lH-indol-3-amine hydrochloride (12 g) as a yellow solid. LCMS Method C: [M+H] ⁺ = 169.

The intermediates in the following table were prepared using the same method described for Intermediate 19.

Synthesis of intermediate 29 (6-chloro-lH-indol-3 -amine hydrogen chloride)

Step 1: 6-chloro-1H -indole-3-carbonyl azide

6-chloro-1H -indole-3 -carboxylic acid (1.0 g, 5.1 mmol, 1.0 equiv.) and DPPA (2.8 g, 10.2 mmol, 2.0 equiv.) were dissolved in THF (10.0 mL), then TEA (1.6 mL, 11.1 mmol, 2.2 equiv.) was added. The resulting mixture was stirred overnight at ambient temperature and concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum to give 6-chloro- 1H -indole-3 -carbonyl azide (900 mg) as a white solid. LCMS Method D: [M+H] ⁺ = 221. Step 2: tert- butyl (6-chloro-1H -indol-3-yl)carbamate 6-Chloro-1H -indole-3 -carbonyl azide (300.0 mg, 1.4 mmol, 1.0 equiv.) was added in t-BuOH (8.0 mL). The resulting mixture was stirred overnight at 100 °C and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl (6-chloro- 1H- indol-3-yl)carbamate (350 mg) as a yellow solid. LCMS Method D: [M+H] ⁺ = 267. Step 3: 6-chloro-1H -indol-3-amine hydrogen chloride tert-Butyl (6-chloro-1H -indol-3-yl)carbamate (300.0 mg, 1.1 mmol, 1.0 equiv.) was dissolved in HC1 in 1,4-dioxane (4M, 10.0 mL). The resulting solution was stirred for 4 hours at ambient temperature and then concentrated under vacuum to give crude 6-chloro- 1H -indol-3-amine hydrogen chloride hydrogen chloride (350 mg) as a yellow solid. LCMS Method D: [M+H] ⁺ = 167.

The intermediates in the following table were prepared using the same method described for Intermediate 29.

Synthesis of intermediate 32 (l-(4-(trifluoromethyl)phenyl)-lH-imidazole-4-carboxylic acid)

Intermediate 32 Step 1: ethyl l-(4-(trifluoromethyl)phenyl)imidazole-4-carboxylate

Ethyl lH-imidazole-4-carboxylate (300.0 mg, 2.1 mmol, 1.0 equiv.) and l-iodo-4- (trifluoromethyl)benzene (698.7 mg, 2.6 mmol, 1.2 equiv.) were dissolved in DMF (10.0 mL), then Cul (40.8 mg, 0.2 mmol, 0.1 equiv.) and CS2CO3 (2.1 g, 6.4 mmol, 3.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 100 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/water (10 mM H4HCO3), increasing from 0 to 100% within 25 min; Detector, UV 254 nm. This resulted in ethyl l-[4- (trifluoromethyl)phenyl]imidazole-4-carboxylate (260 mg) as a white solid. LCMS Method A: [M+H] ⁺ = 285.

Step 2: l-[4-(trifluoromethyl)phenyl]imidazole-4-carboxylic acid

Ethyl l-[4-(trifluoromethyl)phenyl]imidazole-4-carboxylate (270.0 mg, 1.1 mmol, 1.0 equiv.) was dissolved in MeOH (5.0 mL) and water (5.0 mL), then NaOH (84.4 mg,

2.1 mmol, 2.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature and then concentrated under vacuum. The residue was purified by Flash-Prep- HPLC with the following conditions: Column, Cl 8 silica gel; mobile phase, ACN/water (10 mMNLLHCCb), increasing from 0 to 100% within 25 min; Detector, UV 254 nm. This resulted in l-[4-(trifluoromethyl)phenyl]imidazole-4-carboxylic acid (150 mg) as a white solid. LCMS Method F: [M+H] ⁺ = 257.

Synthesis of intermediate 33 (l-(l-bromoethyl)-4-(trifluoromethyl)benzene) l-[4-(trifluoromethyl)phenyl]ethanol (1.0 g, 5.3 mmol, 1.0 equiv.) was dissolved in DCM (20.0 mL) and cooled to 0 °C, then phosphorus tribromide (1.4 g, 5.2 mmol, 1.0 equiv.) was added, maintaining the reaction mixture at 0 °C. The reaction mixture was stirred for 1 hour at ambient temperature and then quenched by the addition of saturated aqueous NaHCCb. The resulting solution was extracted with dichloromethane and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give l-(l-bromoethyl)-4- (trifluoromethyl)benzene (800 mg) as a white solid.

Synthesis of intermediate 34 ( 7-methoxy-lH-pyrrolo[3,2-c]pyridine )

Step 1: 3-methoxy-4-nitropyridin-l-ium-l-olate

3-Fluoro-4-nitropyridin-l-ium-l-olate (10.0 g, 63.3 mmol, 1.0 equiv.) was dissolved in MeOH (200.0 mL), then MeONa (6.8 g, 126.5 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 16 hours at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum to give 3-methoxy-4- nitropyridin-l-ium-l-olate (6.1 g) as a yellow solid. LCMS Method H: [M+H] ⁺ = 171. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.49 (s, 1H), 8.08-8.01 (m, 2H), 4.01 (s, 3H). Step 2: 3-methoxy-4-nitropyridine

3-Methoxy-4-nitropyridin-l-ium-l-olate (5.0 g, 29.4 mmol, 1.0 equiv.) was dissolved in ethyl acetate (200.0 mL) and cooled to 0 °C, then PCb (6.0 g, 44.1 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 1 hour at ambient temperature and quenched by the addition of water. The solution was adjusted to pH 7 with aqueous NaOH (2 M), then extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum to give 3-methoxy-4-nitropyridine (4.2 g) as a yellow solid. LCMS Method H: [M+H] ⁺ =155. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.84 (d, 1H), 8.48- 8.45 (m, 1H), 7.91-7.88 (m, 1H), 4.08 (s, 3H).

Step 3: 7-methoxy-1H -pyrrolo[3,2-c]pyridine 3-Methoxy-4-nitropyridine (15.0 g, 97.3 mmol, 1.0 equiv.) was dissolved in THF

(500.0 mL) and cooled to -50 °C, then vinylmagnesium bromide (1M in THF, 194.6 mL,

194.6 mmol, 2.0 equiv.) was added dropwise, maintaining the reaction mixture at -50 °C.

The reaction mixture was stirred for 5 hours at -50 °C and quenched by the addition of aqueous Na ₂ S ₂ O ₃ (15% wt). The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (10:1) to give 7-methoxy-1H -pyrrolo[3,2-c] pyridine (500 mg) as a white solid. LCMS Method D: [M+H] ⁺ = 149. ¹ H NMR (400 MHz, DMSO-i e): δ 11.73 (s, 1H), 8.51 (d, 1H), 7.90 (s, 1H), 7.38-7.37 (m, 1H), 6.58-6.56 (m, 1H), 4.00 (s, 3H).

Synthesis of intermediate 35 (7-methyl-lH-pyrrolo[3,2-c]pyridine) 35

7-Bromo-1H -pyrrolo[3,2-c]pyridine (1.0 g, 5.1 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (20.0 mL) and water (2.0 mL), then K2CO3 (1.4 g, 10.2 mmol, 2.0 equiv.), Pd(dppf)Cl2 (0.4 g, 0.5 mmol, 0.1 equiv.) and methylboronic acid (0.9 g, 15.2 mmol, 3.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 100 °C overnight and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 7-methyl -1H-pyrrol o[3,2-c]pyri dine (300 mg) as a yellow solid. LCMS Method D: [M+H] ⁺ = 133.

Synthesis of intermediate 36 (1 -azido-4-(trif1uoromethyl) benzene) 6

4-(Trifluoromethyl)aniline (800.0 mg, 5.0 mmol, 1.0 equiv.) was dissolved in ACN and cooled to 0 °C, then /-BuONO (768.0 mg, 7.4 mmol, 1.5 equiv.) was added dropwise, maintaining the internal temperature at 0 °C. After stirring for 0.5 hour at 0 °C, TMSN3 (858.0 mg, 7.4 mmol, 1.5 equiv.) was added. The resulting mixture was stirred for 4 hours at ambient temperature and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:8) to give l-azido-4-(trifluoromethyl)benzene (400 mg) as a colorless oil.

Synthesis of intermediate 37 (l-(azidomethyl)-4-(trifluoromethyl)benzene) 7 (4-(trifluoromethyl)phenyl)methanol (1.0 g, 5.7 mmol, 1.0 equiv.) was dissolved in

THF (20.0 mL), then DBU (1.7 g, 11.2 mmol, 2.0 equiv.) and DPPA (2.3 g, 8.5 mmol, 1.5 equiv.) were added. The reaction mixture was stirred for 2 hours at ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1: 10) to give l-(azidomethyl)- 4-(trifluoromethyl)benzene (400 mg) as colorless oil.

Synthesis of intermediate 39 (7-methoxy-lH-pyrrolo[3,2-c]pyridine)

Step 1: 5-bromo-7-fluoro-3-nitro-1H -indole

5-Bromo-7-fluoro-1H -indole (500.0 mg, 2.3 mmol, 1.0 equiv.) was dissolved in ACN (10 mL) and cooled to 0 °C, then AgNCh (595.3 mg, 3.5 mmol, 1.5 equiv.) and benzoyl chloride (0.4 mL, 3.5 mmol, 1.5 equiv.) were added, maintaining the mixture at 0 °C. The reaction mixture was stirred for 3 hours at ambient temperature, then quenched by the addition of water. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give 5-bromo-7-fluoro-3-nitro- 1H- indole (250 mg) as a brown solid. LCMS Method C: [M+H] ⁺ = 259.

Step 2: tert- butyl N-(5-bromo-7-fluoro-1H -indol-3-yl)carbamate

5-Bromo-7-fluoro-3-nitro-1H -indole (250.0 mg, 1.0 mmol, 1.0 equiv.) and (Boc)20 (252.8 mg, 1.2 mmol, 1.2 equiv.) were added in MeOH (5 mL) and cooled to 0 °C, then NaBH ₄ (73.0 mg, 1.9 mmol, 2.0 equiv.) and NiCl ₂ (250.2 mg, 1.9 mmol, 2.0 equiv.) were added, maintaining the mixture at 0 °C. The resulting mixture was stirred for 0.5 hour at 0 °C and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1: 10) to give tert-butyl N-(5-bromo-7-fluoro-1H-indol-3- yl)carbamate (30.0 mg) as a brown solid. LCMS Method A: [M+H] ⁺ = 329.

Step 3: tert- butyl N-[7-fluoro-5-(l-isopropylpyrazol-4-yl)-1H -indol-3-yl]carbamate tert-Butyl N-(5-bromo-7-fluoro-1H -indol-3-yl)carbamate (30.0 mg, 0.1 mmol, 1.0 equiv.) and l-isopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)p yrazole (32.3 mg, 0.1 mmol, 1.5 equiv.) were dissolved in 1,4-dioxane (1.0 mL) and water (0.1 mL), then CS2CO3 (59.4 mg, 0.2 mmol, 2.0 equiv.) and XPhos Pd G3 (7.7 mg, 0.01 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The resulting mixture was heated to 100 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give tert-butyl N-[7-fluoro- 5-(l-isopropylpyrazol-4-yl)-1H -indol-3-yl]carbamate (15.0 mg) as a yellow solid. LCMS Method A: [M+H] ⁺ = 359. Step 4: 7-fluoro-5-(l-isopropylpyrazol-4-yl)-1H -indol-3-amine hydrochloride tert-Butyl N-[7-fluoro-5-(l-isopropylpyrazol-4-yl)-1H -indol-3-yl]carbamate (15.0 mg, 0.04 mmol, 1.0 equiv.) was dissolved in HC1 in 1,4-dioxane (4M, 1.0 mL). The resulting solution was stirred for 8 hours at ambient temperature and then concentrated under vacuum to give 7-fluoro-5-(l-isopropylpyrazol-4-yl)-1H -indol-3-amine hydrochloride (9.0 mg) as a green solid. LCMS Method C: [M+H] ⁺ = 259.

Synthesis of intermediate 40 (5-phenoxy-lH-indol-3-amine hydrochloride)

Step 1: 2-methyl-l-nitro-4-phenoxybenzene 4-Fluoro-2-m ethyl- 1 -nitrobenzene (19.0 g, 122.5 mmol, 1.0 equiv.) and phenol (23.0 g, 244.7 mmol, 2.0 equiv.) were dissolved in DMF (100 mL), then K2CO3 (50.8 g, 367.4 mmol, 3.0 equiv.) was added. The reaction mixture was heated to 80 °C for 2 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1 :9) to give 2-methyl- l-nitro-4-phenoxybenzene (31.0 g) as a yellow solid. ¹ H NMR

(400 MHz, DMSO-d ₆ ): δ 8.08 (d, J=8.0 Hz, 1H), 7.52-7.47 (m, 2H), 7.31-7.27 (m, 1H),

7.19-7.15 (m, 2H), 7.07-7.06 (m, 1H), 6.94-6.91 (m, 1H), 2.53 (s, 3H). Step 2: dimethyl [(E)-2-(2-nitro-5-phenoxyphenyl)ethenyl] amine

2 -Methyl- l-nitro-4-phenoxybenzene (6.9 g, 30.1 mmol, 1.0 equiv.) was dissolved in DMF (40 mL), then DMF-DMA (12.0 mL, 90.3 mmol, 3.0 equiv.) was added. The reaction mixture was heated to 90 °C for 3 hours, the cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give dimethyl [(E)-2-(2-nitro- 5-phenoxyphenyl)ethenyl]amine (2.2 g) as a red solid.

Step 3: 5-phenoxy-1H - indole

Dimethyl[(E)-2-(2-nitro-5-phenoxyphenyl)ethenyl]amine (11.0 g, 38.7 mmol, 1.0 equiv.) was dissolved in ethyl acetate (20 mL), then Pd/C (10% wt., 2.0 g). The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 16 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give 5- phenoxy-1H -indole (2.2 g) as a dark blue solid. ¹ H NMR (400 MHz, DMSO-dis): δ 7.32- 7.26 (m, 2H), 7.01-6.97 (m, 1H), 6.84-6.76 (m, 2H), 6.70-6.69 (m, 1H), 6.66-6.61 (m, 2H), 4.74 (s, 2H), 2.05 (s, 3H).

Step 4: 3-nitro-5-phenoxy-1H - indole

5-Phenoxy-1H -indole (3.0 g, 14.3 mmol, 1.0 equiv.) was dissolved in ACN (15 mL) and cooled to 0 °C. Then AgNO ₃ (3.7 g, 21.5 mmol, 1.5 equiv.) was added. This was followed by the addition of benzoyl chloride (3.0 g, 21.5 mmol, 1.5 equiv.). The reaction mixture was stirred for 1 hour at ambient temperature and then quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give 3-nitro-5-phenoxy-lH-indole (1.7 g) as a brown solid. LCMS Method A-l: [M+H] ⁺ = 255.

Step 5: tert- butyl A-(5-phenoxy-1H -indol-3-yl)carbamate 3-Nitro-5-phenoxy-1H -indole (3.0 g, 11.8 mmol, 1.0 equiv.) and (BofO (3.9 g, 17.7 mmol, 1.5 equiv.) were dissolved in MeOH (5 mL), then Pd/C (10% wt., 600.0 mg) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 16 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1 :4) to give tert-butyl N-(5-phenoxy-1H -indol-3-yl)carbamate (1.5 g) as a pale pink solid. LCMS Method A-l: [M+H] ⁺ = 325.

Step 6: 5-phenoxy-1H -indol-3-amine hydrochloride tert-Butyl N-(5-phenoxy-1H -indol-3-yl)carbamate (120.0 mg, 0.4 mmol, 1.0 equiv.) was dissolved in HCl/l,4-dioxane (4 M, 5 mL). The reaction mixture was stirred for 30 min at ambient temperature and then concentrated under vacuum to give 5-phenoxy- 1H- indol-3-amine hydrochloride (60.0 mg) as a brown solid. LCMS Method C-l: [M+H] ⁺ = 225. Synthesis of intermediate 41 (5-(l -isopropyl- 1 H-pyraz.ol-4-yl)- 1 H-indol-3-amine hydrochloride)

Step 1: 5-bromo-1H -indole-3-carbonyl azide 5-Bromo-1H -indole-3-carboxylic acid (30.0 g, 124.9 mmol, 1.0 equiv.) was dissolved in THF (150 mL), then TEA (26.1 mL, 187.4 mmol, 1.5 equiv.) and DPPA (37.8 g, 137.4 mmol, 1.1 equiv.) were added. The reaction mixture was stirred for 12 hours at ambient temperature, then quenched by the addition of water and stirred for an additional 10 min. The precipitated solid was collected by filtration and dried to give 5-bromo- 1H-indole-3- carbonyl azide (33.6 g) as an off-white solid. LCMS Method B-l: [M-H]- = 263.

Step 2: tert- butyl (5-bromo-1H -indol-3-yl)carbamate

5-Bromo-1H -indole-3-carbonyl azide (33.6 g, 126.7 mmol, 1.0 equiv.) was dissolved in t-BuOH (300 mL). The reaction mixture was heated to 80 °C for 12 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give tert-butyl (5-bromo- 1H-indol-3-yl)carbamate (22.1 g) as a pale white solid. LCMS Method A- 1: [M+H] ⁺ =311.

Step 3: tert- butyl N- [5-(l-isopropylpyrazol-4-yl)-1H -indol-3-yl] carbamate tert-Butyl N-(5-bromo-1H -indol-3-yl)carbamate (500.0 mg, 1.6 mmol, 1.0 equiv.) and l-isopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)p yrazole (417.3 mg, 1.8 mmol, 1.1 equiv.) were dissolved in 1,4-dioxane (6 mL) and water (0.6 mL), then Xphos Pd G3 (136.0 mg, 0.2 mmol, 0.1 equiv.) and Cs ₂ CO ₃ (2.1 g, 6.4 mmol, 4.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 100 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl N-[5-(l -isopropylpyrazol-4-yl)- 1H-indol- 3 -yl] carbamate (405.0 mg) as a white solid. LCMS Method C-l: [M+H] ⁺ = 341.

Step 4: 5-(l-isopropylpyrazol-4-yl)-1H -indol-3-amine hydrochloride tert- Butyl N-[5-(l -isopropylpyrazol-4-yl)-1H-indol-3-yl]carbamate (400.0 mg, 1.2 mmol, 1.0 equiv.) was dissolved in HCl/l,4-dioxane (4 M, 8 mL). The reaction mixture was stirred for 4 hours at ambient temperature and then concentrated under vacuum to give 5-(l-isopropylpyrazol-4-yl)-lH-indol-3-amine hydrochloride (400.0 mg) as a grey solid. LCMS Method C-l: [M+H] ⁺ = 241.

The intermediates in the following table were prepared using the same method described for Intermediate 41.

Synthesis of intermediate 43 ( 2-((2,2,2-trifluoroethoxy)methyl)pyridin-4-amine )

Ste 1 Step 2

48 49 Intermediate 43

Step 1: 4-nitro-2-[(2,2,2-trifluoroethoxy)methyl]pyridine

(4-Nitropyri din-2 -yl)methanol (2.0 g, 13.0 mmol, 1.0 equiv.) was dissolved in THF (20 mL), then MeONa (2.1 g, 38.9 mmol, 3.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.0 g, 26.0 mmol, 2.0 equiv.) were added. The reaction mixture was heated to 60 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 4-nitro-2-[(2,2,2-trifluoroethoxy)methyl]pyridine (1.0 g) as a yellow solid. LCMS Method A-l: [M+H] ⁺ = 237.

Step 2: 2-[(2,2,2-trifluoroethoxy)methyl]pyridin-4-amine 4-Nitro-2-[(2,2,2-trifluoroethoxy)methyl]pyridine (1.0 g, 4.2 mmol, 1.0 equiv.) was dissolved in EtOH (10 mL), then SnCh (4.0 g, 21.2 mmol, 5.0 equiv.) was added. The reaction mixture was heated to 60 °C for 5 min, then quickly cooled to 0 °C and quenched by the addition of aqueous NaOH (5M). The resulting solution was extracted with ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate, then concentrated under vacuum to give 2-[(2,2,2-trifluoroethoxy)methyl]pyridin-4-amine (478.0 mg) as a yellow oil. LCMS Method B-l : [M+H] ⁺ = 207.

Synthesis of intermediate 44 ( l-(4-(trifluoromethyl)benzyl)-lH-pyrazole-4 - carboxylic acid)

Intermediate 44

Step 1: methyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylate

Methyl 6-chloro-5-methylpyridine-3-carboxylate (1.0 g, 5.4 mmol, 1.0 equiv.) and trifluoroethanol (0.4 mL, 5.4 mmol, 1.0 equiv.) were dissolved in toluene (10 mL), then CS2CO3 (3.5 g, 10.8 mmol, 2.0 equiv.), BrettPhos (578.4 mg, 1.1 mmol, 0.2 equiv.) and BrettPhos Pd G3 (488.4 mg, 0.5 mmol, 0.1 equiv.) were added under atmosphere of nitrogen. The reaction mixture was heated to 80 °C overnight, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give methyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylate (900 mg) as a yellow solid. LCMS Method A-l : [M+H] ⁺ = 250.

Step 2: [5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methanol Methyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylate (900.0 mg, 3.6 mmol, 1.0 equiv.) was dissolved in THF (20 mL) and cooled to 0 °C, then LiAILL (274.2 mg, 7.2 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 2 hours at 0 °C and then quenched by the addition of NaiSOWOLLO. The solids were filtered out and the resolution solution was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give [5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methanol (700 mg) as a yellow solid. LCMS Method A-l : [M+H] ⁺ = 222.

Step 3: -(bromomethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine [5-Methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methanol (700.0 mg, 3.2 mmol, 1.0 equiv.) was dissolved in HBr (10 mL). The reaction mixture was heated to 80 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 5-(bromomethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (510 mg) as a yellow solid. LCMS Method B-l : [M+H] ⁺ = 284.

Synthesis of intermediate 45 ( l-(4-(trifluoromethyl)benzyl)-lH-pyrazole-4 - carboxylic acid) Step 1: ethyl l-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-4-carboxylate Ethyl 1H -pyrazole-4-carboxylate (300.0 mg, 2.1 mmol, 1.0 equiv.) and 1- (bromomethyl)-4-(trifluoromethyl)benzene (511.7 mg, 2.1 mmol, 1.0 equiv.) were dissolved in DMF (6 mL), then CS2CO3 (2.1 g, 6.4 mmol, 3.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature and then quenched by the 5 addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC with the following conditions: Column, C18 silica gel; mobile phase, water (NH4HCO3. 1 g/1 L) and ACN, 0% ACN increasing to 100% ACN within 25 min; Detector, UV 254 nm. This gave ethyl l-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-4-carboxylate (310 mg) as a white solid. 10 LCMS Method A-l : [M+H] ⁺ = 299.

Step 2: l-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-4-carboxylic acid

Ethyl l-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-4-carboxylate (200.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and water (2 mL), then NaOH (53.6 mg, 1.3 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 1 hour at ambient 15 temperature and then concentrated under vacuum. The residue was purified by Flash-Prep- HPLC with the following conditions: Column, C18 silica gel; mobile phase, water (10 mM NH4HCO3) and ACN, 0% ACN increasing to 100% within 25 min; Detector, UV 254 nm. This gave l-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-4-carboxylic acid (130 mg) as a white solid. LCMS Method B-l: [M-H]- = 269.

20 The intermediates in the following table were prepared using the same method described for Intermediate 45. : 9

Step 1: ethyl l-[2-(oxan-2-yloxy)ethyl]pyrazole-4-carboxylate

5 2-(2-Bromoethoxy)oxane (2.0 g, 9.6 mmol, 1.0 equiv.) and ethyl 1H -pyrazole-4- carboxylate (1.3 g, 9.6 mmol, 1.0 equiv.) were dissolved in ACN (15 mL), then K2CO3 (4.0 g, 28.7 mmol, 3.0 equiv.) was added. The reaction mixture was heated to 80 °C overnight, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum 10 ether (1:1) to give ethyl l-[2-(oxan-2-yloxy)ethyl]pyrazole-4-carboxylate (1.8 g) as a colorless oil. LCMS Method A-l: [M+H] ⁺ = 269.

Step 2: ethyl l-(2-hydroxyethyl)pyrazole-4-carboxylate

Ethyl l-[2-(oxan-2-yloxy)ethyl]pyrazole-4-carboxylate (1.0 g, 3.7 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL), then HCl/l,4-dioxane (4 M, 10 mL) was added. The 15 reaction mixture was stirred overnight at ambient temperature, then concentrated under vacuum. The residue was purified by reverse flash chromatography with following conditions: column, C18 silica gel; mobile phase A: water (0.1% TFA), mobile phase B: ACN; 10% Phase B to 30% gradient in 10 min; detector, UV 254 nm. This gave ethyl 1- (2-hydroxyethyl)pyrazole-4-carboxylate (900 mg) as a colorless oil. LCMS Method A-l: [M+H] ⁺ = 185.

Step 3: ethyl l-(2-[[5-(trifluoromethyl)pyridin-3-yl]oxy]ethyl)pyrazole-4- carboxylate

Ethyl l-(2-hydroxyethyl)pyrazole-4-carboxylate (500.0 mg, 2.7 mmol, 1.0 equiv.) and 5-(trifluoromethyl)pyridin-3-ol (442.7 mg, 2.7 mmol, 1.0 equiv.) was dissolved in THF (5 mL) and cooled to 0 °C, then PPh3 (1.1 g, 4.1 mmol, 1.5 equiv.) was added. This was followed by the addition of DIAD (0.7 mL, 4.1 mmol, 1.5 equiv.) dropwise at 0 °C under an atmosphere of nitrogen. The reaction mixture was stirred overnight at ambient temperature and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give ethyl l-(2-[[5-(trifluoromethyl)pyridin-3-yl]oxy]ethyl)pyrazole-4- carboxylate (400 mg) as a yellow oil. LCMS Method A-l : [M+H] ⁺ = 320.

Step 4: -(2-[[5-(trifluoromethyl)pyridin-3-yl]oxy]ethyl)pyrazole-4-c arboxylic acid

Ethyl l-(2-[[5-(trifluoromethyl)pyridin-3-yl]oxy]ethyl)pyrazole-4- carboxylate

(400.0 mg, 1.2 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (97.2 mg, 2.4 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80 °C for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, adjusted to pH 7 with aqueous HC1 (IN), extracted with dichloromethane and concentrated under vacuum. The residue was purified by reverse flash chromatography with following conditions: column, C18 silica gel; mobile phase A: water (0.1% MLCCh), phase B: ACN; 10% phase B to 50% gradient in 10 min; detector, UV 254 nm. This gave l-(2-[[5-(trifluoromethyl)pyridin-3-yl]oxy]ethyl)pyrazole-4- carboxylic acid (320 mg) as a colorless oil. LCMS Method A-l: [M+H] ⁺ = 302.

Synthesis of intermediate 49 (l-(5-fluoro-6-((2,2,2-trifluoroethyl)amino)pyridin- 3-yl)-lH-l,2,3-triazole-4-carboxylic acid)

Step 1: 3-fluoro-5-nitro-A-(2,2,2-trifluoroethyl)pyridin-2-amine

2-Chloro-3-fluoro-5-nitropyridine (1.0 g, 5.7 mmol, 1.0 equiv.) and 2,2,2- trifluoroethylamine (561.1 mg, 5.7 mmol, 1.0 equiv.) were dissolved in ACN (10 mL), then

K2CO3 (2.3 g, 17.0 mmol, 3.0 equiv.) was added. The reaction mixture was heated to 80 °C for 16 hours, then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 3-fluoro-5-nitro-N-(2,2,2- trifluoroethyl)pyridin-2-amine (510.0 mg) as a white solid. LCMS Method A-l: [M+H] ⁺ = 240.

Step 2: 3-fluoro-A2-(2, 2, 2-trifluoroethyl)pyridine-2, 5-diamine

3-Fluoro-5-nitro-N-(2,2,2-trifluoroethyl)pyridin-2-amine (500.0 mg, 2.1 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL), then Pd/C (10% wt., 100.0 mg) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 16 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum to give 3-fluoro-N2-(2,2,2- trifluoroethyl)pyridine-2, 5-diamine (400.0 mg) as a white solid. LCMS Method A-l: [M+H] ⁺ = 210.

Step 3: 5-azido-3-fluoro-N-(2,2,2-trifluoroethyl)pyridin-2-amine

3-Fluoro-N2-(2, 2, 2-trifluoroethyl)pyridine-2, 5-diamine (400.0 mg, 1.9 mmol, 1.0 equiv.) was dissolved in ACN (10 mL) and cooled to 0 °C, then /-BuNCh (295.8 mg, 2.9 mmol, 1.5 equiv.) was added. After 1 hour at 0 °C, TMSN3 (340.1 mg, 2.5 mmol, 1.3 equiv.) was added. The resulting solution was stirred for additional 2 hours at 0 °C, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 5-azido-3-fluoro-N-(2,2,2-trifluoroethyl)pyridin-2- amine (250.0 mg) as a white solid. LCMS Method A-l: [M+H] ⁺ = 236.

Step 4: methyl l-[5-fluoro-6-[(2,2,2-trifluoroethyl)amino]pyridin-3-yl]-l,2 ,3- triazole-4-carboxylate

5-Azido-3-fluoro-N-(2,2,2-trifluoroethyl)pyridin-2-amine (250.0 mg, 1.1 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (10 mL), then CuSCri (17.0 mg, 0.1 mmol, 0.1 equiv.), sodium ascorbate (18.7 mg, 0.1 mmol, 0.1 equiv.) and methyl propiolate (134.1 mg, 1.6 mmol, 1.5 equiv.) were added. The reaction mixture was stirred for 16 hours at ambient temperature, then diluted with ethyl acetate. The resulting solution was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give methyl l-[5-fhioro-6-[(2,2,2-trifluoroethyl)amino]pyridin-3-yl]-l,2 ,3- triazole-4-carboxylate (200.0 mg) as a white solid. LCMS Method A-l: [M+H] ⁺ = 320.

Step 5: l-[5-fluoro-6-[(2,2,2-trifluoroethyl)amino]pyridin-3-yl]-l,2 ,3-triazole-4- carboxylic acid

Methyl l-[5-fluoro-6-[(2,2,2-trifluoroethyl)amino]pyridin-3-yl]-l,2 ,3-triazole-4- carboxylate (200.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and water (2 mL), then NaOH (50.1 mg, 1.3 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80 °C for 30 min, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, adjusted to pH 6 with aqueous HC1 (4N), extracted with dichloromethane and concentrated under vacuum to give l-[5-fluoro-6- [(2,2,2-trifluoroethyl)amino]pyridin-3-yl]-l,2,3-triazole-4- carboxylic acid (110.0 mg) as a white solid. LCMS Method A-l: [M+H] ⁺ = 306.

Synthesis of intermediate 50 (l-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-1H- l,2,3-triazole-4-carboxylic acid)

Step 1: 3-fluoro-5-nitro-2-(2,2,2-trifluoroethoxy)pyridine 2-Chloro-3-fluoro-5-nitropyridine (1.0 g, 5.7 mmol, 1.0 equiv.) and trifluoroethanol

(510.0 mg, 5.1 mmol, 0.9 equiv.) were dissolved in DMF (20 mL), then K ₂ CO ₃ (1.2 g, 8.5 mmol, 1.5 equiv.) was added. The reaction mixture was heated to 80 °C for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC with the following conditions: Column, C18 silica gel; mobile phase, H ₂ O/ACN, 10% ACN increasing to 90% within 30 min; Detector, 254 nm. This gave 3- fluoro-5-nitro-2-(2,2,2-trifluoroethoxy)pyridine (700.0 mg) as a dark yellow solid. LCMS Method A-l: [M+H] ⁺ = 241.

Steps 2-5: l-[5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-l,2,3-tri azole-4- carboxylic acid The title compound was prepared using the same methods described for Intermediate 49, Steps 2-5. LCMS: Method B-l, [M+H] ⁺ = 307.

Synthesis of intermediate 51 (l-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)~ lH-l,2,3-triazole-4-carboxylic acid) p

Step 1: 5-bromo-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine

2,5-Dibromo-3-methylpyridine (1.0 g, 4.0 mmol, 1.0 equiv.) was dissolved in THF (20 mL), then (2,2,2-trifluoroethoxy)sodium (583.6 mg, 4.8 mmol, 1.2 equiv.) was added. The reaction mixture was heated to 60 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give 5-bromo-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (800 mg) as a yellow oil. LCMS Method A-l : [M+H] ⁺ = 270. Step 2: 5-azido-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine

5-Bromo-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (800.0 mg, 3.0 mmol, 1.0 equiv.) was dissolved in DMF (15 mL), then methyl[2-(methylamino)ethyl]amine (0.7 mL, 5.9 mmol, 2.0 equiv.), NaN3 (385.2 mg, 5.9 mmol, 2.0 equiv.), Cul (56.4 mg, 0.3 mmol, 0.1 equiv.) and sodium ascorbate (59.0 mg, 0.3 mmol, 0.1 equiv.) were added. The resulting solution was heated to 80 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give 5-azido-3-methyl-2-(2,2,2- trifluoroethoxy)pyridine (500 mg) as a yellow oil. LCMS Method A-l: [M+H] ⁺ = 233.

Steps 3-4: l-[5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-l,2,3-tri azole-4- carboxylic acid The title compound was prepared using the same methods described for

Intermediate 49, Steps 4-5. LCMS: Method A-l, [M+H] ⁺ = 303.

Synthesis of intermediate 52 (l-(4-(trifluoromethyl)benzyl)-lH-l,2,3-triazole-4- carboxylic acid) Step 1: l-(azidomethyl)-4-(trifluoromethyl)benzene l-(Bromomethyl)-4-(trifluoromethyl)benzene (500.0 mg, 2.1 mmol, 1.0 equiv.) was dissolved in DMF (10 mL), then NalNb (272.0 mg, 4.2 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80 °C for 4 hours, then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum to give l-(azidomethyl)- 4-(trifluoromethyl)benzene (300 mg) as a yellow oil. LCMS Method A-l: [M+H] ⁺ = 202

Step 2: l-[[4-(trifluoromethyl)phenyl]methyl]-l,2,3-triazole-4-carbo xylic acid

The title compound was prepared using the same methods described for Intermediate 49, Steps 4-5. LCMS Method A-l, [M+H] ⁺ = 272.

Synthesis of intermediate 53 (5-(4-(trifluoromethyl)benzyl)isoxazole-3- carboxylic acid)

Intermediate 53

Step 1: N-methoxy-N-methyl-2-[4-(trifluoromethyl)phenyl]acetamide

2-[4-(Trifluoromethyl)phenyl]acetaldehyde (5.0 g, 26.6 mmol, 1.0 equiv.), HATU (15.2 g, 39.9 mmol, 1.5 equiv.) and A,O-dimethylhydroxylamine hydrochloride (1.6 g, 26.5 mmol, 1.0 equiv.) were dissolved in DCM (50 mL), then DIEA (18.5 mL, 106.3 mmol, 4.0 equiv.) was added dropwise. The reaction mixture was stirred for 2 hours at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum to give N-methoxy-N-methyl-2-[4- (trifluoromethyl)phenyl]acetamide (5.0 g) as a yellow solid. LCMS Method A-l: [M+H] ⁺ = 248.

Step 2: l-[4-(trifluoromethyl)phenyl]propan-2-one N-methoxy-N-methyl-2-[4-(trifluoromethyl)phenyl]acetamide (5.0 g, 20.2 mmol,

1.0 equiv.) was dissolved in THF (50 mL) and cooled to 0 °C, then MeMgBr (1M in THF, 24.2 mL, 24.2 mmol, 1.2 equiv.) was added dropwise under an atmosphere of nitrogen, maintaining the solution at 0 °C. The reaction mixture was stirred for 2 hours at 0 °C and then quenched by the addition of saturated aqueous MLCl. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 1- [4-(trifluoromethyl)phenyl]propan-2-one (1.5 g) as a yellow solid. LCMS Method A-l: [M+H] ⁺ = 203.

Step 3: ethyl 2,4-dioxo-5-[4-(trifluoromethyl)phenyl]pentanoate l-[4-(trifluoromethyl)phenyl]propan-2-one (1.0 g, 4.9 mmol, 1.0 equiv.) was dissolved in EtOH (10 mL) and cooled to 0 °C, then EtONa (0.4 g, 5.4 mmol, 1.1 equiv.) was added. This was followed by the addition of ethyl oxalate (0.7 mL, 4.9 mmol, 1.0 equiv.) dropwise at 0 °C. The reaction mixture was stirred for 2 hours at ambient temperature and then quenched by the addition of water. The resulting solution was adjusted to pH 5 with aqueous HC1 (4M), extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum to give ethyl 2,4- dioxo-5-[4-(trifluoromethyl)phenyl]pentanoate (600.0 mg) as a yellow solid. LCMS Method C-l: [M+H] ⁺ = 303.

Step 4: ethyl 5-[[4-(trifluoromethyl)phenyl]methyl]-l,2-oxazole-3-carboxyl ate

Ethyl 2,4-dioxo-5-[4-(trifluoromethyl)phenyl]pentanoate (700.0 mg, 2.3 mmol, 1.0 equiv.) was dissolved in EtOH (10 mL), then hydroxylamine hydrochloride (193.1 mg, 2.8 mmol, 1.2 equiv.) was added. The reaction mixture was irradiated with microwave radiation for 3 hours at 60 °C, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2S04 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give ethyl 5-[[4-(trifluoromethyl)phenyl]methyl]-l,2- oxazole-3-carboxylate (650 mg) as an off-white solid. LCMS Method A-l: [M+H] ⁺ = 300.

Step 5: 5-[[4-(trifluoromethyl)phenyl]methyl]-l,2-oxazole-3-carboxyl ic acid

Ethyl 5-[[4-(trifluoromethyl)phenyl]methyl]-l,2-oxazole-3-carboxyl ate (650.0 mg, 2.2 mmol, 1.0 equiv.) was dissolved in MeOH (4 mL) and water (4 mL), then LiOH (78.0 mg, 3.3 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 1 hour at ambient temperature, then concentrated under vacuum. The residue was diluted with water, adjusted to pH 6 with aqueous HC1 (4M), then extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 5-[[4-(trifluoromethyl)phenyl]methyl]-l,2- oxazole-3 -carboxylic acid (500 mg) as an off-white solid. LCMS Method C-l: [M+H] ⁺ = 272.

Synthesis of intermediate 18 ( l-methyl-5-(4-(trifluoromethyl)benzyl)-lH - pyrazole-3-carboxylic acid)

Step 1: ethyl 5- [[4-(tnfluoromethyl)phenyl| methyl |-1H -pyrazole-3-carboxylate Ethyl 2,4-dioxo-5-[4-(trifluoromethyl)phenyl]pentanoate (850.0 mg, 2.8 mmol, 1.0 equiv.) was dissolved in AcOH (10 mL), then hydrazine hydrochloride (138.0 mg, 2.8 mmol, 1.0 equiv.) was added. The reaction mixture was stirred for 2 hours at ambient temperature, then concentrated under vacuum. The residue was purified by reverse flash chromatography with following conditions: column, C18 silica gel; mobile phase, ACN/water, 0% ACN to 100% gradient in 15 min; detector, UV 254 nm. This gave ethyl 5-[[4-(trifluoromethyl)phenyl]methyl]- 1H-pyrazole-3 -carboxyl ate (400 mg) as a yellow solid. LCMS Method C-l: [M+H] ⁺ = 299.

Step 2: ethyl l-methyl-5-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-3-car boxylate

Ethyl 5-[[4-(trifluoromethyl)phenyl]methyl]-1H-pyrazole-3-carboxyl ate (400.0 mg, 1.3 mmol, 1.0 equiv.) was dissolved in THF (4 mL) and cooled to 0 °C, then NaH (107.3 mg, 2.7 mmol, 2.0 equiv.) was added, maintaining the solution at 0 °C. After 5 min at 0 °C, Mel (0.15 mL, 2.0 mmol, 1.5 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature, then quenched by the addition of aqueous HC1 (1M). The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give ethyl l-methyl-5-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-3- carboxylate (200 mg) as an off-white solid. LCMS Method A-l: [M+H] ⁺ = 313.

Step 3: l-methyl-5-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-3-car boxylic acid

Ethyl l-methyl-5-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-3-car boxylate (300.0 mg, 1.0 mmol, 1.0 equiv.) was dissolved in MeOH (3 mL) and water (3 mL), then NaOH (76.9 mg, 1.9 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80 °C for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, then adjusted to pH 5 with aqueous HC1 (4M). The solid was collected by filtration and dried to give l-methyl-5-[[4- (trifluoromethyl)phenyl]methyl]pyrazole-3-carboxylic acid (210.0 mg) as a white solid. LCMS Method B-l : [M+H] ⁺ = 285.

The intermediates in the following table were prepared using the same method described for Intermediate 18.

Synthesis of intermediate 55 ( 5-((l-(2,2,2-trifluoroethyl)piperidin-4 - yl)methyl)isoxazole-3-carboxylic acid)

Intermediate 55

Steps 1-4: benzyl 4-[[3-(ethoxycarbonyl)-l,2-oxazol-5-yl]methyl]piperidine-l- carboxylate

The title compound was prepared using the same methods described for synthesis of Intermediate 53, Steps 1-4. LCMS Method C-l, [M+H] ⁺ = 373.

Step 5: ethyl 5-(piperidin-4-ylmethyl)-l,2-oxazole-3-carboxylate

Benzyl 4-[[3-(ethoxycarbonyl)-l,2-oxazol-5-yl]methyl]piperidine-l-c arboxylate (700.0 mg, 1.9 mmol, 1.0 equiv.) was dissolved in HBr-AcOH (7 mL). The reaction mixture was stirred for 2 hours at ambient temperature, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give ethyl 5-(piperidin-4-ylmethyl)-l,2-oxazole- 3-carboxylate (400 mg) as a pale-yellow solid. LCMS Method A-l: [M+H] ⁺ = 239.

Step 6: ethyl 5-[[l-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl]-l,2-oxazo le-3- carboxylate Ethyl 5-(piperidin-4-ylmethyl)-l,2-oxazole-3-carboxylate (400.0 mg, 1.7 mmol, 1.0 equiv.) and 2,2,2-trif uoroethyl trifluoromethanesulfonate (304.8 mg, 2.5 mmol, 1.5 equiv.) were dissolved in DMF (4 mL), then CS2CO3 (1.1 g, 3.4 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 60 °C overnight, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give ethyl 5-[[l-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl]-l,2-oxazo le-3-carboxylate (200.0 mg) as a pale yellow solid. LCMS Method B-l: [M+H] ⁺ = 321.

Step 7: 5-[[l-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl]-l,2-oxazo le-3-carboxylic acid

Ethyl 5-[[l-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl]-l,2-oxazo le-3-carboxylate (200.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and water (2 mL), then LiOH (59.8 mg, 2.5 mmol, 4.0 equiv.) was added. The reaction mixture was stirred overnight at room temperature and concentrated under vacuum. The residue was purified by reverse flash chromatography with following conditions: column, C18 silica gel; mobile phase 10% ACN increasing to 90% within 30 min; detector, UV 254 nm. This gave 5-[[l-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl]-l,2-oxazo le-3-carboxylic acid (130.0 mg) as a white solid. LCMS Method A-l: [M+H] ⁺ = 293.

Synthesis of intermediate 56 (3-(4-(trifluoromethyl)phenethyl)isoxazole-5-carboxylic acid)

Step 1: 3-[4-(trifluoromethyl)phenyl]propan-l-ol

3-[4-(Trifluoromethyl)phenyl]propanoic acid (1.0 g, 4.6 mmol, 1.0 equiv.) was dissolved in THF (10 mL) and cooled to 0 °C, then LiAILL (347.9 mg, 9.2 mmol, 2.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature, then quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum to give 3-[4-(trifluoromethyl)phenyl]propan-l-ol (750.0 mg) as a yellow oil that was used without additional purification. LCMS Method A-l: [M+H] ⁺ = 205. Step 2: 3-[4-(trifluoromethyl)phenyl]propanal

3-[4-(Trifhioromethyl)phenyl]propan-l-ol (750.0 mg, 3.7 mmol, 1.0 equiv.) was dissolved in DCM (8 mL) and cooled to 0 °C, then Dess-Martin reagent (3.1 g, 7.3 mmol, 2.0 equiv.) was added at °C. The reaction mixture was stirred overnight at ambient temperature and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1 :9) to give 3-[4-(trifluoromethyl)phenyl]propanal (510.0 mg) as a yellow oil. LCMS Method B-l: [M+H] ⁺ = 203.

Step 3: A-[3-[4-(trifluoromethyl)phenyl]propylidene]hydroxylamine 3-[4-(trifluoromethyl)phenyl]propanal (500.0 mg, 2.5 mmol, 1.0 equiv.) and hydroxylamine hydrochloride (257.8 mg, 3.7 mmol, 1.5 equiv.) were dissolved in EtOH (5 mL) and water (5 mL), then NaOH (197.8 mg, 4.9 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 90 °C for 2 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give N-[3-[4- (trifluoromethyl)phenyl]propylidene]hydroxylamine (405.0 mg) as a yellow solid. LCMS Method A-l: [M+H] ⁺ = 218.

Step 4: N-hydroxy-3-[4-(trifluoromethyl)phenyl]propanecarbonimidoyl chloride N-[3-[4-(trifluoromethyl)phenyl]propylidene]hydroxylamine (400.0 mg, 1.8 mmol, 1.0 equiv.) was dissolved in DMF (4 mL), then NCS (245.9 mg, 1.8 mmol, 1.0 equiv.) was added. The reaction mixture was heated to 50 °C for 2 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum to give N-hydroxy-3-[4-

(trifluoromethyl)phenyl]propanecarbonimidoyl chloride (410.0 mg) as a yellow solid. LCMS Method C-l : [M+H] ⁺ = 252.

Step 5: methyl 3-[2-[4-(trifluoromethyl)phenyl]ethyl]-l,2-oxazole-5-carboxy late N-hydroxy-3-[4-(trifluoromethyl)phenyl]propanecarbonimidoyl chloride (400.0 mg, 1.6 mmol, 1.0 equiv.) and methyl propiolate (133.7 mg, 1.6 mmol, 1.0 equiv.) were dissolved in CHCb (4 mL), then NaOH (127.2 mg, 3.2 mmol, 2.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2S04 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give methyl 3-[2-[4-(trifluoromethyl)phenyl]ethyl]-l,2- oxazole-5-carboxylate (250.0 mg) as a yellow solid. LCMS Method A-l : [M+H] ⁺ = 300.

Step 6: 3-[2-[4-(trifluoromethyl)phenyl]ethyl]-l,2-oxazole-5-carboxy lic acid Methyl 3-[2-[4-(trifluoromethyl)phenyl]ethyl]-l,2-oxazole-5-carboxy late (250.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and water (2 mL), then NaOH (66.8 mg, 1.7 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80 °C for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water and the resulting solution was adjusted to pH 6 with aqueous HC1 (4M), extracted with dichloromethane and concentrated under vacuum to give 3-[2-[4-(trifluoromethyl)phenyl]ethyl]-l,2-oxazole-5-carboxy lic acid (180.0 mg) as a yellow solid. LCMS Method C-l : [M+H] ⁺ = 286.

Synthesis of intermediate 57 (3-(4-(trifluoromethyl)benzyl)isoxazole-5- carboxylic acid)

Intermediate 57

Steps 1-5: 3-[[4-(trifluoromethyl)phenyl]methyl]-l,2-oxazole-5-carboxyl ic acid

The title compound was prepared using the same methods described for synthesis of Intermediate 56, Steps 2-6. LCMS Method C-l, [M+H] ⁺ = 272.

Synthesis of intermediate 58 (7-methyl-lH-pyrrolo[3,2-c]pyridine)

Steps 1-3: tert- butyl 4-[[5-(methoxycarbonyl)-l,2-oxazol-3-yl]methyl]piperidine-l- carboxylate

The title compound was prepared using the same methods described for synthesis of Intermediate 56, Steps 2-4. LCMS Method C-l, [M+H] ⁺ = 325.

Step 4: methyl 3-(piperidin-4-ylmethyl)-l,2-oxazole-5-carboxylate hydrochloride tert-Butyl 4-[[5-(methoxy carbonyl)- l,2-oxazol-3-yl]methyl]piperi dine- 1- carboxylate (1.0 g, 3.1 mmol, 1.0 equiv.) was dissolved in ethyl acetate (10 mL), then HCl/l,4-dioxane (4M, 10 mL) was added. The reaction mixture was stirred for 3 hours at ambient temperature. The precipitated solids were collected by filtration and washed with ethyl ether to give methyl 3-(piperidin-4-ylmethyl)-l,2-oxazole-5-carboxylate hydrochloride (510.0 mg) as a white solid. LCMS Method A-l: [M+H] ⁺ = 225.

Step 5: methyl 3-[[l-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl]-l,2-oxazo le-5- carboxylate Methyl 3-(piperidin-4-ylmethyl)-l,2-oxazole-5-carboxylate hydrochloride (700.0 mg, 3.1 mmol, 1.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (566.8 mg,

4.7 mmol, 1.5 equiv.) was dissolved in DMF (7 mL), then CS2CO3 (2.0 g, 6.2 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 60 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum to give methyl 3-[[l-(2,2,2-trifluoroethyl)piperidin-4- yl]methyl]-l,2-oxazole-5-carboxylate (550.0 mg) as a pale yellow oil. LCMS Method A-l: [M+H] ⁺ = 307.

Step 6: 3-[[l-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl]-l,2-oxazo le-5-carboxylic acid Methyl 3-[[l-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl]-l,2-oxazo le-5- carboxylate (550.0 mg, 1.8 mmol, 1.0 equiv.) was dissolved in MeOH (6 mL) and water (6 mL), then LiOH (172.0 mg, 7.2 mmol, 4.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature and concentrated under vacuum. The residue was diluted with water, adjusted to pH 5 with cone. HC1. The precipitated solids were collected by filtration, washed with water and further purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, 10% ACN to 100% gradient in 20 min; detector, UV 254 nm. This gave 3-[[l-(2,2,2- trifluoroethyl)piperidin-4-yl]methyl]-l,2-oxazole-5-carboxyl ic acid (320.0 mg) as a white solid. LCMS Method C-l: [M+H] ⁺ = 293. Example 1: N-(5,6-difluoro-Li/-indol-3-yl)-5-oxo-l-(4-(trifluoromethyl) benzyl)- 4, 5-dihydro- lH-1, 2, 4-triazole-3-carboxamide (Compound 142)

5-oxo-l-[[4-(trifluoromethyl)phenyl]methyl]-4H-l,2,4-tria zole-3-carboxylic acid (300.0 mg, 1.0 mmol, 1.0 equiv.) was dissolved in DMF (10.0 mL), then 5,6-difluoro-lH- indol-3-amine hydrogen chloride (204.5 mg, 1.0 mmol, 1.0 equiv.), NMM (0.2 mL, 2.1 mmol, 2.0 equiv.) and PyBOP (1.1 g, 2.1 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for 3 hours at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3). The material was further purified by Prep-HPLC with the following conditions: Column, YMC-Actus Triart C18, 30*250, 5μm; mobile phase, Water (10 mM NH4HCO3+0.1% NH4OH) and ACN (20% Phase B up to 45% in 7 min); Detector, UV 254 nm. This resulted in A-(5,6-difluoro-1H -indol-3-yl)-5-oxo-l-[[4- (trifluoromethyl)phenyl]methyl]-4H -l ,2,4-tri azole-3 -carboxamide (106.0 mg) as an off- white solid. LCMS Method C: [M+H] ⁺ = 438. ¹ HNMR (400 MHz, DMSO-d ₆ ): δ 12.61 (s, 1H), 11.17 (s, 1H), 10.54 (s, 1H), 7.86-7.80 (m, 2H), 7.76-7.74 (m, 2H), 7.52 (d, 2H), 7.40-7.35 (m, 1H), 5.10 (s, 2H).

The following compounds were prepared using the same method described for Example 1 Example 4: N-(5-chloro-6-fluoro-1H -indol-3-yl)-l-(4-(trifluoromethyl)benzyl)-Li/- pyrazole-4-carboxamide (Compound 141)

5-chloro-6-fluoro-lH-indol-3-amine hydrochloride (200.0 mg, 0.9 mmol, 1.0 equiv.) was added in ACN (5.0 mL), then l-[[4-(trifluoromethyl)phenyl] methyl]pyrazole-4- carboxylic acid (244.4 mg, 0.9 mmol, 1.0 equiv.), T3P (863.6 mg, 1.3 mmol, 1.5 equiv.) and TEA (0.3 mL, 1.8 mmol, 2.0 equiv.) were added. The reaction mixture was heated to 60 °C for 2 hours, then cooled to ambient temperature and quenched by the addition of aqueous NaOH (IN). The solids were collected by filtration and further purified by Prep- HPLC with the following conditions: Column, XBridge Prep OBD Cl 8 Column, 30*150mm 5μm; mobile phase, Water (10 mM NH4HCO3) and ACN (40% Phase B up to 65% in 7 min); Detector, UV 254nm. This resulted in N-(5 -chi oro-6-fl uoro- 1 H-i ndol -3 - yl)-l-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-4-carboxam ide (96.6 mg) as a pink solid. Method A: [M+H] ⁺ = 437. ¹ HNMR (400 MHz, DMSO-d ₆ ): δ 11.13 (s, 1H), 9.80 (s, 1H), 8.53 (s, 1H), 8.13 (s, 1H), 8.05 (d, 1H), 7.80-7.75 (m, 3H), 7.49 (d, 2H), 7.36 (d, 1H),

5.54 (s, 2H).

The following compounds were prepared using the same method described for Example 4

Example 12: N-(6-chloro-1H -indol-3-yl)-l-[[4-

(trifluoromethyl)phenyl] methyl] pyrazole-4-carboxamide (Compound 102) l-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-4-carboxylic acid (194.6 mg, 0.7 mmol, 1.0 equiv.) was dissolved in DCM (20.0 mL), then DIEA (0.2 mL, 1.4 mmol, 2.0 equiv.), HATU (547.7 mg, 1.4 mmol, 2.0 equiv.) and 6-chloro-1H -indol-3-amine hydrogen chloride (146.2 mg, 0.7 mmol, 1.0 equiv.) were added. The reaction mixture was stirred for 3 hours at ambient temperature and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1 :4). The material was further purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C18, 30*250, 5μm; Mobile Phase A: Water (10NM NH4HCO3+0.1% NH4OH), Mobile Phase B: ACN; Flow rate:60 mL/min; Gradient:45% B to 65% B in 10 min; 254/210 nm. This resulted in A-(6-chloro-1H -indol-3-yl)-l-[[4- (trifluoromethyl)phenyl]methyl]pyrazole-4-carboxamide (116.8 mg) as an off-white solid. LCMS Method C: [M+H] ⁺ = 419. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.03 (s, 1H), 9.82 (s, 1H), 8.52 (s, 1H), 8.13 (s, 1H), 7.83-7.75 (m, 4H), 7.50-7.47 (m, 2H), 7.41 (d, 1H), 7.05-7.02 (m, 1H), 5.54 (s, 2H). The compounds in the following table were prepared using the same method described for Example 12.

Example 30/31: ( R or S)-N-(5,6-difliioro-1H -indol-3-yl)-l-(l-(4-

(trifluoromethyl)phenyl)ethyl)-1H -pyrazole-4-carboxamide; Compound 121 (front peak, stereochemistry unconfirmed) and ( R or »S)-N-(5,6-difluoro-Li/-indol- 3-yl)-l-(l-(4-(trifluoromethyl)phenyl)ethyl)-1H -pyrazole-4-carboxamide; Compound 120 (second peak, stereochemistry unconfirmed).

The racemic N-(5,6-difluoro-1H -indol-3-yl)-l-(l-(4-(trifluoromethyl)phenyl)ethyl)- I H -pyrazole-4-carboxamide was prepared using the same method described for Example 12 with intermediate 4 and intermediate 19, then separated by Prep-chiral -HPLC with the following conditions: Column: CHIRAL ART Cellulose-SC, 2*25cm,5μm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL/min; Gradient: 20 B to 20 B in 12 min; 220/254 nm; RTE5.485; RT2:9.178. This resulted in front peak (stereochemistry unconfirmed, assigned as Compound 121, 76.2 mg) as a pink solid and second peak (stereochemistry unconfirmed, assigned as Compound 120, 68.3 mg) as a pink solid.

Compound 121: (R or 5)-N-(5,6-difluoro-1H -indol-3-yl)-l-(l-(4-

(trifluoromethyl)phenyl)ethyl)-1H-pyrazole-4-carboxamide; LCMS Method C: [M+H] ⁺ = 435. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 11.03 (brs, 1H), 9.71 (s, 1H), 8.55 (s, 1H), 8.10 (s, 1H), 7.81-7.72 (m, 4H), 7.49 (d, 2H), 7.39-7.33 (m, 1H), 5.83 (q, 1H), 1.87 (d, 3H).

Compound 120: (R or ri)-/V-(5,6-difluoro-li7-indol-3-yl)-l-(l-(4-

(tri fluoiOrn ethyl )phenyl)ethyl)- lH -pyrazole-4-carboxamide; LCMS Method C: [M+H] ⁺ = 435. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 11.02 (s, 1H), 9.71 (s, 1H), 8.55 (s, 1H), 8.10 (s,

1H), 7.81-7.72 (m, 4H), 7.49 (d, 2H), 7.39-7.33 (m, 1H), 5.83 (q, 1H), 1.87 (d, 3H).

Example 32: A-(5-(l-isopropyl-Li/-pyrazol-4-yl)-Li/-indol-3-yl)-l-(4-

(trifluoromethyl)phenyl)-1H -imidazole-4-carboxamide (Compound 139)

Compound 139 Step 1: N-(5-bromo-1H -indol-3-yl)-l-(4-(trifluoromethyl)phenyl)-1H -imidazole-4- carboxamide l-[4-(trifluoromethyl)phenyl]imidazole-4-carboxylic acid (200.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved DMF (5.0 mL), then DIEA (0.4 mL, 2.3 mmol, 3.0 equiv.), HATU (445.3 mg, 1.2 mmol, 1.5 equiv.) and 5-bromo-lH-indol-3-amine hydrogen chloride (231.9 mg, 0.9 mmol, 1.2 equiv.) were added. The reaction mixture was stirred overnight at ambient temperature and then concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions: Column, C18 silica gel; mobile phase, water (10 mM NH4HCO3) and ACN (10% ACN to 90% ACN within 40 min); Detector, UV 254 nm. This resulted in 2-(5-bromo-1H -indol-3-yl)-l-[l-[4- (trifluoromethyl)phenyl]imidazol-4-yl]ethanone (140 mg) as a white solid. LCMS Method C: [M+H] ⁺ = 449. Step 2: N-(5-(l-isopropyl-1H -pyrazol-4-yl)-1H -indol-3-yl)-l-(4-

(trifluoromethyl)phenyl)-1H -imidazole-4-carboxamide

2-(5-bromo-1H -indol-3-yl)-l-[l-[4-(trifluoromethyl)phenyl]imidazol-4-yl]e thanone (100.0 mg, 0.2 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (3.0 ml) and water (0.3 mL), then l-isopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)p yrazole (63.2 mg, 0.3 mmol, 1.2 equiv.), CS2CO3 (218.1 mg, 0.7 mmol, 3.0 equiv.) and XPhos (10.6 mg, 0.02 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 90 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column, YMC-Actus Triart C18, 30*250, 5μm; mobile phase, Water (10 mM NH4HCO3) and ACN (42% Phase B up to 66% in 7 min); Detector, UV 254 min. This resulted in N- [5-(l-isopropylpyrazol-4-yl)-1H -indol-3-yl]-l-[4-(trifluoromethyl)phenyl]imidazole-4- carboxamide (13.0 mg) as a white solid. LCMS Method C: [M+H] ⁺ = 479. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.87 (s, 1H), 9.70 (s, 1H), 8.63 (s, 1H), 8.56 (s, 1H), 8.15 (s, 1H), 8.08 (d, 2H), 7.96-7.94 (m, 3H), 7.82 (s, 1H), 7.77 (d, 1H), 7.35 (s, 2H), 4.54-4.50 (m, 1H), 1.46 (d, 6H).

The compounds in the following table were prepared using the same method described for Example 32.

Example 35: N-(5-(3-fluoro-4-(hydroxymethyl)phenyl)-1H -indol-3-yl)-l-(4-

(trifluoromethyl)benzyl)-1H -imidazole-4-carboxamide (Compound 137)

Compound 32 was prepared using the same method desired for Example 32. Methyl 2-fluoro-4-[3-(l-[[4-(trifluoromethyl)phenyl]methyl]imidazol e-4-amido)- 1H -indol-5-yl]benzoate (200.0 mg, 0.4 mmol, 1.0 equiv.) was dissolved in THF (15.0 mL) and the solution was cooled to 0 °C. Then LiAIH ₄ (28.3 mg, 0.7 mmol, 2.0 equiv.) was added in portions, maintaining the internal temperature at 0 °C. The reaction mixture was stirred for 1 hour at ambient temperature and then quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 5μm, 19* 150mm; Mobile Phase A: Water (10 mM NH ₄ HCO ₃ +0.1% MLOH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 38 B to 58 B in 10 min; 210/254 nm. This resulted in A-[5-[3- fluoro-4-(hydroxymethyl)phenyl]- 1H -indol-3 -yl]- 1 -[[4-

(trifluoromethyl)phenyl]methyl]imidazole-4-carboxamide (27.1 mg) as a brown yellow solid. LCMS Method C: [M+H] ⁺ = 509. ¹ H NMR (300 MHz, DMSO-d): δ 10.94 (brs, 1H), 9.76 (s, 1H), 8.18 (s, 1H), 7.99 (s, 1H), 7.91 (s, 1H), 7.79-7.75 (m, 3H), 7.57-7.40 (m, 7H), 5.42 (s, 2H), 5.23 (t, 1H), 4.57 (d, 2H).

Example 36: N-(5,6-difluoro-1H -indol-3-yl)-l-(4-(trifluoromethyl)phenyl)-1H -l,2,3- triazole-4-carboxamide (Compound 106)

Step 1: N-(5,6-difluoro-1H -indol-3-yl)propiolamide 5,6-difluoro-lH-indol-3-amine hydrogen chloride (730.0 mg, 3.6 mmol, 1.0 equiv.) was dissolved in THF (30.0 mL) and cooled to 0 °C, then propiolic acid (499.9 mg, 7.1 mmol, 2.0 equiv.), TEA (1.5 mL, 10.7 mmol, 3.0 equiv.) and T3P (6.8 g, 10.7 mmol, 3.0 equiv) were added at 0 °C. The reaction mixture was stirred for 3 hours at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give N-(5,6-difluoro- 1H-indol- 3-yl)prop-2-ynamide (350 mg) as a pale yellow solid. LCMS Method A: [M+H] ⁺ = 221. Step 2: N-(5,6-difluoro-1H -indol-3-yl)-l-(4-(trifluoromethyl)phenyl)-1H -l,2,3- triazole-4-carboxamide N-(5,6-difluoro-1H -indol-3-yl)prop-2-ynamide (150.0 mg, 0.7 mmol, 1.0 equiv.) and l-azido-4-(trifhioromethyl)benzene (191.2 mg, 1.0 mmol, 1.5 equiv.) were dissolved in MeOH (4.0 mL) and water (1.0 mL), then sodium ascorbate (13.6 mg, 0.1 mmol, 0.1 equiv.) and CuSCri (10.9 mg, 0.1 mmol, 0.1 equiv.) were added. The reaction mixture was stirred at 40 °C for 16 hours, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: Atlantis HILIC OBD Column, 19*150mm*5μm; Mobile Phase A: Water (10 mM NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 40% B to 80% B in 8 min; 254 nm; RTL6.64 min. This resulted in N-( 5,6- difluoro- 1H -indol-3 -yl)- 1 -[4-(trifluoromethyl)phenyl]- 1 ,2,3 -triazole-4-carboxamide (42.5 mg) as a white solid. LCMS Method G: [M+H] ⁺ = 408. ¹ H NMR (300 MHz, DMSO-d ₆ ): d 11.17 (s, 1H), 10.64 (s, 1H), 9.59 (s, 1H), 8.31-8.28 (m, 2H), 8.06 (d, 2H), 7.95-7.91 (m, 1H), 7.88-7.86 (m, 1H), 7.43-7.37 (m, 1H).

The following compound was prepared using the same method described for Example 36

Example 38: Synthesis of 3-(4-chlorophenyl)-N-(5,6-difluoro-lH-indol-3-yl)-lH- pyrazole-5-carboxamide (Compound 108)

5,6-difluoro-lH-indol-3-amine (24.9 mg, 0.148 mmol, 1.0 equiv.) and 3-(4-chlorophenyl)- lH-pyrazole-5-carboxylic acid (42.7 mg, 0.192 mmol, 1.3 equiv.) were dissolved in DMF (1.0 mL). Then DIEA (103 mΐ, 0.592 mmol, 4.0 equiv.) and HATU (59.1 mg, 0.155 mmol, 1.05 equiv.) dissolved in 1 mL DMF was added. The reaction mixture was stirred at 30 °C for 16 hours. The reaction mixture was concentrated by Speedvac. The residue was purified by prep HPLC to give 3-(4-chlorophenyl)-N-(5,6-difluoro-lH-indol-3-yl)-lH-pyrazol e-5- carboxamide (13.7 mg, 0.038 mmol). MS-ESI, 373.1 [M+H ⁺ ], ¹ H NMR (400 MHz, DMSO-d) δ pμm 13.84 (br s, 1 H) 11.29-10.92 (m, 1 H) 10.16 (br s, 1 H) 8.02-7.73 (m, 4 H) 7.69-7.14 (m, 4 H)

The compounds in the following table were prepared using the above procedure.

The following examples were prepared using the same method as described for Example 12:

Example 46: N-(5,6-difluoro-1H -indol-3-yl)-l-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-1H -pyrazole-4-carboxamide (Compound 163) l-[[5-Methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl]py razole-4-carboxylic acid (300.0 mg, 1.0 mmol, 1.0 equiv.) was dissolved in DMF (5 mL), then 5,6-difluoro- 1H -indol-3-amine hydrogen chloride (204.5 mg, 1.0 mmol, 1.0 equiv.), HATU (542.8 mg, 1.4 mmol, 1.5 equiv.), and DIEA (0.5 mL, 2.9 mmol, 3.0 equiv.) were added. The reaction mixture was stirred for 1 hour at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give material that was further purified by Prep-HPLC using the following conditions: Column, YMC-Actus Triart C18, 30*250, 5μm; mobile phase, Water (10 mM NH ₄ HCO ₃ +0.1% NH ₄ OH) and ACN (20% Phase B up to 43% in 7 min); Detector, UV 254 nm. This gave A-(5,6-difluoro-1H -indol-3-yl)-l-[[5-methyl- 6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl]pyrazole-4-carb oxamide (57.7 mg) of as a white solid. LCMS Method D-l: [M+H] ⁺ = 466. ¹ H NMR (400 MHz, DMSO-d ₆ ): d 11.04 (s, 1H), 9.72 (s, 1H), 8.45 (s, 1H), 8.08 (s, 2H), 7.81-7.76 (m, 2H), 7.65-7.64 (m, 1H), 7.39-7.34 (m, 1H), 5.36 (s, 2H), 5.01 (q, J= 8.8 Hz, 2H), 2.18 (s, 3H).

The following compounds were prepared using the same method described for Example 46. Example 62: N-(5,6-difluoro-1H -indol-3-yl)-l-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)-1H -l,2,3-triazole-4-carboxamide (Compound 165) l-[5-Methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-l,2,3-tri azole-4-carboxylic acid (300.0 mg, 1.0 mmol, 1.0 equiv.) was dissolved in DMF (5 mL), then HATU (566.2 mg, 1.5 mmol, 1.5 equiv.), DIEA (0.6 mL, 3.3 mmol, 3.0 equiv.), and 5,6-difluoro-1H - indol-3-amine hydrogen chloride (204.5 mg, 1.0 mmol, 1.0 equiv.) were added. The reaction mixture was stirred overnight at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was washed with MeOH (4 mL) and collected by filtration to give N-(5 ,6-di fl uoro-1H-i ndol - 3-yl)-l-[5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-l,2 ,3-triazole-4-carboxamide (105.2 mg) as a white solid. LCMS Method F-l: [M+H] ⁺ = 453. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.15 (s, 1H), 10.59 (s, 1H), 9.38 (s, 1H), 8.67 (d, J= 2.0 Hz, 1H), 8.36 (s, 1H), 7.93-7.88 (m, 1H), 7.85 (d, J= 2.0 Hz, 1H), 7.42-7.37 (m, 1H), 5.12 (q, J = 8.8 Hz, 2H), 2.32 (s, 3H).

Example 63: N-(5,6-difluoro-1H -indol-3-yl)-l-(2-((2,2,2- trifluoroethoxy)methyl)pyridin-4-yl)- 1 H- 1 ,2,3-triazole-4-carboxamide (Compound 156)

Compound 156

Step 1: N-(5,6-difluoro-1H -indol-3-yl)propiolamide

5,6-difluoro-lH-indol-3-amine hydrogen chloride (730.0 mg, 3.6 mmol, 1.0 equiv.) was dissolved in THF (30.0 mL) and cooled to 0 °C, then propiolic acid (499.9 mg, 7.1 mmol, 2.0 equiv.), TEA (1.5 mL, 10.7 mmol, 3.0 equiv.) and T3P (6.8 g, 10.7 mmol, 3.0 equiv.) were added at 0 °C. The reaction mixture was stirred for 3 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give N- (5,6-difluoro-1H -indol-3-yl)prop-2-ynamide (350 mg) as a pale yellow solid. LCMS Method A- 1 : [M+H] ⁺ = 221.

Step 2: 4-azido-2-[(2,2,2-trifluoroethoxy)methyl]pyridine

2-[(2,2,2-Trifluoroethoxy)methyl]pyridin-4-amine (500.0 mg, 2.4 mmol, 1.0 equiv.) and /-BuONO (0.9 mL, 7.3 mmol, 3.0 equiv.) were dissolved in ACN (10 mL). The resulting solution was heated to 60 °C for 30 min, then trimethyl silyl azide (838.2 mg, 7.3 mmol, 3.0 equiv.) was added dropwise. The resulting mixture was stirred for additional 12 hours at 60 °C, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 4-azido-2-[(2,2,2- trifluoroethoxy)methyl]pyridine (103.5 mg) as a yellow oil. LCMS Method A-l: [M+H] ⁺ = 233.

Step 3: A-(5,6-difluoro-1H -indol-3-yl)-l-[2-[(2,2,2-trifluoroethoxy)methyl]pyridin-4- yl]-l,2,3-triazole-4-carboxamide

4-Azido-2-[(2,2,2-trifluoroethoxy)methyl]pyridine (100.0 mg, 0.4 mmol, 1.0 equiv.) and N-(5,6-difluoro-lH-indol-3-yl)prop-2-ynamide (113.8 mg, 0.5 mmol, 1.2 equiv.) was dissolved in 1,4-dioxane (5 mL) and water (0.5 mL), then sodium ascorbate (17.2 mg, 0.1 mmol, 0.2 equiv.) and CuSO ₄ (13.8 mg, 0.1 mmol, 0.2 equiv.) were added. The reaction mixture was stirred overnight at ambient temperature, then diluted with ethyl acetate. The resulting solution was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column, XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; mobile phase, Water (10 mmol/L NH ₄ HCO ₃ +0.1% NTriOH) and ACN (40% Phase B up to 55% in 7 min); Detector, UV 254 nm. This gave A-(5,6-difluoro-1H -indol-3-yl)- l-[2-[(2,2,2-trifluoroethoxy)methyl]pyridin-4-yl]-l,2,3-tria zole-4-carboxamide (14.4 mg) as a yellow solid. LCMS Method E: [M-H]- = 451. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.16 (s, 1H), 10.65 (s, 1H), 9.68 (s, 1H), 8.81 (d, J= 5.6 Hz, 1H), 8.13 (s, 1H), 8.08- 8.05 (m, 1H), 7.93-7.86 (m, 2H), 7.42-7.38 (m, 1H), 4.90 (s, 2H), 4.33 (q, J= 9.2 Hz, 2H).

The following compounds were prepared using the same method described for Example 63.

Biological Assays

STING pathway activation 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 μM. 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><384 plate: o Solution A: 2 mL Optimem with one of the following stimuli:

■ 60 pL 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 2’3’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% CC>2 _, >98% humidity for 24h. Luciferase reporter activity was then measured. EC so 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 QU ANTI- 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. ECso values were calculated by using standard methods known in the art.

Table BA shows the activity of compounds in STING reporter assay: <0.008 μM = “++++++”; >0.008 and <0.04 μM = “+++++”; >0.04 and <0.2 μM = “++++”; >0.2 and <1 μM = “+++”; >1 and <5 μM = “++”; >5 and <100 μM = “+”.

Table BA

Numbered Clauses

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

1. A compound of Formula I:

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

Z, Y ¹ , Y ² , and Y ³ are independently selected from the group consisting of CR ¹ , C(=O), N, and NR ² ;

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

X ² is selected from the group consisting of O, S, N, NR ⁴ , and CR ⁵ ; provided that when each one of Z, Y ¹ , and Y ² is CR ¹ , then Y ³ cannot be N, or when each one of Z, Y ¹ , Y ² , and Y ³ is CR ¹ , then at least one R ¹ is other than H; each — is independently a single bond or a double bond, provided that the five- membered ring comprising X ¹ and X ² is heteroaryl, and that the six-membered ring comprising Z, Y ¹ , Y ² , and Y ³ is aryl or heteroaryl; each R ¹ is independently selected from the group consisting of: H; R ^c ; R ^g ; and -

(L ¹ ) _b1 -R ^g ; each R ² is independently selected from the group consisting of: H; R ^d ; R ^g ; and -

(L ² ) _b2 -R ^g ;

R ⁴ is selected from the group consisting of: H and R ^d ;

R ⁵ is selected from the group consisting of: H; R ^c ; and R ^h ;

R ⁶ is selected from the group consisting of: H; R ^d ; and R ^h ;

Ring B is a heteroarylene of 5 ring atoms, wherein 1-4 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(R ^d ), O, and S, wherein the heteroarylene of Ring B is optionally substituted with 1-2 substituents independently selected from the group consisting of: oxo and R ^c , provided that Ring B is attached to the C(=O)NR ⁶ group via a ring carbon atom; each L ^A is independently selected from the group consisting of: C _1-3 alkylene optionally substituted with 1-4 R ^a1 ; -O-; -NH-; -NR ^d _; -S(O) _0-2 ; and C(O); al is 0, 1, 2, or 3;

Ring C is selected from the group consisting of:

• C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R ^c ;

• heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R ^c ; • heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R ^c ; and

• C _6-10 aryl optionally substituted with 1-4 R ^c ; each occurrence of R ^a and R ^a1 is independently selected from the group consisting of: -OH; -halo; -NR ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)O(C _1-4 alkyl); -C(=O)(C _1-4 alkyl); -C(=O)OH; -CONR’R”; -S(O) _1-2 NR’R”; -S(O) _1-2 (C _1-4 alkyl); and cyano; each occurrence of R ^c is independently selected from the group consisting of: halo; cyano; C _1-10 alkyl which is optionally substituted with 1-6 independently selected R ^a ; C _2-6 alkenyl; C _2-6 alkynyl; C _1-4 alkoxy; C _1-4 haloalkoxy; -S(O) _1-2 (C _1-4 alkyl); -S(O)(=NH)(C _1-4 alkyl); -NR ^e R ^f ; -OH; -S(O) _1-2 NR’R”; -C _1-4 thioalkoxy; -NO ₂ ; -C(=O)(C _1-10 alkyl); - C(=O)O(C _1-4 alkyl); -C(=O)OH; -C(=O)NR’R”; and -SF ₅ ; each occurrence of R ^d is independently selected from the group consisting of: C _1-6 alkyl optionally substituted with 1-3 independently selected R ^a ; -C(O)(C _1-4 alkyl); - C(O)O(C _1-4 alkyl); -CONR’R”; -S(O) _1-2 NR’R”; - S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; each occurrence of R ^e and R ^f is independently selected from the group consisting of: H; C _1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR’R”, -OH, and R ⁱ ; -C(O)(C _1-4 alkyl); -C(O)O(C _1-4 alkyl); -CONR’R”; -S(O) _1-2 NR’R”; - S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; each occurrence of R ^g is independently selected from the group consisting of:

• C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R ^c , R ^h , and -(L ^g ) _bg ,-R ^h ;

• heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R ^c , R ^h , and -(L ^g ) _bg -R ^h ;

• heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h ; and

• C _6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h ; each occurrence of R ^h is independently selected from the group consisting of:

• C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each of which is optionally substituted with 1-4 R ⁱ ;

• heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 R ⁱ ;

• heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R ⁱ ; and

• C _6-10 aryl optionally substituted with 1-4 R ⁱ ; each occurrence of R ⁱ is independently selected from the group consisting of: C _1-6 alkyl; C _1-4 haloalkyl; C _1-4 alkoxy; C _1-4 haloalkoxy; C _1-6 alkyl-O-C _1-6 alkyl-; C _1-4 haloalkyl- O-C _1-6 alkyl-; halo; cyano; -OH; -NR’R”; and C3-6 cycloalkyl; each occurrence of L ¹ , L ² , and L ^g is independently selected from the group consisting of: -O-, -NH-, -NR ^d , -S(O) _0-2 , C(O), and C _1-3 alkylene optionally substituted with 1-3 R ^a ; bl, b2, and bg are each independently 1, 2, or 3; and each occurrence of R’ and R” is independently selected from the group consisting of: H; -OH; and C _1-4 alkyl.

2. A compound of Formula II:

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

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

X ² is selected from the group consisting of O, S, N, NR ⁴ , and CR ⁵ ; each — is independently a single bond or a double bond, provided that the five- membered ring comprising X ¹ and X ² is heteroaryl;

R ¹ is selected from the group consisting of: H; R ^c ; R ^g ; and -(L ¹ ) _b1 -R ^g ;

R ² is selected from the group consisting of: H; R ^d ; R ^g ; and -(L ² ) _b2 -R ^g ;

R ⁴ is selected from the group consisting of: H and R ^d ;

R ⁵ is selected from the group consisting of: H; R ^c ; and R ^h ;

R ⁶ is selected from the group consisting of: H; R ^d ; and R ^h ;

Ring B is a heteroarylene of 5 ring atoms, wherein 1-4 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(R ^d ), O, and S, wherein the heteroarylene of Ring B is optionally substituted with 1-2 substituents independently selected from the group consisting of: oxo and R ^c , provided that Ring B is attached to the C(=O)NR ⁶ group via a ring carbon atom; each L ^A is independently selected from the group consisting of: C _1-3 alkylene optionally substituted with 1-4 R ^a1 ; -O-; -NH-; -NR ^d _; -S(O) _0-2 ; and C(O); al is 0, 1, 2, or 3; Ring C is selected from the group consisting of:

• C _3-12 cycloalkylene or C _3-12 cycloalkenylene, each optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R ^c ,

• heterocyclylene or heterocycloalkenylene of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R ^c ,

• heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroarylene is optionally substituted with 1-4 R ^c ; and

• C _6-10 aryl optionally substituted with 1-4 R ^c ; each occurrence of R ^a and R ^a1 is independently selected from the group consisting of: -halo; -NR ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)O(C _1-4 alkyl); -C(=O)(C _1-4 alkyl); -C(=O)OH; -CONR’R”; -S(O) _1-2 NR’R”; -S(O) _1-2 (C _1-4 alkyl); and cyano; each occurrence of R ^c is independently selected from the group consisting of: halo; cyano; C _1-10 alkyl which is optionally substituted with 1-6 independently selected R ^a ; C _2-6 alkenyl; C _2-6 alkynyl; C _1-4 alkoxy; C _1-4 haloalkoxy; -S(O) _1-2 (C _1-4 alkyl); -S(O)(=NH)(C _1-4 alkyl); -NR ^e R ^f ; -OH; -S(O) _1-2 NR’R”; -C _1-4 thioalkoxy; -NO ₂ ; -C(=O)(C _1-10 alkyl); - C(=O)O(C _1-4 alkyl); -C(=O)OH; -C(=O)NR’R”; and -SF ₅ ; each occurrence of R ^d is independently selected from the group consisting of: C _1-6 alkyl optionally substituted with 1-3 independently selected R ^a ; -C(O)(C _1-4 alkyl); - C(O)O(C _1-4 alkyl); -CONR’R”; -S(O) _1-2 NR’R”; - S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; each occurrence of R ^e and R ^f is independently selected from the group consisting of: H; C _1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR’R”, -OH, and R ⁱ ; -C(O)(C _1-4 alkyl); -C(O)O(C _1-4 alkyl); -CONR’R”; -S(O) _1-2 NR’R”; -S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; each occurrence of R ^g is independently selected from the group consisting of: • C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R ^c , R ^h , and -(L ^g ) _bg -R ^h ;

• heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R ^c , R ^h , and -(L ^g ) _bg -R ^h ;

• heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h ; and

• C _6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _{b g} -R ^h ; each occurrence of R ^h is independently selected from the group consisting of:

• C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each of which is optionally substituted with 1-4 R ⁱ ;

• heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 R ⁱ ;

• heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R ⁱ ; and

• C _6-10 aryl optionally substituted with 1-4 R ⁱ ; each occurrence of R ⁱ is independently selected from the group consisting of: C _1-6 alkyl; C _1-4 haloalkyl; C _1-4 alkoxy; C _1-4 haloalkoxy; C _1-6 alkyl-O-C _1-6 alkyl-; C _1-4 haloalkyl- O-C _1-6 alkyl-; halo; cyano; -OH; -NR’R”; and C _3-6 cycloalkyl; each occurrence of L ¹ , L ² , and L ^g is independently selected from the group consisting of: -O-, -NH-, -NR ^d , -S(O) _0-2 , C(O), and C _1-3 alkylene optionally substituted with 1-3 R ^a ; bl, b2, and bg are each independently 1, 2, or 3; and each occurrence of R’ and R” is independently selected from the group consisting of: H; -OH; and C _1-4 alkyl; provided that:

1) Ring C is other than: unsubstituted morpholinyl, unsubstituted pyrrolidinyl, unsubstituted tetrahydrofuranyl, unsubstituted cyclopentyl, monosub stituted oxetanyl, methylfuranyl, unsubstituted thiophenyl, or methylpyrrolyl; or

2) -(L ^A ) _a1 -Ring C is other than: unsubstituted benzyl or phenyl that is optionally substituted with one substituent selected from the group consisting of: -F, -OMe, and -OEt.

Formula III or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein: X ¹ is selected from the group consisting of O, S, N, NR ² , and CR ¹ ;

X ² is selected from the group consisting of O, S, N, NR ⁴ , and CR ⁵ ; each — is independently a single bond or a double bond, provided that the five- membered ring comprising X ¹ and X ² is heteroaryl;

R ¹ , R ^1a , R ^1b , and R ^1c are each independently selected from the group consisting of: H; R ^c ; R"; and -(L ¹ ) _b1 -R";

R ² is independently selected from the group consisting of: H; R ^d ; R ^g ; and -(L ² ) _b2 -

R ^g ;

R ⁴ is selected from the group consisting of: H and R ^d ; R ⁵ is selected from the group consisting of: H; R ^c ; and R ^h ;

R ⁶ is selected from the group consisting of: H; R ^d ; and R ^h ;

Ring B is a heteroarylene of 5 ring atoms, wherein 1-4 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(R ^d ), O, and S, wherein the heteroarylene of Ring B is optionally substituted with 1-2 substituents independently selected from the group consisting of: oxo and R ^c , provided that Ring B is attached to the C(=O)NR ⁶ group via a ring carbon atom; each L ^A is independently selected from the group consisting of: C _1-3 alkylene optionally substituted with 1-4 R ^a1 ; -O-; -NH-; -NR ^d _; -S(O) _0-2 ; and C(O); al is 0, 1, 2, or 3;

Ring C is selected from the group consisting of:

• C _3-12 cycloalkylene or C _3-12 cycloalkenylene, each optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R ^c ,

• heterocyclylene or heterocycloalkenylene of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R ^c ,

• heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroarylene is optionally substituted with 1-4 R ^c ; and

• C _6-10 arylene optionally substituted with 1-4 R ^c ; each occurrence of R ^a and R ^a1 is independently selected from the group consisting of: -halo; -NR ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)O(C _1-4 alkyl); -C(=O)(C _1-4 alkyl); -C(=O)OH; -CONR’R”; -S(O) _1-2 NR’R”; -S(O) _1-2 (C _1-4 alkyl); and cyano; each occurrence of R ^c is independently selected from the group consisting of: halo; cyano; C _1-10 alkyl which is optionally substituted with 1-6 independently selected R ^a ; C _2-6 alkenyl; C _2-6 alkynyl; C _1-4 alkoxy; C _1-4 haloalkoxy; -S(O) _1-2 (C _1-4 alkyl); -S(O)(=NH)(C _1-4 alkyl); -NR ^e R ^f ; -OH; -S(O) _1-2 NR’R”; -C _1-4 thioalkoxy; -NO ₂ ; -C(=O)(C _1-10 alkyl); - C(=O)O(C _1-4 alkyl); -C(=O)OH; -C(=O)NR’R”; and -SF ₅ ; each occurrence of R ^d is independently selected from the group consisting of: C _1-6 alkyl optionally substituted with 1-3 independently selected R ^a ; -C(O)(C _1-4 alkyl); - C(O)O(C _1-4 alkyl); -CONR’R”; -S(O) _1-2 NR’R”; - S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; each occurrence of R ^e and R ^f is independently selected from the group consisting of: H; C _1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR’R”, -OH, and R ⁱ ; -C(O)(C _1-4 alkyl); -C(O)O(C _1-4 alkyl); -CONR’R”; -S(O) _1-2 NR’R”; - S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; each occurrence of R ^g is independently selected from the group consisting of:

• C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R ^c , R ^h , and -(L ^g ) _bg -R ^h ;

• heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R ^c , R ^h , and -(L ^g ) _bg -R ^h ;

• heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h ; and

• C _6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h ; each occurrence of R ^h is independently selected from the group consisting of:

• C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each of which is optionally substituted with 1-4 R';

• heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 R';

• heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R'; and

• C _6-10 aryl optionally substituted with 1-4 R'; each occurrence of R' is independently selected from the group consisting of: C _1-6 alkyl; C _1-4 haloalkyl; C _1-4 alkoxy; C _1-4 haloalkoxy; C _1-6 alkyl-O-C _1-6 alkyl-; C _1-4 haloalkyl- O-C _1-6 alkyl-; halo; cyano; -OH; -NR’R”; and C3-6 cycloalkyl; each occurrence of L ¹ , L ² , and L ^g is independently selected from the group consisting of: -O-, -NH-, -NR ^d , -S(O) _0-2 , C(O), and C _1-3 alkylene optionally substituted with 1-3 R ^a ; bl, b2, and bg are each independently 1, 2, or 3; and each occurrence of R’ and R” is independently selected from the group consisting of: H; -OH; and C _1-4 alkyl; provided that when Ring B is unsubstituted wherein aa is the point of connection to (L ^A ) _a1 ; and (L ^A ) _a1 is unsubstituted CH2, then Ring C is other than unsubstituted pyridyl, unsubstituted pyrrolyl, or phenyl which is optionally substituted with one substituent selected from the group consisting of: -F, -Cl, -Me, -OMe, or -CN. 4. The compound of clause 1, wherein each of Z, Y ¹ , Y ² , and Y ³ is independently N or CR ¹ .

5. The compound of clauses 1 or 4, wherein the compound is a compound of Formula (la):

Formula (la) or a pharmaceutically acceptable salt thereof, wherein: R ^1a , R ^1b , R ^1c , and R ^1d are each an independently selected R ¹ .

6. The compound of clauses 1 or 4, wherein one of Z, Y ¹ , and Y ² is N; and each remaining one of Z, Y ¹ , Y ² , and Y ³ is an independently selected CR ¹ .

7. The compound of any one of clauses 1, 4, or 6, wherein the compound is selected from the group consisting of a compound of the following formulae: or a pharmaceutically acceptable salt thereof, wherein: R ^1a , R ^1b , R ^1c , and R ^1d are each an independently selected R ¹ .

8. The compound of any one of clauses 1-7, wherein X ¹ is NR ² .

9. The compound of any one of clauses 1-8, wherein X ¹ is NH.

10. The compound of any one of clauses 1-9, wherein X ² is CR ⁵ .

11. The compound of any one of clauses 1-10, wherein X ² is CH.

12. The compound of any one of clauses 1-7, wherein X ¹ is NR ² ; and X ² is CR ⁵ .

13. The compound of any one of clauses 1-7 or 12, wherein X ¹ is NH; and X ² is CH.

14. The compound of clause 1, wherein the compound is a compound of Formula (la-1):

Formula (la-1) or a pharmaceutically acceptable salt thereof, wherein: R ^1a , R ^1b , R ^1c , and R ^1d are each an independently selected R ¹ .

15. The compound of clause 1, wherein the compound is selected from the group consisting of a compound of the following formulae:

or a pharmaceutically acceptable salt thereof, wherein: R ^1a , R ^1b , R ^1c , and R ^1d are each an independently selected R ¹ .

16. The compound of clause 2, wherein the compound is a compound of Formula (II-l):

Formula (II- 1) or a pharmaceutically acceptable salt thereof.

17. The compound of clause 3, wherein the compound of a compound of Formula (III-l):

Formula (PI-1) or a pharmaceutically acceptable salt thereof. 18. The compound of any one of clauses 14-17, wherein R ² is H.

19. The compound of any one of clauses 14-18, wherein R ⁵ is H. 20. The compound of any one of clauses 1 or 4-15, wherein from 1-2 R ¹ is independently selected from the group consisting of: R ^c1 and R ^g1 ; and each remaining R ¹ is H, wherein R ^c1 is an independently selected R ^c ; and R ^g1 is an independently selected R ^g .

21. The compound of clause 20, wherein two occurrences of R ¹ are independently selected from the group consisting of: R ^c1 and R ^g1 ; and each remaining R ¹ is H.

22. The compound of clauses 20 or 21, wherein two occurrences of R ¹ are independently selected R ^c1 ; and each remaining R ¹ is H.

23. The compound of clause 20, wherein one occurrence of R ¹ is selected from the group consisting of: R ^c1 and R ^g1 ; and each remaining R ¹ is H.

24. The compound of clauses 20 or 23, wherein one occurrence of R ¹ is R ^c1 ; and each remaining R ¹ is H.

25. The compound of clauses 20 or 23, wherein one occurrence of R ¹ is R ^g1 ; and each remaining R ¹ is H. 26. The compound of clause 20, wherein one occurrence of R ¹ is R ^c1 ; one occurrence of R ¹ is R ^g1 ; and each remaining R ¹ is H.

27. The compound of any one of clauses 20-26, wherein each R ^c1 is an independently selected halo or cyano, such as -F, -Cl, or -CN. 28. The compound of clause 27, wherein each R ^c1 is independently -F or -Cl, such as -F.

29. The compound of any one of clauses 20-28, wherein each R ^g1 is independently selected from the group consisting of:

• heteroaryl of 5- 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, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h ; and

• C _6-10 aryl optionally substituted with from 1-4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h

30. The compound of clause 29, wherein each R ^g1 is independently selected from the group consisting of:

• heteroaryl of 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 is optionally substituted with from 1-4 R ^c ; and

• Ce aryl optionally substituted with from 1-4 R ^c .

31. The compound of clauses 29 or 30, wherein each R ^g1 is independently heteroaryl of 5 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 is optionally substituted with from 1-4 R ^c .

32. The compound of clause 31, wherein each R ^g1 is pyrazolyl that is optionally substituted with from 1-2 R ^c , such from 1-2 independently selected C _1-6 (e.g., C _1-3 ) alkyl which is optionally substituted with from 1-6 independently selected R ^a (e.g., unsubstituted C _1-6 (e.g., C _1-3 ) alkyl). 33. The compound of clause 32, wherein R ^g1 is and optionally R ^c is C _1-6 (e.g., C _1-3 ) alkyl which is optionally substituted with from 1-6 independently selected R ^a . 34. The compound of clauses 29 or 30, wherein R ^g1 is phenyl optionally substituted with from 1-4 R ^c , such as phenyl optionally substituted with from 1-2 substituents each independently selected from the group consisting of: C _1-6 alkyl optionally substituted with from 1-6 R ^a ; -halo; -cyano; C _1-4 alkoxy; and C _1-4 haloalkoxy. 35. The compound of clause 29, wherein each R ^g1 is independently selected from the group consisting of:

• heteroaryl of 5- 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, and wherein the heteroaryl is substituted with one occurrence of R ^h1 or -(L ^g ) _{b g} -R ^h1 and further optionally substituted with from 1-2 R ^c ; and

• C _6-10 aryl that is substituted with one occurrence of R ^h1 or -(L ^g ) _{b g} -R ^h1 and further optionally substituted with from 1-2 R ^c , wherein R ^h1 is an independently selected R ^h . 36. The compound of clause 35, wherein each R ^g1 is heteroaryl of 5-6 (such as

5) 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 is substituted with one occurrence of R ^h1 or -(L ^g ) _bg -R ^h1 and further optionally substituted with from 1-2 R ^c , wherein R ^h1 is an independently selected R ^h .

37. The compound of clause 36, wherein each R ^g1 is pyrazolyl that is substituted with R ^h1 or -(L ^g ) _bg -R ^h1 (such as R ^h1 or -CH ₂ R ^h1 ) and further optionally substituted with from 1-2 R ^c . 38. The compound of clause 37, wherein each R ^g1 is , each of which is optionally substituted with R ^c .

39. The compound of any one of clauses 35-38, wherein R ^h1 is selected from the group consisting of:

• heteroaryl of 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(O) _0-2 , and wherein the heteroaryl is optionally substituted with from 1-4 R ⁱ ; and

• Ce aryl optionally substituted with from 1-4 R ⁱ , such as wherein R ^g1 is phenyl optionally substituted with from 1-4 R ⁱ .

40. The compound of clause 39, wherein R ^h1 is selected from the group consisting of:

• heteroaryl of 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(O) _0-2 , and wherein the heteroaryl is optionally substituted with from 1-2 R ⁱ ; and

• Ce aryl optionally substituted with from 1-2 R ⁱ , such as wherein R ^g1 is phenyl optionally substituted with from 1-4 R ⁱ .

41. The compound of any one of clauses 1, 4, 6-13, 15, or 18-19, wherein each R ¹ is H.

42. The compound of any one of clauses 3, 5, 7, 14-15, or 17, wherein R ^1a H.

43. The compound of any one of clauses 3, 5, 7, 14-15, 17, or 42, wherein R ^1b is H.

44. The compound of any one of clauses 3, 5, 7, 14-15, 17, or 42, wherein R ^1b is halo, such as -F or -Cl (e.g., -F). 45. The compound of any one of clauses 3, 5, 7, 14-15, 17, or 42, wherein R ^1b is heteroaryl of 5 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 is optionally substituted with from 1-2 R ^c .

46. The compound of clause 45, wherein R ^1b is pyrazolyl that is optionally substituted with from 1-2 R ^c , such as each R ^c is an independently selected C _1-6 (e.g., C _1-3 ) alkyl which is optionally substituted with from 1-6 independently selected R ^a (e.g., unsubstituted).

47. The compound of any one of clauses 3, 5, 7, 14-15, 17, or 42, wherein R ^1b is phenyl optionally substituted with from 1-4 R ^c , such as phenyl optionally substituted with from 1-2 substituents each independently selected from the group consisting of: C _1-6 alkyl optionally substituted with from 1-6 R ^a ; -halo; -cyano; C _1-4 alkoxy; and C _1-4 haloalkoxy.

48. The compound of any one of clauses 3, 5, 7, 14-15, 17, or 42, wherein R ^1b is heteroaryl of 5-6 (such as 5) 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 is substituted with one occurrence of R ^h1 or -(L ^g ) _bg -R ^h1 and further optionally substituted with from 1-2 R ^c , wherein R ^h1 is an independently selected R ^h .

49. The compound of clause 48, wherein R ^1b is pyrazolyl that is substituted with R ^h1 or -(L ^g ) _bg -R ^h1 (such as R ^h1 or -CH ₂ R ^h1 ) and further optionally substituted with , each of which is optionally substituted with R ^c . 50. The compound of any one of clauses 3, 5, 7, 14-15, 17, or 42-48, wherein R ^1c is H.

51. The compound of any one of clauses 3, 5, 7, 14-15, 17, or 42-48, wherein R ^1c is halo, such as -F or -Cl.

52. The compound of any one of clauses 3, 5, 7, 14-15, 17, or 42-48, wherein R ^1d is H. 53. The compound of any one of clauses 3, 5, 7, 14-15, 17, or 42-51, wherein R ^1d is halo, such as -F or -Cl (e.g., -F).

54. The compound of any one of clauses 3, 5, 7, 14-15, or 17, wherein R ^1a and R ^1d are H; and R ^1b and R ^1c are independently selected halo, such as -F or -Cl, such as -F, such as wherein R ^1b and R ^1c are -F; or wherein R ^1b is -F; and R ^1c is -Cl; or wherein R ^1b is -Cl; and R ^1c is -F.

55. The compound of any one of clauses 3, 5, 7, 14-15, or 17, wherein R ^1a and R ^1d are H; one of R ^1b and R ^1c is H; and the other one of R ^1b and R ^1c is halo, such as -F or -Cl, such as -F, such as wherein R ^1c is H, and R ^1b is halo; or wherein R ^1c is halo, and R ^1b is H.

56. The compound of any one of clauses 3, 5, 7, 14-15, or 17, wherein R ^1a and R ^1d are H; R ^1c is halo or H, such as -F, -Cl, or H; and R ^1b is heteroaryl of 5 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 is optionally substituted with from 1-4 R ^c .

57. The compound of any one of clauses 3, 5, 7, 14-15, or 17, wherein R ^1a and R ^1d are H; R ^1c is halo or H, such as -F, -Cl, or H; and R ^1b is heteroaryl of 5-6 (such as 5) 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 is substituted with one occurrence of R ^h1 or -(L ^g ) _bg -R ^h1 and further optionally substituted with from 1-2 R ^c , wherein R ^h1 is an independently selected R ^h . 58. The compound of any one of clauses 3, 5, 7, 14-15, or 17, wherein R ^1a and R ^1d are H; R ^1c is halo or H, such as -F, -Cl, or H; and R ^1b is phenyl optionally substituted with from 1-4 R ^c , such as phenyl optionally substituted with from 1-2 substituents each independently selected from the group consisting of: C _1-6 alkyl optionally substituted with from 1-6 R ^a ; -halo; -cyano; C _1-4 alkoxy; and C _1-4 haloalkoxy.

59. The compound of any one of clauses 3, 5, 7, 14-15, or 17, wherein R ^1a is H; R ^1d is halo, such as -F or -Cl; R ^1c is H; and R ^1b is R ^g .

60. The compound of any one of clauses 1-59, wherein R ⁶ is H.

61. The compound of any one of clauses 1-60, wherein Ring B is a heteroarylene of 5 ring atoms, wherein from 2-3 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(R ^d ), O, and S, wherein the heteroarylene of Ring B is optionally substituted with from 1-2 R ^c , provided that Ring B is attached to the C(=O)NR ⁶ group via a ring carbon atom;

62. The compound of any one of clauses 1-60, wherein Ring B is selected from the group consisting of: pyrazolylene; imidazolylene; thiazolylene; oxazolylene; triazolylene such as 1,2,3-triazolylene or 1,2,4-triazolylene; isoxazolylene; and isothiazolylene, each of which is optionally substituted with R ^c ; and a ring nitrogen is optionally substituted with R ^d , such as: wherein Ring B is pyrazolylene; imidazolylene; 1,2,3-triazolylene; 1,2,4- triazolylene, each of which is optionally substituted with R ^c ; and a ring nitrogen is optionally substituted with R ^d . 63. The compound of any one of clauses 1-61, wherein Ring B has Formula Bl or B2:

B ⁴ is C or N;

B ¹ , B ² , and B ³ are each independently CH, CR ^C , NH, N(R ^d ), N, O, or S; provided that from 0-2 of B ¹ , B ² , and B ³ is CR ^C ; aa is the point of attachment to (L ^A ) _a1 ; and each ==is independently a single bond or a double bond provided that the ring including B ⁴ -B ⁴ is a heteroaryl.

64. The compound of any one of clauses 1-63, wherein Ring B has Formula

Bl.

65. The compound of any one of clauses 1-64, wherein B ⁴ is N.

66. The compound of any one of clauses 1-65, wherein Ring B is:

67. The compound of clause 66, wherein Ring B is 68. The compound of any one of clauses 1-65, wherein Ring B is , wherein B ¹ and B ² are independently CH, CR ^C , NH, N(R ^d ), N, O, or S.

69. The compound of any one of clauses 1-65 or clause 68, wherein Ring B is

70. The compound of any one of clauses 1-65, wherein Ring B is

72. The compound of clause 71, wherein Ring

73. The compound of any one of clauses 1-65, 68, or 70, wherein Ring B is 74. The compound of clause 73, wherein Ring

75. The compound of any one of clauses 1-65 or 70, wherein Ring B is

76. The compound of clause 75, wherein Ring

77. The compound of clause 64, wherein B ⁴ is C.

78. The compound of any one of clauses 1-64, or 77, wherein Ring B is , wherein one of B ¹ and B ² is NH, NR ^d , O, or S; and the other one of B ¹ and B ² is N.

79. The compound of clause 78, wherein B ³ is CH or CR ^C , such as CH.

80. The compound of clauses 1-64 or 77-79, wherein Ring B is each of which is further optionally substituted with R ^c (such as not further optionally substituted).

81. The compound of any one of clauses 1-64 or 77, wherein Ring B is , wherein one of B ¹ and B ³ is NH, NR ^d , O, or S; and the other one of B ¹ and B ³ is N, wherein Ring B is further optionally substituted with R ^c ; or wherein Ring B is , wherein one of B ² and B ³ is NH, NR ^d , O, or S; and the other one of B ² or B ³ is N, wherein Ring B is further optionally substituted with R ^c .

82. The compound of clause 1-64, 77, or 81, wherein Ring B is or each of which is optionally substituted with R ^c (such as unsubstituted).

83. The compound of clause 63, wherein Ring B has Formula B2. 84. The compound of clause 83, wherein B ⁴ is N.

85. The compound of clauses 83 or 84, wherein Ring B is or each of which is optionally substituted with R ^c (such as unsubstituted).

86. The compound of any one of clauses 61-85, wherein each R ^c substituent of Ring B is independently -OH; C _1-3 alkyl; C _1-3 alkyl optionally substituted with from 1-6 independently selected halo; halo; cyano; Ci-4 alkoxy; or Ci-4 haloalkoxy. 87. The compound of any one of clauses 1-86, wherein al is 0.

88. The compound of any one of clauses 1-87, wherein al is 1.

89. The compound of any one of clauses 1-86 or 88, wherein L ^A is C _1-3 alkylene optionally substituted with from 1-4 R ^a1 .

90. The compound of any one of clauses 1-86 or 88-89, wherein L ^A is CH ₂ optionally substituted with from 1-2 R ^a1 . 91. The compound of any one of clauses 1-86 or 88-89, wherein L ^A is C(H)Me optionally substituted with from 1-4 R ^a1 , such as wherein L ^A is C(H)Me.

92. The compound of any one of clauses 1-86 or 88-89, wherein L ^A is CH2CH2. 93. The compound of any one of clauses 1-86, wherein al is 2; and (L ^A ) _a1 is -

L ^A1 -L ^A2 , wherein L ^A1 and L ^A2 are independently selected L ^A , and L ^A2 is the point of attachment to Ring C. 94. The compound of clause 93, wherein L ^A1 is C _1-3 alkylene optionally substituted with from 1-4 R ^a1 , such as CH2, C(H)Me, or CH2CH2. 95. The compound of clauses 93 or 94, wherein L ^A2 is -0-.

96. The compound of any one of clauses 1-95, wherein Ring C is selected from the group consisting of:

• heteroaryl of 5-12 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(O) _0-2 , and wherein the heteroaryl is optionally substituted with from 1-4 R ^c ; and

• C _6-10 aryl optionally substituted with from 1-4 R ^c .

97. The compound of any one of clauses 1-96, wherein Ring C is selected from the group consisting of:

• heteroaryl of 5-6 ring atoms, wherein from 1-3 (such as 1-2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _0-2 , and wherein the heteroaryl is optionally substituted with from 1-4 R ^c ; and

• phenyl optionally substituted with from 1-4 R ^c .

98. The compound of any one of clauses 1-97, wherein Ring C is , wherein Q ¹ , Q ² , Q ³ , Q ⁴ , and Q ⁵ are independently CH, CR ^C , or N, provided that from 2-5 of Q ⁴ -Q ⁵ are CH. 99. The compound of clause 98, wherein Q ³ is CR ^C .

100. The compound of clause 99, wherein each one of Q ¹ , Q ² , Q ⁴ , and Q ⁵ is independently CH or CR ^C . 101. The compound of any one of clauses 1-100, wherein Ring C is:

102. The compound of clause 99, wherein one of Q ¹ and Q ² is N; and each remaining one of Q ¹ , Q ² , Q ⁴ , and Q ⁵ is independently CH or CR ^C .

103. The compound of any one of clauses 1-99 or 102, wherein Ring C is

, and 104. The compound of clause 98, wherein Q ² is CR ^C .

105. The compound of clause 104, wherein each one of Q ¹ , Q ³ , Q ⁴ , and Q ⁵ is independently CH or CR ^C . 106. The compound of any one of clauses 1-98 or 105, wherein Ring C is 107. The compound of clause 104, wherein one of Q ¹ and Q ³ (such as Q ¹ ) is N; and each remaining one of Q ¹ , Q ³ , Q ⁴ , and Q ⁵ is independently CH or CR ^C .

108. The compound of clause 98, wherein each one of Q ¹ , Q ² , Q ³ , Q ⁴ , and Q ⁵ is CH (i.e., Ring C is unsubstituted phenyl).

109. The compound of clause 98, wherein one of Q ¹ and Q ² is N; and each remaining one of Q ¹ , Q ² , Q ³ , Q ⁴ , and Q ⁵ is CH, such as wherein Ring C is , or wherein Ring C is

110. The compound of any one of clauses 1-95, wherein Ring C is selected from the group consisting of: C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each optionally substituted with from

1-4 substituents independently selected from the group consisting of oxo and R ^c , and heterocyclyl or heterocycloalkenyl of 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(O) _0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R ^c .

111. The compound of any one of clauses 1-95 or 110, wherein Ring C is selected from the group consisting of:

• C3-6 cycloalkyl optionally substituted with from 1-4 R ^c , and

• heterocyclyl of 4-6 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(O) _0-2 , and wherein the heterocyclyl is optionally substituted with from 1-4 R ^c . 112. The compound of clause 111, wherein Ring C is C3-6 cycloalkyl optionally substituted with from 1-2 R ^c , such as wherein Ring C is cyclohexyl; or wherein R ⁶ is cyclohexyl substituted with from 1-2 R ^c (e.g., halo).

113. The compound of any one of clauses 96-112, wherein each R ^c substituent of Ring C is selected from the group consisting of: halo; cyano; C _1-6 alkyl; C _1-6 alkyl substituted with from 1-6 R ^a ; C _1-4 alkoxy; and C _1-4 haloalkoxy.

114. The compound of clause 113, wherein one occurrence of R ^c substituent of Ring C is C _1-6 alkyl or C _1-6 alkyl substituted with from 1-6 R ^a , such as C _1-6 alkyl substituted with from 1-6 independently selected halo, such as -F.

115. The compound clause 1, wherein the compound is a compound of Formula

(Ia-1-1):

Formula (Ia-1-1) or a pharmaceutically acceptable salt thereof, wherein:

B ⁴ is C or N;

B ¹ , B ² , and B ³ are each independently CH, CR ^C , NH, N(R ^d ), N, O, or S; provided that from 0-2 of B ¹ , B ² , and B ³ is CR ^C ; each ==is independently a single bond or a double bond provided that the ring including B'-B ⁴ is a heteroaryl; and

Q ¹ , Q ² , Q ³ , Q ⁴ , and Q ⁵ are independently CH, CR ^C , or N, provided that from 2-5 of Q ⁴ -Q ⁵ are CH.

116. The compound of clause 115, wherein R ² is H; and R ⁵ is H.

117. The compound of clauses 115 or 116, wherein R ⁶ is H. 118. The compound of any one of clauses 115-117, wherein R ^1a and R ^1d are H; and R ^1b and R ^1c are independently selected halo, such as -F or -Cl, such as -F, such as: wherein R ^1b and R ^1c are -F; or wherein R ^1b is -F; and R ^1c is -Cl; or wherein R ^1b is -Cl; and R ^1c is -F.

119. The compound of any one of clauses 115-117, wherein R ^1a and R ^1d are H; one of R ^1b and R ^1c is H; and the other one of R ^1b and R ^1c is halo, such as -F or -Cl, such as -F, such as wherein R ^1c is H, and R ^1b is -F; or wherein R ^1c is H, and R ^1b is -Cl; or wherein R ^1c is -Cl, and R ^1b is H; or wherein R ^1c is -F; and R ^1b is H.

120. The compound of any one of clauses 115-117, wherein R ^1a and R ^1d are H; R ^1c is halo or H, such as -F, -Cl, or H; and R ^1b is heteroaryl of 5 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 is optionally substituted with from 1-4 R ^c , such as wherein R ^1b is pyrazolyl optionally substituted with R ^c .

121. The compound of any one of clauses 115-117, wherein R ^1a and R ^1d are H; R ^1c is halo or H, such as -F, -Cl, or H; and R ^1b is heteroaryl of 5-6 (such as 5) 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 is substituted with one occurrence of R ^h1 or -(L ^g ) _bg -R ^h1 and further optionally substituted with from 1-2 R ^c , wherein R ^h1 is an independently selected R ^h , such as wherein R ^1b is pyrazolyl substituted with R ^h1 .

122. The compound of any one of clauses 115-117, wherein R ^1a and R ^1d are H; R ^1c is halo or H, such as -F, -Cl, or H; and R ^1b is phenyl optionally substituted with from 1-4 R ^c , such as phenyl optionally substituted with from 1-2 substituents each independently selected from the group consisting of: C _1-6 alkyl optionally substituted with from 1-6 R ^a ; - halo; -cyano; C _1-4 alkoxy; and C _1-4 haloalkoxy. 123. The compound of any one of clauses 115-117, wherein R ^1a is H; R ^1d is halo, such as -F or -Cl; R ^1c is H; and R ^1b is R ^g .

124. The compound of any one of clauses 115-123, wherein Ring B is: o _r , such as

125. The compound of any one of clauses 115-123, wherein Ring B is

126. The compound of any one of clauses 115-123, wherein Ring B is

127. The compound of any one of clauses 115-123, wherein Ring B is

128. The compound of any one of clauses 115-123, wherein Ring B is 129. The compound of any one of clauses 115-123, wherein Ring B is , _{each of} which is further optionally substituted with R ^c (such as not further optionally substituted).

130. The compound of any one of clauses 115-130, wherein al is 0.

131. The compound of any one of clauses 115-130, wherein al is 1; and L ^A is Ci-3 alkyl ene optionally substituted with from 1-4 R ^a1 .

132. The compound of clause 131, wherein L ^A is CH ₂ ; or wherein L ^A is C(H)Me.

133. The compound of any one of clauses 115-132, wherein the

134. The compound of any one of clauses 115-132, wherein the moiety is , or , such as

136. The compound of clause 1, wherein the compound is selected from the group consisting of the compounds delineated in Table Cl, and a pharmaceutically acceptable salt thereof.

137. A pharmaceutical composition comprising a compound of clauses 1-136 and one or more pharmaceutically acceptable excipients.

138. A method for inhibiting STING activity, the method comprising contacting STING with a compound or a pharmaceutically acceptable salt thereof as defined in any one of clauses 1-136; or a pharmaceutical composition as defined in clause 137. 139. The method of clause 138, wherein the inhibiting comprises antagonizing

STING.

140. The method of any one of clauses 138-139, which is carried out in vitro. 141. The method of clause 140, wherein the method comprises contacting a sample comprising one or more cells comprising STING with the compound.

142. The method of clause 140 or 141, wherein the one or more cells are one or more cancer cells.

143. The method of clause 141 or 142 wherein the sample further comprises one or more cancer cells, wherein the cancer is selected from the group consisting of 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.

144. The method of clause 138 or 139, which is carried out in vivo.

145. The method of clause 144, wherein the method comprises administering the compound to a subject having a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease. 146. The method of clause 145, wherein the subject is a human.

147. The method of clause 146, wherein the disease is cancer.

148. The method of clause 147, wherein the cancer is selected from the group consisting of 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.

149. The method of clause 147 or 148, wherein the cancer is a refractory cancer. 150. The method of clause 145, wherein the compound is administered in combination with one or more additional cancer therapies. 151. The method of clause 150, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

152. The method of clause 151, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.

153. The method of clause 152, wherein the one or more 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, 4-1BB-4-1BB 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, HVEM-BTL A-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).

154. The method of any one of clauses 145-153, wherein the compound is administered intratum orally.

155. A method of treating cancer, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of clauses 1- 136, or a pharmaceutical composition as defined in clause 137. 156. The method of clause 155, wherein the cancer is selected from the group consisting of 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.

157. The method of clause 155 or 156, wherein the cancer is a refractory cancer. 158. The method of clause 155, wherein the compound is administered in combination with one or more additional cancer therapies.

159. The method of clause 158, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

160. The method of clause 159, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.

161. The method of clause 160, wherein the one or more 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, 4-1BB-4-1BB 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, HVEM-BTL A-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). 162. The method of any one of clauses 155-161, wherein the compound is administered intratum orally.

163. A method of inducing an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as defined in any one of clauses 1-136, or a pharmaceutical composition as defined in clause 137.

164. The method of clause 163, wherein the subject has cancer. 165. The method of clause 164, wherein the subject has undergone and/or is undergoing and/or will undergo one or more cancer therapies.

166. The method of clause 164, wherein the cancer selected from the group consisting of 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.

167. The method of clause any one of clauses 164-166, wherein the cancer is a refractory cancer. 168. The method of clause 163, wherein the immune response is an innate immune response.

169. The method of clause 168, wherein the at least one or more cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

170. The method of clause 169, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents. 171. The method of clause 170, wherein the one or more additional chemotherapeutic agents is selected from 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 antihelminthic 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, 4-1BB-4-1BB 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, HVEM-BTL A-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).

172. A method of treatment of a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of clauses 1-136, or a pharmaceutical composition as defined in clause 137. 173. A method of treatment comprising administering to a subject having a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease an effective amount of a compound as defined in any one of clauses 1-136, or a pharmaceutical composition as defined in clause

137.

174. A method of treatment comprising administering to a subject a compound as defined in any one of clauses 1-136, or a pharmaceutical composition as defined in clause 137, wherein the compound or composition is administered in an amount effective to treat a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease, thereby treating the disease.

175. The method of any one of clauses 172-174, wherein the disease is cancer. 176. The method of clause 175, wherein the cancer is selected from the group consisting of 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.

177. The method of clause 175 or 176, wherein the cancer is a refractory cancer.

178. The method of any one of clauses 175-177, wherein the compound is administered in combination with one or more additional cancer therapies.

179. The method of clause 178, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof. 180. The method of clause 179, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents. 181. The method of clause 180, wherein the one or more 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 antihelminthic 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, 4-1BB-4-1BB 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, HVEM-BTL A-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). 182. The method of any one of clauses 172-181, wherein the compound is administered intratum orally.

183. A method of treatment of a disease, disorder, or condition associated with STING, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of clauses 1-136, or a pharmaceutical composition as defined in clause 137.

184. The method of clause 183, wherein the disease, disorder, or condition is selected from type I interferonopathies, Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, inflammation-associated disorders, and rheumatoid arthritis.

185. The method of clause 184, wherein the disease, disorder, or condition is a type I interferonopathy (e.g., STING-associated vasculopathywith onset in infancy (SAVI)).

186. The method of clause 185, wherein the type I interferonopathy is STING- associated vasculopathy with onset in infancy (SAVI)).

187. The method of clause 184, wherein the disease, disorder, or condition is Aicardi-Goutieres Syndrome (AGS). 188. The method of clause 184, wherein the disease, disorder, or condition is a genetic form of lupus.

189. The method of clause 184 wherein the disease, disorder, or condition is inflammation-associated disorder.

190. The method of clause 189, wherein the inflammation-associated disorder is systemic lupus erythematosus.

191. The method of any one of clauses 138-190, wherein the method further comprises identifying the subject.

192. A combination comprising a compounds defined in any one of clauses 1 to 136 or a pharmaceutially acceptable salt or tautomer thereof, and one or more therapeutically active agents.

193. A compound defined in any one of clauses 1 to 136 or a pharmaceutially acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 137, for use as a medicament.

194. A compound defined in any one of clauses 1 to 136 or a pharmaceutially acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 137, for use in the treatment of a disease, condition or disorder modulated by STING inhibition.

195. A compound defined in any one of clauses 1 to 136 or a pharmaceutially acceptable salt or tautomer thereof, or the pharmaceutical composition defined in clause 137, for use in the treatment of a disease mentioned in any one of clauses 138 to 191.

196. Use of a compound defined in any one of clauses 1 to 136 or a pharmaceutially acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 137, in the manufacture of a medicament for the treatment of a disease mentioned in in any one of clauses 138 to 191.