EP4182028A1 - Compounds and compositions for treating conditions associated with sting activity - Google Patents

Compounds and compositions for treating conditions associated with sting activity

Info

Publication number
EP4182028A1
EP4182028A1 EP21751933.9A EP21751933A EP4182028A1 EP 4182028 A1 EP4182028 A1 EP 4182028A1 EP 21751933 A EP21751933 A EP 21751933A EP 4182028 A1 EP4182028 A1 EP 4182028A1
Authority
EP
European Patent Office
Prior art keywords
group
independently selected
optionally substituted
equiv
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21751933.9A
Other languages
German (de)
French (fr)
Inventor
Shankar Venkatraman
Jason Katz
William R. Roush
Hans Martin Seidel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis Pharma AG
Original Assignee
IFM Due Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by IFM Due Inc filed Critical IFM Due Inc
Publication of EP4182028A1 publication Critical patent/EP4182028A1/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • 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).
  • STING activation e.g., STING signaling
  • 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.
  • 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.
  • cGAMP 2', 3' cyclic GMP-AMP
  • STING can also function as a primary pattern recognition receptor for bacterial cyclic dinucleotides (CDNs) and small molecule agonists.
  • CDNs bacterial cyclic dinucleotides
  • STING 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 signals through the transcription factors IRF-3 to induce type I interferons (IFNs) and other co-regulated antiviral factors.
  • IFNs type I interferons
  • STING was shown to trigger NF- ⁇ B 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- Goutines Syndrome (AGS) and genetic forms of lupus.
  • AGS Aicardi- Goutines Syndrome
  • 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).
  • chemical entities e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound
  • 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).
  • STING activation e.g., STING signaling
  • 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.
  • 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 , a1, Ring C, and R 7 can be as defined anywhere herein.
  • 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.
  • methods for inhibiting (e.g., antagonizing) STING activity 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).
  • 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.
  • STING e.g., innate immune cells, e.g., mast cells, macrophages, dendritic cells (DCs), and natural killer cells
  • 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.
  • 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).
  • 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.
  • STING-associated conditions are featured, e.g., type I interferonopathies (e.g., STING-associated vasculopathywith onset in infancy (SAVI)), Aicardi-Gout Italian Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis.
  • SAVI STING-associated vasculopathywith onset in infancy
  • AVS Aicardi-Gout Italian Syndrome
  • genetic forms of lupus e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same.
  • methods of suppressing STING-dependent type I interferon production in a subject in need thereof 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).
  • 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 of treating a disease in which increased (e.g., excessive) STING activation e.g., STING signaling
  • 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).
  • methods of treatment 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.
  • 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
  • STING activation e.g., STING signaling
  • 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.
  • STING activation e.g., STING signaling
  • 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, described herein for use in the treatment of cancer.
  • 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.
  • a compound, or a pharmaceutically acceptable salt or tautomer thereof as described herein for use in the treatment of type I interferonopathies.
  • 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-Goutines Syndrome (AGS), genetic forms of lupus, and inflammation- associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis.
  • 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.
  • a compound, or a pharmaceutically acceptable salt or tautomer thereof as described herein in the manufacture of a medicament for the treatment of cancer.
  • 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.
  • 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.
  • 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-Goutines Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis.
  • a compound, or a pharmaceutically acceptable salt or tautomer thereof for the treatment of a disease, condition or disorder modulated by STING inhibition.
  • 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.
  • a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for the treatment of cancer there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for the treatment of cancer.
  • 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.
  • a compound, or a pharmaceutically acceptable salt or tautomer thereof as described herein for the treatment of type I interferonopathies.
  • 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-Goutines Syndrome (AGS), genetic forms of lupus, and inflammation- associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis.
  • SAVI STING-associated vasculopathy with onset in infancy
  • AVS Aicardi-Goutines Syndrome
  • 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.
  • 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-Gout Italian Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis.
  • STING-associated conditions e.g., type I interferonopathies (e.g., STING-associated vasculopathywith onset in infancy (SAVI)), Aicardi-Goutines Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic
  • 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.
  • additional cancer therapies e.g., surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof; e.g., chemotherapy that includes administering one or more (e.g., two, three, four, five, six, or more) additional chemotherapeutic agents.
  • Non-limiting examples of additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g.,azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan;.
  • an alkylating agent e.g.,
  • the subject can have cancer; e.g., the subject has undergone and/or is undergoing and/or will undergo one or more cancer therapies.
  • 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.
  • the cancer can be a refractory cancer.
  • the chemical entity can be administered intratumorally.
  • the methods can further include identifying the subject.
  • Other embodiments include those described in the Detailed Description and/or in the claims. Additional Definitions To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
  • 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.
  • an “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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
  • Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt.
  • the salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tart
  • 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.
  • 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.
  • 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.
  • 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.
  • halo refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • 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, iso-propyl, tert-butyl, n-hexyl.
  • saturated means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.
  • haloalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo.
  • alkoxy refers to an -O-alkyl radical (e.g., -OCH 3 ).
  • alkylene refers to a divalent alkyl (e.g., -CH 2 -).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • aryl groups include phenyl, naphthyl, tetrahydronaphthyl, dihydro-1H-indenyl and the like.
  • cycloalkyl 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.
  • 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[1.1.1]pentanyl bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 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).
  • 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.
  • saturated as used in this context means only single bonds present between constituent carbon atoms.
  • 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.
  • 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.
  • heteroaryl 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.
  • 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]pyrimi
  • the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
  • 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.
  • ring atoms e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system
  • heteroatoms selected from O, N, or S (e.g.
  • 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[1.1.1]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[1.1.1
  • Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • spirocyclic heterocyclyls include 2- azaspiro[2.2]pentanyl, 4-azaspiro[2.5]octanyl, 1-azaspiro[3.5]nonanyl, 2- azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[4.4]nonanyl, 6- azaspiro[2.6]nonanyl, 1,7-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, 1-oxaspiro[3.5]
  • 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.
  • heterocycloalkenyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl.
  • 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.
  • a ring when a ring is described as being “aromatic”, it means said ring has a continuous, delocalized ⁇ -electron system. Typically, the number of out of plane ⁇ - electrons corresponds to the Hückel rule (4n+2). Examples of such rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.
  • a ring 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.
  • 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
  • examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.
  • rings and cyclic groups e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein
  • 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., ,
  • atom bridge e.g., a single ring atom (spiro- fused ring systems)
  • bridged ring systems having all bridge lengths > 0
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include 13 C and 14 C.
  • the compounds generically or specifically disclosed herein are intended to include all tautomeric forms.
  • a compound containing the encompasses the tautomeric form containing the moiety: . y, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.
  • 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).
  • STING activation e.g., STING signaling
  • This disclosure also features compositions containing the same as well as methods of using and making the same.
  • each of Z, Y 1 , Y 2 , Y 3 , X 1 , and X 2 is independently N or CR 1 .
  • each of Z, Y 1 , Y 2 , and Y 3 is an independently selected CR 1 .
  • the compound is a compound of Formula (Ia): Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein: R 1a , R 1b , R 1c , and R 1d are each an independently selected R 1 .
  • 1-2 (such as 1) of Z, Y 1 , Y 2 , and Y 3 is N; and each of the remaining of Z, Y 1 , Y 2 , and Y 3 is an independently selected CR 1 .
  • 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 .
  • the compound is a compound of Formula (Ib):
  • the compound is a compound of Formula (Ic): or a pharmaceutically acceptable salt thereof, wherein: R 1a , R 1b , and R 1d are each an independently selected R 1 .
  • the compound is a compound of Formula (Id): or a pharmaceutically acceptable salt thereof, wherein: R 1a , R 1c , and R 1d are each an independently selected R 1 .
  • the compound is a compound of Formula (Ie):
  • R 1b , R 1c , and R 1d are each an independently selected R 1 .
  • X 1 is NR 2 .
  • X 1 is NH.
  • X 2 is CR 5 .
  • X 2 is CH.
  • X 1 is NR 2 ; and X 2 is CR 5 .
  • X 1 is NR 2 ; and X 2 is CH.
  • X 1 is NH; and X 2 is CR 2 .
  • X 1 is NH; and X 2 is CH.
  • the compound is a compound of Formula (Ia-1): Formula (Ia-1) or a pharmaceutically acceptable salt thereof, wherein: R 1a , R 1b , R 1c , and R 1d are each an independently selected R 1 .
  • R 2 is H.
  • R 5 is H.
  • R 2 is H; and R 5 is H.
  • the compound is selected from the group consisting of a compound of the following formulae:
  • R 1a , R 1b , R 1c , and R 1d are each an independently selected R 1 .
  • the compound is a compound of Formula (Ib-1): or a pharmaceutically acceptable salt thereof, wherein: R 1a , R 1b , and R 1c are each an independently selected R 1 .
  • R 2 is H.
  • R 5 is H.
  • R 2 is H; and R 5 is H.
  • the compound is a compound of Formula (Ic-1): or a pharmaceutically acceptable salt thereof, wherein: R 1a , R 1b , and R 1d are each an independently selected R 1 .
  • R 2 is H.
  • R 5 is H.
  • R 1c , and R 1d are each an independently selected R 1 .
  • R 2 is H.
  • R 5 is H. In certain embodiments of Formula (Id-1), R 5 is H. In certain embodiments of Formula (Id-1), R 2 is H; and R 5 is H. In certain embodiments, the compound is a compound of Formula (Ie-1): or a pharmaceutically acceptable salt thereof, wherein: R 1b , R 1c , and R 1d are each an independently selected R 1 . In certain embodiments of Formula (Ie-1), R 2 is H. In certain embodiments of Formula (Ie-1), R 5 is H. In certain embodiments of Formula (Ie-1), R 2 is H; and R 5 is H.
  • the Variable R 1 In some embodiments, each R 1 is H. In some embodiments, 1-2 R 1 is an independently selected non-hydrogen substituent, and each remaining R 1 is H.
  • 1-2 R 1 are each 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 .
  • 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.
  • two occurrences of R 1 are each an independently selected R c1 ; and each remaining R 1 is H.
  • each R c1 is an independently selected halo, such as –F or –Cl.
  • 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 ), one occurrence of R 1 is selected from the group consisting of: R c1 and R g1 ; and each remaining R 1 is H.
  • one occurrence of R 1 is R c1 ; and each remaining R 1 is H.
  • R c1 is halo, such as –F or –Cl, such as –F.
  • each 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 ), one occurrence of R 1 is R g1 ; and each remaining R 1 is H.
  • each R c1 is an independently selected halo, such as –F, -Cl, or –Br.
  • each R c1 is independently – F or –Cl, such as –F.
  • each R g1 is independently selected from the group consisting of: heteroaryl of 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, 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 C6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R c , R h , and
  • each R g1 is independently selected from the group consisting of: heteroaryl of 5-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 R c ; and C 6 aryl optionally substituted with 1-4 R c .
  • each R g1 is independently heteroaryl of 5 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, and wherein the heteroaryl is optionally substituted with 1-4 R c .
  • each R g1 can be pyrazolyl that is optionally substituted with 1-2 R c , such as 1-2 independently selected C 1-6 (e.g., C 1-3 ) alkyl which is optionally substituted with 1-6 independently selected R a (e.g., unsubstituted).
  • the compound is a compound of Formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Id), or (Id-1); and R 1a H.
  • the compound is a compound of Formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Ie), or (Ie-1); and R 1b is H.
  • the compound is a compound of Formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Ie), or (Ie-1); and R 1b is halo, such as –F or –Cl (e.g., -F).
  • the compound is a compound of Formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Ie), or (Ie-1); and R 1b is heteroaryl of 5 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, and wherein the heteroaryl is optionally substituted with 1-2 R c .
  • R 1b is pyrazolyl that is optionally substituted with 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 1-6 independently selected R a (e.g., unsubstituted).
  • the compound is a compound of Formula (Ia), (Ia-1), (Ib), (Ib-1), (Id), (Id-1), (Ie), or (Ie-1); R 1c is H.
  • the compound is a compound of Formula (Ia), (Ia-1), (Ib), (Ib-1), (Id), (Id-1), (Ie), or (Ie-1); R 1c is halo, such as –F or –Cl (e.g., -F).
  • the compound is a compound of Formula (Ia), (Ia-1), (Ic), (Ic-1), (Id), (Id-1), (Ie), or (Ie-1); and R 1d is H.
  • the compound is a compound of Formula (Ia), (Ia-1), (Ic), (Ic-1), (Id), (Id-1), (Ie), or (Ie-1); and R 1d is halo, such as –F or –Cl (e.g., -F).
  • the compound is a compound of Formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Id), (Id-1), (Ie), or (Ie-1); 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.
  • the compound is a compound of Formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Id), (Id-1), (Ie), or (Ie-1); 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.
  • the compound is a compound of Formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Id), (Id-1), (Ie), or (Ie-1); 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 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 1-4 R c .
  • R 6 is H.
  • Ring B is a heteroarylene of 5 ring atoms, wherein 1-3 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, O, and S, wherein the heteroarylene of Ring B is optionally substituted with 1-2 R cB ; and each R cB is an independently selected R c .
  • Ring B is a heteroarylene of 5 ring atoms, wherein 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 1-2 R cB ; and each R cB is an independently selected R c .
  • Ring B is a heteroarylene of 5 ring atoms, wherein 2-3 of the ring atoms are heteroatoms each independently selected from the group consisting of: N and NH, wherein the heteroarylene of Ring B is optionally substituted with 1-2 R cB ; and each R cB is an independently selected R c .
  • Ring B is selected from the group consisting of imidazolylene, pyrazolylene, or triazolylene (such as 1,2,3-triazolylene) which is optionally substituted with one R cB .
  • Ring B is imidazolylene, which is optionally substituted with one R cB .
  • Ring B is which is optionally substituted with one R cB , wherein aa is the point of connection to (L A )a1.
  • Ring B is which is optionally substituted with one R cB , wherein aa is the point of connection to (L A ) a1 .
  • Ring B is triazolylene (such as 1,2,3-triazolylene) which is optionally substituted with one R cB .
  • Ring B is which is optionally substituted with one R cB , wherein aa is the point of connection to (L A )a1.
  • Ring B is pyrazolylene, which is optionally substituted with one R cB .
  • Ring B is , each of which is optionally substituted with one R cB , wherein aa is the point of connection to (L A )a1.
  • Ring each of which is optionally substituted with one R cB wherein aa is the point of connection to (L A )a1.
  • each R cB is independently halo or C 1-3 alkyl optionally which is optionally substituted 1-3 independently selected R a (such as 1-3 independently selected halo).
  • Ring B is selected from the group consisting of isoxazolylene, oxadiazolylene, oxazolylene, thiazolylene, isothiazolylene, or thiadiazolylene, which is optionally substituted with one R cB .
  • Ring each of which is optionally substituted with one R cB wherein aa is the point of connection to (L A ) a1 .
  • Ring each of which is optionally substituted with one R cB wherein aa is the point of connection to (L A ) a1 . In certain embodiments, Ring each of which is optionally substituted with one R cB , wherein aa is the point of connection to (L A )a1. In certain embodiments, Ring which is optionally substituted with one R cB , wherein aa is the point of connection to (L A )a1. In certain embodiments, Ring each of which is optionally substituted with one R cB , wherein aa is the point of connection to (L A ) a1 .
  • Ring each of which is optionally substituted with one R cB wherein aa is the point of connection to (L A )a1.
  • each R cB is independently halo or C 1-3 alkyl optionally which is optionally optionally substituted 1-3 independently selected R a (such as 1-3 independently selected halo).
  • the Variables a1 and L A In some embodiments, a1 is 0. In some other embodiments, a1 is 1. In some embodiments, L A is C 1-3 alkylene optionally substituted with 1-2 R a1 . In certain of these embodiments, L A is CH 2 or CH(Me), such as CH 2 .
  • a1 is 1; and L A is C 1-3 alkylene optionally substituted with 1-2 R a1 .
  • L A is CH 2 or CH(Me), such as CH 2 .
  • the Variable Ring C is selected from the group consisting of: x heteroarylene of 5-10 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 heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of R cC and R hC ; and x C 6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of R cC and R hC , wherein each R cC is an independently selected R c ; and each R hC is an independently selected R h .
  • Ring C is selected from the group consisting of: x heteroarylene of 5-6 (such as 6) ring atoms, wherein 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 heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of R cC ; and x C 6 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of R cC .
  • Ring C is selected from the group consisting of: heteroarylene of 5-10 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 heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of R cC and R hC ; and C 6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of R cC and R hC , wherein each R cC is an independently selected R c ; and each R hC is an independently selected R h ), Ring C is selected from the group consisting of: x pyridylene optionally substituted with 1-3 (such as 1) substituents independently selected from the group consisting of R cC ; and x C6 arylene optionally substituted with 1-4 (such as 1-2) substituents independently selected from
  • Ring C is a group of the following formula: , wherein each one of Q 1 , Q 2 , Q 3 , and Q 4 is independently selected from the group consisting of N, CH, and CR cC ; and bb is the point of connection to R 7 , wherein each R cC is an independently selected R c .
  • each one of Q 1 , Q 2 , Q 3 , and Q 4 is independently CH or CR cC .
  • 1-2 e.g., 1) of Q 1 , Q 2 , Q 3 , and Q 4 are N; and each remaining one of Q 1, Q 2 , Q 3 , and Q 4 are independently CH or CR cC .
  • Q 2 is CH. In certain embodiments, Q 3 is CH. In certain embodiments, Q 4 is N. In certain embodiments, Q 1 is CH. In certain other embodiments, Q 1 is CR cC . . In certain embodiments, each R cC is independently selected from the group consisting of: -halo and C1-6 (e.g., C1-3) alkyl which is optionally substituted with 1-6 independently selected R a (e.g., 1-6 independently selected halo, such as –F). In certain embodiments, each R cC is independently halo, such as –Cl or –F, such as –F.
  • the Variable R 7 In some embodiments, R 7 is R g .
  • R 7 is selected from the group consisting of: x C 3-12 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R c7 , R h7 , and –(L g ) bg -R h7 ; and x heterocyclyl of 4-12 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 is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R c7 , R h7 , and –(L g ) bg -R h7 , wherein each R c7 is an independently selected R c ; and R h7 is an independently selected R h .
  • R 7 is selected from the group consisting of: x C 4-8 (e.g., C 4 , C 5 , or C 6 ) cycloalkyl, which is optionally substituted with 1- 4 substituents independently selected from the group consisting of oxo, R c7 , and R h7 ; and x heterocyclyl of 4-8 (e.g., 4, 5, or 6) 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 is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R c7 , and R h7 .
  • x C 4-8 e.g., C 4 , C 5 , or C 6
  • cycloalkyl which is optionally substituted with 1- 4 substituents independently selected from the group consisting of o
  • R 7 is selected from the group consisting of: x C 6 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of R c7 ; and x heterocyclyl of 6 ring atoms, wherein 1-2 (such as one) 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 1-4 substituents independently selected from the group consisting of R c7 .
  • R 7 is a group of the following formula: wherein X 7 is CH, CR c7 , or N, such as CH or N. In certain embodiments (when R 7 is ), two R c7 groups are present. In certain embodiments, R 7 is a group of the following formula: , wherein X 7 is N or CH; and each R c7 is an independently selected R c .
  • R 7 is wh 7 erein X is N or CH; such as In certain of the foregoing embodiments, R 7 is selected from the group consisting of: x C 4 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of R c7 ; and x heterocyclyl of 4 ring atoms, wherein 1-2 (such as one) 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 1-4 substituents independently selected from the group consisting of R c7 .
  • R 7 is a group of the following formula: , wherein X 7 is CH, CR c7 , or N, such as CH or N. In certain embodiments (when R 7 is , two R c7 groups are present. In certain embodiments, R 7 is a group of the following formula: , wherein X 7 is N or CH; and each R c7 is an independently selected R c . In certain embodiments, R 7 i , wherein X 7 is N or CH; such a .
  • R 7 is selected the group consisting of tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octanyl, or 2-azabicyclo[2.2.1]heptanyl, each of which is optionally substituted with 1-2 R c7 .
  • R 7 can be:
  • each R c7 is an independently selected halo or C 1-3 alkyl optionally substituted with 1-6 R a (e.g., 1-6 independently selected halo).
  • each R c7 is independently halo, such as –F.
  • R 7 is selected from the group consisting of: x C 4-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of R c7 ; and x heterocyclyl of 5-6 ring atoms, wherein 1-2 (such as one) 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 1-4 substituents independently selected from the group consisting of R c7 .
  • R 7 is a group of the following formula: , wherein X 7 is CH, CR c7 , or N, such as CH or N. In certain embodiments, R 7 is a group of the following formula: , wherein R d is is independently selected from the group consisting of: C 1-6 alkyl optionally substituted with 1-3 independently selected R a . In certain embodiments, R 7 is selected from the group consisting of tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octanyl, or 2- azabicyclo[2.2.1]heptanyl, each of which is optionally substituted with 1-2 R c7 . For example, R 7 can be:
  • the compound is a compound of Formula (I-a1-1): Formula (I-a1-1) or a pharmaceutically acceptable salt thereof, wherein: each one of R 1a , R 1b , R 1c , and R 1d is an independently selected R 1 ; B 4 is C or N; B 1 , B 2 , and B 3 are each independently CH, CR cB , NH, N(R d ), N, O, or S; Q 1 , Q 2 , Q 3 , and Q 4 are each independently selected from the group consisting of N, CH, and CR cC ; each occurrence of R cB and R cC is an independently selected R c ; and each is independently a single bond or a double bond provided that the ring including B 1 -B 4 is a heteroaryl.
  • R 1a and R 1d are H; and R 1b and R 1c are independently H or halo. In some embodiments of Formula (I-a1-1), 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. In some embodiments of Formula (I-a1-1), each one of R 1a , R 1b , R 1c , and R 1d is H.
  • 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 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 1-4 substituents independently selected from the group consisting of R c .
  • R 2 is H.
  • R 5 is H.
  • R 2 is H; and R 5 is H.
  • R 6 is H.
  • R 2 is H; R 5 is H; and R 6 is H.
  • B 4 is N; B 1 is N; B 3 is CH or CR cB ; and B 2 is CH or CR cB .
  • B 4 is N; B 1 is N; B 3 is CH; and B 2 is CH.
  • B 4 is N; B 1 is N; B 3 is CH; and B 2 is CR cB .
  • B 4 is N; B 1 is N; B 3 is CH or CR cB ; and B 2 is N. In certain embodiments, B 4 is N; B 1 is N; B 3 is CH; and B 2 is N. In some embodiments of of Formula (I-a1-1), B 4 is N; B 1 is CH or CR cB ; B 3 is CH or CR cB ; and B 2 is N. In certain embodiments, B 4 is N; B 1 is CH; B 3 is CH; and B 2 is N. In some embodiments of Formula (I-a1-1), B 4 is N; B 1 is CH or CR cB ; B 3 is N; and B 2 is CH or CR cB .
  • B 4 is N; B 1 is CH; B 3 is N; and B 2 is CH.
  • B 4 is C; B 1 is N, B 3 is CR cB ; and B 2 is O.
  • B 4 is C; B 1 is N, B 3 is CH; and B 2 is O.
  • B 4 is C; B 1 is O, B 3 is CH; and B 2 is N.
  • a1 is 0.
  • a1 is 1.
  • L A is CH2 or CH(Me).
  • Q 1 and Q 3 are CH or CR cC (such as CH).
  • Q 4 is N; and Q 2 is CH or CR cC , such as CR cC .
  • the ring including Q 1 -Q 4 is: , wherein bb is the point of connection to R 7 .
  • R cC is halo, such as –F or –Cl, such as –F.
  • R 7 is selected from the group consisting of: x C 6 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of R c7 ; and x heterocyclyl of 6 ring atoms, wherein 1-2 (such as one) 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 1-4 substituents independently selected from the group consisting of R c7 , wherein each R c7 is an independently selected R c .
  • R 7 is a group of the following formula: , wherein X 7 is CH, CR 7 , or N, such as CH or N. In certain of these embodiments, two R c7 groups are present.
  • R 7 is a group of the following formula: , wherein X 7 is N or CH; and each R c7 is an independently selected R c . In certain of these embodiments, , wherein X 7 is N or CH, such .
  • R 7 is selected from the group consisting of: x C 4 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of R c7 ; and x heterocyclyl of 4 ring atoms, wherein 1-2 (such as one) 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 1-4 substituents independently selected from the group consisting of R c7 .
  • R 7 is a group of the following formula: , wherein X 7 is CH, CR c7 , or N, such as CH or N. In certain embodiments (when two R c7 groups are present.
  • R 7 is a group of the following formula: , wherein X 7 is N or CH; and each R c7 is an independently selected R c . In certain embodiments, , wherein X 7 is N or CH; such . In some embodiments of Formula (I-a1-1), R 7 is selected the group consisting of tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octanyl, or 2-azabicyclo[2.2.1]heptanyl, each of which is optionally substituted with 1-2 R c7 .
  • R 7 can be: In some embodiments of Formula (I-a1-1), each R c7 is an independently selected halo or C 1-3 alkyl optionally substituted with 1-6 R a (e.g., 1-6 independently selected halo). In certain of these embodiments, each R c7 is independently halo, such as –F.
  • the compound is a compound of Formula (I-a1-1) wherein: R 1a and R 1d is a H; R 1b , 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; Q 1 is an N; Q 2 and Q 3 are each independently a CH; Q 4 is an CR c ; and each is independently a single bond or a double bond provided that the ring including B 1 -B 4 is a heteroaryl; , wherein X 7 is N or CH, 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: –OH; -halo; C 1-4 alkoxy; C 1-4 haloal
  • the compound is a compound of Formula (I-f1-1): Formula (I-f1-1) or a pharmaceutically acceptable salt thereof, wherein: Z is N or CR 1a ; Y 1 is N or CR 1b ; Y 2 is N or CR 1c ; Y 3 is N or CR 1d , provided that 1-2 (e.g., 1) of Z, Y 1 , Y 2 , and Y 3 is N; each one of R 1a , R 1b , R 1c , and R 1d is an independently selected R 1 ; B 4 is C or N; B 1 , B 2 , and B 3 are each independently CH, CR cB , NH, N(R d ), N, O, or S; Q 1 , Q 2 , Q 3 , and Q 4 are each independently selected from the group consisting of N, CH, and CR cC ; each occurrence of R cB and R cC is an independently selected R c ; and
  • Formula (I-b1-1) or a pharmaceutically acceptable salt thereof is a compound of Formula (I-f1-1): Formula (I-c1-1) or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I-d1-1): Formula (I-d1-1) or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I-d1-1):
  • Formula (I-e1-1) or a pharmaceutically acceptable salt thereof in some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), R 1a and R 1d when present are H; and R 1b and R 1c when present are independently H or halo. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), 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.
  • each one of R 1a , R 1b , R 1c , and R 1d when present is H.
  • 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 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 1-4 substituents independently selected from the group consisting of R c .
  • R 1d when present is an independently selected halo, such as –F or –Cl.
  • each one of R 1a , R 1b , and R 1c when present is H.
  • R 2 is H.
  • R 5 is H.
  • R 2 is H; and R 5 is H.
  • R 6 is H.
  • R 2 is H; R 5 is H; and R 6 is H.
  • B 4 is N; B 1 is N; B 3 is CH or CR cB ; and B 2 is CH or CR cB .
  • B 4 is N; B 1 is N; B 3 is CH; and B 2 is CH.
  • B 4 is N; B 1 is N; B 3 is CH; and B 2 is CR cB .
  • B 4 is N; B 1 is N; B 3 is CH or CR cB ; and B 2 is N. In certain embodiments, B 4 is N; B 1 is N; B 3 is CH; and B 2 is N. In some embodiments of of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)), B 4 is N; B 1 is CH or CR cB ; B 3 is CH or CR cB ; and B 2 is N.
  • B 4 is N; B 1 is CH; B 3 is CH; and B 2 is N.
  • B 4 is N; B 1 is CH or CR cB ; B 3 is N; and B 2 is CH or CR cB .
  • B 4 is N; B 1 is CH; B 3 is N; and B 2 is CH.
  • Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), a1 is 0.
  • a1 is 1.
  • L A is CH 2 or CH(Me).
  • Q 1 and Q 3 are CH or CR cC (such as CH).
  • Q 4 is N; and Q 2 is CH or CR cC , such as CR cC .
  • the ring including Q 1 -Q 4 is: , wherein bb is the point of connection to R 7 .
  • R cC is halo, such as –F or –Cl, such as –F.
  • R 7 is selected from the group consisting of: x C 6 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of R c7 ; and x heterocyclyl of 6 ring atoms, wherein 1-2 (such as one) 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 1-4 substituents independently selected from the group consisting of R c7 , wherein each R c7 is an independently selected R c .
  • R 7 is a group of the following formula: , wherein X 7 is CH, CR 7 , or N, such as CH or N. In certain of these embodiments, two R c7 groups are present. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), R 7 is a group of the following formula: , wherein X 7 is N or CH; and each R c7 is an independently selected R c .
  • R 7 is selected from the group consisting of: x C 4 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of R c7 ; and x heterocyclyl of 4 ring atoms, wherein 1-2 (such as one) 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 1-4 substituents independently selected from the group consisting of R c7 .
  • R 7 is a group of the following formula: , wherein X 7 is CH, CR c7 , or N, such as CH or N. In certain embodiments (when c7 two R groups are present.
  • R 7 is a group of the following formula: , wherein X 7 is N or CH; and each R c7 is an independently selected R c .
  • R 7 is selected the group consisting of tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octanyl, or 2-azabicyclo[2.2.1]heptanyl, each of which is optionally substituted with 1-2 R c7 .
  • R 7 can be: , , , , In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), each R c7 is an independently selected halo or C 1-3 alkyl optionally substituted with 1-6 R a (e.g., 1-6 independently selected halo). In certain of these embodiments, each R c7 is independently halo, such as –F.
  • Formula (I-f1-1) such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)
  • each R c7 is an independently selected halo or C 1-3 alkyl optionally substituted with 1-6 R a (e.g., 1-6 independently selected halo).
  • each R c7 is independently halo, such as –F.
  • each R c7 is an independently selected halo or C 1-3 alkyl optionally substituted with 1-6 R a (e.g., 1-6 independently selected halo). In certain of these embodiments, each R c7 is independently halo, such as –F.
  • the compound is selected from the group consisting of the compounds delineated in Table C1 or a pharmaceutically acceptable salt thereof. Table C1
  • 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
  • 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.
  • the chemical entities can be administered in combination with one or more conventional pharmaceutical excipients.
  • compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- ⁇ -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-
  • Cyclodextrins such as ⁇ -, E, and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3- hydroxypropyl- ⁇ -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%.
  • 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, intracisternal, 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, sub
  • compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes.
  • parenteral administration e.g., intratumoral
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • sterile powders for the preparation of sterile injectable solutions the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia. 2006, 10, 788–795.
  • Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p- oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylo
  • 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.
  • 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.
  • compositions for rectal administration are in the form of an enema.
  • 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.
  • 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
  • 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.
  • 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.
  • a diluent such as lactose, sucrose, dicalcium phosphate, or the like
  • a lubricant such as magnesium stearate or the like
  • a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
  • 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.
  • 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.
  • 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.
  • solid oral dosage forms can further include one or more components that chemically and/or structurally predispose the composition for delivery of the chemical entity to the stomach or the lower GI; e.g., the ascending colon and/or transverse colon and/or distal colon and/or small bowel.
  • Exemplary formulation techniques are described in, e.g., Filipski, K.J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety. Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls. Other examples include lower-GI targeting techniques.
  • 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).
  • hydroxypropyl methylcellulose phthalate series Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid–methyl methacrylate copolymers), and Marcoat).
  • 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.)).
  • viscogens e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol
  • Stabilizers e.g., Pluronic (triblock copolymers), Cyclodextrins
  • Preservatives e.g., Benzalkonium chloride, ETDA, SofZ
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • a daily basis e.g., as a single dose or as two or more divided doses
  • 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.
  • 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, 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.
  • 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.
  • a therapeutic compound is administered to an individual for a period of time followed by a separate period of time.
  • 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.
  • 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.
  • 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.
  • 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 for treating a subject having condition, disease or disorder in which increased (e.g., excessive)STING activity e.g., , e.g., STING signaling
  • the condition, disease or disorder is cancer.
  • Non-limiting examples of cancer include melanoma, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
  • 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, es
  • the cancer is melanoma.
  • 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 telegiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet's disease; Bell's palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension;
  • the condition, disease or disorder is STING-associated conditions, e.g., type I interferonopathies (e.g., STING-associated vasculopathywith onset in infancy (SAVI)), Aicardi-Goutines Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis.
  • STING-associated conditions e.g., type I interferonopathies (e.g., STING-associated vasculopathywith onset in infancy (SAVI)), Aicardi-Goutines Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis.
  • SAVI STING-associated vasculopathywith onset in infancy
  • AVS Aicardi-Gout Italian Syndrome
  • genetic forms of lupus e.g., systemic lupus
  • 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.
  • the condition is an inflammatory bowel disease.
  • 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.
  • the condition is alloimmune disease (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs.
  • 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.
  • 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.
  • the infection is a fungal infection (e.g.
  • 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).
  • a parasitic infection e.g., infection by a single-celled or multicellular parasite, including Giardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, and Toxoplasma gondiz.
  • 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)).
  • the condition, disease or disorder is hepatits B (see, e.g., WO 2015/061294).
  • the condition, disease or disorder is selected from cardiovascular diseases (including e.g., myocardial infarction).
  • the condition, disease or disorder is age-related macular degeneration.
  • 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.
  • the condition, disease or disorder is uveitis, which is inflammation of the uvea (e.g., anterior uveitis, e.g., iridocyclitis or ulceris; intermediate uveitis (also known as pars planitis); posterior uveitis; or chorioretinitis, e.g., pan-uveitis).
  • 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.
  • 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.
  • 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.
  • the one or more additional cancer therapies is chemotherapy, which can include administering one or more additional chemotherapeutic agents.
  • the additional chemotherapeutic agent is an immunomodulatory moiety, e.g., an immune checkpoint inhibitor.
  • the immune checkpoint inhibitor targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1 – PD-L1, PD-1 – PD- L2, interleukin ⁇ 2 (IL ⁇ 2), indoleamine 2,3-dioxygenase (IDO), IL ⁇ 10, transforming growth factor- ⁇ (TGF ⁇ ), 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, OX40–OX40 ligand, GITR, GITR ligand – GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25–TL1A, CD40L, CD40–CD40 ligand, HVEM–LIGHT–
  • IL ⁇ 2
  • 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.
  • 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.
  • an alkylating agent includes, but is not limited to, Cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin.
  • 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.
  • an alkylating agent is a synthetic, semisynthetic or derivative.
  • 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.
  • an antimetabolite includes, but is not limited to azathioprine and/or mercaptopurine.
  • an anti- metabolite is a synthetic, semisynthetic or derivative.
  • 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.
  • 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.
  • a vinca alkaloid is derived, without limitation, from the Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea).
  • a vinca alkaloid includes, without limitation, Vincristine, Vinblastine, Vinorelbine and/or Vindesine.
  • a taxane includes, but is not limited, to Taxol, Paclitaxel and/or Docetaxel.
  • a plant alkaloid or terpernoid is a synthetic, semisynthetic or derivative.
  • a podophyllotoxin is, without limitation, an etoposide and/or teniposide.
  • a taxane is, without limitation, docetaxel and/or ortataxel. [021]
  • 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.
  • a topoisomerase is, without limitation, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor.
  • a type I topoisomerase inhibitor is, without limitation, a camptothecin.
  • a camptothecin is, without limitation, exatecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67) and/or ST 1481.
  • a type II topoisomerase inhibitor is, without limitation, epipodophyllotoxin.
  • an epipodophyllotoxin is, without limitation, an amsacrine, etoposid, etoposide phosphate and/or teniposide.
  • 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).
  • the additional chemotherapeutic agent is a stilbenoid.
  • 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.
  • a stilbenoid is a synthetic, semisynthetic or derivative.
  • the additional chemotherapeutic agent is a cytotoxic antibiotic.
  • a cytotoxic antibiotic is, without limitation, an actinomycin, an anthracenedione, an anthracycline, thalidomide, dichloroacetic acid, nicotinic acid, 2- deoxyglucose and/or chlofazimine.
  • an actinomycin is, without limitation, actinomycin D, bacitracin, colistin (polymyxin E) and/or polymyxin B.
  • an antracenedione is, without limitation, mitoxantrone and/or pixantrone.
  • an anthracycline is, without limitation, bleomycin, doxorubicin (Adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, mitomycin, plicamycin and/or valrubicin.
  • a cytotoxic antibiotic is a synthetic, semisynthetic or derivative.
  • 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
  • the additional chemotherapeutic agent is selected from abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t- butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′- deoxy-8′-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cycl
  • 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.
  • 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.
  • 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-Gout Italian Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis and the like.
  • STING-associated conditions e.g., type I interferonopathies (e.g., STING-associated vasculopathywith onset in infancy (SAVI)), Aicardi-Goutines Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis and the like.
  • STING-associated conditions e.g., type I interferonopathies (e.g., STING-associated vasculopathywith
  • 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 biologics (e.g., abatacept (Orencia®), adalimumab (Humira®), anakinra (Kineret®),
  • 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) baricitin
  • 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 biologics (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDI0700, vobarilizumab,
  • 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.
  • 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-Goutines Syndrome 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).
  • nucleoside reverse transcriptase inhibitors e.g., emtricitabine (e.g., Emtriva®), tenofovir (e.g., Viread®), emtricitabine/tenofovir (e.g., Truvada
  • 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, fingolimod, fi
  • 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, farnesoid 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,
  • 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
  • Non-limiting examples of additional therapeutic agents and/or regimens for treating Crohn’s Disease 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, V
  • 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-57
  • 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.
  • corticosteroids e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate
  • sulfasalazine 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.
  • ACE angiotensin-converting enzyme
  • 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.
  • 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.
  • corticosteroids e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate
  • corticosteroids e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate
  • fecal microbial transplantation loperamide, mesalamine, methot
  • Non-limiting examples of additional therapeutic agents and/or regimens for treating alloimmune disease include intrauterine platelet transfusions, intravenous immunoglobin, maternal steroids, abatacept, alemtuzumab, alpha1-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,
  • Non-limiting examples of additional therapeutic agents and/or regimens for treating multiple sclerosis include alemtuzumab (Lemtrada®), ALKS 8700, amiloride, ATX- MS-1467, azathioprine, baclofen (Lioresal®), beta interferons (e.g., IFN- ⁇ -1a, IFN- ⁇ -1b), cladribine, corticosteroids (e.g., methylprednisolone), daclizumab, dimethyl fumarate (Tecfidera®), fingolimod (Gilenya®), fluoxetine, glatiramer acetate (Copaxone®), hydroxychloroquine, ibudilast, idebenone, laquinimod, lipoic acid, losartan, masitinib, MD1003 (biotin), mitoxantrone, montelukast, natalizumab (Tysabri®), NeuroVax
  • Non-limiting examples of additional therapeutic agents and/or regimens for treating graft-vs-host disease include abatacept, alemtuzumab, alpha1-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, rux
  • 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.
  • corticosteroids e.g., methylprednisone, prednisone
  • cyclosporine e.g., methyl
  • 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.
  • corticosteroids e.g., methylprednisone, prednisone
  • corticosteroids e.g., methylpred
  • 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 tocafinib, 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-crème®), topical retinoids (e.g., t
  • 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®) biologics (e.g., alemtuzumab (Campath®), brentuximab vedotin (SGN-35), mogamulizumab, and IPH4102).
  • phototherapy e.g., exposure to sunlight
  • 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), biologics (e.g., infliximab (Remicade®), adalimumab (Humira®), etanercept (Enbrel®), golimumab (Simponi®), certolizumab (Cimzia®), rituximab (Rituxan®
  • 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 hydrochlor
  • 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 xyloc
  • non-limiting examples of treatments for esophageal mucositis include xylocaine (e.g., gel viscous Xylocaine 2%).
  • 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)).
  • an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox)
  • an antifungal e.g., nystatin
  • an analgesic e.g., hurricane liquid
  • 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).
  • the second therapeutic agent or regimen is administered to the subject at about the same time as contacting with or administering the chemical entity.
  • the second therapeutic agent or regimen and the chemical entity are provided to the subject simultaneously in the same dosage form.
  • the second therapeutic agent or regimen and the chemical entity are provided to the subject concurrently in separate dosage forms.
  • 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).
  • 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).
  • the STING protein can serve as a biomarker for certain types of cancer, e.g., colon cancer and prostate cancer.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • triethylamine can be interchanged with other bases, such as non- nucleophilic bases (e.g. diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert- butylpyridine, or tetrabutylphosphazene).
  • bases such as non- nucleophilic bases (e.g. diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert- butylpyridine, or tetrabutylphosphazene).
  • non- nucleophilic bases e.g. diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert- butylpyridine, or tetrabutylphosphazene.
  • analytical methods that can be used to characterize the compounds described herein, including, for example, 1 H NMR, heteronuclear N
  • LCMS Method A Kinetex EVO C18 100A, 30 *3mm, 0.5 ⁇ L 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 ⁇ L injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection.
  • Mobile Phase A 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 XBridge Shield RP18, 50 *4.6mm, 0.5 ⁇ L injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection.
  • Mobile Phase A (MPA): Water/0.04% NH3.H2O and Mobile Phase B (MPB): Acetonitrile.
  • LCMS Method E XBridge BEH C18, 50 *3mm, 4.0 ⁇ L injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection.
  • Mobile Phase A (MPA): Water/5 mM NH 4 HCO 3
  • 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 F Kinetex 2.6 ⁇ m EVO C18 100A, 50 *3mm, 0.6 ⁇ L injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection.
  • Mobile Phase A (MPA): Water/5 mM NH 4 HCO 3
  • 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 G kinetex 2.6 ⁇ m EVO, 50 *3mm, 0.5 ⁇ L injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection.
  • Mobile Phase A (MPA): Water/5 mM NH 4 HCO 3
  • 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 H Titank C18, 50 *3mm, 0.5 ⁇ L injection, 1.5 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection.
  • Mobile Phase A (MPA): Water/5 mM NH 4 HCO 3 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 I XBridge BEH C18, 50 *3mm, 4.0 ⁇ L injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection.
  • Mobile Phase A (MPA): Water/5 mM NH 4 HCO 3 and Mobile Phase B (MPB): Acetonitrile.
  • LCMS Method K Ascentis Express C18, 50 *3mm, 0.5 ⁇ L injection, 1.5 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection.
  • Mobile Phase A (MPA): Water/0.05% TFA
  • Mobile Phase B (MPB): Acetonitrile/0.05% TFA. 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 0.25 min.
  • Step 2 6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-amine 2-(4,4-difluoropiperidin-1-yl)-3-methyl-5-nitropyridine (6.0 g, 23.3 mmol, 1.0 equiv.) was dissolved in MeOH (50 mL), then Pd/C (1.0 g, 10% wt.) was added. 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 to give 6-(4,4-difluoropiperidin-1-yl)-5- methylpyridin-3-amine (4.8 g) as brown oil.
  • Step 3-4 ethyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl]imidazole-4- carboxylate 6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-amine (2.0 g, 8.8 mmol, 1.0 equiv.) was dissolved in EtOH (20 mL) and AcOH (1 mL), then ethyl 2-nitroacetate (1.1 g, 8.8 mmol, 1.0 equiv.) was added. The reaction mixture was heated to 80 °C for 30 min, then cooled to ambient temperature.
  • Step 5 1-[6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl]imidazole-4- carboxylic acid
  • Ethyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl]imidazole-4- carboxylate (500.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in MeOH/H 2 O (5:1, 12 mL), then NaOH (85.6 mg, 2.1 mmol, 1.5 equiv) was added. The resulting solution was heated to 50 °C for 2 hours, then cooled to ambient temperature and concentrated under vacuum.
  • Step 2 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]pyrazole-4- carboxylic acid
  • Ethyl 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]pyrazole-4- carboxylate (300.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and water (2 mL), then NaOH (65.3 mg, 1.6 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80 °C for 1 hour, then cooled to ambient temperature and concentrated under vacuum.
  • Step 2 1-((6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl)methyl)-1H-imidazole-4- carboxylic acid
  • Ethyl 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]imidazole-4- carboxylate (200.0 mg, 0.5 mmol, 1.0 equiv.) was dissolved in MeOH (4 mL) and water (4 mL), then NaOH (65.3 mg, 1.6 mmol, 3.0 equiv.) was added. The reaction mixture was stirred for 2 hours at 80 °C, then concentrated under vacuum.
  • Step 3 1-((6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl)methyl)-1H-imidazole-5- carboxylic acid Same method described for step 2 was used to provide 1-((6-(4,4-difluorocyclohexyl)- 5-fluoropyridin-3-yl)methyl)-1H-imidazole-5-carboxylic acid (160 mg) as a white solid.
  • the following intermediate was prepared using the same method described for Intermediates 7 and 8.
  • Step 2 ethyl 1-(6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl)-1H-pyrazole-4- carboxylate 2-(4,4-difluorocyclohexyl)-3-fluoro-5-iodopyridine (500.0 mg, 1.5 mmol, 1.0 equiv.) was dissolved in DMF (5 mL), then Cs 2 CO 3 (1.4 g, 4.4 mmol, 3.0 equiv.), ethyl 1H- pyrazole-4-carboxylate (246.5 mg, 1.8 mmol, 1.2 equiv.), N 1 ,N 2 -dimethylcyclohexane-1,2- diamine (0.1 mL, 0.7 mmol, 0.5 equiv.) and CuI (57.3 mg, 0.3 mmol, 0.2 equiv.) were added.
  • Step 3 1-(6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl)-1H-pyrazole-4- carboxylic acid
  • Ethyl 1-[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]pyrazole-4-carboxylate (110.0 mg, 0.3 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL), then aqueous NaOH (2 mL, 2M) was added. The reaction mixture was stirred for 2 hours at ambient temperature, then diluted with 5 mL of water. The solution was adjusted to pH 5 with aqueous HCl (2M) and concentrated under vacuum.
  • Step 2 tert-butyl N-(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 (Boc) 2 O (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.
  • Pd/C 2.4 g, wt 10%
  • (Boc) 2 O 39.7 g, 181.7 mmol, 1.5 equiv.
  • 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 HCl/1,4-dioxane (4N, 200 mL). The resulting mixture was stirred for 30 min at ambient temperature and then concentrated under vacuum to give 5,6-difluoro-1H- indol-3-amine hydrochloride (12 g) as a yellow solid.
  • the intermediates in the following table were prepared using the same method described for Intermediate 11.
  • Step 3 5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine hydrogen chloride tert-Butyl N-[5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl]carbamate (300.0 mg) was dissolved in HCl/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 5-fluoro-1H- pyrrolo[2,3-b]pyridin-3-amine hydrogen chloride (350 mg) as a yellow solid.
  • LCMS Method E: [M+H] + 151.
  • Step 3 tert-butyl N-[5-(1-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.) was dissolved in 1,4-dioxane (6 mL) and water (0.6 mL), then 1-isopropyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (417.3 mg, 1.8 mmol, 1.1 equiv.), Xphos Pd G3 (136.0 mg, 0.2 mmol, 0.1 equiv.) and Cs 2 CO 3 (1.0 g, 3.2 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen.
  • Step 4 5-(1-isopropylpyrazol-4-yl)-1H-indol-3-amine hydrogen chloride tert-butyl N-[5-(1-isopropylpyrazol-4-yl)-1H-indol-3-yl]carbamate (400.0 mg, 1.2 mmol, 1.0 equiv.) was dissolved in HCl in 1,4-dioxane (4M, 8.0 mL). The resulting solution was stirred for 4 hours at ambient temperature and then concentrated under vacuum to give crude 5-(1-isopropylpyrazol-4-yl)-1H-indol-3-amine hydrogen chloride (400 mg) as a grey solid.
  • LCMS Method E: [M+H] + 241.
  • the following intermediates were prepared using the same method described for Intermediate 15.
  • Step 2 6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-amine 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridin-3-amine (400.0 mg, 1.8 mmol, 1.0 equiv.) was dissolved MeOH (20 mL), then Pd/C (93.3 mg, 0.9 mmol, 0.5 equiv.) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 2 hours at ambient temperature.
  • Pd/C 93.3 mg, 0.9 mmol, 0.5 equiv.
  • Step 2 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-amine 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-nitropyridine (13.2 g, 50.5 mmol, 1.0 equiv.) was dissolved in MeOH (100 mL), then Pd/C (2.0 g, 18.8 mmol, 0.4 equiv.) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 15 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum.
  • Pd/C 2.0 g, 18.8 mmol, 0.4 equiv.
  • Step 2 methyl 6-(4,4-difluorocyclohexyl)-5-fluoropyridine-3-carboxylate
  • Methyl 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridine-3-carboxylate (2.0 g, 7.4 mmol, 1.0 equiv.) was dissolved in DCM (80 mL), then PtO 2 (837.2 mg, 3.7 mmol, 0.5 equiv.) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred overnight at ambient temperature.
  • Step 3 [6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methanol
  • Methyl 6-(4,4-difluorocyclohexyl)-5-fluoropyridine-3-carboxylate (2.0 g, 7.3 mmol, 1.0 equiv.) was dissolved in THF (20 mL) and cooled to 0 °C, then LiAlH 4 (0.6 g, 14.6 mmol, 2.0 equiv.) was added in portions. The resulting solution was stirred for 30 min at 0 °C and then quenched by the addition of Na 2 SO 4 •10H 2 O. After remove the solid by filtration, the filtrate was concentrated under vacuum.
  • Step 4 5-(bromomethyl)-2-(4,4-difluorocyclohexyl)-3-fluoropyridine [6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methanol (1.0 g, 4.1 mmol, 1.0 equiv.) was dissolved in DCM (10 mL) and cooled to 0 °C, then PBr3 (0.4 mL, 4.1 mmol, 1.0 equiv.) was added, maintaining the mixture at 0 °C. The reaction mixture was stirred for 1 hour at 0 °C and then quenched by the addition of saturated aqueous NaHCO 3 .
  • Scheme 1B Synthesis of intermediate 1B (5,6-difluoro-1H-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 AgNO 3 (33.3 g, 195.9 mmol, 1.2 equiv.) was added.
  • 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 HCl/1,4-dioxane (4N, 200 mL). The resulting mixture was stirred for 30 min at ambient temperature and then concentrated under vacuum to give 5,6-difluoro-1H- indol-3-amine hydrochloride (12.0 g) as a yellow solid.
  • the following intermediates were prepared using the same method described for Intermediate 1B.
  • Step 2 6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-amine 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridin-3-amine (400.0 mg, 1.8 mmol, 1.0 equiv.) was dissolved MeOH (20 mL), then Pd/C (10% wt., 93.3 mg) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 2 hours at ambient temperature.
  • Step 2 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-amine 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-nitropyridine (13.2 g, 50.5 mmol, 1.0 equiv.) was dissolved in MeOH (100 mL), then Pd/C (10% wt., 2.0 g) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 15 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum.
  • Step 2 5-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-amine 3-Chloro-2-(4,4-difluoropiperidin-1-yl)-5-nitropyridine (9.0 g, 32.4 mmol, 1.0 equiv.) was dissolved in EtOH (90 mL), then SnCl 2 (30.7 g, 162.1 mmol, 5.0 equiv.) was added in portions. The reaction mixture was heated to 60 °C overnight, then cooled to ambient temperature and quenched by the addition of water.
  • Step 2 2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-4-amine 1-(4-nitropyridin-2-yl)-4-(2,2,2-trifluoroethyl)piperazine (1.0 g, 3.4 mmol, 1.0 equiv.) was dissolved in MeOH (15 mL), then Pd/C (10% wt., 36.7 mg) was added under an atmosphere of nitrogen. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred overnight at ambient temperature.
  • Step 1 4,4-difluoro-1-methylcyclohexan-1-ol 4,4-difluorocyclohexan-1-one (10.0 g, 74.6 mmol, 1.0 equiv.) was dissolved in Et 2 O (100.0 mL) and cooled to 0 °C, then MeMgBr (3 M in THF, 80.0 mL, 240 mmol, 3.0 equiv.) was added dropwise, maintaining the solution at 0 °C. The reaction mixture was stirred for 2 hours at 0 °C and then quenched by the addition of ice-water.
  • Step 2 4,4-difluoro-1-methylcyclohexyl methyl oxalate 4,4-Difluoro-1-methylcyclohexan-1-ol (10.0 g, 66.6 mmol, 1.0 equiv.) and DMAP (0.8 g, 6.7 mmol, 0.1 equiv.) were dissolved in DCM (200 mL), then TEA (18.7 mL, 133.2 mmol, 2.0 equiv.) was added. This was followed by the addition of methyl oxalochloridate (6.1 mL, 67.3 mmol, 1.0 equiv.) dropwise. The reaction mixture was stirred for 1 hour at ambient temperature and then concentrated under vacuum.
  • Step 3 cesium 2-((4,4-difluoro-1-methylcyclohexyl)oxy)-2-oxoacetate 4,4-Difluoro-1-methylcyclohexyl methyl oxalate (5.0 g, 21.2 mmol, 1.0 equiv.) was dissolved in THF (50 mL) and water (50 mL), then CsOH (3.2 g, 20.9 mmol, 1.0 equiv.) was added. The reaction mixture was stirred for 1 hour at ambient temperature and then concentrated under vacuum to give cesium 2-((4,4-difluoro-1-methylcyclohexyl)oxy)-2- oxoacetate (5.2 g) as a white solid.
  • Step 5 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylic acid
  • Methyl 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylate (2.5 g, 8.7 mmol, 1.0 equiv.) was dissolved in MeOH (25 mL) and water (25 mL), then NaOH (1.0 g, 26.0 mmol, 3.0 equiv.) was added.
  • the reaction mixture was heated to 80 °C for 1 hour, then cooled to ambient temperature and concentrated under vacuum.
  • Step 7 tert-butyl N-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3- yl]carbamate 6-(4,4-Difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carbonyl azide (1.0 g, 3.4 mmol, 1.0 equiv.) was dissolved in t-BuOH (20 mL). The reaction mixture was heated to 80 °C for 2 hours, then cooled to ambient temperature and concentrated under vacuum.
  • Step 8 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-amine tert-Butyl N-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]carbamate (900.0 mg, 2.6 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4N, 20 mL). The resulting mixture was stirred overnight at ambient temperature. The solids were collected by filtration and dried to give 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3- amine (350.0 mg) as a yellow oil.
  • Step 1 tert-butyl 3-fluoro-5-nitro-5,6-dihydro-2H-[2,3-bipyridine]-1-carboxylate
  • 2-Chloro-3-fluoro-5-nitropyridine 2.0 g, 11.3 mmol, 1.0 equiv.
  • tert-butyl 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate 5.3 g, 17.0 mmol, 1.5 equiv.
  • 1,4-dioxane (30 mL) and water (3 mL)
  • Cs 2 CO 3 (11.1 g, 34.0 mmol, 3.0 equiv.
  • Xphos Pd G3 959.0 mg, 1.1 mmol, 0.1 equiv.
  • Step 2 3-fluoro-5-nitro-1,2,5,6-tetrahydro-2,3-bipyridine hydrochloride tert-Butyl 3-fluoro-5-nitro-5,6-dihydro-2H-[2,3-bipyridine]-1-carboxylate (600.0, 1.9 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4N, 15 mL). The reaction mixture was stirred overnight at ambient temperature then concentrated under vacuum to give 3-fluoro-5-nitro-1,2,5,6-tetrahydro-2,3-bipyridine hydrochloride (315.2 mg) as a light yellow solid.
  • LCMS Method A: [M+H] + 224.
  • Step 3 3-fluoro-5-nitro-1-(2,2,2-trifluoroethyl)-5,6-dihydro-2H-2,3-bipyridine 3-Fluoro-5-nitro-1,2,5,6-tetrahydro-2,3-bipyridine hydrochloride (467.5 mg, 1.8 mmol, 1.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (499.1 mg, 2.2 mmol, 1.2 equiv.) were dissolved in ACN (10 mL), then K 2 CO 3 (495.3 mg, 3.6 mmol, 2.0 equiv.) was added.
  • Step 4 5-fluoro-6-[4-(2-methoxyethyl)piperazin-1-yl]pyridin-3-amine 1-(3-Fluoro-5-nitropyridin-2-yl)-4-(2-methoxyethyl)piperazine (1.1 g, 3.9 mmol, 1.0 equiv.) was dissolved in MeOH (20 mL), then Pd/C (10% wt., 110.1 mg) was 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.
  • Step 2 6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3-carboxylic acid Methyl 6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3-carboxylate (2.0 g, 8.2 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL) and water (10 mL), then LiOH (390.7 mg, 16.3 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.
  • Step 3 6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3-carbonyl azide 6-(3,3-Difluorocyclobutyl)-5-fluoropyridine-3-carboxylic acid (2.0 g, 8.7 mmol, 1.0 equiv.) and TEA (2.4 mL, 17.3 mmol, 2.0 equiv.) were dissolved in THF (100 mL), then DPPA (3.6 g, 13.0 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 16 hours at ambient temperature, then concentrated under vacuum.
  • Step 4 tert-butyl N-[6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-yl]carbamate 6-(3,3-Difluorocyclobutyl)-5-fluoropyridine-3-carbonyl azide (1.5 g, 5.9 mmol, 1.0 equiv.) was dissolved in t-BuOH (50 mL). The resulting solution was heated to 80 °C for 16 hours, then cooled to ambient temperature and concentrated under vacuum.
  • Step 5 6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-amine tert-Butyl N-[6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-yl]carbamate (1.5 g, 5.0 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4N, 40 mL). The reaction mixture was stirred 16 hours at ambient temperature and concentrated under vacuum to give 6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-amine hydrogen chloride (1.0 g) as a white solid.
  • LCMS Method C: [M+H] + 203.
  • Step 2 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylic acid Methyl 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate (5.5 g, 20.8 mmol, 1.0 equiv.) was dissolved in MeOH (50 mL) and water (50 mL), then LiOH (12.0 g, 83.2 mmol, 4.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature and then concentrated under vacuum. The residue was diluted with water and adjusted to pH 5 with concentrated HCl.
  • Step 2 methyl 5-chloro-6-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]pyridine-3- carboxylate
  • Methyl 3-chloro-1 1.0 g, 3.0 mmol, 1.0 equiv.
  • DCM 20 mL
  • PtO 2 67.8 mg, 0.3 mmol, 0.1 equiv.
  • the mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 16 hours at ambient temperature.
  • Step 3 5-chloro-6-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]pyridine-3-carboxylic acid Methyl 5-chloro-6-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]pyridine-3-carboxylate (800.0 mg, 2.4 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (190.0 mg, 4.8 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 5 with aqueous HCl (4 M).
  • Step 3 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-4-carboxylic acid
  • Ethyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-4-carboxylate (1.0 g, 2.8 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (225.8 mg, 5.6 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 60 °C for 2 hours, then cooled to ambient temperature and concentrated under vacuum.
  • reaction mixture was stirred for 30 min at 0 °C. This was followed by the addition of TMSN3 (0.3 mL, 2.5 mmol, 1.5 equiv.) dropwise at 0 °C. The resulting mixture was stirred for additional 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.
  • TMSN3 0.3 mL, 2.5 mmol, 1.5 equiv.
  • Step 2 methyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,3-triazole- 4-carboxylate 5-Azido-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (350.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (3.6 mL) and water (0.4 mL), then methyl propiolate (228.8 mg, 2.7 mmol, 2.0 equiv.), sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5- oxo-2,5-dihydrofuran-3-olate (53.9 mg, 0.3 mmol, 0.2 equiv.) and CuSO 4 (21.7 mg, 0.1 mmol, 0.1 equiv.) were added.
  • Step 3 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4- carboxylic acid Methyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4- carboxylate (300.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in MeOH (3 mL) and water (7 mL), then NaOH (70.3 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.
  • Step 1 1-[(4-bromo-2-fluorophenyl)methyl]-3,3-difluoroazetidine 4-Bromo-1-(bromomethyl)-2-fluorobenzene (1.0 g, 3.7 mmol, 1.0 equiv.) was dissolved in ACN (20 mL), then K 2 CO 3 (1.6 g, 11.2 mmol, 3.0 equiv.) and 3,3- difluoroazetidine (347.4 mg, 3.7 mmol, 1.0 equiv.) were added. The reaction mixture was stirred overnight at ambient temperature, and then concentrated under vacuum.
  • Step 2 1-[(4-azido-2-fluorophenyl)methyl]-3,3-difluoroazetidine 1-[(4-Bromo-2-fluorophenyl)methyl]-3,3-difluoroazetidine (800.0 mg, 2.9 mmol, 1.0 equiv.) was dissolved in DMF (10 mL), then methyl[2-(methylamino)ethyl]amine (0.6 mL, 5.7 mmol, 2.0 equiv.), sodium ascorbate (56.9 mg, 0.3 mmol, 0.1 equiv.), CuI (54.4 mg, 0.3 mmol, 0.1 equiv.) and NaN3 (371.4 mg, 5.7 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen.
  • Step 3 methyl 1-[4-[(3,3-difluoroazetidin-1-yl)methyl]-3-fluorophenyl]-1,2,3- triazole-4-carboxylate 1-[(4-Azido-2-fluorophenyl)methyl]-3,3-difluoroazetidine (500.0 mg, 2.1 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (7 mL) and water (3 mL), then methyl propiolate (260.3 mg, 3.1 mmol, 1.5 equiv.), sodium ascorbate (41.1 mg, 0.2 mmol, 0.1 equiv.), and CuSO 4 (33.0 mg, 0.2 mmol, 0.1 equiv.) were added.
  • Step 4 1-[4-[(3,3-difluoroazetidin-1-yl)methyl]-3-fluorophenyl]-1,2,3-triazole-4- carboxylic acid Methyl 1-[4-[(3,3-difluoroazetidin-1-yl)methyl]-3-fluorophenyl]-1,2,3-triazole-4- carboxylate (500.0 mg, 1.5 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (10 mL), then NaOH (122.6 mg, 3.1 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.
  • Step 2 1-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2,3-triazole- 4-carboxylic acid
  • Ethyl 1-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4- carboxylate (400.0 mg, 1.1 mmol, 1.0 equiv.) was dissolved in MeOH (4 mL) and water (4 mL), then NaOH (86.9 mg, 2.2 mmol, 2.0 equiv.) was added.
  • Step 1 ethyl 1-(6-bromo-5-fluoropyridin-3-yl)-1,2,3-triazole-4-carboxylate 6-Bromo-5-fluoropyridin-3-amine (1.0 g, 5.2 mmol, 1.0 equiv) was dissolved in EtOH (30 mL) and HOAc (20 mL), then ethyl 2-diazo-3-oxopropanoate (1.1 g, 7.7 mmol, 1.5 equiv.) was added. The reaction mixture was heated to 50 °C for 16 hours, and then cooled to ambient temperature and concentrated under vacuum.
  • Step 2 ethyl 1-[6-[1-(tert-butoxycarbonyl)-2,5-dihydropyrrol-3-yl]-5-fluoropyridin- 3-yl]-1,2,3-triazole-4-carboxylate
  • Ethyl 1-(6-bromo-5-fluoropyridin-3-yl)-1,2,3-triazole-4-carboxylate (1.0 g, 3.2 mmol, 1.0 equiv.) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5- dihydropyrrole-1-carboxylate 1.1 g, 3.8 mmol, 1.2 equiv.
  • Step 4 ethyl 1-[5-fluoro-6-(pyrrolidin-3-yl)pyridin-3-yl]-1,2,3-triazole-4- carboxylate
  • Ethyl 1-[6-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-5-fluoropyridin-3-yl]-1,2,3- triazole-4-carboxylate 500.0 mg, 1.2 mmol, 1.0 equiv.
  • DCM 3 mL
  • TFA 10 mL
  • the reaction mixture was stirred for 1 hour at ambient temperature, and then quenched by the addition of water.
  • the solution was adjusted to pH 7 with saturated aqueous Na 2 CO 3 .
  • Step 5 ethyl 1-[5-fluoro-6-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]pyridin-3-yl]- 1,2,3-triazole-4-carboxylate
  • Ethyl 1-[5-fluoro-6-(pyrrolidin-3-yl)pyridin-3-yl]-1,2,3-triazole-4-carboxylate (300.0 mg, 1.0 mmol, 1.0 equiv.) and TEA (0.4 mL, 2.9 mmol, 3.0 equiv.) were dissolved in ACN (10 mL), then 2,2,2-trifluoroethyl trifluoromethanesulfonate (273.7 mg, 1.2 mmol, 1.2 equiv.) was added.
  • Step 6 1-[5-fluoro-6-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]pyridin-3-yl]-1,2,3- triazole-4-carboxylic acid
  • Ethyl 1-[5-fluoro-6-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]pyridin-3-yl]-1,2,3- triazole-4-carboxylate (100.0 mg, 0.3 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (62.0 mg, 1.5 mmol, 6.0 equiv.) was added.
  • Step 1 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoro-N-methoxy-N-methylpyridine- 3-carboxamide 6-(4,4-Difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylic acid (2.5 g, 9.1 mmol, 1.0 equiv.) was dissolved in DMF (50 mL), then N,O-dimethylhydroxylamine hydrochloride (1.3 g, 13.7 mmol, 1.5 equiv.), HATU (5.2 g, 13.7 mmol, 1.5 equiv.) and DIEA (6.4 mL, 36.6 mmol, 4.0 equiv.) were added.
  • Step 2 1-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]ethanone 6-(4,4-Difluoro-1-methylcyclohexyl)-5-fluoro-N-methoxy-N-methylpyridine-3- carboxamide (1.7 g, 5.4 mmol, 1.0 equiv.) was dissolved in THF (15 mL) and cooled to 0 °C, then MeMgBr (3M in THF, 3.2 mL, 9.6 mmol, 1.5 equiv.) was added dropwise, maintaining the solution at 0 °C.
  • Step 3 ethyl 4-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-2,4- dioxobutanoate 1-[6-(4,4-Difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]ethanone (1.4 g, 5.2 mmol, 1.0 equiv.) was dissolved in EtOH (14 mL), then sodium ethoxide (351.2 mg, 5.2 mmol, 1.0 equiv.) was added.
  • Step 5 5-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2-oxazole-3- carboxylic acid
  • Ethyl 5-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2-oxazole-3- carboxylate (1.2 g, 3.3 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL) and water (10 mL), then NaOH (260.6 mg, 6.5 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.
  • Step 1 5-chloro-N-methoxy-N-methyl-6-[4-(2,2,2-trifluoroethyl)piperazin-1- yl]pyridine-3-carboxamide
  • 5-Chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridine-3-carboxylic acid (1.8 g, 5.6 mmol, 1.0 equiv.) and N,O-dimethylhydroxylamine hydrochloride (813.6 mg, 8.3 mmol, 1.5 equiv.) were dissolved in DMF (18 mL), then HATU (4.2 g, 11.1 mmol, 2.0 equiv.) and DIEA (3.9 mL, 22.2 mmol, 4.0 equiv.) were added.
  • Step 2 5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridine-3-carbaldehyde 5-Chloro-N-methoxy-N-methyl-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridine-3- carboxamide (1.5 g, 4.1 mmol, 1.0 equiv.) was dissolved in THF (17 mL) and cooled to 0 °C. Then LiAlH 4 (155.2 mg, 4.1 mmol, 1.0 equiv.) was added in portions, maintaining the solution at 0 °C.
  • Step 3 (E)-N-([5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3- yl]methylidene)hydroxylamine
  • 5-Chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridine-3-carbaldehyde (1.0 g, 3.3 mmol, 1.0 equiv.) and hydroxylamine hydrochloride (271.0 mg, 3.9 mmol, 1.2 equiv.) were added to a solution of EtOH (10 mL) and water (10 mL), then NaOH (195.0 mg, 4.9 mmol, 1.5 equiv.) was added.
  • Step 5 3-[5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2- oxazole-5-carboxylic acid Methyl 3-[5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2- oxazole-5-carboxylate (500.0 mg, 1.2 mmol, 1.0 equiv.) was dissolved in MeOH (5.0 mL) and water (5.0 mL), then LiOH (118.3 mg, 4.9 mmol, 4.0 equiv.) was added.
  • Step 1 5-bromo-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine 2,5-Dibromo-3-fluoropyridine (10.0 g, 39.2 mmol, 1.0 equiv.) was dissolved in DMF (100 mL), then Cs 2 CO 3 (25.7 g, 78.5 mmol, 2.0 equiv.) and 4,4-difluoropiperidine (7.1 g, 58.8 mmol, 1.5 equiv.) were added. The reaction mixture was heated to 80 °C for 48 hours, then cooled to ambient temperature and quenched by the addition of water.
  • Step 2 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine 5-Bromo-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (2.0 g, 6.8 mmol, 1.0 equiv.) was dissolved in DMSO (30 mL), then AcOK (1.3 g, 13.6 mmol, 2.0 equiv.), bis(pinacolato)diboron (3.4 g, 13.5 mmol, 2.0 equiv.) and Pd(dppf)Cl2 (495.9 mg, 0.7mmol, 0.1 equiv.) were added under an atmosphere of nitrogen.
  • Step 3 methyl 2-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-thiazole-5- carboxylate 2-(4,4-Difluoropiperidin-1-yl)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (300.0 mg, 0.9 mmol, 1.0 equiv.) and methyl 2-bromo-1,3-thiazole-5- carboxylate (233.6 mg, 1.1 mmol, 1.2 equiv.) were dissolved in 1,4-dioxane (5 mL) and water (5 mL), then Cs 2 CO 3 (857.0 mg, 2.6 mmol, 3.0 equiv.) and Pd(dppf)Cl 2 CH 2 Cl 2 (71.4 mg, 0.09 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen.
  • Step 4 2-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-thiazole-5- carboxylic acid Methyl 2-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-thiazole-5- carboxylate (300.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in MeOH (6 mL) and water (6 mL), then NaOH (167.9 mg, 4.2 mmol, 5.0 equiv.) was added.
  • Step 2 ethyl [(E)-N-[(E)-6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3- carbonyloxy]carbamimidoyl]formate 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carbonyl chloride (1.4 g, 5.0 mmol, 1.0 equiv.) was dissolved in THF (14 mL) and cooled to 0 °C, then ethyl [(E)-N'- hydroxycarbamimidoyl]formate (663.8 mg, 5.0 mmol, 1.0 equiv.) was added.
  • Step 3 ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4- oxadiazole-3-carboxylate
  • Ethyl [(E)-N-[(E)-6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3- carbonyloxy]carbamimidoyl]formate (1.0 g, 2.7 mmol, 1.0 equiv.) was dissolved in EtOH (10 mL) and acetic acid (6 mL). The reaction mixture was heated to 100 °C overnight, then cooled to ambient temperature and concentrated under vacuum.
  • Step 2 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxathiazol-2- one 6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridine-3-carboxamide (3.5 g, 13.5 mmol, 1.0 equiv.) was dissolved in toluene (50 mL), then chloro(chlorosulfanyl)methanone (3.5 g, 27.0 mmol, 2.0 equiv.) was added.
  • Step 3 ethyl 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4- thiadiazole-5-carboxylate 5-[6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxathiazol-2-one (3.0 g, 9.5 mmol, 1.0 equiv.) was dissolved in dodecane (10 mL), then ethyl carbonocyanidate (1.4 g, 14.2 mmol, 1.5 equiv.) was added.
  • Step 4 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-thiadiazole-5- carboxylic acid
  • Ethyl 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-thiadiazole-5- carboxylate (1.2 g, 3.2 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL) and water (10 mL), then NaOH (257.8 mg, 6.4 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 30 min at ambient temperature and then concentrated under vacuum.
  • Step 1 methyl 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2-thiazole-5- carboxylate 5-[6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxathiazol-2-one (1.0 g, 3.2 mmol, 1.0 equiv.) was dissolved in o-dichlorobenzene (10 mL), then methyl propiolate (1.6 g, 19.0 mmol, 6.0 equiv.) was added. The reaction mixture was heated to 135 °C overnight, then cooled to ambient temperature and concentrated under vacuum.
  • Step 2 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2-thiazole-5- carboxylic acid Methyl 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2-thiazole-5- carboxylate (330.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and water (2 mL), then NaOH (55.4 mg, 1.4 mmol, 1.5 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature and the concentrated under vacuum.
  • Step 2 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]ethanone 6-(4,4-Difluoropiperidin-1-yl)-5-fluoro-N-methoxy-N-methylpyridine-3- carboxamide (1.6 g, 5.3 mmol, 1.0 equiv.) was dissolved in THF (20 mL) and cooled to 0 °C, then MeMgBr (3M in THF, 2.7 mL, 8.1 mmol, 1.5 equiv.) was added dropwise under an atmosphere of nitrogen, maintaining the solution at 0 °C.
  • Step 3 2-bromo-1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]ethanone 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]ethanone (3.0 g, 11.6 mmol, 1.0 equiv.) was dissolved in ACN (15 mL), then NBS (3.1 g, 17.4 mmol, 1.5 equiv.) and TsOH (3.0 g, 17.4 mmol, 1.5 equiv.) were added. The reaction mixture was heated to 100 °C overnight, then cooled to ambient temperature and diluted with ethyl acetate.
  • Step 4 2-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-2-oxoethyl acetate 2-Bromo-1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]ethanone (2.0 g, 5.9 mmol, 1.0 equiv.) and acetic acid (0.5 mL g, 8.9 mmol, 1.5 equiv.) were dissolved in MeOH (6 mL) and water (14 mL), then K 2 CO 3 (0.8 g, 5.9 mmol, 1.0 equiv.) was added.
  • Step 5 ethyl 4-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-oxazole-2- carboxylate 2-[6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-2-oxoethyl acetate (1.5 g, 4.7 mmol, 1.0 equiv) and ethyl carbamoylformate (1.7 g, 14.3 mmol, 3.0 equiv.) were dissolved in xylene (30 mL), then BF 3 •Et 2 O (6.3 mL, 23.7 mmol, 5.0 equiv.) was added dropwise.
  • Step 6 4-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-oxazole-2- carboxylic acid
  • Step 2 ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1H-pyrazole-3- carboxylate
  • Step 3 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1H-pyrazole-3- carboxylic acid
  • Ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1H-pyrazole-3- carboxylate (450.0 mg, 1.3 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (101.6 mg, 2.5 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.
  • Step 2 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1-methylpyrazole-3- carboxylic acid
  • Ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1-methylpyrazole-3- carboxylate (150.0 mg, 0.4 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and water (2 mL), then NaOH (32.6 mg, 0.8 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.
  • Step 1 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carbohydrazide Methyl 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carboxylate (2.0 g, 7.3 mmol, 1.0 equiv.) was dissolved in EtOH (30 mL), then NH 2 NH 2 •H 2 O (3.5 mL, 70.0 mmol, 10.0 equiv.) was added. The resulting solution was heated to 90 °C for 16 hours, then cooled to ambient temperature and concentrated under vacuum.
  • Step 2 ethyl 2-[[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3- yl]formohydrazido]-2-oxoacetate 6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridine-3-carbohydrazide (1.3 g, 4.7 mmol, 1.0 equiv.) and TEA (2.0 mL, 14.2 mmol, 3.0 equiv.) were dissolved in DCM (20 mL), then ethyl chloroglyoxylate (0.5 mL, 5.0 mmol, 1.0 equiv.) was added dropwise.
  • Step 3 ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4- oxadiazole-2-carboxylate
  • Step 4 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxadiazole-2- carboxylic acid
  • Ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxadiazole-2- carboxylate (500.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in MeOH (3 mL) and water (3 mL), then NaOH (112.3 mg, 2.8 mmol, 2.0 equiv.) was added.
  • Step 1 ethyl 2-diazo-3-oxopropanoate A mixture of DMF (32.0 g, 438.2 mmol, 33.7 mL, 0.50 equiv.) and SOCl 2 (52.1 g, 438.2 mmol, 31.8 mL, 0.5 equiv.) was heated at 40 oC for 2 hours.
  • Step 2 ethyl 1-(6-bromo-5-fluoropyridin-3-yl)-1H-1,2,3-triazole-4- carboxylate 6-bromo-5-fluoro-pyridin-3-amine (12.1 g, 63.4 mmol, 1.0 equiv.) and ethyl 2-diazo- 3-oxo-propanoate (15.0 g, 95.0 mmol, 90% purity, 1.5 equiv.) were dissolved in EtOH (300 mL). Then AcOH (210.0 g, 3.5 mol, 200 mL, 55.2 equiv.) was added and the mixture was heated at 50 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove solvent.
  • Step 3 1-(6-bromo-5-fluoropyridin-3-yl)-1H-1,2,3-triazole-4-carboxylic acid
  • Ethyl 1-(6-bromo-5-fluoro-3-pyridyl)triazole-4-carboxylate (16 g, 50.8 mmol, 1 equiv.) was dissolved in MeOH (300 mL).
  • Step 4 Synthesis of (1-(6-bromo-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H- indol-3-yl)-1H-1,2,3-triazole-4-carboxamide (intermediate 89B) 1-(6-bromo-5-fluoro-3-pyridyl)triazole-4-carboxylic acid (5.0 g, 17.4 mmol, 1.0 equiv.) and 5,6-difluoro-1H-indol-3-amine (4.0 g, 16.7 mmol, 70% purity, 9.6 equiv.) were dissolved in DMF (300 mL).
  • Example 1 N-(5,6-difluoro-1H-indol-3-yl)-1-((6-(4,4-difluorocyclohexyl)-5- fluoropyridin-3-yl)methyl)-1H-imidazole-4-carboxamide (Compound 105) 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]imidazole-4-carboxylic acid (200.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in DMF (5 mL), then 5,6-difluoro- 1H-indol-3-amine hydrogen chloride (120.5 mg, 0.6 mmol, 1.0 equiv.), HATU (336.2 mg, 0.9 mmol, 1.5 equiv.) and DIEA (0.3 mL, 1.8 mmol, 3.0 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 and concentrated under vacuum.
  • the crude product was purified by Prep-HPLC with the following conditions: Column, YMC-Actus Triart C18, 30*250,5 ⁇ m; mobile phase, Water (10 mM NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (38% Phase B up to 60% in 10 min); Detector, uv 254 nm.
  • Example 12 1-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-N-(5- fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-imidazole-4-carboxamide
  • 1-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-1H-imidazole-4-carboxylic acid (129.5 mg, 0.4 mmol, 1.0 equiv.) was dissolved in THF (10 mL), then 5-fluoro-1H- pyrrolo[2,3-b]pyridin-3-amine hydrogen chloride (74.7 mg, 0.4 mmol, 1.0 equiv.), TEA (0.6 mL, 4.0 mmol, 10.0 equiv.), and T 3 P (189.5 mg, 0.6 mmol, 1.5 equiv.) were added.
  • Example 22 N-(5,6-difluoro-1H-indol-3-yl)-1-(6-(4,4-difluoropiperidin-1-yl)- 5-fluoropyridin-3-yl)-1H-1,2,3-triazole-4-carboxamide ) (Compound 102) Step 1: N-(5,6-difluoro-1H-indol-3-yl)propiolamide 5,6-difluoro-1H-indol-3-amine hydrogen chloride (730.0 mg, 3.6 mmol, 1.0 equiv.) was dissolved in THF (30 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 T 3 P (6.8 g, 10.7 mmol, 3.0 equiv.) were added at 0 °C.
  • Step 2 5-azido-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine 6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridin-3-amine (400.0 mg, 1.7 mmol, 1.0 equiv.) was dissolved in ACN (10 mL) and cooled to 0 °C, then t-BuNO 2 (0.3 mL, 2.7 mmol, 1.6 equiv.) was added dropwise, maintaining the mixture at 0 °C. After 30 min at 0 °C, TMSN3 (0.3 mL, 2.5 mmol, 1.5 equiv.) was added dropwise at 0 °C.
  • Step 3 N-(5,6-difluoro-1H-indol-3-yl)-1-(6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl)-1H-1,2,3-triazole-4-carboxamide 5-Azido-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (150.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in dioxane/water (5/0.5 mL), then N-(5,6-difluoro-1H-indol-3- yl)propiolamide (130.0 mg, 0.6 mmol, 1.0 equiv.), sodium (R)-2-((S)-1,2-dihydroxyethyl)- 4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (24.0 mg, 0.1 mmol, 0.2 equiv.) and CuSO 4 (19
  • reaction mixture was stirred for 15 hours at ambient temperature and then quenched by the addition of water.
  • the reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the residue was further purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30 ⁇ 150mm 5 ⁇ m; Mobile Phase A: Water (10 mM NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 35% B to 80% B in 7 min; 254 nm; RT1:6.95 min.
  • Example 23 N-(5,6-difluoro-1H-indol-3-yl)-5-(6-(4,4-difluoropiperidin-1-yl)- 5-fluoropyridin-3-yl)isoxazole-3-carboxamide (Compound 208) 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2-oxazole-3-carboxylic acid (250.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in DMF (3 mL), then 5,6-difluoro- 1H-indol-3-amine hydrogen chloride (223.1 mg, 1.1 mmol, 1.5 equiv.) and HATU (435.7 mg, 1.1 mmol, 1.5 equiv.) were added.
  • 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.
  • the residue was purified by reverse flash chromatography with following conditions: column, C18 silica gel; mobile phase, ACN/water, 0% to 100% gradient in 20 min; detector, UV 254 nm.
  • Example 77 N-(5,6-difluoro-1H-indol-3-yl)-4-(6-(4,4-difluoropiperidin-1-yl)- 5-fluoropyridin-3-yl)oxazole-2-carboxamide (Compound 193) 4-[6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-oxazole-2-carboxylic acid (200.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in DMF (5 mL), then T 3 P (wt.
  • Example 80 N-(5,6-difluoro-1H-indol-3-yl)-3-(5-fluoro-6-(4-(2,2,2- trifluoroethyl)piperazin-1-yl)pyridin-3-yl)isoxazole-5-carboxamide (Compound 160)
  • Example 82 N-(5-chloro-1H-indol-3-yl)-3-(5-fluoro-6-(4-(2,2,2- trifluoroethyl)piperazin-1-yl)pyridin-3-yl)isoxazole-5-carboxamide (Compound 171) 3-[5-Fluoro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2-oxazole-5- carboxylic acid (300.0 mg, 0.8 mmol, 1.0 equiv.) and 5-chloro-1H-indol-3-amine (160.3 mg, 1.0 mmol, 1.2 equiv.) were dissolved in DMF (10 mL), then NMM (121.6 mg, 1.2 mmol, 1.5 equiv.) and PyBOP (625.7 mg, 1.2 mmol, 1.5 equiv.) were added.
  • Example 83 N-(5,6-difluoro-1H-indol-3-yl)-5-(5-fluoro-6-(4-(2,2,2- trifluoroethyl)piperazin-1-yl)pyridin-3-yl)isoxazole-3-carboxamide (Compound 204) 5-[5-Fluoro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2-oxazole-3- carboxylic acid (300.0 mg, 0.8 mmol, 1.0 equiv.) and DCC (248.1 mg, 1.2 mmol, 1.5 equiv.) were dissolved in DCM (30 mL), then DMAP (146.9 mg, 1.2 mmol, 1.5 equiv.) and 5,6-difluoro-1H-indol-3-amine hydrogen chloride (196.8 mg, 1.0 mmol, 1.2 equiv.) were
  • TMSN 3 (0.5 mL, 4.3 mmol, 3.0 equiv.) was added dropwise at 0 °C.
  • the reaction mixture was stirred for an additional 2 hours at 0 °C, then quenched by the addition of water.
  • the resulting mixture 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 5-azido-3-fluoro-2- (1-methylcyclohexyl)pyridine (260.0 mg) as a yellow oil.
  • Step 3 N-(5,6-difluoro-1H-indol-3-yl)-1-[5-fluoro-6-(1-methylcyclohexyl)pyridin-3- yl]-1,2,3-triazole-4-carboxamide 5-Azido-3-fluoro-2-(1-methylcyclohexyl)pyridine (250.0 mg, 1.1 mmol, 1.0 equiv.) was dissolved in dioxane/water (5/0.5 mL), then N-(5,6-difluoro-1H-indol-3- yl)propiolamide (235.0 mg, 1.1 mmol, 1.0 equiv.), sodium ascorbate (21.2 mg, 0.1 mmol, 0.1 equiv.) and CuSO4 (17.0 mg, 0.1 mmol, 0.1 equiv.) were added.
  • reaction mixture was stirred for 15 hours at ambient temperature and then quenched by the addition of water.
  • the reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the residue was further purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30 ⁇ 150mm 5 ⁇ m; Mobile Phase A: Water (10 mM NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 35% B to 80% B in 7 min; 254 nm; RT1:6.95 min.
  • Example 98 N-(5,6-difluoro-1H-indol-3-yl)-1-(6-((4,4-difluoropiperidin-1- yl)methyl)-5-fluoropyridin-3-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 206) Step 1: 5-bromo-3-fluoropyridine-2-carbaldehyde 2,5-Dibromo-3-fluoropyridine (2.0 g, 7.8 mmol, 1.0 equiv.) was dissolved in THF (40 mL) and cooled to -78 °C.
  • n-BuLi (2 M in THF, 8.0 mL, 16.0 mmol, 1.0 equiv.) was added dropwise, maintaining the solution at -78 °C.
  • a solution of DMF (0.6 mL, 7.8 mmol, 1.0 equiv.) in THF (2 mL) was added dropwise at -78 °C and the reaction mixture was allowed to warm to ambient temperature and stirred for additional 2 hours.
  • the reaction was quenched by the addition of saturated aqueous NH 4 Cl, extracted with ethyl acetate, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under vacuum.
  • Step 3 5-bromo-2-(bromomethyl)-3-fluoropyridine (5-Bromo-3-fluoropyridin-2-yl)methanol (1.0 g, 4.9 mmol, 1.0 equiv.) was dissolved in DCM (10 mL) and cooled to 0 °C, then phosphorus tribromide (1.6 g, 5.8 mmol, 1.2 equiv.) was added, maintaining the solution at 0 °C. The reaction mixture was stirred for 2 hours at 0 °C and then diluted with ethyl acetate.
  • Step 4 5-bromo-2-[(4,4-difluoropiperidin-1-yl)methyl]-3-fluoropyridine
  • 5-Bromo-2-(bromomethyl)-3-fluoropyridine 1.0 g, 3.7 mmol, 1.0 equiv.
  • ACN 10 mL
  • 4,4-difluoropiperidine 540.5 mg, 4.5 mmol, 1.2 equiv.
  • K 2 CO 3 1.5 g, 11.1 mmol, 3.0 equiv.
  • Step 5 5-azido-2-[(4,4-difluoropiperidin-1-yl)methyl]-3-fluoropyridine
  • 5-Bromo-2-[(4,4-difluoropiperidin-1-yl)methyl]-3-fluoropyridine 800.0 mg, 2.6 mmol, 1.0 equiv.
  • EtOH 7 mL
  • water 3 mL
  • (1S,2S)-1,2- diethylcyclohexane (363.0 mg, 2.6 mmol, 1.0 equiv.)
  • CuI 492.9 mg, 2.6 mmol, 1.0 equiv.
  • azidosodium 336.5 mg, 5.2 mmol, 2.0 equiv.
  • Step 6 N-(5,6-difluoro-1H-indol-3-yl)-1-[6-[(4,4-difluoropiperidin-1- yl)methyl]-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxamide 5-Azido-2-[(4,4-difluoropiperidin-1-yl)methyl]-3-fluoropyridine (200.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in dioxane (10 mL) and water (1 mL), then N-(5,6- difluoro-1H-indol-3-yl)prop-2-ynamide (194.8 mg, 0.9 mmol, 1.2 equiv.), CuSO 4 (11.8 mg, 0.1 mmol, 0.1 equiv.) and sodium ascorbate (14.7 mg, 0.1 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen.
  • Example 99/100 (R or S)-N-(5,6-difluoro-1H-indol-3-yl)-1-(6-(4,4- difluoropiperidin-1-yl-3,3,5,5-d4)-5-fluoropyridin-3-yl)-1H-1,2,3-triazole-4- carboxamide; Compound 162 (front peak, absolute stereochemistry unconfirmed) and Compound 163 (second peak, absolute stereochemistry unconfirmed).
  • Example 101 1-(6-cyclohexyl-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3- yl)-1H-1,2,3-triazole-4-carboxamide (Compound 170) Step 1: 1-(6-(cyclohex-1-en-1-yl)-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H- indol-3-yl)-1H-1,2,3-triazole-4-carboxamide 1-(6-bromo-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl)-1H-1,2,3-triazole- 4-carboxamide (130.7 mg, 0.3 mmol, 1.0 equiv.) and 2-(cyclohex-1-en-1-yl)-4,4,5,5- tetramethyl-1,3,2-dio
  • Step 2 1-(6-cyclohexyl-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl)- 1H-1,2,3-triazole-4-carboxamide
  • Example 109 N-(5,6-difluoro-1H-indol-3-yl)-1-(5-fluoro-6-(5-azaspiro[2.4]heptan-5- yl)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 188) 1-(6-bromo-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl)-1H-1,2,3-triazole- 4-carboxamide (130.8 mg, 0.3 mmol, 1.0 equiv.) and 5-azaspiro[2.4]heptane (58.3 mg, 0.6 mmol, 2.0 equiv.) were dissolved in t-AmOH (3 mL).
  • THP1-DualTM KO-IFNAR2 THP1-DualTM KO-IFNAR2 Cells (obtained from invivogen) were maintained in RPMI, 10% FCS, 5 ml P/S, 2mM L-glut, 10mM 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 ⁇ M. Cells were plated into the TC plates at 40 ⁇ L per well, 2 ⁇ 10E6 cells/mL.
  • 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: ⁇ 150 ⁇ M stock o Solution B: 2 mL Optimem with 60 ⁇ L 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 ⁇ L of transfection solution (A+B) was added on top of the plated cells, with a final 2’3’cGAMP concentration of 15 ⁇ M.
  • Luciferase reporter activity was then measured. EC 50 values were calculated by using standard methods known in the art.
  • Luciferase reporter assay 10 ⁇ L of supernatant from the assay was transferred to white 384-plate with flat bottom and squared wells.
  • One pouch of QUANTI-LucTM Plus was dissolved in 25 mL of water. 100 ⁇ L of QLC Stabilizer per 25 mL of QUANTI- LucTM Plus solution was added.50 ⁇ L of QUANTI-LucTM Plus/QLC solution per well was then added.
  • R 1a , R 1b , R 1c , and R 1d are each an independently selected R 1 .
  • R 2 is H.
  • R 5 is H.
  • each R 1 is H.
  • 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 . 18.
  • each R c1 is an independently selected halo, such as –F, -Cl, or –Br. 24.
  • each R c1 is independently –F or –Cl, such as –F. 25.
  • each R g1 is independently selected from the group consisting of: heteroaryl of 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, 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 . 26.
  • each R g1 is independently selected from the group consisting of: heteroaryl of 5-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 R c ; and C 6 aryl optionally substituted with 1-4 R c . 27.
  • each R g1 is independently heteroaryl of 5 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, and wherein the heteroaryl is optionally substituted with 1-4 R c .
  • each R g1 is pyrazolyl that is optionally substituted with 1-2 R c , such as 1-2 independently selected C 1-6 (e.g., C 1-3 ) alkyl which is optionally substituted with 1-6 independently selected R a (e.g., unsubstituted).
  • R 1b is pyrazolyl that is optionally substituted with 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 1-6 independently selected R a (e.g., unsubstituted).
  • R 1c is H.
  • R 1c is halo, such as –F or –Cl (e.g., -F).
  • R 1a and R 1d are H;
  • R 1c is halo or H, such as –F, -Cl, or H;
  • R 1b is heteroaryl of 5 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, and wherein the heteroaryl is optionally substituted with 1-4 R c .
  • R 6 is H. 42.
  • Ring B is a heteroarylene of 5 ring atoms, wherein 1-3 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, O, and S, wherein the heteroarylene of Ring B is optionally substituted with 1-2 R cB ; and each R cB is an independently selected R c . 43.
  • Ring B is a heteroarylene of 5 ring atoms, wherein 2-3 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(R d ), O, and S (such as N and NH), wherein the heteroarylene of Ring B is optionally substituted with 1-2 R cB ; and each R cB is an independently selected R c .
  • Ring B is selected from the group consisting of imidazolylene, pyrazolylene, or triazolylene (such as 1,2,3-triazolylene) which is optionally substituted with one R cB . 45.
  • each R cB is independently halo or C 1-3 alkyl optionally which is optionally substituted 1-3 independently selected R a (such as 1-3 independently selected halo).
  • 50. The compound of any one of clauses 1-49 or 163-169, wherein a1 is 0.
  • 51. The compound of any one of clauses 1-49 or 163-169, wherein a1 is 1.
  • 52. The compound of any one of clauses 1-49, 51, or 163-169, wherein L A is C 1-3 alkylene optionally substituted with 1-2 R a1 .
  • 53. The compound of clause 52, wherein L A is CH 2 or CH(Me), such as CH 2 . 54.
  • Ring C is selected from the group consisting of: x heteroarylene of 5-10 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 heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of R cC and R hC ; and x C 6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of R cC and R hC , wherein each R cC is an independently selected R c ; and each R hC is an independently selected R h .
  • Ring C is selected from the group consisting of: x heteroarylene of 5-6 (such as 6) ring atoms, wherein 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 heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of R cC ; and x C 6 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of R cC . 56.
  • Ring C is selected from the group consisting of: x pyridylene optionally substituted with 1-3 (such as 1) substituents independently selected from the group consisting of R cC ; and x C 6 arylene optionally substituted with 1-4 (such as 1-2) substituents independently selected from the group consisting of R cC .
  • Ring C is , wherein each one of Q 1 , Q 2 , Q 3 , and Q 4 is independently selected from the group consisting of N, CH, and CR cC ; and bb is the point of connection to R 7 . 58.
  • each R cC is independently selected from the group consisting of: -halo and C 1-6 (e.g., C 1-3 ) alkyl which is optionally substituted with 1-6 independently selected R a (e.g., 1-6 independently selected halo, such as –F).
  • R cC is independently halo, such as –Cl or –F, such as –F.
  • R 7 is R g . 67.
  • R 7 is selected from the group consisting of: x C 3-12 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R c7 , R h7 , and –(L g )bg-R h7 ; and x heterocyclyl of 4-12 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 is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R c7 , R h7 , and –(L g )bg-R h7 , wherein each R c7 is an independently selected R c ; and R h7 is an independently selected R h .
  • R 7 is selected from the group consisting of: x C 4-8 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R c7 , and R h7 ; and x heterocyclyl of 4-8 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 is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R c7 , and R h7 .
  • R 7 is selected from the group consisting of: x C 6 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of R c7 ; and x heterocyclyl of 6 ring atoms, wherein 1-2 (such as one) 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 1-4 substituents independently selected from the group consisting of R c7 . 70.
  • each R c7 is an independently selected halo or C 1-3 alkyl optionally substituted with 1-6 R a (e.g., 1-6 independently selected halo).
  • each R c7 is independently halo, such as –F.
  • 75 The compound of any one of clauses 1-74 or 170-173, wherein , wherein X 7 is N or CH.
  • 76 The compound of clause 1, wherein the compound is a compound of Formula (I-a1-1):
  • each one of R 1a , R 1b , R 1c , and R 1d is an independently selected R 1 ;
  • B 4 is C or N;
  • B 1 , B 2 , and B 3 are each independently CH, CR cB , NH, N(R d ), N, O, or S;
  • Q 1 , Q 2 , Q 3 , and Q 4 are each independently selected from the group consisting of N, CH, and CR cC ;
  • each occurrence of R cB and R cC is an independently selected R c ; and each is independently a single bond or a double bond provided that the ring including B 1 -B 4 is a heteroaryl.
  • 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 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 1-4 substituents independently selected from the group consisting of R c . 80.
  • R 7 is selected from the group consisting of: x C 6 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of R c7 ; and x heterocyclyl of 6 ring atoms, wherein 1-2 (such as one) 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 1-4 substituents independently selected from the group consisting of R c7 , wherein each R c7 is an independently selected R c . 97.
  • each R c7 is independently halo, such as –F. 102.
  • the compound of clause 1, wherein the compound is selected from the group consisting of the compounds delineated in Table C1, or a pharmaceutically acceptable salt thereof.
  • 104. A pharmaceutical composition comprising a compound of clauses 1-103 and one or more pharmaceutically accetapble excipients.
  • 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 1-103; or a pharmaceutical composition as defined in clause 104.
  • 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.
  • 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
  • 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.
  • 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;.
  • an alkylating agent e.g.,
  • 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.
  • 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;.
  • an alkylating agent e.g.,
  • 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.
  • 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;.
  • alkylating agent e.g., cis
  • 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 1-103, or a pharmaceutical composition as defined in clause 104.
  • 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 1-103, or a pharmaceutical composition as defined in clause 104.
  • a method of treatment comprising administering to a subject a compound as defined in any one of clauses 1-103, or a pharmaceutical composition as defined in clause 104, 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.
  • 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.
  • 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.
  • 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;.
  • an alkylating agent e.g.,
  • the method of clause 151 wherein the disease, disorder, or condition is a type I interferonopathy (e.g., STING-associated vasculopathywith onset in infancy (SAVI)). 153. The method of clause 152, wherein the type I interferonopathy is STING- associated vasculopathy with onset in infancy (SAVI)). 154. The method of clause 151, wherein the disease, disorder, or condition is Aicardi-Goutines Syndrome (AGS). 155. The method of clause 151, wherein the disease, disorder, or condition is a genetic form of lupus. 156. The method of clause 151, wherein the disease, disorder, or condition is inflammation-associated disorder. 157.
  • a type I interferonopathy e.g., STING-associated vasculopathywith onset in infancy (SAVI)
  • SAVI STING-associated vasculopathy with onset in infancy
  • AGS Aicardi-Goutines Syndrome
  • R 7 is selected from the group consisting of: x C 4-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of R c7 ; and x heterocyclyl of 5-6 ring atoms, wherein 1-2 (such as one) 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 1-4 substituents independently selected from the group consisting of R c7 . 171.
  • R 7 is a group of the following formula: wherein X 7 is CH, CR c7 , or N, such as CH or N. 172.
  • R 7 is a group of the following formula: wherein R d is is independently selected from the group consisting of: C 1-6 alkyl optionally substituted with 1-3 independently selected R a , wherein m7 is 0 or 1. 173.
  • R 7 is selected from the group consisting of tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octanyl, or 2- azabicyclo[2.2.1]heptanyl, each of which is optionally substituted with 1-2 R c7 .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

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.

Description

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. 63/052,117, 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-κB and MAP kinase activation. Following the initiation of signal transduction, STING is rapidly degraded, a step considered important in terminating the inflammatory response. Excessive activation of STING is associated with a subset of monogenic autoinflammatory conditions, the so-called type I interferonopathies. Examples of these diseases include a clinical syndrome referred to as STING-associated vasculopathy with onset in infancy (SAVI), which is caused by gain-of-function mutations in TMEM173 (the gene name of STING). Moreover, STING is implicated in the pathogenesis of Aicardi- Goutières 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, Y1, Y2, Y3, X1, X2, R6, Ring B, LA, a1, Ring C, and R7 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-Goutières 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-Goutières 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-Goutières 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-Goutières 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-Goutières Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis. The chemical entity can be administered in combination with one or more additional cancer therapies (e.g., surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof; e.g., chemotherapy that includes administering one or more (e.g., two, three, four, five, six, or more) additional chemotherapeutic agents. Non-limiting examples of additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g.,azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan;. amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-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-β (TGFβ), 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, OX40–OX40 ligand, GITR, GITR ligand – GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25–TL1A, CD40L, CD40– CD40 ligand, HVEM–LIGHT–LTA, HVEM, HVEM – BTLA, HVEM – CD160, HVEM – LIGHT, HVEM–BTLA–CD160, 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 intratumorally. The methods can further include identifying the subject. Other embodiments include those described in the Detailed Description and/or in the claims. Additional Definitions To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties. 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-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid. The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration. The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human. The terms “treat,” “treating,” and “treatment,” in the context of treating a disease or disorder, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof. The “treatment of cancer”, refers to one or more of the following effects: (1) inhibition, to some extent, of tumor growth, including, (i) slowing down and (ii) complete growth arrest; (2) reduction in the number of tumor cells; (3) maintaining tumor size; (4) reduction in tumor size; (5) inhibition, including (i) reduction, (ii) slowing down or (iii) complete prevention, of tumor cell infiltration into peripheral organs; (6) inhibition, including (i) reduction, (ii) slowing down or (iii) complete prevention, of metastasis; (7) enhancement of anti-tumor immune response, which may result in (i) maintaining tumor size, (ii) reducing tumor size, (iii) slowing the growth of a tumor, (iv) reducing, slowing or preventing invasion and/or (8) relief, to some extent, of the severity or number of one or more symptoms associated with the disorder. The term "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, C1-10 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, iso-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein. The term "haloalkyl" refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo. The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3). The term "alkylene" refers to a divalent alkyl (e.g., -CH2-). The term "alkenyl" refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C2-6 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, C2-6 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-1H-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[1.1.1]pentanyl bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 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- b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2,3- dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]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[1.1.1]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[1.1.1]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, 1-azaspiro[3.5]nonanyl, 2- azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[4.4]nonanyl, 6- azaspiro[2.6]nonanyl, 1,7-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, 1-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, 1-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 π-electron system. Typically, the number of out of plane π- electrons corresponds to the Hückel rule (4n+2). Examples of such rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like. As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or 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 13C and 14C. In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the encompasses the tautomeric form containing the moiety: . y, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms. The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same. Formula Compounds In one aspect, provided herein is a compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein: Z, Y1, Y2, and Y3 are independently selected from the group consisting of CR1, C(=O), N, and NR2; X1 is selected from the group consisting of O, S, N, NR2, and CR1; X2 is selected from the group consisting of O, S, N, NR4, and CR5; each is independently a single bond or a double bond, provided that the five- membered ring comprising X1 and X2 is heteroaryl, and that the six-membered ring comprising Z, Y1, Y2, and Y3 is aryl or heteroaryl; each R1 is independently selected from the group consisting of: H; Rc; Rg; and – (L1)b1-Rg; each R2 is independently selected from the group consisting of: H; Rd; Rg; and – (L2)b2-Rg; R4 is selected from the group consisting of: H and Rd; R5 is selected from the group consisting of: H; Rc; and Rh; R6 is selected from the group consisting of: H; Rd; and Rh; 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(Rd), 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 Rc, provided that Ring B is attached to the C(=O)NR6 group via a ring carbon atom; each LA is independently selected from the group consisting of: C1-3 alkylene optionally substituted with 1-2 Ra1; -O-; -NH-; -NRd; -S(O)0-2; and C(O); a1 is 0, 1, or 2; Ring C is selected from the group consisting of: x C3-12 cycloalkylene or C3-12 cycloalkenylene, each optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc and Rh; x 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(Rd), 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, Rc, and Rh; x heteroarylene of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc and Rh; and x C6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of Rc and Rh; R7 is selected from the group consisting of: Rg and –(L7)b7-Rg; each occurrence of Ra and Ra1 is independently selected from the group consisting of: –OH; -halo; –NReRf; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of Rc is independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; C1-4 haloalkoxy; -S(O)1-2(C1-4 alkyl); -S(O)(=NH)(C1-4 alkyl); -NReRf; –OH; -S(O)1-2NR’R’’; -C1-4 thioalkoxy; -NO2; -C(=O)(C1-10 alkyl); - C(=O)O(C1-4 alkyl); -C(=O)OH; -C(=O)NR’R’’; and –SF5; each occurrence of Rd is independently selected from the group consisting of: C1-6 alkyl optionally substituted with 1-3 independently selected Ra; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; C1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR’R’’, -OH, and Ri; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Rg is independently selected from the group consisting of: x C3-12 cycloalkyl or C3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc, Rh, and –(Lg)bg-Rh; x 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(Rd), 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, Rc, Rh, and –(Lg)bg-Rh; x heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc , Rh, and –(Lg)bg-Rh; and x C6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of Rc, Rh, and –(Lg)bg-Rh; each occurrence of Rh is independently selected from the group consisting of: x C3-12 cycloalkyl or C3-12 cycloalkenyl, each of which is optionally substituted with 1-4 Ri; x 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(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 Ri; x heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Ri; and x C6-10 aryl optionally substituted with 1-4 Ri; each occurrence of Ri is independently selected from the group consisting of: C1-6 alkyl; C1-4 haloalkyl; C1-4 alkoxy; C1-4 haloalkoxy; and halo; each occurrence of L1, L2, L7, and Lg is selected from the group consisting of: -O-, -NH-, -NRd , -S(O)0-2, C(O), and C1-3 alkylene optionally substituted with 1-3 Ra; b1, b2, b7, 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 C1-4 alkyl. The Variables Z, Y1, Y2, Y3, X1, and X2 In some embodiments, each of Z, Y1, Y2, and Y3 is independently N or CR1. In some embodiments, each of Z, Y1, Y2, and Y3 is an independently selected CR1. In certain embodiments, the compound is a compound of Formula (Ia): Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein: R1a, R1b, R1c, and R1d are each an independently selected R1. In some embdoiments, 1-2 (such as 1) of Z, Y1, Y2, and Y3 is N; and each of the remaining of Z, Y1, Y2, and Y3 is an independently selected CR1. In certain of these embodiments, the compound is selected from the group consisting of a compound of the following formulae: or a pharmaceutically acceptable salt thereof, wherein: R1a, R1b, R1c, and R1d are each an independently selected R1. In certain embodiments, the compound is a compound of Formula (Ib):
or a pharmaceutically acceptable salt thereof, wherein: R1a, R1b, and R1c are each an independently selected R1. In certain embodiments, the compound is a compound of Formula (Ic): or a pharmaceutically acceptable salt thereof, wherein: R1a, R1b, and R1d are each an independently selected R1. In certain embodiments, the compound is a compound of Formula (Id): or a pharmaceutically acceptable salt thereof, wherein: R1a, R1c, and R1d are each an independently selected R1. In certain embodiments, the compound is a compound of Formula (Ie):
or a pharmaceutically acceptable salt thereof, wherein: R1b, R1c, and R1d are each an independently selected R1. In some embodiments, X1 is NR2. In certain of these embodiments, X1 is NH. In some embodiments, X2 is CR5. In certain of these embodiments, X2 is CH. In some embodiments, X1 is NR2; and X2 is CR5. In certain embodiments, X1 is NR2; and X2 is CH. In certain embodiments, X1 is NH; and X2 is CR2. In certain embodiments, X1 is NH; and X2 is CH. In some embodiments, the compound is a compound of Formula (Ia-1): Formula (Ia-1) or a pharmaceutically acceptable salt thereof, wherein: R1a, R1b, R1c, and R1d are each an independently selected R1. In certain embodiments of Formula (Ia-1), R2 is H. In certain embodiments of Formula (Ia-1), R5 is H. In certain embodiments of Formula (Ia- 1), R2 is H; and R5 is H. In some embodiments, the compound is selected from the group consisting of a compound of the following formulae:
or a pharmaceutically acceptable salt thereof, wherein: R1a, R1b, R1c, and R1d are each an independently selected R1. In certain embodiments, the compound is a compound of Formula (Ib-1): or a pharmaceutically acceptable salt thereof, wherein: R1a, R1b, and R1c are each an independently selected R1. In certain embodiments of Formula (Ib-1), R2 is H. In certain embodiments of Formula (Ib-1), R5 is H. In certain embodiments of Formula (Ib-1), R2 is H; and R5 is H. In certain embodiments, the compound is a compound of Formula (Ic-1): or a pharmaceutically acceptable salt thereof, wherein: R1a, R1b, and R1d are each an independently selected R1. In certain embodiments of Formula (Ic-1), R2 is H. In certain embodiments of Formula (Ic-1), R5 is H. In certain embodiments of Formula (Ic-1), R2 is H; and R5 is H. In certain embodiments, the compound is a compound of Formula (Id-1): or a pharmaceutically acceptable salt thereof, wherein: R1a, R1c, and R1d are each an independently selected R1. In certain embodiments of Formula (Id-1), R2 is H. In certain embodiments of Formula (Id-1), R5 is H. In certain embodiments of Formula (Id-1), R2 is H; and R5 is H. In certain embodiments, the compound is a compound of Formula (Ie-1): or a pharmaceutically acceptable salt thereof, wherein: R1b, R1c, and R1d are each an independently selected R1. In certain embodiments of Formula (Ie-1), R2 is H. In certain embodiments of Formula (Ie-1), R5 is H. In certain embodiments of Formula (Ie-1), R2 is H; and R5 is H. The Variable R1 In some embodiments, each R1 is H. In some embodiments, 1-2 R1 is an independently selected non-hydrogen substituent, and each remaining R1 is H. In certain embodiments, 1-2 R1 are each independently selected from the group consisting of: Rc1 and Rg1; and each remaining R1 is H, wherein Rc1 is an independently selected Rc; and Rg1 is an independently selected Rg. In certain of these embodiments, two occurrences of R1 are independently selected from the group consisting of: Rc1 and Rg1; and each remaining R1 is H. For example, two occurrences of R1 are each an independently selected Rc1; and each remaining R1 is H. In certain of these embodiments, each Rc1 is an independently selected halo, such as –F or –Cl. In certain embodiments (when 1-2 R1 is independently selected from the group consisting of: Rc1 and Rg1; and each remaining R1 is H, wherein Rc1 is an independently selected Rc; and Rg1 is an independently selected Rg), one occurrence of R1 is selected from the group consisting of: Rc1 and Rg1; and each remaining R1 is H. In certain of these embodiments, one occurrence of R1 is Rc1; and each remaining R1 is H. In certain of these embodiments, Rc1 is halo, such as –F or –Cl, such as –F. In certain embodiments (when 1-2 R1 is independently selected from the group consisting of: Rc1 and Rg1; and each remaining R1 is H, wherein Rc1 is an independently selected Rc; and Rg1 is an independently selected Rg), one occurrence of R1 is Rg1; and each remaining R1 is H. In certain embodiments (when 1-2 R1 is independently selected from the group consisting of: Rc1 and Rg1; and each remaining R1 is H, wherein Rc1 is an independently selected Rc; and Rg1 is an independently selected Rg), each Rc1 is an independently selected halo, such as –F, -Cl, or –Br. In certain of these embodiments, each Rc1 is independently – F or –Cl, such as –F. In certain embodiments (when 1-2 R1 is independently selected from the group consisting of: Rc1 and Rg1; and each remaining R1 is H, wherein Rc1 is an independently selected Rc; and Rg1 is an independently selected Rg), each Rg1 is independently selected from the group consisting of: heteroaryl of 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc , Rh, and –(Lg)bg-Rh; and C6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of Rc, Rh, and –(Lg)bg-Rh. In certain of these embodiments, each Rg1 is independently selected from the group consisting of: heteroaryl of 5-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 Rc; and C6 aryl optionally substituted with 1-4 Rc. In certain of the foregoing embodiments, each Rg1 is independently heteroaryl of 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 Rc. As a non-limiting example of the foregoing embodiments, each Rg1 can be pyrazolyl that is optionally substituted with 1-2 Rc, such as 1-2 independently selected C1-6 (e.g., C1-3) alkyl which is optionally substituted with 1-6 independently selected Ra (e.g., unsubstituted). In some embodiments, the compound is a compound of Formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Id), or (Id-1); and R1a H. In some embodiments, the compound is a compound of Formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Ie), or (Ie-1); and R1b is H. In some embodiments, the compound is a compound of Formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Ie), or (Ie-1); and R1b is halo, such as –F or –Cl (e.g., -F). In some embodiments, the compound is a compound of Formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Ie), or (Ie-1); and R1b is heteroaryl of 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-2 Rc. In certain of these embodiments, R1b is pyrazolyl that is optionally substituted with 1-2 Rc, such as each Rc is an independently selected C1-6 (e.g., C1-3) alkyl which is optionally substituted with 1-6 independently selected Ra (e.g., unsubstituted). In some embodiments, the compound is a compound of Formula (Ia), (Ia-1), (Ib), (Ib-1), (Id), (Id-1), (Ie), or (Ie-1); R1c is H. In some embodiments, the compound is a compound of Formula (Ia), (Ia-1), (Ib), (Ib-1), (Id), (Id-1), (Ie), or (Ie-1); R1c is halo, such as –F or –Cl (e.g., -F). In some embodiments, the compound is a compound of Formula (Ia), (Ia-1), (Ic), (Ic-1), (Id), (Id-1), (Ie), or (Ie-1); and R1d is H. In some embodiments, the compound is a compound of Formula (Ia), (Ia-1), (Ic), (Ic-1), (Id), (Id-1), (Ie), or (Ie-1); and R1d is halo, such as –F or –Cl (e.g., -F). In some embodiments, the compound is a compound of Formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Id), (Id-1), (Ie), or (Ie-1); R1a and R1d when present are H; and R1b and R1c when present are independently selected halo, such as –F or –Cl, such as –F. In some embodiments, the compound is a compound of Formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Id), (Id-1), (Ie), or (Ie-1); R1a and R1d when present are H; one of R1b and R1c when present is H; and the other one of R1b and R1c when present is halo, such as –F or –Cl, such as –F. In some embodiments, the compound is a compound of Formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Id), (Id-1), (Ie), or (Ie-1); R1a and R1d when present are H; R1c when present is halo or H, such as –F, -Cl, or H; and R1b when present is heteroaryl of 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 Rc. The Variable R6 In some embodiments, R6 is H. The Variable Ring B In some embodiments, Ring B is a heteroarylene of 5 ring atoms, wherein 1-3 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, O, and S, wherein the heteroarylene of Ring B is optionally substituted with 1-2 RcB; and each RcB is an independently selected Rc. In some embodiments, Ring B is a heteroarylene of 5 ring atoms, wherein 2-3 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(Rd), O, and S, wherein the heteroarylene of Ring B is optionally substituted with 1-2 RcB; and each RcB is an independently selected Rc. In some embodiments, Ring B is a heteroarylene of 5 ring atoms, wherein 2-3 of the ring atoms are heteroatoms each independently selected from the group consisting of: N and NH, wherein the heteroarylene of Ring B is optionally substituted with 1-2 RcB; and each RcB is an independently selected Rc. As non-limiting examples of the foregoing embodiments, Ring B is selected from the group consisting of imidazolylene, pyrazolylene, or triazolylene (such as 1,2,3-triazolylene) which is optionally substituted with one RcB. In certain embodiments, Ring B is imidazolylene, which is optionally substituted with one RcB. In certain embodiments, Ring B is which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. In certain embodiments, Ring B is which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. In certain embodiments, Ring B is triazolylene (such as 1,2,3-triazolylene) which is optionally substituted with one RcB. In certain embodiments, Ring B is which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. In certain embodiments, Ring B is pyrazolylene, which is optionally substituted with one RcB. In certain embodiments, Ring B is , each of which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. In certain embodiments, Ring each of which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. In certain embodiments, each RcB is independently halo or C1-3 alkyl optionally which is optionally substituted 1-3 independently selected Ra (such as 1-3 independently selected halo). In some embodiments, Ring B is selected from the group consisting of isoxazolylene, oxadiazolylene, oxazolylene, thiazolylene, isothiazolylene, or thiadiazolylene, which is optionally substituted with one RcB. In certain embodiments, Ring each of which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. In certain embodiments, Ring each of which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. In certain embodiments, Ring each of which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. In certain embodiments, Ring which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. In certain embodiments, Ring each of which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. In certain embodiments, Ring each of which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. In certain embodiments, each RcB is independently halo or C1-3 alkyl optionally which is optionally optionally substituted 1-3 independently selected Ra (such as 1-3 independently selected halo). The Variables a1 and LA In some embodiments, a1 is 0. In some other embodiments, a1 is 1. In some embodiments, LA is C1-3 alkylene optionally substituted with 1-2 Ra1. In certain of these embodiments, LA is CH2 or CH(Me), such as CH2. In some embodiments, a1 is 1; and LA is C1-3 alkylene optionally substituted with 1-2 Ra1. In certain of these embodiments, LA is CH2 or CH(Me), such as CH2. The Variable Ring C In some embodiments, Ring C is selected from the group consisting of: x heteroarylene of 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of RcC and RhC; and x C6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of RcC and RhC, wherein each RcC is an independently selected Rc; and each RhC is an independently selected Rh. In certain of these embodiments, Ring C is selected from the group consisting of: x heteroarylene of 5-6 (such as 6) ring atoms, wherein 1-3 (such as 1-2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of RcC; and x C6 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of RcC. In certain embodiments (when Ring C is selected from the group consisting of: heteroarylene of 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of RcC and RhC; and C6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of RcC and RhC, wherein each RcC is an independently selected Rc; and each RhC is an independently selected Rh), Ring C is selected from the group consisting of: x pyridylene optionally substituted with 1-3 (such as 1) substituents independently selected from the group consisting of RcC; and x C6 arylene optionally substituted with 1-4 (such as 1-2) substituents independently selected from the group consisting of RcC. In certain embodiments, Ring C is a group of the following formula: , wherein each one of Q1, Q2, Q3, and Q4 is independently selected from the group consisting of N, CH, and CRcC; and bb is the point of connection to R7, wherein each RcC is an independently selected Rc. In certain embodiments, each one of Q1, Q2, Q3, and Q4 is independently CH or CRcC. In certain other embodiments 1-2 (e.g., 1) of Q1, Q2, Q3, and Q4 are N; and each remaining one of Q1, Q2, Q3, and Q4 are independently CH or CRcC. In certain of embodiments, Q2 is CH. In certain embodiments, Q3 is CH. In certain embodiments, Q4 is N. In certain embodiments, Q1 is CH. In certain other embodiments, Q1 is CRcC. . In certain embodiments, each RcC is independently selected from the group consisting of: -halo and C1-6 (e.g., C1-3) alkyl which is optionally substituted with 1-6 independently selected Ra (e.g., 1-6 independently selected halo, such as –F). In certain embodiments, each RcC is independently halo, such as –Cl or –F, such as –F. The Variable R7 In some embodiments, R7 is Rg. In some embodiments, R7 is selected from the group consisting of: x C3-12 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc7, Rh7, and –(Lg)bg-Rh7; and x heterocyclyl of 4-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc7, Rh7, and –(Lg)bg-Rh7, wherein each Rc7 is an independently selected Rc; and Rh7 is an independently selected Rh. In certain of these embodiments, R7 is selected from the group consisting of: x C4-8 (e.g., C4, C5, or C6) cycloalkyl, which is optionally substituted with 1- 4 substituents independently selected from the group consisting of oxo, Rc7, and Rh7; and x heterocyclyl of 4-8 (e.g., 4, 5, or 6) ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc7, and Rh7. In certain of the foregoing embodiments, R7 is selected from the group consisting of: x C6 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7; and x heterocyclyl of 6 ring atoms, wherein 1-2 (such as one) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7. In certain of these embodiments, R7 is a group of the following formula: wherein X7 is CH, CRc7, or N, such as CH or N. In certain embodiments (when R7 is ), two Rc7 groups are present. In certain embodiments, R7 is a group of the following formula: , wherein X7 is N or CH; and each Rc7 is an independently selected Rc. In certain embodiments, R7 is wh 7 erein X is N or CH; such as In certain of the foregoing embodiments, R7 is selected from the group consisting of: x C4 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7; and x heterocyclyl of 4 ring atoms, wherein 1-2 (such as one) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7. In certain of these embodiments, R7 is a group of the following formula: , wherein X7 is CH, CRc7, or N, such as CH or N. In certain embodiments (when R7 is , two Rc7 groups are present. In certain embodiments, R7 is a group of the following formula: , wherein X7 is N or CH; and each Rc7 is an independently selected Rc. In certain embodiments, R7 i , wherein X7 is N or CH; such a . In certain embodiments, R7 is selected the group consisting of tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octanyl, or 2-azabicyclo[2.2.1]heptanyl, each of which is optionally substituted with 1-2 Rc7. For example, R7 can be: In certain embodiments, each Rc7 is an independently selected halo or C1-3 alkyl optionally substituted with 1-6 Ra (e.g., 1-6 independently selected halo). In certain of these embodiments, each Rc7 is independently halo, such as –F. In some embodiments, R7 is selected from the group consisting of: x C4-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7; and x heterocyclyl of 5-6 ring atoms, wherein 1-2 (such as one) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7. In certain embodiments, R7 is a group of the following formula: , wherein X7 is CH, CRc7, or N, such as CH or N. In certain embodiments, R7 is a group of the following formula: , wherein Rd is is independently selected from the group consisting of: C1-6 alkyl optionally substituted with 1-3 independently selected Ra. In certain embodiments, R7 is selected from the group consisting of tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octanyl, or 2- azabicyclo[2.2.1]heptanyl, each of which is optionally substituted with 1-2 Rc7. For example, R7 can be:
Non-Limiting Combinations In some embodiments, the compound is a compound of Formula (I-a1-1): Formula (I-a1-1) or a pharmaceutically acceptable salt thereof, wherein: each one of R1a, R1b, R1c, and R1d is an independently selected R1; B4 is C or N; B1, B2, and B3 are each independently CH, CRcB, NH, N(Rd), N, O, or S; Q1, Q2, Q3, and Q4 are each independently selected from the group consisting of N, CH, and CRcC; each occurrence of RcB and RcC is an independently selected Rc; and each is independently a single bond or a double bond provided that the ring including B1-B4 is a heteroaryl. In some embodiments of Formula (I-a1-1), R1a and R1d are H; and R1b and R1c are independently H or halo. In some embodiments of Formula (I-a1-1), R1a and R1d are H; and R1b and R1c are independently selected halo, such as –F or –Cl, such as –F. In some embodiments of Formula (I-a1-1), each one of R1a, R1b, R1c, and R1d is H. In some embodiments of Formula (I-a1-1), R1a and R1d are H; R1c is halo or H, such as –F, -Cl, or H; and R1b is heteroaryl of 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc. In some embodiments of Formula (I-a1-1), R2 is H. In some embodiments of Formula (I-a1-1), R5 is H. In some embodiments of Formula (I-a1-1), R2 is H; and R5 is H. In some embodiments of Formula (I-a1-1), R6 is H. In some embodiments of Formula (I-a1-1), R2 is H; R5 is H; and R6 is H. In some embodiments of Formula (I-a1-1), B4 is N; B1 is N; B3 is CH or CRcB; and B2 is CH or CRcB. In certain embodiments, B4 is N; B1 is N; B3 is CH; and B2 is CH. In certain embodiments, B4 is N; B1 is N; B3 is CH; and B2 is CRcB. In some embodiments of Formula (I-a1-1), B4 is N; B1 is N; B3 is CH or CRcB; and B2 is N. In certain embodiments, B4 is N; B1 is N; B3 is CH; and B2 is N. In some embodiments of of Formula (I-a1-1), B4 is N; B1 is CH or CRcB; B3 is CH or CRcB; and B2 is N. In certain embodiments, B4 is N; B1 is CH; B3 is CH; and B2 is N. In some embodiments of Formula (I-a1-1), B4 is N; B1 is CH or CRcB; B3 is N; and B2 is CH or CRcB. In certain embodiments, B4 is N; B1 is CH; B3 is N; and B2 is CH. In some embodiments of Formula (I-a1-1), B4 is C; B1 is N, B3 is CRcB; and B2 is O. In certain embodiments, B4 is C; B1 is N, B3 is CH; and B2 is O. In other embodiments, B4 is C; B1 is O, B3 is CH; and B2 is N. In some embodiments of Formula (I-a1-1), a1 is 0. In some embodiments of Formula (I-a1-1), a1 is 1. In some embodiments of Formula (I-a1-1), LA is CH2 or CH(Me). In some embodiments of Formula (I-a1-1), Q1 and Q3 are CH or CRcC (such as CH). In some embodiments of Formula (I-a1-1), Q4 is N; and Q2 is CH or CRcC, such as CRcC. In some embodiments of Formula (I-a1-1), the ring including Q1-Q4 is: , wherein bb is the point of connection to R7. In some embodiments of Formula (I-a1-1), RcC is halo, such as –F or –Cl, such as –F. In some embodiments of Formula (I-a1-1), R7 is selected from the group consisting of: x C6 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7; and x heterocyclyl of 6 ring atoms, wherein 1-2 (such as one) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7, wherein each Rc7 is an independently selected Rc. In some embodiments of Formula (I-a1-1), R7 is a group of the following formula: , wherein X7 is CH, CR7, or N, such as CH or N. In certain of these embodiments, two Rc7 groups are present.
In some embodiments of Formula (I-a1-1), R7 is a group of the following formula: , wherein X7 is N or CH; and each Rc7 is an independently selected Rc. In certain of these embodiments, , wherein X7 is N or CH, such . In some embodiments of Formula (I-a1-1), R7 is selected from the group consisting of: x C4 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7; and x heterocyclyl of 4 ring atoms, wherein 1-2 (such as one) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7. In some embodiments of Formula (I-a1-1), R7 is a group of the following formula: , wherein X7 is CH, CRc7, or N, such as CH or N. In certain embodiments (when two Rc7 groups are present.
In some embodiments of Formula (I-a1-1), R7 is a group of the following formula: , wherein X7 is N or CH; and each Rc7 is an independently selected Rc. In certain embodiments, , wherein X7 is N or CH; such . In some embodiments of Formula (I-a1-1), R7 is selected the group consisting of tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octanyl, or 2-azabicyclo[2.2.1]heptanyl, each of which is optionally substituted with 1-2 Rc7. For example, R7 can be: In some embodiments of Formula (I-a1-1), each Rc7 is an independently selected halo or C1-3 alkyl optionally substituted with 1-6 Ra (e.g., 1-6 independently selected halo). In certain of these embodiments, each Rc7 is independently halo, such as –F. In some embodiments, the compound is a compound of Formula (I-a1-1) wherein: R1a and R1d is a H; R1b, R1c are each independently selected from: H; and Rc, R2 , R5, R6 are each independently H; B1 is selected from CH and N; B2 and B4 are each independently N; B3 is CH; Q1 is an N; Q2 and Q3 are each independently a CH; Q4 is an CRc; and each is independently a single bond or a double bond provided that the ring including B1-B4 is a heteroaryl; , wherein X7 is N or CH, wherein each occurrence of Rc is independently selected from the group consisting of: halo; C1-10 alkyl which is optionally substituted with 1-6 independently selected Ra; wherein each occurrence of Ra is independently selected from the group consisting of: –OH; -halo; C1-4 alkoxy; C1-4 haloalkoxy. In some embodiments, the compound is a compound of Formula (I-f1-1): Formula (I-f1-1) or a pharmaceutically acceptable salt thereof, wherein: Z is N or CR1a; Y1 is N or CR1b; Y2 is N or CR1c; Y3 is N or CR1d, provided that 1-2 (e.g., 1) of Z, Y1, Y2, and Y3 is N; each one of R1a, R1b, R1c, and R1d is an independently selected R1; B4 is C or N; B1, B2, and B3 are each independently CH, CRcB, NH, N(Rd), N, O, or S; Q1, Q2, Q3, and Q4 are each independently selected from the group consisting of N, CH, and CRcC; each occurrence of RcB and RcC is an independently selected Rc; and each is independently a single bond or a double bond provided that the ring including B1-B4 is a heteroaryl. In some embodiments of Formula (I-f1-1), one of Z, Y1, Y2, and Y3 is N. In some embodiments of Formula (I-f1-1), the compound is a compound of Formula (I-b1-1):
Formula (I-b1-1) or a pharmaceutically acceptable salt thereof. In some embodiments of Formula (I-f1-1), the compound is a compound of Formula (I-c1-1): Formula (I-c1-1) or a pharmaceutically acceptable salt thereof. In some embodiments of Formula (I-f1-1), the compound is a compound of Formula (I-d1-1): Formula (I-d1-1) or a pharmaceutically acceptable salt thereof. In some embodiments of Formula (I-f1-1), the compound is a compound of Formula (I-d1-1):
Formula (I-e1-1) or a pharmaceutically acceptable salt thereof. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), R1a and R1d when present are H; and R1b and R1c when present are independently H or halo. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), R1a and R1d when present are H; and R1b and R1c when present are independently selected halo, such as –F or –Cl, such as –F. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), each one of R1a, R1b, R1c, and R1d when present is H. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), R1a and R1d when present are H; R1c when present is halo or H, such as –F, -Cl, or H; and R1b when present is heteroaryl of 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), R1d when present is an independently selected halo, such as –F or –Cl. In certain of these embodiments, each one of R1a, R1b, and R1c when present is H. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), R2 is H. In some embodiments of Formula (I-a1-1), R5 is H. In some embodiments of Formula (I-a1-1), R2 is H; and R5 is H. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), R6 is H. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), R2 is H; R5 is H; and R6 is H. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), B4 is N; B1 is N; B3 is CH or CRcB; and B2 is CH or CRcB. In certain embodiments, B4 is N; B1 is N; B3 is CH; and B2 is CH. In certain embodiments, B4 is N; B1 is N; B3 is CH; and B2 is CRcB. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), B4 is N; B1 is N; B3 is CH or CRcB; and B2 is N. In certain embodiments, B4 is N; B1 is N; B3 is CH; and B2 is N. In some embodiments of of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)), B4 is N; B1 is CH or CRcB; B3 is CH or CRcB; and B2 is N. In certain embodiments, B4 is N; B1 is CH; B3 is CH; and B2 is N. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), B4 is N; B1 is CH or CRcB; B3 is N; and B2 is CH or CRcB. In certain embodiments, B4 is N; B1 is CH; B3 is N; and B2 is CH. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), a1 is 0. In some embodiments of Formula (I-a1-1), a1 is 1. In some embodiments of Formula (I-f1-1), LA is CH2 or CH(Me). In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), Q1 and Q3 are CH or CRcC (such as CH). In some embodiments of Formula (I-f1-1), Q4 is N; and Q2 is CH or CRcC, such as CRcC. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), the ring including Q1-Q4 is: , wherein bb is the point of connection to R7. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), RcC is halo, such as –F or –Cl, such as –F. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), R7 is selected from the group consisting of: x C6 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7; and x heterocyclyl of 6 ring atoms, wherein 1-2 (such as one) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7, wherein each Rc7 is an independently selected Rc. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), R7 is a group of the following formula: , wherein X7 is CH, CR7, or N, such as CH or N. In certain of these embodiments, two Rc7 groups are present. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), R7 is a group of the following formula: , wherein X7 is N or CH; and each Rc7 is an independently selected Rc. In certain of these embodiments, , wherein X7 is N or CH, such . In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), R7 is selected from the group consisting of: x C4 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7; and x heterocyclyl of 4 ring atoms, wherein 1-2 (such as one) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), R7 is a group of the following formula: , wherein X7 is CH, CRc7, or N, such as CH or N. In certain embodiments (when c7 two R groups are present. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), R7 is a group of the following formula: , wherein X7 is N or CH; and each Rc7 is an independently selected Rc. In certain embodiments, wherein X7 is N or CH; such . In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), R7 is selected the group consisting of tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octanyl, or 2-azabicyclo[2.2.1]heptanyl, each of which is optionally substituted with 1-2 Rc7. For example, R7 can be: , , , In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), each Rc7 is an independently selected halo or C1-3 alkyl optionally substituted with 1-6 Ra (e.g., 1-6 independently selected halo). In certain of these embodiments, each Rc7 is independently halo, such as –F. In some embodiments of Formula (I-f1-1) (such as Formula (I-b1-1), (I-c1-1), (I- d1-1), or (I-e1-1)), each Rc7 is an independently selected halo or C1-3 alkyl optionally substituted with 1-6 Ra (e.g., 1-6 independently selected halo). In certain of these embodiments, each Rc7 is independently halo, such as –F. Non-Limiting Exemplary Compounds In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table C1 or a pharmaceutically acceptable salt thereof. Table C1
Pharmaceutical Compositions and Administration General In some embodiments, a chemical entity (e.g., a compound that inhibits (e.g., antagonizes) STING, or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination thereof) is administered as a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein. In some embodiments, the chemical entities can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as α-, E, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3- hydroxypropyl-β-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, 22nd 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, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral). Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof. Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia. 2006, 10, 788–795. Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p- oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, 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 al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety. Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls. Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric/pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid–methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap. 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, 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. 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., excessive)STING activity (e.g., , e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., immune disorders, cancer) are provided. Indications In some embodiments, the condition, disease or disorder is 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 telegiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet's disease; Bell's palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger's disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome; causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy; chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorders; Cushing's syndrome; cytomegalic inclusion body disease; 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 Kinsbourne 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; Sjögren'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-Goutières 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-dioxygenase (IDO), IL^10, transforming growth factor-β (TGFβ), 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, OX40–OX40 ligand, GITR, GITR ligand – GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25–TL1A, CD40L, CD40–CD40 ligand, HVEM–LIGHT–LTA, HVEM, HVEM – BTLA, HVEM – CD160, HVEM – LIGHT, HVEM–BTLA–CD160, 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). 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, semisynthetic 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- β), vasculostatin, vasostatin (calreticulin fragment) and the like. In certain embodiments, the additional chemotherapeutic agent is selected from abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t- butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′- deoxy-8′-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin (adriamycin), etoposide, 5- fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyureataxanes, ifosfamide, liarozole, lonidamine, lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxanes, nilutamide, onapristone, paclitaxel, prednimustine, procarbazine, RPR109881, stramustine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine. In certain embodiments, the additional chemotherapeutic agent is platinum, cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, azathioprine, mercaptopurine, vincristine, vinblastine, vinorelbine, vindesine, etoposide and teniposide, paclitaxel, docetaxel, irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, teniposide, 5-fluorouracil, leucovorin, methotrexate, gemcitabine, taxane, leucovorin, mitomycin C, tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide and doxorubicin. Additional agents include inhibitors of mTOR (mammalian target of rapamycin), including but not limited to rapamycin, everolimus, temsirolimus and deforolimus. In still other embodiments, the additional chemotherapeutic agent can be selected from those delineated in U.S. Patent 7,927,613, which is incorporated herein by reference in its entirety. In some embodiments, the additional therapeutic agent and/or regimen are those that can be used for treating other STING-associated conditions, e.g., type I interferonopathies (e.g., STING-associated vasculopathywith onset in infancy (SAVI)), Aicardi-Goutières 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 biologics (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 biologics (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDI0700, obinutuzumab, vobarilizumab, lulizumab, atacicept, PF-06823859, and lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirolizumab, edratide, IFN-α-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 biologics (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDI0700, vobarilizumab, lulizumab, atacicept, PF-06823859, lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirolizumab, edratide, IFN-α-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-Goutières 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, fingolimod, firategrast (SB-683699) (formerly T-0047), GED0301, GLPG0634, GLPG0974, guselkumab, golimumab, GSK1399686, 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, farnesoid 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, alpha1-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-β-1a, IFN-β-1b), cladribine, corticosteroids (e.g., methylprednisolone), daclizumab, dimethyl fumarate (Tecfidera®), fingolimod (Gilenya®), fluoxetine, glatiramer acetate (Copaxone®), hydroxychloroquine, ibudilast, idebenone, laquinimod, lipoic acid, losartan, masitinib, MD1003 (biotin), mitoxantrone, montelukast, natalizumab (Tysabri®), NeuroVaxTM, ocrelizumab, ofatumumab, pioglitazone, and RPC1063. Non-limiting examples of additional therapeutic agents and/or regimens for treating graft-vs-host disease include abatacept, alemtuzumab, alpha1-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 tocafinib, 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-crème®), 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®), Apo805K1, baricitinib, FP187, KD025, prurisol, VTP-43742, XP23829, ZPL-389, CF101 (piclidenoson), LAS41008, VPD-737 (serlopitant), upadacitinib (ABT-494), aprmilast, tofacitibin, cyclosporine (Neoral®, Sandimmune®, Gengraf®), biologics (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, MSB11022, 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®) biologics (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), biologics (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 β-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 β-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, 1,8-diazabicycloundec-7-ene, 2,6-di-tert- butylpyridine, or tetrabutylphosphazene). The skilled artisan will recognize a variety of analytical methods that can be used to characterize the compounds described herein, including, for example, 1H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy. The foregoing list is a subset of characterization methods available to a skilled artisan and is not intended to be limiting. To further illustrate the foregoing, the following non-limiting, exemplary synthetic schemes are included. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the invention as described, and claimed herein. The reader will recognize that the skilled artisan, provided with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples. The following abbreviations have the indicated meanings: Ac = acetyl ACN = acetonitrile Boc2O = di-tert-butyl pyrocarbornate Bu = butyl DCM = dichloromethane DIEA = N,N-diisopropylethylamine DMF = N,N-dimethylformamide DMSO = dimethyl sulfoxide DPPA = diphenyl azidophosphate Dppf = bis(diphenylphosphino)ferrocene HATU = 2-(7-azaenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate HPLC = high performance liquid chromatography LC-MS = liquid chromatography – mass spectrometry Me = methyl NMR = nuclear magnetic resonance RT = retention time TEA = triethylamine THF = tetrahydrofuran TMS = tetramethylsilane T3P = 2,4,6-tripropyl-2,4,6-trioxo-1,3,5,2,4,6-trioxatriphosphorinane XPhos = (2-(2,4,6-triisopropylphenethyl)phenyl)dicyclohexylphosphine DCC = N,N'-dicyclohexylcarbodiimide DCE = dichloroethane DMAP = Dimethylaminopyridine Ir[dF(CF3)ppy]2(dtbpy)PF6 = Iridium(1+), [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine- κN1,κN1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC]-, (OC-6-33)-, hexafluorophosphate(1-) (1:1) NBS = N-Bromosuccinimide NCS = N-Chlorosuccinimide NMM = N-methylmorpholinePyBOP = benzotriazole-1-yl-oxytripyrrolininophosphomium hexafluorophosphate Selectfluor = 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) TFA = trifluoroacetic acid Ts = p-toluenesulfonyl t-AmOH = tert-amyl alcohol TES = triethylsilane AcOH = Acetic acid SOCl2 = sulfurous dichloride CHCl3 = chloroform MTBE = 2-methoxy-2-methylpropane MgSO4 = Magnesium sulfate anhydrous EtOH = Ethanol NaOH = Sodium hydroxide HCl = hydrochloric acid EDCI = 1-(3-dimethylaminopropyl)-3-ethyl Py = Pyridine RuPhos Pd G3 = Methanesulfonato (2-dicyclohexylphosphino-2,6-di-i-propoxy-1,1-biphenyl)(2- amino-1,1-biphenyl-2-yl)palladium (II) XPhos Pd G3 = Methanesulfonato(2-dicyclohexylphosphino-2,4,6-tri-i-propyl-1,1-biphenyl)(2- amino-1,1-biphenyl-2-yl)palladium(II) K3PO4 = Potassium phosphate EtOAc = Ethyl acetate Na2SO4 = sodium sulfate FA = formic acid MeOH = methanol SpeedVac = Savant SC250EXP SpeedVac Concentrator Examples 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 μL 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 μL 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: XBridge Shield RP18, 50 *4.6mm, 0.5 μL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.04% NH3.H2O and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.79 min, 95% MPB to 10% in 0.06 min, then equilibration to 10% MPB for 0.15 min. LCMS Method D: Shim-pack XR-ODS, 50 *3mm, 0.3 μL 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 E: XBridge BEH C18, 50 *3mm, 4.0 μL 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 F: Kinetex 2.6μm EVO C18 100A, 50 *3mm, 0.6 μL 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 G: kinetex 2.6μm EVO, 50 *3mm, 0.5 μL 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 H: Titank C18, 50 *3mm, 0.5 μL 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 I: XBridge BEH C18, 50 *3mm, 4.0 μL 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 J: HALOC18, 30 *3mm, 0.5 μL 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 K: Ascentis Express C18, 50 *3mm, 0.5 μL 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 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 0.25 min. NMR was recorded on BRUKER NMR 300.03 Mz, DUL-C-H, ULTRASHIELDTM 300, AVANCE II 300 B-ACSTM 120 or BRUKER NMR 400.13 Mz, BBFO, ULTRASHIELDTM 400, AVANCE III 400, B-ACSTM 120. Preparative examples Scheme for the preparation of Key Intermediates: Schemes below illustrate the preparation of key intermediates. Scheme 1: Synthesis of intermediate 1 (1-(6-(4,4-difluoropiperidin-1-yl)-5- methylpyridin-3-yl)-1H-imidazole-4-carboxylic acid) Step 1: 2-(4,4-difluoropiperidin-1-yl)-3-methyl-5-nitropyridine 2-Chloro-3-methyl-5-nitropyridine (5.0 g, 28.9 mmol, 1.0 equiv.) was dissolved in ACN (100 mL), then 4,4-difluoropiperidine (4.2 g, 34.7 mmol, 1.2 equiv.) and Cs2CO3 (18.8 g, 57.9 mmol, 2.0 equiv.) were added. The resulting mixture was heated to 80 °C for 16 hours and then cooled to room temperature. After filtration and washing the solids with MeOH, the filtrate was concentrated under vacuum to give 2-(4,4-difluoropiperidin-1-yl)- 3-methyl-5-nitropyridine (6 g) as a brown solid. LCMS Method B: [M+H]+ = 258. Step 2: 6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-amine 2-(4,4-difluoropiperidin-1-yl)-3-methyl-5-nitropyridine (6.0 g, 23.3 mmol, 1.0 equiv.) was dissolved in MeOH (50 mL), then Pd/C (1.0 g, 10% wt.) was added. 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 to give 6-(4,4-difluoropiperidin-1-yl)-5- methylpyridin-3-amine (4.8 g) as brown oil. LCMS Method B: [M+H]+ = 228. Step 3-4: ethyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl]imidazole-4- carboxylate 6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-amine (2.0 g, 8.8 mmol, 1.0 equiv.) was dissolved in EtOH (20 mL) and AcOH (1 mL), then ethyl 2-nitroacetate (1.1 g, 8.8 mmol, 1.0 equiv.) was added. The reaction mixture was heated to 80 °C for 30 min, then cooled to ambient temperature. Then triethoxymethane (6.5 g, 44.0 mmol, 5.0 equiv.) was added and the resulting solution was heated at 80 °C for 2 hours. After cooling to ambient temperature, AcOH (10 mL) and triethoxymethane (10 mL) were added, this was followed by the addition of Fe (0.3 g, 5.4 mmol, 1.0 equiv.) in portions. The reaction mixture was heated to 80 °C for 3 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with of water, 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 (1:3) to give ethyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl]imidazole-4- carboxylate (600 mg) as an off-white solid. Method A: [M+H]+ = 351. Step 5: 1-[6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl]imidazole-4- carboxylic acid Ethyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl]imidazole-4- carboxylate (500.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in MeOH/H2O (5:1, 12 mL), then NaOH (85.6 mg, 2.1 mmol, 1.5 equiv) was added. The resulting solution was heated to 50 °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 2 with aqueous HCl (6 M). The solids were collected by filtration and dried to give 1-[6-(4,4- difluoropiperidin-1-yl)-5-methylpyridin-3-yl]imidazole-4-carboxylic acid (300 mg) as an off-white solid. Method A: [M+H]+ = 323. The following intermediates were prepared using the same method described for Intermediate 1. Scheme 2: Synthesis of intermediate 6 (1-((6-(4,4-difluorocyclohexyl)-5- fluoropyridin-3-yl)methyl)-1H-pyrazole-4-carboxylic acid) Step 1: ethyl 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]pyrazole-4- carboxylate 5-(bromomethyl)-2-(4,4-difluorocyclohexyl)-3-fluoropyridine (500.0 mg, 1.6 mmol, 1.0 equiv) was dissolved in ACN (20 mL), then K2CO3 (704.9 mg, 5.1 mmol, 3.0 equiv.) and ethyl 1H-pyrazole-4-carboxylate (238.2 mg, 1.7 mmol, 1.0 equiv.) were added. The reaction mixture was 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 (1:1) to give ethyl 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]pyrazole-4- carboxylate (300 mg) of as a white solid. LCMS Method B: [M+H]+ = 368. Step 2: 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]pyrazole-4- carboxylic acid Ethyl 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]pyrazole-4- carboxylate (300.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and water (2 mL), then NaOH (65.3 mg, 1.6 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80 °C for 1 hour, 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 HCl (6 M). The solids were collected by filtration and dried to give 1-[[6-(4,4- difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]pyrazole-4-carboxylic acid (250 mg) as a white solid.^LCMS Method B: [M+H]+ = 340. Scheme 3: Synthesis of intermediate 7 and 8 (1-((6-(4,4-difluorocyclohexyl)-5- fluoropyridin-3-yl)methyl)-1H-imidazole-4-carboxylic acid and 1-((6-(4,4- difluorocyclohexyl)-5-fluoropyridin-3-yl)methyl)-1H-imidazole-5-carboxylic acid) Step 1: ethyl 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]imidazole- 4-carboxylate and ethyl 3-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3- yl]methyl]imidazole-4-carboxylate 5-(Bromomethyl)-2-(4,4-difluorocyclohexyl)-3-fluoropyridine (800.0 mg, 2.6 mmol, 1.0 equiv.) was dissolved in ACN (15 mL), then K2CO3 (1.1 g, 7.8 mmol, 3.0 equiv.) and ethyl 1H-imidazole-4-carboxylate (363.8 mg, 2.6 mmol, 1.0 equiv.) were added. The reaction mixture was heated to 80 °C for 2 hours. After filtration and washing 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 (1:10 to 1:1) to give ethyl 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]imidazole-4- carboxylate (compound 8A, 350 mg) as a pale yellow solid and ethyl 3-[[6-(4,4- difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]imidazole-4-carboxylate (compound 8B, 370 mg) as a white solid. LCMS of compound 8A, Method B: [M+H]+ = 368.1H NMR of compound 8A (400 MHz, DMSO-d6): δ 8.45 (d, 1H), 8.05 (d, 1H), 7.95 (d, 1H), 7.73–7.69 (m, 1H), 5.30 (s, 2H), 4.21 (q, 2H), 3.20–3.16 (m, 1H), 2.15–1.83 (m, 8H), 1.25 (t, 3H); LCMS of compound 8B, Method B: [M+H]+ = 368.1H NMR of compound 8B (400 MHz, DMSO-d6): δ 8.27 (d, 1H), 8.21 (s, 1H), 7.71 (s, 1H), 7.50–7.45 (m, 1H), 5.57 (s, 2H), 4.23 (q, 2H), 3.19–3.14 (m, 1H), 2.15–1.80 (m, 8H), 1.22 (t, 3H). Step 2: 1-((6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl)methyl)-1H-imidazole-4- carboxylic acid Ethyl 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]imidazole-4- carboxylate (200.0 mg, 0.5 mmol, 1.0 equiv.) was dissolved in MeOH (4 mL) and water (4 mL), then NaOH (65.3 mg, 1.6 mmol, 3.0 equiv.) was added. The reaction mixture was stirred for 2 hours at 80 °C, then concentrated under vacuum. The residue was diluted with water and adjusted to pH 5 with aqueous HCl (6 M). The resulting solid was collected by filtration and purified by Flash-Prep-HPLC with the following conditions: Column, C18; mobile phase, ACN/H2O increasing from 0 to 100% within 30 min; Detector, 254 nm. This resulted in 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]imidazole-4- carboxylic acid (160 mg) as a white solid. LCMS Method B: [M+H]+ = 340. Step 3: 1-((6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl)methyl)-1H-imidazole-5- carboxylic acid Same method described for step 2 was used to provide 1-((6-(4,4-difluorocyclohexyl)- 5-fluoropyridin-3-yl)methyl)-1H-imidazole-5-carboxylic acid (160 mg) as a white solid. LCMS Method B: [M+H]+ = 340. The following intermediate was prepared using the same method described for Intermediates 7 and 8. Scheme 4: Synthesis of intermediate 10 (1-(6-(4,4-difluorocyclohexyl)-5- fluoropyridin-3-yl)-1H-pyrazole-4-carboxylic acid) Step 1: 2-(4,4-difluorocyclohexyl)-3-fluoro-5-iodopyridine 6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-amine (400.0 mg, 1.7 mmol, 1.0 equiv.) was dissolved in aqueous HCl (6 M, 10 mL) and cooled to 0 °C, then a solution of NaNO2 (179.8 mg, 2.6 mmol, 1.5 equiv.) in water (0.5 mL) was added dropwise, maintaining the reaction mixture at 0 °C. After 30 min at 0 °C, KI (576.8 mg, 3.5 mmol, 2.0 equiv.) was added in portions, maintaining the temperature at 0 °C. After addition was complete, the solution was stirred for an additional 2 hours at 0 °C. After quenching with 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 2-(4,4-difluorocyclohexyl)-3-fluoro-5-iodopyridine (120 mg) as a pale yellow solid. LCMS Method A: [M+H]+ = 342. Step 2: ethyl 1-(6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl)-1H-pyrazole-4- carboxylate 2-(4,4-difluorocyclohexyl)-3-fluoro-5-iodopyridine (500.0 mg, 1.5 mmol, 1.0 equiv.) was dissolved in DMF (5 mL), then Cs2CO3 (1.4 g, 4.4 mmol, 3.0 equiv.), ethyl 1H- pyrazole-4-carboxylate (246.5 mg, 1.8 mmol, 1.2 equiv.), N1,N2-dimethylcyclohexane-1,2- diamine (0.1 mL, 0.7 mmol, 0.5 equiv.) and CuI (57.3 mg, 0.3 mmol, 0.2 equiv.) were added. The resulting solution was heated to 80 °C for 8 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 (1:1) to give ethyl 1-[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]pyrazole-4-carboxylate (120 mg) as a pale yellow solid. LCMS Method A: [M+H]+ = 354. Step 3: 1-(6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl)-1H-pyrazole-4- carboxylic acid Ethyl 1-[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]pyrazole-4-carboxylate (110.0 mg, 0.3 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL), then aqueous NaOH (2 mL, 2M) was added. The reaction mixture was stirred for 2 hours at ambient temperature, then diluted with 5 mL of water. The solution was adjusted to pH 5 with aqueous HCl (2M) and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions: Column, silica gel; mobile phase, ACN/water increasing from 0 to 70% within 25 min. This resulted in 1-[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3- yl]pyrazole-4-carboxylic acid (70 mg) as a pale yellow solid. LCMS Method A: [M+H]+ = 326. Scheme 5: Synthesis of intermediate 11 (5,6-difluoro-1H-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 AgNO3 (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 NaHCO3, 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/petroleum 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 N-(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 (Boc)2O (39.7 g, 181.7 mmol, 1.5 equiv.) were added under nitrogen. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred overnight at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give tert-butyl N-(5,6-difluoro-1H-indol-3-yl)carbamate (22 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 HCl/1,4-dioxane (4N, 200 mL). The resulting mixture was stirred for 30 min at ambient temperature and then concentrated under vacuum to give 5,6-difluoro-1H- indol-3-amine hydrochloride (12 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 11. Scheme 6: Synthesis of intermediate 14 (5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine hydrogen chloride) Step 1: 5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl azide 5-Fluoro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (1.0 g, 5.6 mmol, 1.0 equiv.) and DPPA (3.0 g, 11.1 mmol, 2.0 equiv.) were dissolved in THF (10.0 mL), then TEA (1.6 mL, 11.1 mmol, 2.0 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 Na2SO4 and concentrated under vacuum to give 5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl azide (900 mg) as a white solid. LCMS Method E: [M+H]+ = 206. Step 2: tert-butyl N-[5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl]carbamate 5-Fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl azide (300.0 mg, 1.5 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 column, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl N-[5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl]carbamate (350 mg) as a yellow solid. LCMS Method E: [M+H]+ = 251. Step 3: 5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine hydrogen chloride tert-Butyl N-[5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl]carbamate (300.0 mg) was dissolved in HCl/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 5-fluoro-1H- pyrrolo[2,3-b]pyridin-3-amine hydrogen chloride (350 mg) as a yellow solid. LCMS Method E: [M+H]+ = 151.
Scheme 7: Synthesis of intermediate 15 (5-(1-isopropyl-1H-pyrazol-4-yl)-1H- indol-3-amine hydrogen chloride) Step 1: 5-bromo-1H-indole-3-carbonyl azide 5-Bromo-1H-indole-3-carboxylic acid (1.0 g, 4.2 mmol, 1.0 equiv.) was dissolved in THF (10.0 mL), then DPPA (2.3 g, 8.3 mmol, 2.0 equiv.) and TEA (1.8 mL, 12.5 mmol, 3.0 equiv.) were added. The resulting solution was stirred overnight at ambient temperature and then concentrated under vacuum. The residue was diluted with MeOH and the isolated solids were collected by filtration to give 5-bromo-1H-indole-3-carbonyl azide (900 mg) as a white solid. LCMS Method E: [M+H]+ = 265. Step 2: tert-butyl N-(5-bromo-1H-indol-3-yl)carbamate 5-Bromo-1H-indole-3-carbonyl azide (900.0 mg, 3.4 mmol, 1.0 equiv.) was dissolved in t-BuOH (6 mL). The resulting solution was heated at 80 °C overnight, 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 N-(5-bromo-1H-indol-3- yl)carbamate (910 mg) as a yellow solid. LCMS Method E: [M+H]+ = 311. Step 3: tert-butyl N-[5-(1-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.) was dissolved in 1,4-dioxane (6 mL) and water (0.6 mL), then 1-isopropyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (417.3 mg, 1.8 mmol, 1.1 equiv.), Xphos Pd G3 (136.0 mg, 0.2 mmol, 0.1 equiv.) and Cs2CO3 (1.0 g, 3.2 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen. The solution was heated overnight at 100 °C, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and the organic layers 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-(1-isopropylpyrazol-4-yl)-1H-indol-3-yl]carbamate (400 mg) as a white solid. LCMS Method E: [M+H]+ = 341. Step 4: 5-(1-isopropylpyrazol-4-yl)-1H-indol-3-amine hydrogen chloride tert-butyl N-[5-(1-isopropylpyrazol-4-yl)-1H-indol-3-yl]carbamate (400.0 mg, 1.2 mmol, 1.0 equiv.) was dissolved in HCl in 1,4-dioxane (4M, 8.0 mL). The resulting solution was stirred for 4 hours at ambient temperature and then concentrated under vacuum to give crude 5-(1-isopropylpyrazol-4-yl)-1H-indol-3-amine hydrogen chloride (400 mg) as a grey solid. LCMS Method E: [M+H]+ = 241. The following intermediates were prepared using the same method described for Intermediate 15.
Scheme 8: Synthesis of intermediate 18 (6-(4,4-difluorocyclohexyl)-5- fluoropyridin-3-amine) Step 1: 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridin-3-amine 6-bromo-5-fluoropyridin-3-amine (500.0 mg, 2.6 mmol, 1.00 equiv.) was dissolved 1,4-dioxane (10 mL) and water (1 mL), then K2CO3 (1.1 g, 7.9 mmol, 3.0 equiv.), 2-(4,4- difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (766.8 mg, 3.1 mmol, 1.2 equiv.) and Pd(dppf)Cl2 (383.1 mg, 0.5 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 90 °C for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridin-3-amine (420 mg) as an off-white solid. LCMS Method C: [M+H]+ = 229. Step 2: 6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-amine 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridin-3-amine (400.0 mg, 1.8 mmol, 1.0 equiv.) was dissolved MeOH (20 mL), then Pd/C (93.3 mg, 0.9 mmol, 0.5 equiv.) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 2 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum to give 6-(4,4- difluorocyclohexyl)-5-fluoropyridin-3-amine (300 mg) as an off-white solid. LCMS Method C: [M+H]+ = 231. Scheme 9: Synthesis of intermediate 19 (6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-amine) Step 1: 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-nitropyridine 2-Chloro-3-fluoro-5-nitropyridine (10.0 g, 56.6 mmol, 1.0 equiv.) was dissolved in DMF (150 mL), then Cs2CO3 (37.3 g, 114.5 mmol, 2.0 equiv.) and 4,4-difluoropiperidine (9.8 g, 81.0 mmol, 1.4 equiv.) were added. The reaction mixture was heated to 90 °C for 15 hours, then cooled to ambient temperature and quenched by the addition of water. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5- nitropyridine (13.3 g) as a yellow solid. LCMS Method D: [M+H]+ = 262. Step 2: 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-amine 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-nitropyridine (13.2 g, 50.5 mmol, 1.0 equiv.) was dissolved in MeOH (100 mL), then Pd/C (2.0 g, 18.8 mmol, 0.4 equiv.) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 15 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 dichloromethane/methanol (97:3) to give 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-amine (11.4 g) as a yellow solid. LCMS Method D: [M+H]+ = 232.
Scheme 10: Synthesis of intermediate 20 (5-(bromomethyl)-2-(4,4- difluorocyclohexyl)-3-fluoropyridine) Step 1: methyl 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridine-3-carboxylate Methyl 6-bromo-5-fluoropyridine-3-carboxylate (2.0 g, 8.5 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (2 mL) and water (2 mL), then Cs2CO3 (5.6 g, 17.1 mmol, 2.0 equiv.), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 g, 8.5 mmol, 1.0 equiv.) and Pd(dppf)Cl2CH2Cl2 (1.4 g, 1.7 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated overnight at 90 °C, 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 methyl 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridine-3-carboxylate (2.2 g) as a yellow solid. LCMS Method A: [M+H]+ = 272. Step 2: methyl 6-(4,4-difluorocyclohexyl)-5-fluoropyridine-3-carboxylate Methyl 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridine-3-carboxylate (2.0 g, 7.4 mmol, 1.0 equiv.) was dissolved in DCM (80 mL), then PtO2 (837.2 mg, 3.7 mmol, 0.5 equiv.) was added. 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 to give methyl 6- (4,4-difluorocyclohexyl)-5-fluoropyridine-3-carboxylate (2 g) as an off-white oil. LCMS Method I: [M+H]+ = 274. Step 3: [6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methanol Methyl 6-(4,4-difluorocyclohexyl)-5-fluoropyridine-3-carboxylate (2.0 g, 7.3 mmol, 1.0 equiv.) was dissolved in THF (20 mL) and cooled to 0 °C, then LiAlH4 (0.6 g, 14.6 mmol, 2.0 equiv.) was added in portions. The resulting solution was stirred for 30 min at 0 °C and then quenched by the addition of Na2SO4•10H2O. After remove the solid by filtration, the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (10:1) to give [6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methanol (1.1 g) as a white solid. LCMS Method B: [M+H]+ = 246. Step 4: 5-(bromomethyl)-2-(4,4-difluorocyclohexyl)-3-fluoropyridine [6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methanol (1.0 g, 4.1 mmol, 1.0 equiv.) was dissolved in DCM (10 mL) and cooled to 0 °C, then PBr3 (0.4 mL, 4.1 mmol, 1.0 equiv.) was added, maintaining the mixture at 0 °C. The reaction mixture was stirred for 1 hour at 0 °C and then quenched by the addition of saturated aqueous NaHCO3. The resulting solution was extracted with ethyl acetate and concentrated under vacuum to give 5-(bromomethyl)-2-(4,4-difluorocyclohexyl)-3-fluoropyridine (800 mg) as a white solid. LCMS Method A: [M+H]+ =308. Scheme 1B: Synthesis of intermediate 1B (5,6-difluoro-1H-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 AgNO3 (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 NaHCO3, 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/petroleum 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 N-(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 (Boc)2O (39.7 g, 181.7 mmol, 1.5 equiv.) were added under nitrogen. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred overnight at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give tert-butyl N-(5,6-difluoro-1H-indol-3-yl)carbamate (22.0 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 HCl/1,4-dioxane (4N, 200 mL). The resulting mixture was stirred for 30 min at ambient temperature and then concentrated under vacuum to give 5,6-difluoro-1H- indol-3-amine hydrochloride (12.0 g) as a yellow solid. LCMS Method C: [M+H]+ = 169. The following intermediates were prepared using the same method described for Intermediate 1B.
Scheme 2B: Synthesis of intermediate 6B (6-(4,4-difluorocyclohexyl)-5- fluoropyridin-3-amine) Step 1: 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridin-3-amine 6-bromo-5-fluoropyridin-3-amine (500.0 mg, 2.6 mmol, 1.00 equiv.) was dissolved 1,4-dioxane (10 mL) and water (1 mL), then K2CO3 (1.1 g, 7.9 mmol, 3.0 equiv.), 2-(4,4- difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (766.8 mg, 3.1 mmol, 1.2 equiv.) and Pd(dppf)Cl2 (383.1 mg, 0.5 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 90 °C for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridin-3-amine (420 mg) as an off-white solid. LCMS Method C: [M+H]+ = 229. Step 2: 6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-amine 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridin-3-amine (400.0 mg, 1.8 mmol, 1.0 equiv.) was dissolved MeOH (20 mL), then Pd/C (10% wt., 93.3 mg) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 2 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum to give 6-(4,4-difluorocyclohexyl)-5- fluoropyridin-3-amine (300 mg) as an off-white solid. LCMS Method C: [M+H]+ = 231. The following intermediates were prepared using the same method described for Intermediate 6B.
Scheme 3B: Synthesis of intermediate 12B (6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-amine) Step 1: 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-nitropyridine 2-Chloro-3-fluoro-5-nitropyridine (10.0 g, 56.6 mmol, 1.0 equiv.) was dissolved in DMF (150 mL), then Cs2CO3 (37.3 g, 114.5 mmol, 2.0 equiv.) and 4,4-difluoropiperidine (9.8 g, 81.0 mmol, 1.4 equiv.) were added. The reaction mixture was heated to 90 °C for 15 hours, then cooled to ambient temperature and quenched by the addition of water. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5- nitropyridine (13.3 g) as a yellow solid. LCMS Method D: [M+H]+ = 262. Step 2: 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-amine 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-nitropyridine (13.2 g, 50.5 mmol, 1.0 equiv.) was dissolved in MeOH (100 mL), then Pd/C (10% wt., 2.0 g) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 15 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 dichloromethane/methanol (97:3) to give 6-(4,4- difluoropiperidin-1-yl)-5-fluoropyridin-3-amine (11.4 g) as a yellow solid. LCMS Method D: [M+H]+ = 232. The following intermediates were prepared using the same method described for Intermediate 12B.
Scheme 4B: Synthesis of intermediate 21B (5-chloro-6-(4,4-difluoropiperidin-1- yl)pyridin-3-amine) Step 1: 3-chloro-2-(4,4-difluoropiperidin-1-yl)-5-nitropyridine 2-Bromo-3-chloro-5-nitropyridine (10.0 g, 42.1 mmol, 1.0 equiv.) and 4,4- difluoropiperidine (5.6 g, 46.3 mmol, 1.1 equiv.) were dissolved in DMF (100 mL), then Cs2CO3 (27.4 g, 84.2 mmol, 2.0 equiv.) was added. 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, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give 3-chloro-2-(4,4- difluoropiperidin-1-yl)-5-nitropyridine (9.5 g) as a brown solid. LCMS Method A: [M+H]+ = 278. Step 2: 5-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-amine 3-Chloro-2-(4,4-difluoropiperidin-1-yl)-5-nitropyridine (9.0 g, 32.4 mmol, 1.0 equiv.) was dissolved in EtOH (90 mL), then SnCl2 (30.7 g, 162.1 mmol, 5.0 equiv.) was added in portions. The reaction mixture was heated to 60 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resolution was adjusted to pH 12 with solid NaOH, extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give 5-chloro-6-(4,4- difluoropiperidin-1-yl)pyridin-3-amine (7.1 g) as a black solid. LCMS Method E: [M+H]+ = 248. The following intermediates were prepared using the same method described for Intermediate 21B. Scheme 5B: Synthesis of intermediate 23B (2-(4-(2,2,2-trifluoroethyl)piperazin- 1-yl)pyridin-4-amine) Step 1: 1-(4-nitropyridin-2-yl)-4-(2,2,2-trifluoroethyl)piperazine 2-Chloro-4-nitropyridine (2.0 g, 12.6 mmol, 1.0 equiv.) and 1-(2,2,2- trifluoroethyl)piperazine (2.5 g, 15.1 mmol, 1.2 equiv.) were dissolved in 1,4-dioxane (20 mL), then Cs2CO3 (12.3 g, 37.8 mmol, 3.0 equiv.) and XPhos Pd G3 (1.1 g, 1.3 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 80 °C for 12 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 Na2SO4 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 1-(4-nitropyridin-2-yl)-4-(2,2,2-trifluoroethyl)piperazine (1.2 g) as a yellow solid. LCMS Method A: [M+H]+ = 291. Step 2: 2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-4-amine 1-(4-nitropyridin-2-yl)-4-(2,2,2-trifluoroethyl)piperazine (1.0 g, 3.4 mmol, 1.0 equiv.) was dissolved in MeOH (15 mL), then Pd/C (10% wt., 36.7 mg) was added under an atmosphere of 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 to give crude 2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-4-amine (560.0 mg) as a brown solid, which was used to next step directly without further purification. LCMS Method E: [M+H]+ = 261. The following intermediates were prepared using the same method described for Intermediate 23B.
Step 1: 4,4-difluoro-1-methylcyclohexan-1-ol 4,4-difluorocyclohexan-1-one (10.0 g, 74.6 mmol, 1.0 equiv.) was dissolved in Et2O (100.0 mL) and cooled to 0 °C, then MeMgBr (3 M in THF, 80.0 mL, 240 mmol, 3.0 equiv.) was added dropwise, maintaining the solution at 0 °C. The reaction mixture was stirred for 2 hours at 0 °C and then quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give 4,4-difluoro-1-methylcyclohexan-1-ol (9.5 g) as a yellow solid. LCMS Method A: [M+H]+ = 151. Step 2: 4,4-difluoro-1-methylcyclohexyl methyl oxalate 4,4-Difluoro-1-methylcyclohexan-1-ol (10.0 g, 66.6 mmol, 1.0 equiv.) and DMAP (0.8 g, 6.7 mmol, 0.1 equiv.) were dissolved in DCM (200 mL), then TEA (18.7 mL, 133.2 mmol, 2.0 equiv.) was added. This was followed by the addition of methyl oxalochloridate (6.1 mL, 67.3 mmol, 1.0 equiv.) dropwise. The reaction mixture was stirred for 1 hour 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 (1:20) to give 4,4-difluoro-1-methylcyclohexyl methyl oxalate (11.2 g) as a yellow oil. LCMS Method A: [M+H]+ = 237. Step 3: cesium 2-((4,4-difluoro-1-methylcyclohexyl)oxy)-2-oxoacetate 4,4-Difluoro-1-methylcyclohexyl methyl oxalate (5.0 g, 21.2 mmol, 1.0 equiv.) was dissolved in THF (50 mL) and water (50 mL), then CsOH (3.2 g, 20.9 mmol, 1.0 equiv.) was added. The reaction mixture was stirred for 1 hour at ambient temperature and then concentrated under vacuum to give cesium 2-((4,4-difluoro-1-methylcyclohexyl)oxy)-2- oxoacetate (5.2 g) as a white solid. LCMS Method A: [M+H]+ = 272. Step 4: methyl 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylate Cesium 2-((4,4-difluoro-1-methylcyclohexyl)oxy)-2-oxoacetate (5.0 g, 14.1 mmol, 1.0 equiv.) was dissolved in DMSO (30 mL), then (NH4)2S2O8 (2.3 g, 9.9 mmol, 0.7 equiv.), Ir[dF(CF3)ppy]2(dtbpy)PF6 (1.6 g, 1.4 mmol, 0.1 equiv.) and methyl 5- fluoropyridine-3-carboxylate (1.8 g, 11.3 mmol, 0.8 equiv.) were added. The resulting solution was shone with the Royal Blue (450 nm) LED light for 3 hours, with stirring at 1000 rpm, and then 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 methyl 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylate (2.5 g) as a yellow oil. LCMS Method A: [M+H]+ = 272. Step 5: 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylic acid Methyl 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylate (2.5 g, 8.7 mmol, 1.0 equiv.) was dissolved in MeOH (25 mL) and water (25 mL), then NaOH (1.0 g, 26.0 mmol, 3.0 equiv.) was added. The reaction mixture was heated to 80 °C for 1 hour, 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, ACN/H2O=0% increasing to ACN/H2O=100% within 30 min; Detector, 254 nm. This resulted in 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylic acid (2.1 g) as a yellow oil. LCMS Method C: [M+H]+ = 274 Step 6: 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carbonyl azide 6-(4,4-Difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylic acid (1.0 g, 3.7 mmol, 1.0 equiv.) was dissolved in THF (20 mL), then TEA (1.0 mL, 7.3 mmol, 2.0 equiv.) and DPPA (1.5 g, 5.5 mmol, 1.5 equiv.) were added. 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 (1:50) to give 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carbonyl azide (900.0 mg) as a white oil. LCMS Method E: [M+H]+ = 299. Step 7: tert-butyl N-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3- yl]carbamate 6-(4,4-Difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carbonyl azide (1.0 g, 3.4 mmol, 1.0 equiv.) was dissolved in t-BuOH (20 mL). The reaction mixture was heated to 80 °C for 2 hours, then cooled to ambient temperature and concentrated under vacuum. This resulted in tert-butyl N-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3- yl]carbamate (850.0 mg) as a white solid. LCMS Method A: [M+H]+ = 345. Step 8: 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-amine tert-Butyl N-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]carbamate (900.0 mg, 2.6 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4N, 20 mL). The resulting mixture was stirred overnight at ambient temperature. The solids were collected by filtration and dried to give 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3- amine (350.0 mg) as a yellow oil. LCMS Method E: [M+H]+ = 245. The following intermediates were prepared using the same method described for Intermediate 25B. Scheme 7B: Synthesis of intermediate 27B (2-chloro-6-(4,4-difluoropiperidin-1- yl)pyridin-4-amine) 2,6-Dichloropyridin-4-amine (1.0 g, 6.1 mmol, 1.0 equiv.) was dissolved 4,4- difluoropiperidine (5.0 mL). The reaction mixture was heated to 150 °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 sodium sulfate and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC with the following conditions: Column, C18 silica gel; mobile phase, H2O/MeCN=90:10 increasing to H2O/MeCN=10:90 within 30 min; Detector, 254 nm. This resulted in 2- chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-4-amine (260.0 mg) as a yellow solid. LCMS Method E: [M+H]+ = 248. Scheme 8B: Synthesis of intermediate 28B (5-fluoro-6-(1-(2,2,2- trifluoroethyl)piperidin-3-yl)pyridin-3-amine)
Step 1: tert-butyl 3-fluoro-5-nitro-5,6-dihydro-2H-[2,3-bipyridine]-1-carboxylate 2-Chloro-3-fluoro-5-nitropyridine (2.0 g, 11.3 mmol, 1.0 equiv.) and tert-butyl 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (5.3 g, 17.0 mmol, 1.5 equiv.) were dissolved in 1,4-dioxane (30 mL) and water (3 mL), then Cs2CO3 (11.1 g, 34.0 mmol, 3.0 equiv.) and Xphos Pd G3 (959.0 mg, 1.1 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. 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 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 3-fluoro-5-nitro-5,6-dihydro-2H-[2,3-bipyridine]-1-carboxylate (412.1 mg) as a yellow solid. LCMS Method C: [M+H]+ = 324. Step 2: 3-fluoro-5-nitro-1,2,5,6-tetrahydro-2,3-bipyridine hydrochloride tert-Butyl 3-fluoro-5-nitro-5,6-dihydro-2H-[2,3-bipyridine]-1-carboxylate (600.0, 1.9 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4N, 15 mL). The reaction mixture was stirred overnight at ambient temperature then concentrated under vacuum to give 3-fluoro-5-nitro-1,2,5,6-tetrahydro-2,3-bipyridine hydrochloride (315.2 mg) as a light yellow solid. LCMS Method A: [M+H]+ = 224. Step 3: 3-fluoro-5-nitro-1-(2,2,2-trifluoroethyl)-5,6-dihydro-2H-2,3-bipyridine 3-Fluoro-5-nitro-1,2,5,6-tetrahydro-2,3-bipyridine hydrochloride (467.5 mg, 1.8 mmol, 1.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (499.1 mg, 2.2 mmol, 1.2 equiv.) were dissolved in ACN (10 mL), then K2CO3 (495.3 mg, 3.6 mmol, 2.0 equiv.) was 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, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC with the following conditions: Column, C18 silica gel; mobile phase, H2O/MeCN=90:10 increasing to H2O/MeCN=10:90 within 30 min; Detector, 254nm. This resulted in 3-fluoro-5-nitro-1-(2,2,2-trifluoroethyl)-5,6-dihydro- 2H-2,3-bipyridine (250.0 mg) as a yellow solid. LCMS Method A: [M+H]+ = 306. Step 4: 5-fluoro-6-[1-(2,2,2-trifluoroethyl)piperidin-3-yl]pyridin-3-amine 3-Fluoro-5-nitro-1-(2,2,2-trifluoroethyl)-5,6-dihydro-2H-2,3-bipyridine (250.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in MeOH (6 mL), then Pd/C (10% w%, 25.3 mg) was 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 (1:1) to give 5-fluoro-6-[1-(2,2,2-trifluoroethyl)piperidin- 3-yl]pyridin-3-amine (198.2 mg) as a yellow oil. LCMS Method E: [M+H]+ = 278. Scheme 9B: Synthesis of intermediate 29B (5-fluoro-6-(4-(2- methoxyethyl)piperazin-1-yl)pyridin-3-amine) Step 1: tert-butyl 4-(3-fluoro-5-nitropyridin-2-yl)piperazine-1-carboxylate 2-Chloro-3-fluoro-5-nitropyridine (2.0 g, 11.3 mmol, 1.0 equiv.) was dissolved in ACN (20 mL), then tert-butyl piperazine-1-carboxylate (2.0 g, 11.3 mmol, 1.5 equiv.) and K2CO3 (6.3 g, 45.3 mmol, 4.0 equiv.) were added. 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, 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 (1:1) to give tert- butyl 4-(3-fluoro-5-nitropyridin-2-yl)piperazine-1-carboxylate (2.1 g) as a yellow solid. LCMS Method A: [M+H]+ = 327. Step 2: 1-(3-fluoro-5-nitropyridin-2-yl)piperazine tert-Butyl 4-(3-fluoro-5-nitropyridin-2-yl)piperazine-1-carboxylate (2.1 g, 6.4 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4N, 40 mL). The reaction mixture was stirred overnight at ambient temperature and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC with the following conditions: Column, C18 silica gel; mobile phase, H2O/MeCN=90:10 increasing to H2O/MeCN=10:90 within 30 min; Detector, 254nm. This resulted in 1-(3-fluoro-5-nitropyridin-2-yl)piperazine (1.1 g) as a yellow oil. LCMS Method A: [M+H]+ = 227. Step 3: 1-(3-fluoro-5-nitropyridin-2-yl)-4-(2-methoxyethyl)piperazine 1-(3-Fluoro-5-nitropyridin-2-yl)piperazine (1.0 g, 4.4 mmol, 1.0 equiv) and 2- bromoethyl methyl ether (0.9 g, 6.6 mmol, 1.5 equiv.) were dissolved in ACN (20 mL), then K2CO3 (1.2 g, 8.8 mmol, 2.0 equiv.) was added. 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, 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 (1:1) to give 1-(3- fluoro-5-nitropyridin-2-yl)-4-(2-methoxyethyl)piperazine (1.0 g) as a yellow solid. LCMS Method A: [M+H]+ = 285. Step 4: 5-fluoro-6-[4-(2-methoxyethyl)piperazin-1-yl]pyridin-3-amine 1-(3-Fluoro-5-nitropyridin-2-yl)-4-(2-methoxyethyl)piperazine (1.1 g, 3.9 mmol, 1.0 equiv.) was dissolved in MeOH (20 mL), then Pd/C (10% wt., 110.1 mg) was 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-Prep-HPLC with the following conditions: Column, C18 silica gel; mobile phase, H2O/MeCN=90:10 increasing to H2O/MeCN=10:90 within 30 min; Detector, 254nm. This resulted in 5-fluoro-6-[4-(2-methoxyethyl)piperazin-1- yl]pyridin-3-amine (805.2 mg) as a yellow solid. LCMS Method D: [M+H]+ = 255. Scheme 10B: Synthesis of intermediate 30B (6-(3,3-difluorocyclobutyl)-5- fluoropyridin-3-amine) Step 1: methyl 6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3-carboxylate Methyl 5-fluoropyridine-3-carboxylate (6.0 g, 38.7 mmol, 1.0 equiv.) was dissolved in DCE (60 mL) and water (60 mL), then AgNO3 (1.3 g, 7.7 mmol, 0.2 equiv.), Selectfluor (27.4 g, 77.4 mmol, 2.0 equiv.), TFA (4.4 g, 38.7 mmol, 1.0 equiv.) and 3,3- difluorocyclobutane-1-carboxylic acid (10.5 g, 77.4 mmol, 2.0 equiv.) were added. The reaction mixture was heated to 50 °C for 24 hours, then cooled to ambient temperate. The solids were removed by filtration and the filtrated 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 methyl 6-(3,3-difluorocyclobutyl)-5-fluoropyridine- 3-carboxylate (1.4 g) as a white solid. LCMS Method A: [M+H]+ = 246. Step 2: 6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3-carboxylic acid Methyl 6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3-carboxylate (2.0 g, 8.2 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL) and water (10 mL), then LiOH (390.7 mg, 16.3 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 5 with aqueous HCl (2 M), extracted with ethyl acetate and concentrated under vacuum to give 6-(3,3-difluorocyclobutyl)-5- fluoropyridine-3-carboxylic acid (1.5 g) as a white solid. LCMS Method D: [M+H]+ = 232. Step 3: 6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3-carbonyl azide 6-(3,3-Difluorocyclobutyl)-5-fluoropyridine-3-carboxylic acid (2.0 g, 8.7 mmol, 1.0 equiv.) and TEA (2.4 mL, 17.3 mmol, 2.0 equiv.) were dissolved in THF (100 mL), then DPPA (3.6 g, 13.0 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 16 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 6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3-carbonyl azide (1.5 g) as a white solid. LCMS Method A: [M+H]+ = 257. Step 4: tert-butyl N-[6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-yl]carbamate 6-(3,3-Difluorocyclobutyl)-5-fluoropyridine-3-carbonyl azide (1.5 g, 5.9 mmol, 1.0 equiv.) was dissolved in t-BuOH (50 mL). The resulting solution was heated to 80 °C for 16 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 (1:1) to give tert-butyl N-[6-(3,3-difluorocyclobutyl)-5- fluoropyridin-3-yl]carbamate (1.5 g) as a white solid. LCMS Method G: [M+H]+ = 303. Step 5: 6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-amine tert-Butyl N-[6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-yl]carbamate (1.5 g, 5.0 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4N, 40 mL). The reaction mixture was stirred 16 hours at ambient temperature and concentrated under vacuum to give 6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-amine hydrogen chloride (1.0 g) as a white solid. LCMS Method C: [M+H]+ = 203. Scheme 11B: Synthesis of intermediate 31B (5-fluoro-6-(6-azaspiro[2.5]octan-6- yl)nicotinic acid) Step 1: methyl 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate Methyl 6-bromo-5-fluoropyridine-3-carboxylate (5.0 g, 21.4 mmol, 1.0 equiv.) was dissolved in DMF (50 mL), then K2CO3 (8.9 g, 64.1 mmol, 3.0 equiv.) and 6- azaspiro[2.5]octane (2.9 g, 25.6 mmol, 1.2 equiv.) were added. 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, dried over anhydrous Na2SO4 and concentrated under vacuum to give methyl 6-[6-azaspiro[2.5]octan- 6-yl]-5-fluoropyridine-3-carboxylate (5.5 g) as a light yellow solid. LCMS Method A: [M+H]+ = 265. Step 2: 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylic acid Methyl 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate (5.5 g, 20.8 mmol, 1.0 equiv.) was dissolved in MeOH (50 mL) and water (50 mL), then LiOH (12.0 g, 83.2 mmol, 4.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature and then concentrated under vacuum. The residue was diluted with water and adjusted to pH 5 with concentrated HCl. The precipitated solid was collected by filtration and washed with water to afford 6-[6-azaspiro[2.5]octan-6-yl]-5- fluoropyridine-3-carboxylic acid (5.0 g) as a pale yellow solid. LCMS Method E: [M+H]+ = 251. The following intermediates were prepared using the same method described for Intermediate 31B. Scheme 12B: Synthesis of intermediate 38B (5-chloro-6-(1-(2,2,2- trifluoroethyl)piperidin-4-yl)nicotinic acid) Step 1: methyl 3-chloro-1'-(2,2,2-trifluoroethyl)-3',6'-dihydro-2'H-[2,4'-bipyridine]- 5-carboxylate Methyl 6-bromo-5-chloropyridine-3-carboxylate (1.0 g, 4.0 mmol, 1.0 equiv.) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-3,6-dihydro-2H- pyridine (2.3 g, 7.9 mmol, 2.0 equiv.) were dissolved in 1,4-dioxane (10 mL) and water (1 mL), then Cs2CO3 (2.6 g, 8.0 mmol, 2.0 equiv.) and Pd(dppf)Cl2 (292.1 mg, 0.4 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The resulting solution was heated to 90 °C for 16 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 (1:1) to give methyl 3-chloro-1'-(2,2,2-trifluoroethyl)-3',6'- dihydro-2'H-[2,4'-bipyridine]-5-carboxylate (1.0 g) as a white solid. LCMS Method A: [M+H]+ = 335. Step 2: methyl 5-chloro-6-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]pyridine-3- carboxylate Methyl 3-chloro-1 (1.0 g, 3.0 mmol, 1.0 equiv.) was dissolved in DCM (20 mL), then PtO2 (67.8 mg, 0.3 mmol, 0.1 equiv.) 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 methyl 5-chloro-6-[1-(2,2,2-trifluoroethyl)piperidin- 4-yl]pyridine-3-carboxylate (812.2 mg) as a white solid. LCMS Method E: [M+H]+ = 337. Step 3: 5-chloro-6-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]pyridine-3-carboxylic acid Methyl 5-chloro-6-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]pyridine-3-carboxylate (800.0 mg, 2.4 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (190.0 mg, 4.8 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 5 with aqueous HCl (4 M). The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give 5-chloro-6-[1-(2,2,2- trifluoroethyl)piperidin-4-yl]pyridine-3-carboxylic acid (585.5 mg) as a white solid. LCMS Method C: [M+H]+ = 323. The following intermediates were prepared using the same method described for Intermediate 38B. Scheme 13B: Synthesis of intermediate 40B (1-(6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl)-1H-pyrazole-4-carboxylic acid) Step 1: 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-iodopyridine 6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridin-3-amine (3.0 g, 13.0 mmol, 1.0 equiv.) was dissolved in aqueous HCl (6 M, 50 mL) and cooled to 0 °C, then a solution of NaNO2 (1.3 g, 19.5 mmol, 1.5 equiv.) in water (2 mL) was added dropwise, maintaining the reaction mixture at 0 °C. After 30 min at 0 °C, KI (4.3 g, 26.0 mmol, 2.0 equiv.) was added in portions, maintaining the temperature at 0 °C. After addition was complete, the solution was stirred for an additional 2 hours at 0 °C. After quenching with 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 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5- iodopyridine (2.0 g) as a yellow solid. LCMS Method A: [M+H]+ = 343. Step 2: ethyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-4- carboxylate 2-(4,4-Difluoropiperidin-1-yl)-3-fluoro-5-iodopyridine (2.0 g, 5.8 mmol, 1.0 equiv.) was dissolved in DMF (20 mL), then Cs2CO3 (5.7 g, 17.5 mmol, 3.0 equiv.), ethyl 1H- pyrazole-4-carboxylate (1.0 g, 7.0 mmol, 1.2 equiv.), N1,N2-dimethylcyclohexane-1,2- diamine (0.5 mL, 2.9 mmol, 0.5 equiv.) and CuI (220.9 mg, 0.3 mmol, 0.2 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 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 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-4- carboxylate (1.0 g) as a yellow solid. LCMS Method A: [M+H]+ = 355. Step 3: 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-4-carboxylic acid Ethyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-4-carboxylate (1.0 g, 2.8 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (225.8 mg, 5.6 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 60 °C for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, adjusted to pH 6 with aqueous HCl (1 M). The precipitated solid was collected by filtration, washed with water and dried to give 1-[6-(4,4- difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-4-carboxylic acid (510.0 mg) as a white solid. LCMS Method E: [M+H]+ = 327. The following intermediates were prepared using the same method described for Intermediate 40B.
Scheme 14B: Synthesis of intermediate 43B (1-(6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl)-1H-1,2,3-triazole-4-carboxylic acid) Step 1: 5-azido-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine 6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridin-3-amine (400.0 mg, 1.7 mmol, 1.0 equiv.) was dissolved in ACN (10 mL) and cooled to 0 °C, then t-BuNO2 (0.3 mL, 2.7 mmol, 1.6 equiv.) was added dropwise, maintaining the solution at 0 °C. The reaction mixture was stirred for 30 min at 0 °C. This was followed by the addition of TMSN3 (0.3 mL, 2.5 mmol, 1.5 equiv.) dropwise at 0 °C. The resulting mixture was stirred for additional 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 Na2SO4 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 5-azido-2-(4,4- difluoropiperidin-1-yl)-3-fluoropyridine (380.0 mg) as a yellow oil. LCMS Method A: [M+H]+ =258. Step 2: methyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,3-triazole- 4-carboxylate 5-Azido-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (350.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (3.6 mL) and water (0.4 mL), then methyl propiolate (228.8 mg, 2.7 mmol, 2.0 equiv.), sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5- oxo-2,5-dihydrofuran-3-olate (53.9 mg, 0.3 mmol, 0.2 equiv.) and CuSO4 (21.7 mg, 0.1 mmol, 0.1 equiv.) were added. The reaction 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 Na2SO4 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 methyl 1-[6-(4,4- difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylate (150.0 mg) as a yellow solid. LCMS Method G: [M+H]+ = 341. Step 3: 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4- carboxylic acid Methyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4- carboxylate (300.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in MeOH (3 mL) and water (7 mL), then NaOH (70.3 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, adjusted to pH 6 with 1M aqueous HCl. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to afford 1-[6-(4,4-difluoropiperidin- 1-yl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylic acid (200.1 mg) as a yellow solid. LCMS Method E: [M+H]+ = 328. The following intermediates were prepared using the same method described for Intermediate 43B.
fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid) Step 1: 1-[(4-bromo-2-fluorophenyl)methyl]-3,3-difluoroazetidine 4-Bromo-1-(bromomethyl)-2-fluorobenzene (1.0 g, 3.7 mmol, 1.0 equiv.) was dissolved in ACN (20 mL), then K2CO3 (1.6 g, 11.2 mmol, 3.0 equiv.) and 3,3- difluoroazetidine (347.4 mg, 3.7 mmol, 1.0 equiv.) were added. The reaction mixture was stirred overnight at ambient temperature, and then concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to afford 1-[(4-bromo-2- fluorophenyl)methyl]-3,3-difluoroazetidine (821.2 mg) as a yellow oil. LCMS Method A: [M+H]+ = 280. Step 2: 1-[(4-azido-2-fluorophenyl)methyl]-3,3-difluoroazetidine 1-[(4-Bromo-2-fluorophenyl)methyl]-3,3-difluoroazetidine (800.0 mg, 2.9 mmol, 1.0 equiv.) was dissolved in DMF (10 mL), then methyl[2-(methylamino)ethyl]amine (0.6 mL, 5.7 mmol, 2.0 equiv.), sodium ascorbate (56.9 mg, 0.3 mmol, 0.1 equiv.), CuI (54.4 mg, 0.3 mmol, 0.1 equiv.) and NaN3 (371.4 mg, 5.7 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 80 °C overnight, and then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with brine, dried over anhydrous Na2SO4 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 1-[(4-azido-2-fluorophenyl)methyl]-3,3- difluoroazetidine (412.3 mg) as a yellow oil. LCMS Method E: [M+H]+ = 243. Step 3: methyl 1-[4-[(3,3-difluoroazetidin-1-yl)methyl]-3-fluorophenyl]-1,2,3- triazole-4-carboxylate 1-[(4-Azido-2-fluorophenyl)methyl]-3,3-difluoroazetidine (500.0 mg, 2.1 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (7 mL) and water (3 mL), then methyl propiolate (260.3 mg, 3.1 mmol, 1.5 equiv.), sodium ascorbate (41.1 mg, 0.2 mmol, 0.1 equiv.), and CuSO4 (33.0 mg, 0.2 mmol, 0.1 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 Na2SO4 and concentrated under vacuum to give methyl 1-[4-[(3,3-difluoroazetidin-1-yl)methyl]-3- fluorophenyl]-1,2,3-triazole-4-carboxylate (322.2 mg) as a yellow solid. LCMS Method A: [M+H]+ = 327. Step 4: 1-[4-[(3,3-difluoroazetidin-1-yl)methyl]-3-fluorophenyl]-1,2,3-triazole-4- carboxylic acid Methyl 1-[4-[(3,3-difluoroazetidin-1-yl)methyl]-3-fluorophenyl]-1,2,3-triazole-4- carboxylate (500.0 mg, 1.5 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (10 mL), then NaOH (122.6 mg, 3.1 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 6 with 1M aqueous HCl. The resulting solution was extracted with ethyl acetate, washed with brine and concentrated under vacuum to afford 1-[4-[(3,3-difluoroazetidin-1-yl)methyl]-3-fluorophenyl]-1,2,3- triazole-4-carboxylic acid (285.2 mg) as a yellow solid. LCMS Method E: [M+H]+ = 313. Scheme 16B: Synthesis of intermediate 52B (1-(6-(4,4-difluoro-1- methylcyclohexyl)-5-fluoropyridin-3-yl)-1H-1,2,3-triazole-4-carboxylic acid) Step 1: ethyl 1-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2,3- triazole-4-carboxylate 6-(4,4-Difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-amine (300.0 mg, 1.2 mmol, 1.0 equiv.) was dissolved in EtOH (3 mL) and AcOH (3 mL), then ethyl 2-diazo-3- oxopropanoate (261.8 mg, 1.8 mmol, 1.5 equiv.) was added. The reaction mixture was heated to 50 °C overnight, then cooled to ambient temperature and concentrated under vacuum. This resulted in ethyl 1-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3- yl]-1,2,3-triazole-4-carboxylate (400.0 mg) as a yellow solid. LCMS Method A: [M+H]+ = 369. Step 2: 1-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2,3-triazole- 4-carboxylic acid Ethyl 1-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4- carboxylate (400.0 mg, 1.1 mmol, 1.0 equiv.) was dissolved in MeOH (4 mL) and water (4 mL), then NaOH (86.9 mg, 2.2 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 purified by Flash-Prep-HPLC with the following conditions: Column, C18 silica gel; mobile phase, ACN/H2O=0% increasing to ACN/H2O=100% within 15 min; Detector, 254 nm. This resulted in 1-[6-(4,4-difluoro-1-methylcyclohexyl)- 5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylic acid (295.2 mg) as a yellow solid. LCMS Method E: [M+H]+ = 341. The following intermediates were prepared using the same method described for Intermediate 52B. Scheme 17B: Synthesis of intermediate 56B (1-(5-fluoro-6-(1-(2,2,2- trifluoroethyl)pyrrolidin-3-yl)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxylic acid)
Step 1: ethyl 1-(6-bromo-5-fluoropyridin-3-yl)-1,2,3-triazole-4-carboxylate 6-Bromo-5-fluoropyridin-3-amine (1.0 g, 5.2 mmol, 1.0 equiv) was dissolved in EtOH (30 mL) and HOAc (20 mL), then ethyl 2-diazo-3-oxopropanoate (1.1 g, 7.7 mmol, 1.5 equiv.) was added. The reaction mixture was heated to 50 °C for 16 hours, and then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water and the solid was collected by filtration and dried to give ethyl 1-(6-bromo-5- fluoropyridin-3-yl)-1,2,3-triazole-4-carboxylate (1.2 g) as a yellow solid. LCMS Method A: [M+H]+ = 315. Step 2: ethyl 1-[6-[1-(tert-butoxycarbonyl)-2,5-dihydropyrrol-3-yl]-5-fluoropyridin- 3-yl]-1,2,3-triazole-4-carboxylate Ethyl 1-(6-bromo-5-fluoropyridin-3-yl)-1,2,3-triazole-4-carboxylate (1.0 g, 3.2 mmol, 1.0 equiv.) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5- dihydropyrrole-1-carboxylate (1.1 g, 3.8 mmol, 1.2 equiv.) were dissolved in 1,4-dioxane (20 mL) and water (2 mL), then Pd(dppf)Cl2 (232.2 mg, 0.3 mmol, 0.1 equiv.) and Cs2CO3 (4.1 g, 12.7 mmol, 4.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 80 °C for 6 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 Na2SO4 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 1-[6-[1-(tert-butoxycarbonyl)-2,5- dihydropyrrol-3-yl]-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylate (612.2 mg) as an off-white solid. LCMS Method E: [M+H]+ = 404. Step 3: ethyl 1-[6-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-5-fluoropyridin-3-yl]- 1,2,3-triazole-4-carboxylate Ethyl 1-[6-[1-(tert-butoxycarbonyl)-2,5-dihydropyrrol-3-yl]-5-fluoropyridin-3-yl]- 1,2,3-triazole-4-carboxylate (900.0 mg, 2.2 mmol, 1.0 equiv.) was dissolved in MeOH (15 mL), then Pd/C (10% wt., 90.0 mg) was added under an atmosphere of 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 (1:1) to give ethyl 1-[6-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-5-fluoropyridin-3-yl]-1,2,3-triazole-4- carboxylate (605.2 mg) as an off-white solid. LCMS Method A: [M+H]+ = 406. Step 4: ethyl 1-[5-fluoro-6-(pyrrolidin-3-yl)pyridin-3-yl]-1,2,3-triazole-4- carboxylate Ethyl 1-[6-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-5-fluoropyridin-3-yl]-1,2,3- triazole-4-carboxylate (500.0 mg, 1.2 mmol, 1.0 equiv.) was dissolved in DCM (3 mL) and TFA (10 mL). The reaction mixture was stirred for 1 hour at ambient temperature, and then quenched by the addition of water. The solution was adjusted to pH 7 with saturated aqueous Na2CO3. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous MgSO4 and concentrated under vacuum to give ethyl 1-[5-fluoro-6-(pyrrolidin-3-yl)pyridin-3-yl]-1,2,3-triazole-4-carboxylate (351,2 mg) as an off-white solid. The crude product was used for next step directly without further purification. LCMS Method E: [M+H]+ = 306. Step 5: ethyl 1-[5-fluoro-6-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]pyridin-3-yl]- 1,2,3-triazole-4-carboxylate Ethyl 1-[5-fluoro-6-(pyrrolidin-3-yl)pyridin-3-yl]-1,2,3-triazole-4-carboxylate (300.0 mg, 1.0 mmol, 1.0 equiv.) and TEA (0.4 mL, 2.9 mmol, 3.0 equiv.) were dissolved in ACN (10 mL), then 2,2,2-trifluoroethyl trifluoromethanesulfonate (273.7 mg, 1.2 mmol, 1.2 equiv.) was added. The reaction mixture was stirred for 30 min at ambient temperature and then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 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 1-[5-fluoro-6-[1-(2,2,2- trifluoroethyl)pyrrolidin-3-yl]pyridin-3-yl]-1,2,3-triazole-4-carboxylate (252.5 mg) as an off-white solid. LCMS Method A: [M+H]+ = 388. Step 6: 1-[5-fluoro-6-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]pyridin-3-yl]-1,2,3- triazole-4-carboxylic acid Ethyl 1-[5-fluoro-6-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]pyridin-3-yl]-1,2,3- triazole-4-carboxylate (100.0 mg, 0.3 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (62.0 mg, 1.5 mmol, 6.0 equiv.) was added. The reaction mixture was stirred for 2 hours at ambient temperature and then concentrated under vacuum. The residue was diluted with water, adjusted to pH 5 with concentrated HCl, extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give crude 1-[5-fluoro-6-[1-(2,2,2-trifluoroethyl)pyrrolidin- 3-yl]pyridin-3-yl]-1,2,3-triazole-4-carboxylic acid (83.2 mg) as an off-white solid. LCMS Method E: [M+H]+ = 360. Scheme 18B: Synthesis of intermediate 57B (5-(6-(4,4-difluoro-1- methylcyclohexyl)-5-fluoropyridin-3-yl)isoxazole-3-carboxylic acid)
Step 1: 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoro-N-methoxy-N-methylpyridine- 3-carboxamide 6-(4,4-Difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylic acid (2.5 g, 9.1 mmol, 1.0 equiv.) was dissolved in DMF (50 mL), then N,O-dimethylhydroxylamine hydrochloride (1.3 g, 13.7 mmol, 1.5 equiv.), HATU (5.2 g, 13.7 mmol, 1.5 equiv.) and DIEA (6.4 mL, 36.6 mmol, 4.0 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 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 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoro-N-methoxy-N-methylpyridine- 3-carboxamide (1.7 g) as a yellow oil. LCMS Method A: [M+H]+ = 317. Step 2: 1-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]ethanone 6-(4,4-Difluoro-1-methylcyclohexyl)-5-fluoro-N-methoxy-N-methylpyridine-3- carboxamide (1.7 g, 5.4 mmol, 1.0 equiv.) was dissolved in THF (15 mL) and cooled to 0 °C, then MeMgBr (3M in THF, 3.2 mL, 9.6 mmol, 1.5 equiv.) was added dropwise, maintaining the solution at 0 °C. The reaction mixture was stirred for 1 hour at 0 °C and then quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give 1-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]ethanone (1.4 g) as a yellow oil. LCMS Method G: [M+H]+ = 272. Step 3: ethyl 4-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-2,4- dioxobutanoate 1-[6-(4,4-Difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]ethanone (1.4 g, 5.2 mmol, 1.0 equiv.) was dissolved in EtOH (14 mL), then sodium ethoxide (351.2 mg, 5.2 mmol, 1.0 equiv.) was added. This was followed by the addition of ethyl oxalate (1.0 mL, 7.7 mmol, 1.5 equiv.) dropwise. The reaction mixture was stirred for 2 hours at ambient temperature and then cooled to 0 °C and quenched by the addition of water. The resulting solution was adjusted to pH 5 with Aqueous HCl (4 M), extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give ethyl 4-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-2,4-dioxobutanoate (1.5 g) as a brown oil. LCMS Method A: [M+H]+ = 372. Step 4: ethyl 5-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2- oxazole-3-carboxylate Ethyl 4-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-2,4- dioxobutanoate (1.5 g, 4.0 mmol, 1.0 equiv.) was dissolved in EtOH (15 mL), then hydroxylamine hydrochloride (0.4 g, 6.0 mmol, 1.5 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 (1:5) to give ethyl 5-[6-(4,4-difluoro- 1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2-oxazole-3-carboxylate (1.2 g) as a brown oil. LCMS Method G: [M+H]+ = 369. Step 5: 5-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2-oxazole-3- carboxylic acid Ethyl 5-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2-oxazole-3- carboxylate (1.2 g, 3.3 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL) and water (10 mL), then NaOH (260.6 mg, 6.5 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 purified by Flash-Prep-HPLC with the following conditions: Column, C18 silica gel; mobile phase, ACN/H2O=0% increasing to ACN/H2O=100% within 25 min; Detector, 254 nm. This resulted in 5-[6-(4,4-difluoro-1-methylcyclohexyl)- 5-fluoropyridin-3-yl]-1,2-oxazole-3-carboxylic acid (1.0 g) as a brown solid. LCMS Method A: [M+H]+ = 341. The following intermediates were prepared using the same method described for Intermediate 57B.
Scheme 19B: Synthesis of intermediate 66B (3-(5-chloro-6-(4-(2,2,2- trifluoroethyl)piperazin-1-yl)pyridin-3-yl)isoxazole-5-carboxylic acid)
Step 1: 5-chloro-N-methoxy-N-methyl-6-[4-(2,2,2-trifluoroethyl)piperazin-1- yl]pyridine-3-carboxamide 5-Chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridine-3-carboxylic acid (1.8 g, 5.6 mmol, 1.0 equiv.) and N,O-dimethylhydroxylamine hydrochloride (813.6 mg, 8.3 mmol, 1.5 equiv.) were dissolved in DMF (18 mL), then HATU (4.2 g, 11.1 mmol, 2.0 equiv.) and DIEA (3.9 mL, 22.2 mmol, 4.0 equiv.) were added. The reaction 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 Na2SO4 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-chloro-N-methoxy-N-methyl-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridine-3- carboxamide (1.8 g) as a yellow solid. LCMS Method A: [M+H]+ = 367. Step 2: 5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridine-3-carbaldehyde 5-Chloro-N-methoxy-N-methyl-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridine-3- carboxamide (1.5 g, 4.1 mmol, 1.0 equiv.) was dissolved in THF (17 mL) and cooled to 0 °C. Then LiAlH4 (155.2 mg, 4.1 mmol, 1.0 equiv.) was added in portions, 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 NH4Cl aqueous. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 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 5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1- yl]pyridine-3-carbaldehyde (1.0 g) as a yellow solid. LCMS Method E: [M+H]+ = 308. Step 3: (E)-N-([5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3- yl]methylidene)hydroxylamine 5-Chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridine-3-carbaldehyde (1.0 g, 3.3 mmol, 1.0 equiv.) and hydroxylamine hydrochloride (271.0 mg, 3.9 mmol, 1.2 equiv.) were added to a solution of EtOH (10 mL) and water (10 mL), then NaOH (195.0 mg, 4.9 mmol, 1.5 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 Na2SO4 and concentrated under vacuum. The residue was purified by reverse phase flash chromatography with following conditions: column, C18 silica gel; mobile phase, ACN/water, 0% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in (E)-N- ([5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3- yl]methylidene)hydroxylamine (800.0 mg) as a brown solid. LCMS Method A: [M+H]+ = 323. Step 4: methyl 3-[5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]- 1,2-oxazole-5-carboxylate (E)-N-([5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3- yl]methylidene)hydroxylamine (1.0 g, 3.1 mmol, 1.0 equiv.) and methyl propiolate (260.5 mg, 3.1 mmol, 1.0 equiv.) were dissolved in CHCl3 (10 mL), then NaHCO3 (390.5 mg, 4.6 mmol, 1.5 equiv.) and NCS (413.8 mg, 3.1 mmol, 1.0 equiv.) were added. The reaction 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 Na2SO4 and concentrated under vacuum to give methyl 3-[5-chloro-6-[4- (2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2-oxazole-5-carboxylate (811.2 mg) as a yellow solid. LCMS Method A: [M+H]+ = 405. Step 5: 3-[5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2- oxazole-5-carboxylic acid Methyl 3-[5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2- oxazole-5-carboxylate (500.0 mg, 1.2 mmol, 1.0 equiv.) was dissolved in MeOH (5.0 mL) and water (5.0 mL), then LiOH (118.3 mg, 4.9 mmol, 4.0 equiv.) was added. The reaction mixture was stirred for 2 hours at ambient temperature and then concentrated under vacuum. The residue was purified by reverse phase flash chromatography with following conditions: column, C18 silica gel; mobile phase, ACN/water, 0% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in 3-[5-chloro-6-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2-oxazole-5-carboxylic acid (295.4 mg) as an off-white solid. LCMS Method B: [M+H]+ = 391. The following intermediates were prepared using the same method described for Intermediate 66B. 6 6
Step 1: 5-bromo-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine 2,5-Dibromo-3-fluoropyridine (10.0 g, 39.2 mmol, 1.0 equiv.) was dissolved in DMF (100 mL), then Cs2CO3 (25.7 g, 78.5 mmol, 2.0 equiv.) and 4,4-difluoropiperidine (7.1 g, 58.8 mmol, 1.5 equiv.) were added. The reaction mixture was heated to 80 °C for 48 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 Na2SO4 and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC with the following conditions: Column, C18 silica gel; mobile phase, ACN/H2O=60% increasing to ACN/H2O=100% within 20 min; Detector, 254 nm. This resulted in 5-bromo-2-(4,4- difluoropiperidin-1-yl)-3-fluoropyridine (2.0 g) as a yellow solid. LCMS Method A: [M+H]+ = 295. Step 2: 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine 5-Bromo-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (2.0 g, 6.8 mmol, 1.0 equiv.) was dissolved in DMSO (30 mL), then AcOK (1.3 g, 13.6 mmol, 2.0 equiv.), bis(pinacolato)diboron (3.4 g, 13.5 mmol, 2.0 equiv.) and Pd(dppf)Cl2 (495.9 mg, 0.7mmol, 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 flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give 2-(4,4-difluoropiperidin-1-yl)-3- fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.6 g) as a yellow oil. LCMS Method A: [M+H]+ = 343. Step 3: methyl 2-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-thiazole-5- carboxylate 2-(4,4-Difluoropiperidin-1-yl)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (300.0 mg, 0.9 mmol, 1.0 equiv.) and methyl 2-bromo-1,3-thiazole-5- carboxylate (233.6 mg, 1.1 mmol, 1.2 equiv.) were dissolved in 1,4-dioxane (5 mL) and water (5 mL), then Cs2CO3 (857.0 mg, 2.6 mmol, 3.0 equiv.) and Pd(dppf)Cl2CH2Cl2 (71.4 mg, 0.09 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 90 °C for 6 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 (1:3) to give methyl 2-[6-(4,4- difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-thiazole-5-carboxylate (200.0 mg) as an off-white solid. LCMS Method A: [M+H]+ = 358. Step 4: 2-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-thiazole-5- carboxylic acid Methyl 2-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-thiazole-5- carboxylate (300.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in MeOH (6 mL) and water (6 mL), then NaOH (167.9 mg, 4.2 mmol, 5.0 equiv.) was added. The reaction mixture was heated to 60 °C for 3 hours, then cooled to ambient temperature and quenched by the addition of ice-water. The resulting solution was adjusted to pH 4 with concentrated HCl, extracted with ethyl acetate, dried over anhydrous Na2SO4 and concentrated under vacuum to give 2-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-thiazole-5-carboxylic acid (242.1 mg) as an off-white solid. LCMS Method E: [M+H]+ = 344. The following intermediates were prepared using the same method described for Intermediate 70B.
Scheme 21B: Synthesis of intermediate 80B (5-(6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl)-1,2,4-oxadiazole-3-carboxylic acid) Step 1: 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carbonyl chloride 6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridine-3-carboxylic acid (1.7 g, 6.5 mmol, 1.0 equiv.) was dissolved in DCM (17 mL) and cooled to 0 °C, then oxalyl chloride (0.8 mL, 9.8 mmol, 1.5 equiv.) and DMF (0.1 mL) were added dropwise, maintaining the solution at 0 °C. The reaction mixture was stirred for 2 hours at 0 °C, and then concentrated under vacuum to give 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carbonyl chloride (1.5 g) as a white solid. Step 2: ethyl [(E)-N-[(E)-6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3- carbonyloxy]carbamimidoyl]formate 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carbonyl chloride (1.4 g, 5.0 mmol, 1.0 equiv.) was dissolved in THF (14 mL) and cooled to 0 °C, then ethyl [(E)-N'- hydroxycarbamimidoyl]formate (663.8 mg, 5.0 mmol, 1.0 equiv.) was added. The reaction mixture was stirred 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 Na2SO4 and concentrated under vacuum to give ethyl [(E)- N-[(E)-6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3- carbonyloxy]carbamimidoyl]formate (1.0 g) as a white solid. LCMS Method A: [M+H]+ = 375. Step 3: ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4- oxadiazole-3-carboxylate Ethyl [(E)-N-[(E)-6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3- carbonyloxy]carbamimidoyl]formate (1.0 g, 2.7 mmol, 1.0 equiv.) was dissolved in EtOH (10 mL) and acetic acid (6 mL). The reaction mixture was heated to 100 °C overnight, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, then adjusted to pH 8 with saturated aqueous Na2CO3. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN/water, 20% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-oxadiazole-3-carboxylate (800.0 mg) as a white solid. LCMS Method A: [M+H]+ = 357. Step 4: 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-oxadiazole-3- carboxylic acid Ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-oxadiazole-3- carboxylate (600.0 mg, 1.7 mmol, 1.0 equiv.) was dissolved in MeOH (6 mL) and water (6 mL), then LiOH (161.3 mg, 6.7 mmol, 4.0 equiv.) was added. The reaction mixture was stirred for 3 hours at ambient temperature and then concentrated under vacuum. The resulting solution was adjusted to pH 5 with concentrated HCl. The crude product was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN/water, 0% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4- oxadiazole-3-carboxylic acid (505.1 mg) as a red solid. LCMS Method B: [M+H]+ = 329. Scheme 22B: Synthesis of intermediate 81B (3-(6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl)-1,2,4-thiadiazole-5-carboxylic acid) Step 1: 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carboxamide 6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridine-3-carboxylic acid (4.0 g, 15.4 mmol, 1.0 equiv.) was dissolved in DMF (40 mL), then HATU (8.8 g, 23.1 mmol, 1.5 equiv.), DIEA (8.0 mL, 46.1 mmol, 3.0 equiv.) and NH4Cl (1.23 g, 23.058 mmol, 1.5 equiv.) were added. The reaction mixture was stirred overnight at ambient temperature, then quenched by the addition of water. The solids were collected by filtration and dried to give 6-(4,4- difluoropiperidin-1-yl)-5-fluoropyridine-3-carboxamide (3.5 g) as an off-white solid. LCMS Method A: [M+H]+ = 260. Step 2: 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxathiazol-2- one 6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridine-3-carboxamide (3.5 g, 13.5 mmol, 1.0 equiv.) was dissolved in toluene (50 mL), then chloro(chlorosulfanyl)methanone (3.5 g, 27.0 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 100 °C overnight, then cooled to ambient temperature and concentrated under vacuum to give 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxathiazol-2-one (3.0 g) as a yellow solid. LCMS Method C: [M+H]+ = 274. Step 3: ethyl 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4- thiadiazole-5-carboxylate 5-[6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxathiazol-2-one (3.0 g, 9.5 mmol, 1.0 equiv.) was dissolved in dodecane (10 mL), then ethyl carbonocyanidate (1.4 g, 14.2 mmol, 1.5 equiv.) was added. The reaction mixture was heated to 130 °C for 16 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 (1:1) to give ethyl 3-[6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl]-1,2,4-thiadiazole-5-carboxylate (1.2 g) as a yellow solid. LCMS Method A: [M+H]+ = 260. Step 4: 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-thiadiazole-5- carboxylic acid Ethyl 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-thiadiazole-5- carboxylate (1.2 g, 3.2 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL) and water (10 mL), then NaOH (257.8 mg, 6.4 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 30 min at ambient temperature and then concentrated under vacuum. The residue was diluted with water, adjusted to pH 7 with aqueous HCl (0.5 M). The solids were collected by filtration to give 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3- yl]-1,2,4-thiadiazole-5-carboxylic acid (321.2 mg) as a white solid. LCMS Method B: [M+H]+ = 345. Scheme 23B: Synthesis of intermediate 82B (3-(6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl)isothiazole-5-carboxylic acid)
Step 1: methyl 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2-thiazole-5- carboxylate 5-[6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxathiazol-2-one (1.0 g, 3.2 mmol, 1.0 equiv.) was dissolved in o-dichlorobenzene (10 mL), then methyl propiolate (1.6 g, 19.0 mmol, 6.0 equiv.) was added. The reaction mixture was heated to 135 °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 (1:8) to give methyl 3-[6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl]-1,2-thiazole-5-carboxylate (350.0 mg) as a yellow solid. LCMS Method A: [M+H]+ = 358. Step 2: 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2-thiazole-5- carboxylic acid Methyl 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2-thiazole-5- carboxylate (330.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and water (2 mL), then NaOH (55.4 mg, 1.4 mmol, 1.5 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature and the concentrated under vacuum. The residue was diluted with water, adjusted to pH 7 with aqueous HCl (6 M). The precipitated solids were collected by filtration and washed with water to give 3-[6-(4,4- difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2-thiazole-5-carboxylic acid (250.0 mg) as a yellow solid. LCMS Method G: [M+H]+ = 344. Scheme 24B: Synthesis of intermediate 83B (4-(6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl)oxazole-2-carboxylic acid) Step 1: 6-(4,4-difluoropiperidin-1-yl)-5-fluoro-N-methoxy-N-methylpyridine-3- carboxamide 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carboxylic acid (4.6 g, 17.7 mmol, 1.0 equiv.) and N,O-dimethylhydroxylamine hydrochloride (2.6 g, 26.6 mmol, 1.5 equiv.) were dissolved in DMF (50 mL), then HATU (10.1 g, 26.5 mmol, 1.5 equiv.) and DIEA (12.3 mL, 70.7 mmol, 4.0 equiv.) were added. The reaction mixture was stirred for 2 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 Na2SO4 and concentrated under vacuum to give 6-(4,4-difluoropiperidin-1-yl)-5-fluoro-N-methoxy-N- methylpyridine-3-carboxamide (4.2 g) as a yellow oil. LCMS Method A: [M+H]+ = 272. Step 2: 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]ethanone 6-(4,4-Difluoropiperidin-1-yl)-5-fluoro-N-methoxy-N-methylpyridine-3- carboxamide (1.6 g, 5.3 mmol, 1.0 equiv.) was dissolved in THF (20 mL) and cooled to 0 °C, then MeMgBr (3M in THF, 2.7 mL, 8.1 mmol, 1.5 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, then quenched by the addition of saturated NH4Cl aqueous. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give 1-[6-(4,4- difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]ethenone (900.0 mg) as a yellow solid. LCMS Method A: [M+H]+ = 259. Step 3: 2-bromo-1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]ethanone 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]ethanone (3.0 g, 11.6 mmol, 1.0 equiv.) was dissolved in ACN (15 mL), then NBS (3.1 g, 17.4 mmol, 1.5 equiv.) and TsOH (3.0 g, 17.4 mmol, 1.5 equiv.) were added. The reaction mixture was heated to 100 °C overnight, then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with saturated NaHCO3 aqueous, dried over anhydrous Na2SO4 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 2- bromo-1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]ethanone (2.0 g) as a yellow solid. LCMS Method A: [M+H]+ = 337. Step 4: 2-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-2-oxoethyl acetate 2-Bromo-1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]ethanone (2.0 g, 5.9 mmol, 1.0 equiv.) and acetic acid (0.5 mL g, 8.9 mmol, 1.5 equiv.) were dissolved in MeOH (6 mL) and water (14 mL), then K2CO3 (0.8 g, 5.9 mmol, 1.0 equiv.) was added. The reaction mixture was heated to 70 °C for 3 hours, then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with saturated NaHCO3 solution, dried over anhydrous Na2SO4 and concentrated under vacuum to give 2-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-2-oxoethyl acetate (1.5 g) as a yellow solid. LCMS Method E: [M+H]+ = 317. Step 5: ethyl 4-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-oxazole-2- carboxylate 2-[6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-2-oxoethyl acetate (1.5 g, 4.7 mmol, 1.0 equiv) and ethyl carbamoylformate (1.7 g, 14.3 mmol, 3.0 equiv.) were dissolved in xylene (30 mL), then BF3•Et2O (6.3 mL, 23.7 mmol, 5.0 equiv.) was added dropwise. The reaction mixture was heated to 130 °C for 48 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 (1:1) to give ethyl 4-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-oxazole-2-carboxylate (510.0 mg) as a yellow solid. LCMS Method C: [M+H]+ = 356. Step 6: 4-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-oxazole-2- carboxylic acid Ethyl 4-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-oxazole-2- carboxylate (500.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (112.6 mg, 2.8 mmol, 2.0 equiv.) were added. The reaction mixture was heated to 60 °C for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, adjusted to pH 6 with aqueous HCl (0.5 M). The solids were collected by filtration, washed with water and dried to give 4- [6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-oxazole-2-carboxylic acid 215.2 mg) as a yellow solid. LCMS Method C: [M+H]+ = 328. Scheme 25B: Synthesis of intermediate 84B (5-(6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl)-1H-pyrazole-3-carboxylic acid) Step 1: ethyl 4-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-2,4- dioxobutanoate 1-[6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]ethenone (600.0 mg, 2.3 mmol, 1.0 equiv.) and EtONa (158.1 mg, 2.3 mmol, 1.0 equiv.) were dissolve in EtOH (6 mL), then ethyl oxalate (0.3 mL, 2.3 mmol, 1.0 equiv.) was added dropwise. The reaction mixture was stirred for 2 hours at ambient temperature, then quenched by the addition of water. The resulting solution was adjusted to pH 6 with aqueous HCl (4 M), extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give ethyl 4-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-2,4- dioxobutanoate (610.0 mg) as a yellow solid. LCMS Method A: [M+H]+ = 359. Step 2: ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1H-pyrazole-3- carboxylate Ethyl 4-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-2,4-dioxobutanoate (900.0 mg, 2.5 mmol, 1.0 equiv.) and NH2NH2•H2O (0.2 mL, 2.5 mmol, 1.0 equiv.) were dissolved in AcOH (10 mL). The reaction mixture was stirred for 2 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 (1:5) to give ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1H-pyrazole-3- carboxylate (450.0 mg) as a yellow solid. LCMS Method A: [M+H]+ = 355. Step 3: 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1H-pyrazole-3- carboxylic acid Ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1H-pyrazole-3- carboxylate (450.0 mg, 1.3 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (101.6 mg, 2.5 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 6 with aqueous HCl (2 M) and concentrated under vacuum. The residue was purified by reverse flash chromatography with following conditions: column, C18 silica gel; mobile phase, ACN/water, 0% to 100% gradient in 30min; detector, UV 254 nm. This resulted in 5-[6- (4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1H-pyrazole-3-carboxylic acid (320.0 mg) as a white solid. LCMS Method B: [M+H]+ = 327. Scheme 26B: Synthesis of intermediate 85B (5-(6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxylic acid) Step 1: ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1- methylpyrazole-3-carboxylate Ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1H-pyrazole-3- carboxylate (300.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in THF (3 mL) and cooled to 0 °C, then NaH (60% wt., 50.8 mg, 1.3 mmol, 1.5 equiv.) was added under an atmosphere of nitrogen, maintaining the solution at 0 °C. After stirred for 10 min at 9 °C, MeI (0.1 mL, 1.6 mmol, 1.5 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature, and then quenched by the addition of MeOH at 0 °C. The resulting solution was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1-methylpyrazole-3-carboxylate (150.0 mg) as a white solid. LCMS Method A: [M+H]+ = 369. Step 2: 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1-methylpyrazole-3- carboxylic acid Ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1-methylpyrazole-3- carboxylate (150.0 mg, 0.4 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and water (2 mL), then NaOH (32.6 mg, 0.8 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 6 with aqueous HCl (2 M). The resulting solution was concentrated under vacuum, and the residue was purified by reverse phase flash chromatography with following conditions: column, C18 silica gel; mobile phase, ACN/water, 0% to 100% gradient in 25 min; detector, UV 254 nm. This resulted in 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1- methylpyrazole-3-carboxylic acid (105.2 mg) as a white solid. LCMS Method C: [M+H]+ = 341. Scheme 27B: Synthesis of intermediate 86B (1-(6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl)-1H-pyrazole-3-carboxylic acid) Step 1: methyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-3- carboxylate 5-Bromo-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (1.0 g, 3.4 mmol, 1.0 equiv.) and methyl 1H-pyrazole-3-carboxylate (514.1 mg, 4.1 mmol, 1.2 equiv.) were dissolved in DMF (15 mL), then (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (96.4 mg, 0.7 mmol, 0.2 equiv.), CuI (129.1 mg, 0.7 mmol, 0.2 equiv.) and K2CO3 (1.4 g, 10.1 mmol, 3.0 equiv.) were added. The reaction mixture was heated to 80 °C overnight, then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with brine 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 methyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-3-carboxylate (610.0 mg) as a yellow solid. LCMS Method A: [M+H]+ = 341. Step 2:1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-3-carboxylic acid Methyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-3- carboxylate (600.0 mg, 1.8 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (141.0 mg, 3.5 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 60 °C for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water and adjusted to pH 6 with aqueous HCl (1 M). The precipitated solids were collected by filtration, washed with water and dried to give 1- [6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-3-carboxylic acid (421.5 mg) as a white solid. LCMS Method E: [M+H]+ = 327. The following intermediates were prepared using the same method described for Intermediate 86B. Scheme 28B: Synthesis of intermediate 88B (5-(6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl)-1,3,4-oxadiazole-2-carboxylic acid)
Step 1: 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carbohydrazide Methyl 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carboxylate (2.0 g, 7.3 mmol, 1.0 equiv.) was dissolved in EtOH (30 mL), then NH2NH2•H2O (3.5 mL, 70.0 mmol, 10.0 equiv.) was added. The resulting solution was heated to 90 °C for 16 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, and the solid was collected by filtration to give 6-(4,4-difluoropiperidin-1-yl)- 5-fluoropyridine-3-carbohydrazide (1.3 g) as a white solid. LCMS Method A: [M+H]+ = 275. Step 2: ethyl 2-[[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3- yl]formohydrazido]-2-oxoacetate 6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridine-3-carbohydrazide (1.3 g, 4.7 mmol, 1.0 equiv.) and TEA (2.0 mL, 14.2 mmol, 3.0 equiv.) were dissolved in DCM (20 mL), then ethyl chloroglyoxylate (0.5 mL, 5.0 mmol, 1.0 equiv.) was added dropwise. The reaction mixture was stirred for 2 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with dichloromethane, 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 (1:1) to give ethyl 2-[[6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl]formohydrazido]-2-oxoacetate (1.1 g) as a white solid. LCMS Method D: [M+H]+ = 375. Step 3: ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4- oxadiazole-2-carboxylate Ethyl 2-[[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]formohydrazido]-2- oxoacetate (1.0 g, 2.7 mmol, 1.0 equiv.) and TEA (1.1 mL, 8.0 mmol, 3.0 equiv.) were dissolved in DCM (20 mL), then TsCl (764.0 mg, 4.0 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 2 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 (1:2) to give ethyl 5-[6-(4,4-difluoropiperidin-1- yl)-5-fluoropyridin-3-yl]-1,3,4-oxadiazole-2-carboxylate (506.2 mg) as a white solid. LCMS Method A: [M+H]+ = 357. Step 4: 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxadiazole-2- carboxylic acid Ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxadiazole-2- carboxylate (500.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in MeOH (3 mL) and water (3 mL), then NaOH (112.3 mg, 2.8 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 to give crude 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]- 1,3,4-oxadiazole-2-carboxylic acid (212.2 mg) as a white solid, which was used to next step directly without further working up. LCMS Method E: [M+H]+ = 329. Synthesis of intermediate 89B (1-(6-bromo-5-fluoropyridin-3-yl)-N-(5,6- difluoro-1H-indol-3-yl)-1H-1,2,3-triazole-4-carboxamide) Step 1- Step 4: Step 1: ethyl 2-diazo-3-oxopropanoate A mixture of DMF (32.0 g, 438.2 mmol, 33.7 mL, 0.50 equiv.) and SOCl2 (52.1 g, 438.2 mmol, 31.8 mL, 0.5 equiv.) was heated at 40 ºC for 2 hours. The reaction mixture was concentrated under reduced pressure to give a solid that was then dissolved in CHCl3 (250 mL) and cooled to 0 °C. Ethyl 2-diazoacetate (100 g, 876.4 mmol, 1 equiv.) was added dropwise over 1 hour, maintaining the temperature at 0 °C. After addition was compete, the mixture was stirred at 25 °C for 12 hours. The solvent was removed under reduced pressure and then MTBE (800.0 mL) was added to give a slurry. The yellow precipitate collected by filtration, dissolved in 10% aq. acetic acid, then extracted with MTBE (3 × 300 mL). The combined organic extracts were washed with aqueous sodium hydrogen carbonate (2 M; 3 × 300 mL), hydrochloric acid (10%; 3 × 300 mL), water (3 × 300 mL) and brine (3 × 300 mL). The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give ethyl 2-diazo-3-oxo-propanoate (15.0 g, 95.0 mmol, 11% yield, 90% purity) as a yellow oil. Step 2: ethyl 1-(6-bromo-5-fluoropyridin-3-yl)-1H-1,2,3-triazole-4- carboxylate 6-bromo-5-fluoro-pyridin-3-amine (12.1 g, 63.4 mmol, 1.0 equiv.) and ethyl 2-diazo- 3-oxo-propanoate (15.0 g, 95.0 mmol, 90% purity, 1.5 equiv.) were dissolved in EtOH (300 mL). Then AcOH (210.0 g, 3.5 mol, 200 mL, 55.2 equiv.) was added and the mixture was heated at 50 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with cold water and the resulting solid was collected via filtration to give ethyl 1-(6-bromo-5-fluoro-3-pyridyl)triazole-4- carboxylate (16.0 g, 50.8 mmol, 80% yield) as a yellow solid. Step 3: 1-(6-bromo-5-fluoropyridin-3-yl)-1H-1,2,3-triazole-4-carboxylic acid Ethyl 1-(6-bromo-5-fluoro-3-pyridyl)triazole-4-carboxylate (16 g, 50.8 mmol, 1 equiv.) was dissolved in MeOH (300 mL). Then NaOH (2 M, 50.78 mL, 2 equiv.) was added. The mixture was stirred at 20 °C for 4 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. Then H2O (30 mL) was added and the mixture was adjusted to pH 4 by the dropwise addition of aqueous HCl (2 M). The resulting solid was collected by filtration and washed with water to give 1-(6-bromo-5-fluoro-3- pyridyl)triazole-4-carboxylic acid (12 g, 41.8 mmol, 82% yield) as a white solid. Step 4: Synthesis of (1-(6-bromo-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H- indol-3-yl)-1H-1,2,3-triazole-4-carboxamide (intermediate 89B) 1-(6-bromo-5-fluoro-3-pyridyl)triazole-4-carboxylic acid (5.0 g, 17.4 mmol, 1.0 equiv.) and 5,6-difluoro-1H-indol-3-amine (4.0 g, 16.7 mmol, 70% purity, 9.6 equiv.) were dissolved in DMF (300 mL). Then pyridine (11.0 g, 139.3 mmol, 11.3 mL, 8.0 equiv.) and EDCI (3.3 g, 17.4 mmol, 1.0 equiv.) were added. The mixture was stirred at 20 °C for 2 hours, then water (1 L) and DCM (1 L) were added to the reaction mixture. The resulting solid was collected by filtration and washed with water and DCM. Compound 1-(6-bromo- 5-fluoro-3-pyridyl)-N-(5,6-difluoro-1H-indol-3-yl)triazole-4-carboxamide (6.0 g, 13.0 mmol, 75% yield) was obtained as a white solid. Example 1: N-(5,6-difluoro-1H-indol-3-yl)-1-((6-(4,4-difluorocyclohexyl)-5- fluoropyridin-3-yl)methyl)-1H-imidazole-4-carboxamide (Compound 105) 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]imidazole-4-carboxylic acid (200.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in DMF (5 mL), then 5,6-difluoro- 1H-indol-3-amine hydrogen chloride (120.5 mg, 0.6 mmol, 1.0 equiv.), HATU (336.2 mg, 0.9 mmol, 1.5 equiv.) and DIEA (0.3 mL, 1.8 mmol, 3.0 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 and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column, YMC-Actus Triart C18, 30*250,5μm; mobile phase, Water (10 mM NH4HCO3 + 0.1% NH3.H2O) and ACN (38% Phase B up to 60% in 10 min); Detector, uv 254 nm. This resulted in N-(5,6-difluoro-1H-indol-3-yl)-1-[[6-(4,4-difluorocyclohexyl)-5- fluoropyridin-3-yl]methyl]imidazole-4-carboxamide (17.1 mg) as a white solid. LCMS Method D: [M+H]+ = 490. 1H NMR (300 MHz, DMSO-d6): δ 11.02 (s, 1H), 9.74 (s, 1H), 8.46 (s, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.79–7.70 (m, 3H), 7.37–7.31 (m, 1H), 5.32 (s, 2H), 3.19–3.15 (m, 1H), 2.09–1.83 (m, 8H). The analogs in the following table were prepared using the same method described for Example 1.
Example 12: 1-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-N-(5- fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-imidazole-4-carboxamide 1-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-1H-imidazole-4-carboxylic acid (129.5 mg, 0.4 mmol, 1.0 equiv.) was dissolved in THF (10 mL), then 5-fluoro-1H- pyrrolo[2,3-b]pyridin-3-amine hydrogen chloride (74.7 mg, 0.4 mmol, 1.0 equiv.), TEA (0.6 mL, 4.0 mmol, 10.0 equiv.), and T3P (189.5 mg, 0.6 mmol, 1.5 equiv.) were added. The resulting solution was stirred overnight at ambient temperature and then 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: XBridge Prep OBD C18 Column, 30×150mm 5μm; Mobile Phase A: Water (0.05% FA), Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 35% B to 65% B in 7 min; 254 nm. This resulted in 1-(6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl)-N-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-imidazole-4- carboxamide (41.4 mg) as a white solid. LCMS Method J: [M+H]+ = 460. 1H NMR (400 MHz, DMSO-d6): δ 11.63 (s, 1H), 10.14 (s, 1H), 8.56 (d, 1H), 8.45–8.41 (m, 2H), 8.22– 8.18 (m, 3H), 7.92 (s, 1H), 3.62 (t, 4H), 2.16–2.06 (m, 4H). The analogs in the following table were prepared using the same method described for Example 12.
Example 22: N-(5,6-difluoro-1H-indol-3-yl)-1-(6-(4,4-difluoropiperidin-1-yl)- 5-fluoropyridin-3-yl)-1H-1,2,3-triazole-4-carboxamide ) (Compound 102) Step 1: N-(5,6-difluoro-1H-indol-3-yl)propiolamide 5,6-difluoro-1H-indol-3-amine hydrogen chloride (730.0 mg, 3.6 mmol, 1.0 equiv.) was dissolved in THF (30 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 column, 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: 5-azido-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine 6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridin-3-amine (400.0 mg, 1.7 mmol, 1.0 equiv.) was dissolved in ACN (10 mL) and cooled to 0 °C, then t-BuNO2 (0.3 mL, 2.7 mmol, 1.6 equiv.) was added dropwise, maintaining the mixture at 0 °C. After 30 min at 0 °C, TMSN3 (0.3 mL, 2.5 mmol, 1.5 equiv.) was added dropwise at 0 °C. The reaction mixture was stirred for an additional 2 hours at ambient temperature, then quenched by the addition of water. The resulting mixture 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 (1:2) to give 5-azido-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (380 mg) as yellow oil. Step 3: N-(5,6-difluoro-1H-indol-3-yl)-1-(6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl)-1H-1,2,3-triazole-4-carboxamide 5-Azido-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (150.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in dioxane/water (5/0.5 mL), then N-(5,6-difluoro-1H-indol-3- yl)propiolamide (130.0 mg, 0.6 mmol, 1.0 equiv.), sodium (R)-2-((S)-1,2-dihydroxyethyl)- 4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (24.0 mg, 0.1 mmol, 0.2 equiv.) and CuSO4 (19.0 mg, 0.1 mmol, 0.2 equiv.) were added. The reaction mixture was stirred for 15 hours at ambient temperature and then quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was further purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30×150mm 5μm; Mobile Phase A: Water (10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 35% B to 80% B in 7 min; 254 nm; RT1:6.95 min. This resulted in N-(5,6-difluoro-1H-indol-3-yl)- 1-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-1H-1,2,3-triazole-4-carboxamide (135.5 mg) as an off-white solid. LCMS Method H: [M-H]- = 476. 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 10.58 (s, 1H), 9.35 (s, 1H), 8.68 (s, 1H), 8.32–8.28 (m, 1H), 7.92–7.87 (m, 1H), 7.84 (s, 1H), 7.42–7.37 (m, 1H), 3.70–3.67 (m, 4H), 2.17–2.07 (m, 4H). Example 23: N-(5,6-difluoro-1H-indol-3-yl)-5-(6-(4,4-difluoropiperidin-1-yl)- 5-fluoropyridin-3-yl)isoxazole-3-carboxamide (Compound 208) 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2-oxazole-3-carboxylic acid (250.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in DMF (3 mL), then 5,6-difluoro- 1H-indol-3-amine hydrogen chloride (223.1 mg, 1.1 mmol, 1.5 equiv.) and HATU (435.7 mg, 1.1 mmol, 1.5 equiv.) were added. This was followed by the dropwise addition of DIEA (0.5 mL, 2.9 mmol, 4.0 equiv.). 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 Na2SO4 and concentrated under vacuum. The residue was purified by reverse flash chromatography with following conditions: column, C18 silica gel; mobile phase, ACN/water, 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in N-(5,6-difluoro-1H-indol-3-yl)- 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2-oxazole-3-carboxamide (127.2 mg) as a pink solid. LCMS Method J: [M+H]+ = 478. 1H NMR (400 MHz, CD3OD-d4): δ 8.54 (s, 1H), 7.90–7.81 (m, 1H), 7.78 (s, 1H), 7.63–7.58 (m, 1H), 7.27–7.23 (m, 1H), 7.16 (s, 1H), 3.83–3.80 (m, 4H), 2.16–2.06 (m, 4H). The analogs in the following table were prepared using the same method described for Example 23. 9 0 1 2 3 4 5 Example 76: N-(5,6-difluoro-1H-indol-3-yl)-3-(6-(4,4-difluoropiperidin-1-yl)-5- fluoropyridin-3-yl)isoxazole-5-carboxamide (Compound 210)
3-[6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2-oxazole-5-carboxylic acid (200.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in DMF (2 mL), then 5,6-difluoro- 1H-indol-3-amine hydrogen chloride (186.2 mg, 0.9 mmol, 1.5 equiv.) and HATU (348.6 mg, 0.9 mmol, 1.5 equiv.) were added. This was followed by the dropwise addition of DIEA (0.4 mL, 2.4 mmol, 4.0 equiv.). 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 Na2SO4 and concentrated under vacuum. The residue was purified by reverse flash chromatography with following conditions: column, C18 silica gel; mobile phase, ACN/water, 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in N-(5,6-difluoro-1H-indol-3-yl)- 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2-oxazole-5-carboxamide (145.8 mg) as an off-white solid. LCMS Method H: [M+H]+ = 478.1H NMR (400 MHz, DMSO- d6): δ 11.24 (s, 1H), 10.88 (s, 1H), 8.63 (s, 1H), 8.10–8.06 (m, 1H), 7.95–7.89 (m, 2H), 7.81 (s, 1H), 7.44–7.39 (m, 1H), 3.73–3.70 (m, 4H), 2.16–2.06 (m, 4H). Example 77: N-(5,6-difluoro-1H-indol-3-yl)-4-(6-(4,4-difluoropiperidin-1-yl)- 5-fluoropyridin-3-yl)oxazole-2-carboxamide (Compound 193) 4-[6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-oxazole-2-carboxylic acid (200.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in DMF (5 mL), then T3P (wt. 50% in ethyl acetate, 0.6 mL, 0.9 mmol, 1.5 equiv.), and 5,6-difluoro-1H-indol-3-amine hydrogen chloride (187.6 mg, 0.9 mmol, 1.5 equiv.) were added. This was followed by the addition of TEA (0.3 mL, 1.8 mmol, 3.0 equiv.). The reaction 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 sodium sulfate and concentrated under vacuum. The residue was purified by reverse flash chromatography with following conditions: column, C18 silica gel; mobile phase, ACN/water, 0% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in N-(5,6-difluoro-1H-indol-3-yl)- 4-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-oxazole-2-carboxamide (25.9 mg) as an off-white solid. LCMS Method F: [M+H]+ = 478. 1H NMR (400 MHz, DMSO- d6): δ 11.17 (s, 1H), 10.82 (s, 1H), 8.66 (s, 1H), 8.17–8.13 (m, 1H), 7.93–7.86 (m, 2H), 7.45 (s, 1H), 7.43–7.38 (m, 1H), 3.76–3.73 (m, 4H), 2.16–2.06 (m, 4H). The analogs in the following table were prepared using the same method described for Example 77. Example 80: N-(5,6-difluoro-1H-indol-3-yl)-3-(5-fluoro-6-(4-(2,2,2- trifluoroethyl)piperazin-1-yl)pyridin-3-yl)isoxazole-5-carboxamide (Compound 160)
3-[5-Fluoro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2-oxazole-5- carboxylic acid (300.0 mg, 0.8 mmol, 1.0 equiv.) and 5,6-difluoro-1H-indol-3-amine hydrogen chloride (196.8 mg, 1.0 mmol, 1.2 equiv.) were dissolved in DMF (10 mL), then NMM (486.4 mg, 4.8 mmol, 6.0 equiv.) and PyBOP (417.1 mg, 0.8 mmol, 1.0 equiv.) were added. 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 Na2SO4 and concentrated under vacuum. The residue was purified by Prep-HPLC with the following condition: Column, XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; mobile phase, Water (10 mmol/L NH4HCO3+0.1% NH4OH) and ACN (50% Phase B up to 70% in 7 min); Detector, UV 254 nm. This resulted in N-(5,6-difluoro-1H-indol-3-yl)-3-[5-fluoro-6-[4-(2,2,2-trifluoroethyl)piperazin-1- yl]pyridin-3-yl]-1,2-oxazole-5-carboxamide (63.3 mg) as a white solid. LCMS Method H: [M+H]+ = 525.1H NMR (400 MHz, DMSO-d6): δ 11.25 (s, 1H), 10.89 (s, 1H), 8.61 (d, J = 1.6 Hz, 1H), 8.06–8.02 (m, 1H), 7.95–7.89 (m, 2H), 7.80 (s, 1H), 7.44–7.39 (m, 1H), 3.60–3.58 (m, 4H), 3.30–3.25 (m, 2H), 2.79–2,76 (m, 4H). The analogs in the following table were prepared using the same method described for Example 80. Example 82: N-(5-chloro-1H-indol-3-yl)-3-(5-fluoro-6-(4-(2,2,2- trifluoroethyl)piperazin-1-yl)pyridin-3-yl)isoxazole-5-carboxamide (Compound 171) 3-[5-Fluoro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2-oxazole-5- carboxylic acid (300.0 mg, 0.8 mmol, 1.0 equiv.) and 5-chloro-1H-indol-3-amine (160.3 mg, 1.0 mmol, 1.2 equiv.) were dissolved in DMF (10 mL), then NMM (121.6 mg, 1.2 mmol, 1.5 equiv.) and PyBOP (625.7 mg, 1.2 mmol, 1.5 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 Na2SO4 and concentrated under vacuum. The residue was purified by Prep- HPLC with following condition: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 50% B to 75% B in 8 min; Wave Length: 220 nm; RT (min): 7.82. This resulted in N-(5-chloro-1H-indol-3-yl)-3-[5-fluoro-6-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2-oxazole-5-carboxamide (65.3 mg) as a white solid. LCMS Method H: [M+H]+ = 523.1H NMR (400 MHz, DMSO-d6): δ 11.28 (s, 1H), 10.88 (s, 1H), 8.61 (d, J = 1.2 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.81 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.16–7.13 (m, 1H), 3.61–3.58 (m, 4H), 3.30–3.22 (m, 2H), 2.79–2.76 (m, 4H). Example 83: N-(5,6-difluoro-1H-indol-3-yl)-5-(5-fluoro-6-(4-(2,2,2- trifluoroethyl)piperazin-1-yl)pyridin-3-yl)isoxazole-3-carboxamide (Compound 204) 5-[5-Fluoro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2-oxazole-3- carboxylic acid (300.0 mg, 0.8 mmol, 1.0 equiv.) and DCC (248.1 mg, 1.2 mmol, 1.5 equiv.) were dissolved in DCM (30 mL), then DMAP (146.9 mg, 1.2 mmol, 1.5 equiv.) and 5,6-difluoro-1H-indol-3-amine hydrogen chloride (196.8 mg, 1.0 mmol, 1.2 equiv.) were added. 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 Na2SO4 and concentrated under vacuum. The residue was purified by Prep-HPLC with the following condition: Column, XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; mobile phase, Water (10 mmol/L NH4HCO3+0.1% NH4OH) and ACN (50% Phase B up to 75% in 7 min); Detector, UV 254 nm. This resulted in N-(5,6-difluoro-1H-indol-3-yl)-5-[5-fluoro-6-[4-(2,2,2-trifluoroethyl)piperazin-1- yl]pyridin-3-yl]-1,2-oxazole-3-carboxamide (138.2 mg) as a yellow solid. LCMS Method H: [M+H]+ = 525.1H NMR (400 MHz, DMSO-d6): δ 11.20 (s, 1H), 10.81 (s, 1H), 8.61 (d, J = 1.6 Hz, 1H), 8.12–8.08 (m, 1H), 7.93–7.88 (m, 2H), 7.42 (s, 1H), 7.41–7.38 (m, 1H), 3.63–3.60 (m, 4H), 3.30–3.22 (m, 2H), 2.78–2.74 (m, 4H). The analogs in the following table were prepared using the same method described for Example 83.
methylcyclohexyl)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 148) Step 1: N-(5,6-difluoro-1H-indol-3-yl)propiolamide 5,6-difluoro-1H-indol-3-amine hydrogen chloride (730.0 mg, 3.6 mmol, 1.0 equiv.) was dissolved in THF (30 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 (wt. 50% in ethyl acetate, 0.7 mL, 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 column, 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: 5-azido-3-fluoro-2-(1-methylcyclohexyl)pyridine 5-Fluoro-6-(1-methylcyclohexyl)pyridin-3-amine (300.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in ACN (6 mL) and cooled to 0 °C, then t-BuNO2 (0.5 mL, 4.3 mmol, 3.0 equiv.) was added dropwise, maintaining the mixture at 0 °C. After 30 min at 0 °C, TMSN3 (0.5 mL, 4.3 mmol, 3.0 equiv.) was added dropwise at 0 °C. The reaction mixture was stirred for an additional 2 hours at 0 °C, then quenched by the addition of water. The resulting mixture 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 5-azido-3-fluoro-2- (1-methylcyclohexyl)pyridine (260.0 mg) as a yellow oil. Step 3: N-(5,6-difluoro-1H-indol-3-yl)-1-[5-fluoro-6-(1-methylcyclohexyl)pyridin-3- yl]-1,2,3-triazole-4-carboxamide 5-Azido-3-fluoro-2-(1-methylcyclohexyl)pyridine (250.0 mg, 1.1 mmol, 1.0 equiv.) was dissolved in dioxane/water (5/0.5 mL), then N-(5,6-difluoro-1H-indol-3- yl)propiolamide (235.0 mg, 1.1 mmol, 1.0 equiv.), sodium ascorbate (21.2 mg, 0.1 mmol, 0.1 equiv.) and CuSO4 (17.0 mg, 0.1 mmol, 0.1 equiv.) were added. The reaction mixture was stirred for 15 hours at ambient temperature and then quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was further purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30×150mm 5μm; Mobile Phase A: Water (10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 35% B to 80% B in 7 min; 254 nm; RT1:6.95 min. This resulted in N-(5,6-difluoro-1H- indol-3-yl)-1-[5-fluoro-6-(1-methylcyclohexyl)pyridin-3-yl]-1,2,3-triazole-4- carboxamide (121.8 mg) as an off-white solid. LCMS Method K: [M+H]+ = 455.1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 10.63 (s, 1H), 9.50 (s, 1H), 9.09 (s, 1H), 8.42–8.38 (m, 1H), 7.93–7.85 (m, 1H), 7.85 (s, 1H), 7.42–7.38 (m, 1H), 2.34–2,32 (m, 2H), 1.59– 1.54 (m, 4H), 1.44–1.39 (m, 4H), 1.31 (s, 3H). The analogs in the following table were prepared using the same method described for Example 85. Example 98: N-(5,6-difluoro-1H-indol-3-yl)-1-(6-((4,4-difluoropiperidin-1- yl)methyl)-5-fluoropyridin-3-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 206) Step 1: 5-bromo-3-fluoropyridine-2-carbaldehyde 2,5-Dibromo-3-fluoropyridine (2.0 g, 7.8 mmol, 1.0 equiv.) was dissolved in THF (40 mL) and cooled to -78 °C. Then n-BuLi (2 M in THF, 8.0 mL, 16.0 mmol, 1.0 equiv.) was added dropwise, maintaining the solution at -78 °C. After 10 min, a solution of DMF (0.6 mL, 7.8 mmol, 1.0 equiv.) in THF (2 mL) was added dropwise at -78 °C and the reaction mixture was allowed to warm to ambient temperature and stirred for additional 2 hours. The reaction was quenched by the addition of saturated aqueous NH4Cl, extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 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 5-bromo-3-fluoropyridine-2-carbaldehyde (1.3 g) as a yellow oil. LCMS Method C: [M+H]+ = 204. Step 2: (5-bromo-3-fluoropyridin-2-yl)methanol 5-Bromo-3-fluoropyridine-2-carbaldehyde (1.3 g, 6.4 mmol, 1.0 equiv.) was dissolved in THF (20 mL) and cooled to 0 °C. Then NaBH4 (0.5 g, 12.7 mmol, 2.0 equiv.) was added in portions, maintaining the reaction mixture at 0 °C. The reaction mixture was stirred overnight at ambient temperature, and then quenched by the addition of saturated aqueous NH4Cl. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum to afford (5-bromo-3- fluoropyridin-2-yl)methanol (1.1 g) as a yellow oil. LCMS Method C: [M+H]+ = 206. Step 3: 5-bromo-2-(bromomethyl)-3-fluoropyridine (5-Bromo-3-fluoropyridin-2-yl)methanol (1.0 g, 4.9 mmol, 1.0 equiv.) was dissolved in DCM (10 mL) and cooled to 0 °C, then phosphorus tribromide (1.6 g, 5.8 mmol, 1.2 equiv.) was added, maintaining the solution at 0 °C. The reaction mixture was stirred for 2 hours at 0 °C and then diluted with ethyl acetate. The resulting solution was washed with saturated NaHCO3 aqueous, dried over anhydrous sodium sulfate and concentrated under vacuum to afford crude 5-bromo-2-(bromomethyl)-3-fluoropyridine (1.0 g) as a yellow oil. LCMS Method C: [M+H]+ = 206. Step 4: 5-bromo-2-[(4,4-difluoropiperidin-1-yl)methyl]-3-fluoropyridine 5-Bromo-2-(bromomethyl)-3-fluoropyridine (1.0 g, 3.7 mmol, 1.0 equiv.) was dissolved in ACN (10 mL), then 4,4-difluoropiperidine (540.5 mg, 4.5 mmol, 1.2 equiv.) and K2CO3 (1.5 g, 11.1 mmol, 3.0 equiv.) were added. The reaction mixture was heated to 60 °C for 4 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 Na2SO4 and concentrated under vacuum to afford crude 5-bromo-2-[(4,4- difluoropiperidin-1-yl)methyl]-3-fluoropyridine (800.0 mg) as a white solid. LCMS Method C: [M+H]+ = 309. Step 5: 5-azido-2-[(4,4-difluoropiperidin-1-yl)methyl]-3-fluoropyridine 5-Bromo-2-[(4,4-difluoropiperidin-1-yl)methyl]-3-fluoropyridine (800.0 mg, 2.6 mmol, 1.0 equiv.) was dissolved in EtOH (7 mL) and water (3 mL), then (1S,2S)-1,2- diethylcyclohexane (363.0 mg, 2.6 mmol, 1.0 equiv.), CuI (492.9 mg, 2.6 mmol, 1.0 equiv.) and azidosodium (336.5 mg, 5.2 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 80 °C for 2 hours, then cooled to ambient temperature and diluted with ethyl acetate. After removing the solid by filtration, the filtrate was 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 (1:1) to give 5-azido-2-[(4,4-difluoropiperidin-1-yl)methyl]-3-fluoropyridine (400.0 mg) as a brown solid. LCMS Method C: [M+H]+ = 272. Step 6: N-(5,6-difluoro-1H-indol-3-yl)-1-[6-[(4,4-difluoropiperidin-1- yl)methyl]-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxamide 5-Azido-2-[(4,4-difluoropiperidin-1-yl)methyl]-3-fluoropyridine (200.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in dioxane (10 mL) and water (1 mL), then N-(5,6- difluoro-1H-indol-3-yl)prop-2-ynamide (194.8 mg, 0.9 mmol, 1.2 equiv.), CuSO4 (11.8 mg, 0.1 mmol, 0.1 equiv.) and sodium ascorbate (14.7 mg, 0.1 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred overnight 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. The residue was purified by Prep-HPLC with the following condition: Column, XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; mobile phase, Water (10 mmol/L NH4HCO3+0.1% NH4OH) and ACN (40% Phase B up to 58% in 7 min); Detector, UV 254 nm. This resulted in N-(5,6-difluoro-1H-indol-3-yl)-1-[6-[(4,4-difluoropiperidin- 1-yl)methyl]-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxamide (25.0 mg) of as a yellow solid. LCMS Method F: [M+H]+ = 492. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 10.65 (s, 1H), 9.54 (s, 1H), 9.12 (d, J = 1.6 Hz, 1H), 8.51–8.48 (m, 1H), 7.93–7.88 (m, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.42–7.38 (m, 1H), 3.84 (s, 2H), 2.64–2.62 (m, 4H), 2.00–1.93 (m, 4H). Example 99/100: (R or S)-N-(5,6-difluoro-1H-indol-3-yl)-1-(6-(4,4- difluoropiperidin-1-yl-3,3,5,5-d4)-5-fluoropyridin-3-yl)-1H-1,2,3-triazole-4- carboxamide; Compound 162 (front peak, absolute stereochemistry unconfirmed) and Compound 163 (second peak, absolute stereochemistry unconfirmed).
The racemic (N-(5,6-difluoro-1H-indol-3-yl)-1-[5-fluoro-6-[3- (trifluoromethyl)pyrrolidin-1-yl]pyridin-3-yl]-1,2,3-triazole-4-carboxamide (Compound 200), (60.0 mg) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IE, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 15.5 min; Wave Length: 220/254 nm; RT1(min): 11.16; RT2(min): 13.16. This gave Compound 162 (front peak, 27.9 mg) as a white solid and Compound 163 (second peak, 25.3 mg) as a white solid. Compound 162: (R or S)-N-(5,6-difluoro-1H-indol-3-yl)-1-[5-fluoro-6-[3- (trifluoromethyl)pyrrolidin-1-yl]pyridin-3-yl]-1,2,3-triazole-4-carboxamide; LCMS Method H: [M+H]+ = 496. 1H NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H), 10.56 (s, 1H), 9.30 (s, 1H), 8.58 (d, J = 1.6 Hz, 1H), 8.21–8.17 (m, 1H), 7.92–7.87 (m, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.42–7.37 (m, 1H), 3.96–3.91 (m, 1H), 3.84–3.80 (m, 1H), 3.75– 3.71 (m, 2H), 3.41–3.38 (m, 1H), 2.29–2.26 (m, 1H), 2.14–2.09 (m, 1H). Compound 163: (R or S)-N-(5,6-difluoro-1H-indol-3-yl)-1-[5-fluoro-6-[3- (trifluoromethyl)pyrrolidin-1-yl]pyridin-3-yl]-1,2,3-triazole-4-carboxamide; LCMS Method H: [M+H]+ = 496. 1H NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H), 10.55 (s, 1H), 9.30 (s, 1H), 8.58 (d, J = 1.6 Hz, 1H), 8.21–8.17 (m, 1H), 7.92–7.87 (m, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.42–7.37 (m, 1H), 3.96–3.91 (m, 1H), 3.84–3.80 (m, 1H), 3.75– 3.71 (m, 2H), 3.41–3.38 (m, 1H), 2.29–2.26 (m, 1H), 2.14–2.09 (m, 1H). Example 101: 1-(6-cyclohexyl-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3- yl)-1H-1,2,3-triazole-4-carboxamide (Compound 170) Step 1: 1-(6-(cyclohex-1-en-1-yl)-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H- indol-3-yl)-1H-1,2,3-triazole-4-carboxamide 1-(6-bromo-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl)-1H-1,2,3-triazole- 4-carboxamide (130.7 mg, 0.3 mmol, 1.0 equiv.) and 2-(cyclohex-1-en-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (124.8 mg, 0.6 mmol, 2.0 equiv.) were dissolved in dioxane (3 mL). Then XPhos Pd G3 (12.7 mg, 0.015 mmol, 0.05 equiv.) and aqueous K3PO4(450 μl, 2M, 3.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated at 80 oC for 16 hours. The reaction mixture was concentrated to give 1-(6-(cyclohex-1-en-1-yl)-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl)-1H- 1,2,3-triazole-4-carboxamide which was used in the next step without further purification. Step 2: 1-(6-cyclohexyl-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl)- 1H-1,2,3-triazole-4-carboxamide 1-(6-(cyclohex-1-en-1-yl)-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl)-1H- 1,2,3-triazole-4-carboxamide (87.6, 0.2 mmol, 1.0 equiv.) was dissolved in DCM (2 mL). Then Pd(AcO)2 (2.2 mg, 0.01 mmol, 0.05 equiv.), AcOH (50 μl ) and TES (200 μl) were added under an atmosphere of nitrogen. The mixture was stirred at 30 °C for 16 hours. The mixture was concentrated under reduced pressure to remove dioxane. Then H2O (5 mL) was added and extracted with EtOAc, the organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by HPLC to give 1-(6- cyclohexyl-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl)-1H-1,2,3-triazole-4- carboxamide. MS-ESI, 441.2 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.15 (br s, 1 H), 10.62 (s, 1 H), 9.47 (s, 1 H), 9.06 (d, J=1.8 Hz, 1 H), 8.39 (dd, J=10.5, 2.0 Hz, 1 H), 7.97–7.78 (m, 2 H), 7.39 (dd, J=11.3, 7.0 Hz, 1 H), 3.10-3.05 (br t, 1 H), 1.89–1.56 (m, 7 H ), 1.45–1.22 (m, 3 H). The analogs in the following table were prepared using the same method described for Example 101.
Example 109: N-(5,6-difluoro-1H-indol-3-yl)-1-(5-fluoro-6-(5-azaspiro[2.4]heptan-5- yl)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 188) 1-(6-bromo-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl)-1H-1,2,3-triazole- 4-carboxamide (130.8 mg, 0.3 mmol, 1.0 equiv.) and 5-azaspiro[2.4]heptane (58.3 mg, 0.6 mmol, 2.0 equiv.) were dissolved in t-AmOH (3 mL). Then K3PO4 (189.9 mg, 0.9 mmol, 3.0 equiv.) and RuPhos Pd G3 (12.5 mg, 0.15 mmol, 0.05 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated at 100 °C for 16 hours. The mixture was concentrated under reduced pressure to remove t-AmOH. Then H2O (5 mL) was added and extracted with EtOAc, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by HPLC to give N-(5,6-difluoro-1H- indol-3-yl)-1-(5-fluoro-6-(5-azaspiro[2.4]heptan-5-yl)pyridin-3-yl)-1H-1,2,3-triazole-4- carboxamide. MS-ESI, 454.2 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.14 (s, 1 H), 10.55 (s, 1 H), 9.26 (s, 1 H), 8.60–8.46 (m, 1 H), 8.11 (dd, J=13.55, 2.26 Hz, 1 H), 7.96–7.75 (m, 2 H), 7.50–7.30 (m, 1 H), 3.82–3.79 (td, J=6.78, 2.51 Hz, 2 H), 3.56 (d, J=2.76 Hz, 2 H), 1.89 (t, J=6.90 Hz, 2 H), 0.70–0.55 (m, 4 H). The analogs in the following table were prepared using the same method described for Example 109.
Biological Assays STING pathway activation by the compounds described herein was measured using THP1-Dual™ cells (KO-IFNAR2). THP1-Dual™ KO-IFNAR2 Cells (obtained from invivogen) were maintained in RPMI, 10% FCS, 5 ml P/S, 2mM L-glut, 10mM Hepes, and 1 mM sodium pyruvate. Compounds were spotted in empty 384 well tissue culture plates (Greiner 781182) by Echo for a final concentration of 0.0017 - 100 μM. Cells were plated into the TC plates at 40 μL per well, 2×10E6 cells/mL. For activation with STING ligand, 2'3'cGAMP (MW 718.38, obtained from Invivogen), was prepared in Optimem media. The following solutions were prepared for each 1×384 plate: o Solution A: 2 mL Optimem with one of the following stimuli: ^ 150 μM stock o Solution B: 2 mL Optimem with 60 μL Lipofectamine 2000 Æ 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 μL of transfection solution (A+B) was added on top of the plated cells, with a final 2’3’cGAMP concentration of 15 μM. The plates were then centrifuged immediately at 340 g for 1 minute, after which they were incubated at 37 oC, 5% CO2, >98% humidity for 24h. Luciferase reporter activity was then measured. EC50 values were calculated by using standard methods known in the art. Luciferase reporter assay: 10 μL of supernatant from the assay was transferred to white 384-plate with flat bottom and squared wells. One pouch of QUANTI-Luc™ Plus was dissolved in 25 mL of water. 100 μL of QLC Stabilizer per 25 mL of QUANTI- Luc™ Plus solution was added.50 μL of QUANTI-Luc™ Plus/QLC solution per well was then added. Luminescence was measured on a Platereader (e.g., Spectramax I3X (Molecular Devices GF3637001)). Luciferase reporter activity was then measured. EC50 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, Y1, Y2, and Y3 are independently selected from the group consisting of CR1, C(=O), N, and NR2; X1 is selected from the group consisting of O, S, N, NR2, and CR1; X2 is selected from the group consisting of O, S, N, NR4, and CR5; each is independently a single bond or a double bond, provided that the five- membered ring comprising X1 and X2 is heteroaryl, and that the six-membered ring comprising Z, Y1, Y2, and Y3 is aryl or heteroaryl; each R1 is independently selected from the group consisting of: H; Rc; Rg; and – (L1)b1-Rg; each R2 is independently selected from the group consisting of: H; Rd; Rg; and – (L2)b2-Rg; R4 is selected from the group consisting of: H and Rd; R5 is selected from the group consisting of: H; Rc; and Rh; R6 is selected from the group consisting of: H; Rd; and Rh; 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(Rd), 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 Rc, provided that Ring B is attached to the C(=O)NR6 group via a ring carbon atom; each LA is independently selected from the group consisting of: C1-3 alkylene optionally substituted with 1-2 Ra1; -O-; -NH-; -NRd; -S(O)0-2; and C(O); a1 is 0, 1, or 2; Ring C is selected from the group consisting of: x C3-12 cycloalkylene or C3-12 cycloalkenylene, each optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc and Rh; x 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(Rd), 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, Rc, and Rh; x heteroarylene of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc and Rh; and x C6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of Rc and Rh; R7 is selected from the group consisting of: Rg and –(L7)b7-Rg; each occurrence of Ra and Ra1 is independently selected from the group consisting of: –OH; -halo; –NReRf; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of Rc is independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; C1-4 haloalkoxy; -S(O)1-2(C1-4 alkyl); -S(O)(=NH)(C1-4 alkyl); -NReRf; –OH; -S(O)1-2NR’R’’; -C1-4 thioalkoxy; -NO2; -C(=O)(C1-10 alkyl); - C(=O)O(C1-4 alkyl); -C(=O)OH; -C(=O)NR’R’’; and –SF5; each occurrence of Rd is independently selected from the group consisting of: C1-6 alkyl optionally substituted with 1-3 independently selected Ra; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; C1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR’R’’, -OH, and Ri; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Rg is independently selected from the group consisting of: x C3-12 cycloalkyl or C3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc, Rh, and –(Lg)bg-Rh; x 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(Rd), 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, Rc, Rh, and –(Lg)bg-Rh; x heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc , Rh, and –(Lg)bg-Rh; and x C6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of Rc, Rh, and –(Lg)bg-Rh; each occurrence of Rh is independently selected from the group consisting of: x C3-12 cycloalkyl or C3-12 cycloalkenyl, each of which is optionally substituted with 1-4 Ri; x 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(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 Ri; x heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Ri; and x C6-10 aryl optionally substituted with 1-4 Ri; each occurrence of Ri is independently selected from the group consisting of: C1-6 alkyl; C1-4 haloalkyl; C1-4 alkoxy; C1-4 haloalkoxy; and halo; each occurrence of L1, L2, L7, and Lg is selected from the group consisting of: -O-, -NH-, -NRd , -S(O)0-2, C(O), and C1-3 alkylene optionally substituted with 1-3 Ra; b1, b2, b7, 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 C1-4 alkyl. 2. The compound of clause 1, wherein each of Z, Y1, Y2, and Y3 is independently N or CR1. 3. The compound of clauses 1 or 2, wherein the compound is a compound of Formula (Ia): Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein: R1a, R1b, R1c, and R1d are each an independently selected R1. 4. The compound of clauses 1 or 2, wherein 1-2 (such as 1) of Z, Y1, Y2, and Y3 is N; and each remaining of Z, Y1, Y2, and Y3 is an independently selected CR1. 5. The compound of any one of clauses 1-2 or 4, wherein the compound is selected from the group consisting of a compound of the following formulae: or a pharmaceutically acceptable salt thereof, wherein: R1a, R1b, R1c, and R1d are each an independently selected R1. 6. The compound of any one of clauses 1-5, wherein X1 is NR2. 7. The compound of any one of clauses 1-6, wherein X1 is NH. 8. The compound of any one of clauses 1-7, wherein X2 is CR5. 9. The compound of any one of clauses 1-8, wherein X2 is CH. 10. The compound of any one of clauses 1-5, wherein X1 is NR2; and X2 is CR5. 11. The compound of any one of clauses 1-5 or 10, wherein X1 is NH; and X2 is CH. 12. The compound of clause 1, wherein the compound is a compound of Formula (Ia-1): Formula (Ia-1) or a pharmaceutically acceptable salt thereof, wherein: R1a, R1b, R1c, and R1d are each an independently selected R1. 13. 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: R1a, R1b, R1c, and R1d are each an independently selected R1. 14. The compound of clauses 12 or 13, wherein R2 is H. 15. The compound of any one of clauses 12-14, wherein R5 is H. 16. The compound of any one of clauses 1-15, wherein each R1 is H. 17. The compound of any one of clauses 1-15, wherein 1-2 R1 is independently selected from the group consisting of: Rc1 and Rg1; and each remaining R1 is H, wherein Rc1 is an independently selected Rc; and Rg1 is an independently selected Rg. 18. The compound of clause 17, wherein two occurrences of R1 are independently selected from the group consisting of: Rc1 and Rg1; and each remaining R1 is H. 19. The compound of clauses 17 or 18, wherein two occurrences of R1 are independently selected Rc1; and each remaining R1 is H. 20. The compound of clause 17, wherein one occurrence of R1 is selected from the group consisting of: Rc1 and Rg1; and each remaining R1 is H. 21. The compound of clauses 17 or 20, wherein one occurrence of R1 is Rc1; and each remaining R1 is H. 22. The compound of clauses 17 or 20, wherein one occurrence of R1 is Rg1; and each remaining R1 is H. 23. The compound of any one of clauses 17-22, wherein each Rc1 is an independently selected halo, such as –F, -Cl, or –Br. 24. The compound of clause 23, wherein each Rc1 is independently –F or –Cl, such as –F. 25. The compound of any one of clauses 17-24, wherein each Rg1 is independently selected from the group consisting of: heteroaryl of 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc , Rh, and –(Lg)bg-Rh; and C6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of Rc, Rh, and –(Lg)bg-Rh. 26. The compound of clause 25, wherein each Rg1 is independently selected from the group consisting of: heteroaryl of 5-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 Rc; and C6 aryl optionally substituted with 1-4 Rc. 27. The compound of clauses 25 or 26, wherein each Rg1 is independently heteroaryl of 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 Rc. 28. The compound of clause 27, wherein each Rg1 is pyrazolyl that is optionally substituted with 1-2 Rc, such as 1-2 independently selected C1-6 (e.g., C1-3) alkyl which is optionally substituted with 1-6 independently selected Ra (e.g., unsubstituted). 29. The compound of any one of clauses 3, 5, or 12-13, wherein R1a H. 30. The compound of any one of clauses 3, 5, 12-13, or 29, wherein R1b is H. 31. The compound of any one of clauses 3, 5, 12-13, or 29 wherein R1b is halo, such as –F or –Cl (e.g., -F). 32. The compound of any one of clauses 3, 5, 12-13, or 29, wherein R1b is heteroaryl of 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-2 Rc. 33. The compound of clause 32, wherein R1b is pyrazolyl that is optionally substituted with 1-2 Rc, such as each Rc is an independently selected C1-6 (e.g., C1-3) alkyl which is optionally substituted with 1-6 independently selected Ra (e.g., unsubstituted). 34. The compound of any one of clauses 3, 5, 12-13, or 29-33, wherein R1c is H. 35. The compound of any one of clauses 3, 5, 12-13, or 29-33, wherein R1c is halo, such as –F or –Cl (e.g., -F). 36. The compound of any one of clauses 3, 5, 12-13, or 29-35, wherein R1d is H. 37. The compound of any one of clauses 3, 5, 12-13, or 29-35, wherein R1d is halo, such as –F or –Cl (e.g., -F). 38. The compound of any one of clauses 3, 5, or 12-13, wherein R1a and R1d are H; and R1b and R1c are independently selected halo, such as –F or –Cl, such as –F. 39. The compound of any one of clauses 3, 5, or 12-13, wherein R1a and R1d are H; one of R1b and R1c is H; and the other one of R1b and R1c is halo, such as –F or –Cl, such as –F. 40. The compound of any one of clauses 3, 5, or 12-13, wherein R1a and R1d are H; R1c is halo or H, such as –F, -Cl, or H; and R1b is heteroaryl of 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 Rc. 41. The compound of any one of clauses 1-40, wherein R6 is H. 42. The compound of any one of clauses 1-41, wherein Ring B is a heteroarylene of 5 ring atoms, wherein 1-3 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, O, and S, wherein the heteroarylene of Ring B is optionally substituted with 1-2 RcB; and each RcB is an independently selected Rc. 43. The compound of any one of clauses 1-42, wherein Ring B is a heteroarylene of 5 ring atoms, wherein 2-3 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(Rd), O, and S (such as N and NH), wherein the heteroarylene of Ring B is optionally substituted with 1-2 RcB; and each RcB is an independently selected Rc. 44. The compound of clause 43, wherein Ring B is selected from the group consisting of imidazolylene, pyrazolylene, or triazolylene (such as 1,2,3-triazolylene) which is optionally substituted with one RcB. 45. The compound of clause optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. 46. The compound of clause which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. 47. The compound of clause optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. 48. The compound of clause 44, wherein Ring B is , each of which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. 49. The compound of any one of clauses 42-48 or 163-169, wherein each RcB is independently halo or C1-3 alkyl optionally which is optionally substituted 1-3 independently selected Ra (such as 1-3 independently selected halo). 50. The compound of any one of clauses 1-49 or 163-169, wherein a1 is 0. 51. The compound of any one of clauses 1-49 or 163-169, wherein a1 is 1. 52. The compound of any one of clauses 1-49, 51, or 163-169, wherein LA is C1-3 alkylene optionally substituted with 1-2 Ra1. 53. The compound of clause 52, wherein LA is CH2 or CH(Me), such as CH2. 54. The compound of any one of clauses 1-53 or 163-169, wherein Ring C is selected from the group consisting of: x heteroarylene of 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of RcC and RhC; and x C6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of RcC and RhC, wherein each RcC is an independently selected Rc; and each RhC is an independently selected Rh. 55. The compound of any one of clause 54 or 163-169, wherein Ring C is selected from the group consisting of: x heteroarylene of 5-6 (such as 6) ring atoms, wherein 1-3 (such as 1-2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of RcC; and x C6 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of RcC. 56. The compound of any one of clauses 54, 55 or 163-169, wherein Ring C is selected from the group consisting of: x pyridylene optionally substituted with 1-3 (such as 1) substituents independently selected from the group consisting of RcC; and x C6 arylene optionally substituted with 1-4 (such as 1-2) substituents independently selected from the group consisting of RcC. 57. The compound of any one of clauses 54-56 or 163-169, wherein Ring C is , wherein each one of Q1, Q2, Q3, and Q4 is independently selected from the group consisting of N, CH, and CRcC; and bb is the point of connection to R7. 58. The compound of any one of clauses 57 or 163-169, wherein Q2 is CH. 59. The compound of any one of clauses 57 , 58 or 163-169, wherein Q3 is CH. 60. The compound of any one of clauses 57-59 or 163-169, wherein Q4 is N. 61. The compound of any one of clauses 57-60 or 163-169, wherein Q1 is CH. 62. The compound of any one of clauses 57-60 or 163-169, wherein Q1 is CRcC. 63. The compound of any one of clause 57 or 163-169, wherein Ring C is 64. The compound of any one of clauses 54-63 or 163-169, wherein each RcC is independently selected from the group consisting of: -halo and C1-6 (e.g., C1-3) alkyl which is optionally substituted with 1-6 independently selected Ra (e.g., 1-6 independently selected halo, such as –F). 65. The compound of any one of clauses 54-64 or 163-169, wherein each RcC is independently halo, such as –Cl or –F, such as –F. 66. The compound of any one of clauses 1-65 or 170-173, wherein R7 is Rg. 67. The compound of any one of clauses 1-66 or 170-173 , wherein R7 is selected from the group consisting of: x C3-12 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc7, Rh7, and –(Lg)bg-Rh7; and x heterocyclyl of 4-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc7, Rh7, and –(Lg)bg-Rh7, wherein each Rc7 is an independently selected Rc; and Rh7 is an independently selected Rh. 68. The compound of any one of clauses 67 or 170-173, wherein R7 is selected from the group consisting of: x C4-8 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc7, and Rh7; and x heterocyclyl of 4-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc7, and Rh7. 69. The compound of any one of clauses 68 or 170-173, wherein R7 is selected from the group consisting of: x C6 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7; and x heterocyclyl of 6 ring atoms, wherein 1-2 (such as one) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7. 70. The compound of any one of clauses 69 or 170-173, wherein R7 is a group of the following formula: , wherein X7 is CH, CRc7, or N, such as CH or N. 71. The compound of any one of clauses 69 , 70 or 170-173, wherein two Rc7 groups are present. 72. The compound of any one of clauses 1-71 or 170-173, wherein R7 is a group of the following formula: , wherein X7 is N or CH; and each Rc7 is an independently selected Rc. 73. The compound of any one of clauses 67-72 or 170-173, wherein each Rc7 is an independently selected halo or C1-3 alkyl optionally substituted with 1-6 Ra (e.g., 1-6 independently selected halo). 74. The compound of any one of clauses 67-73 or 170-173, wherein each Rc7 is independently halo, such as –F. 75. The compound of any one of clauses 1-74 or 170-173, wherein , wherein X7 is N or CH. 76. The compound of clause 1, wherein the compound is a compound of Formula (I-a1-1):
Formula (I-a1-1) or a pharmaceutically acceptable salt thereof, wherein: each one of R1a, R1b, R1c, and R1d is an independently selected R1; B4 is C or N; B1, B2, and B3 are each independently CH, CRcB, NH, N(Rd), N, O, or S; Q1, Q2, Q3, and Q4 are each independently selected from the group consisting of N, CH, and CRcC; each occurrence of RcB and RcC is an independently selected Rc; and each is independently a single bond or a double bond provided that the ring including B1-B4 is a heteroaryl. 77. The compound of clause 76, wherein R1a and R1d are H; and R1b and R1c are independently H or halo, such as halo (such as –F or –Cl, such as –F). 78. The compound of clause 76, wherein each one of R1a, R1b, R1c, and R1d is H. 79. The compound of clause 76, wherein R1a and R1d are H; R1c is halo or H, such as –F, -Cl, or H; and R1b is heteroaryl of 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc. 80. The compound of any one of clauses 76-79, wherein R2 is H. 81. The compound of any one of clauses 76-80, wherein R5 is H. 82. The compound of any one of clauses 76-81, wherein R6 is H. 83. The compound of any one of clauses 76-82, wherein R2 is H; R5 is H; and R6 is H. 84. The compound of any one of clauses 76-83, wherein B4 is N; B1 is N; B3 is CH; and B2 is CH. 85. The compound of any one of clauses 76-83, wherein B4 is N; B1 is N; B3 is CH; and B2 is N. 86. The compound of any one of clauses 76-83, wherein B4 is N; B1 is N; B3 is CH; and B2 is CRcB. 87. The compound of any one of clauses 76-83, wherein B4 is N; B1 is CH; B3 is CH; and B2 is N. 88. The compound of any one of clauses 76-83, wherein B4 is N; B1 is CH; B3 is N; and B2 is CH. 89. The compound of any one of clauses 76-88, wherein a1 is 0. 90. The compound of any one of clauses 76-88, wherein a1 is 1. 91. The compound of any one of clauses 76-88 or 90, wherein LA is CH2 or CH(Me). 92. The compound of any one of clauses 76-91, wherein Q1 and Q3 are CH. 93. The compound of any one of clauses 76-92, wherein Q4 is N; and Q2 is CH or CRcC, such as CRcC. 94. The compound of any one of clauses 76-93, wherein the ring including Q1- Q4 is: , wherein bb is the point of connection to R7. 95. The compound of any one of clauses 76-94, wherein RcC is halo, such as – F or –Cl, such as –F. 96. The compound of any one of clauses 76-95, wherein R7 is selected from the group consisting of: x C6 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7; and x heterocyclyl of 6 ring atoms, wherein 1-2 (such as one) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7, wherein each Rc7 is an independently selected Rc. 97. The compound of clause 96, wherein R7 is a group of the following formula: , wherein X7 is CH, CR7, or N, such as CH or N. 98. The compound of clauses 96 or 97, wherein two Rc7 groups are present. 99. The compound of any one of clauses 76-98, wherein R7 is a group of the following formula: , wherein X7 is N or CH; and each Rc7 is an independently selected Rc. 100. The compound of any one of clauses 96-99, wherein each Rc7 is an independently selected halo or C1-3 alkyl optionally substituted with 1-6 Ra (e.g., 1-6 independently selected halo). 101. The compound of any one of clauses 96-100, wherein each Rc7 is independently halo, such as –F. 102. The compound of any one of clauses 76-101, wherein , wherein 103. The compound of clause 1, wherein the compound is selected from the group consisting of the compounds delineated in Table C1, or a pharmaceutically acceptable salt thereof. 104. A pharmaceutical composition comprising a compound of clauses 1-103 and one or more pharmaceutically accetapble excipients. 105. 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 1-103; or a pharmaceutical composition as defined in clause 104. 106. The method of clause 105, wherein the inhibiting comprises antagonizing STING. 107. The method of any one of clauses 105-106, which is carried out in vitro. 108. The method of clause 107, wherein the method comprises contacting a sample comprising one or more cells comprising STING with the compound. 109. The method of clause 107 or 108, wherein the one or more cells are one or more cancer cells. 110. The method of clause 108 or 109 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. 111. The method of clause 105 or 106, which is carried out in vivo. 112. The method of clause 111, 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. 113. The method of clause 112, wherein the subject is a human. 114. The method of clause 113, wherein the disease is cancer. 115. The method of clause 114, 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. 116. The method of clause 114 or 115, wherein the cancer is a refractory cancer. 117. The method of clause 112, wherein the compound is administered in combination with one or more additional cancer therapies. 118. The method of clause 117, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof. 119. The method of clause 118, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents. 120. The method of clause 119, 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, Muromonab-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-β (TGFβ), 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, OX40–OX40 ligand, GITR, GITR ligand – GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25–TL1A, CD40L, CD40– CD40 ligand, HVEM–LIGHT–LTA, HVEM, HVEM – BTLA, HVEM – CD160, HVEM – LIGHT, HVEM–BTLA–CD160, 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). 121. The method of any one of clauses 112-120, wherein the compound is administered intratumorally. 122. 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- 103, or a pharmaceutical composition as defined in clause 104. 123. The method of clause 122, 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. 124. The method of clause 122 or 123, wherein the cancer is a refractory cancer. 125. The method of clause 122, wherein the compound is administered in combination with one or more additional cancer therapies. 126. The method of clause 125, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof. 127. The method of clause 126, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents. 128. The method of clause 126, 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, Muromonab-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-β (TGFβ), 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, OX40–OX40 ligand, GITR, GITR ligand – GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25–TL1A, CD40L, CD40– CD40 ligand, HVEM–LIGHT–LTA, HVEM, HVEM – BTLA, HVEM – CD160, HVEM – LIGHT, HVEM–BTLA–CD160, 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). 129. The method of any one of clauses 122-128, wherein the compound is administered intratumorally. 130. 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 1-103, or a pharmaceutical composition as defined in clause 104. 131. The method of clause 130, wherein the subject has cancer. 132. The method of clause 131, wherein the subject has undergone and/or is undergoing and/or will undergo one or more cancer therapies. 133. The method of clause 131, 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. 134. The method of clause any one of clauses 131-133, wherein the cancer is a refractory cancer. 135. The method of clause 130, wherein the immune response is an innate immune response. 136. The method of clause 135, wherein the at least one or more cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof. 137. The method of clause 136, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents. 138. The method of clause 137, 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, Muromonab-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-β (TGFβ), 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, OX40–OX40 ligand, GITR, GITR ligand – GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25–TL1A, CD40L, CD40– CD40 ligand, HVEM–LIGHT–LTA, HVEM, HVEM – BTLA, HVEM – CD160, HVEM – LIGHT, HVEM–BTLA–CD160, 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). 139. 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 1-103, or a pharmaceutical composition as defined in clause 104. 140. 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 1-103, or a pharmaceutical composition as defined in clause 104. 141. A method of treatment comprising administering to a subject a compound as defined in any one of clauses 1-103, or a pharmaceutical composition as defined in clause 104, 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. 142. The method of any one of clauses 139-141, wherein the disease is cancer. 143. The method of clause 142, 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 142 or 143, wherein the cancer is a refractory cancer. 145. The method of any one of clauses 142-144, wherein the compound is administered in combination with one or more additional cancer therapies. 146. The method of clause 145, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof. 147. The method of clause 146, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents. 148. The method of clause 147, 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, Muromonab-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-β (TGFβ), 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, OX40–OX40 ligand, GITR, GITR ligand – GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25–TL1A, CD40L, CD40– CD40 ligand, HVEM–LIGHT–LTA, HVEM, HVEM – BTLA, HVEM – CD160, HVEM – LIGHT, HVEM–BTLA–CD160, 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). 149. The method of any one of clauses 139-148, wherein the compound is administered intratumorally. 150. 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 1-103, or a pharmaceutical composition as defined in clause 104. 151. The method of clause 150, wherein the disease, disorder, or condition is selected from type I interferonopathies, Aicardi-Goutières Syndrome (AGS), genetic forms of lupus, inflammation-associated disorders, and rheumatoid arthritis. 152. The method of clause 151, wherein the disease, disorder, or condition is a type I interferonopathy (e.g., STING-associated vasculopathywith onset in infancy (SAVI)). 153. The method of clause 152, wherein the type I interferonopathy is STING- associated vasculopathy with onset in infancy (SAVI)). 154. The method of clause 151, wherein the disease, disorder, or condition is Aicardi-Goutières Syndrome (AGS). 155. The method of clause 151, wherein the disease, disorder, or condition is a genetic form of lupus. 156. The method of clause 151, wherein the disease, disorder, or condition is inflammation-associated disorder. 157. The method of clause 156, wherein the inflammation-associated disorder is systemic lupus erythematosus. 158. A combination comprising a compounds defined in any one of clauses 1 to 103 or a pharmaceutially acceptable salt or tautomer thereof, and one or more therapeutically active agents. 159. A compound defined in any one of clauses 1 to 103 or a pharmaceutially acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 104, for use as a medicament. 160. A compound defined in any one of clauses 1 to 103 or a pharmaceutially acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 104, for use in the treatment of a disease, condition or disorder modulated by STING inhibition. 161. A compound defined in any one of clauses 1 to 103 or a pharmaceutially acceptable salt or tautomer thereof, or the pharmaceutical composition defined in clause 104, for use in the treatment of a disease mentioned in any one of clauses 105 to 157. 162. Use of a compound defined in any one of clauses 1 to 103 or a pharmaceutially acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 104, in the manufacture of a medicament for the treatment of a disease mentioned in in any one of clauses 105 to 157. 163. The compound of clause 43, wherein Ring B is selected from the group consisting of isoxazolylene, oxadiazolylene, oxazolylene, thiazolylene, isothiazolylene, or thiadiazolylene, which is optionally substituted with one RcB. 164. The compound of clause or each of which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. 165. The compound of clause 43 or 163, wherein Ring each of which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. 166. The compound of clause 43 or 163, wherein Ring each of which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. 167. The compound of clause 43 or 163, wherein Ring which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1.
168. The compound of clause 43 or 163, wherein Ring or each of which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. 169. The compound of clause 43 or 163, wherein Ring or each of which is optionally substituted with one RcB, wherein aa is the point of connection to (LA)a1. 170. The compound of clause 68, wherein R7 is selected from the group consisting of: x C4-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7; and x heterocyclyl of 5-6 ring atoms, wherein 1-2 (such as one) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7. 171. The compound of clause 68, wherein R7 is a group of the following formula: wherein X7 is CH, CRc7, or N, such as CH or N. 172. The compound of clause 68, wherein R7 is a group of the following formula: wherein Rd is is independently selected from the group consisting of: C1-6 alkyl optionally substituted with 1-3 independently selected Ra, wherein m7 is 0 or 1. 173. The compound of clause 68, wherein R7 is selected from the group consisting of tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octanyl, or 2- azabicyclo[2.2.1]heptanyl, each of which is optionally substituted with 1-2 Rc7. For

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein: Z, Y1, Y2, and Y3 are independently selected from the group consisting of CR1, C(=O), N, and NR2; X1 is selected from the group consisting of O, S, N, NR2, and CR1; X2 is selected from the group consisting of O, S, N, NR4, and CR5; each is independently a single bond or a double bond, provided that the five- membered ring comprising X1 and X2 is heteroaryl, and that the six-membered ring comprising Z, Y1, Y2, and Y3 is aryl or heteroaryl; each R1 is independently selected from the group consisting of: H; Rc; Rg; and – (L1)b1-Rg; each R2 is independently selected from the group consisting of: H; Rd; Rg; and – (L2)b2-Rg; R4 is selected from the group consisting of: H and Rd; R5 is selected from the group consisting of: H; Rc; and Rh; R6 is selected from the group consisting of: H; Rd; and Rh; 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(Rd), 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 Rc, provided that Ring B is attached to the C(=O)NR6 group via a ring carbon atom; each LA is independently selected from the group consisting of: C1-3 alkylene optionally substituted with 1-2 Ra1; -O-; -NH-; -NRd ; -S(O)0-2; and C(O); a1 is 0, 1, or 2; Ring C is selected from the group consisting of: x C3-12 cycloalkylene or C3-12 cycloalkenylene, each optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc and Rh; x 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(Rd), 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, Rc , and Rh; x heteroarylene of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc and Rh; and x C6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of Rc and Rh; R7 is selected from the group consisting of: Rg and –(L7)b7-Rg; each occurrence of Ra and Ra1 is independently selected from the group consisting of: –OH; -halo; –NReRf; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of Rc is independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; C1-4 haloalkoxy; -S(O)1-2(C1-4 alkyl); -S(O)(=NH)(C1-4 alkyl); -NReRf; –OH; -S(O)1-2NR’R’’; -C1-4 thioalkoxy; -NO2; -C(=O)(C1-10 alkyl); - C(=O)O(C1-4 alkyl); -C(=O)OH; -C(=O)NR’R’’; and –SF5; each occurrence of Rd is independently selected from the group consisting of: C1-6 alkyl optionally substituted with 1-3 independently selected Ra; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; C1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR’R’’, -OH, and Ri; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Rg is independently selected from the group consisting of: x C3-12 cycloalkyl or C3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc, Rh, and –(Lg)bg-Rh; x 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(Rd), 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, Rc, Rh, and –(Lg)bg-Rh; x heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc , Rh, and –(Lg)bg-Rh; and x C6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of Rc, Rh, and –(Lg)bg-Rh; each occurrence of Rh is independently selected from the group consisting of: x C3-12 cycloalkyl or C3-12 cycloalkenyl, each of which is optionally substituted with 1-4 Ri; x 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(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 Ri; x heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Ri; and x C6-10 aryl optionally substituted with 1-4 Ri; each occurrence of Ri is independently selected from the group consisting of: C1-6 alkyl; C1-4 haloalkyl; C1-4 alkoxy; C1-4 haloalkoxy; and halo; each occurrence of L1, L2, L7, and Lg is selected from the group consisting of: -O-, -NH-, -NRd , -S(O)0-2, C(O), and C1-3 alkylene optionally substituted with 1-3 Ra; b1, b2, b7, 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 C1-4 alkyl.
2. The compound of claim 1, wherein the compound is a compound of Formula (Ia): Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein: R1a, R1b, R1c, and R1d are each an independently selected R1.
3. The compound of claim 1, wherein one of Z, Y1, Y2, and Y3 is N; and each remaining of Z, Y1, Y2, and Y3 is an independently selected CR1.
4. The compound of any one of claims 1-3, wherein X1 is NR2, and X2 is CR5; optionally wherein X1 is NH, and X2 is CH.
5. The compound of any one of claims 1-4, wherein 1-2 R1 is independently selected from the group consisting of: Rc and Rg; and each remaining R1 is H.
6. The compound of any one of claims 1-5, wherein each Rc is an independently selected halo, such as –F, -Cl, or –Br, such as wherein each Rc is independently –F or –Cl, such as –F; and each Rg is independently heteroaryl of 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 Rc.
7. The compound of claim 2 or of claims 4 to 6 when dependent on claim 2, wherein R1a and R1d are H; and R1b and R1c are independently selected halo, such as –F or –Cl, such as –F; or wherein R1a and R1d are H; one of R1b and R1c is H; and the other one of R1b and R1c is halo, such as –F or –Cl, such as –F; or wherein R1a and R1d are H; R1c is halo or H, such as –F, -Cl, or H; and R1b is heteroaryl of 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 Rc.
8. The compound of any one of claims 1-7, wherein Ring B is a heteroarylene of 5 ring atoms, wherein 2-3 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(Rd), O, and S, such as N and NH, wherein the heteroarylene of Ring B is optionally substituted with 1-2 Rc, such as: wherein Ring B is selected from the group consisting of imidazolylene, pyrazolylene, or triazolylene such as 1,2,3-triazolylene, each of which is optionally substituted with one Rc; such as: wherein the heteroarylene of Ring B is selected from: each of which is optionally substituted with one Rc; wherein aa is the point of connection to (LA)a1.
9. The compound of any one of claims 1-8, wherein a1 is 0; or wherein a1 is 1, and optionally LA is C1-3 alkylene optionally substituted with 1-2 Ra1, such as wherein LA is CH2 or CH(Me).
10. The compound of any one of claims 1-9, wherein Ring C is selected from the group consisting of: x heteroarylene of 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc and Rh; and x C6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of Rc and Rh; such as: wherein Ring C is selected from the group consisting of: x heteroarylene of 5-6, such as 6, ring atoms, wherein 1-3, such as 1-2, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc; and x C6 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of Rc; such as: wherein Ring C is selected from the group consisting of: x pyridylene optionally substituted with 1-3, such as 1, substituents independently selected from the group consisting of Rc; and x C6 arylene optionally substituted with 1-4, such as 1-2, substituents independently selected from the group consisting of Rc; such as: wherein Ring C is a group of the following formula: , wherein each one of Q1, Q2, Q3, and Q4 is independently selected from the group consisting of N, CH, and CRc; and bb is the point of connection to R7.
11. The compound of any one of claims 1-10, wherein R7 is selected from the group consisting of: x C3-12 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc7, Rh, and –(Lg)bg-Rh; and x heterocyclyl of 4-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc7, Rh, and –(Lg)bg-Rh, wherein each Rc7 is an independently selected Rc; such as: wherein R7 is selected from the group consisting of: x C4-8 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc7, and Rh; and x heterocyclyl of 4-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc7, and Rh; such as: wherein R7 is selected from the group consisting of: x C6 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7; and x heterocyclyl of 6 ring atoms, wherein 1-2,such as one, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rc7; such as: wherein R7 is a group of the following formula: , wherein X7 is CH, CRc7, or N, such as CH or N; such as: R7 is a group of the following formula: , wherein X7 is N or CH; and each Rc7 is an independently selected Rc; and optionally, wherein each Rc7 is an independently selected halo or C1-3 alkyl optionally substituted with 1-6 Ra, such as halo or C1-3 alkyl optionally substituted with 1-6 independently selected halo.
12. The compound of claim 1, wherein the compound is a compound of Formula (I-a1-1): Formula (I-a1-1) or a pharmaceutically acceptable salt thereof, wherein: each one of R1a, R1b, R1c, and R1d is an independently selected R1; B4 is C or N; B1, B2, and B3 are each independently CH, CRcB, NH, N(Rd), N, O, or S; Q1, Q2, Q3, and Q4 are each independently selected from the group consisting of N, CH, and CRcC; each occurrence of RcB and RcC is an independently selected Rc; and each is independently a single bond or a double bond provided that the ring including B1-B4 is a heteroaryl.
13. The compound of claim 1, wherein the compound is selected from the group consisting of the compounds delineated in Table C1, or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound of claims 1-13 and one or more pharmaceutically accetapble excipients.
15. A method for inhibiting STING activity, the method comprising contacting STING with a compound as claimed in any one of claims 1-13, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition as claimed in claim 14.
16. 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 claimed in any one of claims 1-13, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition as claimed in claim 14.
17. A method of treatment of disease, disorder, or condition associated with STING, such as a disease, disorder, or condition, in which increased STING signaling, such as excessive STING signaling, contributes to the pathology and/or symptoms and/or progression of the disease, such as cancer, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1- 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 14.
EP21751933.9A 2020-07-15 2021-07-15 Compounds and compositions for treating conditions associated with sting activity Pending EP4182028A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063052117P 2020-07-15 2020-07-15
PCT/US2021/041792 WO2022015957A1 (en) 2020-07-15 2021-07-15 Compounds and compositions for treating conditions associated with sting activity

Publications (1)

Publication Number Publication Date
EP4182028A1 true EP4182028A1 (en) 2023-05-24

Family

ID=77249909

Family Applications (1)

Application Number Title Priority Date Filing Date
EP21751933.9A Pending EP4182028A1 (en) 2020-07-15 2021-07-15 Compounds and compositions for treating conditions associated with sting activity

Country Status (8)

Country Link
EP (1) EP4182028A1 (en)
JP (1) JP2023540672A (en)
CN (1) CN116528862A (en)
AR (1) AR122976A1 (en)
PY (1) PY2157405A (en)
TW (1) TW202216685A (en)
UY (1) UY39328A (en)
WO (1) WO2022015957A1 (en)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN120004785A (en) 2018-07-03 2025-05-16 诺华制药股份有限公司 Compounds and compositions for treating diseases associated with STING activity
WO2020051424A1 (en) 2018-09-07 2020-03-12 Pic Therapeutics Eif4e inhibitors and uses thereof
TW202146393A (en) 2020-03-03 2021-12-16 美商皮克醫療公司 Eif4e inhibitors and uses thereof
EP4274824A1 (en) 2021-01-08 2023-11-15 IFM Due, Inc. Heterobicyclic compounds having an urea or analogue and their compositions for treating conditions associated with sting activity
IL310724A (en) 2021-08-10 2024-04-01 Ifm Due Inc Compounds and compositions for treating conditions associated with sting activity
CA3229560A1 (en) 2021-08-25 2023-03-02 Christopher L. Vandeusen Eif4e inhibitors and uses thereof
US12157732B2 (en) 2021-08-25 2024-12-03 PIC Therapeutics, Inc. eIF4E inhibitors and uses thereof
WO2024059559A1 (en) * 2022-09-12 2024-03-21 Hotspot Therapeutics, Inc. Isothiazolylcarboxamide compounds and their use in therapy
WO2024064358A1 (en) 2022-09-23 2024-03-28 Ifm Due, Inc. Compounds and compositions for treating conditions associated with sting activity
WO2026023667A1 (en) * 2024-07-25 2026-01-29 カルナバイオサイエンス株式会社 Phenylpiperazine derivative

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7927613B2 (en) 2002-02-15 2011-04-19 University Of South Florida Pharmaceutical co-crystal compositions
EP1710233A4 (en) * 2004-01-28 2009-07-15 Kissei Pharmaceutical Novel benzofuran derivative, medicinal composition containing the same, and uses of these
JP2007056004A (en) * 2005-07-26 2007-03-08 Kissei Pharmaceut Co Ltd New furopyridine derivative, pharmaceutical composition containing the same and application thereof
KR101263920B1 (en) * 2010-10-07 2013-05-14 서울대학교산학협력단 1H-Indazole compounds having GSK-3 inhibitory activity
US8497285B2 (en) 2010-12-03 2013-07-30 The Trustees Of The University Of Pennsylvania Therapy of autoimmune colitis using a TIP60 inhibitor
GB201201566D0 (en) * 2012-01-30 2012-03-14 Vernalis R&D Ltd New chemical compounds
CA2927009C (en) 2013-10-21 2019-04-23 Drexel University Use of sting agonists to treat chronic hepatitis b virus infection
WO2016115360A1 (en) * 2015-01-14 2016-07-21 Coferon, Inc. C-myc ligands capable of dimerizing in an aqueous solution, and methods of using same
EP3556362A1 (en) * 2018-04-16 2019-10-23 Ecole Polytechnique Federale De Lausanne (Epfl) Sting inhibitors
CN110396089A (en) * 2018-04-24 2019-11-01 杭州健昵福生物科技有限公司 Target compound and the application of kidney type glutaminase allosteric site
TW202043198A (en) * 2019-01-17 2020-12-01 美商Ｉｆｍ Ｄｕｅ有限公司 Compounds and compositions for treating conditions associated with sting activity

Also Published As

Publication number Publication date
CN116528862A (en) 2023-08-01
AR122976A1 (en) 2022-10-19
TW202216685A (en) 2022-05-01
PY2157405A (en) 2022-04-22
JP2023540672A (en) 2023-09-26
WO2022015957A1 (en) 2022-01-20
UY39328A (en) 2022-01-31

Similar Documents

Publication Publication Date Title
WO2020010092A1 (en) Compounds and compositions for treating conditions associated with sting activity
EP4182028A1 (en) Compounds and compositions for treating conditions associated with sting activity
WO2020010155A1 (en) Compounds and compositions for treating conditions associated with sting activity
EP4085051A1 (en) Compounds and compositions for treating conditions associated with sting activity
US12152018B2 (en) Compounds and compositions for treating conditions associated with STING activity
US20230002320A1 (en) Compounds and compositions for treating conditions associated with sting activity
WO2021067805A1 (en) Oxalamide heterobycyclic compounds and compositions for treating conditions associated with sting activity
WO2022015975A1 (en) Compounds and compositions for treating conditions associated with sting activity
WO2021067791A1 (en) Oxalamide compounds and compositions for treating conditions associated with sting activity
WO2022015977A1 (en) Compounds and compositions for treating conditions associated with sting activity
EP4182030A1 (en) Compounds and compositions for treating conditions associated with sting activity
WO2022150543A1 (en) Compounds and compositions for treating conditions associated with sting activity
WO2022015938A1 (en) Compounds and compositions for treating conditions associated with sting activity
US20240076285A1 (en) Compounds and compositions for treating conditions associated with sting activity
US20250136597A1 (en) Compounds and compositions for treating conditions associated with sting activity
WO2023137034A1 (en) Compounds and compositions for treating conditions associated with sting activity
WO2022150560A1 (en) Compounds and compositions for treating conditions associated with sting activity
EP4274826A1 (en) Oxalamide compounds and compositions for treating conditions associated with sting activity
US20240051970A1 (en) Compounds and compositions for treating conditions associated with sting activity
EP4384503A1 (en) Compounds and compositions for treating conditions associated with sting activity

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20230210

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: NOVARTIS PHARMA AG