WO2020150417A2 - Compounds and compositions for treating conditions associated with sting activity - Google Patents

Compounds and compositions for treating conditions associated with sting activity Download PDF

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WO2020150417A2
WO2020150417A2 PCT/US2020/013786 US2020013786W WO2020150417A2 WO 2020150417 A2 WO2020150417 A2 WO 2020150417A2 US 2020013786 W US2020013786 W US 2020013786W WO 2020150417 A2 WO2020150417 A2 WO 2020150417A2
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independently selected
alkyl
group
optionally substituted
compound
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PCT/US2020/013786
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French (fr)
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WO2020150417A3 (en
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Hans Martin Seidel
William R. Roush
Shankar Venkatraman
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Ifm Due, Inc.
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Publication of WO2020150417A2 publication Critical patent/WO2020150417A2/en
Publication of WO2020150417A3 publication Critical patent/WO2020150417A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
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    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING).
  • Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject
  • compositions containing the same as well as methods of using and making the same.
  • 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.
  • 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
  • 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-KB and MAP kinase activation. Following the initiation of signal transduction, STING is rapidly degraded, a step considered important in terminating the inflammatory response.
  • STING-associated vasculopathy with onset in infancy SAVI
  • TMEM173 the gene name of STING
  • STING is implicated in the pathogenesis of Aicardi- Goutieres Syndrome (AGS) and genetic forms of lupus.
  • AGS Aicardi- Goutieres 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).
  • Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human).
  • This disclosure also features compositions containing the same as well as methods of using and making the same.
  • An "antagonist" of STING includes compounds that, at the protein level, directly bind or modify STING such that an activity of STING is decreased, e.g., by inhibition, blocking or dampening agonist-mediated responses, altered distribution, or otherwise.
  • STING antagonists include chemical entities, which interfere or inhibit STING signaling.
  • A, B, W 1 , and W 2 can be as defined anywhere herein.
  • Z, Y 1 , Y 2 , Y 3 , R 6 , B, R 2N , L 3 , and R 4 can be as defined anywhere herein.
  • 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.
  • 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
  • one or more pharmaceutically acceptable excipients e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same.
  • 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 subject e.g., a human
  • increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease.
  • methods of treating a condition, disease or disorder ameliorated by antagonizing STING are featured, e.g., treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human).
  • the methods include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).
  • methods of treating cancer 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-Goutieres 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-Goutieres Syndrome
  • 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 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 genetically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).
  • a chemical entity described herein e.g., a compound described genetically 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 contributes to the pathology and/or symptoms and/or progression of the disease are featured.
  • the methods include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).
  • 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.
  • 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
  • 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-Goutieres 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-Goutieres 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 va
  • 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 topoisom erase; e.g., camptothecins, such as irinotecan and/or topotecan;.
  • an alkylating agent e.g.,
  • T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9 - TIM3, Phosphatidylserine - TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II
  • ICOS ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2,
  • Butyrophilins including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86 - CD28, CD86 - CTLA, CD80 - CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL 12, Phosphatidylserine, TIM3, Phosphatidylserine - TIM3, SIRPA-CD47, VEGF, Neuropilin, CD 160, CD30, and CD155 (e.g., CTLA-4 or PDl or PD-Ll).
  • CTLA-4 or PDl or PD-Ll e.g., CTLA-4 or PDl or PD-Ll
  • the subject can have cancer; e.g., the subject has undergone and/or is undergoing and/or will undergo one or more cancer therapies.
  • Non-limiting examples of cancer include melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma.
  • the cancer can be a refractory cancer.
  • the chemical entity can be administered intratumorally.
  • the methods can further include identifying the subject.
  • 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.
  • API refers to an active pharmaceutical ingredient.
  • 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.
  • An appropriate“effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.
  • 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. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.
  • pharmaceutically acceptable salt refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • 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.
  • 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, /V-m ethyl -D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
  • 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, /V-m ethyl -D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine,
  • 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.
  • primate e.g ., human
  • monkey cow, pig, sheep, goat
  • horse dog, cat, rabbit, rat
  • patient refers to a mammalian subject, such as a human.
  • treat 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 hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms.
  • Ci-io indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it.
  • Non-limiting examples include methyl, ethyl, No-propyl, N/V-butyl, «-hexyl.
  • 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., -OCH3).
  • alkylene refers to a divalent alkyl (e.g., -CH2-).
  • alkenyl refers to a hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds.
  • the alkenyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it.
  • alkynyl refers to a hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds.
  • the alkynyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it.
  • 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, and the like.
  • cycloalkyl as used herein includes cyclic hydrocarbon groups having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted.
  • cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Cycloalkyl may include multiple fused and/or bridged rings.
  • Non-limiting examples of fused/bridged cycloalkyl includes: bicyclo[TT0]butane, bicyclo[2.T0]pentane, bicyclo[l. Tl]pentane, bicyclo[3.T0]hexane, bicyclo[2. Tl]hexane, bicyclo[3.2.0]heptane, bicyclo[4. T0]heptane, bicyclo[2.2.1]heptane, bicyclo[3. Tl]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like.
  • Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.
  • cycloalkenyl as used herein includes partially unsaturated cyclic hydrocarbon groups having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkenyl group may be optionally substituted.
  • Examples of cycloalkenyl groups include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Cycloalkenyl groups may have any degree of saturation provided that none of the rings in the ring system are aromatic; and the cycloalkenyl group is not fully saturated overall. Cycloalkenyl may include multiple fused and/or bridged and/or spirocyclic rings.
  • 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 (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl), and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S.
  • heteroatoms independently selected from the group consisting of N, O, and S.
  • 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-i/]pyr
  • the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
  • heterocyclyl refers to a mon-, bi-, tri-, or polycyclic nonaromatic ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S 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
  • heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.
  • Heterocyclyl may include multiple fused and bridged rings.
  • fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2- azabicyclo[l. l.
  • 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]pentane, 4-azaspiro[2.5 ] octane, 1-azaspiro[3.5]nonane, 2- azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6- azaspiro[2.6]nonane, l,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5- diazaspiro[3 6]decane, 3 -azaspiro[5.5 Jundecane, 2-oxaspiro[2.2]pentane, 4- oxaspiro[2.5]octane, l-oxaspiro
  • atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms.
  • 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.
  • moiety encompasses the tautomeric form containing the moiety:
  • a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.
  • A is:
  • This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING).
  • Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human).
  • This disclosure also features compositions containing the same as well as methods of using and making the same.
  • W 1 and W 2 is -N(H)-, -N(R d )- (e.g., -N(H)- or -N(CI-3 alkyl)-), -N(H)- (W 12 )-, or -N(R d )-(W 12 )-,
  • W 1 and W 2 is a bond, -0-, -0-(W 12 )-, or C1-C 6 alkylene optionally substituted with from 1-3 R a (e.g., C1-C3, e.g., CFh, CHR a , or CR3 ⁇ 4;
  • W 12 is C1-C6 alkylene optionally substituted with from 1-3 R a ,
  • A is selected from the group consisting of:
  • heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R 2 ), O, S, and S(0)2, and wherein from 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR 1 , and CR 3 ; and
  • heteroaryl including from 7-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R 2 ), O, and S(0)o-2, and wherein from 3-19 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH2, CR 1 , CHR 1 , C(R')2, CR 3 , CHR 3 , and C(R 3 ) 2 ;
  • B is:
  • Ci-15 alkyl which is optionally substituted with from 1-6 independently selected R a ;
  • heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected R c ; or
  • heterocyclyl including from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R b ;
  • R 1 is:
  • U 1 is Ci- 6 alkylene, which is optionally substituted with from 1-6 R a ;
  • heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected R c , or
  • heterocyclyl including from 3-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R b , OR
  • Ci-io alkyl which is optionally substituted with from 1-6 independently selected R a ; each occurrence of R 2 is independently selected from the group consisting of:
  • Ci- 6 alkyl which is optionally substituted with from 1-4 independently selected R a ;
  • heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2;
  • Ci-15 alkyl which is optionally substituted with from 1-6 independently selected R a ;
  • Ci-4 alkoxy optionally substituted with Ci-4 alkoxy
  • R d is selected from the group consisting of: Ci-6 alkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); - C(0)0(Ci-4 alkyl); -CON(R’)(R”); -S(0)i.
  • R e and R f are independently selected from the group consisting of: H; Ci-6 alkyl; Ci-6 haloalkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); -C(0)0(Ci-4 alkyl); - CON(R’)(R”); -S(0)I-2(NR’R”); - S(0)i- 2 (Ci-4 alkyl); -OH; and CM alkoxy; or R e and R f together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to
  • -L 1 is a bond or C1-3 alkylene
  • -L 2 is -O-, -N(H)-, -S-, or a bond
  • R h is selected from:
  • heterocyclyl wherein the heterocyclyl includes from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, CM alkyl, and CM haloalkyl;
  • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci- 4 alkyl, and CM haloalkyl; and
  • W 1 and W 2 is -N(H)-, -N(R d )- (e.g., -N(H)- or -N(CI-3 alkyl)-), -N(H)- (W 12 )-, or -N(R d )-(W 12 )-,
  • W 1 and W 2 is a bond, -0-, -0-(W 12 )-, or C1-C 6 alkylene optionally substituted with from 1-3 R a (e.g., C1-C3, e.g., CFh, CHR a , or CR3 ⁇ 4;
  • W 12 is C1-C6 alkylene optionally substituted with from 1-3 R a ,
  • A is selected from the group consisting of:
  • heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R 2 ), O, S, and S(0)2, and wherein from 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR 1 , and CR 3 ; and
  • heteroaryl including from 7-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R 2 ), O, and S(0)o-2, and wherein from 3-19 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH2, CR 1 , CHR 1 , C(R 1 )2, CR 3 , CHR 3 , and C(R 3 ) 2 ;
  • Ci-15 alkyl which is optionally substituted with from 1-6 independently selected R a ;
  • heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected R c ; or
  • heterocyclyl including from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R b ;
  • R 1 is:
  • U 1 is Ci- 6 alkylene, which is optionally substituted with from 1-6 R a ;
  • heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected R c , or (d) heterocyclyl including from 3-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R b , OR
  • Ci-io alkyl which is optionally substituted with from 1-6 independently selected R a ; each occurrence of R 2 is independently selected from the group consisting of: (i) Ci- 6 alkyl, which is optionally substituted with from 1-4 independently selected R a ;
  • heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2;
  • Ci-15 alkyl which is optionally substituted with from 1-6 independently selected R a ;
  • R d is selected from the group consisting of: Ci- 6 alkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); - C(0)0(Ci-4 alkyl); -CON(R’)(R”); -S(0)i.
  • R e and R f are independently selected from the group consisting of: H; Ci- 6 alkyl; Ci- 6 haloalkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); -C(0)0(Ci-4 alkyl); - CON(R’)(R”); -S(0)I-2(NR’R”); - S(0)i-2(Ci-4 alkyl); -OH; and CM alkoxy; or R e and R f together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C 1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom
  • -L 1 is a bond or C1- 3 alkylene
  • -L 2 is -O-, -N(H)-, -S-, or a bond
  • R h is selected from:
  • heterocyclyl wherein the heterocyclyl includes from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, CM alkyl, and CM haloalkyl;
  • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci- 4 alkyl, and Ci-4 haloalkyl; and
  • Embodiments can include any one or more of the features delineated below and/or in the claims.
  • W 1 and W 2 is -N(H)-, -N(R d )- (e.g., -N(H)- or -N(CI- 3 alkyl)-), -N(H)- (W 12 )-, or -N(R d )-(W 12 )-,
  • A is selected from the group consisting of:
  • heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R 2 ), O, S, and S(0)2, and wherein from 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR 1 , and CR 3 ; and
  • heteroaryl including from 7-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R 2 ), O, and S(0)o-2, and wherein from 3-19 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR 3 , CHR 3 , and C(R 3 ) 2 ;
  • Ci-15 alkyl which is optionally substituted with from 1-6 independently selected R a ;
  • heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected R c ; or
  • heterocyclyl including from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R b ;
  • R 1 is:
  • heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected R c , or
  • heterocyclyl including from 3-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R b ,
  • Ci-10 alkyl which is optionally substituted with from 1-6 independently selected R a ; each occurrence of R 2 is independently selected from the group consisting of:
  • Ci- 6 alkyl which is optionally substituted with from 1-4 independently selected R a ;
  • heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2;
  • Ci-15 alkyl which is optionally substituted with from 1-6 independently selected R a ;
  • Ci-4 alkoxy optionally substituted with Ci-4 alkoxy
  • R d is selected from the group consisting of: Ci- 6 alkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); - C(0)0(Ci-4 alkyl); -CON(R’)(R”); -S(0)i.
  • R e and R f are independently selected from the group consisting of: H; Ci- 6 alkyl; Ci- 6 haloalkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); -C(0)0(Ci-4 alkyl); - CON(R’)(R”); -S(0)I- 2 (NR’R”); - S(0)I- 2 (CM alkyl); -OH; and CM alkoxy; or R e and R f together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C 1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom
  • -L 1 is a bond or C1-3 alkylene
  • -L 2 is -O-, -N(H)-, -S-, or a bond
  • R h is selected from:
  • heterocyclyl wherein the heterocyclyl includes from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, wherein the heterocyclyl is optionally substituted with from 1-4 independently selected R* 1 ’; • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected R* 1 ’; and
  • each occurrence of R’ and R” is independently selected from the group consisting of: H, Ci-4 alkyl, and C6-10 aryl optionally substituted with from 1-2 substituents selected from halo, Ci-4 alkyl, and Ci-4 haloalkyl; or R’ and R” together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from the group consisting of H and C 1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R’ and R”), which are each independently selected from the group consisting of N(H), N(R d ), O, and S.
  • A when A is heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R 2 ), O, S, and S(0)2, and wherein from 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR 1 , and CR 3 , then at least one ring atom is substituted with R 1 .
  • A is: heteroaryl including from 7-20 (e.g., 8-16) ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R 2 ), O, and S(0)o-2, and wherein from 3-19 (e.g., 4-15) ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH 2, CR 1 , CHR 1 , C(R 1 ) 2 , CR 3 , CHR 3 , and C(R 3 ) 2 .
  • A is: heteroaryl including from 8-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R 2 ), O, and S(0)o-2, and wherein from 4-9 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH2, CR 1 , CHR 1 , C(R 1 )2, CR 3 , CHR 3 , and C(R 3 ) 2 .
  • A is: heteroaryl including from 8-9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R 2 ), O, and S(0)o-2, and wherein from 4-8 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH2, CR 1 , CHR 1 , C(R 1 )2, CR 3 , CHR 3 , and C(R 3 ) 2 .
  • A is (A-l):
  • Z is selected from the group consisting of:
  • each of Y 1 , Y 2 , and Y 3 is independently selected from the group consisting of O, S, CH, CR 1 , CR 3 , N, NH, N(R 3 ), and NR 2 ;
  • Y 4 is C or N;
  • X° is C or N;
  • X 1 is selected from the group consisting of O, S, N, NH, NR 1 , NR 2 , CH, CR 1 , and CR 3 ;
  • X 2 is selected from the group consisting of O, S, N, NH, NR 1 , NR 2 , CH, CR 1 , and CR 3 ; and each— is independently a single bond or a double bond, provided that the five- membered ring comprising Y 4 , X°, X 1 , and X 2 is heteroaryl; and
  • the ring comprising Z, Y 1 , Y 2 , Y 3 , and Y 4 is aromatic (i.e., carbocyclic aromatic or heteroaromatic).
  • Z is selected from the group consisting of:
  • Z is selected from the group consisting of: CH, CR 1 , CR 3 , and N.
  • Z is selected from the group consisting of CH, CR 1 , and CR 3 (e.g., Z is CH).
  • each of Y 1 , Y 2 , and Y 3 is independently selected from the group consisting of CH, CR 1 , CR 3 , and N.
  • each of Y 1 , Y 2 , and Y 3 is independently selected from the group consisting of CH, CR 1 , and CR 3 .
  • one of Y 1 , Y 2 , and Y 3 is independently N.
  • each of the remaining Y 1 , Y 2 , and Y 3 is independently selected from the group consisting of CH, CR 1 , and CR 3 , provided that one or more of Y 1 , Y 2 , and Y 3 is independently CH.
  • the moiety is
  • the 3 ⁇ 4 moiety is m3 ⁇ R ) , wherein: the asterisk denotes point of attachment to Y 4 ; and
  • (A-l) e.g., when each of Y 1 , Y 2 , and Y 3 is independently selected from the group consisting of CH, CR 1 , CR 3 , and N), two of Y 1 , Y 2 , and Y 3 are independently N.
  • Y 4 is C.
  • X 1 is selected from the group consisting of O, S, N, CH, NH, NR 1 , and NR 2 .
  • X 1 is selected from the group consisting of NH, NR 1 , and NR 2 .
  • X 1 is selected from the group consisting of NH and NR 2 (e.g., NH or NAc (e.g., NH)).
  • X 1 is S.
  • X 1 is N or CH.
  • X 2 is selected from the group consisting of N, CH,
  • X 2 is selected from the group consisting of N, C(Ci- 3 alkyl), and CH.
  • X 2 is CH.
  • X° is N.
  • X° is C.
  • X 1 is NH, NR 1 , or NR 2 ; and X° is C.
  • X 1 is NH or NR 2 (e.g., NH or NAc (e.g.,
  • X 1 is NH, NR 1 , or NR 2 ; and X° is C (e.g., when X 1 is NH or NR 2 (e.g., NH or NAc (e.g., NH))
  • X 2 is selected from the group consisting of N, C(Ci-3 alkyl), and CH (e.g., X 2 is CH).
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • X 1 is N or CH; and X° is N.
  • X 2 is selected from the group consisting of N, C(Ci-3 alkyl), and CH (e.g., X 2 is CH).
  • A is:
  • X 1 is S
  • X 2 is selected from the group consisting of N, C(Ci-3 alkyl), and CH (e.g., X 2 is CH); and X° is C.
  • A is:
  • A is:
  • A is (A-2):
  • Z is selected from the group consisting of:
  • each of Y 1 and Y 3 is independently selected from the group consisting of O, S, CH, CR 1 , CR 3 , N, NH, N(R 3 ), and NR 2 ;
  • Y 4 is C or N
  • X° is selected from the group consisting of O, S, N, NH, NR 1 , NR 2 , CH, CR 1 , and CR 3 (e g ⁇ , X° is CH);
  • X 1 is selected from the group consisting of O, S, N, NH, NR 1 , NR 2 , CH, CR 1 , and CR 3
  • X 2 is selected from the group consisting of O, S, N, NH, NR 1 , NR 2 , CH, CR 1 , and CR 3
  • each— is independently a single bond or a double bond, provided that the five- membered ring comprising Y 4 , X 1 , and X 2 is heteroaryl;
  • the ring comprising Z, Y 1 , Y 3 , and Y 4 is aromatic (i.e., carbocyclic aromatic or heteroaromatic).
  • Z is selected from the group consisting of: CH,
  • Z is selected from the group consisting of CH, CR 1 , and CR 3 (e.g., Z is CH).
  • each of Y 1 and Y 3 is independently selected from the group consisting of CH, CR 1 , CR 3 , and N.
  • each of Y 1 and Y 3 is independently selected from the group consisting of CH, CR 1 , and CR 3 .
  • the moiety is
  • Y 4 is C.
  • X 1 is selected from group consisting of O, S, N, CH, NH, NR 1 , and NR 2 (e.g., X 1 is selected from NH and NR 2 (e.g., X 1 is NH)).
  • X° is selected from the group consisting of CH and
  • N e.g., X° is CH
  • X 2 is selected from the group consisting of CR 1 , CH, and N (e.g., X 2 is CH).
  • A is:
  • A is heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R 2 ), O, S, and S(0)2, and wherein from 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR 1 , and CR 3 ; provided that at least one ring atom is substituted with R 1 .
  • A is heteroaryl including 5 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R 2 ), O, and S, and wherein from 1-4 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR 1 , and CR 3 ; provided that at least one ring atom is substituted with R 1 .
  • A is heteroaryl including 5 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N , N(R 2 ), O, and S, and wherein from 1-4 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR 1 , and CR 3 ; provided that the heteroaryl is substituted with from 1-2 R 1 (e.g., 1).
  • U 7 is N or C
  • Z 2 is selected from CH, CR 2 , and N;
  • X 3 is selected from O, S, N, NH, NR 1 , NR 2 , CH, CR 1 , and CR 3 ; each of Y 5 and Y 6 is independently selected from O, S, CH, CR 1 , CR 3 , NR 1 , NR 2 , NH, and N; and
  • each— is independently a single bond or a double bond, provided that the five- membered ring comprising Y 5 , Y 6 , Y 7 , X 3 , and Z 2 is heteroaromatic.
  • each of Y 5 and Y 6 is independently selected from O, S, CH, CR 3 , NR 2 , NH, and N;
  • Y 5 and Y 6 when X 3 is selected from O, S, N, NH, NR 2 , CH, and CR 3 , then one of Y 5 and Y 6 is CR 1 or NR 1 (in certain embodiments, the other of Y 5 and Y 6 is selected from O, S, CH, CR 3 , NR 2 , NH, and N).
  • X 3 is NR 1 or CR 1 .
  • Z 2 is selected from N or CH.
  • Y 6 is selected from S, CH, CR 3 , and N.
  • Y 6 is selected from S, N and CH (e.g., Y 6 is CH; or Y 6 is S).
  • Y 5 is selected from CH, CR 3 , and N (e.g., CH and N).
  • Y 7 is C.
  • A is selected from:
  • X 3 is S, N, CH, CR 3 , NH, or NR 2 .
  • X 3 is selected from N, CH, or NH (e.g., CH or NH).
  • Z 2 is selected from N or CH (e.g., Z 2 is CH).
  • Y 6 is selected from CH and N (e.g., Y 6 is N).
  • Y 5 is selected from NR 1 and CR 1 .
  • A is selected from:
  • each occurrence of R 1 is independently selected from:
  • U 1 is Ci- 6 alkylene, which is optionally substituted with from 1-6 R a ;
  • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected R c , or
  • heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2 , and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R b ,
  • Ci-6 alkyl which is optionally substituted with from 1-6 independently selected R a .
  • R 1 is -(U 1 ) q -U 2 .
  • q is 0.
  • U 2 is C6-10 aryl, which is optionally substituted with from 1-4 R c .
  • U 2 is C6-10 aryl, which is optionally substituted with from 1-2 R c .
  • U 2 is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R c .
  • R c substituent on U 2 is selected from:
  • halo e.g., Cl, F
  • Ci-io alkyl which is optionally substituted with from 1-6 independently selected R a ;
  • each occurrence of R c substituent on U 2 is selected from: halo (e.g., Cl, F; e.g., F), cyano, Ci-6 alkyl, and Ci-4 haloalkyl.
  • R 1 is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R c .
  • each occurrence of R c substituent on U 2 is selected from the group consisting of: (a) halo (e.g., Cl, F); (b) cyano; (c) Ci-io alkyl which is optionally substituted with from 1-6 independently selected R a ; (f) Ci-4 haloalkyl; (g) Ci- 4 alkoxy; (h) Ci-4 haloalkoxy; and (m) -Ci-4 thioalkoxy.
  • each occurrence of R c substituent on U 2 is selected from: halo (e.g., Cl, F; e.g., F), cyano, Ci-6 alkyl, and Ci-4 haloalkyl.
  • R 1 is unsubstituted phenyl.
  • each occurrence of R 3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy (e.g., halo or cyano).
  • each occurrence of R 3 is independently halo (e.g., -F) or cyano.
  • each occurrence of R 2 is independently selected from:
  • Ci- 6 alkyl e.g., methyl
  • each occurrence of R 2 is independently selected from (viii) - S(0)i- 2 (Ci-4 alkyl) (e.g., S(0) 2 Me) and (iv) -C(0)(Ci- 4 alkyl) (e.g., C(O)Me).
  • each occurrence of R 3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy (e.g., halo or cyano).
  • R 3 can be halo (e.g., F) or cyano.
  • A is:
  • m3 1 or 2.
  • each occurrence of R 3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy (e.g., halo or cyano).
  • m3 can be 2; and each R 3 can be F.
  • R 3 can be halo (e.g., F) or cyano.
  • m3 1 or 2.
  • each occurrence of R 3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy (e.g., halo or cyano).
  • R 3 is halo or cyano (e.g., R 3 is cyano).
  • A is selected from the group consisting of:
  • R 1 is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R c .
  • each occurrence of R c is selected from: (a) halo (e.g., Cl, F); (b) cyano; (c) Ci-io alkyl which is optionally substituted with from 1-6 independently selected R a ; (f) Ci-4 haloalkyl; (g) Ci-4 alkoxy; (h) Ci-4 haloalkoxy; and (m) -Ci-4 thioalkoxy.
  • each occurrence of R c can be selected from: halo (e.g., Cl, F; e.g., F), cyano, Ci- 6 alkyl, and Ci-4 haloalkyl.
  • R 1 can be phenyl optionally substituted with one R c .
  • R 1 can be unsubstituted phenyl.
  • R c is heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R c .
  • each occurrence of R c is selected from: (a) halo (e.g., Cl, F); (b) cyano; (c) Ci-10 alkyl which is optionally substituted with from 1-6 independently selected R a ; (f) Ci-4 haloalkyl; (g) Ci-4 alkoxy; (h) Ci-4 haloalkoxy; and (m) -Ci-4 thioalkoxy.
  • each occurrence of R c can be selected from: halo (e.g., Cl, F; e.g., F), cyano, Ci-6 alkyl, and Ci-4 haloalkyl.
  • one of W 1 and W 2 is -N(H)- or -N(R d )- (e.g., -N(H)- or - N(CI-3 alkyl)-) ;
  • the other one of W 1 and W 2 is a bond, -0-, CH2, CHR a , or CR3 ⁇ 4.
  • W 1 is -NH-.
  • W 1 is CH2 or CH(CI-3 alkyl) (e.g., CH2).
  • W 1 is a bond
  • W 2 is a bond
  • W 2 is CH2 or CH(CI-3 alkyl) (e.g., CH2).
  • W 2 is -NH-.
  • W 1 is -NH-; and W 2 is a bond.
  • W 1 is -NH-; and W 2 is CH2 or CH(CI-3 alkyl) (e.g., CH2).
  • W 1 is -NH; and W 2 is -(W 12 )-0-*, -(W 12 )-N(H)-*, or - (W 12 )-N(R d )-*, wherein the asterisk represents point of attachment to B.
  • W 2 is -(W 12 )-N(H)-*, such as -C1-3 alkylene-N(H)-*, such as -CH2NH-*.
  • W 2 is -NH-; and W 1 is a bond.
  • W 2 is -NH-; and W 1 is CH2 or CH(CI-3 alkyl) (e.g., CH2).
  • B is phenyl substituted with from 1-4 R c .
  • each R c substituent of B is independently selected from the group consisting of:
  • Ci-io alkyl which is optionally substituted with from 1-6 independently selected R a ;
  • each R c substituent of B is independently selected from the group consisting of:
  • each R c substituent of B is independently selected from Ci- lo alkyl which is optionally substituted with from 1-6 independently selected R a .
  • each occurrence of R a is independently selected from: -halo (e.g., F); -OH; Ci-4 alkoxy; and Ci-4 haloalkoxy.
  • each R c substituent of B is Ci-io (e.g., Ci-6, C1-3, C1-2, Ci) alkyl optionally substituted with from 1-3 halo (e.g., F) (e.g., R c is CF 3 ).
  • each R c substituent of B is independently selected from unsubstituted Ci-10 (e.g., C2-io (e.g., C3-8)) alkyl.
  • each R c substituent of B is independently selected from unsubstituted Ci- 6 alkyl.
  • each R c substituent of B is independently selected from unsubstituted C2-6 (e.g., C2-4, e.g., C2 or C4) alkyl.
  • each R c substituent of B is ethyl or butyl (e.g., n-butyl).
  • R c is Ci- 6 alkyl optionally substituted with from 1-3 independently selected R a . In certain of the foregoing embodiments, R c is Ci- 6 alkyl substituted with from 1-3 independently selected R a .
  • B is C3-20 cycloalkyl, which is optionally substituted with from 1-4 R b .
  • B is C3-12 cycloalkyl, which is optionally substituted with from 1-2 R b .
  • B is C6-12 cycloalkyl, which is optionally substituted with from 1-2 R b .
  • B is C6-12 cycloalkyl (e.g.,
  • B is heterocyclyl including from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R b .
  • B is heterocyclyl including from 3-12 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R b .
  • B is heterocyclyl including from 3-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-3 independently selected R b .
  • B is heterocyclyl including from 5-6 (e.g., 6) ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-2 independently selected
  • each occurrence of R b is independently selected from the group consisting of: Ci-io alkyl; Ci-4 haloalkyl; -OH; oxo; -F; -Cl; Ci-4 alkoxy; and Ci-4 haloalkoxy.
  • the compound has Formula I-a:
  • R c is as defined in any one of claims 122-130 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
  • R c is Ci- 6 alkyl optionally substituted with from 1- 3 independently selected R a (e.g., R c can be Ci-4 (e.g., C2-4) alkyl; or R c can be CF3).
  • A is (A-l).
  • A is as defined in claim 37 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
  • A is as defined in claim 25.
  • A is: As a non-limiting example of the foregoing embodiments, A can be:
  • A is as defined in claims any one of claims 38-40 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
  • A is A is A is
  • A is: ein ml 0, 1, 2, or 3; and m3 0, 1, 2, or 3 (e.g., ml 0 or 1; and
  • A is (A-2).
  • A is:
  • A is (A-3).
  • A is selected from: In certain embodiments of [I-a], A is selected from:
  • m3 1 or 2.
  • each occurrence of R 3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy (e.g., halo or cyano).
  • R 3 is halo or cyano (e.g., R 3 is cyano).
  • R 1 is phenyl optionally substituted with from 1-2 independently substituted R c (e.g., unsubstituted phenyl).
  • A is H n orr R r2 ; and R 1 is -(U 1 ) q -U 2 .
  • q is 0; and U 2 is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R c ; or U 2 is heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R c .
  • each occurrence of R c is selected from: (a) halo (e.g., Cl, F); (b) cyano; (c) Ci-io alkyl which is optionally substituted with from 1-6 independently selected R a ; (f) Ci-4 haloalkyl; (g) Ci-4 alkoxy; (h) Ci-4 haloalkoxy; and (m) -Ci-4 thioalkoxy.
  • each occurrence of R c can be selected from: halo (e.g., Cl, F; e.g., F), cyano, Ci- 6 alkyl, and Ci-4 haloalkyl.
  • the compound has Formula I-b:
  • heterocyclyl including from 3-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-3 independently selected R b ; or
  • B 2 is heterocyclyl including from 3-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-3 independently selected R b .
  • B 2 is heterocyclyl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally
  • R b substituted with from 1-2 independently selected R b (e.g.,
  • B 2 is C3-12 cycloalkyl, which is optionally substituted with from 1-2 R b .
  • B 2 is C 6 -12 cycloalkyl, which is optionally substituted
  • A is (A-l).
  • A is A is:
  • A can be:
  • A is as defined in any one of claims 38-43 (e.g., any one of claims 38-40) of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • m3 0.
  • m3 1 or 2.
  • each occurrence of R 3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy (e.g., halo or cyano).
  • R 3 is halo or cyano (e.g., R 3 is cyano).
  • the compound has Formula I-c:
  • R w is H or C1-3 alkyl (e.g., H or Me (e.g., H));
  • R c is as defined in any one of claims 122-130 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
  • R c is Ci- 6 alkyl optionally substituted with from 1-3 independently selected R a (e.g., R c can be Ci-4 (e.g., C2-4) alkyl; or R c can be CF3).
  • A is (A-l).
  • A can be:
  • A is as defined in claims any one of claims 38-40 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
  • A is A is A is
  • A is (A-2).
  • A is (A-3).
  • A is selected from:
  • A is selected from: , and
  • A is H 0 r R , such as H
  • m3 0.
  • m3 1 or 2.
  • each occurrence of R 3 is independently selected from the group consisting of: halo, cyano, CM alkoxy, and CM haloalkoxy (e.g., halo or cyano).
  • R 3 is halo or cyano (e.g., R 3 is cyano).
  • R 1 is phenyl optionally substituted with from 1-2 independently substituted R c (e.g., unsubstituted phenyl). In certain embodiments
  • q is 0; and U 2 is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R c ; or U 2 is heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R c .
  • each occurrence of R c is selected from: (a) halo (e.g., Cl, F); (b) cyano; (c) Ci-io alkyl which is optionally substituted with from 1-6 independently selected R a ; (f) Ci-4 haloalkyl; (g) Ci-4 alkoxy; (h) Ci-4 haloalkoxy; and (m) -Ci-4 thioalkoxy.
  • each occurrence of R c can be selected from: halo (e.g., Cl,
  • F e.g., F
  • cyano Ci-6 alkyl
  • Ci-4 haloalkyl e.g., F
  • the compound has Formula I-d:
  • R c is as defined in any one of claims 122-130 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
  • R c is Ci-6 alkyl optionally substituted with from 1-3 independently selected R a (e.g., R c can be Ci-4 (e.g., C2-4) alkyl; or R c can be CF3).
  • A is (A-l).
  • A can be
  • A is as defined in any one of claims 38-43 (e.g., any one of claims 38-40) of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
  • A is (A-2).
  • A is A is:
  • A is (A-3).
  • A is as defined in any one of claims 66 and 72 of
  • R 3 is as defined in any one of claims 84-86 (e.g., R 3 can be halo (e.g., F) or cyano) ofU.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
  • R 3 can be halo (e.g., F) or cyano) ofU.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
  • R 1 is as defined in any one of claims 73-82 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
  • R 1 is phenyl optionally substituted with from 1-2 independently substituted R c (e.g., unsubstituted phenyl).
  • the compound has Formula I-e:
  • R w is H or C1-3 alkyl (e.g., H or Me (e.g., H));
  • R c is as defined in any one of claims 122-130 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
  • R c is Ci- 6 alkyl optionally substituted with from 1-3 independently selected R a (e.g., R c can be Ci-4 (e.g., C2-4) alkyl; or R c can be CF3).
  • A is (A-l).
  • A is:
  • A is as defined in any one of claims 38-43 (e.g., any one of claims 38-40) of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
  • A is (A-2).
  • A is (A-3).
  • A is as defined in any one of claims 66 and 72 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
  • R 3 is as defined in any one of claims 84-86 (e.g., R 3 can be halo (e.g., F) or cyano) ofU.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
  • R 3 can be halo (e.g., F) or cyano) ofU.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
  • R 1 is as defined in any one of claims 73-82 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
  • R 1 is phenyl optionally substituted with from 1-2 independently substituted R c (e.g., unsubstituted phenyl).
  • the compound has Formula I-f:
  • W 1 is attached to the carbon atom adjacent to * or the carbon atom adjacent to **;
  • ml is 0, 1, 2, or 3;
  • n2 0, 1, 2, or 3;
  • Z A and Z A are independently selected from the group consisting of N, CH, CR 1 , and
  • W 1 and W 2 is -N(H)- or -N(R d )- (e.g., -N(H)- or -N(CI-3 alkyl)-); and the other one of W 1 and W 2 is a bond or C1-C6 alkylene optionally substituted with from 1-3 R a (e.g., C1-C3, e.g., CH 2, CHR a , or CR a 2 ).
  • W 1 is -N(H)- or -N(R d )- (e.g., -N(H)- or -N(CI-3 alkyl)-);
  • W 2 is a bond or C1-C6 alkylene optionally substituted with from 1-3 R a (e.g., C1-C3, e.g, CH 2, CHR a , or CR a 2 ).
  • W 1 is -N(H)-
  • W 2 is a bond or CH2.
  • W 1 is -N(H)-
  • W 2 is a bond
  • W 1 is -N(H)-
  • W 2 is CH2.
  • W 1 is attached to the carbon atom adjacent to **.
  • Z A and Z A are each N.
  • ml is 0 or 1 and m2 is 1 or 2. In certain embodiments of [I-e], ml is 0 and m2 is 1. In certain of these embodiments, Z B is CR 3 and one R 3 is attached to the position of the indole ring between Z A and the Z B CR 3 .
  • each occurrence of R 3 is independently selected from the group consisting of halo, cyano, -NR e R f , -OH and -NO2. In some of these embodiments, each occurrence of R 3 is an independently selected halo. For example, each occurrence of R 3 is -F.
  • B is heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected R c .
  • B is heteroaryl including 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), N(R C ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected R c .
  • B is heteroaryl including 5 ring atoms, wherein 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), S, and N(R d ), N(R C ), and wherein the heteroaryl ring is optionally substituted with 1 independently selected R c .
  • B is heteroaryl including 6 ring atoms, wherein 2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R d ), and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R c .
  • B is selected from the group consisting of:
  • R c is Ci-15 alkyl which is optionally substituted with from 1-6 independently selected R a or -L'-L 2 -R h In some of these embodiments, R c is selected from the group consisting of: isopropyl, CF3, phenyl,
  • A is selected from the group consisting of:
  • nl is 0 or 1; and m3 is 0, 1, or 2;
  • B is selected from the group consisting of:
  • heteroaryl including from 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is substituted with from 1-4 independently selected R c ;
  • bicyclic or tricyclic heteroaryl including from 9-15 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected R c ; and
  • C5-15 alkyl which is optionally substituted with from 1-6 R a .
  • R 2N is H.
  • ml is 1.
  • m3 is 1 or 2.
  • ml is 0; and m3 is 1 or 2 (e.g., 2).
  • each R 3 can be halo (e.g., F).
  • each occurrence of R 3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy (e.g., R 3 can be halo).
  • R 1 is -(U 1 ) q -U 2 .
  • q is 0.
  • U 2 is C6-10 aryl, which is optionally substituted with from 1-4 R c .
  • U 2 is C6-10 aryl, which is optionally substituted with from 1-2 R c .
  • U 2 is phenyl, which is optionally substituted with from 1-2 (e.g., 1) R c .
  • each occurrence of R c substituent on U 2 is independently selected from: halo, cyano, Ci- 6 alkyl, and Ci-4 haloalkyl.
  • each occurrence of R c substituent on U 2 is independently selected from halo.
  • B is selected from the group consisting of:
  • each of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 is independently selected from the group consisting of N and CH, provided that at least one of Q 1 and Q 2 is N; and at least one of Q 3 , Q 4 , Q 5 , and Q 6 is N.
  • nl is 0.
  • nl is 1.
  • R cA is halo (e.g., -F, or -Cl) or Ci- 6 alkyl which is optionally substituted with from 1-3 independently selected R a (e.g., methyl or CF3).
  • R cB is Ci- 6 alkyl which is optionally substituted with from 1-6 independently selected R a .
  • R cB can be unsubstituted C2-10 (e.g., C2-3 , e.g., C3-4, e.g., C4-10) alkyl.
  • R cB can be Ci- 6 alkyl which is substituted with from 1-6 independently selected R a .
  • each R a can be halo (e.g., F), NR e R f , OH, Ci- 3 alkoxy, or C1-3 haloalkoxy.
  • R cB is -L 1 -L 2 -R h .
  • each of L 1 and L 2 is a bond.
  • L 1 is a bond; and L 2 is -0-.
  • R h is selected from the group consisting of:
  • heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, and Ci-4 haloalkyl; and
  • Ce aryl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, or Ci-4 haloalkyl.
  • B is heteroaryl including 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is substituted with from 1-4 independently selected R c , provided that one occurrence of R c is iAlAR* 1 .
  • each of L 1 and L 2 is a bond.
  • L 1 is a bond; and L 2 is -O-.
  • R h is selected from the group consisting of:
  • heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, and Ci-4 haloalkyl; and
  • Ce aryl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, or Ci-4 haloalkyl.
  • Z is selected from the group consisting of: CH, CR 1 , CR 3 , N, NH, N(R') and N(R 2 ); each of Y 1 , Y 2 , and Y 3 is independently selected from the group consisting of CH, CR 1 , CR 3 , N, NH, N(R 3 ), and NR 2 ;
  • each— is independently a single bond or a double bond, provided that:
  • the 6-membered ring comprising Z, Y 1 , Y 2 , and Y 3 is aromatic;
  • R 2N is H or R 2 ;
  • R 6 is selected from the group consisting of H and R d ;
  • B is a monocyclic heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R c ;
  • -L 3 is a bond or C1-3 alkylene
  • R 4 is selected from the group consisting of:
  • heterocyclyl including from 3-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heterocyclyl is optionally substituted with from 1-4 independently selected R 4 ’;
  • heteroaryl including from 5-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with from 1-4 independently selected R 4 ’; and
  • R 1 is:
  • U 1 is Ci-6 alkylene, which is optionally substituted with from 1-6 R a ;
  • Ci-io alkyl which is optionally substituted with from 1-6 independently selected R a ; each occurrence of R 2 is independently selected from the group consisting of:
  • Ci- 6 alkyl which is optionally substituted with from 1-4 independently selected R a ;
  • heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2;
  • each occurrence of R c is independently selected from the group consisting of:
  • Ci-15 alkyl which is optionally substituted with from 1-6 independently selected R a ;
  • Ci-4 alkoxy optionally substituted with Ci-4 alkoxy
  • R d is selected from the group consisting of: Ci- 6 alkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); -C(0)0(Ci- 4 alkyl); -CON(R’)(R”); -S(0)i.
  • R e and R f are independently selected from the group consisting of: H; Ci- 6 alkyl; Ci- 6 haloalkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); -C(0)0(Ci-4 alkyl); - CON(R’)(R”); -S(0)i- 2 (NR’R”); - S(0)i- 2 (Ci-4 alkyl); -OH; and CM alkoxy; or R e and R f together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atoms
  • -L 1 is a bond or C1-3 alkylene
  • -L 2 is -O-, -N(H)-, -S-, or a bond
  • R h is selected from:
  • heterocyclyl wherein the heterocyclyl includes from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o- 2 , wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, and Ci-4 haloalkyl;
  • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, and Ci-4 haloalkyl; and
  • Y 3 cannot be N when each of each of Y 1 , Y 2 , and Y 3 is independently selected from the group consisting of CH, CR 1 , CR 3 ;
  • each of Z, Y 1 , Y 2 , and Y 3 is independently selected from the group consisting of CH, CR 1 , and CR 3 , from 1-4 of Z, Y 1 , Y 2 , and Y 3 is selected from the group consisting of CR 1 and CR 3 .
  • Y 3 is N; and each of each of Y 1 , Y 2 , and Y 3 is independently selected from the group consisting of CH, CR 1 ,
  • B-L 3 - is other than: , wherein the asterisk represents point of attachment to R 4 .
  • each of each of Y 1 , Y 2 , and Y 3 is independently selected from the group consisting of CH, CR 1 , CR 3 , then B is other than pyrazolyl.
  • each of each of Y 1 , Y 2 , and Y 3 is independently selected from the group consisting of CH, CR 1 ,
  • B-L 3 is other than , wherein the asterisk represents point of attachment to R 4 .
  • -L 3 -R 4 is other than CH2-cyclopropyl.
  • the compound is other than:
  • B is other than furanyl, pyrazolyl, 1,2,3-triazolyl, isoxazolyl, oxazolyl, hydroxy-imidazolyl, pyrimidyl, thiazolyl, thiophenyl, each of which is further optionally substituted with one R c .
  • the compound of Formula II is other than compounds disclosed in WO 2013/114113 which is incorporated herein by reference in its entirety.
  • the compound of Formula II is other than compounds disclosed in U.S. Patent No. 10,000,481 which is incorporated herein by reference in its entirety.
  • the compound of Formula II is other than compounds disclosed in WO 2009/140320 which is incorporated herein by reference in its entirety.
  • the compound of Formula II is other than compounds disclosed in U.S. Patent No. 8,981,085 which is incorporated herein by reference in its entirety.
  • the compound of Formula II is other than compounds disclosed in WO 2003/028724 which is incorporated herein by reference in its entirety.
  • Embodiments can include any one or more of the features delineated below and/or in the claims.
  • each of Z, Y 1 , Y 2 , and Y 3 is independently selected from the group consisting of: CH, CR 1 , CR 3 , and N. In certain embodiments, each of Z, Y 1 , Y 2 , and Y 3 is independently selected from the group consisting of: CH, CR 1 , and CR 3 .
  • from 1-2 of Z, Y 1 , Y 2 , and Y 3 is independently selected from the group consisting of CR 1 and CR 3 ; and each remaining Z, Y 1 , Y 2 , and Y 3 is CH.
  • the compound has Formula Il-a:
  • the compound has Formula Il-b or II-c:
  • the compound has Formula Il-d, Il-e, or Il-f:
  • one of Z, Y 1 , and Y 2 is N; and each remaining Z, Y 1 , Y 2 , and Y 3 is independently selected from the group consisting of CH, CR 1 , and CR 3 .
  • Z is N.
  • Y 1 is N.
  • Y 2 is N.
  • Y 2 , and Y 3 is independently selected from the group consisting of CH, CR 1 , and CR 3 ), the compound has Formula Il-g, Il-h, or Il-i:
  • ml is 0.
  • ml is 1.
  • m3 is 0.
  • m3 is 1 or 2.
  • ml is 0; and m3 is 1 or 2
  • m3 is 1).
  • ml is 1; and m3 is 0.
  • ml is 1; and m3 is 1.
  • R 2N is H.
  • R 2N is R 2 , wherein said R 2 is selected from the group consisting of: (iv) -C(0)(Ci-4 alkyl) (e.g., -C(O)Me); (v) -C(0)0(Ci-4 alkyl); (vi) -
  • R 2N can be (iv) -C(0)(Ci- 4 alkyl) (e.g., -C(O)Me) or (viii) - S(0)i- 2 (Ci-4 alkyl) (e.g., S(0)2Me).
  • R 1 is Ci- 6 alkyl, which is optionally substituted with from 1- 6 (e.g., 1-3) independently selected R a .
  • R 1 is C 1-3 alkyl, which is optionally substituted with from 1-3 independently selected R a .
  • R 1 is -(U 1 ) q -U 2 , wherein:
  • q is 0 or 1, such as q is 0;
  • U 1 is Ci- 6 alkylene, which is optionally substituted with from 1-6 R a ;
  • heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R c , or
  • heterocyclyl including from 3-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2 , and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected R b .
  • each occurrence of R 3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy.
  • each occurrence of R 3 can be halo or cyano, such as -F or cyano.
  • B is a monocyclic heteroaryl including 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R c .
  • B is a monocyclic heteroaryl including 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R c .
  • B is a monocyclic heteroaryl including 5 ring atoms, wherein from 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R c .
  • B is a monocyclic heteroaryl including 5 ring atoms, wherein from 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R d ), and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R c .
  • B can be imidazolyl, pyrazolyl, or triazolyl, each of which is optionally substituted with one independently selected R c .
  • B can be imidazolyl or triazolyl, each of which is optionally substituted with one independently selected R c .
  • B can be selected from the group consisting of:
  • B can be selected from the group consisting of:
  • B can be selected from the group consisting of:
  • B can be selected from the group consisting of: and each of which is optionally substituted with one R c , wherein aa denotes point of attachment to L 3 .
  • B is selected from the group consisting of: each of which is optionally substituted with one R c , wherein aa denotes point of attachment to L 3 .
  • B is selected from the
  • aa and aa each of which is optionally substituted with one R c , wherein aa denotes point of attachment to L 3 .
  • B is a monocyclic heteroaryl including 5 ring atoms, wherein from 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, provided that one ring atom is O or S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R c .
  • B is selected from the group consisting of oxazolyl, thiazolyl, thiadiazolyl, and oxadiazolyl, each of which is optionally substituted with one R c .
  • B is selected from the group consisting of: each of which is optionally substituted with one R c , wherein aa denotes point of attachment to L 3 .
  • B can be selected from the
  • B is a monocyclic heteroaryl including 6 ring atoms, wherein from 1-3 ring atoms are ring nitrogen atoms, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R c .
  • B is pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl, each of which is optionally substituted with from 1-2 independently selected R c , such as pyridyl optionally substituted with R c .
  • B can be
  • B can be selected from
  • L 3 is a bond
  • L 3 is C1-3 alkylene.
  • L 3 is CH2.
  • R 4 is C6-10 aryl optionally substituted with from 1-4 independently selected R 4 ’.
  • R 4 is phenyl optionally substituted with from 1-4 independently selected R 4 ’.
  • R 4 is phenyl optionally substituted with from 1-2 independently selected R 4 ’.
  • R 4 can be unsubstituted phenyl.
  • R 4 can be phenyl substituted with from 1-2 independently selected R 4 ’.
  • R 4 is phenyl substituted with from 1-2 independently selected R 4 ’, wherein one occurrence of R 4 ’ is para to the point of attachment to L 3 , such
  • R 4 is heteroaryl including from 5-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with from 1-4 independently selected R 4 ’.
  • R 4 is heteroaryl including from 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with from 1-4 independently selected R 4 ’.
  • R 4 is heteroaryl including 6 ring atoms, wherein from 1-3 ring atoms are ring nitrogen atoms, and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with from 1-4 independently selected R 4 ’, such as pyridyl which is optionally substituted with from 1-2 independently selected R 4 ’.
  • R 4 is C3-8 cycloalkyl, which is optionally substituted with from 1-4 independently selected R 4 ’.
  • R 4 is C4-6 cycloalkyl, which is optionally substituted with from 1-4 independently selected R 4 ’.
  • R 4 can be unsubstituted C4-6 cycloalkyl, such as unsubstituted cyclohexyl and unsubstituted cyclopentyl.
  • R 4 can be C4-6 cycloalkyl, which is substituted
  • R 4 ' with from 1-3 (e.g., from 2-3) independently selected R 4 ’, such as 1 — ' R ' .
  • R 4 is heterocyclyl including from 4-7 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heterocyclyl is optionally substituted with from 1-4 independently selected R 4 ’
  • each R 4 ’ is independently selected from the group consisting of: halo; -CN; -Ci-4 alkyl optionally substituted with one independently selected R a ; and -Ci-4 haloalkyl.
  • each R 4 ’ is independently selected from the group consisting of: halo (such as -F), -CN, -Ci-4 alkyl, and -C i-4 haloalkyl.
  • R 4 i i s s which is optionally substituted with an additional R 4 .
  • each R 4 ’ is independently selected from the group consisting of: halo (such as -F), -CN, -CM alkyl, and -CM haloalkyl.
  • the >ara-placed R 4 ’ is -CF3.
  • each occurrence of R c is independently selected from the group consisting of halo; cyano; C1-3 alkyl which is optionally substituted with from 1-3 independently selected R a (such as methyl or CF3); Ci-4 alkoxy optionally substituted with Ci-4 alkoxy; and Ci-4 haloalkoxy.
  • R c is C1- 3 alkyl which is optionally substituted with from 1-3 independently selected R a (such as methyl or CF3).
  • the compound of Formula II has Formula II-l:
  • B is a monocyclic heteroaryl including 5 ring atoms, wherein from 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected R c .
  • m3 is 1 or 2.
  • m3 is 2.
  • the compound has Formula Il-la:
  • each R 3 is independently selected from the group consisting of halo and cyano.
  • each R 3 can be halo, such as -F.
  • R 2N is H.
  • R 2N is (iv) -C(0)(Ci-4 alkyl) (e.g., - C(O)Me) or (viii) - S(0)I- 2 (CM alkyl) (e.g., S(0) 2 Me).
  • B is selected from the group consisting of imidazolyl and triazolyl, each of which is optionally substituted with one R c .
  • B can be selected from
  • KJ each of which is optionally substituted with one R c , wherein aa denotes point of attachment to L 3 .
  • B is pyrazolyl optionally substituted with one R c .
  • B can be aa and aa , each of which is optionally substituted with one R c , wherein aa denotes point of attachment to L 3 .
  • B is selected from the group consisting of oxazolyl, thiazolyl, oxadiazolyl, and thiadiazolyl, wherein the oxazolyl and thiazolyl are optionally substituted with one R c .
  • B can be selected from the group consisting of: each of which is optionally substituted with one R c , wherein aa denotes point of attachment to L 3 .
  • each R c when present is independently selected from the group consisting of halo; cyano; C1-3 alkyl which is optionally substituted with from 1-3 independently selected R a (such as methyl or CF3); Ci-4 alkoxy optionally substituted with Ci-4 alkoxy; and Ci-4 haloalkoxy.
  • R c is C1-3 alkyl which is optionally substituted with from 1-3 independently selected R a (such as methyl or CF 3 ).
  • B is not substituted with R c .
  • L 3 is a bond
  • L 3 is CFh.
  • R 4 is selected from the group consisting of:
  • heteroaryl including 6 ring atoms, wherein from 1-3 ring atoms are ring nitrogen atoms, and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with from 1-4 independently selected R 4 ’, such as pyridyl which is optionally substituted with from 1-2 independently selected R 4 ’;
  • heterocyclyl including from 4-7 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heterocyclyl is optionally substituted with from 1-4 independently selected R 4 ’; and phenyl optionally substituted with from 1-2 independently selected R 4 ’.
  • R 4 is phenyl optionally substituted with from 1-2 independently selected R 4 ’.
  • each R 4 ’ is independently selected from the group consisting of: halo (such as -F), -CN, -Ci-4 alkyl, and -Ci-4 haloalkyl.
  • each R 4 ’ is independently selected from the group consisting of: halo (such as -F), -CN, -Ci-4 alkyl, and -Ci-4 haloalkyl.
  • the /3 ⁇ 4/ra-placed R 4 ’ is -CF3.
  • R 4 when R 4 is i— r . , which is optionally substituted with an additional R 4 ’), R 4 • i i.s KD- CFS , which is optionally substituted with an additional R 4 .
  • R 4 can
  • the compound is selected from the compounds in Table Cl below:
  • 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.
  • Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium, sodium
  • Cyclodextrins such as a-, b, and g-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl- b-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein.
  • Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non toxic excipient may be prepared.
  • the contemplated compositions may contain 0.001%- 100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy , 22 nd Edition (Pharmaceutical Press, London, UK. 2012).
  • the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration.
  • Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intraci sternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parent
  • 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., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes.
  • 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.
  • 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, methyl oxybenzoate, macrogol cetostearyl ether, cocoyl capryl
  • 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 mono
  • 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).
  • 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.
  • Upper-GI targeting techniques e.g., Accordion Pill (Intec Pharma)
  • floating capsules e.g., floating capsules, and materials capable of adhering to mucosal walls.
  • enteric/pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers), and Marcoat).
  • Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap.
  • Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).
  • 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.
  • the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant.
  • an ointment base should be inert, stable, nonirritating and non-sensitizing.

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Abstract

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

Description

Compounds and Compositions for Treating Conditions Associated with STING Activity
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application Serial No. 62/793,795, filed on January 17, 2019; U.S. Provisional Application Serial No. 62/861,865, filed on June 14, 2019; U.S. Provisional Application Serial No. 62/869,914, filed on July 2, 2019; and U.S. Provisional Application Serial No. 62/955,891, filed on December 31, 2019, each of which is incorporated herein by reference in its entirety.
TECHNICAL FIELD
This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject
(e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.
BACKGROUND
STING, also known as transmembrane protein 173 (TMEM173) and MPYS/MITA/ERIS, is a protein that in humans is encoded by the TMEM173 gene. STING has been shown to play a role in innate immunity. STING induces type I interferon production when cells are infected with intracellular pathogens, such as viruses, mycobacteria and intracellular parasites. Type I interferon, mediated by STING, protects infected cells and nearby cells from local infection in an autocrine and paracrine manner.
The STING pathway is pivotal in mediating the recognition of cytosolic DNA. In this context, STING, a transmembrane protein localized to the endoplasmic reticulum (ER), acts as a second messenger receptor for 2', 3' cyclic GMP-AMP (hereafter cGAMP), which is produced by cGAS after dsDNA binding. In addition, STING can also function as a primary pattern recognition receptor for bacterial cyclic dinucleotides (CDNs) and small molecule agonists. The recognition of endogenous or prokaryotic CDNs proceeds through the carboxy -terminal domain of STING, which faces into the cytosol and creates a V-shaped binding pocket formed by a STING homodimer. Ligand-induced activation of STING triggers its re-localization to the Golgi, a process essential to promote the interaction of STING with TBK1. This protein complex, in turn, signals through the transcription factors IRF-3 to induce type I interferons (IFNs) and other co-regulated antiviral factors. In addition, STING was shown to trigger NF-KB and MAP kinase activation. Following the initiation of signal transduction, STING is rapidly degraded, a step considered important in terminating the inflammatory response.
Excessive activation of STING is associated with a subset of monogenic autoinflammatory conditions, the so-called type I interferonopathies. Examples of these diseases include a clinical syndrome referred to as STING-associated vasculopathy with onset in infancy (SAVI), which is caused by gain-of-function mutations in TMEM173 (the gene name of STING). Moreover, STING is implicated in the pathogenesis of Aicardi- Goutieres Syndrome (AGS) and genetic forms of lupus. As opposed to SAVI, it is the dysregulation of nucleic acid metabolism that underlies continuous innate immune activation in AGS. Apart from these genetic disorders, emerging evidence points to a more general pathogenic role for STING in a range of inflammation-associated disorders such as systemic lupus erythematosus, rheumatoid arthritis and cancer. Thus, small molecule-based pharmacological interventions into the STING signaling pathway hold significant potential for the treatment of a wide spectrum of diseases
SUMMARY
This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.
An "antagonist" of STING includes compounds that, at the protein level, directly bind or modify STING such that an activity of STING is decreased, e.g., by inhibition, blocking or dampening agonist-mediated responses, altered distribution, or otherwise. STING antagonists include chemical entities, which interfere or inhibit STING signaling.
In one aspect, compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are featured:
Figure imgf000004_0001
in which A, B, W1, and W2 can be as defined anywhere herein.
In another aspect, compounds of Formula (II), or a pharmaceutically acceptable salt thereof, are featured:
Figure imgf000004_0002
in which Z, Y1, Y2, Y3, R6, B, R2N, L3, and R4 can be as defined anywhere herein.
In one aspect, pharmaceutical compositions are featured that include a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same) and one or more pharmaceutically acceptable excipients.
In one aspect, methods for inhibiting (e.g., antagonizing) STING activity are featured that include contacting STING with a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same). Methods include in vitro methods, e.g., contacting a sample that includes one or more cells comprising STING (e.g., innate immune cells, e.g., mast cells, macrophages, dendritic cells (DCs), and natural killer cells) with the chemical entity. Methods can also include in vivo methods; e.g., administering the chemical entity to a subject (e.g., a human) having a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease.
In one aspect, methods of treating a condition, disease or disorder ameliorated by antagonizing STING are featured, e.g., treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). The methods include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).
In another aspect, methods of treating cancer are featured that include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).
In a further aspect, methods of treating other STING-associated conditions are featured, e.g., type I interferonopathies (e.g., STING-associated vasculopathywith onset in infancy (SAVI)), Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis. The methods include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).
In another aspect, methods of suppressing STING-dependent type I interferon production in a subject in need thereof are featured that include administering to the subject an effective amount of a chemical entity described herein (e.g., a compound described genetically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).
In a further aspect, methods of treating a disease in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the disease are featured. The methods include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).
In another aspect, methods of treatment are featured that include administering an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same) to a subject; wherein the subject has (or is predisposed to have) a disease in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the disease .
In a further aspect, methods of treatment that include administering to a subject a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same), wherein the chemical entity is administered in an amount effective to treat a disease in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the disease, thereby treating the disease.
Embodiments can include one or more of the following features.
The chemical entity can be administered in combination with one or more additional therapeutic agents and/or regimens. For examples, methods can further include administering one or more (e.g., two, three, four, five, six, or more) additional agents.
The chemical entity can be administered in combination with one or more additional therapeutic agents and/or regimens that are useful for treating other STING-associated conditions, e.g., type I interferonopathies (e.g., STING-associated vasculopathywith onset in infancy (SAVI)), Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis. The chemical entity can be administered in combination with one or more additional cancer therapies (e.g., surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof; e.g., chemotherapy that includes administering one or more (e.g., two, three, four, five, six, or more) additional chemotherapeutic agents. Non-limiting examples of additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g.,azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisom erase; e.g., camptothecins, such as irinotecan and/or topotecan;. amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab- CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti-helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1 - PD-L1, PD-1 - PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-b (TGFP),
T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9 - TIM3, Phosphatidylserine - TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II
- LAG3, 4-1BB-4-1BB ligand, 0X40-0X40 ligand, GITR, GITR ligand - GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM- LIGHT-LTA, HVEM, HVEM - BTLA, HVEM - CD 160, HVEM - LIGHT, HVEM- BTLA-CD160, CD80, CD80 - PDL-1, PDL2 - CD80, CD244, CD48 - CD244, CD244,
ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2,
Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86 - CD28, CD86 - CTLA, CD80 - CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL 12, Phosphatidylserine, TIM3, Phosphatidylserine - TIM3, SIRPA-CD47, VEGF, Neuropilin, CD 160, CD30, and CD155 (e.g., CTLA-4 or PDl or PD-Ll).
The subject can have cancer; e.g., the subject has undergone and/or is undergoing and/or will undergo one or more cancer therapies.
Non-limiting examples of cancer include melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma. In certain embodiments, the cancer can be a refractory cancer.
The chemical entity can be administered intratumorally.
The methods can further include identifying the subject.
Other embodiments include those described in the Detailed Description and/or in the claims.
Additional Definitions
To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.
As used herein, the term“STING” is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous STING molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.
The term“acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.
“API” refers to an active pharmaceutical ingredient.
The terms“effective amount” or“therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entity being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an“effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate“effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.
The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is“pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed. ; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed. ; Rowe el al. , Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed. ; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed !; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.
The term“pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, /V-m ethyl -D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid. The term“pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as“excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
The term“subject” refers to an animal, including, but not limited to, a primate ( e.g ., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and“patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.
The terms“treat,”“treating,” and“treatment,” in the context of treating a disease or disorder, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof. The“treatment of cancer”, refers to one or more of the following effects: (1) inhibition, to some extent, of tumor growth, including, (i) slowing down and (ii) complete growth arrest; (2) reduction in the number of tumor cells; (3) maintaining tumor size; (4) reduction in tumor size; (5) inhibition, including (i) reduction, (ii) slowing down or (iii) complete prevention, of tumor cell infiltration into peripheral organs; (6) inhibition, including (i) reduction, (ii) slowing down or (iii) complete prevention, of metastasis; (7) enhancement of anti-tumor immune response, which may result in (i) maintaining tumor size, (ii) reducing tumor size, (iii) slowing the growth of a tumor, (iv) reducing, slowing or preventing invasion and/or (8) relief, to some extent, of the severity or number of one or more symptoms associated with the disorder.
The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
The term "alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci-io indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, No-propyl, N/V-butyl, «-hexyl. The term "haloalkyl" refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo.
The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).
The term "alkylene" refers to a divalent alkyl (e.g., -CH2-).
The term "alkenyl" refers to a hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it.
The term "alkynyl" refers to a hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it.
The term "aryl" refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.
The term "cycloalkyl" as used herein includes cyclic hydrocarbon groups having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl includes: bicyclo[TT0]butane, bicyclo[2.T0]pentane, bicyclo[l. Tl]pentane, bicyclo[3.T0]hexane, bicyclo[2. Tl]hexane, bicyclo[3.2.0]heptane, bicyclo[4. T0]heptane, bicyclo[2.2.1]heptane, bicyclo[3. Tl]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.
The term "cycloalkenyl" as used herein includes partially unsaturated cyclic hydrocarbon groups having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkenyl groups may have any degree of saturation provided that none of the rings in the ring system are aromatic; and the cycloalkenyl group is not fully saturated overall. Cycloalkenyl may include multiple fused and/or bridged and/or spirocyclic rings.
The term“heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl), and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S. Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-i/]pyrimidinyl, pyrrolo[2,3- />] pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-Z>]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-Z>]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[Z>][l,4]dioxine, benzo[<i][l,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[Z>][l,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
The term "heterocyclyl" refers to a mon-, bi-, tri-, or polycyclic nonaromatic ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2- azabicyclo[l. l. l]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3- azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7- azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2- azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2- oxabicyclo[2.1.0]pentane, 2-oxabicyclo[l.l. l]pentane, 3-oxabicyclo[3.1.0]hexane, 5- oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7- oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2- oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2- azaspiro[2.2]pentane, 4-azaspiro[2.5 ] octane, 1-azaspiro[3.5]nonane, 2- azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6- azaspiro[2.6]nonane, l,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5- diazaspiro[3 6]decane, 3 -azaspiro[5.5 Jundecane, 2-oxaspiro[2.2]pentane, 4- oxaspiro[2.5]octane, l-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7- oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7- dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, l-oxaspiro[5.5]undecane, 3- oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane and the like.
In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13C and 14C.
In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the
moiety:
Figure imgf000015_0002
encompasses the tautomeric form containing the moiety:
Figure imgf000015_0001
. Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.
This specification concludes with 278 claims, which are incorporated herein in this disclosure in their entireties. For ease of exposition, certain variable definitions refer to one or more specific claim numbers. For the avoidance of doubt, use of a phrase, such as“A is as defined in claim 25” is intended to mean that:
A is:
Figure imgf000015_0003
or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2).
The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.
DETAILED DESCRIPTION
This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.
Formula Compounds
In one aspect, compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are featured:
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof or a tautomer thereof,
wherein:
one of W1 and W2 is -N(H)-, -N(Rd)- (e.g., -N(H)- or -N(CI-3 alkyl)-), -N(H)- (W12)-, or -N(Rd)-(W12)-,
provided the one of W1 and W2 is attached to the C(=0) moiety of Formula I through a nitrogen atom;
the other one of W1 and W2 is a bond, -0-, -0-(W12)-, or C1-C6 alkylene optionally substituted with from 1-3 Ra (e.g., C1-C3, e.g., CFh, CHRa, or CR¾;
wherein W12 is C1-C6 alkylene optionally substituted with from 1-3 Ra,
A is selected from the group consisting of:
(i) heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R2), O, S, and S(0)2, and wherein from 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR1, and CR3; and
(ii) heteroaryl including from 7-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R2), O, and S(0)o-2, and wherein from 3-19 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH2, CR1, CHR1, C(R')2, CR3, CHR3, and C(R3)2; B is:
(a) Ci-15 alkyl which is optionally substituted with from 1-6 independently selected Ra;
(b) C3-20 cycloalkyl, which is optionally substituted with from 1-4 Rb;
(c) phenyl substituted with from 1-4 Rc;
(d) C8-20 aryl optionally substituted with from 1-4 Rc;
(e) heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected Rc; or
(f) heterocyclyl including from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected Rb;
R1 is:
(i) -(U1)q-U2, wherein:
• q is O or l;
• U1 is Ci-6 alkylene, which is optionally substituted with from 1-6 Ra; and
• U2 is:
(a) C3-12 cycloalkyl, which is optionally substituted with from 1-4 Rb,
(b) C6-10 aryl, which is optionally substituted with from 1-4 Rc;
(c) heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected Rc, or
(d) heterocyclyl including from 3-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected Rb, OR
(ii) Ci-io alkyl, which is optionally substituted with from 1-6 independently selected Ra; each occurrence of R2 is independently selected from the group consisting of:
(i) Ci-6 alkyl, which is optionally substituted with from 1-4 independently selected Ra;
(ii) C3-6 cycloalkyl;
(iii) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2;
(iv) -C(0)(Ci-4 alkyl);
(v) -C(0)0(Ci-4 alkyl);
(vi) -CON(R’)(R”);
(vii) -S(0)I-2(NR’R”);
(viii) - S(0)i-2(Ci-4 alkyl);
(ix) -OH; and
(x) Ci-4 alkoxy; each occurrence of R3 is independently selected from the group consisting of halo, cyano, C2-6 alkenyl, C2-6 alkynyl, Ci-4 alkoxy optionally substituted with C3-6 cycloalkyl, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NReRf, -OH, oxo, -S(0)I-2(NR’R”), -Ci-4 thioalkoxy, - NO2, -C(=0)(Ci-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)OH, and -C(=0)N(R’)(R”); each occurrence of Ra is independently selected from the group consisting of: -OH; -F; - Cl; -Br; -NReRf; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)0(Ci-4 alkyl); -C(=0)(Ci-4 alkyl); - C(=0)OH; -CON(R’)(R”); -S(0)i.2(NR’R”); -S(0)I-2(CM alkyl); cyano, and C3-6 cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl; each occurrence of Rb is independently selected from the group consisting of: Ci-10 alkyl optionally substituted with from 1-6 independently selected Ra; Ci-4 haloalkyl; -OH; oxo; - F; -Cl; -Br; -NReRf; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)(Ci-4 alkyl); -C(=0)0(Ci-4 alkyl); -C(=0)0H; -C(=0)N(R’)( ”); -S(0)i.2(NR’R”); -S(0)i-2(Ci-4 alkyl); cyano; and -ΐLΐ Rh; each occurrence of Rc is independently selected from the group consisting of:
(a) halo;
(b) cyano;
(c) Ci-15 alkyl which is optionally substituted with from 1-6 independently selected Ra;
(d) C2-6 alkenyl;
(e) C2-6 alkynyl;
(g) Ci-4 alkoxy optionally substituted with Ci-4 alkoxy;
(h) Ci-4 haloalkoxy;
(i) -S(0)i-2(Ci-4 alkyl);
G) -NReRf;
(k) -OH;
(l) -S(0)I-2(NR’R”);
(m) -Ci-4 thioalkoxy optionally substituted with from 1-4 halo;
(n) -NO2;
(o) -C(=0)(Ci-4 alkyl);
(p) -C(=0)0(Ci-4 alkyl);
(q) -C(=0)OH;
(r) -C(=0)N(R’)(R”); and
(s) -L1-L2-Rh; Rd is selected from the group consisting of: Ci-6 alkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); - C(0)0(Ci-4 alkyl); -CON(R’)(R”); -S(0)i.2(NR’R”); - S(0)i-2(Ci-4 alkyl); -OH; and CM alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; Ci-6 alkyl; Ci-6 haloalkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); -C(0)0(Ci-4 alkyl); - CON(R’)(R”); -S(0)I-2(NR’R”); - S(0)i-2(Ci-4 alkyl); -OH; and CM alkoxy; or Re and Rf together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to Re and R1), which are each independently selected from the group consisting of N(Rd), NH, O, and S;
-L1 is a bond or C1-3 alkylene;
-L2 is -O-, -N(H)-, -S-, or a bond;
Rh is selected from:
• C3-8 cycloalkyl optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, CM alkyl, and CM haloalkyl (in certain embodiments, it is provided that when Rh is C3-6 cycloalkyl optionally substituted with from 1-4 independently selected CM alkyl, -L1 is a bond, or-L2 is -O-, -N(H)-, or -S-);
• heterocyclyl, wherein the heterocyclyl includes from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, CM alkyl, and CM haloalkyl;
• heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci- 4 alkyl, and CM haloalkyl; and
• C6-10 aryl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, CM alkyl, or CM haloalkyl; and each occurrence of R’ and R” is independently selected from the group consisting of: H, Ci-4 alkyl, and C6-10 aryl optionally substituted with from 1-2 substituents selected from halo, Ci-4 alkyl, and Ci-4 haloalkyl; or R’ and R” together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from the group consisting of H and C1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R’ and R”), which are each independently selected from the group consisting of N(H), N(Rd), O, and S.
In one aspect, compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are featured:
Figure imgf000021_0001
or a pharmaceutically acceptable salt thereof or a tautomer thereof,
wherein:
one of W1 and W2 is -N(H)-, -N(Rd)- (e.g., -N(H)- or -N(CI-3 alkyl)-), -N(H)- (W12)-, or -N(Rd)-(W12)-,
provided the one of W1 and W2 is attached to the C(=0) moiety of Formula I through a nitrogen atom;
the other one of W1 and W2 is a bond, -0-, -0-(W12)-, or C1-C6 alkylene optionally substituted with from 1-3 Ra (e.g., C1-C3, e.g., CFh, CHRa, or CR¾;
wherein W12 is C1-C6 alkylene optionally substituted with from 1-3 Ra,
A is selected from the group consisting of:
(i) heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R2), O, S, and S(0)2, and wherein from 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR1, and CR3; and
(ii) heteroaryl including from 7-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R2), O, and S(0)o-2, and wherein from 3-19 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH2, CR1, CHR1, C(R1)2, CR3, CHR3, and C(R3)2;
B is:
(a) Ci-15 alkyl which is optionally substituted with from 1-6 independently selected Ra;
(b) C3-20 cycloalkyl, which is optionally substituted with from 1-4 Rb;
(c) phenyl substituted with from 1-4 Rc;
(d) C8-20 aryl optionally substituted with from 1-4 Rc;
(e) heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected Rc; or
(f) heterocyclyl including from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected Rb;
R1 is:
(i) -(U1)q-U2, wherein:
• q is O or l;
• U1 is Ci-6 alkylene, which is optionally substituted with from 1-6 Ra; and
• U2 is:
(a) C3-12 cycloalkyl, which is optionally substituted with from 1-4 Rb,
(b) C6-10 aryl, which is optionally substituted with from 1-4 Rc;
(c) heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected Rc, or (d) heterocyclyl including from 3-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected Rb, OR
(ii) Ci-io alkyl, which is optionally substituted with from 1-6 independently selected Ra; each occurrence of R2 is independently selected from the group consisting of: (i) Ci-6 alkyl, which is optionally substituted with from 1-4 independently selected Ra;
(ii) C3-6 cycloalkyl;
(iii) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2;
(iv) -C(0)(Ci-4 alkyl);
(v) -C(0)0(Ci-4 alkyl);
(vi) -CON(R’)(R”);
(vii) -S(0)I-2(NR’R”);
(viii) - S(0)i-2(Ci-4 alkyl);
(ix) -OH; and
(x) Ci-4 alkoxy; each occurrence of R3 is independently selected from the group consisting of halo, cyano, C2-6 alkenyl, C2-6 alkynyl, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NReRf, -OH, oxo, -S(0)I-2(NR’R”), -Ci-4 thioalkoxy, -NO2, -C(=0)(Ci-4 alkyl), -C(=0)0(Ci-4 alkyl), - C(=0)OH, and -C(=0)N(R’)(R”); each occurrence of Ra is independently selected from the group consisting of: -OH; -F; - Cl; -Br; -NReRf; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)0(Ci-4 alkyl); -C(=0)(Ci-4 alkyl); - C(=0)0H; -CON(R’)(R”); -S(0)i-2(NR’R”); -S(0)I-2(CM alkyl); cyano, and C3-6 cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl; each occurrence of Rb is independently selected from the group consisting of: Ci-10 alkyl optionally substituted with from 1-6 independently selected Ra; Ci-4 haloalkyl; -OH; oxo; - F; -Cl; -Br; -NReRf; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)(Ci-4 alkyl); -C(=0)0(Ci-4 alkyl); -C(=0)0H; -C(=0)N(R’)(R”); -S(0)i-2(NR’R”); -S(0)i-2(Ci-4 alkyl); cyano; and -ΐLΐ Rh; each occurrence of Rc is independently selected from the group consisting of:
(a) halo;
(b) cyano;
(c) Ci-15 alkyl which is optionally substituted with from 1-6 independently selected Ra;
(d) C2-6 alkenyl;
(e) C2-6 alkynyl;
(g) Ci-4 alkoxy;
(h) Ci-4 haloalkoxy;
(i) -S(0)i-2(Ci-4 alkyl);
G) -NReRf;
(k) -OH;
(l) -S(0)i-2(NR’R”);
(m) -Ci-4 thioalkoxy;
(n) -NO2;
(o) -C(=0)(Ci-4 alkyl);
(p) -C(=0)0(Ci-4 alkyl);
(q) -C(=0)OH;
(r) -C(=0)N(R’)(R”); and
(s) -L1-L2-Rh; Rd is selected from the group consisting of: Ci-6 alkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); - C(0)0(Ci-4 alkyl); -CON(R’)(R”); -S(0)i.2(NR’R”); - S(0)i-2(Ci-4 alkyl); -OH; and CM alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; Ci-6 alkyl; Ci-6 haloalkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); -C(0)0(Ci-4 alkyl); - CON(R’)(R”); -S(0)I-2(NR’R”); - S(0)i-2(Ci-4 alkyl); -OH; and CM alkoxy; or Re and Rf together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C 1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to Re and Rr), which are each independently selected from the group consisting of N(Rd), NH, O, and S;
-L1 is a bond or C1-3 alkylene;
-L2 is -O-, -N(H)-, -S-, or a bond;
Rh is selected from:
• C3-8 cycloalkyl optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, CM alkyl, and CM haloalkyl (in certain embodiments, it is provided that when Rh is C3-6 cycloalkyl optionally substituted with from 1-4 independently selected CM alkyl, -L1 is a bond, or-L2 is -O-, -N(H)-, or -S-);
• heterocyclyl, wherein the heterocyclyl includes from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, CM alkyl, and CM haloalkyl;
• heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci- 4 alkyl, and Ci-4 haloalkyl; and
• C6-io aryl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, or Ci-4 haloalkyl; and each occurrence of R’ and R” is independently selected from the group consisting of: H, Ci-4 alkyl, and C6-10 aryl optionally substituted with from 1-2 substituents selected from halo, Ci-4 alkyl, and Ci-4 haloalkyl; or R’ and R” together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from the group consisting of H and C1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R’ and R”), which are each independently selected from the group consisting of N(H), N(Rd), O, and S.
Embodiments can include any one or more of the features delineated below and/or in the claims.
In one aspect, compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are featured:
Figure imgf000026_0001
or a pharmaceutically acceptable salt thereof or a tautomer thereof,
wherein:
one of W1 and W2 is -N(H)-, -N(Rd)- (e.g., -N(H)- or -N(CI-3 alkyl)-), -N(H)- (W12)-, or -N(Rd)-(W12)-,
the other one of W1 and W2 is a bond, -0-, -0-(W12)-*, -(W12)-0-*, -(W12)-N(H)- *, or -(W12)-N(Rd)-*, or C1-C6 alkylene optionally substituted with from 1-3 Ra (e.g., Ci- C3, e.g., CH2, CHRa, or CRa 2), wherein the asterisk represents point of attachment to B; provided the one of W1 and W2 is attached to the C(=0) moiety of Formula I through a nitrogen atom; wherein W12 is C1-C6 alkylene optionally substituted with from 1-3 Ra,
A is selected from the group consisting of:
(i) heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R2), O, S, and S(0)2, and wherein from 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR1, and CR3; and
(ii) heteroaryl including from 7-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R2), O, and S(0)o-2, and wherein from 3-19 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH,
Figure imgf000027_0001
CR3, CHR3, and C(R3)2;
B is:
(a) Ci-15 alkyl which is optionally substituted with from 1-6 independently selected Ra;
(b) C3-20 cycloalkyl, which is optionally substituted with from 1-4 Rb;
(c) phenyl substituted with from 1-4 Rc;
(d) C8-20 aryl optionally substituted with from 1-4 Rc;
(e) heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected Rc; or
(f) heterocyclyl including from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected Rb;
R1 is:
(i) -(U1)q-U2, wherein:
• q is O or l; • U1 is Ci-6 alkylene, which is optionally substituted with from 1-6 Ra; and
• U2 is:
(a) C3-12 cycloalkyl, which is optionally substituted with from 1-4 Rb,
(b) C6-10 aryl, which is optionally substituted with from 1-4 Rc;
(c) heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected Rc, or
(d) heterocyclyl including from 3-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected Rb,
OR
(ii) Ci-10 alkyl, which is optionally substituted with from 1-6 independently selected Ra; each occurrence of R2 is independently selected from the group consisting of:
(i) Ci-6 alkyl, which is optionally substituted with from 1-4 independently selected Ra;
(ii) C3-6 cycloalkyl;
(iii) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2;
(iv) -C(0)(Ci-4 alkyl);
(v) -C(0)0(Ci-4 alkyl);
(vi) -CON(R’)(R”);
(vii) -S(0)I-2(NR’R”);
(viii) - S(0)i-2(Ci-4 alkyl);
(ix) -OH; and
(x) Ci-4 alkoxy; each occurrence of R3 is independently selected from the group consisting of halo, cyano, C2-6 alkenyl, C2-6 alkynyl, Ci-4 alkoxy optionally substituted with C3-6 cycloalkyl, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NReRf, -OH, oxo, -S(0)I-2(NR’R”), -Ci-4 thioalkoxy, - NO2, -C(=0)(Ci-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)0H, and -C(=0)N(R’)(R”); each occurrence of Ra is independently selected from the group consisting of: -OH; -F; - Cl; -Br; -NReRf; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)0(Ci-4 alkyl); -C(=0)(Ci-4 alkyl); - C(=0)0H; -CON(R’)(R”); -S(0)i.2(NR’R”); -S(0)I-2(CM alkyl); cyano, and C3-6 cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl; each occurrence of Rb is independently selected from the group consisting of: Ci-10 alkyl optionally substituted with from 1-6 independently selected Ra; Ci-4 haloalkyl; -OH; oxo; - F; -Cl; -Br; -NReRf; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)(Ci-4 alkyl); -C(=0)0(Ci-4 alkyl); -C(=0)0H; -C(=0)N(R’)(R”); -S(0)I-2(NR’R”); -S(0)i-2(Ci-4 alkyl); cyano; and -ΐLΐ Rh; each occurrence of Rc is independently selected from the group consisting of:
(a) halo;
(b) cyano;
(c) Ci-15 alkyl which is optionally substituted with from 1-6 independently selected Ra;
(d) C2-6 alkenyl;
(e) C2-6 alkynyl;
(g) Ci-4 alkoxy optionally substituted with Ci-4 alkoxy;
(h) Ci-4 haloalkoxy;
(i) -S(0)i-2(Ci-4 alkyl);
G) -NReRf;
(k) -OH;
(l) -S(0)I-2(NR’R”);
(m) -Ci-4 thioalkoxy optionally substituted with from 1-4 halo;
(n) -NO2; (o) -C(=0)(Ci-4 alkyl);
(p) -C(=0)0(Ci-4 alkyl);
(q) -C(=0)0H;
(r) -C(=0)N(R’)(R”); and
(s) -L'-L2-Rh;
Rd is selected from the group consisting of: Ci-6 alkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); - C(0)0(Ci-4 alkyl); -CON(R’)(R”); -S(0)i.2(NR’R”); - S(0)i-2(Ci-4 alkyl); -OH; and CM alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; Ci-6 alkyl; Ci-6 haloalkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); -C(0)0(Ci-4 alkyl); - CON(R’)(R”); -S(0)I-2(NR’R”); - S(0)I-2(CM alkyl); -OH; and CM alkoxy; or Re and Rf together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C 1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to Re and R1), which are each independently selected from the group consisting of N(Rd), NH, O, and S;
-L1 is a bond or C1-3 alkylene;
-L2 is -O-, -N(H)-, -S-, or a bond;
Rh is selected from:
• C3-8 cycloalkyl optionally substituted with from 1-4 independently selected R*1’ (in certain embodiments, it is provided that when Rh is C3-6 cycloalkyl optionally substituted with from 1-4 independently selected CM alkyl, -L1 is a bond, or -L2 is -O-, -N(H)-, or -S-);
• heterocyclyl, wherein the heterocyclyl includes from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, wherein the heterocyclyl is optionally substituted with from 1-4 independently selected R*1’; • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected R*1’; and
• C6-io aryl, which is optionally substituted with from 1-4 independently selected R*1’; wherein each R*1’ is independently selected from the group consisting of: halo; -CN; -NO2; -OH; -Ci-4 alkyl optionally substituted with from 1-2 independently selected Ra; -C2-4 alkenyl; -C2-4 alkynyl; -Ci-4 haloalkyl; -Ci-6 alkoxy optionally substituted with from 1-2 independently selected Ra; -Ci-6 haloalkoxy; S(0)i-2(Ci-4 alkyl); -NR’R”; oxo; -S(0)i- 2(NR’R”); -CI-4 thioalkoxy; -C(=0)(Ci-4 alkyl); -C(=0)0(Ci-4 alkyl); -C(=0)OH; and -
C(=0)N(R’)(R”); each occurrence of R’ and R” is independently selected from the group consisting of: H, Ci-4 alkyl, and C6-10 aryl optionally substituted with from 1-2 substituents selected from halo, Ci-4 alkyl, and Ci-4 haloalkyl; or R’ and R” together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from the group consisting of H and C 1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R’ and R”), which are each independently selected from the group consisting of N(H), N(Rd), O, and S.
In some embodiments, when A is heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R2), O, S, and S(0)2, and wherein from 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR1, and CR3, then at least one ring atom is substituted with R1. The Variable A
In some embodiments, A is: heteroaryl including from 7-20 (e.g., 8-16) ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R2), O, and S(0)o-2, and wherein from 3-19 (e.g., 4-15) ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH 2, CR1, CHR1, C(R1)2, CR3, CHR3, and C(R3)2.
In some embodiments, A is: heteroaryl including from 8-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R2), O, and S(0)o-2, and wherein from 4-9 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH2, CR1, CHR1, C(R1)2, CR3, CHR3, and C(R3)2.
In certain of these embodiments, A is: heteroaryl including from 8-9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R2), O, and S(0)o-2, and wherein from 4-8 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH2, CR1, CHR1, C(R1)2, CR3, CHR3, and C(R3)2.
In certain embodiments, A is (A-l):
Figure imgf000032_0001
wherein
Z is selected from the group consisting of:
a bond, CH, CR1, CR3, N, NH, N(R') and N(R2); each of Y1, Y2, and Y3 is independently selected from the group consisting of O, S, CH, CR1, CR3, N, NH, N(R3), and NR2;
Y4 is C or N; X° is C or N;
X1 is selected from the group consisting of O, S, N, NH, NR1, NR2, CH, CR1, and CR3;
X2 is selected from the group consisting of O, S, N, NH, NR1, NR2, CH, CR1, and CR3; and each— is independently a single bond or a double bond, provided that the five- membered ring comprising Y4, X°, X1, and X2 is heteroaryl; and
the ring comprising Z, Y1, Y2, Y3, and Y4 is aromatic (i.e., carbocyclic aromatic or heteroaromatic).
In some embodiments of (A-l), Z is selected from the group consisting of:
CH, CR1, CR3, N, and N(R2).
In certain embodiments of (A-l), Z is selected from the group consisting of: CH, CR1, CR3, and N.
In certain of these embodiments, Z is selected from the group consisting of CH, CR1, and CR3 (e.g., Z is CH).
In some embodiments of (A-l), each of Y1, Y2, and Y3 is independently selected from the group consisting of CH, CR1, CR3, and N.
In certain of these embodiments, each of Y1, Y2, and Y3 is independently selected from the group consisting of CH, CR1, and CR3.
As a non-limiting example, the
Figure imgf000033_0002
moiety i
Figure imgf000033_0001
wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2). In certain embodiments of (A-l) (when each of Y1, Y2, and Y3 is independently selected from the group consisting of CH, CR1, CR3, and N), from 1-2 of Y1, Y2, and Y3 is independently N.
In certain of these embodiments, one of Y1, Y2, and Y3 is independently N.
In certain of the foregoing embodiments, each of the remaining Y1, Y2, and Y3 is independently selected from the group consisting of CH, CR1, and CR3, provided that one or more of Y1, Y2, and Y3 is independently CH.
As a non-limiting example of the foregoing embodiments, the
Figure imgf000034_0001
moiety is
Figure imgf000034_0002
, wherein:
the asterisk denotes point of attachment to Y4; and
m3 = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1). ml(R1)
Figure imgf000034_0003
As another non-limting example, the ¾ moiety ism3^R ) , wherein: the asterisk denotes point of attachment to Y4; and
ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
In certain embodiments of (A-l) (e.g., when each of Y1, Y2, and Y3 is independently selected from the group consisting of CH, CR1, CR3, and N), two of Y1, Y2, and Y3 are independently N.
Figure imgf000035_0001
non-limiting example of the foregoing embodiments, the moiety is
Figure imgf000035_0002
wherein:
the asterisk denotes point of attachment to Y4; and
ml = 0 or 1; and m3 = 0 or 1.
In some embodiments of (A-l), Y4 is C.
In some embodiments of (A-l), X1 is selected from the group consisting of O, S, N, CH, NH, NR1, and NR2.
In certain of these embodiments, X1 is selected from the group consisting of NH, NR1, and NR2.
As a non-limiting example of the foregoing embodiments, X1 is selected from the group consisting of NH and NR2 (e.g., NH or NAc (e.g., NH)).
In certain embodiments of (A-l), X1 is S.
In certain embodiments of (A-l), X1 is N or CH.
In some embodiments of (A-l), X2 is selected from the group consisting of N, CH,
CR1, and CR3.
In certain embodiments of (A-1),X2 is selected from the group consisting of N, C(Ci- 3 alkyl), and CH.
As a non-limiting example of the foregoing embodiments, X2 is CH.
In some embodiments of (A-l), X° is N.
In some embodiments of (A-l), X° is C.
In certain embodiments of (A-l), X1 is NH, NR1, or NR2; and X° is C.
In certain of the foregoing embodiments, X1 is NH or NR2 (e.g., NH or NAc (e.g.,
NH)). In certain of the foregoing embodiments (when X1 is NH, NR1, or NR2; and X° is C (e.g., when X1 is NH or NR2 (e.g., NH or NAc (e.g., NH))), X2 is selected from the group consisting of N, C(Ci-3 alkyl), and CH (e.g., X2 is CH).
As non-limiting examples of the foregoing embodiments of (A-l), A is:
Figure imgf000036_0001
wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2). As additional non-limiting examples, A is:
Figure imgf000036_0002
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1). As additional non-limiting examples, A is:
Figure imgf000036_0003
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1). As further non-limiting examples, A is:
Figure imgf000036_0004
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1). As further non-limiting examples, A is:
Figure imgf000037_0001
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
As further non-limiting examples, A is:
Figure imgf000037_0002
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
In certain embodiments of (A-l), X1 is N or CH; and X° is N.
In certain of the foregoing embodiments, X2 is selected from the group consisting of N, C(Ci-3 alkyl), and CH (e.g., X2 is CH).
As non-limiting examples of the foregoing embodiments of (A-l), A is:
ml(R1 ) ^ ml(R1 )
-N
ir //
mslR O^r n Orf ms ,lRR D*^rT wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2).
In certain embodiments of (A-l), X1 is S; X2 is selected from the group consisting of N, C(Ci-3 alkyl), and CH (e.g., X2 is CH); and X° is C.
As non-limiting examples of the foregoing embodiments of (A-l), A is:
Figure imgf000037_0003
wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2). As further non-limiting examples, A is:
Figure imgf000038_0001
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
In some embodiments, A is (A-2):
Figure imgf000038_0002
(A-2)
wherein:
Z is selected from the group consisting of:
a bond, CH, CR1, CR3, N, NH, N(R') and N(R2); each of Y1 and Y3 is independently selected from the group consisting of O, S, CH, CR1, CR3, N, NH, N(R3), and NR2;
Y4 is C or N;
X° is selected from the group consisting of O, S, N, NH, NR1, NR2, CH, CR1, and CR3 (e g·, X° is CH);
X1 is selected from the group consisting of O, S, N, NH, NR1, NR2, CH, CR1, and CR3; X2 is selected from the group consisting of O, S, N, NH, NR1, NR2, CH, CR1, and CR3; and each— is independently a single bond or a double bond, provided that the five- membered ring comprising Y4, X1, and X2 is heteroaryl; and
the ring comprising Z, Y1, Y3, and Y4 is aromatic (i.e., carbocyclic aromatic or heteroaromatic).
In some embodiments of (A-2), Z is selected from the group consisting of: CH,
CR1, CR3, and N.
In certain of these embodiments, Z is selected from the group consisting of CH, CR1, and CR3 (e.g., Z is CH).
In some embodiments of (A-2), each of Y1 and Y3 is independently selected from the group consisting of CH, CR1, CR3, and N.
In certain of these embodiments, each of Y1 and Y3 is independently selected from the group consisting of CH, CR1, and CR3.
As a non-limiting example of the foregoing embodiments, the
Figure imgf000039_0001
moiety is
Figure imgf000039_0002
wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2); and the asterisk denotes point of attachment to W1.
In some embodiments of (A-2), Y4 is C.
In some embodiments of (A-2), X1 is selected from group consisting of O, S, N, CH, NH, NR1, and NR2 (e.g., X1 is selected from NH and NR2 (e.g., X1 is NH)).
In some embodiments of (A-2), X° is selected from the group consisting of CH and
N (e.g., X° is CH).
In some embodiments of (A-2), X2 is selected from the group consisting of CR1, CH, and N (e.g., X2 is CH).
As non-limiting examples of (A-2), A is:
Figure imgf000040_0001
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
In some embodiments, A is heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R2), O, S, and S(0)2, and wherein from 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR1, and CR3; provided that at least one ring atom is substituted with R1.
In certain of these embodiments, A is heteroaryl including 5 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R'), N(R2), O, and S, and wherein from 1-4 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR1, and CR3; provided that at least one ring atom is substituted with R1.
In certain of the foregoing embodiments, A is heteroaryl including 5 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N
Figure imgf000040_0002
, N(R2), O, and S, and wherein from 1-4 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR1, and CR3; provided that the heteroaryl is substituted with from 1-2 R1 (e.g., 1).
In certain embodiments,
Figure imgf000040_0003
wherein:
U7 is N or C;
Z2 is selected from CH, CR2, and N;
X3 is selected from O, S, N, NH, NR1, NR2, CH, CR1, and CR3; each of Y5 and Y6 is independently selected from O, S, CH, CR1, CR3, NR1, NR2, NH, and N; and
each— is independently a single bond or a double bond, provided that the five- membered ring comprising Y5, Y6, Y7, X3, and Z2 is heteroaromatic.
In some embodiments of (A-3), when X3 is NR1 or CR1, then each of Y5 and Y6 is independently selected from O, S, CH, CR3, NR2, NH, and N; and
when X3 is selected from O, S, N, NH, NR2, CH, and CR3, then one of Y5 and Y6 is CR1 or NR1 (in certain embodiments, the other of Y5 and Y6 is selected from O, S, CH, CR3, NR2, NH, and N).
In some embodiments of (A-3), X3 is NR1 or CR1.
In certain of these embodiments, Z2 is selected from N or CH.
In some embodiments of (A-3) (e.g., when X3 is NR1 or CR1), Y6 is selected from S, CH, CR3, and N.
In certain embodiments, Y6 is selected from S, N and CH (e.g., Y6 is CH; or Y6 is S).
In some embodiments of (A-3) (e.g., when X3 is NR1 or CR1), Y5 is selected from CH, CR3, and N (e.g., CH and N).
In some embodiments of (A-3), Y7 is C.
As non-limiting examples of (A-3), A is selected from:
Figure imgf000041_0001
Figure imgf000041_0002
In some embodiments of (A-3), X3 is S, N, CH, CR3, NH, or NR2.
In some embodiments of (A-3), X3 is selected from N, CH, or NH (e.g., CH or NH). In some embodiments of (A-3), Z2 is selected from N or CH (e.g., Z2 is CH).
In some embodiments of (A-3), Y6 is selected from CH and N (e.g., Y6 is N).
In some embodiments of (A-3) (e.g., when X3 is S, N, CH, CR3, NH, or NR2), Y5 is selected from NR1 and CR1.
As non4imiting examples of (A-3), A is selected from:
Figure imgf000042_0001
and
Figure imgf000042_0002
The Variable R1
In some embodiments, each occurrence of R1 is independently selected from:
(i) -(U1)q-U2, wherein:
• q is O or l;
• U1 is Ci-6 alkylene, which is optionally substituted with from 1-6 Ra; and
• U2 is:
(a) C3-10 cycloalkyl, which is optionally substituted with from 1-4 Rb,
(b) C6-10 aryl, which is optionally substituted with from 1-4 Rc;
(c) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected Rc, or
(d) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2 , and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected Rb,
AND (ii) Ci-6 alkyl, which is optionally substituted with from 1-6 independently selected Ra.
In certain embodiments, R1 is -(U1)q-U2.
In certain of these embodiments, q is 0.
In certain embodiments (when R1 is -(U1)q-U2), U2 is C6-10 aryl, which is optionally substituted with from 1-4 Rc.
In certain of the foregoing embodiments, U2 is C6-10 aryl, which is optionally substituted with from 1-2 Rc.
As a non-limting example of the foregoing embodiments, U2 is phenyl, which is optionally substituted with from 1-2 (e.g., 1) Rc.
In certain embodiments (when R1 is -(U1)q-U2), Rc substituent on U2 is selected from:
(a) halo (e.g., Cl, F);
(b) cyano;
(c) Ci-io alkyl which is optionally substituted with from 1-6 independently selected Ra;
(f) Ci-4 haloalkyl;
(g) Ci-4 alkoxy;
(h) Ci -4 haloalkoxy; and
(m) -Ci-4 thioalkoxy.
In certain of these embodiments, each occurrence of Rc substituent on U2 is selected from: halo (e.g., Cl, F; e.g., F), cyano, Ci-6 alkyl, and Ci-4 haloalkyl.
In certain embodiments, R1 is phenyl, which is optionally substituted with from 1-2 (e.g., 1) Rc.
In certain of the foregoing embodiments, each occurrence of Rc substituent on U2 is selected from the group consisting of: (a) halo (e.g., Cl, F); (b) cyano; (c) Ci-io alkyl which is optionally substituted with from 1-6 independently selected Ra; (f) Ci-4 haloalkyl; (g) Ci- 4 alkoxy; (h) Ci-4 haloalkoxy; and (m) -Ci-4 thioalkoxy.
In certain embodiments, each occurrence of Rc substituent on U2 is selected from: halo (e.g., Cl, F; e.g., F), cyano, Ci-6 alkyl, and Ci-4 haloalkyl.
In certain embodiments, R1 is unsubstituted phenyl. In some embodiments, R1 is Ci-6 alkyl, which is optionally substituted with from 1- 6 independently selected Ra (in certain embodiments, each Ra substituent of R1 is independently selected from: -OH; -F; -Cl; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)0(Ci-4 alkyl); -C(=0)OH, and C3-6 cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl).
The Variable R3
In some embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NReRf, -OH, -S(0)I-2(NR,R”), -CI-4 thioalkoxy, -C(=0)(Ci-4 alkyl), -C(=0)0(Ci-4 alkyl), - C(=0)0H, and -C(=0)N(R’)(R”).
In some embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -S(0)i- 2(NR’R”), -C(=0)(CI-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)0H, and -C(=0)N(R’)(R”).
In certain of these embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy (e.g., halo or cyano).
As a non-limiting example, each occurrence of R3 is independently halo (e.g., -F) or cyano.
The Variable R2
In some embodiments, each occurrence of R2 is independently selected from:
(i) Ci-6 alkyl (e.g., methyl);
(ii) C3-6 cycloalkyl;
(iv) -C(0)(Ci-4 alkyl) (e.g., C(O)Me);
(v) -C(0)0(Ci-4 alkyl);
(vi) -CON(R’)(R”);
(vii) -S(0)I-2(NR’R”); and
(viii) - S(0)i-2(Ci-4 alkyl) (e.g., S(0)2Me). In certain embodiments, each occurrence of R2 is independently selected from (viii) - S(0)i-2(Ci-4 alkyl) (e.g., S(0)2Me) and (iv) -C(0)(Ci-4 alkyl) (e.g., C(O)Me).
Non-Limiting Combinations of R1, R3, and A
. . (R¾ h .
In some embodiments when A is (A-l), the
Figure imgf000045_0001
moiety is m3' wherein
Figure imgf000045_0002
wherein m3 is 0, 1, or
Figure imgf000045_0003
wherein m3 is 0, 1, or 2, wherein the asterisk denotes point of attachment
to Y4; and ml = 0. For example, the
Figure imgf000045_0004
In certain of these embodiments, and m3 = 0.
In certain other embodiments, m3 = 1 or 2 (e.g., m3 = 2).
In certain of these embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NReRf, -OH, -S(0)I-2(NR’R”), -CI-4 thioalkoxy, -C(=0)(Ci-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)OH, and -C(=0)N(R’)(R”)·
In certain embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -S(0)i- 2(NR’R”), -C(=0)(CI-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)OH, and -C(=0)N(R’)(R”)· In certain embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy (e.g., halo or cyano).
As non-limiting examples of the foregoing embodiments, R3 can be halo (e.g., F) or cyano.
Figure imgf000046_0002
In some embodiments, A is as defined in any one of claims 37-43 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety; and ml = 0.
(R1)
Figure imgf000046_0003
wherein ml = 0; and m3 = 0, 1, 2, or 3 (e.g., m3 = 0, 1, or 2).
In some embodiments
Figure imgf000046_0001
wherein ml = 0; and m3 = 0, 1, or 2 (e.g., m3 = 0 or 1). In some embodiments, A is:
Figure imgf000047_0001
Figure imgf000047_0002
, wherein ml = 0; and m3 = 0, 1, or 2 (e.g., m3 = 0 or 1).
In certain of the foregoing embodiments (when A is
Figure imgf000047_0003
Figure imgf000047_0004
In certain other embodiments, m3 = 1 or 2.
In certain of these embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NReRf, -OH, -S(0)I-2(NR’R”), -CI-4 thioalkoxy, -C(=0)(Ci-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)0H, and -C(=0)N(R’)(R”)·
In certain embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -S(0)i- 2(NR’R”), -C(=0)(CI-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)0H, and -C(=0)N(R’)(R”)·
In certain embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy (e.g., halo or cyano). For example, m3 can be 2; and each R3 can be F. As non-limiting examples of the foregoing embodiments, R3 can be halo (e.g., F) or cyano.
In some embodiments when A is (A-2), the
Figure imgf000048_0002
moiety i
Figure imgf000048_0001
wherein ml = 0; and m3 = 0, 1, 2, or 3 (e.g., m3 = 0, 1, or 2); and the asterisk denotes point of attachment to W1.
In certain embodiments,
Figure imgf000048_0003
, wherein ml = 0; and m3 = 0, 1, or 2 (e.g., m3 = 0 or 1).
In certain of these embodiments (when the
Figure imgf000048_0004
wherein
Figure imgf000048_0005
wherein ml = 0), m3 = 0.
In certain other embodiments, m3 = 1 or 2.
In certain of these embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NReRf, -OH, -S(0)I-2(NR’R”), -CI-4 thioalkoxy, -C(=0)(Ci-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)OH, and -C(=0)N(R’)(R”)·
In certain embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -S(0)i- 2(NR’R”), -C(=0)(CI-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)OH, and -C(=0)N(R’)(R”)· In certain embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy (e.g., halo or cyano).
As non-limiting examples of the foregoing embodiments, R3 is halo or cyano (e.g., R3 is cyano).
In some embodiments, A is selected from the group consisting of:
Figure imgf000049_0001
Figure imgf000049_0002
defined in any one of claims 73-83 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety (e.g., any one of claims 74-82 of U.S. provisional application serial no. 62/955,891).
In certain of these embodiments, R1 is phenyl, which is optionally substituted with from 1-2 (e.g., 1) Rc. In certain of these embodiments, each occurrence of Rc is selected from: (a) halo (e.g., Cl, F); (b) cyano; (c) Ci-io alkyl which is optionally substituted with from 1-6 independently selected Ra; (f) Ci-4 haloalkyl; (g) Ci-4 alkoxy; (h) Ci-4 haloalkoxy; and (m) -Ci-4 thioalkoxy. For example, each occurrence of Rc can be selected from: halo (e.g., Cl, F; e.g., F), cyano, Ci-6 alkyl, and Ci-4 haloalkyl.
As non-limiting examples of the foregoing embodiments, R1 can be phenyl optionally substituted with one Rc. For example, R1 can be unsubstituted phenyl.
In certain embodiments,
Figure imgf000049_0003
certain of these embodiments, q is 0; and U2 is phenyl, which is optionally substituted with from 1-
2 (e.g., 1) Rc; or U2 is heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc.
In certain of the foregoing embodiments, each occurrence of Rc is selected from: (a) halo (e.g., Cl, F); (b) cyano; (c) Ci-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; (f) Ci-4 haloalkyl; (g) Ci-4 alkoxy; (h) Ci-4 haloalkoxy; and (m) -Ci-4 thioalkoxy. For example, each occurrence of Rc can be selected from: halo (e.g., Cl, F; e.g., F), cyano, Ci-6 alkyl, and Ci-4 haloalkyl.
The Variables W1 and W2
In some embodiments, one of W1 and W2 is -N(H)- or -N(Rd)- (e.g., -N(H)- or - N(CI-3 alkyl)-) ;
the other one of W1 and W2 is a bond, -0-, CH2, CHRa, or CR¾.
In some embodiments, W1 is -NH-.
In some embodiments, W1 is CH2 or CH(CI-3 alkyl) (e.g., CH2).
In some embodiments, W1 is a bond.
In some embodiments, W2 is a bond.
In some embodiments, W2 is CH2 or CH(CI-3 alkyl) (e.g., CH2).
In some embodiments, W2 is -NH-.
In certain embodiments, W1 is -NH-; and W2 is a bond.
In certain embodiments, W1 is -NH-; and W2 is CH2 or CH(CI-3 alkyl) (e.g., CH2). In certain embodiments, W1 is -NH; and W2 is -(W12)-0-*, -(W12)-N(H)-*, or - (W12)-N(Rd)-*, wherein the asterisk represents point of attachment to B. In certain of these embodiments, W2 is -(W12)-N(H)-*, such as -C1-3 alkylene-N(H)-*, such as -CH2NH-*.
In certain embodiments, W2 is -NH-; and W1 is a bond.
In certain embodiments, W2 is -NH-; and W1 is CH2 or CH(CI-3 alkyl) (e.g., CH2). The Variable B
In some embodiments, B is phenyl substituted with from 1-4 Rc.
In certain embodiments, B is phenyl substituted with from 1-2 Rc, wherein from 1- 2 Rc is at the ring carbons para or me la (e.g., one Rc is at the ring carbon para ) to the point of attachment to the -W1-C(=0)-W2- moiety in Formula I.
As a non-limiting example of the foregoing embodiments, B is phenyl substituted with one Rc at the ring carbon para to the point of attachment to the -W1-C(=0)-W2- moiety
Figure imgf000051_0001
In some embodiments, each Rc substituent of B is independently selected from the group consisting of:
(a) halo;
(b) cyano;
(c) Ci-io alkyl which is optionally substituted with from 1-6 independently selected Ra;
(g) Ci-4 alkoxy;
(h) Ci-4 haloalkoxy;
(i) -S(0)i-2(Ci-4 alkyl);
(m) -Ci-4 thioalkoxy;
(o) -C(=0)(Ci-4 alkyl);
(p) -C(=0)0(Ci-4 alkyl);
(r) -C(=0)N(R’)(R”); and
(s) -L1-L2-Rh.
In some embodiments, each Rc substituent of B is independently selected from the group consisting of:
(a) halo;
(b) cyano; (c) Ci-io alkyl which is optionally substituted with from 1-6 independently selected
Ra;
(g) Ci-4 alkoxy; and
(h) Ci -4 haloalkoxy.
In certain embodiments, each Rc substituent of B is independently selected from Ci- lo alkyl which is optionally substituted with from 1-6 independently selected Ra.
In certain of the foregoing embodiments, each occurrence of Ra is independently selected from: -halo (e.g., F); -OH; Ci-4 alkoxy; and Ci-4 haloalkoxy.
As non-limiting examples of the foregoing embodiments, each Rc substituent of B is Ci-io (e.g., Ci-6, C1-3, C1-2, Ci) alkyl optionally substituted with from 1-3 halo (e.g., F) (e.g., Rc is CF3).
In some embodiments, each Rc substituent of B is independently selected from unsubstituted Ci-10 (e.g., C2-io (e.g., C3-8)) alkyl.
In certain of these embodiments, each Rc substituent of B is independently selected from unsubstituted Ci-6 alkyl.
In certain of the foregoing embodiments, each Rc substituent of B is independently selected from unsubstituted C2-6 (e.g., C2-4, e.g., C2 or C4) alkyl.
As a non-limiting example, each Rc substituent of B is ethyl or butyl (e.g., n-butyl).
In certain embodiments, Rc is Ci-6 alkyl optionally substituted with from 1-3 independently selected Ra. In certain of the foregoing embodiments, Rc is Ci-6 alkyl substituted with from 1-3 independently selected Ra.
In some embodiments, B is C3-20 cycloalkyl, which is optionally substituted with from 1-4 Rb.
In some embodiments, B is C3-12 cycloalkyl, which is optionally substituted with from 1-2 Rb.
In certain of these embodiments, B is C6-12 cycloalkyl, which is optionally substituted with from 1-2 Rb.
As a non-limiting example of the foregoing embodiments, B is C6-12 cycloalkyl (e.g.,
B can
Figure imgf000052_0001
In some embodiments, B is heterocyclyl including from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected Rb.
In certain embodiments, B is heterocyclyl including from 3-12 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected Rb.
In certain embodiments, B is heterocyclyl including from 3-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-3 independently selected Rb.
As non-limiting examples of the foregoing embodiments, B is heterocyclyl including from 5-6 (e.g., 6) ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-2 independently selected
Figure imgf000053_0001
In some embodiments, each occurrence of Rb is independently selected from the group consisting of: Ci-io alkyl; Ci-4 haloalkyl; -OH; oxo; -F; -Cl; -NReRf; Ci-4 alkoxy; Ci- 4 haloalkoxy; -C(=0)(Ci-4 alkyl); -C(=0)0(Ci-4 alkyl); -S(0)i-2(Ci-4 alkyl); cyano; and -L1- L2-Rh.
In certain embodiments, each occurrence of Rb is independently selected from the group consisting of: Ci-io alkyl; Ci-4 haloalkyl; -OH; oxo; -F; -Cl; Ci-4 alkoxy; and Ci-4 haloalkoxy. Non-Limiting Combinations
[I-a]
In some embodiments, the compound has Formula I-a:
Figure imgf000054_0001
I-a
or a pharmaceutically acceptable salt thereof.
In some embodiments of [I-a], Rc is as defined in any one of claims 122-130 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
In certain embodiments of [I-a], Rc is Ci-6 alkyl optionally substituted with from 1- 3 independently selected Ra (e.g., Rc can be Ci-4 (e.g., C2-4) alkyl; or Rc can be CF3).
In some embodiments of [I-a], A is (A-l).
In certain embodiments of [I-a], A is as defined in claim 37 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
In certain embodiments of [I-a], A is as defined in claim 25.
In certain embodiments of [I-a], A is:
Figure imgf000054_0002
Figure imgf000054_0003
As a non-limiting example of the foregoing embodiments, A can be:
Figure imgf000055_0001
In certain embodiments of [I-a] (when A is (A-l)), A is as defined in claims any one of claims 38-40 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
In certain of these embodiments, A is:
Figure imgf000055_0002
, wherein ml = 0, 1, or 2; and m3 0, 1, or 2 (e.g., ml 0 or 1 ; and m3 = 0 or 1).
In certain embodiments, A is
Figure imgf000055_0003
, wherein ml = 0, 1, or 2; and m3 0, 1, or 2 (e.g., ml 0 or 1 ; and m3 = 0 or 1).
In certain embodiments, A is
Figure imgf000055_0004
wherein ml = 0, 1, or 2; and m3 0, 1, or 2 (e.g., ml 0 or 1 ; and m3 = 0 or 1).
In certain embodiments, A is
Figure imgf000055_0005
wherein ml = 0, 1, or 2; and m3 0, 1, or 2 (e.g., ml 0 or 1 ; and m3 = 0 or 1).
In certain embodiments, A is A is
Figure imgf000056_0001
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
In certain embodiments of [I-a] (when A is (A-l)), A is: ein ml 0, 1, 2, or 3; and m3 0, 1, 2, or 3 (e.g., ml 0 or 1; and
Figure imgf000056_0002
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
In some embodiments of [I-a], A is (A-2).
In certain embodiments of [I-a], A is:
Figure imgf000056_0003
, wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 =
0 or 1).
In some embodiments of [I-a], A is (A-3).
In certain embodiments of [I-a], A is selected from:
Figure imgf000056_0004
In certain embodiments of [I-a], A is selected from:
Figure imgf000057_0001
Figure imgf000057_0002
In certain other embodiments, m3 = 1 or 2.
In certain of these embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NReRf, -OH, -S(0)I-2(NR’R”), -CI-4 thioalkoxy, -C(=0)(Ci-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)0H, and -C(=0)N(R’)(R”)·
In certain embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -S(0)i- 2(NR’R”), -C(=0)(CI-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)0H, and -C(=0)N(R’)(R”)· In certain embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy (e.g., halo or cyano).
As non-limiting examples of the foregoing embodiments, R3 is halo or cyano (e.g., R3 is cyano).
In certain embodiments of [I-a] (when A is :
Figure imgf000058_0001
Figure imgf000058_0002
defined in any one of claims 73-82 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
In certain of these embodiments, R1 is phenyl optionally substituted with from 1-2 independently substituted Rc (e.g., unsubstituted phenyl).
Figure imgf000058_0003
In certain embodiments of [I-a], A is H n orr Rr2 ; and R1 is -(U1)q-U2. In certain of these embodiments, q is 0; and U2 is phenyl, which is optionally substituted with from 1-2 (e.g., 1) Rc; or U2 is heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc.
In certain of the foregoing embodiments, each occurrence of Rc is selected from: (a) halo (e.g., Cl, F); (b) cyano; (c) Ci-io alkyl which is optionally substituted with from 1-6 independently selected Ra; (f) Ci-4 haloalkyl; (g) Ci-4 alkoxy; (h) Ci-4 haloalkoxy; and (m) -Ci-4 thioalkoxy. For example, each occurrence of Rc can be selected from: halo (e.g., Cl, F; e.g., F), cyano, Ci-6 alkyl, and Ci-4 haloalkyl. [I-b]
In some embodiments, the compound has Formula I-b:
Figure imgf000059_0001
I-b
or a pharmaceutically acceptable salt thereof,
wherein:
B2 is
a) heterocyclyl including from 3-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-3 independently selected Rb; or
b) C3-12 cycloalkyl, which is optionally substituted with from 1-2 Rb.
In some embodiments of [I-b], B2 is heterocyclyl including from 3-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-3 independently selected Rb.
In some embodiments of [I-b], B2 is heterocyclyl including from 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally
substituted with from 1-2 independently selected Rb (e.g.,
Figure imgf000059_0002
In some embodiments of [I-b], B2 is C3-12 cycloalkyl, which is optionally substituted with from 1-2 Rb.
In some embodiments of [I-b], B2 is C6-12 cycloalkyl, which is optionally substituted
Figure imgf000059_0003
In some embodiments of [I-b], A is (A-l).
In certain embodiments of [I-b], A is A is:
Figure imgf000060_0001
Figure imgf000060_0002
wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2).
As a non-limiting example, A can be:
Figure imgf000060_0003
2 (e.g., m3 =2)).
In certain embodiments of [I-b], A is as defined in any one of claims 38-43 (e.g., any one of claims 38-40) of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
In certain of these embodiments, A is:
Figure imgf000060_0004
, wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 =
0 or 1).
In certain embodiments, A is
Figure imgf000060_0005
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
In certain embodiments, A is
Figure imgf000061_0001
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
In certain embodiments, A is
Figure imgf000061_0002
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
In certain embodiments, A is
Figure imgf000061_0003
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
In certain embodiments of [I-b] (when
Figure imgf000061_0004
Figure imgf000061_0005
ml = 0.
In certain of these embodiments, m3 = 0.
In certain other embodiments, m3 = 1 or 2.
In certain of these embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NReRf, -OH, -S(0)I-2(NR’R”), -CI-4 thioalkoxy, -C(=0)(Ci-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)OH, and -C(=0)N(R’)(R”)· In certain embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -S(0)i- 2(NR’R”), -C(=0)(CI-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)0H, and -C(=0)N(R’)(R”).
In certain embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy (e.g., halo or cyano).
As non-limiting examples of the foregoing embodiments, R3 is halo or cyano (e.g., R3 is cyano).
[I-c]
In some embodiments, the compound has Formula I-c:
Figure imgf000062_0001
wherein Rw is H or C1-3 alkyl (e.g., H or Me (e.g., H));
or a pharmaceutically acceptable salt thereof.
In some embodiments of [I-c], Rc is as defined in any one of claims 122-130 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
In certain of the foregoing embodiments, Rc is Ci-6 alkyl optionally substituted with from 1-3 independently selected Ra (e.g., Rc can be Ci-4 (e.g., C2-4) alkyl; or Rc can be CF3).
In some embodiments of [I-c], A is (A-l).
In certain embodiments of [I-c], A is A is:
Figure imgf000063_0001
Figure imgf000063_0002
wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2). As a non-limiting example of the foregoing embodiments, A can be:
Figure imgf000063_0003
In some embodiments of [I-c], A is as defined in claims any one of claims 38-40 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
In certain of these embodiments, A is:
Figure imgf000063_0004
, wherein ml = 0, 1, or 2; and m3 0, 1, or 2 (e.g., ml 0 or 1 ; and m3 =
0 or 1).
In certain embodiments, A is
Figure imgf000063_0005
, wherein ml = 0, 1, or 2; and m3 0, 1, or 2 (e.g., ml 0 or 1 ; and m3 =
0 or 1).
In certain embodiments, A is
Figure imgf000064_0001
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
In certain embodiments, A is
Figure imgf000064_0002
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
In certain embodiments, A is A is
Figure imgf000064_0003
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
In some embodiments of [I-c], A is:
Figure imgf000064_0004
wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2).
In certain embodiments of [I-a] (when A is (A-l)), A is: ein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and
Figure imgf000064_0005
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1). In some embodiments of [I-c], A is (A-2).
In certain embodiments of [I-c], A is:
Figure imgf000065_0001
, wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
In some embodiments of [I-c], A is (A-3).
In certain embodiments of [I-a], A is selected from:
Figure imgf000065_0002
In certain embodiments of [I-a], A is selected from:
Figure imgf000065_0003
, and
Figure imgf000065_0004
In certain embodiments of [I-a], A is H 0r R , such as H
Figure imgf000065_0005
Figure imgf000066_0001
), ml = 0.
In certain of these embodiments, m3 = 0.
In certain other embodiments, m3 = 1 or 2.
In certain of these embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NReRf, -OH, -S(0)I-2(NR’R”), -CM thioalkoxy, -C(=0)(CM alkyl), -C(=0)0(CM alkyl), -C(=0)OH, and -C(=0)N(R’)(R”)
In certain embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, CM alkoxy, CM haloalkoxy, -S(0)I-2(CM alkyl), -S(0)i- 2(NR’R”), -C(=0)(CM alkyl), -C(=0)0(CM alkyl), -C(=0)OH, and -C(=0)N(R’)( ”)·
In certain embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, CM alkoxy, and CM haloalkoxy (e.g., halo or cyano).
As non-limiting examples of the foregoing embodiments, R3 is halo or cyano (e.g., R3 is cyano).
In certain embodiments of [I-c] (when
Figure imgf000066_0002
R1
Ό , o orr
Figure imgf000066_0003
defined in any one of claims 73-82 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
In certain of these embodiments, R1 is phenyl optionally substituted with from 1-2 independently substituted Rc (e.g., unsubstituted phenyl). In certain embodiments
Figure imgf000067_0001
certain of these embodiments, q is 0; and U2 is phenyl, which is optionally substituted with from 1-2 (e.g., 1) Rc; or U2 is heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc.
In certain of the foregoing embodiments, each occurrence of Rc is selected from: (a) halo (e.g., Cl, F); (b) cyano; (c) Ci-io alkyl which is optionally substituted with from 1-6 independently selected Ra; (f) Ci-4 haloalkyl; (g) Ci-4 alkoxy; (h) Ci-4 haloalkoxy; and (m) -Ci-4 thioalkoxy. For example, each occurrence of Rc can be selected from: halo (e.g., Cl,
F; e.g., F), cyano, Ci-6 alkyl, and Ci-4 haloalkyl.
[I-d]
In some embodiments, the compound has Formula I-d:
Figure imgf000067_0002
I-d
or a pharmaceutically acceptable salt thereof.
In some embodiments of [I-d], Rc is as defined in any one of claims 122-130 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
In certain embodiments of [I-d], Rc is Ci-6 alkyl optionally substituted with from 1-3 independently selected Ra (e.g., Rc can be Ci-4 (e.g., C2-4) alkyl; or Rc can be CF3).
In some embodiments of [I-d], A is (A-l).
Figure imgf000068_0001
wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2).
As a non-limiting example of the foregoing embodiments, A can be
Figure imgf000068_0002
In some embodiments of [I-d], A is as defined in any one of claims 38-43 (e.g., any one of claims 38-40) of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
In some embodiments of [I-d], A is (A-2).
In certain embodiments of [I-d], A is A is:
Figure imgf000068_0003
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
In some embodiments of [I-d], A is (A-3).
In certain embodiments of [I-d], A is as defined in any one of claims 66 and 72 of
U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety. In certain embodiments of [I-d] (when A is as defined in any one of claims 37, 38- 43 (e.g., any one of claims 38-40), and 54 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety), ml = 0.
In certain embodiments of [I-d] (when A is as defined in any one of claims 37, 38- 43 (e.g., any one of claims 38-40), and 54 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety), m3 = 0.
In certain embodiments of [I-d] (when A is as defined in any one of claims 37, 38- 43 (e.g., any one of claims 38-40), and 54 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety), m3 = 1 or 2.
In certain of these embodiments, R3 is as defined in any one of claims 84-86 (e.g., R3 can be halo (e.g., F) or cyano) ofU.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
In certain embodiments of [I-d] (when A is as defined in any one of claims 66 and 72 of U.S. provisional application serial no. 62/955,891), R1 is as defined in any one of claims 73-82 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
In certain of these embodiments, R1 is phenyl optionally substituted with from 1-2 independently substituted Rc (e.g., unsubstituted phenyl).
[I-e]
In some embodiments, the compound has Formula I-e:
Figure imgf000069_0001
I-e
wherein Rw is H or C1-3 alkyl (e.g., H or Me (e.g., H));
or a pharmaceutically acceptable salt thereof. In some embodiments of [I-e], Rc is as defined in any one of claims 122-130 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
In certain of these embodiments, Rc is Ci-6 alkyl optionally substituted with from 1-3 independently selected Ra (e.g., Rc can be Ci-4 (e.g., C2-4) alkyl; or Rc can be CF3).
In some embodiments of [I-e], A is (A-l).
In certain embodiments of [I-e], A is:
Figure imgf000070_0001
wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2).
As a non-limiting example of the foreoing embodiments,
Figure imgf000070_0002
In some embodiments of [I-e], A is as defined in any one of claims 38-43 (e.g., any one of claims 38-40) of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
In some embodiments
Figure imgf000070_0003
In some embodiments of [I-e], A is (A-2).
In certain embodiments
Figure imgf000070_0004
wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1). In some embodiments of [I-e], A is (A-3).
In certain embodiments of [I-e], A is as defined in any one of claims 66 and 72 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
In certain embodiments of [I-e] (when A is as defined in any one of claims 37, 38-
43 (e.g., any one of claims 38-40), 41, and 54 of U.S. provisional application serial no. 62/955,891), ml = 0.
In certain embodiments of [I-e] (when A is as defined in any one of claims 37, 38- 43 (e.g., any one of claims 38-40), 41, and 54 of U.S. provisional application serial no. 62/955,891), m3 = 0.
In certain embodiments of [I-e] (when A is as defined in any one of claims 37, 38- 43 (e.g., any one of claims 38-40), 41, and 54 of U.S. provisional application serial no. 62/955,891), m3 = 1 or 2.
In certain of these embodiments, R3 is as defined in any one of claims 84-86 (e.g., R3 can be halo (e.g., F) or cyano) ofU.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
In certain embodiments of [I-e] (when A is as defined in any one of claims 66 and 72 of U.S. provisional application serial no. 62/955,891), R1 is as defined in any one of claims 73-82 of U.S. provisional application serial no. 62/955,891 which is incorporated herein by reference in its entirety.
In certain of these embodiments, R1 is phenyl optionally substituted with from 1-2 independently substituted Rc (e.g., unsubstituted phenyl).
[I-f]
In some embodiments, the compound has Formula I-f:
Figure imgf000071_0001
I-f
wherein W1 is attached to the carbon atom adjacent to * or the carbon atom adjacent to **; ml is 0, 1, 2, or 3;
m2 is 0, 1, 2, or 3; and
ZA and ZA are independently selected from the group consisting of N, CH, CR1, and
CR3
In some embodiments of [I-f],
one of W1 and W2 is -N(H)- or -N(Rd)- (e.g., -N(H)- or -N(CI-3 alkyl)-); and the other one of W1 and W2 is a bond or C1-C6 alkylene optionally substituted with from 1-3 Ra (e.g., C1-C3, e.g., CH 2, CHRa, or CRa 2).
In certain embodiments of [I-f],
W1 is -N(H)- or -N(Rd)- (e.g., -N(H)- or -N(CI-3 alkyl)-); and
W2 is a bond or C1-C6 alkylene optionally substituted with from 1-3 Ra (e.g., C1-C3, e.g, CH 2, CHRa, or CRa 2).
In certain embodiments of [I-f],
W1 is -N(H)-; and
W2 is a bond or CH2.
In certain embodiments of [I-f],
W1 is -N(H)-; and
W2 is a bond.
In certain embodiments of [I-f],
W1 is -N(H)-; and
W2 is CH2.
In some embodiments of [I-f], W1 is attached to the carbon atom adjacent to **. In some embodiments of [I-f], ZA and ZA are each N.
In some embodiments of [I-f], ml is 0 or 1 and m2 is 1 or 2. In certain embodiments of [I-e], ml is 0 and m2 is 1. In certain of these embodiments, ZB is CR3 and one R3 is attached to the position of the indole ring between ZA and the ZB CR3.
In some embodiments of [I-f], each occurrence of R3 is independently selected from the group consisting of halo, cyano, -NReRf, -OH and -NO2. In some of these embodiments, each occurrence of R3 is an independently selected halo. For example, each occurrence of R3 is -F.
In some embodiments of [I-f],
B is heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected Rc.
In certain embodiments of [I-f],
B is heteroaryl including 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), N(RC), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected Rc.
In certain of these embodiments of [I-f],
B is heteroaryl including 5 ring atoms, wherein 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), S, and N(Rd), N(RC), and wherein the heteroaryl ring is optionally substituted with 1 independently selected Rc.
Figure imgf000073_0001
In certain of these embodiments of [I-f],
B is heteroaryl including 6 ring atoms, wherein 2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(Rd), and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc.
In certain embodiments of [I-f], B is selected from the group consisting of:
Figure imgf000074_0001
In any of the foregoing embodiments of [I-f], Rc is Ci-15 alkyl which is optionally substituted with from 1-6 independently selected Ra or -L'-L2-Rh In some of these embodiments, Rc is selected from the group consisting of: isopropyl, CF3, phenyl,
Figure imgf000074_0002
[i-g]
In some embodiments, A is selected from the group consisting of:
Figure imgf000074_0003
ml is 0 or 1; and m3 is 0, 1, or 2;
W1 is NH; W2 is a bond or C1-3 alkylene (e.g., -CH(Me)-); and
B is selected from the group consisting of:
phenyl substituted with from 1-4 Rc;
heteroaryl including from 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is substituted with from 1-4 independently selected Rc;
bicyclic or tricyclic heteroaryl including from 9-15 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected Rc; and
C5-15 alkyl which is optionally substituted with from 1-6 Ra.
In certain embodiments of [I-g], R2N is H.
In certain embodiments of [I-g], ml is 0.
In certain other embodiments of [1-g], ml is 1.
In certain embodiments of [I-g], m3 is 0.
In certain other embodiments, m3 is 1 or 2.
In certain embodiments of [1-g], ml is 0; and m3 is 1 or 2 (e.g., 2).
In certain embodiments
Figure imgf000075_0001
example, each R3 can be halo (e.g., F).
In certain embodiments of [1-g], each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -S(0)I-2(NR’R”), -C(=0)(CI-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)OH, and -
C(=0)N(R’)(R”). In certain embodiments of [1-g], each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy (e.g., R3 can be halo).
In certain embodiments of [1-g], R1 is -(U1)q-U2.
In certain of these embodiments, q is 0.
In certain embodiments of [1-g] (when R1 is -(U1)q-U2), U2 is C6-10 aryl, which is optionally substituted with from 1-4 Rc.
In certain of these embodiments of [1-g], U2 is C6-10 aryl, which is optionally substituted with from 1-2 Rc.
As a non-limiting example, U2 is phenyl, which is optionally substituted with from 1-2 (e.g., 1) Rc.
In certain embodiments of [1-g] (when U2 is C6-10 aryl, which is optionally substituted with from 1-2 Rc), each occurrence of Rc substituent on U2 is independently selected from: halo, cyano, Ci-6 alkyl, and Ci-4 haloalkyl.
In certain embodiments of [1-g] (when U2 is C6-10 aryl, which is optionally substituted with from 1-2 Rc), each occurrence of Rc substituent on U2 is independently selected from halo.
In certain embodiments of [1-g], B is selected from the group consisting of:
Figure imgf000076_0001
is an independently selected Rc; nl is 0, 1, or 2; each of Q1, Q2, Q3, Q4, Q5, and Q6 is independently selected from the group consisting of N and CH, provided that at least one of Q1 and Q2 is N; and at least one of Q3, Q4, Q5, and Q6 is N.
In certain of these embodiments, nl is 0.
In certain other embodiments, nl is 1. In certain of these embodiments, RcA is halo (e.g., -F, or -Cl) or Ci-6 alkyl which is optionally substituted with from 1-3 independently selected Ra (e.g., methyl or CF3). In certain embodiments, RcB is Ci-6 alkyl which is optionally substituted with from 1-6 independently selected Ra.
For example, RcB can be unsubstituted C2-10 (e.g., C2-3 , e.g., C3-4, e.g., C4-10) alkyl.
As another non-limiting example, RcB can be Ci-6 alkyl which is substituted with from 1-6 independently selected Ra. For example, each Ra can be halo (e.g., F), NReRf, OH, Ci-3 alkoxy, or C1-3 haloalkoxy.
In certain embodiments, RcB is -L1-L2-Rh. In certain of these embodiments, each of L1 and L2 is a bond. In certain other embodiments, L1 is a bond; and L2 is -0-.
In certain embodiments, Rh is selected from the group consisting of:
C3-6 cycloalkyl optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, and Ci-4 haloalkyl (in certain embodiments, it is provided that when Rh is C3-6 cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl, -L1 is a bond, or -L2 is -0-, -N(H)-, or -S-);
heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, and Ci-4 haloalkyl; and
Ce aryl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, or Ci-4 haloalkyl.
In certain embodiments of [1-g], B is heteroaryl including 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is substituted with from 1-4 independently selected Rc, provided that one occurrence of Rc is iAlAR*1. In certain of these embodiments, each of L1 and L2 is a bond. In certain other embodiments, L1 is a bond; and L2 is -O-.
In certain embodiments, Rh is selected from the group consisting of:
C3-6 cycloalkyl optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, and Ci-4 haloalkyl (in certain embodiments, it is provided that when Rh is C3-6 cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl, -L1 is a bond, or -L2 is -0-, -N(H)-, or -S-);
heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, and Ci-4 haloalkyl; and
Ce aryl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, or Ci-4 haloalkyl.
Formula Compounds
In another aspect, provided herein is a compound of Formula II:
Figure imgf000078_0001
II
or a pharmaceutically acceptable salt thereof or a tautomer thereof,
wherein:
Z is selected from the group consisting of: CH, CR1, CR3, N, NH, N(R') and N(R2); each of Y1, Y2, and Y3 is independently selected from the group consisting of CH, CR1, CR3, N, NH, N(R3), and NR2;
each— is independently a single bond or a double bond, provided that:
the 6-membered ring comprising Z, Y1, Y2, and Y3 is aromatic;
R2N is H or R2;
R6 is selected from the group consisting of H and Rd; B is a monocyclic heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc;
-L3 is a bond or C1-3 alkylene;
R4 is selected from the group consisting of:
(a) C3-12 cycloalkyl, which is optionally substituted with from 1-4 independently selected R4’,
(b) heterocyclyl including from 3-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heterocyclyl is optionally substituted with from 1-4 independently selected R4’;
(c) heteroaryl including from 5-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with from 1-4 independently selected R4’; and
(d) C6-10 aryl optionally substituted with from 1-4 independently selected R4’; wherein each R4’ is independently selected from the group consisting of: halo; -CN;
-NO2; -OH; -Ci-4 alkyl optionally substituted with from 1-2 independently selected Ra; -C2- 4 alkenyl; -C2-4 alkynyl; -Ci-4 haloalkyl; -Ci-6 alkoxy optionally substituted with from 1-2 independently selected Ra; -Ci-6 haloalkoxy; S(0)i-2(Ci-4 alkyl); -NR’R”; oxo; -S(0)i- 2(NR’R”); -CI-4 thioalkoxy; -C(=0)(Ci-4 alkyl); -C(=0)0(Ci-4 alkyl); -C(=0)OH; and -
C(=0)N(R’)(R”);
R1 is:
(i) -(U1)q-U2, wherein:
• q is O or l;
• U1 is Ci-6 alkylene, which is optionally substituted with from 1-6 Ra; and
• U2 is:
(a) C3-12 cycloalkyl, which is optionally substituted with from 1-4 Rb,
(b) C6-10 aryl, which is optionally substituted with from 1-4 Rc; (c) heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected Rc, or (d) heterocyclyl including from 3-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected Rb,
OR
(ii) Ci-io alkyl, which is optionally substituted with from 1-6 independently selected Ra; each occurrence of R2 is independently selected from the group consisting of:
(i) Ci-6 alkyl, which is optionally substituted with from 1-4 independently selected Ra;
(ii) C3-6 cycloalkyl;
(iii) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2;
(iv) -C(0)(Ci-4 alkyl);
(v) -C(0)0(Ci-4 alkyl);
(vi) -CON(R’)(R”);
(vii) -S(0)I-2(NR’R”);
(viii) - S(0)i-2(Ci-4 alkyl);
(ix) -OH; and
(x) Ci-4 alkoxy; each occurrence of R3 is independently selected from the group consisting of halo, cyano, C2-6 alkenyl, C2-6 alkynyl, Ci-4 alkoxy optionally substituted with C3-6 cycloalkyl, Ci- 4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NReRf, -OH, oxo, -S(0)I-2(NR’R”), -Ci-4 thioalkoxy, - NO2, -C(=0)(Ci-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)OH, and -C(=0)N(R’)(R”); each occurrence of Ra is independently selected from the group consisting of: -OH; -F; -Cl; -Br; -NReRf; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)0(Ci-4 alkyl); -C(=0)(Ci-4 alkyl);
-C(=0)OH; -CON(R’)(R”); -S(0)I-2(NR’R”); -S(0)I-2(CM alkyl); cyano, and C3-6 cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl; each occurrence of Rb is independently selected from the group consisting of: Ci-10 alkyl optionally substituted with from 1-6 independently selected Ra; Ci-4 haloalkyl; -OH; oxo; -F; -Cl; -Br; -NReRf; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)(Ci-4 alkyl); -C(=0)0(Ci-4 alkyl); -C(=0)OH; -C(=0)N(R’)(R”); -S(0)I-2(NR’R”); -S(0)I-2(CM alkyl); cyano; and -
IAU-R*1; each occurrence of Rc is independently selected from the group consisting of:
(a) halo;
(b) cyano;
(c) Ci-15 alkyl which is optionally substituted with from 1-6 independently selected Ra;
(d) C2-6 alkenyl;
(e) C2-6 alkynyl;
(g) Ci-4 alkoxy optionally substituted with Ci-4 alkoxy;
(h) Ci-4 haloalkoxy;
(i) -S(0)i-2(Ci-4 alkyl);
(j) -NReRf;
(k) -OH;
(l) -S(0)I-2(NR’R”);
(m) -Ci-4 thioalkoxy optionally substituted with from 1-4 halo;
(n) -NO2;
(o) -C(=0)(Ci-4 alkyl); (p) -C(=0)0(Ci-4 alkyl);
(q) -C(=0)0H;
(r) -C(=0)N(R’)(R”); and
(s) -L1-L2-Rh;
Rd is selected from the group consisting of: Ci-6 alkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); -C(0)0(Ci-4 alkyl); -CON(R’)(R”); -S(0)i.2(NR’R”); - S(0)i-2(Ci-4 alkyl); -OH; and Ci-4 alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; Ci-6 alkyl; Ci-6 haloalkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); -C(0)0(Ci-4 alkyl); - CON(R’)(R”); -S(0)i-2(NR’R”); - S(0)i-2(Ci-4 alkyl); -OH; and CM alkoxy; or Re and Rf together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to Re and R1), which are each independently selected from the group consisting of N(Rd), NH, O, and S;
-L1 is a bond or C1-3 alkylene;
-L2 is -O-, -N(H)-, -S-, or a bond;
Rh is selected from:
• C3-8 cycloalkyl optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, and Ci-4 haloalkyl (in certain embodiments, it is provided that when Rh is C3-6 cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl, -L1 is a bond, or -L2 is -O-, -N(H)-, or -S-);
• heterocyclyl, wherein the heterocyclyl includes from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, and Ci-4 haloalkyl;
• heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, and Ci-4 haloalkyl; and
• C6-io aryl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, or Ci-4 haloalkyl; and each occurrence of R’ and R” is independently selected from the group consisting of: H, Ci-4 alkyl, and C6-10 aryl optionally substituted with from 1-2 substituents selected from halo, Ci-4 alkyl, and Ci-4 haloalkyl; or R’ and R” together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from the group consisting of H and C1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R’ and R”), which are each independently selected from the group consisting of N(H), N(Rd), O, and S.
In some embodiments, it is provided that one or more of the compound provisions (infra) applies:
Compound Provisions
In some embodiments of Formula II, it is provided that Y3 cannot be N when each of each of Y1, Y2, and Y3 is independently selected from the group consisting of CH, CR1, CR3; and
when each of Z, Y1, Y2, and Y3 is independently selected from the group consisting of CH, CR1, and CR3, from 1-4 of Z, Y1, Y2, and Y3 is selected from the group consisting of CR1 and CR3. In some embodiments of Formula II, it is provided that when Y3 is N; and each of each of Y1, Y2, and Y3 is independently selected from the group consisting of CH, CR1,
CR3, then B-L3- is other than:
Figure imgf000084_0001
, wherein the asterisk represents point of attachment to R4.
In some embodiments of Formula II, it is provided that when Y3 is N; and each of each of Y1, Y2, and Y3 is independently selected from the group consisting of CH, CR1, CR3, then B is other than pyrazolyl.
In some embodiments of Formula II, it is provided that when Y3 is N; and each of each of Y1, Y2, and Y3 is independently selected from the group consisting of CH, CR1,
CR3, then B-L3 is other than
Figure imgf000084_0002
, wherein the asterisk represents point of attachment to R4.
In some embodiments, it is provided that -L3-R4 is other than CH2-cyclopropyl.
In some embodiments, the compound is other than:
Figure imgf000084_0003
Figure imgf000085_0001
Figure imgf000086_0001
In some embodiments, when each of Z, Y1, Y2, and Y3 is CH, then B is other than furanyl, pyrazolyl, 1,2,3-triazolyl, isoxazolyl, oxazolyl, hydroxy-imidazolyl, pyrimidyl, thiazolyl, thiophenyl, each of which is further optionally substituted with one Rc.
In some embodiments, the compound of Formula II is other than compounds disclosed in WO 2013/114113 which is incorporated herein by reference in its entirety.
In some embodiments, the compound of Formula II is other than compounds disclosed in U.S. Patent No. 10,000,481 which is incorporated herein by reference in its entirety.
In some embodiments, the compound of Formula II is other than compounds disclosed in WO 2009/140320 which is incorporated herein by reference in its entirety.
In some embodiments, the compound of Formula II is other than compounds disclosed in U.S. Patent No. 8,981,085 which is incorporated herein by reference in its entirety.
In some embodiments, the compound of Formula II is other than compounds disclosed in WO 2003/028724 which is incorporated herein by reference in its entirety.
Embodiments can include any one or more of the features delineated below and/or in the claims.
In some embodiments, each of Z, Y1, Y2, and Y3 is independently selected from the group consisting of: CH, CR1, CR3, and N. In certain embodiments, each of Z, Y1, Y2, and Y3 is independently selected from the group consisting of: CH, CR1, and CR3.
In certain embodiments, from 1-2 of Z, Y1, Y2, and Y3 is independently selected from the group consisting of CR1 and CR3; and each remaining Z, Y1, Y2, and Y3 is CH.
In certain of the foregoing embodiments, the compound has Formula Il-a:
Figure imgf000087_0001
In certain embodiments, the compound has Formula Il-b or II-c:
Figure imgf000087_0002
In certain embodiments, the compound has Formula Il-d, Il-e, or Il-f:
Figure imgf000087_0003
In certain embodiments, one of Z, Y1, and Y2 is N; and each remaining Z, Y1, Y2, and Y3 is independently selected from the group consisting of CH, CR1, and CR3.
In certain of these embodiments, Z is N.
In certain embodiments (when one of Z, Y1, and Y2 is N; and each remaining Z, Y1, Y2, and Y3 is independently selected from the group consisting of CH, CR1, and CR3), Y1 is N.
In certain embodiments (when one of Z, Y1, and Y2 is N; and each remaining Z, Y1, Y2, and Y3 is independently selected from the group consisting of CH, CR1, and CR3), Y2 is N.
In certain embodiments (when one of Z, Y1, and Y2 is N; and each remaining Z, Y1,
Y2, and Y3 is independently selected from the group consisting of CH, CR1, and CR3), the compound has Formula Il-g, Il-h, or Il-i:
Figure imgf000088_0001
In certain embodiments of Formulae Il-g, Il-h, or Il-i, ml is 0.
In certain other embodiments, ml is 1.
In certain embodiments of Formulae Il-g, Il-h, or Il-i, m3 is 0.
In certain other embodiments, m3 is 1 or 2.
In certain embodiments of Formulae Il-g, Il-h, or Il-i, ml is 0; and m3 is 1 or 2
(e.g., m3 is 1). In certain embodiments of Formulae Il-g, Il-h, or Il-i, ml is 1; and m3 is 0.
In certain embodiments of Formulae Il-g, Il-h, or Il-i, ml is 1; and m3 is 1.
In some embodiments, R2N is H.
In some embodiments, R2N is R2, wherein said R2 is selected from the group consisting of: (iv) -C(0)(Ci-4 alkyl) (e.g., -C(O)Me); (v) -C(0)0(Ci-4 alkyl); (vi) -
CON(R’)(R”); (vii) -S(0)i-2(NR’R”); and (viii) - S(0)i-2(Ci-4 alkyl) (e.g., S(0)2Me).
As a non-limiting example of the foregoing embodiments, R2N can be (iv) -C(0)(Ci- 4 alkyl) (e.g., -C(O)Me) or (viii) - S(0)i-2(Ci-4 alkyl) (e.g., S(0)2Me).
In some embodiments, R1 is Ci-6 alkyl, which is optionally substituted with from 1- 6 (e.g., 1-3) independently selected Ra.
In certain embodiments, R1 is C 1-3 alkyl, which is optionally substituted with from 1-3 independently selected Ra.
In some embodiments, R1 is -(U1)q-U2, wherein:
q is 0 or 1, such as q is 0;
U1 is Ci-6 alkylene, which is optionally substituted with from 1-6 Ra; and
U2 is:
(C3-10 cycloalkyl, which is optionally substituted with from 1-4 Rb,
(C6-10 aryl, which is optionally substituted with from 1-2 Rc;
(heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc, or
(heterocyclyl including from 3-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2 , and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected Rb.
In some embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NReRf, -OH, -S(0)I-2(NR’R”), -CI-4 thioalkoxy, -C(=0)(Ci-4 alkyl), -C(=0)0(Ci-4 alkyl), - C(=0)OH, and -C(=0)N(R’)(R”). In certain embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -S(0)i- 2(NR’R”), -C(=0)(CI-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)OH, and -C(=0)N(R’)(R”).
In certain of these embodiments, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy.
As a non-limiting example of the foregoing embodiments, each occurrence of R3 can be halo or cyano, such as -F or cyano.
In some embodiments, B is a monocyclic heteroaryl including 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc.
In certain embodiments, B is a monocyclic heteroaryl including 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc.
In certain embodiments, B is a monocyclic heteroaryl including 5 ring atoms, wherein from 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc.
In certain embodiments, B is a monocyclic heteroaryl including 5 ring atoms, wherein from 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(Rd), and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc.
In certain embodiments, B can be imidazolyl, pyrazolyl, or triazolyl, each of which is optionally substituted with one independently selected Rc.
As a non-limiting example of the foregoing embodiments, B can be imidazolyl or triazolyl, each of which is optionally substituted with one independently selected Rc. For example, B can be selected from the group consisting of:
Figure imgf000091_0001
Figure imgf000091_0002
each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
For example, B can be selected from the group consisting of:
Figure imgf000091_0003
,
Figure imgf000091_0004
, each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
As another non-limiting example, B can be selected from the group consisting of:
Figure imgf000091_0005
each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
Figure imgf000091_0006
For example, B can be selected from the group consisting of: and
Figure imgf000091_0007
each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3. In certain embodiments, B is selected from the group consisting of:
Figure imgf000092_0001
Figure imgf000092_0002
each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
As a non-limiting example of the foregoing embodiments, B is selected from the
N
N
Figure imgf000092_0003
group consisting of: aa and aa, each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
In certain embodiments, B is a monocyclic heteroaryl including 5 ring atoms, wherein from 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, provided that one ring atom is O or S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc.
In certain of these embodiments, B is selected from the group consisting of oxazolyl, thiazolyl, thiadiazolyl, and oxadiazolyl, each of which is optionally substituted with one Rc.
As a non-limiting example of the foregoing embodiments, B is selected from the group consisting of:
Figure imgf000092_0004
each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
In certain embodiments, B is a monocyclic heteroaryl including 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc, wherein the point of attachment to the C(=0)NR6 group of Formula II is meta to the point of attachment to L3.
As non-limiting examples of the foregoing embodiments, B can be selected from the
Figure imgf000093_0001
of which is optionally substituted with one Rc, wherein aa denotes point of attachment to
L3
In some embodiments, B is a monocyclic heteroaryl including 6 ring atoms, wherein from 1-3 ring atoms are ring nitrogen atoms, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc.
In certain of these embodiments, B is pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl, each of which is optionally substituted with from 1-2 independently selected Rc, such as pyridyl optionally substituted with Rc.
In certain embodiments (when B is a monocyclic heteroaryl including 6 ring atoms, wherein from 1-3 ring atoms are ring nitrogen atoms, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc), the point of attachment of B to the C(=0)NR6 group of Formula II is para to the point of attachment to L3.
As a non-limiting example of the foregoing embodiments, B can be
Figure imgf000093_0002
which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
In certain embodiments (when B is a monocyclic heteroaryl including 6 ring atoms, wherein from 1-3 ring atoms are ring nitrogen atoms, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc), the point of attachment of B to the C(=0)NR6 group of Formula II is meta to the point of attachment to L3. As a non-limiting example of the foregoing embodiments, B can be selected from
the group consisting of:
Figure imgf000094_0001
each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
In some embodiments, L3 is a bond.
In some embodiments, L3 is C1-3 alkylene.
In certain of these embodiments, L3 is CH2.
In some embodiments, R4 is C6-10 aryl optionally substituted with from 1-4 independently selected R4’.
In certain embodiments, R4 is phenyl optionally substituted with from 1-4 independently selected R4’.
In certain embodiments, R4 is phenyl optionally substituted with from 1-2 independently selected R4’.
As a non-limiting example, R4 can be unsubstituted phenyl.
As another non-limiting example, R4 can be phenyl substituted with from 1-2 independently selected R4’.
In certain embodiments, R4 is phenyl substituted with from 1-2 independently selected R4’, wherein one occurrence of R4’ is para to the point of attachment to L3, such
-R 4' .
as
In some embodiments, R4 is heteroaryl including from 5-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with from 1-4 independently selected R4’. In certain embodiments, R4 is heteroaryl including from 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with from 1-4 independently selected R4’.
In certain embodiments, R4 is heteroaryl including 6 ring atoms, wherein from 1-3 ring atoms are ring nitrogen atoms, and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with from 1-4 independently selected R4’, such as pyridyl which is optionally substituted with from 1-2 independently selected R4’.
In some embodiments, R4 is C3-8 cycloalkyl, which is optionally substituted with from 1-4 independently selected R4’.
In certain embodiments, R4 is C4-6 cycloalkyl, which is optionally substituted with from 1-4 independently selected R4’.
As a non-limiting example, R4 can be unsubstituted C4-6 cycloalkyl, such as unsubstituted cyclohexyl and unsubstituted cyclopentyl.
As another non-limiting example, R4 can be C4-6 cycloalkyl, which is substituted
1 / \<R4' with from 1-3 (e.g., from 2-3) independently selected R4’, such as 1 — ' R ' .
In some embodiments, R4 is heterocyclyl including from 4-7 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heterocyclyl is optionally substituted with from 1-4 independently selected R4’
In some embodiments, each R4’ is independently selected from the group consisting of: halo; -CN; -Ci-4 alkyl optionally substituted with from 1-2 independently selected Ra; -Ci-4 haloalkyl; -Ci-6 alkoxy optionally substituted with from 1-2 independently selected Ra; -Ci-6 haloalkoxy; S(0)i-2(Ci-4 alkyl); -S(0)I-2(NR’R”); -Ci- 4 thioalkoxy; -C(=0)(Ci-4 alkyl); -C(=0)0(Ci-4 alkyl); and -C(=0)N(R’)(R”)· In certain embodiments, each R4’ is independently selected from the group consisting of: halo; -CN; -Ci-4 alkyl optionally substituted with one independently selected Ra; and -Ci-4 haloalkyl.
As non-limiting examples of the foregoing embodiments, each R4’ is independently selected from the group consisting of: halo (such as -F), -CN, -Ci-4 alkyl, and -C i-4 haloalkyl.
In certain embodiments, L3 is a bond or CFh; R4 is phenyl optionally substituted with from 1-2 independently selected R4’; and R4’ is independently selected from the group consisting of: halo; -CN; -Ci-4 alkyl optionally substituted with from 1-2 independently selected Ra; -Ci-4 haloalkyl; -Ci-6 alkoxy optionally substituted with from 1-2 independently selected Ra; -Ci-6 haloalkoxy; S(0)i-2(Ci-4 alkyl); -S(0)I-2(NR’R”); -CM thioalkoxy; -C(=0)(CM alkyl); -C(=0)0(CM alkyl); and -C(=0)N(R’)(R”)·
In certain of these embodiments, R4 i i ss
Figure imgf000096_0001
, which is optionally substituted with an additional R4.
In certain embodiments (when R H4
Figure imgf000096_0002
which is optionally substituted with an additional R4), each R4’ is independently selected from the group consisting of: halo (such as -F), -CN, -CM alkyl, and -CM haloalkyl.
In certain embodiments (when R4
Figure imgf000096_0003
, which is optionally substituted with an additional R4), the >ara-placed R4’ is -CF3.
In some embodiments, each occurrence of Rc is independently selected from the group consisting of: halo; cyano; Ci-6 alkyl which is optionally substituted with from 1- 6 independently selected Ra; CM alkoxy optionally substituted with CM alkoxy; CM haloalkoxy; S(0)I-2(CM alkyl); -S(0)I-2(NR’R”); -CM thioalkoxy optionally substituted with from 1-4 halo;-C(=0)(Ci-4 alkyl); -C(=0)0(CM alkyl); and -
C(=0)N(R’)(R”).
In certain embodiments, each occurrence of Rc is independently selected from the group consisting of halo; cyano; C1-3 alkyl which is optionally substituted with from 1-3 independently selected Ra (such as methyl or CF3); Ci-4 alkoxy optionally substituted with Ci-4 alkoxy; and Ci-4 haloalkoxy.
In certain of these embodiments, one occurrence of Rc is C1-3 alkyl which is optionally substituted with from 1-3 independently selected Ra (such as methyl or CF3).
In certain embodiments, the compound of Formula II has Formula II-l:
Figure imgf000097_0001
II-l ml is 0 or 1; m3 is 0, 1, or 2, provided that ml+m3>0; and
B is a monocyclic heteroaryl including 5 ring atoms, wherein from 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc.
In certain embodiments of Formula II-l, m3 is 1 or 2.
In certain of these embodiments, m3 is 2.
In certain embodiments of Formula II-l (e.g., when m3 is 2), ml is 0.
In certain embodiments of Formula II-l, the compound has Formula Il-la:
Figure imgf000097_0002
-la.
In certain embodiments of Formula II-l, each R3 is independently selected from the group consisting of halo and cyano. For example, each R3 can be halo, such as -F.
In certain embodiments of Formula II-l, R2N is H. In certain embodiments of Formula II- 1, R2N is (iv) -C(0)(Ci-4 alkyl) (e.g., - C(O)Me) or (viii) - S(0)I-2(CM alkyl) (e.g., S(0)2Me).
In certain embodiments of Formula II-l, B is a monocyclic heteroaryl including 5 ring atoms, wherein from 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc, wherein the point of attachment to the C(=0)NH group of Formula II-l is me let to the point of attachment to L3
In certain embodiments, B is selected from the group consisting of imidazolyl and triazolyl, each of which is optionally substituted with one Rc.
As non-limiting examples of the foregoing embodiments, B can be selected from
the group consisting of:
Figure imgf000098_0002
aa and
H \aa
KJ , each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
In certain embodiments of Formula II-l, B is pyrazolyl optionally substituted with one Rc.
Figure imgf000098_0001
As non-limiting examples, B can be aa and aa, each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3. In certain embodiments of Formula II-l, B is selected from the group consisting of oxazolyl, thiazolyl, oxadiazolyl, and thiadiazolyl, wherein the oxazolyl and thiazolyl are optionally substituted with one Rc.
As non-limiting examples, B can be selected from the group consisting of:
Figure imgf000099_0001
each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
In certain embodiments of Formula II-l, each Rc when present is independently selected from the group consisting of halo; cyano; C1-3 alkyl which is optionally substituted with from 1-3 independently selected Ra (such as methyl or CF3); Ci-4 alkoxy optionally substituted with Ci-4 alkoxy; and Ci-4 haloalkoxy.
In certain embodiments of Formula II- 1, one occurrence of Rc is C1-3 alkyl which is optionally substituted with from 1-3 independently selected Ra (such as methyl or CF3).
In certain embodiments of Formula II-l, B is not substituted with Rc.
In certain embodiments of Formula II-l, L3 is a bond.
In certain embodiments of Formula II-l, L3 is CFh.
In certain embodiments of Formula II-l, R4 is selected from the group consisting of:
C4-6 cycloalkyl, which is optionally substituted with from 1-4 independently selected R4’;
heteroaryl including 6 ring atoms, wherein from 1-3 ring atoms are ring nitrogen atoms, and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with from 1-4 independently selected R4’, such as pyridyl which is optionally substituted with from 1-2 independently selected R4’;
heterocyclyl including from 4-7 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heterocyclyl is optionally substituted with from 1-4 independently selected R4’; and phenyl optionally substituted with from 1-2 independently selected R4’.
In certain embodiments of Formula II-l, R4 is phenyl optionally substituted with from 1-2 independently selected R4’.
In certain embodiments of Formula II- 1,
Figure imgf000100_0001
, which is optionally substituted with an additional R4’.
In certain embodiments of Formula II-l, each R4’ is independently selected from the group consisting of: halo (such as -F), -CN, -Ci-4 alkyl, and -Ci-4 haloalkyl.
In certain embodiments of Formula II-l (when R4 is I— 0-r4' , which is optionally substituted with an additional R4’), each R4’ is independently selected from the group consisting of: halo (such as -F), -CN, -Ci-4 alkyl, and -Ci-4 haloalkyl.
In certain embodiments of Formula II-l (when R4 is I— - r4. , which is optionally substituted with an additional R4’), the /¾/ra-placed R4’ is -CF3.
In certain embodiments of Formula II-l (when R4 is i— r . , which is optionally substituted with an additional R4’), R4 • i i.s KD-CFS , which is optionally substituted with an additional R4.
For example, R4 can
Figure imgf000100_0002
Non-Limiting Exemplary Formula I and/or Formula II Compounds
In some embodiments, the compound is selected from the compounds in Table Cl below:
Table Cl
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Pharmaceutical Compositions and Administration
General
In some embodiments, a chemical entity (e.g., a compound that inhibits (e.g., antagonizes) STING, or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination thereof) is administered as a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.
In some embodiments, the chemical entities can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as a-, b, and g-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl- b-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non toxic excipient may be prepared. The contemplated compositions may contain 0.001%- 100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy , 22nd Edition (Pharmaceutical Press, London, UK. 2012).
Routes of Administration and Composition Components
In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intraci sternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral).
Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof. Intratumoral injections are discussed, e.g., in Lammers, et 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, methyl oxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabi sulfite, grapefruit seed extract, methyl sulfonyl methane (MSM) , lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.
In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.
In other embodiments, the compounds described herein or a pharmaceutical composition thereof are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g, in propylene carbonate, vegetable oils, PEG’s, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g. , capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two- compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.
Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.
In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP/NF standard is usually sufficient. In certain embodiments, solid oral dosage forms can further include one or more components that chemically and/or structurally predispose the composition for delivery of the chemical entity to the stomach or the lower GI; e.g., the ascending colon and/or transverse colon and/or distal colon and/or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K.J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.
Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.
Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric/pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap.
Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).
Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water- washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the“internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non-sensitizing.
In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.
Dosages
The dosages may be varied depending on the requirement of the patient, the severity of the condition being treating and the particular compound being employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.
In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about 0.001 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 150 mg/Kg; from about 0.01 mg/Kg to about 100 mg/Kg; from about 0.01 mg/Kg to about 50 mg/Kg; from about 0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg; from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about 0.5 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0. 1 mg/Kg to about 200 mg/Kg; from about 0. 1 mg/Kg to about 150 mg/Kg; from about 0. 1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 50 mg/Kg; from about 0. 1 mg/Kg to about 10 mg/Kg; from about 0. 1 mg/Kg to about 5 mg/Kg; from about 0. 1 mg/Kg to about 1 mg/Kg; from about 0. 1 mg/Kg to about 0.5 mg/Kg). Regimens
The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).
In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days,
12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks,
10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 1 1 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days,
13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,
11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. Methods of Treatment
In some embodiments, methods for treating a subject having condition, disease or disorder in which increased (e.g., excessivejSTING activity (e.g., , e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., immune disorders, cancer) are provided.
Indications
In some embodiments, the condition, disease or disorder is cancer. Non-limiting examples of cancer include melanoma, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include breast cancer, colon cancer, rectal cancer, colorectal cancer, kidney or renal cancer, clear cell cancer lung cancer including small-cell lung cancer, non- small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, squamous cell cancer (e.g. epithelial squamous cell cancer), cervical cancer, ovarian cancer, prostate cancer, prostatic neoplasms, liver cancer, bladder cancer, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, gastrointestinal stromal tumor, pancreatic cancer, head and neck cancer, glioblastoma, retinoblastoma, astrocytoma, thecomas, arrhenoblastomas, hepatoma, hematologic malignancies including non-Hodgkins lymphoma (NHL), multiple myeloma, myelodysplasia disorders, myeloproliferative disorders, chronic myelogenous leukemia, and acute hematologic malignancies, endometrial or uterine carcinoma, endometriosis, endometrial stromal sarcoma, fibrosarcomas, choriocarcinoma, salivary gland carcinoma, vulval cancer, thyroid cancer, esophageal carcinomas, hepatic carcinoma, anal carcinoma, penile carcinoma, nasopharyngeal carcinoma, laryngeal carcinomas, Kaposi's sarcoma, mast cell sarcoma, ovarian sarcoma, uterine sarcoma, melanoma, malignant mesothelioma, skin carcinomas, Schwannoma, oligodendroglioma, neuroblastomas, neuroectodermal tumor, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcomas, Ewing Sarcoma, peripheral primitive neuroectodermal tumor, urinary tract carcinomas, thyroid carcinomas, Wilm's tumor, as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome. In some cases, the cancer is melanoma.
In some embodiments, the condition, disease or disorder is a neurological disorder, which includes disorders that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Non-limiting examples of cancer include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; age-related macular degeneration; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers' disease; alternating hemiplegia; Alzheimer's disease; Vascular dementia; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Anronl-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telegiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet's disease; Bell's palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger's disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome; causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy; chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorders; Cushing's syndrome; cytomegalic inclusion body disease; cytomegalovirus infection; dancing eyes- dancing feet syndrome; Dandy -Walker syndrome; Dawson disease; De Morsier's syndrome; Dejerine-Klumke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb's palsy; essential tremor; Fabry's disease; Fahr's syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich's ataxia; fronto-temporal dementia and other“tauopathies”; Gaucher's disease; Gerstmann's syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1 -associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (also neurological manifestations of AIDS); holoprosencephaly; Huntington's disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile phytanic acid storage disease; infantile refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh's disease; Lennox-Gustaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; Lissencephaly; locked-in syndrome; Lou Gehrig's disease (i.e., motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; Lyme disease— neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neuron disease; Moyamoya disease; mucopolysaccharidoses; milti-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; p muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O'Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson's disease; paramyotonia congenital; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus- Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick's disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; post-polio syndrome; postherpetic neuralgia; postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (types I and II); Rasmussen's encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye's syndrome; Saint Vitus dance; Sandhoff disease; Schilder's disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren's syndrome; sleep apnea; Soto's syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; Stiff-Person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subcortical arteriosclerotic encephalopathy; Sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; Tic Douloureux; Todd's paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau disease; Wallenberg's syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wildon's disease; amyotrophe lateral sclerosis and Zellweger syndrome. In some embodiments, the condition, disease or disorder is STING-associated conditions, e.g., type I interferonopathies (e.g., STING-associated vasculopathywith onset in infancy (SAVI)), Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis. In certain embodiments, the condition, disease or disorder is an autoimmune disease (e.g., a cytosolic DNA-triggered autoinflammatory disease). Non-limiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel diseases (IBDs) comprising Crohn disease (CD) and ulcerative colitis (UC), which are chronic inflammatory conditions with polygenic susceptibility. In certain embodiments, the condition is an inflammatory bowel disease. In certain embodiments, the condition is Crohn’s disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated by one or more alloimmune diseases (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In certain of these embodiments, the condition is alloimmune disease (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis or intestinal mucositis).
In some embodiments, modulation of the immune system by STING provides for the treatment of diseases, including diseases caused by foreign agents. Exemplary infections by foreign agents which may be treated and/or prevented by the method of the present invention include an infection by a bacterium (e.g., a Gram-positive or Gram-negative bacterium), an infection by a fungus, an infection by a parasite, and an infection by a virus. In one embodiment of the present invention, the infection is a bacterial infection (e.g., infection by E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella spp., Staphylococcus aureus, Streptococcus spp., or vancomycin-resistant enterococcus), or sepsis. In another embodiment, the infection is a fungal infection (e.g. infection by a mould, a yeast, or a higher fungus). In still another embodiment, the infection is a parasitic infection (e.g., infection by a single-celled or multicellular parasite, including Giardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, and Toxoplasma gondiz). In yet another embodiment, the infection is a viral infection (e.g., infection by a virus associated with AIDS, avian flu, chickenpox, cold sores, common cold, gastroenteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, and lower or upper respiratory tract infection (e.g., respiratory syncytial virus)).
In some embodiments, the condition, disease or disorder is hepatits B (see, e.g., WO 2015/061294).
In some embodiments, the condition, disease or disorder is selected from cardiovascular diseases (including e.g., myocardial infarction).
In some embodiemnts, the condition, disease or disorder is age-related macular degeneration.
In some embodiments, the condition, disease or disorder is mucositis, also known as stomatitits, which can occur as a result of chemotherapy or radiation therapy, either alone or in combination as well as damage caused by exposure to radiation outside of the context of radiation therapy.
In some embodiments, the condition, disease or disorder is uveitis, which is inflammation of the uvea (e.g., anterior uveitis, e.g., iridocyclitis or iritis; intermediate uveitis (also known as pars planitis); posterior uveitis; or chorioretinitis, e.g., pan-uveitis).
In some embodiments, the condition, disease or disorder is selected from the group consisting of a cancer, a neurological disorder, an autoimmune disease, hepatitis B, uvetitis, a cardiovascular disease, age-related macular degeneration, and mucositis.
Still other examples can include those indications discussed herein and below in contemplated combination therapy regimens.
Combination therapy
This disclosure contemplates both monotherapy regimens as well as combination therapy regimens.
In some embodiments, the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and/or one or more therapeutic regimens) in combination with administration of the compounds described herein.
In certain embodiments, the methods described herein can further include administering one or more additional cancer therapies.
The one or more additional cancer therapies can include, without limitation, surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine, hepatitis B vaccine, Oncophage, Provenge) and gene therapy, as well as combinations thereof. Immunotherapy, including, without limitation, adoptive cell therapy, the derivation of stem cells and/or dendritic cells, blood transfusions, lavages, and/or other treatments, including, without limitation, freezing a tumor.
In some embodiments, the one or more additional cancer therapies is chemotherapy, which can include administering one or more additional chemotherapeutic agents.
In certain embodiments, the additional chemotherapeutic agent is an immunomodulatory moiety, e.g., an immune checkpoint inhibitor. In certain of these embodiments, the immune checkpoint inhibitor targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1 - PD-L1, PD-1 - PD-
L2, interleukin-2 (IL-2), indoleamine 2,3 -di oxygenase (IDO), IL-10, transforming growth factor-b (TGFP), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9 - TIM3, Phosphatidylserine - TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II - LAG3, 4- 1BB-4- IBB ligand, 0X40-0X40 ligand, GITR, GITR ligand - GITR,
CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM - BTLA, HVEM - CD 160, HVEM - LIGHT, HVEM-BTL A-CD 160, CD80, CD80 - PDL-1, PDL2 - CD80, CD244, CD48 - CD244,
CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86 - CD28, CD86 - CTLA, CD80 - CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL 12, Phosphatidylserine, TIM3, Phosphatidylserine - TIM3, SIRPA-CD47, VEGF, Neuropilin, CD 160, CD30, and CD155; e.g., CTLA-4 or PDl or PD-L1). See, e.g., Postow, M. J Clin. Oncol. 2015, 33, 1.
In certain of these embodiments, the immune checkpoint inhibitor is selected from the group consisting of: Urelumab, PF-05082566, MEDI6469, TRX518, Varlilumab, CP-870893, Pembrolizumab (PD1), Nivolumab (PD1), Atezolizumab (formerly
MPDL3280A) (PDL1), MEDI4736 (PD-L1), Avelumab (PD-L1), PDR001 (PD1), BMS-986016, MGA271, Lirilumab, IPH2201, Emactuzumab, INCB024360, Galunisertib,
Ulocuplumab, BKT140, Bavituximab, CC-90002, Bevacizumab, and MNRP1685A, and MGA271.
In certain embodiments, the additional chemotherapeutic agent is an alkylating agent. Alkylating agents are so named because of their ability to alkylate many nucleophilic functional groups under conditions present in cells, including, but not limited to cancer cells. In a further embodiment, an alkylating agent includes, but is not limited to, Cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin. In an embodiment, alkylating agents can function by impairing cell function by forming covalent bonds with the amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules or they can work by modifying a cell's DNA. In a further embodiment an alkylating agent is a synthetic, semisynthetic or derivative.
In certain embodiments, the additional chemotherapeutic agent is an anti-metabolite. Anti-metabolites masquerade as purines or pyrimidines, the building-blocks of DNA and in general, prevent these substances from becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Anti-metabolites can also affect RNA synthesis. In an embodiment, an antimetabolite includes, but is not limited to azathioprine and/or mercaptopurine. In a further embodiment an anti-metabolite is a synthetic, semisynthetic or derivative.
In certain embodiments, the additional chemotherapeutic agent is a plant alkaloid and/or terpenoid. These alkaloids are derived from plants and block cell division by, in general, preventing microtubule function. In an embodiment, a plant alkaloid and/or terpenoid is a vinca alkaloid, a podophyllotoxin and/or a taxane. Vinca alkaloids, in general, bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules, generally during the M phase of the cell cycle. In an embodiment, a vinca alkaloid is derived, without limitation, from the Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). In an embodiment, a vinca alkaloid includes, without limitation, Vincristine, Vinblastine, Vinorelbine and/or Vindesine. In an embodiment, a taxane includes, but is not limited, to Taxol, Paclitaxel and/or Docetaxel. In a further embodiment a plant alkaloid or terpernoid is a synthetic, semisynthetic or derivative. In a further embodiment, a podophyllotoxin is, without limitation, an etoposide and/or teniposide. In an embodiment, a taxane is, without limitation, docetaxel and/or ortataxel. [021] In an embodiment, a cancer therapeutic is a topoisom erase. Topoisomerases are essential enzymes that maintain the topology of DNA. Inhibition of type I or type II topoisomerases interferes with both transcription and replication of DNA by upsetting proper DNA supercoiling. In a further embodiment, a topoisomerase is, without limitation, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In an embodiment a type I topoisomerase inhibitor is, without limitation, a camptothecin. In another embodiment, a camptothecin is, without limitation, exatecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67) and/or ST 1481. In an embodiment, a type II topoisomerase inhibitor is, without limitation, epipodophyllotoxin. In a further embodiment an epipodophyllotoxin is, without limitation, an amsacrine, etoposid, etoposide phosphate and/or teniposide. In a further embodiment a topoisomerase is a synthetic, semisynthetic or derivative, including those found in nature such as, without limitation, epipodophyllotoxins, substances naturally occurring in the root of American Mayapple (Podophyllum peltatum).
In certain embodiments, the additional chemotherapeutic agent is a stilbenoid. In a further embodiment, a stilbenoid includes, but is not limited to, Resveratrol, Piceatannol, Pinosylvin, Pterostilbene, Alpha- Viniferin, Ampelopsin A, Ampelopsin E, Diptoindonesin C, Diptoindonesin F, Epsilon- Vinferin, Flexuosol A, Gnetin H, Hemsleyanol D, Hopeaphenol, Trans-Diptoindonesin B, Astringin, Piceid and Diptoindonesin A. In a further embodiment a stilbenoid is a synthetic, semisynthetic or derivative. In certain embodiments, the additional chemotherapeutic agent is a cytotoxic antibiotic. In an embodiment, a cytotoxic antibiotic is, without limitation, an actinomycin, an anthracenedione, an anthracycline, thalidomide, dichloroacetic acid, nicotinic acid, 2- deoxyglucose and/or chlofazimine. In an embodiment, an actinomycin is, without limitation, actinomycin D, bacitracin, colistin (polymyxin E) and/or polymyxin B. In another embodiment, an antracenedione is, without limitation, mitoxantrone and/or pixantrone. In a further embodiment, an anthracycline is, without limitation, bleomycin, doxorubicin (Adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, mitomycin, plicamycin and/or valrubicin. In a further embodiment a cytotoxic antibiotic is a synthetic, semi sy ntheti c or derivative .
In certain embodiments, the additional chemotherapeutic agent is selected from endostatin, angiogenin, angiostatin, chemokines, angioarrestin, angiostatin (plasminogen fragment), basement-membrane collagen-derived anti -angiogenic factors (tumstatin, canstatin, or arrestin), anti -angiogenic antithrombin III, signal transduction inhibitors, cartilage-derived inhibitor (CDI), CD59 complement fragment, fibronectin fragment, gro- beta, heparinases, heparin hexasaccharide fragment, human chorionic gonadotropin (hCG), interferon alpha/beta/gamma, interferon inducible protein (IP- 10), interleukin- 12, kringle 5 (plasminogen fragment), metalloproteinase inhibitors (TIMPs), 2-methoxyestradiol, placental ribonuclease inhibitor, plasminogen activator inhibitor, platelet factor-4 (PF4), prolactin 16 kD fragment, proliferin-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin- 1 (TSP-1), transforming growth factor-beta (TGF-b), vasculostatin, vasostatin (calreticulin fragment) and the like.
In certain embodiments, the additional chemotherapeutic agent is selected from abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly- 1 -Lproline-t- butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3',4'-didehydro-4'- deoxy-8'-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin (adriamycin), etoposide, 5- fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyureataxanes, ifosfamide, liarozole, lonidamine, lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxanes, nilutamide, onapristone, paclitaxel, prednimustine, procarbazine, RPR109881, stramustine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine.
In certain embodiments, the additional chemotherapeutic agent is platinum, cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, azathioprine, mercaptopurine, vincristine, vinblastine, vinorelbine, vindesine, etoposide and teniposide, paclitaxel, docetaxel, irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, teniposide, 5 -fluorouracil, leucovorin, methotrexate, gemcitabine, taxane, leucovorin, mitomycin C, tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide and doxorubicin. Additional agents include inhibitors of mTOR (mammalian target of rapamycin), including but not limited to rapamycin, everolimus, temsirolimus and deforolimus.
In still other embodiments, the additional chemotherapeutic agent can be selected from those delineated in U.S. Patent 7,927,613, which is incorporated herein by reference in its entirety.
In some embodiments, the additional therapeutic agent and/or regimen are those that can be used for treating other STING-associated conditions, e.g., type I interferonopathies (e.g., STING-associated vasculopathywith onset in infancy (SAVI)), Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis and the like.
Non-limiting examples of additional therapeutic agents and/or regimens for treating rheumatoid arthritis include non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g, prednisone), disease-modifying antirheumatic drugs (DMARDs; e.g., methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), leflunomide (Arava®), hydroxychloroquine (Plaquenil), PF-06650833, iguratimod, tofacitinib (Xeljanz®), ABBV-599, evobrutinib, and sulfasalazine (Azulfidine®)), and biologies (e.g., abatacept (Orencia®), adalimumab (Humira®), anakinra (Kineret®), certolizumab (Cimzia®), etanercept (Enbrel®), golimumab (Simponi®), infliximab (Remicade®), rituximab (Rituxan®), tocilizumab (Actemra®), vobarilizumab, sarilumab (Kevzara®), secukinumab, ABP 501, CHS-0214, ABC-3373, and tocilizumab (ACTEMRA®)).
Non-limiting examples of additional therapeutic agents and/or regimens for treating lupus include steroids, topical immunomodulators (e.g., tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel®)), thalidomide (Thalomid®), non-steroidal anti inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarial drugs (e.g., Hydroxychloroquine (Plaquenil)), corticosteroids (e.g, prednisone) and immunomodulators (e.g., evobrutinib, iberdomide, voclosporin, cenerimod, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®, Gengraf®), and mycophenolate mofetil) baricitinb, iguratimod, filogotinib, GS-9876, rapamycin, and PF-06650833), and biologies (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDI0700, obinutuzumab, vobarilizumab, lulizumab, atacicept, PF-06823859, and lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin
(Proleukin®), dapirolizumab, edratide, IFN-a-kinoid, OMS721, RC18, RSLV-132, theralizumab, XmAb5871, and ustekinumab (Stelara®)). For example, non-limiting treatments for systemic lupus erythematosus include non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarial drugs (e.g., Hydroxychloroquine (Plaquenil)), corticosteroids (e.g, prednisone) and immunomodulators (e.g., iberdomide, voclosporin, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®, Gengraf®), and mycophenolate mofetil, baricitinb, filogotinib, and PF-06650833), and biologies (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDI0700, vobarilizumab, lulizumab, atacicept, PF-06823859, lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirolizumab, edratide, IFN-a-kinoid, RC18, RSLV-132, theralizumab, XmAb5871, and ustekinumab (Stelara®)). As another example, non-limiting examples of treatments for cutaneous lupus include steroids, immunomodulators (e.g., tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel®)), GS-9876, filogotinib, and thalidomide (Thalomid®). Agents and regimens for treating drug-induced and/or neonatal lupus can also be administered.
Non-limiting examples of additional therapeutic agents and/or regimens for treating STING-associated vasculopathy with onset in infancy (SAVI) include JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).
Non-limiting examples of additional therapeutic agents and/or regimens for treating Aicardi-Goutieres Syndrome (AGS) include physiotherapy, treatment for respiratory complications, anticonvulsant therapies for seizures, tube-feeding, nucleoside reverse transcriptase inhibitors (e.g., emtricitabine (e.g., Emtriva®), tenofovir (e.g., Viread®), emtricitabine/tenofovir (e.g., Truvada®), zidovudine, lamivudine, and abacavir), and JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).
Non-limiting examples of additional therapeutic agents and/or regimens for treating IBDs include 6-mercaptopurine, AbGn-168H, ABX464, ABT-494, adalimumab, AJM300, alicaforsen, AMG139, anrukinzumab, apremilast, ATR-107 (PF0530900), autologous CD34-selected peripheral blood stem cells transplant, azathioprine, bertilimumab, BI 655066, BMS-936557, certolizumab pegol (Cimzia®), cobitolimod, corticosteroids (e.g., prednisone, Methylprednisolone, prednisone), CP-690,550, CT-P13, cyclosporine, DIMS0150, E6007, E6011, etrasimod, etrolizumab, fecal microbial transplantation, figlotinib, fmgolimod, firategrast (SB-683699) (formerly T-0047), GED0301, GLPG0634, GLPG0974, guselkumab, golimumab, GSK 1399686, HMPL-004 (. Andrographis paniculata extract), IMU-838, infliximab, Interleukin 2 (IL-2), Janus kinase (JAK) inhibitors, laquinimod, masitinib (ABIOIO), matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, mirikizumab (LY3074828), natalizumab, NNC 0142-0000-0002, NNC0114-0006, ozanimod, peficitinib (JNJ- 54781532), PF-00547659, PF-04236921, PF-06687234, QAX576, RHB-104, rifaximin, risankizumab, RPC1063, SB012, SHP647, sulfasalazine, TD-1473, thalidomide, tildrakizumab (MK 3222), TJ301, TNF-Kinoid®, tofacitinib, tralokinumab, TRK-170, upadacitinib, ustekinumab, UTTR1147A, V565, vatelizumab, VB-201, vedolizumab, and vidofludimus. Non-limiting examples of additional therapeutic agents and/or regimens for treating irritable bowel syndrome include alosetron, bile acid sequesterants (e.g., cholestyramine, colestipol, colesevelam), chloride channel activators (e.g., lubiprostone), coated peppermint oil capsules, desipramine, dicyclomine, ebastine, eluxadoline, farnesoid X receptor agonist (e.g., obeticholic acid), fecal microbiota transplantation, fluoxetine, gabapentin, guanylate cyclase-C agonists (e.g., linaclotide, plecanatide), ibodutant, imipramine, JCM-16021, loperamide, lubiprostone, nortriptyline, ondansetron, opioids, paroxetine, pinaverium, polyethylene glycol, pregabalin, probiotics, ramosetron, rifaximin, and tanpanor.
Non-limiting examples of additional therapeutic agents and/or regimens for treating scleroderma include non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g, prednisone), immunomodulators (e.g., azathioprine, methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral®, Sandimmune®, Gengraf®), antithymocyte globulin, mycophenolate mofetil, intravenous immunoglobulin, rituximab, sirolimus, and alefacept), calcium channel blockers (e.g., nifedipine), alpha blockers, serotonin receptor antagonists, angiotensin II receptor inhibitors, statins, local nitrates, iloprost, phosphodiesterase 5 inhibitors (e.g., sildenafil), bosentan, tetracycline antibiotics, endothelin receptor antagonists, prostanoids, and tyrosine kinase inhibitors (e.g., imatinib, nilotinib and dasatinib).
Non-limiting examples of additional therapeutic agents and/or regimens for treating Crohn’s Disease (CD) include adalimumab, autologous CD34-selected peripheral blood stem cells transplant, 6-mercaptopurine, azathioprine, certolizumab pegol (Cimzia®), corticosteroids (e.g., prednisone), etrolizumab, E6011, fecal microbial transplantation, figlotinib, guselkumab, infliximab, IL-2, JAK inhibitors, matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, natalizumab, ozanimod, RHB-104, rifaximin, risankizumab, SHP647, sulfasalazine, thalidomide, upadacitinib, V565, and vedolizumab.
Non-limiting examples of additional therapeutic agents and/or regimens for treating UC include AbGn-168H, ABT-494, ABX464, apremilast, PF-00547659, PF-06687234, 6- mercaptopurine, adalimumab, azathioprine, bertilimumab, brazikumab (MEDI2070), cobitolimod, certolizumab pegol (Cimzia®), CP-690,550, corticosteroids (e.g., multimax budesonide, Methylprednisolone), cyclosporine, E6007, etrasimod, etrolizumab, fecal microbial transplantation, figlotinib, guselkumab, golimumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitors (e.g., GS-5745), mesalamine, mesalamine, mirikizumab (LY3074828), RPC1063, risankizumab (BI 6555066), SHP647, sulfasalazine, TD-1473, TJ301, tildrakizumab (MK 3222), tofacitinib, tofacitinib, ustekinumab, UTTR1147A, and vedolizumab.
Non-limiting examples of additional therapeutic agents and/or regimens for treating autoimmune colitis include corticosteroids (e.g., budesonide, prednisone, prednisolone, Beclometasone dipropionate), diphenoxylate/atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012/0202848), and vedolizumab.
Non-limiting examples of additional therapeutic agents and/or regimens for treating iatrogenic autoimmune colitis include corticosteroids (e.g., budesonide, prednisone, prednisolone, Beclometasone dipropionate), diphenoxylate/atropine, infliximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012/0202848), and vedolizumab.
Non-limiting examples of additional therapeutic agents and/or regimens for treating colitis induced by one or more chemotherapeutics agents include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), diphenoxylate/atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012/0202848), and vedolizumab.
Non-limiting examples of additional therapeutic agents and/or regimens for treating colitis induced by treatment with adoptive cell therapy include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), diphenoxylate/atropine, infliximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012/0202848), and vedolizumab.
Non-limiting examples of additional therapeutic agents and/or regimens for treating colitis associated with one or more alloimmune diseases include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), sulfasalazine, and eicopentaenoic acid.
Non-limiting examples of additional therapeutic agents and/or regimens for treating radaiation enteritis include teduglutide, amifostine, angiotensin-converting enzyme (ACE) inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril), probiotics, selenium supplementation, statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin), sucralfate, and vitamin E.
Non-limiting examples of additional therapeutic agents and/or regimens for treating collagenous colitis include 6-mercaptopurine, azathaioprine, bismuth subsalicate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.
Non-limiting examples of additional therapeutic agents and/or regimens for treating lyphocytic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), loperamide, mesalamine, methotrexate, and sulfasalazine.
Non-limiting examples of additional therapeutic agents and/or regimens for treating microscopic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), fecal microbial transplantation, loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.
Non-limiting examples of additional therapeutic agents and/or regimens for treating alloimmune disease include intrauterine platelet transfusions, intravenous immunoglobin, maternal steroids, abatacept, alemtuzumab, alphal -antitrypsin, AMG592, antithymocyte globulin, barcitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.
Non-limiting examples of additional therapeutic agents and/or regimens for treating multiple sclerosis (MS) include alemtuzumab (Lemtrada®), ALKS 8700, amiloride, ATX- MS-1467, azathioprine, baclofen (Lioresal®), beta interferons (e.g., IFN-b- I a, IFN-b- 1 b), cladribine, corticosteroids (e.g., methylprednisolone), daclizumab, dimethyl fumarate (Tecfidera®), fmgolimod (Gilenya®), fluoxetine, glatiramer acetate (Copaxone®), hydroxychloroquine, ibudilast, idebenone, laquinimod, lipoic acid, losartan, masitinib, MD1003 (biotin), mitoxantrone, montelukast, natalizumab (Tysabri®), NeuroVax™, ocrelizumab, ofatumumab, pioglitazone, and RPC 1063.
Non-limiting examples of additional therapeutic agents and/or regimens for treating graft-vs-host disease include abatacept, alemtuzumab, alphal -antitrypsin, AMG592, antithymocyte globulin, barcitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.
Non-limiting examples of additional therapeutic agents and/or regimens for treating acute graft-vs-host disease include alemtuzumab, alpha-1 antitrypsin, antithymocyte globulin, basiliximab, brentuximab, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, ibrutinib, infliximab, itacitinib, LBH589, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, photopheresis, ruxolitinib, sirolimus, tacrolimus, and tocilizumab.
Non-limiting examples of additional therapeutic agents and/or regimens for treating chronic graft vs. host disease include abatacept, alemtuzumab, AMG592, antithymocyte globulin, basiliximab, bortezomib, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, mycophenolate mofetil, pentostatin, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib. Non-limiting examples of additional therapeutic agents and/or regimens for treating celiac disease include AMG 714, AM Y01 , Aspergillus niger prolyl endoprotease, BL-7010, CALY-002, GBR 830, Hu-Mik-Beta-1, IMGX003, KumaMax, Larazotide Acetate, Nexvan2®, pancrelipase, TIMP-GLIA, vedolizumab, and ZED1227.
Non-limiting examples of additional therapeutic agents and/or regimens for treating psoriasis include topical corticosteroids, topical crisaborole/AN2728, topical SNA-120, topical SAN021, topical tapinarof, topical tocafmib, topical IDP-118, topical M518101, topical calcipotriene and betamethasone dipropionate (e.g., MC2-01 cream and Taclonex®), topical P-3073, topical LEO 90100 (Enstilar®), topical betamethasone dipropriate (Semivo®), halobetasol propionate (Ultravate®), vitamin D analogues (e.g., calcipotriene (Dovonex®) and calcitriol (Vectical®)), anthralin (e.g., Dritho-scalp® and Dritho-creme®), topical retinoids (e.g., tazarotene (e.g., Tazorac® and Avage®)), calcineurin inhibitors (e.g., tacrolimus (Prograf®) and pimecrolimus (Elidel®)), salicylic acid, coal tar, moisturizers, phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrow band UVB phototherapy, Goeckerman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), retinoids (e.g., acitretin (Soriatane®)), methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), Apo805Kl, baricitinib, FP187, KD025, prurisol, VTP-43742, XP23829, ZPL-389, CF101 (piclidenoson), LAS41008, VPD-737
(serlopitant), upadacitinib (ABT-494), aprmilast, tofacitibin, cyclosporine (Neoral®, Sandimmune®, Gengraf®), biologies (e.g., etanercept (Enbrel®), entanercept-szzs (Elrezi®), infliximab (Remicade®), adalimumab (Humira®), adalimumab-adbm (Cyltezo®), ustekinumab (Stelara®), golimumab (Simponi®), apremilast (Otezla®), secukinumab (Cosentyx®), certolixumab pegol, secukinumab, tildrakizumab-asmn, infliximab-dyyb, abatacept, ixekizumab (Taltz®), ABP 710, BCD-057, BI695501, bimekizumab (UCB4940), CHS-1420, GP2017, guselkumab (CNTO 1959), HD203, M923, MSB 11022, Mirikizumab (LY3074828), PF-06410293, PF-06438179, risankizumab (BI655066), SB2, SB4, SB5, siliq (brodalumab), namilumab (MT203, tildrakizumab (MK- 3222), and ixekizumab (Taltz®)), thioguanine, and hydroxyurea (e.g., Droxia® and Hydrea®). Non-limiting examples of additional therapeutic agents and/or regimens for treating cutaneous T-cell lymphoma include phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrow band UVB phototherapy, Goeckerman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), extracorporeal photopheresis, radiation therapy (e.g., spot radiation and total skin body electron beam therapy), stem cell transplant, corticosteroids, imiquimod, bexarotene gel, topical bis-chloroethyl-nitrourea, mechlorethamine gel, vorinostat (Zolinza®), romidepsin (Istodax®), pralatrexate (Folotyn®) biologies (e.g., alemtuzumab (Campath®), brentuximab vedotin (SGN-35), mogamulizumab, and IPH4102).
Non-limiting examples of additional therapeutic agents and/or regimens for treating uveitis include corticosteroids (e.g., intravitreal triamcinolone acetonide injectable suspensions), antibiotics, antivirals (e.g., acyclovir), dexamethasone, immunomodulators (e.g., tacrolimus, leflunomide, cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral®, Sandimmune®, Gengraf®), chlorambucil, azathioprine, methotrexate, and mycophenolate mofetil), biologies (e.g., infliximab (Remicade®), adalimumab (Humira®), etanercept (Enbrel®), golimumab (Simponi®), certolizumab (Cimzia®), rituximab (Rituxan®), abatacept (Orencia®), basiliximab (Simulect®), anakinra (Kineret®), canakinumab (Ilaris®), gevokixumab (XOMA052), tocilizumab (Actemra®), alemtuzumab (Campath®), efalizumab (Raptiva®), LFG316, sirolimus (Santen®), abatacept, sarilumab (Kevzara®), and daclizumab (Zenapax®)), cytotoxic drugs, surgical implant (e.g., fluocinolone insert), and vitrectomy.
Non-limiting examples of additional therapeutic agents and/or regimens for treating mucositis include AGO 13, SGX942 (dusquetide), amifostine (Ethyol®), cryotherapy, cepacol lonzenges, capsaicin lozenges, mucoadhesives (e.g., MuGard®) oral diphenhydramine (e.g., Benadry® elixir), oral bioadherents (e.g., polyvinylpyrrolidone- sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), caphosol, chamomilla recutita mouthwash, edible grape plant exosome, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., Peridex® or Periogard®), topical pain relievers (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and Ulcerease® (0.6% phenol)), corticosteroids (e.g., prednisone), pain killers (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor; Kepivance®), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble b-1,3/1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, granules comprising vaccinium myrtillus extract, macleaya cordata alkaloids and echinacea angustifolia extract (e.g., SAMITAL®), and gastrointestinal cocktail (an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid)). For example, non-limiting examples of treatments for oral mucositis include AGO 13, amifostine (Ethyol®), cryotherapy, cepacol lonzenges, mucoadhesives (e.g., MuGard®) oral diphenhydramine (e.g., Benadry® elixir), oral bioadherents (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), caphosol, chamomilla recutita mouthwash, edible grape plant exosome, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., Peridex® or Periogard®), topical pain relievers (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and Ulcerease® (0.6% phenol)), corticosteroids (e.g., prednisone), pain killers (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor; Kepivance®), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble b-1,3/1,6 glucan, P276, LP- 0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, and gastrointestinal cocktail (an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid)). As another example, non-limiting examples of treatments for esophageal mucositis include xylocaine (e.g., gel viscous Xylocaine 2%). As another example, treatments for intestinal mucositis, treatments to modify intestinal mucositis, and treatments for intestinal mucositis signs and symptoms include gastrointestinal cocktail (an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid)).
In certain embodiments, the second therapeutic agent or regimen is administered to the subject prior to contacting with or administering the chemical entity (e.g., about one hour prior, or about 6 hours prior, or about 12 hours prior, or about 24 hours prior, or about 48 hours prior, or about 1 week prior, or about 1 month prior). In other embodiments, the second therapeutic agent or regimen is administered to the subject at about the same time as contacting with or administering the chemical entity. By way of example, the second therapeutic agent or regimen and the chemical entity are provided to the subject simultaneously in the same dosage form. As another example, the second therapeutic agent or regimen and the chemical entity are provided to the subject concurrently in separate dosage forms.
In still other embodiments, the second therapeutic agent or regimen is administered to the subject after contacting with or administering the chemical entity (e.g., about one hour after, or about 6 hours after, or about 12 hours after, or about 24 hours after, or about 48 hours after, or about 1 week after, or about 1 month after).
Patient Selection
In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of such treatment (e.g., by way of biopsy, endoscopy, or other conventional method known in the art). In certain embodiments, the STING protein can serve as a biomarker for certain types of cancer, e.g., colon cancer and prostate cancer. In other embodiments, identifying a subject can include assaying the patient’s tumor microenvironment for the absence of T-cells and/or presence of exhausted T-cells, e.g., patients having one or more cold tumors. Such patients can include those that are resistant to treatment with checkpoint inhibitors. In certain embodiments, such patients can be treated with a chemical entity herein, e.g., to recruit T-cells into the tumor, and in some cases, further treated with one or more checkpoint inhibitors, e.g., once the T-cells become exhausted.
In some embodiments, the chemical entities, methods, and compositions described herein can be administered to certain treatment-resistant patient populations (e.g., patients resistant to checkpoint inhibitors; e.g., patients having one or more cold tumors, e.g., tumors lacking T-cells or exhausted T-cells). Compound Preparation
As can be appreciated by the skilled artisan, methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. For example, the compounds described herein can be synthesized, e.g., using one or more of the methods described herein and/or using methods described in, e.g., US 2015/0056224, the contents of each of which are hereby incorporated by reference in their entirety. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available. The skilled artisan will also recognize that conditions and reagents described herein that can be interchanged with alternative art-recognized equivalents. For example, in many reactions, triethylamine can be interchanged with other bases, such as non-nucleophilic bases (e.g. diisopropylamine, l,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene).
The skilled artisan will recognize a variety of analytical methods that can be used to characterize the compounds described herein, including, for example, ¾ NMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy. The foregoing list is a subset of characterization methods available to a skilled artisan and is not intended to be limiting.
To further illustrate the foregoing, the following non-limiting, exemplary synthetic schemes are included. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the invention as described, and claimed herein. The reader will recognize that the skilled artisan, provided with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples. Examples
For illustrative purposes, general methods for synthesizing compounds of Formula I are depicted in Schemes 1 and 2.
Figure imgf000165_0001
2-1 l-I 3-1
Scheme 1
Referring to Scheme 1, a compound of Formula I (shown as compound 3-1 in scheme 1) wherein W1 is NH; W2 is a bond, CFh, CHRa, or CRa2 (e.g., CFh); and Ring A and Ring B are as defined for Formula I can be prepared through the coupling of carboxylic acid l-I and amine 2-1 (in l-I, Ring B is as defined for Formula I; and in 2-1, Ring A is as defined for Formula I). The coupling can take place under standard conditions for amide bond formation (e.g., in the presence of a carboxyl activating agent such as HATU, DCC, EDCI, etc ).
Figure imgf000165_0002
2-II l-II 3-II
Scheme 2
Referring to Scheme 2, a compound of Formula I (shown as compound 3-II in scheme 2) wherein W1 is a bond or CFh, CHRa, or CRa2 (e.g., CFh); W2 is NH; and Ring A and Ring B are as defined for Formula I can be prepared through the coupling of carboxylic acid 2-II and amine l-II (in l-II, Ring B is as defined for Formula I; and in 2- II, Ring A is as defined for Formula I). The coupling can take place under standard conditions for amide bond formation (e.g., in the presence of a carboxyl activating agent such as HATU, DCC, EDCI, etc ). The following examples are prepared according to methods shown in Schemes 1 and 2. LC-MS was performed on the compounds using the following column and settings: Shim-pack XR-ODS, C18, 3x50 mm, 2.5 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 5-100% (1.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA) and water (0.05% TFA), with 2.0 minute as total run time.
Abbreviation of chemical terms
ACN = acetonitrile
AcOH = acetic acid
BTC = trichloromethyl chloroformate
DBU = l,8-diazabicycloundec-7-ene
DCM = dichloromethane
Dess-Martin = (1,1,1 -triacetoxy)- 1 , 1 -dihydro- 1 ,2-benziodoxol-3 ( lH)-one
DIEA = N-ethyl-N-isopropylpropan-2-amine
DMEDA = N,N'-dimethylethylenediamine
DMF = N,N-dimethylformamide
DMSO = dimethyl sulfoxide
Et = ethyl
EtOH = ethanol
FA = formic acid
HATU = N-[(Dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide
HPLC = high-performance liquid chromatography
LC-MS = liquid chromatography - mass spectrometry
LDA = lithium diisopropylamide
Me = methyl
MeOH = methanol
n-Bu = n-butyl
NBS = N-bromosuccinimide NCS = N-chlorosuccinimide
NIS = N-iodosuccinimide
NMR = nuclear magnetic resonance
Pd(dppf)Cl2 = dichloro[l, l'-bis(diphenylphosphino)ferrocene]palladium
Pd(PPh3)4 = tetrakis(triphenylphosphine)Palladium(0)
Ph = phenyl
HPLC = high performance liquid chromatography
PTSA = p-toluenesulfonic acid
Py = pyridine
RT = room temperature
Speedvac = Savant SC250EXP SpeedVac Concentrator
TBAF = tetrabutylammonium fluoride
TBDPSC1 = tert-butyldiphenylsilyl chloride
t-Bu = tert-butyl
TEA = triethylamine
TFA = trifluoroacetic acid
THF = tetrahydrofuran
Ti(i-PrO)4 = tetraisopropyl titanate
TLC = thin layer chromatography
Materials and Methods
The progress of reactions was often monitored by TLC or LC-MS. The identity of the products was often confirmed by LC-MS. The LC-MS was recorded using one of the following methods.
Method A: Titank Cl 8, 50x3 mm, 3 um column, 0.3 uL injection, 1.5 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: Water+5mMNH4HC03 and Mobile Phase B: Acetonitrile. 10% MPB to 95.0% in 1.39 min, hold at 95% MPB for 0.8 min, 95% MPB to 10% in 0.03 min, then equilibration to 10% MPB for 0.27 min. Method B: XBridge C18, 50x3mm, 2.8 um column, 0.2 uL injection, 1.2 mL/min flow rate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: Water+5mMNH4HC03 and Mobile Phase B: Acetonitrile. 10% MPB to 95.0% in 1.99 min, hold at 95% MPB for 0.6 min, 95% MPB to 10% in 0.20 min, then equilibration to 10% MPB for 0.2 min.
Method C: Shim-pack XR-ODS, 50x3 mm, 2.2 um column, 2 uL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: :Water/0.05%TFA and Mobile Phase B: Acetonitrile/0.05%TFA. 5% MPB to 100.0% in 1.09 min, hold at 100% MPB for 0.6 min, 100% MPB to 5% in 0.02 min, then equilibration to 5% MPB for 0.38 min.
Method D: CORTECS C18+, 50x2.1 mm, 2.7 um column, 0.8 uL injection, 0.8 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: :Water/0.1%FA and Mobile Phase B: Acetonitrile/0.1%F A. 10% MPB to 95.0% in 1.09 min, hold at 95% MPB for 0.5 min, 95% MPB to 5% in 0.03 min, then equilibration to 5% MPB for 0.2 min.
Method E: SPD-M20A, 0.8 uL injection, 0.8 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: : Water/SmMNFLFICCh and Mobile Phase B: Acetonitrile. 10% MPB to 95.0% in 1.09 min, hold at 95% MPB for 0.5 min, 95% MPB to 5% in 0.1 min, then equilibration to 10% MPB for 0.1 min.
Method F: Shim-pack XR-ODS, 50x3 mm, 3.0 um column, 0.5 uL injection, 0.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: Water/0.05%TFA and Mobile Phase B: Acetonitrile/0.05%TFA. 5% MPB to 100.0% in 1.09 min, hold at 100% MPB for 0.6 min, 100% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.15 min
Method G: Shim-pack XR-ODS, 50x3 mm, 2.2 um column, 0.5 uL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: : Water/0.05 %TF A and Mobile Phase B: Acetonitrile/0.05%TFA. 5% MPB to 95.0% in 1.99 min, hold at 95% MPB for 0.7 min, 95% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.25 min. Method H: Shim-pack XR-ODS, 50 *3.0 mm, 2.2 uL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: Water (0.05%TFA) and Mobile Phase B: Acetonitrile/0.05%TFA. 20% MPB to 70.0% in 2.49 min, 70.0% MPB to 95.0% in 0.5 min, hold at 95% MPB for 0.6 min, 95% MPB to 5% in 0.1 min, then equilibration to 5% MPB for 0.3 min.
Method I: CORTECS C18+ MVK,50 *2.1 mm 0.4 uL injection ,1.0 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A:Water+0.1%FA, Mobile phase B:Acetonitrile+0.05%FA. 10% MPB to 100% in 2.0 min, hold at 100% MPB for 0.75 min, 100% MPB to 10% in 0.02 min, then equilibration to 10% MPB for 0.23min.
Method J: EVO C18, 50 *3.0 mm 2.6 um ,1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A:Water/5mM NH4HCO3 Mobile phase B: Acetonitrile; 10% MPB to 95% in 1.99 min, hold at 95% MPB for 0.6 min, 95% MPB to 10% in 0.15 min, then equilibration to 10% MPB for 0.25 min.
Method K: Shim-pack XR-ODS, 50 *3.0 mm, 1.0 uL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A: Water/5mM NH4HCO3; Mobile Phase B: Acetonitrile; 65% MPB to 95% in 2.79 min, hold at 95% MPB for 0.6 min, 95% MPB to 5% in 0.15 min, then equilibration to 5% MPB for 0.15 min.
Method L: XBridge C18, 50 *3.0 mm, 0.3 uL injection, 1.2 mL/min flowrate, 90-
900 amu scan range, 254 nm UV detection. Mobile phase A: Water (5 mmoL/L NH4HCO3) and Mobile Phase B: MeCN. 10% MPB to 70.0% in 3.0 min, 70% MPB to 95% in 0.25 min, hold at 95% MPB for 0.35 min, 95% MPB to 10% in 0.3 min, then equilibration to 10% MPB for 0.10 min.
Method M: kinetex XB-C18 100A, 30 *2. lmm, 1.7 um, 0.8 uL injection , 1.0 mL/min flowrate, 90-900 amu scan range, 210 nm UV detection. Mobile phase A:Water+0.05%TFA; Mobile phase B:Acetonitrile+0.05%TFA, 5% MPB to 100% in 1.5 min, hold at 100% MPB for 0.8 min, 100% MPB to 5% in 0.03 min, then equilibration to 5% MPB for 0.17 min. Method N: XBridge Cl 8, 50 *2.1 mm, 0.7 uL injection, 1.2 mL/min flowrate, 90- 900 amu scan range, 254 nm UV detection. Mobile phase A: Water (5 mmoL/L NH4HCO3) and Mobile Phase B: MeCN. 30% MPB to 80.0% in 1.79 min, 80% MPB to 95% in 0.2 min, hold at 95% MPB for 0.3 min, 95% MPB to 10% in 0.1 min, then equilibration to 10% MPB for 0.20 min.
Method O: Kinetex EVO Cl 8, 50 *3 mm, 3 uL injection, 1.2 mL/min flowrate, 90- 900 amu scan range, 254 nm UV detection. Mobile phase A: Water (5 mmoL/L NH4HCO3) and Mobile Phase B: MeCN. 10% MPB to 95.0% in 1.99 min, hold at 95% MPB for 0.6 min, 95% MPB to 10% in 0.15 min, then equilibration to 10% MPB for 0.25 min.
Method P: SPD-M20A, 0.8 uL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: 0.04%NH3.H20 and Mobile Phase B: MeCN. 10% MPB to 95.0% in 1.10 min, hold at 95% MPB for 0.5 min, 95% MPB to 10% in 0.01 min, then equilibration to 10% MPB for 0.21 min.
Method Q: Shim-pack XR-ODS, 50 *3.0 mm, 5.0 uL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A:
Water/0.05 %TF A; Mobile Phase B: Acetonitrile/0.05%TFA; 5% MPB to 95% in 1.99 min, hold at 95% MPB for 0.7 min, 95% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.25 min.
Method R: Titank Cl 8, 50x3 mm, 3 um column, 0.3 uL injection, 1.5 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A:
Water+5mMNH4HC03 and Mobile Phase B: Acetonitrile. 10% MPB to 95.0% in 1.79 min, hold at 95% MPB for 0.8 min, 95% MPB to 10% in 0.15 min, then equilibration to 10% MPB for 0.25 min.
Method S: Titank C18, 50 *3.0 mm, 2.2 uL injection, 1.5 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: Water (0.05%NH4HC03) and Mobile Phase B: MeCN. 20% MPB to 70% in 2.25 min, 70% MPB to 95% in 0.75 min, hold at 95% MPB for 0.5 min, 95% MPB to 10% in 0.05 min, then equilibration to 10% MPB for 0.25 min.
Method T: Titank Cl 8, 50 *3.0 mm, 1 uL injection, 1.5 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: Water (0.05%NH4HC03) and Mobile Phase B: MeCN. 10% MPB to 95% in 1.79 min, hold at 95% MPB for 0.8 min, 95% MPB to 10% in 0.15 min, then equilibration to 10% MPB for 0.25 min.
Method U: SPD-M20A, 0.5 uL injection, 1.5 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: Water (0.05%NH4HC03) and Mobile Phase B : MeCN. 40% MPB to 95% in 1.99 min, hold at 95% MPB for 0.6 min, 95% MPB to 10% in 0.15 min, then equilibration to 10% MPB for 0.25 min.
Method V: SPD-M20A, 0.5 uL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: Water/SmMNLLHCCb and Mobile Phase B: Acetonitrile. 10% MPB to 95.0% in 1.99 min, hold at 95% MPB for 0.6 min, 95% MPB to 10% in 0.15 min, then equilibration to 10% MPB for 0.25 min.
Method W : SPD-M20A, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: Water (0.05%TFA) and Mobile Phase B: Acetonitrile/0.05%TFA. 30% MPB to 100.0% in 2.99 min, hold at 100% MPB for 0.7 min, 100% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.25 min.
Method X:
Instrument: Agilent LCMS system equipped with DAD and ELSD detector
Ion mode: Positive
Column: Waters X-Bridge Cl 8, 50*2.1 mm*5 pm or equivalent
Mobile Phase: A: H2O (0.04% TFA); B: CFLCN (0.02% TFA)
Gradient: 4.5 min gradient method, actual method would depend on clogP of compound. Flow Rate: 0.6 mL/min or 0.8 mL/min
Column Temp: 40 °C or 50 °C
UV: 220 nm
Method Y :
Instrument: Agilent LCMS system equipped with DAD and ELSD detector
Ion mode: Positive
Column: Waters X-Bridge ShieldRP18, 50*2.1 mm*5 pm or equivalent
Mobile Phase:A: H2O (0.05% NFL FLO) or 10 mM ammonia bicarbonate; B: CFLCN Gradient: 4.5 min gradient method; actual method would depend on the clogP of the compound. Flow Rate: 0.6 mL/min or 0.8 mL/min
Column Temp: 40 °C
UV: 220 nm
Some compounds were purified by preparative HPLC. The preparative HPLC parameters used are described below.
Instrument:
1. GILSON 281 and Shimadzu LCMS 2010A
2. GILSON 215 and Shimadzu LC-20AP
3. GILSON 215
Mobile phase:
A: NH4OH/H2O = 0.05% v/v; B: ACN
A: FA/H2O = 0.225% v/v; B: ACN
Column
Xtimate C18 150*25mm*5pm
Flow rate: 25 mL/min or 30 mL/min
Monitor wavelength: 220&254 nm
Gradient: actual method would depend on clog P of compound
Detector: MS Trigger or UV
Preparative examples
Scheme for the preparation of Intermediates: Schemes below illustrate the preparation of intermediates.
Scheme for the preparation of Intermediates:
Scheme 1: Synthesis of intermediate 1 (3-phenyl-lH-pyrazol-4-amine)
Figure imgf000173_0001
1. Synthesis of 2-(2-oxo-2-phenylethyl)-2,3-dihydro-lH-isoindole-l,3- dione
Figure imgf000173_0002
2-Bromo-l-phenylethan-l-one (10.0 g, 50.2 mmol, 1.0 equiv) was dissolved in DMF (100 mL). 2,3-Dihydro-lH-isoindole-l,3-dione potassium (18.7 g, 100.5 mmol, 2.0 equiv) was added, and the resulting solution was stirred for 4 hrs at 80 °C. The resulting solution was extracted with 3x500 mL of ethyl acetate. The resulting mixture was washed with 5x500 mL of LhO. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column and ethyl acetate/petroleum ether (1 : 1) was used as an eluent. 2-(2-Oxo-2-phenylethyl)-2,3- dihydro-lH-isoindole-l,3-dione(12.9 g, 96.8%) was obtained as a yellow solid. LCMS Method A, MS-ESI, 266.2[M+H+]
2. Synthesis of 2-[(lZ)-l-(dimethylamino)-3-oxo-3-phenylprop-l-en-2- yl]-2,3-dihydro-lH-isoindole-l,3-dione
Figure imgf000174_0001
2-(2-Oxo-2-phenylethyl)-2,3-dihydro-lH-isoindole-l,3-dione (12.5 g, 41.5 mmol,
1.0 equiv, 88%) was dissolved in (dimethoxymethyl)dimethylamine (200 mL) and stirred for 3 hrs at 90 °C. The resulting solution was extracted with 3x 500 mL of EtOAc. The resulting mixture was washed with 3x1 L of EhO. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 1) as an eluent. 2-[(lZ)-l- (dimethylamino)-3-oxo-3-phenylprop-l-en-2-yl]-2,3-dihydro-lH-isoindole-l,3-dione (9.5 g, 71.5%) was obtained as a yellow solid. LCMS Method B, MS-ESI: 321.1M+EE]
3. Synthesis of 3-phenyl-lH-pyrazol-4-amine
Figure imgf000174_0002
2- [( 1 Z)- 1 -(dimethylamino)-3 -oxo-3 -phenylprop- 1 -en-2-yl]i soindole- 1 , 3 -dione (9.5 g, 29.7 mmol, 1.0 equiv) was dissolved in EtOH (100.0 mL). Hydrazine hydrate (3.7 g, 59.3 mmol, 2.0 equiv, 80%) was added, and sthe solution was tirred for 3 hrs at 70 °C. The resulting solution was extracted with 3x500 mL of EtOAc. The resulting mixture was washed with 3x500 mL of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :1) as an eluent. 3-Phenyl-lH-pyrazol-4-amine (3.7 g, 78.4%) was obtained as a dark yellow solid. LCMS Method A, MS-ESI: 160.1M+H+] Scheme 2: Synthesis of intermediate 2 (l-phenyl-lH-pyrazol-3-amine)
Figure imgf000175_0001
1. Synthesis of 3-nitro-l-phenylpyrazole
Figure imgf000175_0002
3-Nitro-lH-pyrazole (500.0 mg, 4.4 mmol, 1.0 equiv) was dissolved in DCM (20 mL). TEA (894.9 mg, 8.8 mmol, 2.0 equiv) and phenyl boronic acid (647.0 mg, 5.3 mmol, 1.2 equiv) were added under nitrogen atmosphere. The resulting mixture was stirred for 16 hrs at RT. The resulting mixture was diluted with EhO (50 mL) and extracted with DCM (3x50 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1 :5). 3-Nitro-l-phenylpyrazole (300 mg, 35.9%) was isolated as a yellow solid. LCMS Method E, MS-ESI: 190.2 [M+EE]
2. Synthesis of l-phenyl-lH-pyrazol-3-amine
Figure imgf000175_0003
3-Nitro-l-phenylpyrazole (300.0 mg, 1.6 mmol, 1.0 equiv) was dissolved in MeOH (20 mL). Pd/C (10% wt, 30 mg) was added into solution under nitrogen atmosphere. The resulting mixture was degassed and back filled with hydrogen. The resulting mixture was stirred for 5 hrs at RT. The resulting mixture was filtered, and the filtrate was collected and concentrated. This resulted in 300 mg (crude) of 1 -phenyl- lH-pyrazol-3 -amine as a light yellow crude solid. LCMS Method E, MS-ESI: 160.1 [M+EE]
Scheme 3: Synthesis of intermediate 3 (l-phenyl-lH-pyrazol-5-amine)
Figure imgf000176_0001
1. Synthesis of 5-nitro-l-phenylpyrazole
Figure imgf000176_0002
Synthesized using the method as described for scheme 2. LCMS Method E, MS- ESE 190.2 [M+EE]
2. Synthesis of l-phenyl-lH-pyrazol-5-amine
Figure imgf000176_0003
Synthesized using the method as described for scheme 2. LCMS Method C, MS- ESE 160.0 [M+EE]
Scheme 4: Synthesis of intermediate 4 ( l-phenyl-lH-imidazol-4-amine )
Figure imgf000177_0001
1. Synthesis of 4-nitro-l-phenyl-lH-imidazole
Figure imgf000177_0002
Synthesized using the method as described for scheme 2. LCMS Method E, MS- ESI: 190.2 [M+H+]
2. Synthesis of l-phenyl-lH-imidazol-4-amine
Figure imgf000177_0003
2' intermediate 4
Synthesized using the method as described for scheme 2. LCMS Method E, MS- ESI: 160.2 [M+H+]
Scheme 5: Synthesis of intermediate 5 ( 2-(2-phenyl-lH-imidazol-l-yl)acetic acid)
Figure imgf000177_0004
intermediate 5
Figure imgf000178_0001
1. Synthesis of 2-(2-phenyl-lH-imidazol-l-yl)acetate
Figure imgf000178_0002
2-Phenyl-lH-imidazole (3.0 g, 20.8 mmol, 1.0 equiv) was dissolved in THF (100 mL). Ethyl 2-bromoacetate (7.0 g, 41.6 mmol, 2.0 equiv) and CS2CO3 (13.6 g, 41.6 mmol, 2.0 equiv) were added in solution. The resulting solution was stirred for 2 hrs at RT. The resulting mixture was concentrated in vacuo. The residue was purified on silica gel column, and eluted with EtO Ac/PE (1 :5) to give 2-(2-phenyl-lH-imidazol-l-yl)acetate (1.1 g, 22.9%) as yellow solid. LCMS Method B, MS-ESI: 231.2 [M+H+]
2. Synthesis of 2-(2-phenyl-lH-imidazol-l-yl)acetic acid
Figure imgf000178_0003
Ethyl 2-(2-phenyl-lH-imidazol-l-yl)acetate (1.0 g, 4.3 mmol, 1.0 equiv) was dissolved in THF/H20(5: 1) (30 mL). MeiSiOK (1.11 g, 8.7 mmol, 2.0 equiv) was added to the solution in portions. The resulting solution was stirred for 2 hrs at RT. The resulting mixture was concentrated under vacuo. The residue was purified with silica gel column, eluted with EtO Ac/PE (1 : 1) to give 2-(2-phenyl-lH-imidazol-l-yl)acetic acid (300 mg, 34.6%) was obtained as a white solid. LCMS Method D, MS-ESI: 203.3 [M+EC] Scheme 6: Synthesis of intermediate 6 ( 2-(lH-benzo[d]imidazol-l-yl)propanoic acid)
Figure imgf000179_0001
1. Synthesis of methyl 2-(lH-benzo[d]imidazol-l-yl)propanoate
Figure imgf000179_0002
CH2CO3, D-
Sfep 1
r 2
Synthesized using the method as described for Scheme 5. LCMS Method F, MS- ESI: 205.3[M+H+]
2. Synthesis of 2-(lH-benzo[d]imidazol-l-yl)propanoic acid
Figure imgf000179_0003
2' intermediate 6
Methyl 2-(lH-benzo[d]imidazol-l-yl)propanoate (900.0 mg, 4.4 mmol, 1.0 equiv) was dissolved in THF (20.0 mL) and FFO (5 mL). LiOH (528.0 mg, 22.1mmol, 5.0 equiv) was added to the solution. The resulting mixture was stirred for 3 hrs at RT. The resulting mixture was concentrated. The residue was purified by reverse phasechromatography with the following conditions: column, C18; mobile phase A: Water (10 mmol/L NH4HCO3) and mobile phase B: MeCN, 0 to 50% gradient in 20 min; detector, UV 210 nm. 2-(lH-benzo[d]imidazol-l-yl)propanoic acid(600 mg, 71.6%) was obtained as a dark yellow solid. LCMS Method C, MS-ESI: 191.1[M+H+]
Scheme 7: Synthesis of intermediate 7 (3-cyclohexyl-4-isocyanato-lH-pyrazole)
Figure imgf000180_0001
3-Cyclohexyl-lH-pyrazol-4-amine (150.0 mg, 0.9 mmol, 1.0 equiv) was added in THF (10.0 mL). TEA (183.7 mg, 1.8 mmol, 2.0 equiv) and BTC (62.1 mg, 0.3 mmol, 0.3 equiv) were added. The resulting mixture was stirred for 1 h at 60 °C. The resulting mixture was concentrated and then was used in the next step direrctly.
Scheme 8: Synthesis of intermediate 8 ( 4-isocyanato-3-(thiophen-3-yl)-lH - pyrazole)
Figure imgf000180_0002
1. Synthesis of 3-(thiophen-3-yl)-lH-pyrazol-4-amine
Figure imgf000181_0001
3-Bromo-lH-pyrazol-4-amine (200.0 mg, 1.2 mmol, 1.0 equiv) was dissolved in dioxane (10.0 mL) and H20(l mL). CS2CO3 (804.6 mg, 2.5 mmol, 2.0 equiv), thiophen- 3-ylboronic acid (237.0 mg, 1.9 mmol, 1.5 equiv) and Pd(dppf)Cl2 (100.8 mg, 0.1 mmol, 0.1 equiv) were added. The resulting mixture purged and maintained with an inert atmosphere of nitrogen and stirred for 12 hrs at 90 °C. The resulting mixture was diluted with H2O (20 mL), and extracted with 3x20 mL of EtOAc. The organic layers were combined and concentrated. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1/1). 3-(Thiophen-3-yl)-lH-pyrazol-4-amine (120 mg, 58.8%) was isolated as a yellow solid. LCMS Method S, MS-ESL 166.1[M+H+]
2. Synthesis of 4-isocyanato-3-(thiophen-3-yl)-lH-pyrazole
Figure imgf000181_0002
Synthesized using the method as described for scheme 7. The crude product was used in the next step directly without further purification.
Scheme 9: Synthesis of intermediate 6 ( 7-fluoro-lH-pyrrolo[3,2-c]pyridin-3-amine hydrochloride)
Figure imgf000181_0003
1. Synthesis of 7-fluoro-lH-pyrrolo[3,2-c]pyridine-3-carbonyl azide
Figure imgf000182_0001
Same synthetic method as in scheme 2. LCMS: Method L, MS-ESI, 206.2 [M+H+]
2. Synthesis of t-butyl (7-fluoro-lH-pyrrolo[3,2-c]pyridin-3- yl)carbamate
Figure imgf000182_0002
7-Fluoro-lH-pyrrolo[3,2-c]pyridine-3-carbonyl azide (1.0 g, 4.9 mmol, 1.0 equiv) was dissolved in /-BuOH (50 mL) and stirred for 12 hours at 80 °C. The resulting mixture was concentrated under vacuum and purified on silical-gel column with EtO Ac/PE (1 :8) as an eluent. /-Butyl (7-fluoro-lH-pyrrolo[3,2-c]pyridin-3-yl)carbamate (430.0 mg, 17.6%) was isolated as a brown solid. LCMS: Method L, MS-ESI, 252.3 [M+EC]
3. Synthesis of 7-fluoro-lH-pyrrolo[3,2-c]pyridin-3-amine hydrochloride
Figure imgf000182_0003
t-Butyl (7-fluoro-lH-pyrrolo[3,2-c]pyridin-3-yl)carbamate (430.0 mg, 1.7 mmol, 1.0 equiv) was dissolved in 1,4-dioxane (10.0 mL). Then HC1 in 1, 4-dioxane (4 M, 10 mL) was added dropwise. The resulting mixture was stirred for 3 hours at RT and was concentrated under vacuum. 7-Fluoro-lH-pyrrolo[3,2-c]pyridin-3-amine hydrochloride (400 mg, crude) was obtained as a yellow solid. LCMS: Method L, MS-ESI, 188.6 [M+EC]
Scheme 10: Synthesis of Intermediate 10: ( lH-pyrrolo[3,2-b]pyridin-3-amine dihydrochloride)
Figure imgf000183_0001
Synthesized using method as described for scheme 9. LCMS: Method A, MS-ESI, 206.0 [M+H+]
Scheme for preparation of example 1
Example 1: Synthesis of 2-(4-butylphenyl)-N-(3-phenyl-lH-pyrazol-4- yl)acetamide (Compound 5)
Figure imgf000183_0002
3-Phenyl-lH-pyrazol-4-amine (200.0 mg, 1.3 mmol, 1.0 equiv) was dissolved in THF (15 mL). 2-(4-butylphenyl)acetic acid (265.7 mg, 1.4 mmol, 1.1 equiv), T3P (2.4 g, 3.8 mmol, 3.0 equiv, 50%) and TEA (254.3 mg, 2.5 mmol, 2.0 equiv) were added and stirred for 1 h at RT. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (2# SHIM ADZU (HPLC-01)): Column, XBridge Shield RP18 OBD Column, 30xl50mm,5um ; mobile phase, Water(10MMOL/L NH4HCO3) and ACN (38% Phase B up to 68% in 8 min); detector, UV 254nm. 2-(4-Butylphenyl)-N-(3-phenyl-lH- pyrazol-4-yl)acetamide (73.5 mg, 17.5%) was isolated as a white solid. LCMS Method G, MS-ESI: 334.0 [M+H+]
Analoss prepared by the method above
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0002
The following compounds were synthesized from the corresponding starting materials using TEA as the base and THF as solvent.
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0002
Example 15: Synthesis of N-(lH-pyrrolo[3,2-b]pyridin-3-yl)spiro[3.5]nonane-7- carboxamide (Compound 51)
Figure imgf000191_0001
N-(lH-pyrrolo[3,2-b]pyridin-3-yl)spiro[3.5]nonane-7-carboxamide was synthesized through coupling of lH-pyrrolo[3,2-b]pyridin-3-amine dihydrochloride (Intermediate 10) and spiro[3.5]nonane-7-carboxylic acid.
LCMS (Method A): MS-ESI: 284.2 [M+H+]
1HNMR (400 MHz, DMSO-i¾) d 10.96 (d, J= 12.9 Hz, 1H), 9.85 (d, J= 12.8 Hz, 1H), 8.38 - 8.30 (m, 1H), 8.01 (d, J= 13.0 Hz, 1H), 7.75 (dd, = 14.1, 7.9 Hz, 1H), 7.21 - 7.10 (m, 1H), 2.85 - 2.62 (m, 1H), 1.93 - 1.62 (m, 8H), 1.59 - 1.39 (m, 3H), 1.37 - 1.20
(m, 3H).
LC-MS Methods X and Y can be used in the analysis of Examples 16-67.
Example 16: Preparation of Compound 114
Figure imgf000192_0001
Synthesis of N-i5,6-difluoro-lH-indol-3-yl)-4-inyrimidin-2-yl)benzamide
5,6-difluoro-lH-indol-3-amine (48.1 mg, 0.286 mmol, 1.0 equiv.) and 4-(pyrimidin-2- yl)benzoic acid (74.3 mg, 0.343 mmol, 1.2 equiv.) were dissolved in DMF (2.0 mL). Then DIEA (188 mΐ, 1.14 mmol, 4 equiv.) and HATU (114.1 mg, 0.3 mmol, 1.1 equiv.) dissolved in 1 mL DMF was added. The reaction mixture was stirred at 30 °C for 16 hours. The reaction mixture was concentrated by Speedvac. The residue was purified by preparative HPLC to give N-(5,6-difluoro-lH-indol-3-yl)-4-(pyrimidin-2-yl)benzamide (41.6 mg, 0.119 mmol). MS-ESI, 351.2 [M+H+]
¾ NMR (400 MHz, DMSO-i¾) d ppm 11.12 (br s, 1 H) 10.33 (s, 1 H) 8.97 (d, 2 H) 8.54 (d, 2 H) 8.15 (d, 2 H) 7.90-7.99 (m, 2 H) 7.52 (t, 1 H) 7.39 (dd, 1 H). Table 1. The compounds in Table 1 were prepared using the above procedure.
Figure imgf000192_0002
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
The following compounds in Table Cl were prepared according to procedures similar to those described elsewhere herein. LC-MS was performed on the compounds using the following column and settings: Shim-pack XR-ODS, Cl 8, 3x50 mm, 2.5 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 5- 100% (1.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA) and water (0.05% TFA), with 2.0 minute as total run time.
Figure imgf000200_0002
Figure imgf000201_0001
Figure imgf000202_0001
Compounds 156-168 (Table Cl) were prepared according to procedures similar to those described elsewhere herein.
Biological Assays
STING pathway activation by the compounds described herein was measured using
THPl-Dual™ cells (KO-IFNAR2).
THPl-Dual™ KO-IFNAR2 Cells (obtained from invivogen) were maintained in RPMI, 10% FCS, 5 ml P/S, 2mM L-glut, lOmM Hepes, and 1 mM sodium pyruvate. Compounds were spotted in empty 384 well tissue culture plates (Greiner 781182) by Echo for a final concentration of 0.0017 - 100 mM. Cells were plated into the TC plates at 40 pL per well, 2>< 10E6 cells/mL. For activation with STING ligand, 2'3'cGAMP (MW 718.38, obtained from Invivogen), was prepared in Optimem media.
The following solutions were prepared for each 1 ><384 plate: o Solution A: 2 mL Optimem with one of the following stimuli:
60 uL of 10 mM 2'3'cGAMP -> 150 mM stock o Solution B: 2 mL Optimem with 60 pL Lipofectamine 2000 -> Incubate 5 min at RT
2 mL of solution A and 2 ml Solution B was mixed and incubated for 20 min at room temperature (RT). 20 uL of transfection solution (A+B) was added on top of the plated cells, with a final 2’3’cGAMP concentration of 15 mM. The plates were then centrifuged immediately at 340 g for 1 minute, after which they were incubated at 37 °C, 5% CO2, >98% humidity for 24h. Luciferase reporter activity was then measured. EC50 and/or IC50 values were calculated by using standard methods known in the art.
Luciferase reporter assay: 10 pL of supernatant from the assay was transferred to white 384-plate with flat bottom and squared wells. One pouch of QUANTI-Luc™ Plus was dissolved in 25 mL of water. 100 pL of QLC Stabilizer per 25 mL of QU ANTI- Luc™ Plus solution was added. 50 pL of QUANTI-Luc™ Plus/QLC solution per well was then added. Luminescence was measured on a Platereader (e.g., Spectramax I3X (Molecular Devices GF3637001)).
Luciferase reporter activity was then measured. EC50 and/or IC50 values were calculated by using standard methods known in the art.
Table BA shows the activity of compounds in STING reporter assay: <0.008 pM =
“++++++”; >0.008 and <0.04 pM =“+++++”; >0.04 and <0.2 pM =“++++”; >0.2 and <1 pM =“+++”; >1 and <5 pM =“++”; >5 and <100 pM =“+”.
Table BA.
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001

Claims

WHAT IS CLAIMED IS:
1. A method for inhibiting STING activity, the method comprising contacting STING with a compound of Formula I:
Figure imgf000207_0001
I
or a pharmaceutically acceptable salt thereof or a tautomer thereof,
wherein:
one of W1 and W2 is -N(H)-, -N(Rd)- (e.g., -N(H)- or -N(CI-3 alkyl)-), -N(H)- (W12)-, or -N(Rd)-(W12)-,
the other one of W1 and W2 is a bond, -0-, -0-(W12)-, or C1-C6 alkylene optionally substituted with from 1-3 Ra (e.g., C1-C3, e.g., CH2, CHRa, or CR¾; wherein W12 is Ci- Ce alkylene optionally substituted with from 1-3 Ra,
provided the one of W1 and W2 is attached to the C(=0) moiety of Formula I through a nitrogen atom;
A is selected from the group consisting of (A-l), (A-2), and (A-3):
Figure imgf000207_0002
(A-l)
wherein
Z is selected from the group consisting of: a bond, CH, CR1, CR3, N, NH, N(R') and N(R2);
each of Y1, Y2, and Y3 is independently selected from the group consisting of O, S, CH, CR1, CR3, N, NH, N(R4), and NR2;
Y4 is C or N;
X° is C or N; X1 is selected from the group consisting of O, S, N, NH, NR1, NR2, CH, CR1, and
CR3;
X2 is selected from the group consisting of O, S, N, NH, NR1, NR2, CH, CR1, and CR3; and
each— is independently a single bond or a double bond, provided that the five- membered ring comprising Y4, X°, X1, and X2 is heteroaryl; and
the ring comprising Z, Y1, Y2, Y3, and Y4 is aromatic (i.e., carbocyclic aromatic or heteroaromatic);
Figure imgf000208_0001
wherein:
Z is selected from the group consisting of:
a bond, CH, CR1, CR3, N, NH, N(R4) and N(R2);
each of Y1 and Y3 is independently selected from the group consisting of O, S, CH, CR1, CR3, N, NH, N(R4), and NR2;
Y4 is C or N;
X° is selected from the group consisting of O, S, N, NH, NR1, NR2, CH, CR1, and
CR3;
X1 is selected from the group consisting of O, S, N, NH, NR1, NR2, CH, CR1, and
CR3;
X2 is selected from the group consisting of O, S, N, NH, NR1, NR2, CH, CR1, and CR3; and
each— is independently a single bond or a double bond, provided that the five- membered ring comprising Y4, X1, and X2 is heteroaryl; and
the ring comprising Z, Y1, Y3, and Y4 is aromatic (i.e., carbocyclic aromatic or heteroaromatic);
Figure imgf000209_0001
wherein:
Y7 is N or C;
Z2 is selected from CH, CR2, and N;
X3 is selected from O, S, N, NH, NR1, NR2, CH, CR1, and CR3;
each of Y5 and Y6 is independently selected from O, S, CH, CR1, CR3, NR1, NR2, NH, and N; and
each— is independently a single bond or a double bond, provided that the five- membered ring comprising Y5, Y6, Y7, X3, and Z2 is heteroaromatic, and
further provided that:
when X3 is NR1 or CR1, then each of Y5 and Y6 is independently selected from O, S, CH, CR3, NR2, NH, and N; and
when X3 is selected from O, S, N, NH, NR2, CH, and CR3, then one of Y5 and Y6 is CR1 or NR1;
B is:
(a) Ci-15 alkyl which is optionally substituted with from 1-6 independently selected Ra;
(b) C3-20 cycloalkyl, which is optionally substituted with from 1-4 Rb;
(c) phenyl substituted with from 1-4 Rc;
(d) C8-20 aryl optionally substituted with from 1-4 Rc;
(e) heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected Rc; or
(f) heterocyclyl including from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected Rb;
R1 is:
(i) -(U1)q-U2, wherein:
• q is O or l;
• U1 is Ci-6 alkylene, which is optionally substituted with from 1-6 Ra; and
• U2 is:
(a) C3-12 cycloalkyl, which is optionally substituted with from 1-4 Rb,
(b) C6-10 aryl, which is optionally substituted with from 1-4 Rc;
(c) heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected Rc, or
(d) heterocyclyl including from 3-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected Rb,
OR
(ii) Ci-10 alkyl, which is optionally substituted with from 1-6 independently selected Ra; each occurrence of R2 is independently selected from the group consisting of:
(i) Ci-6 alkyl, which is optionally substituted with from 1-4 independently selected Ra;
(ii) C3-6 cycloalkyl;
(iii) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2;
(iv) -C(0)(Ci-4 alkyl);
(v) -C(0)0(Ci-4 alkyl); (vi) -CON(R’)(R”);
(vii) -S(0)I-2(NR’R”);
(viii) - S(0)i-2(Ci-4 alkyl);
(ix) -OH; and
(x) Ci-4 alkoxy; each occurrence of R3 is independently selected from the group consisting of halo, cyano, C2-6 alkenyl, C2-6 alkynyl, Ci-4 alkoxy optionally substituted with C3-6 cycloalkyl, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NReRf, -OH, oxo, -S(0)I-2(NR’R”), -Ci-4 thioalkoxy, - NO2, -C(=0)(Ci-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)OH, and -C(=0)N(R’)(R”); each occurrence of Ra is independently selected from the group consisting of: -OH; -F; - Cl; -Br; -NReRf; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)0(Ci-4 alkyl); -C(=0)(Ci-4 alkyl); - C(=0)OH; -CON(R’)(R”); -S(0)I-2(NR’R”); -S(0)i-2(Ci-4 alkyl); cyano, and C3-6 cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl; each occurrence of Rb is independently selected from the group consisting of: Ci-10 alkyl optionally substituted with from 1-6 independently selected Ra; Ci-4 haloalkyl; -OH; oxo; -F; -Cl; -Br; -NReRf; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)(Ci-4 alkyl); -C(=0)0(Ci-4 alkyl); -C(=0)OH; -C(=0)N(R’)(R”); -S(0)I-2(NR’R”); -S(0)i-2(Ci-4 alkyl); cyano; and
-L1-L2-Rh; each occurrence of Rc is independently selected from the group consisting of:
(a) halo;
(b) cyano;
(c) Ci-15 alkyl which is optionally substituted with from 1-6 independently selected Ra;
(d) C2-6 alkenyl;
(e) C2-6 alkynyl;
(g) Ci-4 alkoxy optionally substituted with Ci-4 alkoxy;
(h) Ci-4 haloalkoxy; (i) -S(0)i-2(Ci-4 alkyl);
(j) -NReRf;
(k) -OH;
(l) -S(0)I-2(NR’R”);
(m) -Ci-4 thioalkoxy optionally substituted with from 1-4 halo;
(n) -NO2;
(o) -C(=0)(Ci-4 alkyl);
(p) -C(=0)0(Ci-4 alkyl);
(q) -C(=0)0H;
(r) -C(=0)N(R’)(R”); and
(s) -L1-L2-Rh;
Rd is selected from the group consisting of: Ci-6 alkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); -C(0)0(Ci-4 alkyl); -CON(R’)(R”); -S(0)I-2(NR’R”); - S(0)i-2(Ci-4 alkyl); -OH; and Ci- 4 alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; Ci-6 alkyl; Ci-6 haloalkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); -C(0)0(Ci-4 alkyl); - CON(R’)(R”); -S(0)I-2(NR,R”); - S(0)I-2(CM alkyl); -OH; and CM alkoxy; or Re and Rf together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to Re and Rr), which are each independently selected from the group consisting of N(Rd), NH, O, and S;
-L1 is a bond or C1-3 alkylene;
-L2 is -O-, -N(H)-, -S-, or a bond;
Rh is selected from:
• C3-8 cycloalkyl optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, CM alkyl, and CM haloalkyl (in certain embodiments, it is provided that when Rh is C3-6 cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl, -L1 is a bond, or -L2 is -0-, - N(H)-, or -S-);
• heterocyclyl, wherein the heterocyclyl includes from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, and Ci-4 haloalkyl;
• heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci- 4 alkyl, and Ci-4 haloalkyl; and
• C6-10 aryl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, or Ci-4 haloalkyl; and each occurrence of R’ and R” is independently selected from the group consisting of: H, Ci-4 alkyl, and C6-10 aryl optionally substituted with from 1-2 substituents selected from halo, Ci-4 alkyl, and Ci-4 haloalkyl; or R’ and R” together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from the group consisting of H and C1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R’ and R”), which are each independently selected from the group consisting of N(H), N(Rd), O, and S.
2. The method of claim 1, wherein A is (A-l).
3. The method of claim 2, wherein Z is selected from the group consisting of: CH, CR1, CR3, N, and N(R2).
4. The method of any one of claims 2-3, wherein Z is selected from the group consisting of: CH, CR1, CR3, and N.
5. The method of any one of claims 2-4, wherein Z is selected from the group consisting of CH, CR1, and CR3 (e.g., Z is CH).
6. The method of any one of claims 2-5, wherein each of Y1, Y2, and Y3 is
independently selected from the group consisting of CH, CR1, CR3, and N.
7. The method of any one of claims 2-6, wherein each of Y1, Y2, and Y3 is
independently selected from the group consisting of CH, CR1, and CR3.
Y, 'z¾t
li 4
8. The method of any one of claims 2-7, wherein the
Figure imgf000214_0002
moiety
Figure imgf000214_0001
, wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2 (e.g., ml = 0; and m3 = 2)).
9. The method of any one of claims 2-6, wherein from 1-2 of Y1, Y2, and Y3 is independently N. 10. The method of any one of claims 2-6 and 9, wherein one of Y1, Y2, and Y3 is independently N.
11. The method of any one of claim 2-6 and 9-10, wherein the
Figure imgf000215_0001
moiety is
Figure imgf000215_0002
wherein the asterisk denotes point of attachment to Y4; and ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
12. The method of any one of claims 2-6 and 9-10, wherein the
Figure imgf000215_0003
moiety is
Figure imgf000215_0004
wherein: the asterisk denotes point of attachment to Y4; and ml = 0,
1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
13. The method of any one of claims 2-6 and 9, wherein two of Y1, Y2, and Y3 are independently N.
; I,:, l¾4
14. The method of any one of claims 2-6, 9, and 13, wherein the moiety is
Figure imgf000215_0005
, wherein: the asterisk denotes point of attachment to Y4; and ml 0 or 1 ; and m3 = 0 or 1.
15. The method of any one of claims 2-14, wherein Y4 is C.
16. The method of any one of claims 2-15, wherein X1 is selected from the group consisting of NH, NR1, and NR2.
17. The method of any one of claims 2-16, wherein X1 is selected from the group consisting of NH and NR2, such as X1 isNH or NAc, such as X1 is NH.
18. The method of any one of claims 2-17, wherein X2 is selected from the group consisting of N, CH, CR1, and CR3. 19. The method of any one of claims 2-18, wherein X2 is selected from the group consisting of N, C(Ci-3 alkyl), and CH.
20. The method of any one of claims 2-19, wherein X2 is CH. 21. The method of any one of claims 2-20, wherein X° is C.
22. The method of any one of claims 2-15, wherein X1 is NH, NR1, or NR2; and X° is C. 23. The method of claim 22, wherein X1 is NH or NR2, such as X1 isNH or NAc, such as X1 is NH.
24. The method of any one of claims 22-23, wherein X2 is CH; X1 is NH; and X° is C. 25. The method of any one of claims 1-2, wherein A is:
Figure imgf000216_0001
, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2).
26. The method of claim 25, wherein m3 = 2; and ml = 0.
27. The method of any one of claims 1-2, wherein A is:
, wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml 0 or 1; ny one of claims 1-2, wherein A is
, wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml 0 or 1;
Figure imgf000217_0001
29. The method of any one of claims 1-2, wherein A is
Figure imgf000217_0002
, wherein ml = 0, 1, or 2; and m3 = 0, 1, or 2 (e.g., ml = 0 or 1; and m3 = 0 or 1).
30. The method of claim 1, wherein A is (A-2).
31. The method of claim 30, wherein Z is selected from the group consisting of: CH, CR1, CR3, and N. 32. The method of any one of claims 30-31, wherein Z is selected from the group consisting of CH, CR1, and CR3, such as Z is CH.
33. The method of any one of claims 30-32, wherein each of Y1 and Y3 is independently selected from the group consisting of CH, CR1, CR3, and N.
34. The method of any one of claims 30-33, wherein each of Y1 and Y3 is independently selected from the group consisting of CH, CR1, and CR3.
Y' A¾i
35. The method of any one of claims 30-34, wherein the moiety is
Figure imgf000218_0001
wherein ml = 0, 1, 2, or 3; and m3 = 0, 1, 2, or 3 (e.g., ml = 0 or 1; and m3 = 0, 1, or 2); and the asterisk denotes point of attachment to W1.
36. The method of any one of claims 30-35, wherein Y4 is C.
37. The method of any one of claims 30-36, wherein X1 is selected from NH and NR2, such as X1 is NH.
38. The method of any one of claims 30-37, wherein X° is selected from the group consisting of CH and N, such as X° is CH.
39. The method of any one of claims 30-37, wherein X° is CR3.
40. The method of any one of claims 30-39, wherein X2 is selected from the group consisting of CR1, CH, and N, such as X2 is CH.
41. The method of any one of claims 30-40, wherein A is:
Figure imgf000219_0001
and m3 = 0 or 1).
42. The method of claim 1, wherein A is (A-3).
43. The method of claim 42, wherein X3 is NR1 or CR1.
44. The method of claim 43, wherein Z2 is selected from N or CH. 45. The method of any one of claims 43-44, wherein Y6 is selected from S, CH, CR3, and N.
46. The method of any one of claims 43-45, wherein Y6 is selected from S, N and CH (e.g., Y6 is CH; or Y6 is S).
47. The method of any one of claims 43-46, wherein Y5 is selected from CH, CR3, and N (e.g., CH and N).
48. The method of any one of claims 42-47, wherein Y7 is C.
49. The method of any one of claims 42-43, wherein A is selected from:
Figure imgf000219_0002
Figure imgf000219_0003
50. The method of claim 42, wherein X3 is S, N, CH, CR3, NH, or NR2.
51. The method of claim 50, wherein X3 is selected from N, CH, or NH (e.g., CH or NH).
52. The method of any one of claims 50-51 and , wherein Z2 is selected from N or CH (e.g., Z2 is CH). 53. The method of any one of claims 50-52, wherein Y6 is selected from CH and N
(e.g., Y6 is N).
54. The method of any one of claims 50-53, wherein Y5 is selected from NR1 and CR1, such as CR1
55. The method of any one of claims 1, 42, and 50, wherein A is selected from:
Figure imgf000220_0001
56. The method of claim 55, wherein
Figure imgf000220_0002
57. The method of any one of claims 1-56, wherein each occurrence of R1 is independently selected from the group consisting of:
(i) -(U1)q-U2, wherein:
• q is O or l;
• U1 is Ci-6 alkylene, which is optionally substituted with from 1-6 Ra; and
• U2 is: o C3-10 cycloalkyl, which is optionally substituted with from 1-4 Rb, o C6-10 aryl, which is optionally substituted with from 1-4 Rc;
o heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected Rc, or
o heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2 , and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected Rb,
AND
(ii) Ci-6 alkyl, which is optionally substituted with from 1-6 independently selected Ra.
58. The method of any one of claims 1-57, wherein R1 is -(U1)q-U2.
59. The method of any one of claims 1-58, wherein q is 0.
60. The method of any one of claims 1-59, wherein U2 is C6-10 aryl, which is optionally substituted with from 1-4 Rc.
61. The method of any one of claims 1-60, wherein U2 is C6-10 aryl, which is optionally substituted with from 1-2 Rc.
62. The method of any one of claims 1-61, wherein U2 is phenyl, which is optionally substituted with from 1-2 (e.g., 1) Rc.
63. The method of any one of claims 57-62, wherein each occurrence of Rc substituent on U2 is selected from the group consisting of: halo (e.g., Cl, F); cyano; Ci-io alkyl which is optionally substituted with from 1-6 independently selected Ra; Ci-4 haloalkyl; Ci-4 alkoxy; Ci-4 haloalkoxy; and -Ci-4 thioalkoxy.
64. The method of any one of claims 57-62, wherein each occurrence of Rc substituent on U2 is selected from the group consisting of: halo (e.g., Cl, F; e.g., F), cyano, Ci- 6 alkyl, and Ci-4 haloalkyl.
65. The method of any one of claims 57-58, wherein R1 is phenyl, which is optionally substituted with from 1-2 (e.g., 1) Rc.
66. The method of claim 65, wherein each Rc is independently selected from the group consisting of: halo (e.g., Cl, F); cyano; Ci-io alkyl which is optionally substituted with from 1-6 independently selected Ra; Ci-4 haloalkyl; Ci-4 alkoxy; Ci-4 haloalkoxy; and -Ci-4 thioalkoxy, optionally, each occurrence of Rc substituent on U2 is independently selected from the group consisting of: halo (e.g., Cl, F; e.g., F), cyano, Ci-6 alkyl, and Ci-4 haloalkyl.
67. The method of any one of claims 1-57, wherein R1 is Ci-6 alkyl, which is optionally substituted with from 1-6 independently selected Ra (in certain embodiments, each Ra substituent of R1 is independently selected from: -OH; -F; -Cl; Ci-4 alkoxy; Ci- 4 haloalkoxy; -C(=0)0(Ci-4 alkyl); -C(=0)OH, and C3-6 cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl).
68. The method of any one of claims 1-67, wherein each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NReRf, -OH, -S(0)I-2(NR’R”), -Ci-4 thioalkoxy, -C(=0)(Ci-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)OH, and -C(=0)N(R’)(R”)
69. The method of any one of claims 1-68, wherein each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -S(0)i-2(NR’R”), -C(=0)(Ci-4 alkyl), - C(=0)0(Ci-4 alkyl), -C(=0)0H, and -C(=0)N(R’)(R”)
70. The method of any one of claims 1-69, wherein each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy (e.g., halo or cyano). 71. The method of any one of claims 1-70, wherein each occurrence of R2 is independently selected from the group consisting of: Ci-6 alkyl (e.g., methyl); C3-6 cycloalkyl; C(0)(Ci-4 alkyl) (e.g., C(O)Me); -C(0)0(Ci-4 alkyl); -CON(R’)(R”); - S(0)I.2(NR’R”); and S(0)i-2(Ci-4 alkyl) (e.g., S(0)2Me). 72. The method of any one of claims 1-71, wherein each occurrence of R2 is independently selected from (viii) - S(0)i-2(Ci-4 alkyl) (e.g., S(0)2Me) and (iv) - C(0)(Ci-4 alkyl) (e.g., C(O)Me).
73. The method of any one of claims 8, 11, 12, 14, 25-29, 35, and 41, wherein ml = 0.
74. The method of claim 73, wherein m3 = 0, 1, or 2.
75. The method of any one of claims 73-74, wherein m3 = 0. 76. The method of any one of claims 73-74, wherein m3 = 1 or 2.
77. The method of claim 76, wherein each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci- 4 alkyl), -NReRf, -OH, -S(0)i-2(NR’R”), -CM thioalkoxy, -C(=0)(Ci-4 alkyl), - C(=0)0(Ci-4 alkyl), -C(=0)OH, and -C(=0)N(R’)(R”X such as, each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -S(0)i- 2(NR’R”), -C(=0)(CI-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)OH, and - C(=0)N(R’)(R”),
such as each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy (e.g., halo or cyano).
78. The method of claims 77, wherein R3 is halo (e.g., F) or cyano.
79. The method of any one of claims 49 and 55-56, wherein R1 is as defined in any one of claims 57-67 (e.g., any one of claims 58-66).
80. The method of claim 79, wherein R1 is phenyl, which is optionally substituted with from 1-2 (e.g., 1) Rc, optionally wherein each Rc is independently selected from the group consisting of: halo (e.g., Cl, F); cyano; Ci-io alkyl which is optionally substituted with from 1-6 independently selected Ra; Ci-4 haloalkyl; Ci-4 alkoxy; Ci-4 haloalkoxy; and -Ci-4 thioalkoxy, such as each occurrence of Rc substituent on U2 is independently selected from the group consisting of: halo (e.g., Cl, F; e.g., F), cyano, Ci-6 alkyl, and Ci-4 haloalkyl.
81. The method of any one of claims 49 and 55-56, wherein R1 is phenyl optionally substituted with one Rc.
82. The method of claim 81, wherein R1 is unsubstituted phenyl.
83. The method of any one of claims 1-82, wherein W1 is -NH-.
84. The method of any one of claims 1-82, wherein W1 is CFh or CH(CI-3 alkyl) (e.g., CH2).
85. The method of any one of claims 1-82, wherein W1 is a bond.
86. The method of any one of claims 1-83, wherein W2 is a bond. 87. The method of any one of claims 1-83, wherein W2 is CFh or CH(CI-3 alkyl) (e.g.,
CH2).
88. The method of any one of claims 1-82 and 84-86, wherein W2 is -NH-. 89. The method of any one of claims 1-82, wherein W1 is -NH-; and W2 is a bond.
90. The method of any one of claims 1-82, wherein W1 is -NH-; and W2 is CFh or CH(CI-3 alkyl) (e.g., CH2 or CH(Me)). 91. The method of any one of claims 1-82, wherein W2 is -NH-; and W1 is a bond.
92. The method of any one of claims 1-82, wherein W2 is -NH-; and W1 is CH2 or CH(CI-3 alkyl) (e.g., CH2). 93. The method of any one of claims 1-92, wherein B is phenyl substituted with from
1-4 Rc.
94. The method of any one of claims 1-93, wherein B is phenyl substituted with from 1-2 Rc, wherein from 1-2 Rc is at the ring carbons para or me la (e.g., one Rc is at the ring carbon para ) to the point of attachment to the -W1-C(=0)-W2- moiety in
Formula I.
95. The method of any one of claims 1-94, wherein B is phenyl substituted with one Rc at the ring carbon para to the point of attachment to the -W1-C(=0)-W2- moiety in Formula I.
96. The method of any one of claims 93-95, wherein each Rc substituent of B is independently selected from the group consisting of: halo; cyano; Ci-io alkyl which is optionally substituted with from 1-6 independently selected Ra; Ci-4 alkoxy; Ci- 4 haloalkoxy; -S(0)i-2(Ci-4 alkyl); -Ci-4 thioalkoxy; -C(=0)(Ci-4 alkyl); -
C(=0)0(Ci-4 alkyl); -C(=0)N(R’)(R”); and - -V-R"
97. The method of any one of claims 93-96, wherein each Rc substituent of B is independently selected from the group consisting of: halo; cyano; Ci-io alkyl which is optionally substituted with from 1-6 independently selected Ra; Ci-4 alkoxy; and Ci-4 haloalkoxy.
98. The method of any one of claims 93-97, wherein each Rc substituent of B is independently selected from Ci-io alkyl which is optionally substituted with from 1-6 independently selected Ra.
99. The method of claim 98, wherein each occurrence of Ra is independently selected from: -halo (e.g., F); -OH; Ci-4 alkoxy; and Ci-4 haloalkoxy. 100. The method of any one of claims 98-99, wherein each Rc substituent of B is Ci-io
(e.g., Ci-6, Ci-3, Ci-2, Ci) alkyl optionally substituted with from 1-3 halo (e.g., F) (e.g., Rc is CF3).
101. The method of any one of claims 93-97, wherein each Rc substituent of B is independently selected from unsubstituted Ci-10 (e.g., C2-10 (e.g., C3-8)) alkyl.
102. The method of claim 101, wherein each Rc substituent of B is independently selected from unsubstituted Ci-6 alkyl.
103. The method of claim 102, wherein each Rc substituent of B is independently selected from unsubstituted C2-6 (e.g., C2-4, e.g., C2 or C4) alkyl.
104. The method of any one of claims 101-103, wherein each Rc substituent of B is ethyl or butyl (e.g., n-butyl).
105. The method of any one of claims 93-95, wherein Rc is Ci-6 alkyl optionally substituted with from 1-3 independently selected Ra. 106. The method of any one of claims 1-92, wherein B is C3-20 cycloalkyl, which is optionally substituted with from 1-4 Rb.
107. The method of any one of claims 1-92 and 106, wherein B is C3-12 cycloalkyl, which is optionally substituted with from 1-2 Rb.
108. The method of any one of claims 1-92 and 106-107, wherein B is C6-12 cycloalkyl, which is optionally substituted with from 1-2 Rb.
109. The method of any one of claims 1-92 and 106-108, wherein B is C6-12 (e.g., C7-12)
cycloalkyl (e.g., B can
Figure imgf000227_0001
110. The method of any one of claims 1-92, wherein B is heterocyclyl including from 3- 16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected
Rb.
111. The method of any one of claims 1-92 and 110, wherein B is heterocyclyl including from 3-12 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o- 2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected Rb.
112. The method of any one of claims 1-92 and 110-111, wherein B is heterocyclyl including from 3-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o- 2, and wherein the heterocyclyl ring is optionally substituted with from 1-3 independently selected Rb.
113. The method of any one of claims 1-92 and 110-112, wherein B is heterocyclyl including from 5-6 (e.g., 6) ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted
with from 1-2 independently selected Rb (e.g., B can be
Figure imgf000228_0001
114. The method of any one of claims 106-113, wherein each occurrence of Rb is independently selected from the group consisting of: Ci-io alkyl; Ci-4 haloalkyl; - OH; oxo; -F; -Cl; -NReRf; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)(Ci-4 alkyl); - C(=0)0(Ci-4 alkyl); -S(0)i-2(Ci-4 alkyl); cyano; and -LClARh
115. The method of any one of claims 106-114, wherein each occurrence of Rb is independently selected from the group consisting of: Ci-io alkyl; Ci-4 haloalkyl; -
OH; oxo; -F; -Cl; Ci-4 alkoxy; and Ci-4 haloalkoxy.
116. Th method of claim 1, wherein the compound is selected from the compounds in Table Cl, or a pharmaceutically acceptable salt thereof.
117. A compound of Formula II:
Figure imgf000229_0001
II
or a pharmaceutically acceptable salt thereof or a tautomer thereof,
wherein:
Z is selected from the group consisting of: CH, CR1, CR3, N, NH, N(R') and N(R2); each of Y1, Y2, and Y3 is independently selected from the group consisting of CH, CR1, CR3, N, NH, N(R4), and NR2;
each— is independently a single bond or a double bond, provided that:
the 6-membered ring comprising Z, Y1, Y2, and Y3 is aromatic;
provided that Y3 cannot be N when each of each of Y1, Y2, and Y3 is independently selected from the group consisting of CH, CR1, CR3; and
when each of Z, Y1, Y2, and Y3 is independently selected from the group consisting of CH, CR1, and CR3, from 1-4 of Z, Y1, Y2, and Y3 is selected from the group consisting of CR1 and CR3;
R2N is H or R2;
R6 is selected from the group consisting of H and Rd;
B is a monocyclic heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc;
-L3 is a bond or C1-3 alkylene;
R4 is selected from the group consisting of:
(a) C3-12 cycloalkyl, which is optionally substituted with from 1-4 independently selected R4’, (b) heterocyclyl including from 3-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heterocyclyl is optionally substituted with from 1-4 independently selected R4’;
(c) heteroaryl including from 5-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with from 1-4 independently selected R4’; and
(d) C6-io aryl optionally substituted with from 1-4 independently selected R4’; wherein each R4’ is independently selected from the group consisting of: halo; -
CN; -NO2; -OH; -Ci-4 alkyl optionally substituted with from 1-2 independently selected Ra; -C2-4 alkenyl; -C2-4 alkynyl; -Ci-4 haloalkyl; -Ci-6 alkoxy optionally substituted with from 1-2 independently selected Ra; -Ci-6 haloalkoxy; S(0)i-2(Ci-4 alkyl); -NR’R”; oxo; - S(0)I-2(NR’R”); -CI-4 thioalkoxy; -C(=0)(Ci-4 alkyl); -C(=0)0(Ci-4 alkyl); -C(=0)OH; and -C(=0)N(R’)(R”);
R1 is:
(i) -(U1)q-U2, wherein:
• q is O or l;
• U1 is Ci-6 alkylene, which is optionally substituted with from 1-6 Ra; and
• U2 is:
(a) C3-12 cycloalkyl, which is optionally substituted with from 1-4 Rb,
(b) C6-10 aryl, which is optionally substituted with from 1-4 Rc;
(c) heteroaryl including from 5-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected Rc, or
(d) heterocyclyl including from 3-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected Rb,
OR
(ii) Ci-io alkyl, which is optionally substituted with from 1-6 independently selected Ra; each occurrence of R2 is independently selected from the group consisting of:
(i) Ci-6 alkyl, which is optionally substituted with from 1-4 independently selected Ra;
(ii) C3-6 cycloalkyl;
(iii) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2;
(iv) -C(0)(Ci-4 alkyl);
(v) -C(0)0(Ci-4 alkyl);
(vi) -CON(R’)(R”);
(vii) -S(0)I-2(NR’R”);
(viii) - S(0)i-2(Ci-4 alkyl);
(ix) -OH; and
(x) Ci-4 alkoxy; each occurrence of R3 is independently selected from the group consisting of halo, cyano, C2-6 alkenyl, C2-6 alkynyl, Ci-4 alkoxy optionally substituted with C3-6 cycloalkyl, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NReRf, -OH, oxo, -S(0) I-2(NR’R”), -CM thioalkoxy, -NO2, -C(=0)(Ci-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)OH, and - C(=0)N(R’)(R”); each occurrence of Ra is independently selected from the group consisting of: - OH; -F; -Cl; -Br; -NReRf; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)0(Ci-4 alkyl); -C(=0)(Ci- 4 alkyl); -C(=0)0H; -CON(R’)(R”); -S(0)I-2(NR’R”); -S(0)I-2(CM alkyl); cyano, and C3-6 cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl; each occurrence of Rb is independently selected from the group consisting of: Ci- 10 alkyl optionally substituted with from 1-6 independently selected Ra; Ci-4 haloalkyl; -
OH; oxo; -F; -Cl; -Br; -NReRf; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)(Ci-4 alkyl); - C(=0)0(Ci-4 alkyl); -C(=0)0H; -C(=0)N(R’)(R”); -S(0)I-2(NR’R”); -S(0)i-2(Ci-4 alkyl); cyano; and -L1-L2-Rh; each occurrence of Rc is independently selected from the group consisting of:
(a) halo;
(b) cyano;
(c) Ci-15 alkyl which is optionally substituted with from 1-6 independently selected Ra;
(d) C2-6 alkenyl;
(e) C2-6 alkynyl;
(g) Ci-4 alkoxy optionally substituted with Ci-4 alkoxy;
(h) Ci-4 haloalkoxy;
(i) -S(0)i-2(Ci-4 alkyl);
(j) -NReRf;
(k) -OH;
(l) -S(0)I-2(NR’R”);
(m) -Ci-4 thioalkoxy optionally substituted with from 1-4 halo;
(n) -NO2;
(o) -C(=0)(Ci-4 alkyl);
(p) -C(=0)0(Ci-4 alkyl);
(q) -C(=0)OH;
(r) -C(=0)N(R’)(R”); and
(s) -L1-L2-Rh; Rd is selected from the group consisting of: Ci-6 alkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); -C(0)0(Ci-4 alkyl); -CON(R’)(R”); -S(0)i-2(NR’R”); - S(0)i-2(Ci-4 alkyl); -OH; and Ci-4 alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; Ci-6 alkyl; Ci-6 haloalkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl); -C(0)0(Ci-4 alkyl); - CON(R’)(R”); -S(0)i-2(NR’R”); - S(0)I-2(CM alkyl); -OH; and CM alkoxy; or Re and Rf together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to Re and Rr), which are each independently selected from the group consisting of N(Rd), NH, O, and S;
-L1 is a bond or C1-3 alkylene;
-L2 is -O-, -N(H)-, -S-, or a bond;
Rh is selected from:
• C3-8 cycloalkyl optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, CM alkyl, and CM haloalkyl (in certain embodiments, it is provided that when Rh is C3-6 cycloalkyl optionally substituted with from 1-4 independently selected CM alkyl, -L1 is a bond, or -L2 is -O-, -N(H)-, or -S-);
• heterocyclyl, wherein the heterocyclyl includes from 3-16 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, CM alkyl, and CM haloalkyl;
• heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, and Ci-4 haloalkyl; and
• C6-io aryl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of halo, Ci-4 alkyl, or Ci-4 haloalkyl; and each occurrence of R’ and R” is independently selected from the group consisting of: H, Ci-4 alkyl, and C6-10 aryl optionally substituted with from 1-2 substituents selected from halo, Ci-4 alkyl, and Ci-4 haloalkyl; or R’ and R” together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from the group consisting of H and C 1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R’ and R”), which are each independently selected from the group consisting of N(H), N(Rd), O, and S.
118. The compound of claim 117, wherein each of Z, Y1, Y2, and Y3 is independently selected from the group consisting of: CH, CR1, CR3, and N.
119. The compound of any one of claims 117-118, wherein each of Z, Y1, Y2, and Y3 is independently selected from the group consisting of: CH, CR1, and CR3.
120. The compound of any one of claims 117-119, wherein from 1-2 of Z, Y1, Y2, and Y3 is independently selected from the group consisting of CR1 and CR3; and each remaining Z, Y1, Y2, and Y3 is CH.
121. The compound of claim 120, wherein the compound has Formula Il-a:
Figure imgf000235_0001
122. The compound of claim 120, wherein the compound has Formula Il-b or
Figure imgf000235_0002
123. The compound of claim 120, wherein the compound has Formula Il-d, II- e, or Il-f:
Figure imgf000235_0003
124. The compound of any one of claims 117-118, wherein one of Z, Y1, and Y2 is N; and each remaining Z, Y1, Y2, and Y3 is independently selected from the group consisting of CH, CR1, and CR3.
125. The compound of claim 124, wherein Z is N.
126. The compound of claim 124, wherein Y1 is N.
127. The compound of claim 124, wherein Y2 is N.
128. The compound of claim 124, wherein the compound has Formula Il-g, II- h, or Il-i:
Figure imgf000236_0001
129. The compound of claim 128, wherein ml is 0.
130. The compound of claim 128, wherein ml is 1.
131. The compound of claim 128, wherein m3 is 0.
132. The compound of claim 128, wherein m3 is 1 or 2.
133. The compound of claim 128, wherein ml is 0; and m3 is 1 or 2.
134. The compound of claim 128, wherein ml is 1; and m3 is 0.
135. The compound of claim 128, wherein ml is 1; and m3 is 1.
136. The compound of any one of claims 117-135, wherein R2N is H.
137. The compound of any one of claims 117-135, wherein R2N is R2, wherein said R2 is selected from the group consisting of: (iv) -C(0)(Ci-4 alkyl) (e.g., - C(O)Me); (v) -C(0)0(Cw alkyl); (vi) -CON(R’)(R”); (vii) -S(0)i.2(NR’R”); and (viii) - S(0)i-2(Ci-4 alkyl) (e.g., S(0)2Me).
138. The compound of claim 137, wherein R2N is (iv) -C(0)(Ci-4 alkyl) (e.g., - C(O)Me) or (viii) - S(0)I-2(CM alkyl) (e.g., S(0)2Me).
139. The compound of any one of claims 117-138, wherein R1 is Ci-6 alkyl, which is optionally substituted with from 1-6 (e.g., 1-3) independently selected Ra.
140. The compound of any one of claims 117-138, wherein R1 is C1-3 alkyl, which is optionally substituted with from 1-3 independently selected Ra.
141. The compound of any one of claims 117-138, wherein R1 is -(U1)q-U2, wherein:
• q is 0 or 1, such as q is 0;
• U1 is Ci-6 alkylene, which is optionally substituted with from 1-6 Ra;
and
• U2 is:
o (C3-10 cycloalkyl, which is optionally substituted with from 1-4 Rb,
o (C6-10 aryl, which is optionally substituted with from 1-2 Rc; o (heteroaryl including from 5-6 ring atoms, wherein from 1 -4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc, or
o (heterocyclyl including from 3-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2 , and wherein the heterocyclyl ring is optionally substituted with from 1-4 independently selected Rb.
142. The compound of any one of claims 117-141, wherein each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, Ci-4 haloalkoxy, -S(0)i-2(Ci-4 alkyl), -NReRf, -OH, -S(0) I-2(NR’R”), -CM thioalkoxy, -C(=0)(Ci-4 alkyl), -C(=0)0(Ci-4 alkyl), -C(=0)OH, and - C(=0)N(R’)(R”).
143. The compound of any one of claims 117-142, wherein each occurrence of R3 is independently selected from the group consisting of: halo, cyano, Ci-4 alkoxy, CM haloalkoxy, -S(0)I-2(CM alkyl), -S(0)I-2(NR’R”), -C(=0)(CM alkyl), - C(=0)0(Ci-4 alkyl), -C(=0)OH, and -C(=0)N(R’)(R”)·
144. The compound of any one of claims 117-143, wherein each occurrence of R3 is independently selected from the group consisting of: halo, cyano, CM alkoxy, and CM haloalkoxy.
145. The compound of claim 144, wherein each occurrence of R3 is halo or cyano, such as -F or cyano.
146. The compound of any one of claims 117-145, wherein B is a monocyclic heteroaryl including 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc.
147. The compound of any one of claims 117-146, wherein B is a monocyclic heteroaryl including 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc.
148. The compound of any one of claims 117-147, wherein B is a monocyclic heteroaryl including 5 ring atoms, wherein from 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc.
149. The compound of claim 148, wherein B is a monocyclic heteroaryl including 5 ring atoms, wherein from 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(Rd), and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc.
150. The compound of claim 149, wherein B is imidazolyl, pyrazolyl, or triazolyl, each of which is optionally substituted with one independently selected Rc.
151. The compound of claim 150, wherein B is imidazolyl or triazolyl, each of which is optionally substituted with one independently selected Rc.
152. The compound of any one of claims 150-151, wherein B is selected from
the group consisting of:
Figure imgf000240_0001
Figure imgf000240_0002
, each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
153. The compound of claim 152, wherein B is selected from the group
c
Figure imgf000240_0003
each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
154. The compound of any one of claims 150-151, wherein B is selected from
the group
Figure imgf000240_0004
each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
155. The compound of claim 154, wherein B is selected from the group
consisting of:
Figure imgf000240_0005
each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
156. The compound of claim 150, wherein B is selected from the group
consisting of:
Figure imgf000241_0001
each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
157. The compound of claim 156, wherein B is selected from the group
IL> N
consisting of: aa and aa , each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
158. The compound of any one of claims 117-148, wherein B is a monocyclic heteroaryl including 5 ring atoms, wherein from 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, provided that one ring atom is O or S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc. 159. The compound of claim 158, wherein B is selected from the group consisting of oxazolyl, thiazolyl, thiadiazolyl, and oxadiazolyl, each of which is optionally substituted with one Rc.
160. The compound of claim 159, wherein B is selected from the group consisting of:
Figure imgf000241_0002
each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
161. The compound of any one of claims 117-146, wherein B is a monocyclic heteroaryl including 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc, wherein the point of attachment to the C(=0)NR6 group of Formula II is meta to the point of attachment to L3.
162. The compound of claim 161, wherein B is selected from the group
Figure imgf000242_0002
Figure imgf000242_0001
each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
163. The compound of any one of claims 117-145, wherein B is a monocyclic heteroaryl including 6 ring atoms, wherein from 1-3 ring atoms are ring nitrogen atoms, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc.
164. The compound of claim 163, wherein B is pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl, each of which is optionally substituted with from 1-2 independently selected Rc, such as pyridyl optionally substituted with Rc.
165. The compound of any one of claims 163-164, wherein the point of attachment of B to the C(=0)NR6 group of Formula II is para to the point of attachment to L3.
166. The compound of any one of claims 163-165, wherein B
Figure imgf000243_0001
which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
167. The compound of any one of claims 163-164, wherein the point of attachment of B to the C(=0)NR6 group of Formula II is meta to the point of attachment to L3.
168. The compound of any one of claims 163-164 and 167, wherein B is selected
aa from the group consisting of:
Figure imgf000243_0002
, each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
169. The compound of any one of claims 117-168, wherein L3 is a bond.
170. The compound of any one of claims 117-168, wherein L3 is C1-3 alkylene.
171. The compound of claim 170, wherein L3 is CFh.
172. The compound of any one of claims 117-171, wherein R4 is C6-10 aryl optionally substituted with from 1-4 independently selected R4’.
173. The compound of any one of claims 117-172, wherein R4 is phenyl optionally substituted with from 1-4 independently selected R4’.
174. The compound of any one of claims 117-173, wherein R4 is phenyl optionally substituted with from 1-2 independently selected R4’.
175. The compound of claim 174, wherein R4 is unsubstituted phenyl.
176. The compound of claim 174, wherein R4 is phenyl substituted with from 1- 2 independently selected R4’.
177. The compound of claim 176, wherein R4 is phenyl substituted with from 1- 2 independently selected R4’, wherein one occurrence of R4’ is para to the point of attachment to L3, such
Figure imgf000244_0001
178. The compound of any one of claims 117-171, wherein R4 is heteroaryl including from 5-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-
2, and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with from 1-4 independently selected R4’.
179. The compound of any one of claims 117-171 and 178, wherein R4 is heteroaryl including from 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with from 1-4 independently selected R4’. 180. The compound of claim 179, wherein R4 is heteroaryl including 6 ring atoms, wherein from 1-3 ring atoms are ring nitrogen atoms, and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with from 1- 4 independently selected R4’, such as pyridyl which is optionally substituted with from 1-2 independently selected R4’.
181. The compound of any one of claims 117-171, wherein R4 is C3-8 cycloalkyl, which is optionally substituted with from 1-4 independently selected R4’. 182. The compound of any one of claims 117-171, wherein R4 is C4-6 cycloalkyl, which is optionally substituted with from 1-4 independently selected R4’.
183. The compound of claim 182, wherein R4 is unsubstituted C4-6 cycloalkyl, such as unsubstituted cyclohexyl and unsubstituted cyclopentyl.
184. The compound of claim 182, wherein R4 is C4-6 cycloalkyl, which is substituted with from 1-3 (e.g., from 2-3) independently selected R4’, such as h < 185. The compound of any one of claims 117-171, wherein R4 is heterocyclyl including from 4-7 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o- 2, and wherein one or more ring carbon atoms of the heterocyclyl is optionally substituted with from 1-4 independently selected R4’.
186. The compound of any one of claims 117-185, wherein each R4’ is independently selected from the group consisting of: halo; -CN; -Ci-4 alkyl optionally substituted with from 1-2 independently selected Ra; -Ci-4 haloalkyl; - Ci-6 alkoxy optionally substituted with from 1-2 independently selected Ra; -Ci-6 haloalkoxy; S(0)i-2(Ci-4 alkyl); -S(0)I-2(NR’R”); -CM thioalkoxy; -C(=0)(CM alkyl); -C(=0)0(CM alkyl); and -C(=0)N(R’)(R”)·
187. The compound of any one of claims 117-186, wherein each R4’ is independently selected from the group consisting of: halo; -CN; -CM alkyl optionally substituted with one independently selected Ra; and -CM haloalkyl.
188. The compound of claim 187, wherein each R4’ is independently selected from the group consisting of: halo (such as -F), -CN, -CM alkyl, and -CM haloalkyl.
189. The compound of any one of claims 117-171, wherein L3 is a bond or CFh;
R4 is phenyl optionally substituted with from 1-2 independently selected R4’; and R4’ is independently selected from the group consisting of: halo; -CN; -Ci-4 alkyl optionally substituted with from 1-2 independently selected Ra; -Ci-4 haloalkyl; - Ci-6 alkoxy optionally substituted with from 1-2 independently selected Ra; -Ci-6 haloalkoxy; S(0)i-2(Ci-4 alkyl); -S(0)I-2(NR’R”); -CM thioalkoxy; -C(=0)(CM alkyl); -C(=0)0(CM alkyl); and -C(=0)N(R’)(R”)·
190. The compound of claim 189, wherein R4 is
Figure imgf000246_0001
which is optionally substituted with an additional R4.
191. The compound of claim 190, wherein each R4’ is independently selected from the group consisting of: halo (such as -F), -CN, -CM alkyl, and -CM haloalkyl.
192. The compound of any one of claims 190-191, wherein the para- placed R4’ is -CPs.
193. The compound of any one of claims 117-192, wherein each occurrence of Rc is independently selected from the group consisting of: halo; cyano; Ci-6 alkyl which is optionally substituted with from 1-6 independently selected Ra; CM alkoxy optionally substituted with CM alkoxy; CM haloalkoxy; S(0)I-2(CM alkyl); -S(0)I-2(NR’R”); -Ci-4 thioalkoxy optionally substituted with from 1-4 halo;- C(=0)(Ci-4 alkyl); -C(=0)0(Ci-4 alkyl); and -C(=0)N(R’)(R”)
194. The compound of claim 193, wherein each occurrence of Rc is independently selected from the group consisting of halo; cyano; C1-3 alkyl which is optionally substituted with from 1-3 independently selected Ra (such as methyl or CF3); Ci-4 alkoxy optionally substituted with Ci-4 alkoxy; and Ci-4 haloalkoxy.
195. The compound of claim 194, wherein one occurrence of Rc is C1-3 alkyl which is optionally substituted with from 1-3 independently selected Ra (such as methyl or CF3).
196. The compound of claim 117, wherein the compound has Formula II- 1:
Figure imgf000247_0001
II-l
ml is 0 or 1; m3 is 0, 1, or 2, provided that ml+m3>0; and
B is a monocyclic heteroaryl including 5 ring atoms, wherein from 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc.
197. The compound of claim 196, wherein m3 is 1 or 2.
198. The compound of claim 197, wherein m3 is 2.
199. The compound of any one of claims 196-198, wherein ml is 0.
200. The compound of any one of claims 196-199, wherein the compound has Formula Il-la:
Figure imgf000248_0001
la.
201. The compound of any one of claims 196-200, wherein each R3 is independently selected from the group consisting of halo and cyano. 202. The compound of claim 201, wherein each R3 is halo, such as -F.
203. The compound of any one of claims 196-202, wherein R2N is H.
204. The compound of any one of claims 196-202, wherein R2N is (iv) -C(0)(Ci- 4 alkyl) (e.g., -C(O)Me) or (viii) - S(0)i-2(Ci-4 alkyl) (e.g., S(0)2Me).
205. The compound of any one of claims 196-204, wherein B is a monocyclic heteroaryl including 5 ring atoms, wherein from 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl ring is optionally substituted with from 1-2 independently selected Rc, wherein the point of attachment to the C(=0)NH group of Formula II-l is me la to the point of attachment to L3.
206. The compound of any one of claims 196-205, wherein B is selected from the group consisting of imidazolyl and triazolyl, each of which is optionally substituted with one Rc.
207. The compound of claim 206, wherein B is selected from the group
,
Figure imgf000249_0001
, , and
Figure imgf000249_0002
, which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
208. The compound of any one of claims 196-205, wherein B is pyrazolyl optionally substituted with one Rc.
209. The comppound off claim 208,, wherein
Figure imgf000249_0003
each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
210. The compound of any one of claims 196-205, wherein B is selected from the group consisting of oxazolyl, thiazolyl, oxadiazolyl, and thiadiazolyl, wherein the oxazolyl and thiazolyl are optionally substituted with one Rc.
211. The compound of claim 210, wherein B is selected from the group
consisting of:
Figure imgf000249_0004
each of which is optionally substituted with one Rc, wherein aa denotes point of attachment to L3.
212. The compound of any one of claims 205-211, wherein each Rc when present is independently selected from the group consisting of halo; cyano; C1-3 alkyl which is optionally substituted with from 1-3 independently selected Ra (such as methyl or CF3); Ci-4 alkoxy optionally substituted with Ci-4 alkoxy; and Ci-4 haloalkoxy.
213. The compound of any one of claims 205-211, wherein one occurrence of Rc is Ci-3 alkyl which is optionally substituted with from 1-3 independently selected Ra (such as methyl or CF3).
214. The compound of any one of claims 205-211, wherein B is not substituted with Rc.
215. The compound of any one of claims 200-215, wherein L3 is a bond.
216. The compound of any one of claims 200-215, wherein L3 is CFh.
217. The compound of any one of claims 200-216, wherein R4 is selected from the group consisting of:
C4-6 cycloalkyl, which is optionally substituted with from 1-4 independently selected R4’;
heteroaryl including 6 ring atoms, wherein from 1-3 ring atoms are ring nitrogen atoms, and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with from 1-4 independently selected R4’, such as pyridyl which is optionally substituted with from 1-2 independently selected R4’;
heterocyclyl including from 4-7 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heterocyclyl is optionally substituted with from 1-4 independently selected R4’; and phenyl optionally substituted with from 1-2 independently selected R4’.
218. The compound of claim 217, wherein R4 is phenyl optionally substituted with from 1-2 independently selected R4’.
219. The compound of claim 218, wherein R4 is
Figure imgf000251_0001
which is optionally substituted with an additional R4’.
220. The compound of claim 219, wherein each R4’ is independently selected from the group consisting of: halo (such as -F), -CN, -Ci-4 alkyl, and -Ci-4 haloalkyl.
221 The compound of any one of claims 219-220, wherein the para- placed R4’ is -CPs.
222 The compound of claim 219, wherein R4 is
Figure imgf000251_0002
which is optionally substituted with an additional R4.
223. The compound of claim 222, wherein R4 is
Figure imgf000251_0003
224. A pharmaceutical composition comprising a compound of Formula I as claimed in any one of claims 1-116 or a compound of Formula II as claimed in any one of claims 117-223, and one or more pharmaceutically acceptable excipients.
225. A method for inhibiting STING activity, the method comprising contacting STING with a compound of Formula II as claimed in any one of claims 117-223.
226. The method of any one of claims 1-116 and 225, wherein the inhibiting comprises antagonizing STING.
227. The method of any one of claims 1-116 and 225-226, which is carried out in vitro.
228. The method of claim 227, wherein the method comprises contacting a sample comprising one or more cells comprising STING with the compound.
229. The method of claim 228, wherein the one or more cells are one or more cancer cells.
230. The method of claim 228 or 229 wherein the sample further comprises one or more cancer cells (e.g., 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).
231. The method of any one of claims 1-116 and 225, which is carried out in vivo.
232. The method of claim 231, wherein the method comprises administering the compound to a subject having a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease.
233. The method of claim 232, wherein the subject is a human.
234. The method of claim 232, wherein the disease is cancer.
235. The method of claim 234, 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.
236. The method of claim 234 or 235, wherein the cancer is a refractory cancer.
237. The method of claim 236, wherein the compound is administered in combination with one or more additional cancer therapies.
238. The method of claim 237, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof. 239. The method of claim 238, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.
240. The method of claim 239, wherein the one or more additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g.,azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan;. amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Murom onab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti- angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1 - PD-L1, PD-
1 - PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-b (TGFP), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9 - TIM3, Phosphatidylserine - TIM3, lymphocyte activation gene 3 protein
(LAG3), MHC class II - LAG3, 4-1BB-4-1BB ligand, 0X40-0X40 ligand, GITR, GITR ligand - GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40- CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM - BTLA, HVEM - CD 160, HVEM - LIGHT, HVEM-BTL A-CD 160, CD80, CD80 - PDL-1, PDL2 - CD80, CD244, CD48 - CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2,
HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86 - CD28, CD86 - CTLA, CD80 - CD28, CD39, CD73 Adenosine-CD39- CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine - TIM3, SIRPA-CD47, VEGF, Neuropilin, CD 160, CD30, and CD 155 (e.g., CTLA-4 or PD1 or PD-L1).
241. The method of any one of claims 232-240, wherein the compound is administered intratum orally.
242. A method of treating cancer, comprising administering to a subject in need of such treatment an effective amount of a compound of Formula I as claimed in any one of claims 1-116 or a compound of Formula II as claimed in any one of claims 117-223, or a pharmaceutical composition as claimed in claim 224.
243. The method of claim 242, 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.
244. The method of claim 242 or 243, wherein the cancer is a refractory cancer. 245. The method of claim 242, wherein the compound is administered in combination with one or more additional cancer therapies.
246. The method of claim 245, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.
247. The method of claim 246, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.
248. The method of claim 247, wherein the one or more additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g.,azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan;. amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Murom onab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti- angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1 - PD-L1, PD-
1 - PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-b (TGFP), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9 - TIM3, Phosphatidylserine - TIM3, lymphocyte activation gene 3 protein
(LAG3), MHC class II - LAG3, 4-1BB-4-1BB ligand, 0X40-0X40 ligand, GITR, GITR ligand - GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40- CD40 ligand, HVEM-LIGHT -LT A, HVEM, HVEM - BTLA, HVEM - CD 160, HVEM
- LIGHT, HVEM-BTL A-CD 160, CD80, CD80 - PDL-1, PDL2 - CD80, CD244, CD48
- CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86 - CD28, CD86 - CTLA, CD80 - CD28, CD39, CD73 Adenosine-CD39- CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine - TIM3, SIRPA-CD47, VEGF, Neuropilin, CD 160, CD30, and CD 155 (e.g., CTLA-4 or PD1 or PD-L1).
249. The method of any one of claims 242-248, wherein the compound is administered intratum orally.
250. A method of inducing an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula I as claimed in any one of claims 1-116 or a compound of Formula II as claimed in any one of claims 117-223, or a pharmaceutical composition as claimed in claim 224.
251. The method of claim 250, wherein the subject has cancer.
252. The method of claim 251, wherein the subject has undergone and/or is undergoing and/or will undergo one or more cancer therapies.
253. The method of claim 251, wherein the cancer selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma .
254. The method of claim 253, wherein the cancer is a refractory cancer.
255. The method of claim 250, wherein the immune response is an innate immune response. 256. The method of claim 255, wherein the at least one or more cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.
257. The method of claim 256, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.
258. The method of claim 257, wherein the one or more additional chemotherapeutic agents is selected from alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g.,azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan;. amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Murom onab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti- angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti- helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1 - PD-L1, PD- 1 - PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-b (TGFP), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9 - TIM3, Phosphatidylserine - TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II - LAG3, 4- 1BB-4- IBB ligand, 0X40-0X40 ligand, GITR, GITR ligand - GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40- CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM - BTLA, HVEM - CD 160, HVEM
- LIGHT, HVEM-BTL A-CD 160, CD80, CD80 - PDL-1, PDL2 - CD80, CD244, CD48
- CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86 - CD28, CD86 - CTLA, CD80 - CD28, CD39, CD73 Adenosine-CD39- CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine - TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PDl or PD-L1).
259. 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 of Formula I as claimed in any one of claims 1-116 or a compound of Formula II as claimed in any one of claims 117-223, or a pharmaceutical composition as claimed in claim 224.
260. 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 of Formula I as claimed in any one of claims 1-116 or a compound of Formula II as claimed in any one of claims 117-223, or a pharmaceutical composition as claimed in claim 224.
261. A method of treatment comprising administering to a subject a compound of Formula I as claimed in any one of claims 1-116 or a compound of Formula II as claimed in any one of claims 117-223, or a pharmaceutical composition as claimed in claim 224, 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.
262. The method of any one of claims 259-261, wherein the disease is cancer.
263. The method of claim 262, 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.
264. The method of claim 262 or 263, wherein the cancer is a refractory cancer.
265. The method of any one of claims 262-264, wherein the compound is administered in combination with one or more additional cancer therapies.
266. The method of claim 265, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.
267. The method of claim 266, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.
268. The method of claim 267, wherein the one or more additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g.,azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan;. amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracy clines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Murom onab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti- angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti- helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1 - PD-L1, PD-
1 - PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-b (TGFP), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9 - TIM3, Phosphatidylserine - TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II - LAG3, 4- 1BB-4- IBB ligand, 0X40-0X40 ligand, GITR, GITR ligand - GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40- CD40 ligand, HVEM-LIGHT -LT A, HVEM, HVEM - BTLA, HVEM - CD 160, HVEM
- LIGHT, HVEM-BTL A-CD 160, CD80, CD80 - PDL-1, PDL2 - CD80, CD244, CD48
- CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86 - CD28, CD86 - CTLA, CD80 - CD28, CD39, CD73 Adenosine-CD39- CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine - TIM3, SIRPA-CD47, VEGF, Neuropilin, CD 160, CD30, and CD 155 (e.g., CTLA-4 or PD1 or PD-L1).
269. The method of any one of claims 259-268, wherein the compound is administered intratum orally.
270. A method of treatment of a disease, disorder, or condition associated with STING, comprising administering to a subject in need of such treatment an effective amount of a compound of Formula I as claimed in any one of claims 1-116 or a compound of Formula II as claimed in any one of claims 117-223, or a pharmaceutical composition as claimed in claim 224.
271. The method of claim 270, wherein the disease, disorder, or condition is selected from type I interferonopathies, Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, inflammation-associated disorders, and rheumatoid arthritis.
272. The method of claim 271, wherein the disease, disorder, or condition is a type I interferonopathy (e.g., STING-associated vasculopathywith onset in infancy (SAVI)). 273. The method of claim 272, wherein the type I interferonopathy is STING- associated vasculopathy with onset in infancy (SAVI)).
274. The method of claim 271, wherein the disease, disorder, or condition is Aicardi-Goutieres Syndrome (AGS).
275. The method of claim 271, wherein the disease, disorder, or condition is a genetic form of lupus.
276. The method of claim 271, wherein the disease, disorder, or condition is inflammation-associated disorder.
277. The method of claim 276, wherein the inflammation-associated disorder is systemic lupus erythematosus. 278. The method of any one of claims 225-277, wherein the method further comprises identifying the subject.
279. A compound selected from the compounds in Table Cl, or a pharmaceutically acceptable salt thereof.
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