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 .

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