Compounds and compositions for treating diseases associated with sting activity

Abstract

The present invention provides chemical entities (e.g., compounds or pharmaceutically acceptable salts and / or hydrates and / or co-crystals and / or drug combinations of compounds) that inhibit (e.g., antagonize) stimulator of interferon genes (STING). The chemical entities can be used, for example, to treat a condition, disease, or disorder (e.g., cancer) in which activation of STING (e.g., STING signaling) is increased (e.g., over) resulting in a pathologic condition and / or symptoms and / or progression of a condition, disease, or disorder in a subject (e.g., a human). The present invention also provides compositions comprising the chemical entities and methods of using and making the compositions.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 955,839, filed December 31, 2019; and U.S. Provisional Application No. 63 / 090,538, filed October 12, 2020; each of which is incorporated herein by reference in its entirety. Technical Field

[0003] This invention provides chemical entities (e.g., compounds or pharmaceutically acceptable salts, and / or hydrates, and / or cocrystals, and / or prodrugs, and / or tautomers, and / or combinations of compounds) that inhibit (e.g., antagonize) interferon gene stimulators (STING). These chemical entities can be used, for example, to treat, pathological / or symptom and / or progression of a condition, disease, or symptom (e.g., cancer) in a subject (e.g., a human) where increased (e.g., excessive) STING activation (e.g., STING signaling) leads to the condition, disease, or symptom (e.g., cancer). The invention also provides compositions comprising the chemical entity and methods for using and preparing the compositions. Background Technology

[0004] STING, also known as transmembrane protein 173 (TMEM173) and MPYS / MITA / ERIS, is a protein encoded by the TMEM173 gene in the human body. STING has been shown to play a role in innate immunity. When cells are infected with intracellular pathogens such as viruses, mycobacteria, and intracellular parasites, STING induces the production of type I interferon. STING-mediated type I interferon protects infected cells and nearby cells from local infection in both autocrine and paracrine modes.

[0005] The STING pathway is critical in mediating the recognition of cytosolic DNA. In this context, STING is a transmembrane protein localized to the endoplasmic reticulum (ER) that acts as a second messenger receptor for 2',3' cyclic GMP-AMP (hereafter cGAMP), produced by cGAS upon binding of dsDNA. In addition, STING can also serve as a primary pattern recognition receptor for bacterial cyclic dinucleotides (CDNs) and small molecule agonists. Recognition of endogenous or prokaryotic CDNs occurs through the carboxy-terminal domain of STING, which faces the cytosol and creates a V-shaped binding pocket formed by STING homodimers. Ligand-induced activation of STING triggers its relocalization to the Golgi, a process that is essential to promote the interaction of STING with TBK1. In turn, this protein complex signals through the transcription factor IRF-3, inducing type I interferons (IFNs) and other co-regulated antiviral factors. In addition, it was shown that STING triggers NF-KB and MAP kinase activation. After the initiation of signal transduction, STING is rapidly degraded, which is important in terminating the inflammatory response.

[0006] Hyperactivation of STING has been linked to a subset of monogenic autoinflammatory disorders, the so-called type I interferonopathies. Examples of these diseases include the clinical syndrome known as STING-associated vasculopathy with onset in infancy (SAVI), which is caused by gain-of-function mutations in TMEM173, the gene name for STING. In addition, STING is involved in the pathogenesis of Aicardi-Goutieres Syndrome (AGS) and genetic forms of lupus. Unlike SAVI, continuous innate immune activation in AGS is based on nucleic acid metabolism dysregulation. In addition to these genetic diseases, emerging evidence suggests that STING has a more general pathogenic role in a range of inflammation-related diseases such as systemic lupus erythematosus, rheumatoid arthritis and cancer. Therefore, small-molecule based pharmacological intervention of the STING signaling pathway has a great potential in treating a variety of diseases. SUMMARY

[0007] The present invention provides chemical entities (e.g., compounds or pharmaceutically acceptable salts, and / or hydrates, and / or co-crystals, and / or and / or prodrugs, and / or tautomers, and / or pharmaceutical combinations of compounds) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). The chemical entities can be used, for example, to treat a condition, disease or disorder (e.g., cancer) in which activation of STING (e.g., STING signaling) is increased (e.g., hyperactivated) leading to a pathological condition and / or symptoms and / or progression of a condition, disease or disorder in a subject (e.g., a human). The present invention also provides compositions comprising the chemical entities and methods of using and making the compositions.

[0008] An "antagonist" of STING includes a compound that directly binds to or modifies STING at the protein level such that the activity of STING is reduced, e.g., by inhibiting, blocking, or attenuating an agonist-mediated response, altering distribution, or otherwise. STING antagonists include chemical entities that interfere with or inhibit STING signaling.

[0009] In one aspect, the disclosure features a compound of Formula I, or a pharmaceutically acceptable salt thereof:

[0010]

[0011] wherein R 1a , R 1b , R 1c , R 1d , X 1 , X 2 , R 6 , W, Q, P 1 , P 2 , P 3 , P 4 , and P 5 may be as defined anywhere herein.

[0012] In an aspect, provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a tautomer thereof, or any combination of the foregoing. A "prodrug" refers to a compound that can be converted, under physiological conditions or by solvolysis, to a biologically active compound described herein (e.g., a compound of Formula (I)). Thus, the term "prodrug" refers to a precursor of a pharmaceutically acceptable biologically active compound. In some aspects, a prodrug is inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. Prodrug compounds often offer advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985) at pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is

[0013] In an aspect, the present application provides a pharmaceutical composition comprising a chemical entity described herein (e.g., a compound generally or specifically described herein or a pharmaceutically acceptable salt thereof or a composition comprising the compound) and one or more pharmaceutically acceptable excipients.

[0014] In an aspect, the present application provides a method of inhibiting (e.g., antagonizing) STING activity comprising contacting STING with a chemical entity described herein (e.g., a compound generally or specifically described herein or a pharmaceutically acceptable salt thereof or a composition comprising the compound). Methods include in vitro methods, e.g., contacting a sample comprising 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 STING signaling is increased (e.g., overabundant) leading to pathology and / or symptoms and / or progression of the disease.

[0015] In one aspect, the application provides a method of treating a condition, disease, or disorder that is ameliorated by antagonizing STING, wherein an increase (e.g., excess) in STING activation (e.g., STING signaling) contributes to and / or progression of the condition, disease, or disorder in a subject (e.g., a human). The method includes administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound generally or specifically described herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same).

[0016] In another aspect, the application provides a method of treating cancer, including administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound generally or specifically described herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same).

[0017] In another aspect, the application provides a method of treating other STING-associated diseases, e.g., Type I interferonopathy (e.g., STING-associated vasculopathy with onset in infancy (SAVI)), Aicardi-Goutieres Syndrome (AGS), a genetic form of lupus, and inflammation-associated diseases, e.g., systemic lupus erythematosus and rheumatoid arthritis. The method includes administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound generally or specifically described herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same).

[0018] In another aspect, the application provides a method of inhibiting STING-dependent Type I interferon production in a subject in need thereof, including administering to the subject an effective amount of a chemical entity described herein (e.g., a compound generally or specifically described herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same).

[0019] In another aspect, the application provides a method of treating a disease wherein an increase (e.g., excess) in STING activation (e.g., STING signaling) contributes to and / or progression of the disease. The method includes administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound generally or specifically described herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same).

[0020] In another aspect, the application provides a method of treatment, including administering to a subject an effective amount of a chemical entity described herein (e.g., a compound generally or specifically described herein or a pharmaceutically acceptable salt thereof or a composition comprising the same); wherein the subject has (or is predisposed to having) a disease wherein an increase (e.g., excess) in STING activation (e.g., STING signaling) contributes to and / or progression of the disease.

[0021] In another aspect, the application provides methods of treatment comprising administering to a subject a chemical entity described herein (e.g., a compound generally or specifically described herein or a pharmaceutically acceptable salt thereof or a composition comprising the same), wherein the chemical entity is administered in an amount effective to treat a disease in which increased (e.g., excessive) activation of STING (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the disease, thereby treating the disease.

[0022] In another aspect, a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, is used to treat a disease, condition, or disorder modulated by STING inhibition.

[0023] In another aspect, a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, is used to treat a condition, disease, or disorder associated with increased (e.g., excessive) activation of STING.

[0024] In another aspect, a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, is used to treat a cancer.

[0025] In another aspect, a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, is used to treat a cancer selected from melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms’ tumor, or hepatocellular carcinoma.

[0026] In another aspect, a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, is used to treat a Type I interferonopathy.

[0027] In another aspect, a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, is used to treat a Type I interferonopathy selected from STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières Syndrome (AGS), a genetic form of lupus, and inflammation-related diseases such as systemic lupus erythematosus and rheumatoid arthritis.

[0028] In another aspect, a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, is used to treat a condition, disease, or disorder associated with increased (e.g., excessive) activation of STING.

[0029] On the other hand, the use of the compounds described herein, or their pharmaceutically acceptable salts or tautomers, in the preparation of medicaments for the treatment of cancer.

[0030] On the other hand, the use of the compounds described herein, or their pharmaceutically acceptable salts or tautomers, in the preparation of a medicament for the treatment of cancers selected from: 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 tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms' tumor, or hepatocellular carcinoma.

[0031] On the other hand, the use of the compounds described herein, or their pharmaceutically acceptable salts or tautomers, in the preparation of medicaments for the treatment of type I interferon disease.

[0032] On the other hand, the use of the compounds described herein, or pharmaceutically acceptable salts or tautomers thereof, in the preparation of medicaments for the treatment of type I interferon diseases selected from: infantile-onset STING-associated vascular disease (SAVI), Aicardi-Goutières Syndrome (AGS), hereditary forms of lupus, and inflammatory-related diseases such as systemic lupus erythematosus and rheumatoid arthritis.

[0033] On the other hand, the use of the compounds described herein, or their pharmaceutically acceptable salts or tautomers, in the treatment of diseases, symptoms, or conditions regulated by STING inhibition.

[0034] On the other hand, the use of the compounds described herein, or their pharmaceutically acceptable salts or tautomers, in the treatment of symptoms, diseases, or conditions associated with increased (e.g., excessive) STING activation.

[0035] On the other hand, the use of the compounds described herein, or their pharmaceutically acceptable salts or tautomers, in the treatment of cancer.

[0036] On the other hand, the use of the compounds described herein, or their pharmaceutically acceptable salts or tautomers, in the treatment of cancers selected from: 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 tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms' tumor, or hepatocellular carcinoma.

[0037] In another aspect, use of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, in the treatment of a type I interferonopathy is described.

[0038] In another aspect, use of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, in the treatment of a type I interferonopathy selected from infantile-onset STING-associated vasculopathy (SAVI), Aicardi-Goutieres Syndrome (AGS), a genetic form of lupus, and an inflammation-related disease, such as systemic lupus erythematosus and rheumatoid arthritis, is described.

[0039] Implementations can include one or more of the following features.

[0040] The chemical entity can be administered in combination with one or more other therapeutic agents and / or regimens. For example, the method can further include administering one or more (e.g., two, three, four, five, six or more) other agents.

[0041] The chemical entity can be administered in combination with one or more other therapeutic agents and / or regimens useful in treating other diseases associated with STING, such as a type I interferonopathy (e.g., infantile-onset STING-associated vasculopathy (SAVI), Aicardi-Goutieres Syndrome (AGS), a genetic form of lupus, and an inflammation-related disease, such as systemic lupus erythematosus and rheumatoid arthritis.

[0042] 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); for example, chemotherapy comprising administration of one or more (e.g., two, three, four, five, six or more) other chemotherapeutic agents. Non-limiting examples of other chemotherapeutic agents are selected from the group consisting of: alkylating agents (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, and / or oxaliplatin); antimetabolites (e.g., thioguanine and / or mercaptopurine); terpenoids (e.g., vinca alkaloids and / or taxoids; e.g., vincristine, vinblastine, vinorelbine, and / or vindesine, taxol, paclitaxel, and / or docetaxel); topoisomerases (e.g., type I topoisomerase and / or type 2 topoisomerase; e.g., camptothecin, e.g., irinotecan and / or topotecan; amsacrine, etoposide, etoposide phosphate, and / or teniposide); cytotoxic antibiotics (e.g., dactinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin, and / or mitomycin); hormones (e.g., luteinizing hormone-releasing hormone agonists; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide, and / or nilutamide);antibodies (e.g., Ablciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Brentuximab Vedotin, Canakinumab, Cetuximab, Certolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumumab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab, and / or Trastuzumab); anti-angiogenic agents; cytokines; thrombogenic agents; growth inhibitory agents; antihelmintic agents;and an immune checkpoint inhibitor targeting 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-beta (TGF ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 adenosine-CD39-CD73, CXCR4-CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

[0043] The subject can have cancer; for example, the subject has undergone and / or is undergoing and / or will undergo one or more cancer treatments.

[0044] Non-limiting examples of cancers include melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms' tumor, or hepatocellular carcinoma. In some embodiments, the cancer can be a refractory cancer.

[0045] The chemical entity can be administered intratumorally.

[0046] The method can further include identifying the object.

[0047] Other implementations include those described in the detailed description and / or claims.

[0048] Further definitions

[0049] To facilitate understanding of the disclosure set forth herein, a number of other 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 used in the art. Unless defined otherwise, all technical and scientific terms used herein 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, and appended

[0050] As used herein, the term "STING" is intended to include, but is not limited to, 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.

[0051] As used herein, the term "acceptable" with respect to a formulation, composition or ingredient means having no persistent detrimental effects on the general health of the subject being treated.

[0052] "API" refers to active pharmaceutical ingredient.

[0053] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of a chemical entity which is sufficient to alleviate, to some extent, a symptom or symptoms of the disease or condition being treated. Results include reduction and / or alleviation of 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 a compound disclosed herein comprising sufficient quantity of a compound to provide clinically significant relief from symptoms of the disease. In any event, the appropriate "effective" amount can be ascertained by any appropriate techniques, such as a dose escalation study.

[0054] The term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulation 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, immunogenecity, or other problems or complications commensurate with a reasonable benefit / risk ratio. For example, see Remington: The Science and Practice of Pharmacy, 21stEdition; LWW Publishing Company (Lippincott Williams & Wilkins): Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6thEdition; Rowe et al., eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rdEdition; Ash and Ash, eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2ndEdition, Gibson, ed., CRC Press LLC: Boca Raton, FL, 2009).

[0055] The term "pharmaceutically acceptable salt" refers to a preparation of a compound that does not cause significant irritation to the biological subject to which it is administered and does not abrogate the biological activity and properties of the compound. In some cases, a pharmaceutically acceptable salt is obtained by reacting a compound described herein with an acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some cases, a salt is formed by reacting a compound described herein that has an acidic group with a base, for example, ammonium salt, alkali metal salts, for example, sodium or potassium salts, alkaline earth metal salts, for example, calcium or magnesium salts, salts of organic bases, for example, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids, for example, arginine, lysine and the like, or by other previously determined methods. There is no particular limitation on the pharmaceutically acceptable salt as long as it can be used for a drug. Examples of the salt of the compound described herein with a base include the following: salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salts with organic bases such as methylamine, ethylamine and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salt can be an acid addition salt, which is specifically exemplified by an addition salt with an acid: inorganic acids, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids, for example, 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, for example, aspartic acid and glutamic acid.

[0056] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components, which are pharmaceutically acceptable, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickeners. 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, ocular, pulmonary, and topical administration.

[0057] The term "subject" can refer to an animal, including, but not limited to, primates (e.g., humans), monkeys, cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably herein, for example, to refer to a mammalian subject, for example, a human subject.

[0058] In the context of treating a disease, disorder, or condition, the terms "treatment," "treat," and "therapy" are intended to include alleviating or abrogating a disease, disorder, or condition or one or more symptoms associated with the disease, disorder, or condition; or to exasperate, slow or stop the progression of a disease, disorder, or condition or one or more symptoms associated with the disease, disorder, or condition. "Cancer treatment" refers to one or more of the following effects: (1) inhibition of tumor growth to some extent, including (i) reduction and (ii) complete halt of growth; (2) reduction in the number of tumor cells; (3) maintenance of 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 cancer metastasis; (7) enhancement of anti-tumor immune response which can (i) maintain tumor size, (ii) reduce tumor size, (iii) slow down tumor growth, (iv) reduce, slow down, or prevent invasion, and / or (8) reduction in severity or number of one or more symptoms associated with the disorder to some extent.

[0059] The term "halogen" refers to fluorine (F), chlorine (CI), bromine (Br), or iodine (I).

[0060] The term "alkyl" refers to an acyclic saturated hydrocarbon chain that can be straight- chained or branched, which contains the indicated number of carbon atoms. For example, C 1-10 indicates that the group can have 1 to 10 (and inclusive) carbon atoms. The alkyl group can be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, t-butyl, n-hexyl. The term "saturated" used herein means that only single bonds exist between the constituent carbon atoms and other available valences are occupied by hydrogen and / or other substituents as defined herein.

[0061] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by an independently selected halogen.

[0062] The term "alkoxy" refers to -O-alkyl (e.g., -OCH3).

[0063] The term "alkylene" refers to a divalent alkyl group (e.g., -CH2-).

[0064] The term "alkenyl" refers to an acyclic straight-chain or branched-chain hydrocarbon that can have one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C 2-6 indicates that the group can have 2 to 6 (and inclusive) carbon atoms. The alkenyl group can be unsubstituted or substituted with one or more substituents.

[0065] The term "alkynyl" refers to an acyclic straight-chain or branched-chain hydrocarbon that can have one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C2-6 represents that the group can have 2 to 6 (inclusive) carbon atoms. Alkynyl groups can be unsubstituted or substituted with one or more substituents.

[0066] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group of 6-20 carbons in which at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and in which 0, 1, 2, 3, or 4 atoms of each ring can be substituted with a substituent. Examples of aryl groups also include phenyl, naphthyl, tetrahydronaphthyl, dihydro-lH-indenyl, and the like.

[0067] The term "cycloalkyl" as used herein refers to a cyclic saturated hydrocarbon group having, for example, 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 can be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups can include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl groups include: bicyclo[l.l.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[l.l.l]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, and the like. Cycloalkyl also includes spirocyclic (e.g., spirocyclic bicyclic, where two rings are connected by only one atom). Non-limiting examples of spirocyclic cycloalkyl groups include: spiro[2.2]pentyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[2.6]nonyl, spiro[4.5]decyl, spiro[3.6]decyl, spiro[5.5]undecyl, and the like. The term "saturated" as used herein means that only single bonds exist between constituent carbon atoms.

[0068] The term "cycloalkenyl" as used herein refers to a partially unsaturated cyclic hydrocarbon group 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 can be optionally substituted. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As a partially unsaturated cyclic hydrocarbon group, cycloalkenyl groups can have any degree of unsaturation, provided that one or more double bonds are present in the ring, none of the rings in the ring system are aromatic, and the cycloalkenyl group is not fully saturated overall. Cycloalkenyl groups can include multiple fused and / or bridged and / or spirocyclic rings.

[0069] As used herein, the term "heteroaryl" refers to a mono, bi, tri or polycyclic radical having 5 to 20 ring atoms, or 5, 6, 9, 10, or 14 ring atoms; and sharing 6, 10, or 14 π electrons in the cyclic array; wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms independently selected from N, O, and S (but not necessarily a ring containing a heteroatom, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). The heteroaryl radical can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include: thienyl, pyridyl, furanyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, benzothiophenyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromenyl, 2,3-dihydrobenzo[b][l,4]dioxinyl, benzo[d][l,3]dioxolyl, benzo[d]thiazolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][l,4]oxathiinyl, isoindolyl, and the like. In some embodiments, the heteroaryl is selected from: thienyl, pyridyl, furanyl, pyrazolyl, imidazolyl, isoindolyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0070] The term "heterocyclyl" refers to a 3-16 membered ring (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic monocyclic, bicyclic, tricyclic or polycyclic saturated ring system) having 1-3 heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic) or 1-9 heteroatoms (if tricyclic or polycyclic), the heteroatoms selected from O, N or S (e.g., if monocyclic, bicyclic or tricyclic, respectively, having carbon atoms and 1-3, 1-6 or 1-9 heteroatoms selected from N, O or S), wherein 0, 1, 2 or 3 atoms of each ring can be substituted with a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl and the like. Heterocyclyl groups can include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged heterocyclyl groups include: 2-azabicyclo[l. l.0]butyl, 2-azabicyclo[2. l.0]pentyl, 2-azabicyclo[l. l. l]pentyl, 3-azabicyclo[3. l.0]hexyl, 5-azabicyclo[2. l. l]hexyl, 3-azabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrolyl, 3-azabicyclo[4. l.0]heptyl, 7-azabicyclo[2.2. l]heptyl, 6-azabicyclo[3. l. l]heptyl, 7-azabicyclo[4.2.0]octyl, 2-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2. l]octyl, 2-oxabicyclo[l. l.0]butyl, 2-oxabicyclo[2. l.0]pentyl, 2-oxabicyclo[l. l. l]pentyl, 3-oxabicyclo[3. l.0]hexyl, 5-oxabicyclo[2. l. l]hexyl, 3-oxabicyclo[3.2.0]heptyl, 3-oxabicyclo[4. l.0]heptyl, 7-oxabicyclo[2.2. l]heptyl, 6-oxabicyclo[3. l. l]heptyl, 7-oxabicyclo[4.2.0]octyl, 2-oxabicyclo[2.2.2]octyl, 3-oxabicyclo[3.2. l]octyl, and the like. Heterocyclyl groups also include spirocyclic (e.g., spirocyclic bicyclic rings in which two rings are connected by only one atom).Non-limiting examples of spirocyclic heterocyclyl groups include: 2-azaspiro[2.2]pentyl, 4-azaspiro[2.5]octyl, 1 -azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[4.4]nonanyl, 6-azaspiro[2.6]nonanyl, 1,7-diazaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl, 2,5-diazaspiro[3.6]decanyl, 3-azaspiro[5.5]undecanyl, 2-oxaspiro[2.2]pentyl, 4-oxaspiro[2.5]octyl, 1 -oxaspiro[3.5]nonanyl, 2-oxaspiro[3.5]nonanyl, 7-oxaspiro[3.5]nonanyl, 2-oxaspiro[4.4]nonanyl, 6-oxaspiro[2.6]nonanyl, 1,7-dioxaspiro[4.5]decanyl, 2,5-dioxaspiro[3.6]decanyl, 1 -oxaspiro[5.5]undecanyl, 3-oxaspiro[5.5]undecanyl, 3-oxa-9-azaspiro[5.5]undecanyl, and the like. The term "saturated" as used herein means that only single bonds exist between the constituent ring atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0071] The term "heteroaralkyl," as used herein, refers to an alkyl group substituted with a heteroaromatic group. The heteroaromatic group can be substituted with one or more substituents as described herein. Examples of heteroaralkyl groups include, but are not limited to, pyridinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, pyridinyloxy, pyrimidinyloxy, pyrazinyloxy, and the like.

[0072] As used herein, when a ring is described as "aromatic," it is meant to indicate that the ring has a continuous, delocalized π-electron system. Typically, the number of π-electrons corresponds to the Hückel rule (4n+2). Examples of such rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridinone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like.

[0073] As used herein, when a ring is described as "partially unsaturated", it is meant that the ring has one or more additional degrees of unsaturation (in addition to that due to the ring itself; e.g., one or more double or triple bonds between members of the ring) with the proviso that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0074] For the avoidance of doubt, unless otherwise specified, rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like as described herein) containing a sufficient number of ring atoms to form a bicyclic or higher order ring system (e.g., tricyclic, polycyclic systems) are understood to include those having fused rings, including the following cases: (i) the site of fusion is on adjacent ring atoms (e.g., [x.x.0] ring systems, where 0 represents a zero atom bridge (e.g. (ii) the site of fusion is on a single ring atom (spiro-fused ring systems) (e.g. or (iii) the site of fusion is on a contiguous array of ring atoms (all bridge rings systems with bridge lengths > 0) (e.g.

[0075] Further, atoms comprising the compounds of the embodiments are intended to include all isotopes of such atoms. Isotopes as used herein include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 C.

[0076] Further, the compounds generally or specifically disclosed herein are intended to include all tautomeric forms. Thus, for example, compounds containing a moiety include tautomeric forms containing a moiety Similarly, pyridyl or pyrimidinyl moieties described as optionally substituted with hydroxyl include pyridinone or pyrimidinone tautomeric forms.

[0077] The details of one or more embodiments of the application are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the application will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION

[0079] The present invention provides chemical entities (e.g., compounds or pharmaceutically acceptable salts, and / or hydrates, and / or co-crystals, and / or and / or prodrugs, and / or tautomers, and / or pharmaceutical combinations of compounds) that inhibit (e.g., antagonize) stimulator of interferon genes (STING). The chemical entities can be used, for example, to treat a condition, disease, or disorder (e.g., cancer) in which activation of STING (e.g., STING signaling) is increased (e.g., over) leading to a pathologic and / or symptom and / or progression of a condition, disease, or disorder in a subject (e.g., a human). The present invention also provides compositions comprising the chemical entities and methods of using and making the compositions.

[0080] Compounds of formula I

[0081] In one aspect, the present invention provides a compound of Formula (I):

[0082]

[0083] or a pharmaceutically acceptable salt or tautomer thereof, wherein:

[0084] X 1 is selected from: O, S, N, NR 2 and CR 1 ;

[0085] X 2 is selected from: O, S, N, NR 4 and CR 5 ;

[0086] each is independently a single or double bond, provided that:

[0087] the 5-membered ring comprising X 1 and X 2 is heteroaryl;

[0088] the 6-membered ring is aromatic; and

[0089] the ring comprising P 1 , P 2 , P 3 , P 4 and P 5 is aromatic;

[0090] P 1 , P 2 , P 3 , P 4 and P 5 are defined according to (AA) or (BB):

[0091] (AA)

[0092] P1 , P 2 , P 3 , P 4 , and P 5 are each independently selected from: N, CH, CR 7 , and CR c , provided that 1-2 of P 1 , P 2 , P 3 , P 4 , and P 5 are independently selected CR 7 ; or

[0093] (BB)

[0094] P 1 is absent, thereby providing a 5-membered ring,

[0095] P 2 , P 3 , P 4 , and P 5 are each independently selected from: O, S, N, NH, NR d , NR 7 , CH, CR 7 , and CR c , provided that 1-3 of P 2 , P 3 , P 4 , and P 5 are O, S, N, NH, NR d , or NR 7 ; and 1-2 of P 2 , P 3 , P 4 , and P 5 are independently selected NR 7 or CR 7 ;

[0096] each R 7 is independently selected from: -R 8 and –L 3 -R 9 ;

[0097] R 8 and R 9 are independently selected from:

[0098] (a) C 3-12 cycloalkyl or C 3-12 cycloalkenyl, each optionally substituted with 1-4 independently selected R 7 ’;

[0099] (b) heterocyclyl or heterocyclenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl or heterocyclenyl ring is optionally substituted with 1-4 independently selected R 7 '; and

[0100] (c) heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with 1-4 independently selected R 7 '; and

[0101] (d) C 7 ary! optionally substituted with 1-4 independently selected R 6-10 '; and

[0102] -L 3 is selected from: -0-, -C 1-4 alkylene, -S-, -NH-, S(O) 1-2 , C(=0)NH, NHC(=0), C(=0)0, OC(=0), C(=0), NHS(0)2, and S(0)2NH;

[0103] each occurrence of R 7 ' is independently selected from: halo; -CN; -N02; -OH; -C a alkyl optionally substituted with 1-2 independently selected R 1-4 ; -C 2-4 alkenyl; -C 2-4 alkynyl; -C 1-4 haloalkyl; -C a alkoxy optionally substituted with 1-2 independently selected R 1-6 ; -C 1-6 haloalkoxy; S(O) 1-2 (C 1-4 alkyl); -NR'R"; oxo; -S(O) 1-2 (NR'R"); -C 1-4 thioalkoxy; -C(=0)(C 1-4 alkyl); -C(=0)0(C 1-4 alkyl); -C(=0)OH; and -C(=0)N(R')(R"),

[0104] W is selected from:

[0105] (i) C(=O); (ii) C(=S); (iii) S(O) 1-2 ; (iv) C(=NR d ) or C(=N-CN); (v) C(=NH); (vi) C(=C-NO2); (vii) S(=O)(=N(R d )); and (viii) S(=O)(=NH);

[0106] Q is selected from the group consisting of: NH, N(C 1-6 alkyl), *-NH-(C 1-3 alkylene)-, and *-N(C 1-6 alkyl)-(C 1-3 alkylene)-, wherein C 1-6 alkyl is optionally substituted with 1-2 independently selected R a , and the asterisk indicates the point of attachment to W;

[0107] R 1a , R 1b , R 1c , and R 1d are each independently selected from the group consisting of: H; halo; cyano; C a alkyl optionally substituted with 1-2 R 1-6 ; C 2-6 alkenyl; C 2-6 alkynyl; C 1-4 haloalkyl; C 1-4 alkoxy; C 1-4 haloalkoxy; -S(O) 1-2 (C 1-4 alkyl); -S(O)(=NH)(C 1-4 alkyl); SF5; -NR e R f ; -OH; -S(O) 1-2 (NR’R”); -C 1-4 thioalkoxy; -NO2; -C(=O)(C 1-4 alkyl); -C(=O)O(C 1-4 alkyl); -C(=O)OH; and -C(=O)N(R’)(R”);

[0108] each occurrence of R 2 is independently selected from the group consisting of:

[0109] (i) H;

[0110] (ii) C 1-6 alkyl optionally substituted with 1-3 independently selected R a ;

[0111] (iii) -C(O)(C a alkyl) optionally substituted with 1-3 independently selected R 1-6 alkyl groups;

[0112] (iv) -C(O)O(C a alkyl) optionally substituted with 1-3 independently selected R 1-4 alkyl groups;

[0113] (v) -CON(R')(R");

[0114] (vi) -S(O) 1-2 (NR'R") ;

[0115] (vii) -S(O) a (C 1-2 alkyl) optionally substituted with 1-3 independently selected R 1-4 alkyl groups;

[0116] (viii) -OH;

[0117] (ix) C 1-4 alkoxy; and

[0118] (x) -L 4 -L 5 -R i ;

[0119] R 4 is selected from H and C a alkyl optionally substituted with 1-3 independently selected R 1-6 alkyl groups;

[0120] R 5 is selected from: H; halogen; -OH; -C 1-4 alkyl; -C 1-4 haloalkyl; C 1-4 alkoxy; C 1-4 haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); -S(O) 1-2 (NR'R") ; -S(O) 1-2 (C 1-4 alkyl); cyano; and C 3-6 cycloalkyl or C 3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected C 1-4 alkyl groups;

[0121] R 6 is selected from: H; C a alkyl optionally substituted with 1-3 independently selected RReplacement C 1-6 Alkyl; -OH; C 1-4 Alkyl group; C(=O)H; C(=O)(C 1-4 Alkyl); optionally with 1-4 independently selected C 1-4 Alkyl-substituted C 6-10 Aryl; and heteroaryl groups with 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S(O) 0-2 And wherein the heteroaryl ring is optionally composed of 1-4 independently selected C 1-4 Alkyl substitution;

[0122] Each occurrence of R a Independently selected from the following groups: –OH; -F; -Cl; -Br; –NR e R f C 1-4 Alkoxy; C 1-4 Haloalkoxy group; -C(=O)O(C 1-4 Alkyl); -C(=O)(C 1-4 Alkyl); -C(=O)OH; -CON(R')(R”); -S(O) 1-2 (NR'R”);-S(O) 1-2 (C 1-4 Alkyl); cyano; and C 3-6 cycloalkyl or C 3-6 Cycloalkenyl groups, each optionally composed of 1-4 independently selected C groups. 1-4 Alkyl substitution;

[0123] Each occurrence of R b Independently selected from the following group: R selected arbitrarily by 1-6 independent choices a Replacement C 1-10 Alkyl; C 1-4 Halogenated alkyl; –OH; oxo; -F; -Cl; -Br; –NR e R f C 1-4 Alkoxy; C 1-4 Haloalkoxy group; -C(=O)(C 1-10 Alkyl); -C(=O)O(C 1-4 Alkyl); -C(=O)OH; -C(=O)N(R')(R”); -S(O) 1-2 (NR'R”);-S(O) 1-2 (C 1-4 Alkyl); cyano; and –L 1 -L 2 -R h ;

[0124] each occurrence of R c is independently selected from the group consisting of halogen; cyano; optionally substituted C a substituted C 1-10 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 1-4 alkoxy; C 1-4 haloalkoxy; -S(O) 1-2 (C 1-4 alkyl); -NR e R f ; -OH; -S(O) 1-2 (NR'R"); -C 1-4 thioalkoxy; -NO2; -C(=O)(C 1-10 alkyl); -C(=O)O(C 1-4 alkyl); -C(=O)OH; -C(=O)N(R')(R"); and -L 1 -L 2 -R h ;

[0125] R d is selected from the group consisting of C 1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halogen, C 1-3 alkoxy, C 1-3 haloalkoxy, OH, and C 3-6 cycloalkyl; C 3-6 cycloalkyl or C 3-6 cycloalkenyl, each optionally substituted with 1-3 substituents each independently selected from the group consisting of halogen and OH; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 N(R')(R"); -S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 alkoxy;

[0126] each occurrence of R e and R f are independently selected from the group consisting of H; C 1-6 alkyl; C 1-6 haloalkyl; C 3-6 cycloalkyl or C 3-6 cycloalkenyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2N(R')(R"); -S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 alkoxy; or

[0127] R e and R f together with the nitrogen atom to which they are each attached form a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each carbon atom being substituted with 1-2 substituents independently selected from H and C 1-3 alkyl; (b) 0-3 ring heteroatoms (in addition to the nitrogen atom to which R e and R f are attached) each independently selected from N(R d ), NH, O, and S;

[0128] -L 1 is a bond or C 1-3 alkylene; -L 2 is -O-, -N(H)-, -S(O) 0-2 - or a bond;

[0129] R h is selected from:

[0130] • C 3-8 cycloalkyl or C 3-8 cycloalkenyl; each optionally substituted with 1-4 substituents independently selected from halogen; C a alkyl optionally substituted with 1-2 independently selected R 1-4 ; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0131] • heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from halogen; C a alkyl optionally substituted with 1-2 independently selected R 1-4 ; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0132] • heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms each independently selected from N, N(H), N(R d), O and S(O) 0-2 , and wherein the heteroaromatic ring is optionally substituted with 1-4 substituents independently selected from the group consisting of: halo; OH; NR a substituted C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy; and

[0133] • C 6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of: halo; OH; NR a substituted C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0134] -L 4 - selected from the group consisting of: a bond, -C(O)-, -C(O)O-, -C(O)NH-, C(O)NR d , S(O) 1-2 , S(O) 1-2 NH, and S(O) 1- 2NR d ;

[0135] -L 5 - selected from the group consisting of: a bond and C 1-4 alkylene;

[0136] R i is selected from the group consisting of:

[0137] • C 3-8 cycloalkyl or C 3-8 cycloalkenyl; each optionally substituted with 1-4 substituents independently selected from the group consisting of: halo; OH; NR e R f ; optionally substituted with 1-2 independently selected R a substituted C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0138] • heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2The heterocyclic or heterocyclic alkenyl group is optionally substituted by 1 to 4 substituents independently selected from the following: halogen; OH; NR. e R f ; R is arbitrarily selected by 1-2 independent choices a Replacement C 1-4 Alkyl; C 1-4 Haloalkyl; cyano; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups;

[0139] • A heteroaryl group with 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S(O) 0-2 Furthermore, the heteroaryl ring is optionally substituted by 1-4 independent substituents selected from the following: halogen; OH; NR. e R f ; R is arbitrarily selected by 1-2 independent choices a Replacement C 1-4 Alkyl; C 1-4 Haloalkyl; cyano; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups; and

[0140] ·C 6-10 aryl group, optionally substituted by 1 to 4 independent substituents selected from the following: halogen; OH; NR. e R f ; R is arbitrarily selected by 1-2 independent choices a Replacement C 1-4 Alkyl; C 1-4 Haloalkyl; cyano; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups; and

[0141] Each occurrence of R' and R” is independently selected from the following groups: H; -OH; C 1-4 Alkyl group; optionally surrounded by 1-2 alkyl groups selected from halogens, C 1-4 Alkyl and C 1-4 The C-substituent of the haloalkyl group 6-10 Aryl groups; and heteroaryl groups with 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R). d ), O and S(O) 0-2 Furthermore, the heteroaryl ring is optionally substituted by 1-4 independent substituents selected from the following: halogen, -OH, NH2, NH(C 1-4 Alkyl), N(C) 1-4 Alkyl)2, C 1-4 Alkyl and C1-4 haloalkyl;

[0142] or R' and R" together with the nitrogen atom to which each is attached form a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each carbon atom being substituted with 1-2 substituents independently selected from the group consisting of H and C 1-3 alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom to which R' and R" are attached) each independently selected from the group consisting of: N(H), N(C 1-6 alkyl), O, and S.

[0143] In one aspect, the present application provides a compound of Formula (I):

[0144]

[0145] or a pharmaceutically acceptable salt or tautomer thereof, wherein:

[0146] X 1 is selected from the group consisting of: O, S, N, NR 2 , and CR 1 ;

[0147] X 2 is selected from the group consisting of: O, S, N, NR 4 , and CR 5 ;

[0148] each is independently a single or double bond, provided that:

[0149] the 5-membered ring comprising X 1 and X 2 is heteroaryl;

[0150] the 6-membered ring is aromatic; and

[0151] the ring comprising P 1 , P 2 , P 3 , P 4 , and P 5 is aromatic;

[0152] P 1 , P 2 , P 3 , P 4 , and P 5 are defined according to (AA) or (BB):

[0153] (AA)

[0154] P 1 , P 2 , P 3 , P 4and P 5 each P is independently selected from the group consisting of: N, CH, CR 7 and CR c , provided that 1-2 of P 1 , P 2 , P 3 , P 4 and P 5 are independently selected CR 7 ; or

[0155] (BB)

[0156] P 1 is absent, thereby providing a 5-membered ring,

[0157] P 2 , P 3 , P 4 and P 5 each is independently selected from the group consisting of: O, S, N, NH, NR d , NR 7 , CH, CR 7 and CR c , provided that 1-3 of P 2 , P 3 , P 4 and P 5 are O, S, N, NH, NR d , or NR 7 ; and 1-2 of P 2 , P 3 , P 4 and P 5 are independently selected NR 7 or CR 7 ;

[0158] each R 7 is independently selected from the group consisting of: -R 8 and –L 3 -R 9 ;

[0159] R 8 and R 9 are independently selected from the group consisting of:

[0160] (a) C 3-12 cycloalkyl or C 3-12 cycloalkenyl, each optionally substituted with 1-4 independently selected R 7 '; and

[0161] (b) heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from the group consisting of: N, N(H), N(R d ), O and S(O)0-2 And one or more ring carbon atoms of the heterocyclic or heterocyclic alkenyl ring are optionally separated by 1-4 independently chosen R 7 'replace;

[0162] (c) A heteroaryl group with 5-12 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S(O) 0-2 And one or more ring carbon atoms of the heteroaryl ring are optionally separated by 1-4 independently chosen R 7 'replace; and

[0163] (d) Randomly select 1-4 independently chosen R 7 'Replacement of C' 6-10 Aryl;

[0164] -L 3 Selected from: –O-, -CH2-, -S-, -NH-, S(O) 1-2 , C(=O)NH, NHC(=O), C(=O)O, OC(=O), C(=O), NHS(O)2 and S(O)2NH;

[0165] Each occurrence of R 7 'Selected independently from:'

[0166] Halogen; -CN; -NO2; -OH; optionally selected by 1-2 independent R a Replacement -C 1-4 Alkyl; -C 2-4 alkenyl; -C 2-4 alkynyl group; -C 1-4 Halogenated alkyl; optionally with 1-2 independently selected R a Replacement -C 1-6 Alkoxy; -C 1-6 Halogenated alkoxy groups; S(O) 1-2 (C 1-4 Alkyl); -NR'R"; Oxygenated; -S(O) 1-2 (NR'R”); -C 1-4 Thioalkoxy group; -C(=O)(C 1-4 Alkyl); -C(=O)O(C 1-4 Alkyl); -C(=O)OH; and -C(=O)N(R')(R”),

[0167] W is selected from:

[0168] (i) C(=O); (ii) C(=S); (iii) S(O) 1-2 (iv) C(=NR) d(viii) S(=0)(=NH); d (viii) S(=0)(=NH);

[0169] Q is selected from the group consisting of NH, N(C 1-6 alkyl), *-NH-(C 1-3 alkylene)- and *-N(C 1-6 alkyl)-(C 1-3 alkylene)-, wherein C 1-6 alkyl is optionally substituted with 1-2 independently selected R a , and the asterisk indicates the point of attachment to W;

[0170] R 1a , R 1b , R 1c and R 1d are each independently selected from the group consisting of H; halo; cyano; C a alkyl optionally substituted with 1-2 R 1-6 ; C 2-6 alkenyl; C 2-6 alkynyl; C 1-4 haloalkyl; C 1-4 alkoxy; C 1-4 haloalkoxy; -S(O) 1-2 (C 1-4 alkyl); -S(O)(=NH)(C 1-4 alkyl); SF5; -NR e R f ; -OH; -S(O) 1-2 (NR’R”); -C 1-4 thioalkoxy; -NO2; -C(=O)(C 1-4 alkyl); -C(=O)O(C 1-4 alkyl); -C(=O)OH; and -C(=O)N(R’)(R”);

[0171] each occurrence of R 2 is independently selected from the group consisting of:

[0172] (i) H;

[0173] (ii) C 1-6 alkyl optionally substituted with 1-3 independently selected R a ;

[0174] (iii) -C(O)(C 1-6 alkyl) optionally substituted with 1-3 independently selected R a ;

[0175] (iv) R, which is arbitrarily selected by 1-3 independent choices a Substituted -C(O)O(C 1-4 alkyl);

[0176] (v)-CON(R')(R”);

[0177] (vi)-S(O) 1-2 (NR'R”);

[0178] (vii) R is arbitrarily selected by 1-3 independent choices a Replacement -S(O) 1-2 (C 1-4 alkyl);

[0179] (viii)–OH;

[0180] (ix)C 1-4 alkoxy groups; and

[0181] (x)–L 4 -L 5 -R i ;

[0182] R 4 Selected from H and R, which are optionally chosen independently from 1 to 3 other options. a Replacement C 1-6 alkyl;

[0183] R 5 Selected from: H; halogen; –OH; -C 1-4 Alkyl; -C 1-4 Halogenated alkyl; C 1-4 Alkoxy; C 1-4 Haloalkoxy group; -C(=O)O(C 1-4 Alkyl); -C(=O)(C 1-4 Alkyl); -C(=O)OH; -CON(R')(R”); -S(O) 1-2 (NR'R”);-S(O) 1-2 (C 1-4 Alkyl); cyano; and C 3-6 cycloalkyl or C 3-6 Cycloalkenyl groups, each optionally composed of 1-4 independently selected C groups. 1-4 Alkyl substitution;

[0184] R 6 Selected from: H; R, which is arbitrarily chosen by 1-3 independent selections. a Replacement C 1-6 Alkyl; -OH; C 1-4 Alkyl group; C(=O)H; C(=O)(C 1-4Alkyl); optionally with 1-4 independently selected C 1-4 Alkyl-substituted C 6-10 Aryl; and heteroaryl groups with 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S(O) 0-2 And wherein the heteroaryl ring is optionally composed of 1-4 independently selected C 1-4 Alkyl substitution;

[0185] Each occurrence of R a Independently selected from the following groups: –OH; -F; -Cl; -Br; –NR e R f C 1-4 Alkoxy; C 1-4 Haloalkoxy group; -C(=O)O(C 1-4 Alkyl); -C(=O)(C 1-4 Alkyl); -C(=O)OH; -CON(R')(R”); -S(O) 1-2 (NR'R”);-S(O) 1-2 (C 1-4 Alkyl); cyano; and C 3-6 cycloalkyl or C 3-6 Cycloalkenyl groups, each optionally composed of 1-4 independently selected C groups. 1-4 Alkyl substitution;

[0186] Each occurrence of R b Independently selected from the following group: R selected arbitrarily by 1-6 independent choices a Replacement C 1-10 Alkyl; C 1-4 Halogenated alkyl; –OH; oxo; -F; -Cl; -Br; –NR e R f C 1-4 Alkoxy; C 1-4 Haloalkoxy group; -C(=O)(C 1-10 Alkyl); -C(=O)O(C 1-4 Alkyl); -C(=O)OH; -C(=O)N(R')(R”); -S(O) 1-2 (NR'R”);-S(O) 1-2 (C 1-4 Alkyl); cyano; and –L 1 -L 2 -R h ;

[0187] Each occurrence of R c Select independently from the following groups:

[0188] halogen; cyano; optionally substituted C a substituted C 1-10 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 1-4 alkoxy; C 1-4 haloalkoxy; -S(O) 1-2 (C 1-4 alkyl); -NR e R f ; -OH; -S(O) 1-2 (NR'R"); -C 1-4 thioalkoxy; -NO2; -C(=O)(C 1-10 alkyl); -C(=O)O(C 1-4 alkyl); -C(=O)OH; -C(=O)N(R')(R"); and -L 1 -L 2 -R h ;

[0189] R d is selected from the group consisting of C 1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halogen, C 1-3 alkoxy, C 1-3 haloalkoxy, and OH; C 3-6 cycloalkyl or C 3-6 cycloalkenyl, each optionally substituted with 1-3 substituents each independently selected from the group consisting of halogen and OH; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 N(R')(R"); -S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 alkoxy;

[0190] each occurrence of R e and R f are independently selected from the group consisting of H; C 1-6 alkyl; C 1-6 haloalkyl; C 3-6 cycloalkyl or C 3-6 cycloalkenyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 N(R')(R"); -S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4alkyl; C

[0191] R e and R f , together with the nitrogen atom to which they are both attached, form a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each carbon atom being substituted with 1-2 substituents independently selected from H and C 1-3 alkyl; (b) 0-3 ring heteroatoms (in addition to the nitrogen atom to which R e and R f are attached), each independently selected from N(R d ), NH, O, and S;

[0192] -L 1 is a bond or C 1-3 alkylene; -L 2 is -O-, -N(H)-, -S(O) 0-2 -, or a bond;

[0193] R h is selected from:

[0194] • C 3-8 cycloalkyl or C 3-8 cycloalkenyl; each optionally substituted with 1-4 substituents independently selected from halo; C a alkyl optionally substituted with 1-2 independently selected R 1-4 ; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0195] • heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from halo; C a alkyl optionally substituted with 1-2 independently selected R 1-4 ; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0196] • heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2and wherein the heteroaromatic ring is optionally substituted with 1-4 substituents independently selected from the group consisting of: halo; OH; NR a substituted C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy; and

[0197] • C 6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of: halo; OH; NR a substituted C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0198] -L 4 - selected from the group consisting of: a bond, -C(O)-, -C(O)O-, -C(O)NH-, C(O)NR d , S(O) 1-2 , S(O) 1-2 NH, and S(O) 1- 2NR d ;

[0199] -L 5 - selected from the group consisting of: a bond and C 1-4 alkylene;

[0200] R i selected from the group consisting of:

[0201] • C 3-8 cycloalkyl or C 3-8 cycloalkenyl; each optionally substituted with 1-4 substituents independently selected from the group consisting of: halo; OH; NR e R f ; optionally substituted with 1-2 R a substituted C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0202] • heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: halo; OH; NR eR f ; R is arbitrarily selected by 1-2 independent choices a Replacement C 1-4 Alkyl; C 1-4 Haloalkyl; cyano; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups;

[0203] • A heteroaryl group with 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S(O) 0-2 Furthermore, the heteroaryl ring is optionally substituted by 1-4 independent substituents selected from the following: halogen; OH; NR. e R f ; R is arbitrarily selected by 1-2 independent choices a Replacement C 1-4 Alkyl; C 1-4 Haloalkyl; cyano; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups;

[0204] ·C 6-10 aryl group, optionally substituted by 1 to 4 independent substituents selected from the following: halogen; OH; NR. e R f ; R is arbitrarily selected by 1-2 independent choices a Replacement C 1-4 Alkyl; C 1-4 Haloalkyl; cyano; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups; and

[0205] Each occurrence of R' and R” is independently selected from the following groups: H; -OH; C 1-4 Alkyl group; optionally surrounded by 1-2 alkyl groups selected from halogens, C 1-4 Alkyl and C 1-4 The C-substituent of the alkyl halogroup 6-10 Aryl groups; and heteroaryl groups with 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R). d ), O and S(O) 0-2 Furthermore, the heteroaryl ring is optionally substituted by 1-4 independent substituents selected from the following: halogen, -OH, NH2, NH(C 1-4 Alkyl), N(C) 1-4 Alkyl)2, C 1-4 Alkyl and C 1-4haloalkyl; or R' and R" together with the nitrogen atom to which they are each attached form a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each carbon atom being substituted with 1-2 substituents independently selected from the group consisting of H and C 1-3 substituents; (b) 0-3 ring heteroatoms (in addition to the nitrogen atom to which R' and R" are attached), each independently selected from the group consisting of: N(H), N(C 1-6 alkyl), O, and S.

[0206] In one aspect, the present application provides a compound of Formula (I):

[0207]

[0208] or a pharmaceutically acceptable salt thereof or a tautomer thereof,

[0209] X 1 is selected from the group consisting of: O, S, N, NR 2 and CR 1 ;

[0210] X 2 is selected from the group consisting of: O, S, N, NR 4 and CR 5 ;

[0211] each is independently a single bond or a double bond, provided that:

[0212] the 5-membered ring containing X 1 and X 2 is heteroaryl;

[0213] the 6-membered ring is aromatic:

[0214] and

[0215] the ring containing P 1 , P 2 , P 3 , P 4 and P 5 is aromatic;

[0216] P 1 , P 2 , P 3 , P 4 and P 5 is defined according to (AA) or (BB):

[0217] (AA)

[0218] P 1 , P 2 , P 3 , P 4 and P5 each of P 7 and P c is independently selected from the group consisting of N, CH, CR 1 ; provided that 1-2 of P 2 , P 3 , P 4 , and P 5 are independently selected CR 7 ; or

[0219] (BB)

[0220] P 1 is absent, thereby providing a 5-membered ring,

[0221] P 2 , P 3 , P 4 , and P 5 are each independently selected from the group consisting of O, S, N, NH, NR d , NR 7 , CH, CR 7 , and CR c ; provided that 1-3 of P 2 , P 3 , P 4 , and P 5 are O, S, N, NH, NR d , or NR 7 ; and 1-2 of P 2 , P 3 , P 4 , and P 5 are independently selected NR 7 or CR 7 ;

[0222] each R 7 is independently selected from the group consisting of -R 8 , and -L 3 -R 9 ;

[0223] R 8 and R 9 are independently selected from the group consisting of:

[0224] (a) C 3-12 cycloalkyl or C 3-12 cycloalkenyl, each optionally substituted with 1-4 independently selected R 7 ', and

[0225] (b) heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2And one or more ring carbon atoms of the heterocyclic or heterocyclic alkenyl ring are optionally separated by 1-4 independently chosen R 7 'replace;

[0226] (c) A heteroaryl group with 5-12 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S(O) 0-2 And one or more ring carbon atoms of the heteroaryl ring are optionally separated by 1-4 independently chosen R 7 'replace; and

[0227] (d) Randomly select 1-4 independently chosen R 7 'Replacement of C' 6-10 Aryl;

[0228] -L 3 Selected from: –O-, -CH2-, -S-, -NH-, S(O) 1-2 , C(=O)NH, NHC(=O), C(=O)O, OC(=O), C(=O), NHS(O)2 and S(O)2NH;

[0229] Each occurrence of R 7 'Selected independently from:'

[0230] Halogen; -CN; -NO2; -OH; optionally selected by 1-2 independent R a Replacement -C 1-4 Alkyl; -C 2-4 alkenyl; -C 2-4 alkynyl group; -C 1-4 Halogenated alkyl; optionally with 1-2 independently selected R a Replacement -C 1-6 Alkoxy; -C 1-6 Halogenated alkoxy groups; S(O) 1-2 (C 1-4 Alkyl); -NR'R"; Oxygenated; -S(O) 1-2 (NR'R”); -C 1-4 Thioalkoxy group; -C(=O)(C 1-4 Alkyl); -C(=O)O(C 1-4 Alkyl); -C(=O)OH; and -C(=O)N(R')(R”);

[0231] W is selected from:

[0232] (i) C(=O); (ii) C(=S); (iii) S(O) 1-2 (iv) C(=NR) d) or C(=N-CN); (v) C(=NH); (vi) C(=C-NO2); (vii) S(O)N(R d ); and (viii) S(O)NH;

[0233] Q is selected from the group consisting of: NH, N(C 1-6 alkyl), *-NH-(C 1-3 alkylene)-, and *-N(C 1-6 alkyl)-(C 1-3 alkylene)-, wherein C 1-6 alkyl is optionally substituted with 1-2 independently selected R a , and the asterisk indicates the point of attachment to W;

[0234] R 1a , R 1b , R 1c , and R 1d are each independently selected from the group consisting of: H; halo; cyano; C a alkyl optionally substituted with 1-2 R 1-6 ; C 2-6 alkenyl; C 2-6 alkynyl; C 1-4 haloalkyl; C 1-4 alkoxy; C 1-4 haloalkoxy; -S(O) 1-2 (C 1-4 alkyl); -S(O)(=NH)(C 1-4 alkyl); SF5; -NR e R f ; -OH; -S(O) 1-2 (NR’R”); -C 1-4 thioalkoxy; -NO2; -C(=O)(C 1-4 alkyl); -C(=O)O(C 1-4 alkyl); -C(=O)OH; and -C(=O)N(R’)(R”);

[0235] each occurrence of R 2 is independently selected from the group consisting of:

[0236] (i) H;

[0237] (ii) C 1-6 alkyl optionally substituted with 1-3 independently selected R a ;

[0238] (iii) -C(O)(C 1-6 alkyl) optionally substituted with 1-3 independently selected R a ;

[0239] (iv) R, which is arbitrarily selected by 1-3 independent choices a Substituted -C(O)O(C 1-4 alkyl);

[0240] (v)-CON(R')(R”);

[0241] (vi)-S(O) 1-2 (NR'R”);

[0242] (vii) R is arbitrarily selected by 1-3 independent choices a Replacement -S(O) 1-2 (C 1-4 alkyl);

[0243] (viii)–OH;

[0244] (ix)C 1-4 alkoxy groups; and

[0245] (x)–L 4 -L 5 -R i ;

[0246] R 4 Selected from H and R, which are optionally chosen independently from 1 to 3 other options. a Replacement C 1-6 alkyl;

[0247] R 5 Selected from: H; halogen; –OH; -C 1-4 Alkyl; -C 1-4 Halogenated alkyl; C 1-4 Alkoxy; C 1-4 Haloalkoxy group; -C(=O)O(C 1-4 Alkyl); -C(=O)(C 1-4 Alkyl); -C(=O)OH; -CON(R')(R”); -S(O) 1-2 (NR'R”);-S(O) 1-2 (C 1-4 Alkyl); cyano; and C 3-6 cycloalkyl or C 3-6 Cycloalkenyl groups, each optionally composed of 1-4 independently selected C groups. 1-4 Alkyl substitution;

[0248] R 6 Selected from: H; R, which is arbitrarily chosen by 1-3 independent selections. a Replacement C 1-6 Alkyl; -OH; C 1-4 Alkyl group; C(=O)H; C(=O)(C 1-4Alkyl); optionally with 1-4 independently selected C 1-4 Alkyl-substituted C 6-10 Aryl; and heteroaryl groups with 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S(O) 0-2 And wherein the heteroaryl ring is optionally composed of 1-4 independently selected C 1-4 Alkyl substitution;

[0249] Each occurrence of R a Independently selected from the following groups: –OH; -F; -Cl; -Br; –NR e R f C 1-4 Alkoxy; C 1-4 Haloalkoxy group; -C(=O)O(C 1-4 Alkyl); -C(=O)(C 1-4 Alkyl); -C(=O)OH; -CON(R')(R”); -S(O) 1-2 (NR'R”);-S(O) 1-2 (C 1-4 Alkyl); cyano; and C 3-6 cycloalkyl or C 3-6 Cycloalkenyl groups, each optionally composed of 1-4 independently selected C groups. 1-4 Alkyl substitution;

[0250] Each occurrence of R b Independently selected from the following group: R selected arbitrarily by 1-6 independent choices a Replacement C 1-10 Alkyl; C 1-4 Halogenated alkyl; –OH; oxo; -F; -Cl; -Br; –NR e R f C 1-4 Alkoxy; C 1-4 Haloalkoxy group; -C(=O)(C 1-10 Alkyl); -C(=O)O(C 1-4 Alkyl); -C(=O)OH; -C(=O)N(R')(R”); -S(O) 1-2 (NR'R”);-S(O) 1-2 (C 1-4 Alkyl); cyano; and –L 1 -L 2 -R h ;

[0251] Each occurrence of R c Select independently from the following groups:

[0252] (a) Halogen; (b) Cyano group; (c) R group optionally selected by 1-6 independently chosen groups. a Replacement C 1-10 Alkyl; (d)C 2-6 alkenyl; (e)C 2-6 alkynyl group; (g)C 1-4 Alkyl group; (h)C 1-4 Haloalkoxy groups; (i)-S(O) 1-2 (C 1-4 Alkyl); (j)-NR e R f ;(k)–OH;(l)-S(O) 1-2 (NR'R”); (m)-C 1-4 Thioalkoxy; (n)-NO2; (o)-C(=O)(C 1-10 Alkyl); (p)-C(=O)O(C 1-4 Alkyl); (q)-C(=O)OH; (r)-C(=O)N(R')(R”); and (s)–L 1 -L 2 -R h ;

[0253] R d Selected from the following group: C 1-6 Alkyl group, optionally substituted with 1-3 substituents, each independently selected from halogens and OH; C 3-6 cycloalkyl or C 3-6 The cycloalkenyl groups are each optionally substituted by 1-3 substituents, each independently selected from halogens and OH; -C(O)(C 1-4 Alkyl); -C(O)O(C 1-4 Alkyl); -CON(R')(R”); -S(O) 1-2 N(R')(R”);-S(O) 1-2 (C 1-4 Alkyl); -OH; and C 1-4 Alkoxy;

[0254] Each occurrence of R e and R f Independently selected from the following groups: H; C 1-6 Alkyl; C 1-6 Halogenated alkyl; C 3-6 cycloalkyl or C 3-6 Cycloalkenyl; -C(O)(C 1-4 Alkyl); -C(O)O(C 1-4 Alkyl); -CON(R')(R”); -S(O) 1-2 (NR'R”);-S(O) 1-2 (C 1-4alkyl); -OH; and C 1-4 alkoxy; or R e and R f together with the nitrogen atom to which they are each attached form a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each carbon atom being substituted with 1-2 substituents independently selected from H and C 1-3 alkyl; (b) 0-3 ring heteroatoms (in addition to the nitrogen atom to which R e and R f are attached), each being independently selected from N(R d ), NH, O, and S;

[0255] -L 1 is a bond or C 1-3 alkylene; -L 2 is -O-, -N(H)-, -S(O) 0-2 -, or a bond;

[0256] R h is selected from:

[0257] • C 3-8 cycloalkyl or C 3-8 cycloalkenyl; each optionally substituted with 1-4 substituents independently selected from halogen; C a alkyl optionally substituted with 1-2 independently selected R 1-4 ; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0258] • heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from halogen; C a alkyl optionally substituted with 1-2 independently selected R 1-4 ; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0259] • heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2and wherein the heteroaromatic ring is optionally substituted with 1-4 substituents independently selected from the group consisting of: halo; OH; NR a substituted C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy; and

[0260] • C 6-10 aryl, optionally substituted with 1-4 substituents independently selected from the group consisting of: halo; OH; NR a substituted C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0261] -L 4 - selected from the group consisting of: a bond, -C(O)-, -C(O)O-, -C(O)NH-, C(O)NR d , S(O) 1-2 , S(O) 1-2 NH, and S(O) 1- 2NR d ;

[0262] -L 5 - selected from the group consisting of: a bond and C 1-4 alkylene;

[0263] R i selected from the group consisting of:

[0264] • C 3-8 cycloalkyl or C 3-8 cycloalkenyl; each optionally substituted with 1-4 substituents independently selected from the group consisting of: halo; OH; NR e R f ; optionally substituted with 1-2 R a substituted C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0265] • heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: halo; OH; NR eR f ; R is arbitrarily selected by 1-2 independent choices a Replacement C 1-4 Alkyl; C 1-4 Haloalkyl; cyano; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups;

[0266] • A heteroaryl group with 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S(O) 0-2 Furthermore, the heteroaryl ring is optionally substituted by 1-4 independent substituents selected from the following: halogen; OH; NR. e R f ; R is arbitrarily selected by 1-2 independent choices a Replacement C 1-4 Alkyl; C 1-4 Haloalkyl; cyano; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups;

[0267] ·C 6-10 aryl group, optionally substituted by 1 to 4 independent substituents selected from the following: halogen; OH; NR. e R f ; R is arbitrarily selected by 1-2 independent choices a Replacement C 1-4 Alkyl; C 1-4 Haloalkyl; cyano; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups; and

[0268] Each occurrence of R' and R” is independently selected from the following groups: H; -OH; C 1-4 Alkyl group; optionally surrounded by 1-2 alkyl groups selected from halogens, C 1-4 Alkyl and C 1-4 The C-substituent of the alkyl halogroup 6-10 Aryl groups; and heteroaryl groups with 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R). d ), O and S(O) 0-2 Furthermore, the heteroaryl ring is optionally substituted by 1-4 independent substituents selected from the following: halogen, -OH, NH2, NH(C 1-4 Alkyl), N(C) 1-4 Alkyl)2, C 1-4 Alkyl and C 1-4Haloalkyl; or R' and R" together with their respective nitrogen atoms to form a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each carbon atom being supported by 1-2 independently selected H and C atoms. 1-3 Alkyl substituents; (b) 0-3 cyclic heteroatoms (except for the nitrogen atom bonded to R' and R'"), each independently selected from: N(H), N(C) 1-6 Alkyl), O and S.

[0269] In some implementations, the conditions are:

[0270] (a) When X 1 It is NR 2 ;X 2 It is CH; each R 1a R 1b R 1c R 1d and R 6 It is H; W is C (=O); Q is NH; and P 1 P 2 P 3 P 4 and P 5 According to the definition of (AA); then:

[0271] ·R 2 Not CH2CH2OCH3, CH3, CH2CH3, or SO2-(p-tolyl), when Part of it is Time; and -L 3 It is –O-, -NH-, or C (=O), and

[0272] ·R 2 It is not CH2CH2CH2N(CH3)2 or CH2CH2CH2N(CH2CH3)2, when Part of it is pyrimidinyl or pyridinyl, R 7 It is R 8 R 8 When it is an unsubstituted phenyl; and

[0273] (b) The compound is not:

[0274] variable P 1 P 2 P 3 P 4 and P 5

[0275] P 1 , P 2 , P 3 , P 4 and P 5 According to the embodiments defined under (AA)

[0276] In some implementations, P 1 P 2 P 3 P 4 and P 5 According to the definition of (AA).

[0277] In some implementations, P 1 P 2 P 3 P 4 and P 5 One of them is N.

[0278] In some implementations, P 1 P 2 P 3 P 4 and P 5 The two in it are N.

[0279] In some implementations, P 1 P 2 P 3 P 4 and P 5 Each is independently selected from: CH, CR 7 and CR c .

[0280] In some implementations, P 1 P 2 P 3 P 4 and P 5 One of them is CR 7 .

[0281] In some of these implementations, P 3 It is CR 7 .

[0282] In some implementations, P 4 It is N. In some implementations, P 3 It is CR 7 ;P 4 It is N.

[0283] In some implementations, P 1 P 2 and P 5 Each was independently selected from CH and CR c In some implementations, P 3 It is CR 7 ;P 4 It is N; and P 1 P 2 and P 5Each was independently selected from CH and CR c .

[0284] In some implementations, P 1 P 2 and P 5 One of them is N; and the rest are P. 1 P 2 and P 5 Each was independently selected from CH and CR c In some implementations, P 3 It is CR 7 ;P 4 It is N; and P 1 P 2 and P 5 One of them is N; and the rest are P. 1 P 2 and P 5 Each was independently selected from CH and CR c .

[0285] In some implementations, P 1 It is N.

[0286] In some of these implementations, P 2 P 4 and P 5 Each was independently selected from CH and CR c .

[0287] In some other implementations, P 2 P 4 and P 5 One of them is N; and the rest are P. 2 P 4 and P 5 Each was independently selected from CH and CR c .

[0288] In some implementations, P 3 It is CR 7 ;P 4 It is N; and P 1 P 2 and P 5 Each was independently selected from CH and CR c .

[0289] In some implementations, P 3 It is CR 7 ;P 4 It is N; P 1 It is N; and P 2 and P 5 Each was independently selected from CH and CRc .

[0290] In certain embodiments, P 3 is CR 7 ; P 4 is N; P 5 is N; and P 2 and P 1 are each independently selected from CH and CR c .

[0291] In certain embodiments, P 3 is CR 7 ; and P 1 , P 2 , P 4 , and P 5 are each independently selected from CH and CR c .

[0292] In certain embodiments, P 3 is CR 7 ; P 1 is N; and P 2 , P 4 , and P 5 are each independently selected from CH and CR c .

[0293] In certain embodiments, P 3 is CR 7 ; P 4 and P 2 are N; and P 1 and P 5 are each independently selected from CH and CR c .

[0294] In some embodiments, P 4 is CR 7 .

[0295] In some of these embodiments, P 1 , P 2 , P 3 , and P 5 are each independently selected from N, CH, and CR c . As non-limiting examples, P 1 , P 2 , P 3 , and P 5 are each independently selected from CH and CR c .

[0296] In certain other embodiments, P 1 , P 2 , P 3 , and P5 one of P 1 , P 2 , P 3 and P 5 is N; and the rest are CH c .

[0297] In certain embodiments, P 4 is CR 7 ; P 3 is N; and P 1 , P 2 and P 5 are each independently selected from CH and CR c .

[0298] In certain embodiments, P 4 is CR 7 ; P 2 is N; and P 1 , P 3 and P 5 are each independently selected from CH and CR c .

[0299] P 1 , P 2 , P 3 , P 4 and P 5 According to the embodiment defined by (BB)

[0300] In some embodiments, P 1 , P 2 , P 3 , P 4 and P 5 are defined according to (BB).

[0301] In some embodiments, one of P 2 , P 3 , P 4 and P 5 is CR 7 or NR 7 . For example, P 3 is CR 7 or NR 7 . In some of these embodiments, the rest of P 2 , P 3 , P 4 and P 5 are each independently selected from CH, CR c , S, N, NH and NR d , provided that 1-3 (e.g., 1-2) of P 2 , P 3 , P 4 and P 5 is S, N, NH or NR d .

[0302] In some implementations, P 3 It is CR 7 or NR 7 ; and P 2 P 4 and P 5 Each is independently selected from: O, S, N, NH, NR d CH and CR c The condition is 1-3 P 2 P 3 P 4 and P 5 It is O, S, N, NH, NR d or NR 7 .

[0303] In some of these implementations, P 3 It is NR 7 ; and P 2 P 4 and P 5 Each is independently selected from: O, S, N, NH, NR d CH and CR c .

[0304] In some of the foregoing embodiments, P 3 It is NR 7 ; and P 2 P 4 and P 5 Each is independently selected from: N, CH and CR c .

[0305] In some implementations, P 3 It is NR 7 ;P 2 Is it CH or CR? c (For example, CH); P 4 It is N; and P 5 Is it CH or CR? c (e.g., CH).

[0306] In some implementations, P 3 It is NR 7 ;P 2 It is N; P 4 Is it CH or CR? c For example, CH; and P 5 Is it CH or CR? c For example, CH.

[0307] In some implementations, P 3 It is NR 7 ;P 2 Is it CH or CR?c , for example, C; P 4 is CH or CR c , for example, CH; and P 5 is N.

[0308] In certain embodiments, P 3 is CR 7 ; and P 2 , P 4 , and P 5 are each independently selected from the group consisting of: CH, CR c , S, N, NH, and NR d , provided that 1-2 (e.g., 2) P 2 , P 4 , and P 5 are S, N, NH, or NR d .

[0309] In certain embodiments, P 3 is CR 7 ; P 2 is NH, NR d , or S (e.g., S); P 5 is N; and P 4 is CH or CR c (e.g., CH).

[0310] In certain embodiments, P 3 is CR 7 ; P 2 is NH, NR d , or S (e.g., S); P 5 is CH or CR c ; and P 4 is N.

[0311] P 1 , P 2 , P 3 , P 4 and P 5 in non-limiting combinations

[0312] In some embodiments, moieties have the formula: wherein n2 is 0, 1, or 2.

[0313] In certain embodiments, moieties have the formula:

[0314] In certain embodiments, moieties have the formula:

[0315] In some embodiments, moieties have the formula: wherein n2 is 0, 1, or 2.

[0316] In some of these embodiments, In some of these embodiments,

[0317] In some of these embodiments, In some of these embodiments,

[0318] In some of these embodiments, In some of these embodiments, wherein n2 is 0, 1, or 2.

[0319] In some of these embodiments, In some of these embodiments, wherein n2 is 0, 1, or 2.

[0320] In some of these embodiments, In some of these embodiments,

[0321] In some of these embodiments, In some of these embodiments, wherein n2 is 0, 1, or 2.

[0322] In some of these embodiments, In some of these embodiments, wherein n2 is 0, 1, or 2.

[0323] In some of these embodiments, In some of these embodiments,

[0324] In some of these embodiments, In some of these embodiments,

[0325] In some of these embodiments, In some of these embodiments,

[0326] In some of these embodiments, In some of these embodiments,

[0327] In some of these embodiments, In some of these embodiments, wherein n2 is 0 or 1, e.g., 0.

[0328] In some of these embodiments, In some of these embodiments,

[0329] In some embodiments, moieties have the formula: wherein n2 is 0 or 1, e.g., 0.

[0330] In some embodiments, moieties have the formula: wherein n2 is 0 or 1, e.g., 0.

[0331] The variable R 7

[0332] In some embodiments, R 7 is R 8 .

[0333] In some embodiments, R 8 is selected from:

[0334] (a) C 3-12 cycloalkyl or C 3-12 cycloalkenyl, each of which is optionally substituted with 1-4 independently selected R 7 '; and

[0335] (b) heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring is optionally substituted with 1-4 independently selected R 7 '.

[0336] In certain embodiments, R 8 is selected from:

[0337] (a) C 3-12 cycloalkyl or C 3-12 cycloalkenyl, each of which is substituted with 1-4 independently selected R 7 '; and

[0338] (b) heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring is substituted with 1-4 independently selected R 7 '.

[0339] In certain embodiments, R 8 is C 3-12 cycloalkyl or C 3-12 cycloalkenyl, each of which is substituted with 1-4 independently selected R 7 '.

[0340] In certain embodiments, R 8 is C 4-10 cycloalkyl or C 4-10 cycloalkenyl, each of which is substituted with 1-4 independently selected R 7 '.

[0341] In some of these embodiments, R 8 is C 4-8 cycloalkyl or C 4-8 cycloalkenyl, each of which is substituted with 1-4 independently selected R 7 '.

[0342] In some of these embodiments, R 8 is C 7 cycloalkyl substituted with 1-4 independently selected R 4-8 '.

[0343] In certain embodiments, R 8 is C 7 cycloalkyl substituted with 1-3 R 4-8 '.

[0344] In some of these embodiments, R 8 is cyclohexyl substituted with 1-3 (e.g., 1 or 2) R 7 '.

[0345] As non-limiting examples of the above embodiments, R 8 may be (e.g.,

[0346] In certain embodiments, R 8 is cyclobutyl substituted with 1-3 (e.g., 1 or 2) R 7 '.

[0347] As non-limiting examples of the above embodiments, R 8 may be (e.g.,

[0348] As another non-limiting example, R 8 may be (e.g.,

[0349] In certain embodiments, R 8 is spiro C 7 cycloalkyl substituted with 1-4 independently selected R 6-12 '. In some of these embodiments, R 8 is (e.g.,

[0350] In some implementations, R 8 It is a heterocyclic group or heterocyclic alkenyl group with 3-12 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S(O) 0-2 And one or more ring carbon atoms of said heterocyclic or heterocyclic alkenyl ring are separated by 1-4 independently selected R 7 'replace.

[0351] In some implementations, R 8 It is a heterocyclic group or heterocyclic alkenyl group with 4-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S(O) 0-2 And one or more ring carbon atoms of said heterocyclic or heterocyclic alkenyl group are selected by 1-4 independently chosen R 7 'replace.

[0352] In some implementations, R 8 It is a heterocyclic group or heterocyclic alkenyl group with 4-8 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S(O) 0-2 And one or more ring carbon atoms of said heterocyclic or heterocyclic alkenyl ring are separated by 1-4 independently selected R 7 'replace.

[0353] In some of these implementations, R 8 It is a heterocyclic group with 4-8 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R). d ), O and S(O) 0-2 And one or more ring carbon atoms of the said heterocyclic base ring are selected by 1-4 independently chosen R 7 'replace.

[0354] In some implementations, R 8 It is a heterocyclic group with 4-6 ring atoms, of which 1-2 ring atoms are heteroatoms, each independently selected from N, N(H), N(R). d ), O and S(O) 0-2 And one or more ring carbon atoms of the said heterocyclic base ring are selected by 1-3 independently chosen R 7 'replace.

[0355] In some of these implementations, R 8selected from: azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, dioxanyl (e.g., 1,3-dioxanyl), piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl, each of which is substituted with one to three (e.g., one or two) independently selected R 7 substituted.

[0356] In some of the foregoing embodiments, R 8 selected from: azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, dioxanyl (e.g., 1,3-dioxanyl), piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl, each of which is substituted with one to three (e.g., one or two) independently selected R 7 substituted.

[0357] In certain embodiments, R 8 selected from: azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, dioxanyl (e.g., 1,3-dioxanyl), piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl, each of which is substituted with one to three (e.g., one or two) independently selected R 7 substituted.

[0358] In certain embodiments, R 8 selected from: azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, dioxanyl (e.g., 1,3-dioxanyl), piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl, each of which is substituted with one to three (e.g., one or two) independently selected R 7 substituted.

[0359] As non-limiting examples, R 8 may be selected from: (e.g.,

[0360] As non-limiting examples of the foregoing embodiments, R 8 may be selected from: (e.g.,

[0361]

[0362] As further non-limiting examples, R 8 may be selected from: (e.g., (e.g., and (e.g.,

[0363] As another non-limiting example, R 8 may be selected from: (e.g., and (e.g., wherein R 7 is C 1-4 haloalkyl, e.g., -CF3).

[0364] As a further non-limiting example, R 8 may be (e.g.,

[0365] As a non-limiting example, R 8 may be selected from: (e.g., (e.g., and (e.g., wherein R d2 is H or R d .

[0366] In certain embodiments, R 8 is a spirocycloheteroaryl group of 6-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with 1-4 independently selected R 7 '.

[0367] In some of the foregoing embodiments, R 8 is selected from: 2-azaspiro[3.3]heptyl, 1-oxa-9-azaspiro[5.5]undecyl, 6-azaspiro[2.5]octyl, 1,5-dioxaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, and 2,6-diazaspiro[3.3]heptyl, each of which is optionally substituted on one or more ring carbon atoms with 1-4 independently selected R 7 ', wherein the ring nitrogen is optionally substituted with R d .

[0368] In some of these embodiments, R 8 is selected from: 2-azaspiro[3.3]heptyl, 1-oxa-9-azaspiro[5.5]undecyl, and 6-azaspiro[2.5]octyl, each of which is optionally substituted on a ring carbon atom with 1-4 independently selected R 7 '.

[0369] As a non-limiting example of the foregoing embodiments, R 8 may be for example

[0370] As a further non-limiting example, R 8 may be selected from: (e.g., (e.g., and

[0371] As a further non-limiting example, R 8 may be (e.g.,

[0372] As a further non-limiting example, R 8 may be optionally wherein R d is C 1-6 alkyl optionally substituted with 1-3 substituents each independently selected from halo, C 1-3 alkoxy, and C 1-3 haloalkoxy, e.g., wherein R d is C 2-4 alkyl substituted with 1-3 independently selected halo (e.g.,

[0373] In certain embodiments, R 8 is a bridged heterocyclyl of 6-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring are optionally substituted with 1-4 independently selected R 7 '. For example, R 8 may be which is optionally substituted on one or more ring atoms with 1-2 R 7 '.

[0374] In certain embodiments, R 8 is C 3-12 cycloalkyl or C 3-12 cycloalkenyl, which are unsubstituted.

[0375] In certain of these embodiments, R 8 is unsubstituted C 3-8 (e.g., C 3-5 or C 7-8 )monocyclic cycloalkyl. For example, R 8 may be unsubstituted C 4-6 monocyclic cycloalkyl, e.g., cyclobutyl or cyclopentyl. As a further non-limiting example, R 8 may be cyclohexyl.

[0376] In certain embodiments, R 8 is unsubstituted C 7-12 bicyclic cycloalkyl.

[0377] In certain of these embodiments, R 8 is unsubstituted C 7-12Spirocycloalkyl. As a non-limiting example of the foregoing embodiments, R 8 may be

[0378] In certain embodiments, R 8 is unsubstituted C 7-12 Bridged bicycloalkyl. As a non-limiting example of the foregoing embodiments, R 8 may be

[0379] In certain embodiments, R 8 is heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from the group consisting of: N, N(H), N(R d ), O, and S(O) 0-2 .

[0380] In certain embodiments, R 8 is heterocyclyl or heterocycloalkenyl of 3-8 ring atoms, wherein 1-2 ring atoms are heteroatoms each independently selected from the group consisting of: N, N(H), N(R d ), O, and S(O) 0-2 .

[0381] In certain of these embodiments, R 8 is selected from the group consisting of: azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, and oxepanyl, wherein the ring nitrogen atom is optionally substituted with R d .

[0382] In certain of the foregoing embodiments, R 8 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxepanyl, wherein the ring nitrogen atom is optionally substituted with R d .

[0383] As a non-limiting example of the foregoing embodiments, R 8 may be morpholinyl, piperidinyl (e.g., e.g. or azepanyl, wherein the ring nitrogen atom is optionally substituted with R d .

[0384] In certain embodiments, R 8 is azetidinyl (e.g., pyrrolidinyl (e.g., piperidinyl (e.g., e.g. or piperazinyl (e.g., wherein the ring nitrogen atom is substituted with Rd substituted with 1-3 substituents each independently selected from the group consisting of halo, C d alkyl, C 1-6 alkoxy, and C 1-3 haloalkoxy, e.g., wherein R 1-3 is C d alkyl substituted with 1-3 independently selected halo (e.g., 2-4 substituted with 1-3 independently selected halo (e.g.,

[0385] optionally wherein R 8 is C d alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo, C 8 alkoxy, and C d haloalkoxy, e.g., wherein R d is C 1-6 alkyl substituted with 1-3 independently selected halo (e.g., 1-3 substituted with 1-3 independently selected halo (e.g.,

[0386] In certain embodiments, R 8 is pyrrolidinyl, piperidinyl, or piperazinyl, wherein a ring nitrogen atom is substituted with R d .

[0387] In certain of these embodiments, R 8 is piperidinyl (e.g., e.g. or piperazinyl (e.g., wherein a ring nitrogen atom is substituted with R d , optionally wherein R d is C 1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo, C 1-3 alkoxy, and C 1-3 haloalkoxy, e.g., wherein R d is C 2-4 alkyl substituted with 1-3 independently selected halo (e.g.,

[0388] In certain embodiments, R 8 is selected from:

[0389] · wherein m1 and m2 are independently 0, 1, or 2; T 1 is CH or N; and T 2 is CH2, NH, NR d , or O;

[0390] · a spirocyclic heterocyclyl of 6-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring are optionally substituted with 1-4 independently selected R 7 ; and

[0391] · a spirocyclic C 6-12cycloalkyl, optionally substituted with 1-4 independently selected R 7 substituted,

[0392] optionally wherein each R 7 is independently selected from C 1-3 alkyl; C 1-3 haloalkyl; and halo, for example wherein each R 7 is independently selected from methyl, CF3, and -F; and

[0393] optionally wherein R d is C 1-6 alkyl, for example C 2-4 alkyl, optionally substituted with 1-3 independently selected halo, such as -F.

[0394] In certain embodiments, R 8 is selected from:

[0395] · wherein m1and m2are independently 0, 1, or 2, and T 1 is CH or N; and

[0396] • a spirocyclic heterocyclyl of 6-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring are optionally substituted with 1-4 independently selected R 7 ; for example:

[0397] optionally wherein each R 7’ is independently selected from C 1-3 alkyl and halo, for example methyl and -F; and optionally wherein R d is C 1-6 alkyl, for example C 2-4 alkyl, optionally substituted with 1-3 independently selected halo, such as -F.

[0398] In certain of these embodiments, R 8 is selected from: (for example, (for example, (for example, (for example, (for example, and (for example,

[0399] In certain embodiments, R 8 is wherein m1and m2are independently 0, 1, or 2, and T 1 is CH or N, for example:

[0400] wherein R 8 is selected from:

[0401] optionally wherein each R 7 is independently selected from C 1-3 alkyl; C 1-3 haloalkyl; and halo, for example wherein each R 7 is independently selected from methyl, CF3, and -F, for example wherein each R 7 is an independently selected halo, for example -F.

[0402] In certain embodiments, R 8 is wherein m1and m2are independently 0, 1, or 2, and T 1 is CH or N, for example: wherein R 8 is selected from:

[0403] optionally wherein R d is C 1-6 alkyl, for example C 2-4 alkyl, optionally substituted with 1-3 independently selected halos such as -F.

[0404] In certain embodiments, R 8 is selected from: wherein m1and m2are independently 0, 1, or 2; T 1 is CH or N; and T 2 is CH2, NH, NR d , or O; for example: wherein R 8 is selected from:

[0405] optionally wherein each R 7 is independently selected from C 1-3 alkyl and C 1-3 haloalkyl.

[0406] In certain embodiments, R 8 is selected from:

[0407] • a spirocyclic heterocyclyl of 6-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring are optionally substituted with 1-4 independently selected R7 substituted; and

[0408] • spirocyclic C 6-12 cycloalkyl, optionally substituted with 1-4 independently selected R 7 substituted;

[0409] optionally wherein each R 7 is independently selected from C 1-3 alkyl; C 1-3 haloalkyl; and halo, e.g., wherein each R 7 is independently selected from methyl, CF3, and -F.

[0410] In certain of these embodiments, R 8 is wherein m1, m2, m3, and m4 are independently 0, 1, or 2, provided that m1+m2+m3+m4≤6, and T 1 is CH or N, e.g., wherein R 8 is selected from:

[0411] optionally wherein each R 7 is independently selected from C 1-3 alkyl; C 1-3 haloalkyl; and halo, e.g., wherein each R 7 is independently selected from methyl, CF3, and -F, e.g., wherein each R 7 is an independently selected halo, e.g., -F.

[0412] In certain of these embodiments, R 8 is wherein m1, m2, m3, and m4 are independently 0, 1, or 2, provided that m1+m2+m3+m4≤6, and T 1 is CH or N, e.g., wherein R 8 is

[0413] optionally wherein R d is C 1-6 alkyl, e.g., C 2-4 alkyl, optionally substituted with 1-3 independently selected halo, e.g., -F.

[0414] In certain embodiments, R 8 is wherein m3 and m4 are independently 0, 1, or 2, provided that m3+m4≤4, e.g., wherein R 8 is

[0415] optionally wherein each R7 independently selected from C 1-3 alkyl; C 1-3 haloalkyl; and halo, e.g., wherein each R 7 is independently selected from methyl, CF3, and -F, e.g.: wherein each R 7 is an independently selected halo, e.g., -F.

[0416] In certain embodiments, R 8 is a bicyclic or polycyclic heterocyclyl or heterocycloalkenyl of 7-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from the group consisting of: N, N(H), N(R d ), O, and S(O) 0-2 .

[0417] In certain of these embodiments, R 8 is a bicyclic or polycyclic heterocyclyl of 7-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from the group consisting of: N, N(H), N(R d ), O, and S(O) 0-2 .

[0418] As non-limiting examples of the foregoing embodiments, R 8 may be

[0419] In certain embodiments, R 8 is a heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from the group consisting of: N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heteroaryl ring are optionally substituted with 1-4 independently selected R 7 .

[0420] In certain embodiments, R 8 is a heteroaryl of 5-6 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from the group consisting of: N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heteroaryl ring are optionally substituted with 1-2 independently selected R 7 .

[0421] In certain of these embodiments, R 8 is a heteroaryl of 5 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from the group consisting of: N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heteroaryl ring are optionally substituted with 1-2 independently selected R7 substituted.

[0422] In certain of the foregoing embodiments, R 8 is pyrazolyl, imidazolyl, thiazolyl, oxazolyl, triazolyl, each of which is optionally substituted on one or more ring carbon atoms with 1-2 independently selected R 7 and on a ring nitrogen atom with 1 R d .

[0423] As non-limiting examples of the foregoing embodiments, R 8 may be thiazolyl optionally substituted with 1-2 independently selected R 7 .

[0424] In certain embodiments, R 8 is bicyclic heteroaryl of 7-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with 1-2 independently selected R 7 .

[0425] As non-limiting examples of the foregoing embodiments, R 8 may be

[0426] In certain embodiments, R 8 is C 6-10 aryl optionally substituted with 1-4 independently selected R 7 .

[0427] In certain of these embodiments, R 8 is phenyl optionally substituted with 1-2 independently selected R 7 .

[0428] In some embodiments, R 7 is -L 3 -R 9 .

[0429] In certain of these embodiments, -L 3 is -O-. In certain embodiments, -L 3 is -NH-. In certain embodiments, -L 3 is -S- or S(O) 1-2 . In certain embodiments, -L 3 is -CH2-. In certain embodiments, -L 3selected from: C(=O)NH, NHC(=O), C(=O)O, OC(=O), C(=O), NHS(O)2, and S(O)2NH. In certain embodiments, -L 3 is C 1-4 alkylene, for example CH2or wherein aa is the point of attachment to R 9 .

[0430] In certain embodiments (when R 7 is -L 3 -R 9 ), R 9 is selected from:

[0431] (a) C 3-12 cycloalkyl or C 3-12 cycloalkenyl, each optionally substituted with 1-4 independently selected R 7 '; and

[0432] (b) heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring are optionally substituted with 1-4 independently selected R 7 '.

[0433] In certain embodiments, R 9 is C 3-12 cycloalkyl or C 3-12 cycloalkenyl, each optionally substituted with 1-4 independently selected R 7 '.

[0434] In certain of these embodiments, R 9 is C 4-8 cycloalkyl, optionally substituted with 1-2 R 7 '.

[0435] As non-limiting examples, R 9 may be cyclobutyl, cyclopentyl, cyclohexyl, or spiro[3.3]heptyl, each of which is optionally substituted (e.g., unsubstituted) with 1-2 R 7 '.

[0436] In certain embodiments, R 9 is heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2and wherein one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring is optionally substituted with 1-4 independently selected R 7 ’.

[0437] In some of these embodiments, R 9 is heterocyclyl of 4-8 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring is optionally substituted with 1-2 independently selected R 7 ’.

[0438] As non-limiting examples of the foregoing embodiments, R 9 is selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and azepinyl, each of which is optionally substituted with 1-2 independently selected R 7 ’ (e.g., unsubstituted).

[0439] In certain embodiments, R 7 is L 3 -R 9 ; L 3 is -O- or -NH-; and R 9 is selected from:

[0440] C 4-8 cycloalkyl, optionally substituted with 1-2 R 7 ’; and

[0441] heterocyclyl of 4-8 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring is optionally substituted with 1-2 independently selected R 7 ’.

[0442] In certain of these embodiments, R 7 is L 3 -R 9 ; L 3 is -O- or -NH-; and R 9 is selected from cyclobutyl, cyclopentyl, cyclohexyl, and oxetanyl, each of which is optionally substituted with 1-2 independently selected R 7 ’ (e.g., unsubstituted). For example, L 3 may be -O-.

[0443] In certain embodiments, R 7is -L 3 -R 9 when R 7 non-limiting examples can include: (e.g., (e.g.,

[0444] In certain embodiments, moieties having the following formula: (e.g., wherein n2 is 0, 1, or 2; and R 7 is R 8 , wherein R 8 is selected from:

[0445] C 4-8 cycloalkyl optionally substituted with 1-4 independently selected R 7 ’; and

[0446] heterocyclyl of 4-12 (e.g., 4-8) ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring are optionally substituted with 1-4 independently selected R 7 ’.

[0447] In certain embodiments, moieties having the following formula: (e.g., or (e.g., wherein n2 is 0, 1, or 2; and R 7 is R 8 , wherein R 8 is selected from:

[0448] C 4-8 cycloalkyl optionally substituted with 1-4 independently selected R 7 ’; and

[0449] heterocyclyl of 4-12 (e.g., 4-8) ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring are optionally substituted with 1-4 independently selected R 7 ’.

[0450] In certain embodiments, moieties having the following formula: (e.g., or (e.g., wherein n2 is 0, 1, or 2; and R 7 is R 8 , wherein R 8 is selected from:

[0451] C 4-8 cycloalkyl optionally substituted with 1-4 independently selected R 7 ; and

[0452] heterocyclyl of 4-8 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring are optionally substituted with 1-4 independently selected R 7 .

[0453] In certain embodiments, moieties have the following formula: (e.g., wherein n2 is 0 or 1 (e.g., 0); and R 7 is R 8 , wherein R 8 is selected from:

[0454] C 4-8 cycloalkyl optionally substituted with 1-4 independently selected R 7 ; and

[0455] heterocyclyl of 4-8 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring are optionally substituted with 1-4 independently selected R 7 .

[0456] In certain embodiments (when moieties have the following formula:

[0457] n2 is 0.

[0458] In certain embodiments (when moieties have the following formula:

[0459] n2 is 1.

[0460] In certain of these embodiments, R c is located at R 7ortho position.

[0461] In certain embodiments (when moieties have the formula:

[0462] R 7 is R 8 ; and R 8 is C 7 cycloalkyl substituted with 1-3 R 4-8 ’.

[0463] In certain of these embodiments, R 8 is cyclohexyl substituted with 1-3 R 7 ’ such as, In certain embodiments, R 8 is cyclobutyl substituted with 1-3 R 7 ’ such as, For example,

[0464] In certain embodiments (when moieties have the formula:

[0465] R 7 is R 8 ; and R 8 is heterocyclyl of 4-8 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring are optionally substituted with 1-4 independently selected R 7 ’.

[0466] In certain of these embodiments, R 8 is heterocyclyl of 4-6 ring atoms, wherein 1-2 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl are substituted with 1-3 independently selected R 7 ’.

[0467] In certain embodiments, R 8 is selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl, each of which is substituted with 1-3 (e.g., 1 or 2) independently selected R 7'replace.

[0468] In some implementations, R 8 Selected from: azahexacyclic butyl, pyrrolidinyl, and piperidinyl, each of which is independently selected by 2-4 (e.g., 1 or 2) Rs. 7 'replace.

[0469] As a non-limiting example of the foregoing implementation, R 8 You can choose from: (For example, For example, R 8 It can be (For example,

[0470] In some implementations (when) Some have the following formula:

[0471] R 7 It is R 8 ;R 8 It is a spirocyclic heterocyclic group with 6-12 (e.g., 6-8) ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R). d ), O and S(O) 0-2 And one or more ring carbon atoms of the heterocyclic base ring are optionally separated by 1-4 independently chosen R 7 'Replace, for example:' (For example, (For example,

[0472] In some implementations (when) Some have the following formula:

[0473] (Time), R 7 It is R 8 ; and R 8 It is a heterocyclic group with 4-8 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R). d ), O and S(O) 0-2 The precursor is R 8 Contains ring N(R) d ) group.

[0474] In some of these implementations, R 8selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and 2,6-diazaspiro[3.3]heptanyl, wherein the ring nitrogen atom is substituted with R d is, for example, where R 8 is is optionally where R d is C 1-6 alkyl optionally substituted with 1-3 substituents each independently selected from halo, C 1-3 alkoxy, and C 1-3 haloalkoxy, for example, where R d is C 2-4 alkyl substituted with 1-3 independently selected halo (e.g.,

[0475] In certain embodiments (when moieties have the following formula: R 7 is R 8 ; and R 8 is unsubstituted C 4-6 monocyclic cycloalkyl (e.g., cyclopentyl, cyclobutyl, or cyclohexyl); or R 8 is unsubstituted C 7-8 bicyclic (e.g., spirocyclic) cycloalkyl (e.g.,

[0476] In certain embodiments, moieties have the following formula: where n2 is 0, 1, or 2; R 7 is -L 3 -R 9 , where:

[0477] L 3 is -NH- or -O-; R 9 is selected from:

[0478] C 4-8 cycloalkyl optionally substituted with 1-2 R 7 ; and

[0479] heterocyclyl of 4-8 ring atoms wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring are optionally substituted with 1-2 independently selected R 7 .

[0480] In certain embodiments, moieties have the following formula: wherein n2 is 0, 1, or 2; R 7 is -L 3 -R 9 , wherein:

[0481] L 3 is -NH- or -O-; R 9 is selected from:

[0482] C 4-8 cycloalkyl optionally substituted with 1-2 R 7 ; and

[0483] heterocyclyl of 4-8 ring atoms wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring are optionally substituted with 1-2 independently selected R 7 .

[0484] In certain embodiments (when moieties have the following formula: R 7 is L 3 -R 9 ; L 3 is -O- or -NH-; and R 9 is selected from: cyclobutyl, cyclopentyl, cyclohexyl, and oxetanyl, each of which is optionally substituted with 1-2 independently selected R 7 . In certain of these embodiments, L 3 is -O-.

[0485] In certain embodiments (when moieties have the following formula:

[0486] R 7 is , for example, , for example,

[0487] the variable R 7 '

[0488] In certain embodiments, when present, each R 7 ' is independently selected from: halo, -CN, -OH, -C a alkyl optionally substituted with R 1-4 , -C1-4 Halogenated alkyl, optionally R a Replacement -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, S(O) 1-2 (C 1-4 Alkyl groups, -NR'R", -S(O) 1-2 (NR'R”), -C 1-4 Thioalkoxy, -C(=O)(C 1-4 Alkyl), -C(=O)O(C 1-4 Alkyl groups, -C(=O)OH and -C(=O)N(R')(R”).

[0489] In some implementations, when present, each R 7 'Independently selected from: halogen, -CN, optionally R a Replacement -C 1-4 Alkyl, -C 1-4 Halogenated alkyl, optionally R a Replacement -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, S(O) 1-2 (C 1-4 Alkyl groups, -NR'R", -S(O) 1-2 (NR'R”), -C 1-4 Thioalkoxy, -C(=O)(C 1-4 Alkyl), -C(=O)O(C 1-4 Alkyl groups and -C(=O)N(R')(R”).

[0490] In some implementations, when present, each R 7 'Independently, it is a halogen. For example, when present, each R...' 7 'It can be -F.'

[0491] In some implementations, when present, each R 7 'Independently is C' 1-3 Alkyl groups, such as methyl groups.

[0492] In some implementations, when present, each R 7 'Is C an independent choice 1-3 Halogenated alkyl groups, such as –CF3.

[0493] In some implementations, R appears once 7 'Is it optional to be R' a Replacement -C 1-4 Alkyl groups, such as unsubstituted C4 groups 1-4 Alkyl (e.g., methyl, ethyl, n-propyl), or R 7'Is R a Replacement -C 1-4 Alkyl groups (e.g., those with OH or C) 3-6 Cycloalkyl-substituted -C 1-4 alkyl).

[0494] In some implementations, R appears once 7 'is-CN.'

[0495] In some implementations, R appears once 7 'Is it optional to be R' a Replacement C 1-6 Alkoxy groups, such as unsubstituted C4 groups 1-6 Alkyl groups (e.g., methoxy groups); or those containing R a Replacement C 1-6 Alkyl groups (e.g., those formed by OH or C) 3-6 cycloalkyl-substituted -C 1-4 Alkyl groups).

[0496] In one occurrence of R 7 In some of the aforementioned embodiments, when present, each of the remaining occurrences of R 7 'Independently halogens (e.g., -F).

[0497] In some implementations, when present, each R c Independently selected from: (a) halogen; (b) cyano; (c) optionally selected from 1-6 independently selected R a Replacement C 1-10 Alkyl; (g)C 1-4 Alkyl group; (h)C 1-4 Haloalkoxy groups; (i)-S(O) 1-2 (C 1-4 Alkyl); (j)-NR e R f ;(k)–OH;(l)-S(O) 1-2 (NR'R”); (m)-C 1-4 Thioalkoxy; (n)-NO2; (o)-C(=O)(C 1-10 Alkyl); (p)-C(=O)O(C 1-4 Alkyl); (q)-C(=O)OH; and (r)-C(=O)N(R')(R”).

[0498] In some implementations, when present, each R c Independently selected from: (a) halogen; (b) cyano; (c) C groups optionally substituted with 1-6 independently selected –F or -Cl groups. 1-10 Alkyl; (g)C 1-4 Alkyl group; (h)C1-4 Haloalkoxy groups; (i)-S(O) 1-2 (C 1-4 Alkyl); and -C(=O)(C 1-10 alkyl).

[0499] In some implementations, when present, each R c Independently selected from: halogen, cyano, C 1-3 Alkyl and C 1-3 Alkyl group.

[0500] In some implementations, each R c It is an independently chosen halogen (e.g., -F or -Cl), C 1-4 Alkyl groups (e.g., CH3), or CF3. For example, each R c It can be –F. As another non-restrictive instance, each R c It can be –Cl.

[0501] Variables Q and W

[0502] In some implementations, Q is NH.

[0503] In some implementations, Q is N(C 1-3 Alkyl), wherein C 1-3 Alkyl groups are optionally separated by 1-2 independently selected R groups. a Substitution (e.g., Q is NMe or NCH2CH2CH2OH).

[0504] In some implementations, Q is *-NH-(C 1-3 Alkylene)-, where the asterisk represents the junction with W.

[0505] In some implementations, W is C (=O).

[0506] In some implementations, W is S(O)2, C(=S) or C(=NR) d ).

[0507] In some implementations, W is C (=C-NO2) or C (=N-CN).

[0508] In some implementations, Q is NH; and W is C (=O).

[0509] VARIABLE X 1 ,X 2

[0510] In some implementations, X 1 It is NR 2 In some implementations, X 1 It is NH.

[0511] In some embodiments, X 2 is CR 5 In some embodiments, X 2 is CH.

[0512] In some embodiments, X 1 is NR 2 ; and X 2 is CR 5 In some of these embodiments, X 1 is NH; and X 2 is CH.

[0513] R 1a , R 1b , R 1c , and R 1d

[0514] In some embodiments, R 1a , R 1b , R 1c , and R 1d are each independently selected from the group consisting of: H; halogen; cyano; C a alkyl optionally substituted with 1-2 R 1-6 ; C 2-6 alkenyl; C 2-6 alkynyl; C 1-4 haloalkyl; C 1-4 alkoxy; C 1-4 haloalkoxy; -S(O) 1-2 (C 1-4 alkyl); -S(O)(=NH)(C 1-4 alkyl); SF5; -NR e R f ; -OH; -S(O) 1-2 (NR’R”); -C 1-4 thioalkoxy; -NO2; -C(=O)(C 1-4 alkyl); -C(=O)O(C 1-4 alkyl); and -C(=O)N(R’)(R”).

[0515] In some embodiments, R 1a , R 1b , R 1c , and R 1d are each H.

[0516] In certain other embodiments, 1-2 of R 1a , R 1b , R 1c , and R 1d are not H; the remaining R1a R 1b R 1c and R 1d Each is H.

[0517] In some implementations, R 1a R 1b R 1c and R 1d One of them is not H; the rest are R. 1a R 1b R 1c and R 1d Each is H.

[0518] In some implementations, R 1a R 1b R 1c and R 1d Two of them are not H; the rest are R. 1a R 1b R 1c and R 1d Each is H.

[0519] In some implementations, R 1a It is H or a halogen. For example, R 1a It can be H.

[0520] In some implementations, R 1d It is H or a halogen. For example, R 1d It can be H.

[0521] In some implementations, R 1b Not H; R 1a R 1c and R 1d Each is H.

[0522] In some implementations, R 1b and R 1c Each is not H; R 1a and R 1d Each is H.

[0523] In some implementations, R 1b It is a halogen, such as –F, -Cl, or –Br. For example, R 1b It can be –F or –Cl (e.g., -F). For example, R 1b It can be –F. As another non-restrictive instance, R 1b It can be –Cl.

[0524] In some implementations, R 1b It is optional to be 1-2 R a Replacement C1-6 alkyl, e.g., unsubstituted C 1-6 alkyl.

[0525] In certain embodiments, R 1b is C 1-4 haloalkyl (e.g., -CF3or -CHF2).

[0526] In certain embodiments, R 1b is -CN.

[0527] In certain embodiments, R 1b is -SF5.

[0528] In certain embodiments, R 1b is C 1-4 thioalkoxy (e.g., SMe).

[0529] In certain embodiments, R 1b is S(O)2(C 1-4 alkyl) (e.g., S(O)2Me).

[0530] In certain embodiments, R 1b is C 1-4 alkoxy or C 1-4 haloalkoxy (e.g., OCHF2).

[0531] In certain embodiments, R 1c is halogen (e.g., -F).

[0532] In certain embodiments, R 1c is selected from the group consisting of C 1-6 alkyl and C 1-4 haloalkyl.

[0533] In certain embodiments, R 1c is selected from the group consisting of C 1-4 alkoxy, C 1-4 haloalkoxy (e.g., CHF2), -CN, -SF5, C 1-4 thioalkoxy (e.g., SMe), and S(O)2(C 1-4 alkyl) (e.g., S(O)2Me).

[0534] In certain embodiments, R 1b and R 1c are each independently halogen; and R 1a and R 1d are each H. For example, R 1b and R 1c may each be -F.

[0535] In certain embodiments, R1c is H; R 1b is halogen, for example, -F or -Cl, for example, -Cl; R 1a and R 1d each is H.

[0536] In certain embodiments, R 1c is halogen; R 1b is selected from: C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy (for example, OCHF2), -CN, -SF5, C 1-4 thioalkoxy (for example, SMe), and S(O)2(C 1-4 alkyl) (for example, S(O)2Me); R 1a and R 1d each is H. For example, R 1c is -F.

[0537] In certain embodiments, R 1c is H; R 1b is selected from: C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy (for example, OCHF2), -CN, -SF5, C 1-4 thioalkoxy (for example, SMe), and S(O)2(C 1-4 alkyl) (for example, S(O)2Me); R 1a and R 1d each is H.

[0538] The variable R 2

[0539] In some embodiments, R 2 is H.

[0540] In some embodiments, R 2 is selected from:

[0541] (iii) -C(O)(C a alkyl) optionally substituted with 1-3 independently selected R 1-6 groups;

[0542] (iv) -C(O)O(C a alkyl) optionally substituted with 1-3 independently selected R 1-4 groups;

[0543] (v) -CON(R’)(R”); and

[0544] (vi) -S(O) 1-2 (NR'R"); and

[0545] (vii) optionally substituted -S(O) a (viii) -S(O) 1-2 (C 1-4 alkyl).

[0546] In certain embodiments, R 2 is -C(O)(C 1-6 alkyl), optionally substituted with 1-3 independently selected R a groups. In certain of these embodiments, each R 2 substituent of R a is independently -F, -Cl, -OH, or -NR e R f .

[0547] As non-limiting examples of the foregoing embodiments, R 2 may be selected from: C(=O)Me,

[0548] In certain embodiments, R 2 is -S(O) 1-2 (C 1-4 alkyl), optionally substituted with 1-3 independently selected R a groups (e.g., S(O)2Me).

[0549] In certain embodiments, R 2 is -L 4 -L 5 -R i . In some of these embodiments, -L 4 is a bond. In certain embodiments, -L 4 is C(=O). In certain embodiments, -L 4 is S(O)2. In certain embodiments, -L 5 is a bond. In some other embodiments, -L 5 is C 1-4 alkylene (e.g., C 1-2 alkylene).

[0550] In certain embodiments (when R 2 is -L 4 -L 5 -R i ), R i is selected from: (a) C 3-8cycloalkyl, optionally substituted with 1-4 substituents independently selected from the group consisting of: halo; OH; NR e R f ; optionally substituted with 1-2 independently selected R a substituted C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy (e.g., R i is wherein "Boc" represents tert-butyloxycarbonyl); and

[0551] (b) heterocyclyl, wherein the heterocyclyl has 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: halo; OH; NR e R f ; optionally substituted with 1-2 independently selected R a substituted C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy (e.g., R i is wherein "Boc" represents tert-butyloxycarbonyl).

[0552] In certain embodiments (when R 2 is -L 4 -L 5 -R i ), R i is selected from: (a) heteroaryl of 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of: halo; OH; NR e R f ; optionally substituted with 1-2 independently selected R a substituted C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy (e.g., R i is pyridinyl, pyrimidinyl, or pyrazolyl, optionally substituted with 1-2 substituents independently selected from the group consisting of: halo; C 1-4 alkyl; C1-4 Haloalkyl; cyano; C 1-4 Alkoxy; and C 1-4 (haloalkoxy); and

[0553] (b)C 6-10 Aryl group, optionally substituted with 1-4 substituents, said substituents being independently selected from: halogen; OH; NR. e R f ; R is arbitrarily selected by 1-2 independent choices a Replacement C 1-4 Alkyl; C 1-4 Haloalkyl; cyano; C 1-4 Alkoxy; and C 1-4 Haloalkoxy (e.g., a phenyl group optionally substituted with 1-2 substituents, said substituents being independently selected from: halogens; C 1-4 Alkyl; C 1-4 Haloalkyl; cyano; C 1-4 Alkoxy; and C 1-4 (haloalkoxy group).

[0554] In some implementations, R 2 Yes –L 4 -L 5 -R i L 4 It is a key; L 5 Is it a key or C? 1-4 Alkylene; and R i Selected from:

[0555] (a)C 3-8 Cycloalkyl group, optionally substituted with 1 to 4 independent substituents selected from the following: halogen; OH; NR. e R f ; R is arbitrarily selected by 1-2 independent choices a Replacement C 1-4 Alkyl; C 1-4 Haloalkyl; cyano; C 1-4 Alkoxy; and C 1-4 Haloalkoxy (e.g., R) i yes Where “Boc” represents tert-butoxycarbonyl);

[0556] (b) Heterocyclic groups, wherein the heterocyclic group has 3-8 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R). d ), O and S(O) 0-2 The heterocyclic group is optionally substituted by 1-4 substituents independently selected from the following: halogen; OH; NR. e R f; optionally substituted with 1-2 independently selected R a substituted C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy (e.g., wherein "Boc" represents tert-butyloxycarbonyl);

[0557] (c) heteroaryl of 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from halo; OH; NR e R f ; optionally substituted with 1-2 independently selected R a substituted C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy (e.g., phenyl, optionally substituted with 1-2 substituents independently selected from halo; C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy); and

[0558] (d) C 6-10 aryl, optionally substituted with 1-4 substituents independently selected from halo; OH; NR e R f ; optionally substituted with 1-2 independently selected R a substituted C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy (e.g., phenyl, optionally substituted with 1-2 substituents independently selected from halo; C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy).

[0559] In certain embodiments (when R 2 is -L 4 -L 5 -R i ), R 2 is -L 4-L 5 -R i ; L 4 is C(=O) or S(O)2; L 5 is a bond or C 1-4 alkylene; and R i is selected from:

[0560] (c) heteroaryl of 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from halo; OH; NR e R f ; C a alkyl optionally substituted with 1-2 independently selected R 1-4 ; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy (e.g., pyridinyl, pyrimidinyl, or pyrazolyl, optionally substituted with 1-2 substituents independently selected from halo; C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy); and

[0561] (d) C 6-10 aryl optionally substituted with 1-4 substituents independently selected from halo; OH; NR e R f ; C a alkyl optionally substituted with 1-2 independently selected R 1-4 ; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy (e.g., phenyl optionally substituted with 1-2 substituents independently selected from halo; C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; and C 1-4 haloalkoxy).

[0562] As non-limiting examples, R 2 may be selected from:

[0563] wherein R j is H; halo; C 1-4 alkyl; C 1-4 haloalkyl; cyano; C1-4 alkoxy; or C 1-4 haloalkoxy.

[0564] variable R 5

[0565] In some embodiments, R 5 is H.

[0566] variable R 6

[0567] In some embodiments, R 6 is H.

[0568] In some embodiments, R 6 is C 1-3 alkyl.

[0569] non-limiting combinations

[0570] In some embodiments, the compound is a compound of Formula (I-1):

[0571]

[0572]

[0573] or a pharmaceutically acceptable salt thereof, wherein n2 is 0, 1, or 2. In certain of these embodiments, the compound is of Formula (I-1-1):

[0574]

[0575] In some embodiments, the compound is a compound of Formula (I-2):

[0576]

[0577] or a pharmaceutically acceptable salt thereof, wherein n2 is 0, 1, or 2. In certain of these embodiments, the compound is of Formula (I-2-1):

[0578]

[0579] In some embodiments, the compound is a compound of Formula (I-3):

[0580]

[0581] or a pharmaceutically acceptable salt thereof, wherein n2 is 0, 1, or 2. In certain of these embodiments, the compound is of Formula (I-3-1):

[0582]

[0583] In some embodiments, the compound is a compound of Formula (I-4):

[0584]

[0585] or a pharmaceutically acceptable salt thereof, wherein n2 is 0, 1, or 2. In certain of these embodiments, the compound is of Formula (I-4-1):

[0586]

[0587] In some embodiments, the compound is a compound of Formula (I-5):

[0588]

[0589] or a pharmaceutically acceptable salt thereof, wherein n2 is 0, 1, or 2.

[0590] In certain of these embodiments, the compound is of Formula (I-5-1):

[0591]

[0592] In some embodiments, the compound is a compound of Formula (I-6):

[0593]

[0594] or a pharmaceutically acceptable salt thereof, wherein n2 is 0 or 1.

[0595] In certain of these embodiments, the compound is of Formula (I-6-1):

[0596]

[0597] In some embodiments, the compound is a compound of Formula (I-7):

[0598]

[0599] or a pharmaceutically acceptable salt thereof, wherein: P 1 and P 2 is N; and the other of P 1 and P 2 is CH or CR c (e.g., CH).

[0600] In certain embodiments of Formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R7 is -R 8 .

[0601] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7) (when R 7 is -R 8 ), R 8 is C 3-12 cycloalkyl or C 3-12 cycloalkenyl, each optionally substituted with 1-4 independently selected R 7 '.

[0602] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7) (when R 7 is -R 8 ), R 8 is C 7 cycloalkyl substituted with 1-3 R 4-8 '.

[0603] In certain of these embodiments, R 8 is cyclohexyl substituted with 1-3 R 7 '. In certain of these embodiments, R 8 is cyclobutyl substituted with 1-3 R 7 '.

[0604] As non-limiting examples of the foregoing embodiments, R 8 may be (e.g., or As another non-limiting example, R 8 may be (e.g.,

[0605] In certain embodiments, R 8 is unsubstituted C 4-6 monocyclic cycloalkyl (e.g., cyclopentyl, cyclobutyl, or cyclohexyl); or R 8 is unsubstituted C 7-8 bicyclic (e.g., spirocyclic) cycloalkyl (e.g.,

[0606] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7) (when R 7 is -R 8 ), R 8 is heterocyclyl or heterocycloalkenyl of 4-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring is substituted with 1-4 independently selected R 7 '.

[0607] In some of these embodiments, R 8 is heterocyclyl of 4-8 ring atoms, wherein 1-2 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl is substituted with 1-3 independently selected R 7 '.

[0608] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7) (when R 7 is -R 8 ), R 8 is selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl, each of which is substituted with 1-3 (e.g., 2) independently selected R 7 ' (e.g., R 8 is selected from: (e.g.,

[0609]

[0610] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7) (when R 7 is -R 8 ), R8 is selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl, each of which is optionally substituted on one or more ring carbon atoms with 1-3 (e.g., 2) independently selected R 7 ’groups (e.g., R 8 is selected from: (e.g., R

[0611] (e.g., R 8 may be selected from the group consisting of, for example, R 8 is selected from: (e.g., R

[0612] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7) (when R 7 is -R 8 ), R 8 is a spirocyclic heterocyclyl of 6-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring is optionally substituted with 1-4 independently selected R 7 ’groups, for example: Optionally, each R 7 ’is an independently selected halo, for example -F.

[0613] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7) (when R 7 is -R 8 ), R 8 is a monocyclic heterocyclyl of 3-8 ring atoms, wherein 1-2 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 .

[0614] In certain of these embodiments, R 8is azetidinyl (e.g., oxetanyl, pyrrolidinyl (e.g., tetrahydrofuranyl, tetrahydropyranyl, piperidinyl (e.g., for example piperazinyl (e.g., morpholinyl and azepanyl, wherein the ring nitrogen atom is optionally substituted with R d .

[0615] In certain of these embodiments, R d is C 1-6 alkyl optionally substituted with 1-3 substituents each independently selected from halo, C 1-3 alkoxy and C 1-3 haloalkoxy, e.g., wherein R d is C 2-4 alkyl substituted with 1-3 independently selected halo (e.g.,

[0616] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1) or (I-7), R 7 is -L 3 -R 9 .

[0617] In certain of these embodiments, L 3 is -O-.

[0618] In certain embodiments, L 3 is -NH-.

[0619] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1) or (I-7), when R 7 is -L 3 -R 9 , R 9 is C 3-12 cycloalkyl or C 3-12 cycloalkenyl, each optionally substituted with 1-4 independently selected R 7 .

[0620] In certain embodiments of Formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), when R 7 is -L 3 -R 9 , R 9 is C 7 cycloalkyl optionally substituted with 1-2 independently selected R 4-8 '.

[0621] In certain of these embodiments, R 9 is cyclobutyl, cyclopentyl, cyclohexyl, or spiro[3.3]heptyl, each of which is optionally substituted with 1-2 independently selected R 7 ' (e.g., unsubstituted).

[0622] In certain embodiments of Formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), when R 7 is -L 3 -R 9 , R 9 is heterocyclyl of 4-8 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring are substituted with 1-2 independently selected R 7 '.

[0623] In certain embodiments, R 9 is selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and azepanyl, each of which is optionally substituted with 1-2 independently selected R 7 ' (e.g., unsubstituted).

[0624] In certain embodiments of Formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), when R 7 is -L 3 -R 9 , R7 yes

[0625] In some embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), when present, R 7 Independently selected from: halogen, -CN, -OH, optionally by R a Replacement -C 1-4 Alkyl, -C 1-4 Halogenated alkyl, optionally R a Replacement -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, S(O) 1-2 (C 1-4 Alkyl groups, -NR'R", -S(O) 1-2 (NR'R”), -C 1-4 Thioalkoxy, -C(=O)(C 1-4 Alkyl), -C(=O)O(C 1-4 Alkyl groups, -C(=O)OH and -C(=O)N(R')(R”).

[0626] In some of these implementations, when present, each R 7 'Independently selected from: halogen, -CN, optionally R a Replacement -C 1-4 Alkyl, -C 1-4 Halogenated alkyl, optionally R a Replacement -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, S(O) 1-2 (C 1-4 Alkyl groups, -NR'R", -S(O) 1-2 (NR'R”), -C 1-4 Thioalkoxy, -C(=O)(C 1-4 Alkyl), -C(=O)O(C 1-4 Alkyl groups) and -C(=O)N(R')(R”). For example, when present, each R 7 'Can be -F.' As another non-restrictive instance, when present, each R 7 'Is C an independent choice 1-3 Alkyl groups, such as methyl groups. As a further non-limiting example, when present, each R... 7 'Is C an independent choice 1-3haloalkyl, e.g., -CF3.

[0627] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), each occurrence of R 7 is independently selected from:

[0628] optionally substituted with R a -C 1-4 alkyl, e.g., unsubstituted C 1-4 alkyl (e.g., methyl, ethyl, n-propyl); -C a -C 1-4 alkyl (e.g., substituted with OH or C 3-6 cycloalkyl; -CN; -C 1-4 alkyl); -CN; -C a alkoxy, e.g., unsubstituted C 1-6 alkoxy (e.g., methoxy); or -C 1-6 alkoxy (e.g., substituted with OH or C a cycloalkyl; -CN; -C 1-6 alkoxy (e.g., substituted with OH or C 3-6 cycloalkyl; -CN; -C 1-4 alkoxy); and

[0629] each remaining R 7 is independently halogen (e.g., -F).

[0630] In certain embodiments of formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), or (I-7), n2 is 0.

[0631] In certain embodiments of formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), or (I-7), n2 is 1 or 2. For example, n2 can be 1.

[0632] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), each occurrence of R c is independently selected from: halogen; cyano; C 1-10 alkyl; C 1-4 alkoxy; C 1-4 haloalkoxy; -S(O)1-2 (C 1-4 alkyl); -C(=O)(C 1-10 alkyl); and -C(=O)O(C 1-4 alkyl).

[0633] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), each R c is, independently, selected from the group consisting of: (a) halogen; (b) cyano; (c) C 1-10 alkyl; (g) C 1-4 alkoxy; (h) C 1-4 haloalkoxy; (i) -S(O) 1-2 (C 1-4 alkyl); and -C(=O)(C 1-10 alkyl).

[0634] In certain of these embodiments, each R c is halogen (e.g., -F, -Br, or -Cl) or cyano. For example, R c may be -F. As another non-limiting example, R c may be -Cl.

[0635] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), Q is NH.

[0636] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), Q is N(C 1-3 alkyl), wherein C 1-3 alkyl is optionally substituted with R a .

[0637] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), Q is *-NH-(C 1-3 alkylene), where the asterisk represents the point of attachment to W.

[0638] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), W is C(=O).

[0639] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), W is C(=C-NO2) or C(=N-CN).

[0640] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), W is S(O)2, C(=S), or C(=NR d ).

[0641] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), Q is NH; and W is C(=O).

[0642] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 1a , R 1b , R 1c , and R 1dEach group is independently selected from: H; halogen; cyano; optionally surrounded by 1-2 R groups. a Replacement C 1-6 Alkyl; C 2-6 alkenyl; C 2-6 alkynyl group; C 1-4 Halogenated alkyl; C 1-4 Alkoxy; C 1-4 Halogenated alkoxy group; -S(O) 1-2 (C 1-4 Alkyl); -S(O)(=NH)(C 1-4 Alkyl); SF5; -NR e R f ;–OH;-S(O) 1-2 (NR'R”); -C 1-4 Thioalkoxy group; -NO2; -C(=O)(C 1-4 Alkyl); -C(=O)O(C 1-4 Alkyl); and -C(=O)N(R')(R”).

[0643] In some embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 1a R 1b R 1c and R 1d Each is H.

[0644] In some other implementations, R 1a R 1b R 1c and R 1d One or two of them are not H; the rest are R. 1a R 1b R 1c and R 1d Each is H.

[0645] In some embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 1a and R 1d Each is independently selected from H and halogens. For example, R 1a and R 1d Each can be H.

[0646] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 1b is not H; R 1a , R 1c , and R 1d are each H.

[0647] In certain of these embodiments, R 1b is halogen (e.g., -F or -Cl (e.g., -F)).

[0648] In other embodiments, R 1b is selected from: C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy (e.g., OCHF2), -CN, -SF5, C 1-4 thioalkoxy (e.g., SMe), and S(O)2(C 1-4 alkyl) (e.g., S(O)2Me); and R 1a and R 1d are each H.

[0649] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 1b and R 1c are each not H; R 1a and R 1d are each H.

[0650] In certain of these embodiments, R 1c is halogen (e.g., -F); R 1b is selected from: C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy (e.g., OCHF2), -CN, -SF5, C 1-4 thioalkoxy (e.g., SMe), and S(O)2(C 1-4 alkyl) (e.g., S(O)2Me); and R 1a and R 1d are each H.

[0651] In some other implementations, R 1b and R 1c Each is an independently chosen halogen. For example, R 1b and R 1c Each is –F.

[0652] In some embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 2 It's H.

[0653] In some embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 2 R is arbitrarily selected by 1-3 independent choices a Substituted -C(O)(C 1-6 Alkyl); or optionally alkyl groups selected independently by 1-3 R groups. a Replacement -S(O) 1-2 (C 1-4 Alkyl groups (e.g., S(O)2Me).

[0654] As a non-limiting example of the foregoing implementation, R 2 It can be selected from: C(=O)Me, S(O)2Me,

[0655]

[0656] In some embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 6 It is H.

[0657] In some embodiments, the compound of formula (I) is a compound of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a):

[0658]

[0659]

[0660] or a pharmaceutically acceptable salt thereof, wherein:

[0661] R 1a , R 1b , R 1c , R 1d each independently is selected from the group consisting of: H; halogen; cyano; C a 1-6C 1-6 alkyl optionally substituted with 1-2 R 1-4 ; C 1-4 haloalkyl; C 1-4 alkoxy; and C c haloalkoxy;

[0662] n2 is 0, 1, or 2;

[0663] each R 1-3 is independently selected from the group consisting of: halogen, cyano, C 1-3 1-6C 8 alkyl and C 1 alkoxy;

[0664] R 2 is selected from the group consisting of:

[0665] · wherein m1 and m2 are independently 0, 1, or 2; T d is CH or N; and T d is CH2, NH, NR 0-2 , or O;

[0666] · a spirocyclic heterocyclyl ring of 6-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N(R 7 ), O, and S(O) 6-12 , and wherein one or more ring carbon atoms of the heterocyclyl ring are optionally substituted with 1-4 independently selected R 7 '; and

[0667] · a spirocyclic C 1a cycloalkyl, optionally substituted with 1-4 independently selected R 1b '.

[0668] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-1a), (I-2a), or (I-3a):

[0669]

[0670] or a pharmaceutically acceptable salt thereof, wherein:

[0671] R 1c , R 1deach independently selected from the group consisting of: H; halo; cyano; optionally substituted C a substituted C 1-6 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0672] n2 is 0, 1, or 2;

[0673] each R c is, independently selected from the group consisting of: halo, cyano, C 1-3 alkyl and C 1-3 alkoxy;

[0674] R 8 is selected from the group consisting of:

[0675] · wherein m1 and m2 are independently 0, 1, or 2, T 1 is CH or N; and

[0676] • a spirocyclic heterocyclyl of 6-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring are optionally substituted with 1-4 independently selected R 7 .

[0677] In some embodiments, the compound is of Formula (I-1a). In some embodiments, the compound is of Formula (I-2a). In some embodiments, the compound is of Formula (I-3a).

[0678] In certain embodiments of Formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 2 is H. In certain embodiments of Formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 6 is H.

[0679] In certain embodiments of Formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), n2 is 1; R c is at the ortho position of R 8 . In certain embodiments, R c is halo, for example, -Cl. In certain embodiments, R c is C 1-3 alkyl, for example, methyl.

[0680] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 1a is H; R 1d is H or halogen. 1c

[0681] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 1b is halogen, e.g., -F or -Cl. In certain embodiments of formula (I-1a), (I-2a), or (I-3a), R 1b is C 1-6 alkyl or C 1-4 haloalkyl, e.g., methyl or -CHF2.

[0682] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 8 is wherein m1and m2are independently 0, 1, or 2; T 1 is CH or N. For example, R 8 may be selected from:

[0683] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 8 is wherein m1and m2are independently 0, 1, or 2; T 1 is CH or N. For example, R 8 may be selected from:

[0684] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 8 is selected from: wherein m1and m2are independently 0, 1, or 2; T 1 is CH or N; and T 2 is CH2, NH, NR d , or O.

[0685] For example, R 8 may be selected from:

[0686] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R​8 is wherein m1, m2, m3, and m4 are independently 0, 1, or 2, provided that m1+m2+m3+m4≤6, T 1 is CH or N. For example, R 8 may be selected from:

[0687] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 8 is wherein m1, m2, m3, and m4 are independently 0, 1, or 2, provided that m1+m2+m3+m4≤6, T 1 is CH or N. For example, R 8 may be

[0688] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 8 is selected from:

[0689] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), each R 7 is independently selected from: C 1-3 alkyl; C 1-3 haloalkyl; and halogen, for example wherein each R 7 is independently selected from: methyl, CF3, and -F; and R d is C 1-6 alkyl, for example C 2-4 alkyl, optionally substituted with 1-3 independently selected halogens, for example -F.

[0690] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), each R 7’ is independently selected from C 1-3 alkyl and halogen, for example methyl and -F.

[0691] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R d is C 1-6 alkyl, for example C 2-4 alkyl, optionally substituted with 1-3 independently selected halogens, for example -F.

[0692] In some embodiments, the compound of formula (I) is the compound of formula (I-3a):

[0693]

[0694] Or its pharmaceutically acceptable salt, wherein:

[0695] R 1a R 1b R 1c R 1d Each group is independently selected from: H; halogen; cyano; optionally surrounded by 1-2 R groups. a Replacement C 1-6 Alkyl; C 1-4 Halogenated alkyl; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups;

[0696] n2 is 0, 1, or 2;

[0697] When it exists, each R c Independently selected from: halogen, cyano, C 1-3 Alkyl and C 1-3 Alkoxy;

[0698] R 8 Selected from:

[0699] · Where m1 and m2 are independently 0, 1, or 2; T 1 It is CH or N; T 2 It is CH2, NH, NR d Or O;

[0700] • Spirocyclic heterocyclic groups with 6-12 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S(O) 0-2 And one or more ring carbon atoms of the heterocyclic base ring are optionally separated by 1-4 independently chosen R 7 'replace; and

[0701] · Spiroring C 6-12 Cycloalkyl groups, optionally defined by 1-4 independently selected R groups 7 'replace.

[0702] In some embodiments of formula (I-3a), R 8 yes And optionally, each R 7 ' is an independently chosen halogen, such as –F. In some of these implementations, R 8 Selected from: and optionally wherein each R 7 is -F. For example, R 8 may be

[0703] In certain embodiments of formula (I-3a), R 1a and R 1d are H; R 1b is halogen, for example -F; R 1c is -H or halogen, for example -H or -F; and R 2 is H.

[0704] In certain embodiments of formula (I-3a), the compound is of formula (I-3a-1):

[0705]

[0706] In certain embodiments of formula (I-3a) or formula (I-3a-1), R c is halogen, for example -F or -Cl.

[0707] In certain embodiments of formula (I-3a) or formula (I-3a-1), R 8 is and / or R 1a and R 1d are H; and / or R 1b is -F; and / or R 1c is -H or -F; and / or R 2 is H; and / or R c is halogen.

[0708] In certain embodiments, the compound of formula (I) is a compound of formula (I-2a):

[0709]

[0710] or a pharmaceutically acceptable salt thereof, wherein:

[0711] R 1a , R 1b , R 1c , R 1d are each independently selected from the group consisting of: H; halogen; cyano; C a alkyl optionally substituted with 1-2 R 1-6 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0712] n2 is 0, 1, or 2;

[0713] R c is independently selected from the group consisting of: halogen, cyano, C 1-3 alkyl and C 1-3 alkoxy;

[0714] R 8 is selected from the group consisting of:

[0715] · wherein m1and m2are independently 0, 1 or 2; T 1 is CH or N; T 2 is CH2, NH, NR d or O;

[0716] • a spirocyclic heterocyclyl of 6-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring are optionally substituted with 1-4 independently selected R 7 ; and

[0717] • a spirocyclic C 6-12 cycloalkyl, optionally substituted with 1-4 independently selected R 7 .

[0718] In certain embodiments of formula (I-2a), R 8 is and optionally wherein each R 7 ’ is an independently selected halogen, for example -F; and optionally wherein R d is C 2-4 alkyl substituted with 1-3 independently selected halogens, for example -F. In certain of these embodiments, R 8 is selected from the group consisting of: and optionally wherein each R 7 ’ is -F; and optionally wherein R d is C 2-4 alkyl optionally substituted with 1-3 -F. For example, R 8 may be

[0719] In certain embodiments of formula (I-2a), R 1a , R 1d and R 1c are each H; R 1b is -H or halogen, for example -H, -Cl or -F; and R 2 is H.

[0720] In certain embodiments of formula (I-2a), the compound is of formula (I-2a-1):

[0721]

[0722] In certain embodiments of formula (I-2a) or (I-2a-1), R c is -halo.

[0723] In certain embodiments of formula (I-2a) or (I-2a-1), R 8 is and / or R 1a , R 1d , and R 1c are H; and / or R 1b is -H, -Cl, or -F; and / or R 2 is H; and / or R c is halo.

[0724] In certain embodiments, the compound of formula (I) is a compound of formula (I-7a):

[0725]

[0726] or a pharmaceutically acceptable salt thereof, wherein:

[0727] P 1 and P 2 are each independently selected from N and CH; 1 and P 2 are each independently selected from N and CH;

[0728] R 1a , R 1b , R 1c , R 1d are each independently selected from H; halo; cyano; C a alkyl optionally substituted with 1-2 R 1-6 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0729] R 8 is selected from:

[0730] · wherein m1and m2are independently 0, 1, or 2; T 1 is CH or N; T 2 is CH2, NH, NR d , or O;

[0731] • a spirocyclic heterocyclyl group of 6-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring is optionally substituted with 1-4 independently selected R 7 ; and

[0732] • a spirocyclic C 6-12 cycloalkyl group, optionally substituted with 1-4 independently selected R 7 .

[0733] In certain embodiments of formula (I-7a), R 8 is and optionally wherein each R 7 is an independently selected halogen, e.g., -F. In certain of these embodiments, R 8 is selected from the group consisting of: and optionally wherein each R 7 is -F. For example, R 8 is

[0734] In certain embodiments of formula (I-7a), R 1a , R 1d , and R 1c are H; R 1b is halogen, e.g., -Cl; and R 2 is H.

[0735] In certain embodiments of formula (I-7a), R 8 is and / or R 1a , R 1d , and R 1c are H; and / or R 1b is -Cl; and / or R 2 is H.

[0736] In certain embodiments, the compound of formula (I) is a compound of formula (I-1a):

[0737]

[0738] or a pharmaceutically acceptable salt thereof, wherein:

[0739] R 1a , R 1b , R 1c , R 1d are each independently selected from the group consisting of: H; halogen; cyano; C1-6alkyl optionally substituted with 1-2 R a ; and1-6 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0740] n2 is 0, 1, or 2;

[0741] each R c is independently selected from the group consisting of: halo, cyano, C 1-3 alkyl and C 1-3 alkoxy;

[0742] R 8 is selected from:

[0743] · wherein m1 and m2 are independently 0, 1, or 2; T 1 is CH or N; T 2 is CH2, NH, NR d or O;

[0744] • a spirocyclic heterocyclyl of 6-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring are optionally substituted with 1-4 independently selected R 7 '; and

[0745] • spirocyclic • C 6-12 cycloalkyl, optionally substituted with 1-4 independently selected R 7 '.

[0746] In certain embodiments of Formula (I-1a), R 8 is and optionally wherein each R 7 ' is an independently selected halo, e.g., -F. In certain of these embodiments, R 8 is selected from: and optionally wherein each R 7 ' is -F. For example, R 8 may be selected from:

[0747] In certain embodiments of Formula (I-1a), R 8 is wherein: m1, m2, m3, and m4 are independently 0, 1, or 2, provided that m1+m2+m3+m4≤6; T 1 is CH or N; and each R 7 ' is independently selected from C1-3 Alkyl; C 1-3 Halogenated alkyl groups; and halogens, such as methyl, CF3, and –F. In some of these embodiments, R 8 Selected from: And optionally, each R 7 'is –F. For example, R 8 You can choose from:

[0748] In some embodiments of formula (I-1a), R 1a and R 1d It is H; R 1b It is a halogen, such as –F or -Cl; R 1c It is -H or a halogen, such as –H, -F or -Cl; and R 2 It is H.

[0749] In some embodiments of formula (I-1a), the compound has formula (I-1a-1):

[0750]

[0751] In some embodiments of formula (I-1a) or formula (I-1a-1), R c It is a halogen, such as –F or –Cl.

[0752] In some embodiments of formula (I-1a) or (I-1a-1), R 8 Selected from: and / or R 1a and R 1d It is H; and / or R 1b It is –F or –Cl; and / or R 1c It is –H, -F, or –Cl; and / or R 2 It is H; and / or R c It is halogen.

[0753] In some embodiments of formula (I-1a) or (I-1a-1), R 8 Selected from: and / or R 1a and R 1d It is H; and / or R 1b It is –F or –Cl; and / or R 1c It is –H, -F, or –Cl; and / or R 2 It is H; and / or R c It is halogen.

[0754] In some embodiments, the compound of formula (I) is the compound of formula (I-1a):

[0755]

[0756] Or its pharmaceutically acceptable salt, wherein:

[0757] R 1a R 1b R 1c R 1d Each group is independently selected from: H; halogen; cyano; optionally surrounded by 1-2 R groups. a Replacement C 1-6 Alkyl; C 1-4 Halogenated alkyl; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups;

[0758] R 2 It is H;

[0759] n2 is 0, 1, or 2;

[0760] When it exists, each R c Independently selected from: halogen, cyano, C 1-3 Alkyl and C 1-3 Alkoxy;

[0761] R 8 yes in:

[0762] m1 and m2 are independently 0, 1 or 2;

[0763] T 1 Is it CH or N; and

[0764] Each R 7 'Selected independently from: C' 1-3 Alkyl; C 1-3 Halogenated alkyl groups; and halogens, such as methyl, CF3 and –F.

[0765] In some of these embodiments, the compound is a compound of formula (I-1a):

[0766]

[0767] Or its pharmaceutically acceptable salt, wherein:

[0768] R 1a and R 1d It is H;

[0769] R 1b and R 1c Each group is independently selected from: H; halogen; cyano; optionally surrounded by 1-2 R groups.a substituted C 1-6 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0770] R 2 is H;

[0771] n2 is 0, 1;

[0772] R c is selected from the group consisting of: halo and cyano;

[0773] R 8 is selected from the group consisting of: and

[0774] each R 7 ’ is independently halo or C 1-3 alkyl, for example, -F or C 1-3 alkyl.

[0775] In certain of the foregoing embodiments, the compound is a compound of Formula (I-1a-1):

[0776]

[0777] or a pharmaceutically acceptable salt thereof, wherein:

[0778] R 1a and R 1d are H;

[0779] R 1b is halo;

[0780] R 1c is H or halo;

[0781] R 2 is H;

[0782] R c is selected from the group consisting of: -F, -Cl, -Br, and cyano; and

[0783] R 8 is selected from the group consisting of:

[0784] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-1a):

[0785]

[0786] or a pharmaceutically acceptable salt thereof, wherein:

[0787] R 1a , R 1b , R1c , R 1d each independently selected from the group consisting of: H; halogen; cyano; C a substituted C 1-6 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0788] R 2 is H;

[0789] n2 is 0, 1, or 2;

[0790] each R c is independently selected from the group consisting of: halogen, cyano, C 1-3 alkyl, and C 1-3 alkoxy;

[0791] R 8 is wherein:

[0792] m1 and m2 are independently 0, 1, or 2;

[0793] T 1 is CH or N; and

[0794] R d is C 1-6 alkyl, for example C 2-4 alkyl optionally substituted with 1-3 independently selected halogen, for example -F.

[0795] In certain of these embodiments, the compound is of Formula (I-1a):

[0796]

[0797] or a pharmaceutically acceptable salt thereof, wherein:

[0798] R 1a and R 1d are H;

[0799] R 1b and R 1c each independently selected from the group consisting of: H; halogen; cyano; C a substituted C 1-6 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0800] R 2 is H;

[0801] n2 is 0, 1;

[0802] R is H or halogen; c is selected from the group consisting of: halogen and cyano;

[0803] R 8 is selected from the group consisting of: and

[0804] R d is C 2-4 alkyl optionally substituted with 1-3 independently selected halogen, e.g., -F. In certain of the foregoing embodiments, the compound is a compound of formula (I-1a-1):

[0805]

[0806] or a pharmaceutically acceptable salt thereof, wherein:

[0807] R 1a and R 1d is H;

[0808] R 1b is halogen;

[0809] R 1c is H or halogen;

[0810] R 2 is H;

[0811] R c is selected from the group consisting of: -F, -Cl, -Br, and cyano;

[0812] R 8 is selected from the group consisting of: and

[0813] R d is C 2-4 alkyl substituted with 1-3 independently selected halogen, e.g., -F.

[0814] In certain embodiments, the compound of formula (I) is a compound of formula (I-1a):

[0815]

[0816] or a pharmaceutically acceptable salt thereof, wherein:

[0817] R 1a , R 1b , R 1c , R 1d are each independently selected from the group consisting of: H; halogen; cyano; C a alkyl optionally substituted with 1-2 R 1-6 ; C 1-4 haloalkyl; C 1-4 alkoxy; and C1-4 haloalkoxy;

[0818] R 2 is H;

[0819] n2 is 0, 1, or 2;

[0820] each R c is independently selected from the group consisting of: halo, cyano, C 1-3 alkyl, and C 1-3 haloalkyl;

[0821] R 8 is selected from the group consisting of: wherein:

[0822] m1 and m2 are independently 0, 1, or 2;

[0823] T 1 is CH or N;

[0824] T 2 is CH2, NH, NR d , or O; and

[0825] each R 7 is independently selected from the group consisting of C 1-3 alkyl, and C 1-3 haloalkyl.

[0826] In certain of these embodiments, the compound is of Formula (I-1a):

[0827]

[0828] or a pharmaceutically acceptable salt thereof, wherein:

[0829] R 1a and R 1d are H;

[0830] R 1b and R 1c are each independently selected from the group consisting of: H; halo; cyano; C a alkyl optionally substituted with 1-2 R 1-6 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0831] R 2 is H;

[0832] n2 is 0, 1;

[0833] R c is selected from the group consisting of: halo and cyano;

[0834] R 8 is selected from: and

[0835] each R 7 ' is independently selected from C 1-3 alkyl and C 1-3 haloalkyl.

[0836] In certain of the foregoing embodiments, the compound is a compound of Formula (I-1a-1):

[0837]

[0838] or a pharmaceutically acceptable salt thereof, wherein:

[0839] R 1a and R 1d is H;

[0840] R 1b is halogen;

[0841] R 1c is H or halogen;

[0842] R 2 is H;

[0843] R c is selected from: -F, -Cl, -Br, and cyano;

[0844] R 8 is selected from: and

[0845] each R 7 ' is independently selected from C 1-3 alkyl and C 1-3 haloalkyl.

[0846] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-1a):

[0847]

[0848] or a pharmaceutically acceptable salt thereof, wherein:

[0849] R 1a , R 1b , R 1c , R 1d are each independently selected from: H; halogen; cyano; C a alkyl optionally substituted with 1-2 R 1-6 ; C 1-4 haloalkyl; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0850] R 2 is H;

[0851] n2 is 0, 1, or 2;

[0852] each R c is independently selected from the group consisting of: halogen, cyano, C 1-3 alkyl, and C 1-3 haloalkyl; and halogen, for example, methyl, CF3, and -F.

[0853] R 8 is wherein:

[0854] m1, m2, m3, and m4 are independently 0, 1, or 2, provided that m1+m2+m3+m4≤6;

[0855] T 1 is CH or N; and

[0856] each R 7 is independently selected from the group consisting of: C 1-3 alkyl; C 1-3 haloalkyl; and halogen, for example, methyl, CF3, and -F.

[0857] In certain of these embodiments, the compound is of Formula (I-1a):

[0858]

[0859] or a pharmaceutically acceptable salt thereof, wherein:

[0860] R 1a and R 1d are H;

[0861] R 1b and R 1c are each independently selected from the group consisting of: H; halogen; cyano; C a alkyl optionally substituted with 1-2 R 1-6 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0862] R 2 is H;

[0863] n2 is 0, 1;

[0864] R c is selected from the group consisting of: halogen and cyano;

[0865] R 8 is selected from the group consisting of: and

[0866] each R 7independently selected from the group consisting of: C 1-3 alkyl and halo, for example, methyl and -F.

[0867] In certain of the foregoing embodiments, the compound is a compound of Formula (I-1a-1):

[0868]

[0869] or a pharmaceutically acceptable salt thereof, wherein:

[0870] R 1a and R 1d are H;

[0871] R 1b is halo;

[0872] R 1c is H or halo;

[0873] R 2 is H;

[0874] R c is selected from the group consisting of: -F, -Cl, -Br, and cyano; and

[0875] R 8 is selected from the group consisting of:

[0876] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-1a):

[0877]

[0878] or a pharmaceutically acceptable salt thereof, wherein:

[0879] R 1a , R 1b , R 1c , R 1d are each independently selected from the group consisting of: H; halo; cyano; C a alkyl optionally substituted with 1-2 R 1-6 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0880] R 2 is H;

[0881] n2 is 0, 1, or 2;

[0882] when present, each R c is independently selected from the group consisting of: halo, cyano, C 1-3 alkyl, and C 1-3 alkoxy;

[0883] R 8 is wherein:

[0884] m1, m2, m3, and m4 are independently 0, 1, or 2, provided that m1+m2+m3+m4≤6;

[0885] T 1 is CH or N; and

[0886] R d is C 1-6 alkyl, optionally substituted with 1-3 independently selected halo, e.g., -F. 2-4

[0887] In certain of these embodiments, the compound is of Formula (I-1a):

[0888]

[0889] or a pharmaceutically acceptable salt thereof, wherein:

[0890] R 1a and R 1d are H;

[0891] R 1b and R 1c are each independently selected from the group consisting of: H; halo; cyano; C a alkyl optionally substituted with 1-2 R 1-6 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; and C 1-4 haloalkoxy;

[0892] R 2 is H;

[0893] n2 is 0, 1;

[0894] when present, R c is selected from the group consisting of: halo and cyano;

[0895] R 8 is and

[0896] R d is C 2-4 alkyl, optionally substituted with 1-3 independently selected halo, e.g., -F.

[0897] In certain of the foregoing embodiments, the compound is of Formula (I-1a-1):

[0898]

[0899] ​Or its pharmaceutically acceptable salt, wherein:

[0900] R 1a and R 1d It is H;

[0901] R 1b It is halogen;

[0902] R 1c It is H or halogen;

[0903] R 2 It is H;

[0904] R c Selected from: -F, -Cl, -Br and cyano groups; and

[0905] R 8 yes and

[0906] R d C is replaced by 1-3 independently selected halogens, such as –F. 2-4 alkyl.

[0907] In some embodiments, the compound of formula (I) is a compound of formula (I-6a):

[0908]

[0909] Or its pharmaceutically acceptable salt, wherein:

[0910] R 1a R 1b R 1c R 1d Each group is independently selected from: H; halogen; cyano; optionally surrounded by 1-2 R groups. a Replacement C 1-6 Alkyl; C 1-4 Halogenated alkyl; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups;

[0911] n2 is 0, 1, or 2;

[0912] When it exists, each R c Independently selected from: halogen, cyano, C 1-3 Alkyl and C 1-3 Alkoxy;

[0913] R 8 Selected from:

[0914] · Where m1 and m2 are independently 0, 1, or 2; and T 2 It is CH2, NH, NRd or O;

[0915] • a spirocyclic heterocyclyl of 6-12 ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein one or more ring carbon atoms of the heterocyclyl ring are optionally substituted with 1-4 independently selected R 7 '; and

[0916] • spirocyclic • C 6-12 cycloalkyl, optionally substituted with 1-4 independently selected R 7 '.

[0917] In certain embodiments of formula (I-6a), R 8 is wherein: m1, m2, m3, and m4 are independently 0, 1, or 2, provided that m1+m2+m3+m4≤6; and

[0918] each R 7 ' is independently selected from the group consisting of: C 1-3 alkyl; C 1-3 haloalkyl; and halogen, for example, methyl, CF3, and -F.

[0919] In certain of these embodiments, R 8 is For example, R 8 may be

[0920] In certain embodiments of formula (I-6a), R 1a , R 1d , and R 1c are H; R 1b is halogen, for example, -Cl; and R 2 is H.

[0921] In certain embodiments of formula (I-6a), n2 is 0.

[0922] In certain embodiments of formula (I-6a), n2 is 0; and / or R 8 is and / or R 1a , R 1d , and R 1c are H; and / or R 1b is -Cl; and / or R 2 is H.

[0923] In certain embodiments, the compound of formula (I) is a compound of formula (I-4a):

[0924]

[0925] Or its pharmaceutically acceptable salt, wherein:

[0926] R 1a R 1b R 1c R 1d Each group is independently selected from: H; halogen; cyano; optionally surrounded by 1-2 R groups. a Replacement C 1-6 Alkyl; C 1-4 Halogenated alkyl; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups;

[0927] n2 is 0, 1, or 2;

[0928] When it exists, each R c Independently selected from: halogen, cyano, C 1-3 Alkyl and C 1-3 Alkoxy;

[0929] R 8 Selected from:

[0930] · Where m1 and m2 are independently 0, 1, or 2; T 1 It is CH or N; T 2 It is CH2, NH, NR d Or O;

[0931] • Spirocyclic heterocyclic groups with 6-12 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S(O) 0-2 And one or more ring carbon atoms of the heterocyclic base ring are optionally separated by 1-4 independently chosen R 7 'replace; and

[0932] Spiroring C 6-12 Cycloalkyl groups, optionally defined by 1-4 independently selected R groups 7 'replace.

[0933] In some embodiments of formula (I-4a), R 8 yes And optionally, each R 7 ' is an independently chosen halogen, such as –F. In some of these implementations, R 8 Selected from: And optionally, each R 7 'is –F. For example, R8 may be

[0934] In certain embodiments of formula (I-4a), R 1a and R 1d is H; R 1b is halogen, e.g., -F or -Cl; R 1c is -H or halogen, e.g., -H or -F; and R 2 is H.

[0935] In certain embodiments of formula (I-4a), n2 is 1; the compound has formula (I-4a-1):

[0936]

[0937] In certain embodiments of formula (I-4a) or formula (I-4a-1), R c is halogen.

[0938] In certain embodiments of formula (I-4a), n2 is 0.

[0939] In certain embodiments of formula (I-4a) or formula (I-4a-1), R 8 and / or R 1a and R 1d is H; and / or R 1b is -F or -Cl; and / or R 1c is -H or -F; and / or R 2 is H.

[0940] In certain embodiments of formula (I-1a) (e.g., I-1a-1), (I-2a) (e.g., I-2a-1), (I-3a) (e.g., I-3a-1), (I-4a) (e.g., I-4a-1), (I-5a), (I-6a), or (I-7a), R 6 is H.

[0941] Non-limiting exemplary compounds of formula I

[0942] In some embodiments, the compound is selected from the compounds described in Table I, or a pharmaceutically acceptable salt thereof.

[0943] Table I

[0944]

[0945]

[0946]

[0947] ​

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970] Pharmaceutical compositions and administration

[0971] SUMMARY

[0972] In some embodiments, the chemical entity (e.g., a compound that inhibits (e.g., antagonizes) STING, or a pharmaceutically acceptable salt thereof, and / or a hydrate, and / or a co-crystal, and / or a pharmaceutical combination thereof) is administered as a pharmaceutical composition comprising the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents described herein.

[0973] In some embodiments, the chemical entity 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 polyethyleneglycol 1000 succinate, surfactants used in making drug delivery vehicles, 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 carboxymethylcellulose, 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-cyclodextrin, or other solubilized derivatives can also be used to provide delivery of the compounds described herein. Dosage forms or compositions comprising a range of 0.005-100% of the chemical entities described herein can be prepared, with the balance being non-toxic excipients. Compositions contemplated can comprise 0.001-100% of the chemical entities provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, and in yet another embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK, 2012).

[0974] Routes of administration and composition components

[0975] In some embodiments, the chemical entities described herein, or pharmaceutical compositions thereof, can be administered to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, transdermal, intracervical, intrasinus, intratracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intradural, intradermal, intragastric, gingival, intrarectal, intralymphatic, intramedullary, intramembranous, intramuscular, intranodal, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, transdermal, peridural, rectal, respiratory (inhaled), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, and vaginal. In some embodiments, the preferred route of administration is parenteral (e.g., intratumoral).

[0976] The compositions can be formulated for parenteral administration, e.g., formulated for injection by intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. Typically, such compositions can be presented in unit dosage form, e.g., in ampules or in multidose containers. The compositions can be suspensions, solutions or emulsions in oily or aqueous vehicles, or can be presented as dry products for reconstitution with a liquid medium. The compositions can be formulated for injection at controlled release, e.g., using biodegradable polymers, e.g., polylactide-polyglycolide.

[0977] 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 reconstitution into sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0978] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., 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. Prevention of the action of microorganisms can be achieved 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.

[0979] Aqueous and non-aqueous sterile injection solutions are prepared by dissolving the active compound in a suitable solvent with a desired amount of the various 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, 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.

[0980] Intratumoral injection see for example 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.

[0981] Pharmaceutically acceptable excipients that can be used in rectal compositions as gels, creams, enemas or rectal suppositories include, but are not limited to, one or more of the following: cocoa butter glycerides, synthetic polymers (such as polyvinylpyrrolidone, PEG (such as PEG ointment)), glycerin, glycerogelatin, hydrogenated vegetable oil, poloxamer, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycols, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, Anoxid SBN, vanilla flavouring oil, aerosol, parahydroxybenzoic acid esters in phenoxyethanol, methyl paraben sodium, propyl paraben sodium, diethylamine, carbomer, carbopol, methyl methoxybenzoate, polyoxyl cetylstearyl ether, caprylocaproyl macrogolglycerides, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-disulfit, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins (such as vitamins A and E) and potassium acetate.

[0982] In some embodiments, suppositories can be prepared by mixing a chemical entity described herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melt in the rectum to release the active compound. In other embodiments, the compositions for rectal administration are in the form of enemas.

[0983] In other embodiments, the compounds described herein, or pharmaceutical compositions thereof, are suitable for local delivery to the digestive tract or gastrointestinal tract by oral administration (e.g., solid or liquid dosage forms).

[0984] 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 carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, 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 retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as 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 forms can also contain buffering agents. Solid compositions of a similar type can 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.

[0985] In one embodiment, the composition can take the form of unit dosage forms such as, for example, pills or tablets, and therefore can contain, in addition to the 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, acacia, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives, or the like. In another solid dosage form, a powder, pill, solution, or suspension (e.g., in propylene glycol, vegetable oils, PEG’s, poloxamer 124, or triglycerides) is encapsulated in a capsule (gelatin or cellulose-based capsule). Unit dosage forms in which the chemical entity or other active agent provided herein is physically separated are also contemplated, such as capsules containing individual drug particles (or tablets in capsules); bilayer tablets; bilumen gel capsules; and the like. Enteric-coated or delayed release oral dosage forms are also contemplated.

[0986] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents, or preservatives, which are particularly useful in avoiding the growth or action of microorganisms. A variety of preservatives are well known, including, for example, phenol and ascorbic acid.

[0987] In certain embodiments, the excipients are sterile and generally free of undesirable substances. The compositions can be sterilized by conventional, well-known sterilization techniques. Sterility is not required for various oral dosage forms of excipients, such as tablets and capsules. The USP / NF standards are generally adequate.

[0988] In some embodiments, the solid oral dosage form can further comprise one or more components that chemically and / or structurally render the composition susceptible to delivery of the chemical entity to the stomach or lower Gl; for example, the ascending colon and / or transverse colon and / or distal colon and / or small intestine. See, e.g., Filipski, K.J. et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated by reference herein in its entirety, for exemplary formulation techniques.

[0989] Examples include upper Gl targeting techniques, such as the Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to the mucosal wall.

[0990] Other examples include lower Gl targeting techniques. To target various regions of the intestinal tract, several enteric / pH responsive coatings and excipients can be used. These materials are generally polymers designed to dissolve or erode at a specific pH range, selected based on the Gl region of desired drug release. These materials also serve to protect acid-labile drugs from erosion by gastric fluids or limit exposure in cases where the active ingredient can irritate the upper Gl (e.g., the hydroxypropyl methylcellulose phthalate series, Coateric (ethyl vinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methyl acrylate-methyl methacrylate copolymer), and Marcoat. Other techniques include dosage forms responsive to local gut flora, pressure-controlled colon delivery capsules, and Pulsincap.

[0991] Ophthalmic compositions can include, but are not limited to, any one or more of the following: viscosogens (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin); preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories Inc.), Purite (stabilized chlorine oxide complex; Allergan, Inc.).

[0992] Topical compositions can include ointments and creams. Ointments are semisolid formulations, usually based on petrolatum or other petroleum derivatives. Creams generally are viscous liquids or semisolid emulsions, usually either oil-in-water or water-in-oil, that contain the selected active agent. Cream bases generally are water-washable and include an oil phase, an emulsifier, and an aqueous phase. The oil phase is sometimes also called the "internal phase" and is usually composed of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase, which usually exceeds the oil phase in volume, and often contains a humectant, although not necessarily. The emulsifier in a cream formulation is usually a nonionic, anionic, cationic, or amphoteric surfactant. As with other carriers or vehicles, the ointment base should be inert, stable, nonirritating, and nontoxic.

[0993] In any of the foregoing embodiments, the pharmaceutical compositions described herein can comprise one or more of the following: a lipid, a bilayer-crosslinked multilamellar vesicle, a biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or a polyanhydride-based nanoparticle or microparticle, and a nanoporous particle-supported lipid bilayer.

[0994] Dosage

[0995] The dosage can vary depending upon the requirements of the patient, the severity of the disease being treated, and the particular compound being employed. Determination of the proper dosage for a particular situation is within the skill of those in the medical arts. The total daily dosage can be divided and administered in portions during the day, or by means of continuous delivery.

[0996] In some embodiments, the compounds described herein are administered at a dosage of about 0.001 mg / Kg to about 500 mg / Kg (e.g., about 0.001 mg / Kg to about 200 mg / Kg; about 0.01 mg / Kg to about 200 mg / Kg; about 0.01 mg / Kg to about 150 mg / Kg; about 0.01 mg / Kg to about 100 mg / Kg; about 0.01 mg / Kg to about 50 mg / Kg; about 0.01 mg / Kg to about 10 mg / Kg; about 0.01 mg / Kg to about 5 mg / Kg; about 0.01 mg / Kg to about 1 mg / Kg; about 0.01 mg / Kg to about 0.5 mg / Kg; about 0.01 mg / Kg to about 0.1 mg / Kg; about 0.1 mg / Kg to about 200 mg / Kg; about 0.1 mg / Kg to about 150 mg / Kg; about 0.1 mg / Kg to about 100 mg / Kg; about 0.1 mg / Kg to about 50 mg / Kg; about 0.1 mg / Kg to about 10 mg / Kg; about 0.1 mg / Kg to about 5 mg / Kg; about 0.1 mg / Kg to about 1 mg / Kg; about 0.1 mg / Kg to about 0.5 mg / Kg).

[0997] Dosing regimen

[0998] The foregoing doses can be administered daily (e.g., as a single dose or as two or more divided doses) or non-daily (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[0999] In some embodiments, the administration of the compound described herein is for a period of 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 another embodiment, the period of non-administration is for a period of 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 one embodiment, an individual is administered a therapeutic compound for a period of time, followed by a separate period of time. In another embodiment, an individual is administered a therapeutic compound for a first period of time, followed by a second period of time in which administration is ceased, followed by a third period of time in which administration of the therapeutic compound is resumed, followed by a fourth period of time in which administration is ceased. In one aspect of this embodiment, the period of administration of the therapeutic compound and the subsequent period of non-administration are repeated for a determined or undetermined period of time. In another embodiment, the period of administration is for a period of 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 another embodiment, the period of non-administration is for a period of 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.

[1000] Methods of treatment

[1001] In some embodiments, methods are provided for treating a subject having a condition, disease or disorder in which increased (e.g., excessive) STING activity (e.g., STING signaling) contributes to the pathogenesis and / or symptoms and / or progression of the condition, disease or disorder (e.g., an immune disorder, a cancer).

[1002] Indications

[1003] In some embodiments, the condition, disease or disorder is a cancer. Non-limiting examples of cancers include melanoma, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include breast cancer, colon cancer, rectal cancer, cancer of the kidney, lung cancer including small cell lung cancer and non-small cell lung cancer, lung adenocarcinoma and squamous carcinoma of the lung, squamous cell cancer (e.g., epithelial squamous cell cancer), cervical cancer, ovarian cancer, prostate cancer, prostate tumor, liver cancer, bladder cancer, peritoneal cancer, hepatocellular cancer, stomach cancer including gastrointestinal cancer, gastrointestinal stromal tumor, pancreatic cancer, head and neck cancer, glioblastoma, retinoblastoma, astrocytoma, theca cell tumor, nephroblastoma, hepatoma, hematological malignancies including non-Hodgkin's lymphoma (NHL), multiple myeloma, myelodysplasia, myeloproliferative disorder, chronic myelogenous leukemia, and acute hematological malignancies, endometrial cancer or uterine cancer, endometriosis, endometrial stromal sarcoma, fibrosarcoma, choriocarcinoma, salivary gland carcinoma, vulvar cancer, thyroid cancer, esophageal cancer, hepatic carcinoma, anal cancer, penile cancer, nasopharyngeal cancer, laryngeal cancer, Kaposi's sarcoma, mast cell sarcoma, ovarian sarcoma, uterine sarcoma, melanoma, malignant mesothelioma, skin cancer, Schwannoma, glioma, neuroblastoma, neuroectodermal tumor, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcoma, Ewing's sarcoma, peripheral primitive neuroectodermal tumor, urinary tract cancer, thyroid cancer, Wilms' tumor, and abnormal vascular proliferation associated with phagocytosis, edema (e.g., that associated with brain tumors) and Meigs' syndrome. In some cases, the cancer is melanoma.

[1004] In some embodiments, the condition, disease or disorder is a nervous system disease, which includes diseases involving the central nervous system (brain, brainstem, and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (part of which is located in the central and peripheral nervous systems). Non-limiting examples of such nervous system diseases 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; angioma; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Aronl-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet's disease; Bell's palsy; benign essential blepharospasm; benign focal; muscle atrophy; benign intracranial hypertension; Binswanger's disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal column tumors; 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 paralysis; cortical basal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorder; Cushing's syndrome; cytomegalic inclusion disease; cytomegalic virus 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; Dystonia; Early infantile epileptic encephalopathy; Empty sella syndrome; Encephalitis; Encephalocele; Encephalotrigeminal angiomatosis; Epilepsy; Erb's palsy; Essential tremor; Fabry's disease; Fahr's syndrome; Fainting; Familial spastic paralysis; Febrile convulsions; Fisher syndrome; Friedreich's ataxia; Frontotemporal 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 cotiter; Herpes zoster; Hirayama syndrome; HIV-related dementia and neuropathy (also a neurological manifestation of AIDS); Holoprosencephaly; Huntington's disease and other polyglutamine repeat diseases; Hydranencephaly; Hydrocephalus; Hypercortisolism; Hypoxia; Immune-mediated encephalomyelitis; Inclusion body myositis; Incontinentia pigmenti; Infantile phosphaturia; Infantile refsum disease; Infantile spasms; Inflammatory myopathy; Intracranial cysts; 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 disability; 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 intervertebral 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-stroke; mitochondrial myopathy; Mobius syndrome; monomelic amyotrophy; motor neuron disease; Moyamoya disease; mucopolysaccharidoses; multi-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating diseases; multiple system atrophy with postural hypotension; myotonic dystrophy; myasthenia gravis; myelolysis diffuse bone marrow sclerosis; neonatal onset encephalopathy with muscle rigidity; neonatal seizures; neuromyotonia; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorder; 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; paroxysmal attacks;Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralysis; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick disease; pinched nerve; pituitary tumor; polymyositis; porencephaly; post-polio syndrome; post-herpetic neuralgia; post-infectious encephalomyelitis; postural orthostatic tachycardia syndrome; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive spinal subacute combined degeneration; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (type I and type II); Rasmussen's encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorder; restless leg syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye's syndrome; Saint Vitus dance; Sandhoff disease; Schilder's disease; schizophrenia; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren's syndrome; syndrome); sleep apnea; Soto's syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumor; 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 cord syndrome; Thomsen disease; thoracic outlet syndrome; Tic Douloureux; Todd's paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathy; 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; amyotrophic lateral sclerosis, and Zelweger syndrome.

[1005] In some embodiments, the condition, disease or disorder is a STING-associated condition, e.g., a type I interferonopathy (e.g., STING-associated vasculopathy with onset in infancy (SAVI)), Aicardi-Goutieres Syndrome (AGS), a genetic form of lupus and inflammation-related diseases, e.g., systemic lupus erythematosus and rheumatoid arthritis. In some 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 disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), which are chronic inflammatory diseases with polygenic predisposition. In some embodiments, the disorder is inflammatory bowel disease. In some 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 with one or more alloimmune diseases (e.g., graft versus host disease, e.g., acute graft versus host disease and chronic graft versus host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In some of these embodiments, the condition is an alloimmune disease (e.g., graft versus host disease, e.g., acute graft versus host disease and chronic graft versus 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).

[1006] In some embodiments, the modulation of the immune system through STING provides treatment of a disease, including diseases caused by foreign agents. Exemplary infections of foreign agents that can be treated and / or prevented by the methods of the application include: infection by bacteria (e.g., gram-positive or gram-negative bacteria), fungal infection, parasitic infection, and viral infection. In one embodiment of the application, the infection is a bacterial infection (e.g., infection by E. coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Salmonella spp., Staphylococcus aureus, Streptococcus, or vancomycin-resistant Enterococcus) or sepsis. In another embodiment, the infection is a fungal infection (e.g., infection by a mold, yeast, or higher fungus). In another embodiment, the infection is a parasitic infection (e.g., infection by a single-celled or multi-celled parasite, including Giardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, and Toxoplasma gondiz). In yet another embodiment, the infection is a viral infection (e.g., viral infection associated with AIDS, avian flu, chickenpox, cold sores, common cold, gastroenteritis, adenovirus, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, and lower or upper respiratory tract infection (e.g., respiratory syncytial virus).

[1007] In some embodiments, the condition, disease or disorder is hepatitis B (see, e.g., WO 2015 / 061294).

[1008] In some embodiments, the condition, disease or disorder is selected from cardiovascular disease (including, e.g., myocardial infarction).

[1009] In some embodiments, the condition, disease or disorder is age-related macular degeneration.

[1010] In some embodiments, the condition, disease or disorder is mucositis, also known as stomatitis, which can occur as a result of chemotherapy or radiation therapy used alone or in combination, as well as damage caused by exposure to radiation outside the range of radiation therapy.

[1011] In some embodiments, the condition, disease or disorder is uveitis, which is inflammation of the uvea (e.g., anterior uveitis, such as iridocyclitis or iritis; intermediate uveitis (also known as pars planitis); posterior uveitis; or chorioretinitis, e.g., pan-uveitis).

[1012] In some embodiments, the condition, disease or disorder is selected from the group consisting of: cancer, a neurological disease, an autoimmune disease, hepatitis B, uveitis, a cardiovascular disease, age-related macular degeneration, and mucositis.

[1013] Other examples can include those indications discussed herein and below in contemplated combination therapy regimens.

[1014] Combination therapy

[1015] The present disclosure encompasses monotherapy regimens as well as combination therapy regimens.

[1016] In some embodiments, the methods described herein can further comprise administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more therapeutic regimens) in conjunction with the compounds described herein.

[1017] In some embodiments, the methods described herein can further comprise administering one or more additional cancer therapies.

[1018] The one or more additional cancer therapies can include, but are not limited to: surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine, hepatitis B vaccine, Oncophage, Provenge), and gene therapy, and combinations thereof. Immunotherapy, including but not limited to, adoptive cell therapy, derivation of stem cells and / or dendritic cells, transfusions, lavage, and / or other therapies, including but not limited to, cryoablation of tumors.

[1019] In some embodiments, the one or more additional cancer therapies is chemotherapy, which can include administration of one or more additional chemotherapeutic agents.

[1020] In some embodiments, the other chemotherapeutic agent is an immunomodulatory molecule, e.g., an immune checkpoint inhibitor. In some of these embodiments, the immune checkpoint inhibitor targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-beta (TGF ), T cell immunoglobulin and mucin protein 3 (TIM3 or HAVCR2), galectin 9-TIM3, phosphatidylserine-TIM3, lymphocyte-activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 adenosine-CD39-CD73, CXCR4-CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155; e.g., CTLA-4 or PD1 or PD-L1). See, e.g., Postow, M. J. Clin. Oncol. 2015, 33, 1.

[1021] In some 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, MNRP1685A, and MGA271.

[1022] In some embodiments, the other chemotherapeutic agent is an alkylating agent. Alkylating agents are so named because they are able to alkylate many nucleophilic functional groups present in cells, including but not limited to cancer cells, under conditions that exist in cells. In another embodiment, alkylating agents include, but are not limited to: cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, and / or oxaliplatin. In one embodiment, alkylating agents can act by forming covalent bonds with amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules, thereby disrupting cellular function, or they can act by modifying the DNA of cells. In another embodiment, the alkylating agent is synthetic, semi-synthetic, or a derivative.

[1023] In some embodiments, the other chemotherapeutic agent is an antimetabolite. Antimetabolites mimic either purines or pyrimidines, which are essential components of DNA, and usually prevent these substances from being incorporated into DNA during the "S" phase of the cell cycle, thereby preventing normal development and division. Antimetabolites also affect RNA synthesis. In one embodiment, antimetabolites include, but are not limited to: azathioprine and / or mercaptopurine. In another embodiment, the antimetabolite is synthetic, semi-synthetic, or a derivative.

[1024] In some embodiments, the other chemotherapeutic agent is a plant alkaloid and / or a terpenoid. These alkaloids are typically derived from plants and prevent cell division by preventing microtubule function. In one embodiment, the plant alkaloid and / or terpenoid is a vinca alkaloid, a podophyllotoxin, and / or a taxane. Typically, vinca alkaloids bind to specific sites on tubulin, generally inhibiting tubulin assembly into microtubules during the M phase of the cell cycle. In one embodiment, the vinca alkaloid is not limited to: Madagascar periwinkle (Catharanthus roseus) (formerly known as Vinca rosea). In one embodiment, the vinca alkaloid includes, but is not limited to: vincristine, vinblastine, vinorelbine, and / or vindesine. In one embodiment, the taxane includes, but is not limited to: Taxol, paclitaxel, and / or docetaxel. In another embodiment, the plant alkaloid or terpenoid is synthetic, semi-synthetic, or a derivative. In another embodiment, the podophyllotoxin is, but is not limited to, etoposide and / or teniposide. In one embodiment, the taxane is, but is not limited to, docetaxel and / or otaplatin. In one embodiment, the cancer therapeutic agent is a topoisomerase. Topoisomerases are essential enzymes that maintain the topology of DNA. Inhibition of type I or type II topoisomerases interferes with the transcription and replication of DNA by disrupting proper DNA supercoiling. In another embodiment, the topoisomerase is, but is not limited to, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In one embodiment, the type I topoisomerase inhibitor is, but is not limited to, camptothecin. In another embodiment, the camptothecin is, but is not limited to, exatecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67), and / or ST 1481. In one embodiment, the type II topoisomerase inhibitor is, but is not limited to, an epipodophyllotoxin. In another embodiment, the epipodophyllotoxin is, but is not limited to, amsacrine, etoposide, etoposide phosphate, and / or teniposide. In another embodiment, the topoisomerase is synthetic, semi-synthetic, or a derivative, including those found in nature, such as, but not limited to, epipodophyllotoxins, which are substances naturally occurring in the roots of the American Mayapple (Podophyllum peltatum).

[1025] In some embodiments, the other chemotherapeutic agent is a stilbenoid. In further embodiments, the 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, Gnetinins D, Hopeaphenol, Trans-Diptoindonesin B, Astringin, Piceid, and Diptoindonesin A. In another embodiment, the stilbenoid is synthetic, semi-synthetic, or a derivative.

[1026] In some embodiments, the other chemotherapeutic agent is a cytotoxic antibiotic. In one embodiment, the cytotoxic antibiotic is, but is not limited to: actinomycin, anthracenedione, anthracycline, thalidomide, dichloroacetic acid, nicotinic acid, 2-deoxyglucose, and / or chlofazimine. In one embodiment, the actinomycin is, but is not limited to: actinomycin D, bacitracin, colistin (polymyxin E), and / or polymyxin B. In another embodiment, the anthraquinone is, but is not limited to: mitoxantrone and / or pixantrone. In another embodiment, the anthracycline is, but is not limited to: bleomycin, doxorubicin (Adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, mitomycin, puromycin, and / or valrubicin. In another embodiment, the cytotoxic antibiotic is synthetic, semi-synthetic, or a derivative.

[1027] In some embodiments, the additional chemotherapeutic agent is selected from the group consisting of: endostatin, angiopoietin, vasostatin, chemokines, angioarrestin, vasostatin (plasminogen fragment), basement membrane collagen-derived antiangiogenic factors (tumstatin, canstatin or arrestin), antiangiogenic antithrombin III, signal transduction inhibitors, cartilage-derived inhibitor (CDI), CD59 complement fragment, fibronectin fragment, gro-beta, heparanase, 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 16kD fragment, prolactin-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin 1 (TSP-1), transforming growth factor-beta (TGF-beta), vasculostatin, vasostatin (calreticulin fragment), and the like.

[1028] In some embodiments, the additional chemotherapeutic agent is selected from the group consisting of abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, bleomycin, cachexin, cemadotin, chlorambucil, cyclophosphamide, cytarabine tartrate (3',4'-didehydro-4'-deoxy-8'-norvin-caleukoblastine), docetaxel, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine, dolastatin, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxylurea and hydroxylurea amides taxoids, ifosfamide, liarozole, lonidamide, lomustine (CCNU), MDV3100, mechloroethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxoids, nilutamide, onapristone, paclitaxel, prednimustine, procarbazine, RPR109881, stramustine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine.

[1029] In some 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, calcium folinate, methotrexate, gemcitabine, taxane, folinic acid, mitomycin C, tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide, and doxorubicin. Other agents include mTOR (mammalian target of rapamycin) inhibitors, including but not limited to rapamycin, everolimus, temsirolimus, and deforolimus.

[1030] In other embodiments, the additional chemotherapeutic agent can be selected from those described in U.S. Patent 7,927,613, which is incorporated by reference herein in its entirety.

[1031] In some embodiments, the additional therapeutic agent and / or regimen can be used to treat other STING-associated conditions, e.g., Type I interferonopathy, e.g., STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutieres Syndrome (AGS), a genetic form of lupus, an inflammation-associated condition, e.g., systemic lupus erythematosus, and rheumatoid arthritis, among others.

[1032] Non-limiting examples of additional therapeutic agents and / or therapeutic regimens for treating rheumatoid arthritis include: non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g., prednisone), disease-modifying anti-rheumatic drugs (DMARDs; e.g., methotrexate Leflunomide Hydroxychloroquine (Plaquenil), PF-06650833, iguratimod, tofacitinib ABBV-599, evobrutinib, and sulfasalazine and biologics (e.g., abatacept Adalimumab Anakinra Certolizumab Etanercept Golimumab Infliximab Rituximab Tocilizumab Vobarilizumab, Sarilumab Secukinumab, ABP 501, CHS-0214, ABC-3373, and Tocilizumab

[1033] Non-limiting examples of additional therapeutic agents and / or therapeutic regimens for treating lupus include: steroids, topical immunomodulators (e.g., tacrolimus ointment and pimecrolimus cream Thalidomide Non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), anti-malarial drugs (e.g., hydroxychloroquine (Plaquenil)), corticosteroids (e.g., prednisone), immunomodulators (e.g., evobrutinib, iberdomide, voclosporin, cenerimod, azathioprine Cyclophosphamide Cyclosporine (Neoral, Mycophenolate), baricitinb, iguratimod, filogotinib, GS-9876, rapamycin, and PF-06650833), biologies (e.g., belimumab Anifrolumab, prezlumab, MEDI0700, obinutuzumab, vobarilizumab, lulizumab, atacicept, PF-06823859, and lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin Dapirolizumab, Edratide, IFN-alpha-kinoid, OMS721, RC18, RSLV-132, Theralizumab, XmAb5871, and Ustekinumab For example, non-limiting treatments for systemic lupus erythematosus include nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarials (e.g., hydroxychloroquine (Plaquenil)), corticosteroids (e.g., prednisone), and immunomodulators (e.g., iberdomide, voclosporin, azathioprine Cyclophosphamide and cyclosporine (Neoral, and mycophenolate, baricitinb, filogotinib, and PF-06650833), as well as biologies (e.g., belimumab Anifrolumab, Prezlalumab, MEDI0700, Vobarilizumab, Lulizumab, Atacicept, PF-06823859, Lupizor, Rituximab, BT063, BI655064, BIIB059, Aldesleukin Dapirolizumab, Edratide, IFN-alpha-kinoid, RC18, RSLV-132, Theralizumab, XmAb5871, and Ustekinumab As another example, non-limiting examples of treatments for cutaneous lupus include steroids, immunomodulators (e.g., tacrolimus ointment and pimecrolimus cream GS-9876, Filogotinib, and Thalidomide Medications and regimens for treating drug-induced and / or neonatal lupus can also be administered.

[1034] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating STING-associated vasculopathy with onset in infancy (SAVI) include JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).

[1035] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating Aicardi-Goutieres Syndrome (AGS) include: physical therapy, treatment of respiratory complications, anti-convulsive therapy for seizures, tube feeding, nucleoside reverse transcriptase inhibitors (e.g., emtricitabine (e.g., Tenofovir (e.g., VIREAD®) Emtricitabine / tenofovir (e.g., TRUVADA®) Zidovudine, lamivudine, and abacavir), and JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).

[1036] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating IBD include: 6-mercaptopurine, AbGn-168H, ABX464, ABT-494, Adalimumab, AJM300, alicaforsen, AMG139, anrukinzumab, apremilast, ATR-107 (PF0530900), autologous CD34 selected peripheral blood stem cell transplantation, azathioprine, bertilimumab, BI 655066, BMS-936557, certolizumab pegol Cobitolimod, corticosteroids (e.g., prednisone, methylprednisolone, prednisolone), CP-690,550, CT-P13, cyclosporine, DIMS0150, E6007, E6011, etrasimod, etrolizumab, fecal microbiota transplant, figlotinib, fingolimod, firategrast (SB-683699) (formerly T-0047), GED0301, GLPG0634, GLPG0974, guselkumab, golimumab, GSK1399686, HMPL-004 (Andrographis paniculata extract), IMU-838, infliximab, interleukin 2 (IL-2), Janus kinase (JAK) inhibitors, laquinimod, masitinib (AB1010), matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, mirikizumab (LY3074828), natalizumab, NNC 0142-0000-0002, NNC0114-0006, ozanimod, peficitinib (JNJ-54781532), PF-00547659, PF-04236921, PF-06687234, QAX576, RHB-104, rifaximin, risankizumab, RPC1063, SB012, SHP647, sulfasalazine, TD-1473, thalidomide, tildrakizumab (MK 3222), TJ301, tofacitinib, tralokinumab, TRK-170, upadacitinib, ustekinumab, UTTR1147A, V565, vatelizumab, VB-201, vedolizumab, and vidofludimus.

[1037] Non-limiting examples of additional therapeutic agents and / or therapeutic regimens for treating irritable bowel syndrome include: alosetron, bile acid sequestrants (e.g., cholestyramine, celestipol, colesevelam), chloride channel activators (e.g., lubiprostone), coated peppermint oil capsules, desipramine, dicyclomine, ebastine, eluxadoline, farnesoid X receptor agonists (e.g., obeticholic acid), fecal microbiota transplant, 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.

[1038] Non-limiting examples of additional therapeutic agents and / or therapeutic 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 cyclophosphamide and cyclosporine 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, topical nitrates, iloprost, phosphodiesterase 5 inhibitors (e.g., sildenafil), bosentan, tetracycline antibiotics, endothelin receptor antagonists, prostaglandins, and tyrosine kinase inhibitors (e.g., imatinib, nilotinib, and dasatinib).

[1039] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating CD include: Adalimumab, autologous CD34-selected peripheral blood stem cell transplantation, 6-mercaptopurine, azathioprine, PEGsitamab Corticosteroids (e.g., prednisone), etrolizumab, E6011, fecal microbiota transplant, 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.

[1040] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating UC include: AbGn-168H, ABT-494, ABX464, apremilast, PF-00547659, PF-06687234, 6-mercaptopurine, adalimumab, azathioprine, belimumab, brazikumab (MEDI2070), cobitolimod, PEGsitamab CP-690,550, corticosteroids (e.g., multimax budesonide, methylprednisolone), cyclosporine, E6007, esaxerenad, etrolizumab, fecal microbiota transplant, filgotinib, 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.

[1041] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating autoimmune colitis include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), benztropine / atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[1042] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating iatrogenic autoimmune colitis include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), benztropine / atropine, infliximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[1043] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating colitis induced by one or more chemotherapeutic agents include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), benztropine / atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[1044] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating colitis caused by adoptive cell therapy include: corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), benztropine / atropine, infliximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[1045] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating colitis associated with one or more allogeneic immune diseases include: corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), sulfasalazine, and eicosapentaenoic acid.

[1046] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating radiation 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.

[1047] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating collagenous colitis include: 6-mercaptopurine, azathioprine, bismuth subsalicylate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), mesalamine, methotrexate, probiotics, and sulfasalazine.

[1048] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating lymphocytic colitis include: 6-mercaptopurine, azathioprine, bismuth subsalicylate, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), mesalamine, methotrexate, and sulfasalazine.

[1049] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating microbial colitis include: 6-mercaptopurine, azathioprine, bismuth subsalicylate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), fecal microbiota transplant, loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.

[1050] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating alloimmune diseases include: intrauterine platelet transfusion, intravenous immunoglobulin, maternal steroids, abatacept, alemtuzumab, alpha 1 -antitrypsin, AMG 592, anti-thymocyte globulin, barcitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, infliximab, itacitinib, LBH 589, maraviroc, mycophenolate, natalizumab, neihulizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[1051] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating multiple sclerosis (MS) include: alemtuzumab ALKS 8700, amiloride, ATX-MS-1467, azathioprine, baclofen beta interferon (e.g., IFN-beta-1a, IFN-beta-1b), cladribine, corticosteroids (e.g., methylprednisolone), daclizumab, dimethyl fumarate fingolimod fluoxetine, glatiramer acetate hydroxychloroquine, ibudilast, idebenone, laquinimod, lipoic acid, losartan, masitinib, MD1003 (biotin), mitoxantrone, montelukast, natalizumab NeuroVax TM , ocrelizumab, ofatumumab, pioglitazone, and RPC1063.

[1052] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating acute graft-versus-host disease include: alemtuzumab, alpha 1 -antitrypsin, anti-thymocyte globulin, basiliximab, brentuximab, corticosteroids (e.g., methylprednisolone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, ibrutinib, infliximab, itacitinib, LBH589, mycophenolate, natalizumab, neihulizumab, pentostatin, photopheresis, ruxolitinib, sirolimus, tacrolimus, and tocilizumab.

[1053] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating acute graft-versus-host disease include: alemtuzumab, alpha 1 -antitrypsin, anti-thymocyte globulin, basiliximab, brentuximab, corticosteroids (e.g., methylprednisolone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, ibrutinib, infliximab, itacitinib, LBH589, mycophenolate, natalizumab, neihulizumab, pentostatin, photopheresis, ruxolitinib, sirolimus, tacrolimus, and tocilizumab.

[1054] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating chronic graft versus host disease include: abatacept, alemtuzumab, AMG 592, anti-thymocyte globulin, basiliximab, bortezomib, corticosteroids (e.g., methylprednisolone, prednisone), cyclosporine, dacilzumab, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, mycophenolate mofetil, pentostatin, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[1055] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating celiac disease include: AMG 714, AMY01, Aspergillus niger prolyl endoprotease, BL-7010, CALY-002, GBR 830, Hu-Mik-Beta-1, IMGX003, KumaMax, Larazotide Acetate, Pancrelipase, TIMP-GLIA, Vedolizumab, and ZED1227.

[1056] 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 tocafimib, topical IDP-118, topical M518101, topical calcipotriene and betamethasone dipropionate (e.g., MC2-01 cream and topical P-3073, topical LEO 90100 topical use of betamethasone dipropionate betamethasone propionate vitamin D analogs (e.g., calcipotriene and calcitriol anthralin (e.g., and Topical retinoids (e.g., tazarotene (e.g., and Calcineurin inhibitors (e.g., tacrolimus and pimecrolimus Salicylic acid, coal tar, moisturizers, phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrowband UVB phototherapy, Goeckerman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), retinoids (e.g., acitretin Methotrexate Apo805K1, baricitinib, FP187, KD025, prurisol, VTP-43742, XP23829, ZPL-389, CF101 (piclidenoson), LAS41008, VPD-737 (servopitant), upadacitinib (ABT-494), aprmilast, tofacitibin, cyclosporine Biologics (e.g., etanercept etanercept-szzs infliximab adalimumab adalimumab-adbm ustekinumab golimumab apremilast secukinumab pegsiticimab, secukinumab, tildrakizumab-asmn, infliximab-dyyb, abatacept, ixekizumab ABP 710, BCD-057, BI695501, bimekizumab (UCB4940), CHS-1420, GP2017, guselkumab (CNTO 1959), HD203, M923, MSB11022, Mirikizumab (LY3074828), PF-06410293, PF-06438179, risankizumab (BI655066), SB2, SB4, SB5, siliq (brodalumab), namilumab (MT203, tildrakizumab (MK-3222), and ixekizumab thioguanine, and hydroxyurea (e.g., and

[1057] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating cutaneous T-cell lymphoma include: phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrowband UVB phototherapy, Goeckerman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), extracorporeal photopheresis, radiation therapy (e.g., electron beam therapy and total skin electron beam therapy), stem cell transplantation, corticosteroids, imiquimod, bexarotene gel, topical dichloroethylnitrosourea, methoxymelamine gel, vorinostat romidepsin pralatrexate biological agents (e.g., alemtuzumab brentuximab vedotin (SGN-35), mogamulizumab, and IPH4102).

[1058] Non-limiting examples of additional therapeutic agents and / or regimens for treating uveitis include: corticosteroids (e.g., intravitreal triamcinolone acetonide injection), antibiotics, antivirals (e.g., acyclovir), dexamethasone, immunomodulators (e.g., tacrolimus, leflunomide, cyclophosphamide and cyclosporine Chlorambucil, azathioprine, methotrexate, and mycophenolate mofetil), biologies (e.g., infliximab Adalimumab Etanercept Golimumab Certolizumab Rituximab Abatacept Basiliximab Anakinra Canakinumab Gevokizumab (XOMA 052), Tocilizumab Alemtuzumab Efalizumab LFG316, Sirolimus Abatacept, Sarilumab and Daclizumab Cytotoxic drugs, surgical implants (e.g., fluocinolone inserts), and vitrectomy.

[1059] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating mucositis include: AG013, SGX942 (dusquetide), amifostine Cryotherapy, Cepacol lonzenges, mucosal adhesives (e.g., Oral diphenhydramine (e.g., Elixirs), oral bioadhesives (e.g., polyvinylpyrrolidone-sodium hyaluronate gel Oral lubricants (e.g., Oral Caphosol, chamomilla recutita mouthwash, edible grape plant exosomes, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., or Topical analgesics (e.g., lidocaine, benzocaine, dyclonine hydrochloride, dimethocaine (e.g., Cetacaine®), and (0.6% phenol), corticosteroids (e.g., prednisone), analgesics (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor; ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble beta-1,3 / 1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, granules containing Vaccinium myrtillus extract, macleaya cordata alkaloids and echinacea angustifolia extract (e.g., and gastrointestinal mixture (an acid-reducing agent, such as aluminum and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid). For example, non-limiting examples of additional therapeutic agents and / or treatment regimens for the treatment of oral mucositis include: AG013, amifostine cryotherapy, cepacol lonzenges, mucosal adhesive (e.g., oral diphenhydramine (e.g., elixir), oral bioadhesive (e.g., polyvinylpyrrolidone-sodium hyaluronate gel oral lubricant (e.g., Oral caphosol, chamomilla recutita mouthwash, edible grape plant exosome, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., or topical analgesic (e.g., lidocaine, benzocaine, dyclonine hydrochloride, dimethocaine (e.g., Citanest®), and (0.6% phenol), corticosteroid (e.g., prednisone), analgesic (e.g., ibuprofen, naproxen, acetaminophen, and opioid), GC4419, palifermin (keratinocyte growth factor; ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble beta-1,3 / 1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, and a gastrointestinal cocktail (an acid reducer such as aluminum 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 treatment of esophageal mucositis include: dyclonine (e.g., dyclonine 2% gel). As another example, treatment of intestinal mucositis, alteration of treatment of intestinal mucositis, and treatment of signs and symptoms of intestinal mucositis include: a gastrointestinal cocktail (an acid reducer such as aluminum and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid).

[1060] In some embodiments, the second therapeutic agent or regimen is administered to the subject prior to (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, about 1 week prior, or about 1 month prior) contacting or administering the chemical entity.

[1061] In other embodiments, the second therapeutic agent or regimen is administered to the subject at about the same time as contacting or administering the chemical entity. For 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 simultaneously in separate dosage forms.

[1062] In other embodiments, the second therapeutic agent or regimen is administered to the subject after (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, about 1 week after, or about 1 month after) contacting or administering the chemical entity.

[1063] Patient selection

[1064] In some embodiments, the methods described herein further comprise the step of identifying a subject (e.g., a patient) in need of such treatment (e.g., by biopsy, endoscopy, or other conventional methods known in the art). In some embodiments, STING proteins can be used as biomarkers for some types of cancer, such as colon cancer and prostate cancer. In other embodiments, identifying a subject can comprise analyzing whether T cells are present and / or whether T cells are exhausted in the tumor microenvironment of a patient (e.g., a patient having one or more cold tumors). Such patients can include patients who are resistant to treatment with checkpoint inhibitors. In some embodiments, such patients can be treated with the chemical entities 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 are exhausted.

[1065] In some embodiments, the chemical entities, methods, and compositions described herein can be administered to some patient population that is resistant to treatment (e.g., patients who are resistant to checkpoint inhibitors; e.g., patients having one or more cold tumors (e.g., tumors that lack T cells or T cells are exhausted)).

[1066] Compound preparation

[1067] As will be appreciated by those skilled in the art, methods of synthesizing the compounds of the formulae described herein will be apparent to those of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodology (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those 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); L. Paquette, Ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. Starting materials used to make the compounds of the application are known, can be prepared by known methods, or are commercially available. Those skilled in the art will further recognize that the conditions and reagents described herein can be interchanged with alternative art-recognized equivalents. For example, in many reactions, triethylamine can be interchanged with other bases, such as non-nucleophilic bases (e.g., diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphonium phosphate).

[1068] The skilled artisan will recognize a variety of analytical methods that can be used to characterize the compounds described herein, including, for example 1 HNMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy. The foregoing list is a subset of the characterization methods available to one of skill in the art and is not intended to be limiting.

[1069] 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 knowledge of persons of skill in the art and should be considered to fall within the scope of the described claimed invention. The reader will recognize that one of skill in the art, on the basis of the present disclosure, is capable of preparing and using the present invention without undue experimentation.

[1070] The following abbreviations have the indicated meanings:

[1071] Examples

[1072] Materials and Methods

[1073] Reactions were generally monitored by TLC or LC-MS. Product identity was generally confirmed by LC-MS. LC-MS was recorded using one of the following methods.

[1074] Method AB: Poroshell HPH-C18, 50*3.0mm, 2.7um, 4uL injection, 1.2mL / min flow rate, 90-900amu scan range, 254nm UV detection. Mobile Phase A: water / 0.04% NH3H2O and Mobile Phase B (MPB): ACN. 10% MPB to 95% in 1.99 minutes, hold at 95% MPB for 0.6 minutes, 95% MPB to 10% in 0.2 minutes, then equilibrate at 10% MPB for 0.5 minutes.

[1075] Method AH: EVO C18, 50*3mm, 2.0uL injection, 1.2mL / min flow rate, 90-900amu scan range, 254nm UV detection. Mobile Phase A (MPA): water / 5mM NH4HCO3 and Mobile Phase B (MPB): acetonitrile. 10% MPB to 95% in 2.00 minutes, hold at 95% MPB for 0.6 minutes, 95% MPB to 10% in 0.05 minutes, then equilibrate at 10% MPB for 0.25 minutes.

[1076] LCMS Method A: Kinetex EVO C18 100A, 30*3mm, 0.5μL injection, 1.2 mL / min flow rate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water / 5mM NH4HC03and Mobile Phase B (MPB): Acetonitrile. 10% MPB to 95% over 2.0 min, hold at 95% MPB for 0.30 min, 95% MPB to 10% over 0.10 min.

[1077] LCMS Method B: Xselect CSH C18, 50*3mm, 1.0μL injection, 1.2 mL / min flow rate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water / 0.1% FA and Mobile Phase B (MPB): Acetonitrile / 0.1% FA. 5% MPB to 100% over 2.00 min, hold at 100% MPB for 0.70 min, 100% MPB to 5% over 0.05 min, then equilibrate at 5% MPB for 0.15 min.

[1078] LCMS Method C: XBridge Shield RP18, 50*4.6mm, 0.5μL injection, 1.2 mL / min flow rate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water / 0.04% NH3.H20 and Mobile Phase B (MPB): Acetonitrile. 10% MPB to 95% over 2.00 min, hold at 95% MPB for 0.79 min, 95% MPB to 10% over 0.06 min, then equilibrate at 10% MPB for 0.15 min.

[1079] LCMS Method D: Shim-pack XR-ODS, 50*3mm, 0.3μL injection, 1.2 mL / min flow rate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water / 0.05TFA and Mobile Phase B (MPB): Acetonitrile / 0.05% TFA. 5% MPB to 100% over 1.10 min, hold at 100% MPB for 0.60 min, 100% MPB to 5% over 0.05 min, then equilibrate at 5% MPB for 0.25 min.

[1080] LCMS Method E: Kinetex 2.6um EVO C18 100A, 50*3mm, 0.6uL injection, 1.2 mL / min flow rate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water / 5 mM NH4HCO3 and Mobile Phase B (MPB): Acetonitrile. 10% MPB to 95% over 1.20 min, 95% MPB for 0.50 min, 95% MPB to 10% over 0.05 min, then 10% MPB for 0.10 min.

[1081] LCMS Method F: EVO C18, 50*3mm, 0.1uL injection, 1.2 mL / min flow rate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water / 5 mM NH4HCO3 and Mobile Phase B (MPB): Acetonitrile. 10% MPB to 95% over 2.00 min, 95% MPB for 0.60 min, 95% MPB to 10% over 0.15 min, then 10% MPB for 0.25 min.

[1082] LCMS Method G: Titank C18, 50*3mm, 0.5uL injection, 1.5 mL / min flow rate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water / 5 mM NH4HCO3 and Mobile Phase B (MPB): Acetonitrile. 10% MPB to 95% over 1.80 min, 95% MPB for 0.80 min, 95% MPB to 10% over 0.15 min, then 10% MPB for 0.25 min.

[1083] LCMS Method H: Poroshell HPH C18, 50*3mm, 0.5uL injection, 1.2 mL / min flow rate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water / 5 mM NH4HCO3 + 5 mM NH4OH and Mobile Phase B (MPB): Acetonitrile. 10% MPB to 95% over 2.00 min, 95% MPB for 0.70 min, 95% MPB to 5% over 0.05 min, then 5% MPB for 0.25 min.

[1084] LCMS Method I: HALO C18, 30*3mm, 0.5μL injection, 1.5 mL / min flow rate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): water / 0.05% TFA and Mobile Phase B (MPB): acetonitrile / 0.05% TFA. 5% MPB eluted to 100% in 1.20 min, 100% MPB for 0.60 min, 100% MPB to 5% in 0.02 min, then equilibrate at 5% MPB for 0.18 min.

[1085] LCMS Method J: HALO C18, 30*3mm, 0.5μL injection, 1.5 mL / min flow rate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): water / 0.1% FA and Mobile Phase B (MPB): acetonitrile / 0.1% FA. 5% MPB eluted to 100% in 1.20 min, 100% MPB for 0.60 min, 100% MPB to 5% in 0.02 min, then equilibrate at 5% MPB for 0.18 min.

[1086] Recorded on a BRUKER NMR 300.03 Mz, DUL-C-H, ULTRASHIELD TM 300, AVANCE II 300B-ACS TM 120 or BRUKER NMR 400.13 Mz, BBFO, ULTRASHIELD TM 400, AVANCE III 400, B-ACS TM 120.

[1087] Synthesis of exemplary intermediates

[1088] Intermediate 1 : 5,6-difluoro-1 H-indol-3-amine

[1089]

[1090] Step 1 - Synthesis of 5,6-difluoro-3-nitro-1H-indole:Dissolve 5,6-difluoro-lH-indole (5.0 g, 32.7 mmol, 1.0 equiv) in CH3CN (50.0 mL), add AgNO3(6.1 g, 36.0 mmol, 1.1 equiv) portion-wise. Then cool the resulting solution to 0 °C, after 5 min, add benzoyl chloride (4.1 mL, 36.0 mmol, 1.1 equiv). Warm the resulting solution to room temperature for 2 h, then adjust the pH of the reaction mixture to pH 8 by dropwise addition of 1 M aqueous Na2CO3. Extract the mixture with EtOAc (150 mL x 3), combine the organic layers and concentrate in vacuo. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (5 / 95) to give 5,6-difluoro-3-nitro-lH-indole (3.5 g, 17.7 mmol) as a yellow solid. LC-MS Method B, MS-ESI: 199.1 [M+H + ] Alternatively, it can be purified by flash silica gel chromatography 24g Purify the residue by flash column chromatography on silica gel eluting with a gradient of 0-100% EtOAc / petroleum ether @ 30 mL / min to give 5,6-difluoro-3-nitro-lH-indole (2.9 g, 13.5 mmol) as a yellow solid. MS-ESI, 199.1 [M+H + ].

[1091] Step 2 - Synthesis of 5,6-difluoro-1H-indol-3-amine (Intermediate 1): Dissolve 5,6-difluoro-3-nitro-lH-indole (3.5 g, 17.7 mmol, 1.0 equiv) in 40% HBr / H2O (40 mL), then add SnCl2(16.8 g, 88.5 mmol, 5.0 equiv) and heat the reaction mixture to 70 °C for 30 min. Cool the reaction mixture to room temperature, and adjust the pH to pH 8 by dropwise addition of 1 M aqueous NaOH. Extract the mixture with DCM (150 mL x 5), combine the organic layers and concentrate in vacuo. The residue is used directly in the next step without further purification. LCMS Method B, MS-ESI: 169.1 [M+H + ].

[1092] Intermediate 2: Synthesis of (6-(4,4-difluorocyclohexyl)pyridin-3-yl)amine

[1093]

[1094] Step 1: (6-(4,4-difluorocyclohex-l-en-l-yl)pyridin-3-yl)amine

[1095] 6-iodopyridin-3-amine (5.0 g, 22.7 mmol, 1.0 eq.) was dissolved in dioxane (80 mL) and H2O (8 mL) then K2CO3 (9.4 g, 68.2 mmol, 3.0 eq.), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.5 g, 27.3 mmol, 1.2 eq.) and Pd(dppf)Cl2CH2Cl2 (185.6 mg, 0.2 mmol, 0.1 eq.) were added under nitrogen. The resulting solution was stirred at 90 °C for 12 h then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluted with ethyl acetate / petroleum ether (1:5) to give 6-(4,4-difluorocyclohex-1-en-1-yl)pyridin-3-amine (5.2 g) as a light yellow solid. LCMS Method H: [M+H] = 211. + = 211.

[1096] Step 2: 6-(4,4-difluorocyclohexyl)pyridin-3-amine

[1097] 6-(4,4-difluorocyclohex-1-en-1-yl)pyridin-3-amine (5.2 g, 14.3 mmol, 1.0 eq.) was dissolved in MeOH (50 mL) then Pd / C (10% wt, 1.5 g, 1.4 mmol, 0.1 eq.) was added. The reaction vessel was evacuated then backfilled with hydrogen three times then stirred under a hydrogen atmosphere for 16 h. Filtration and concentration gave 6-(4,4-difluorocyclohexyl)pyridin-3-amine (4.4 g) as an off-white solid. LCMS Method H: [M+H] = 213. + = 213.

[1098] Intermediate 3: 2-(4,4-difluorocyclohexyl)-5-isocyanatopyridine

[1099]

[1100] 6-(4,4-difluorocyclohexyl)pyridin-3-amine (1 mmol) was dissolved in 5 mL DCM / water (1:1 mixture) and cooled to 0 °C. Trifluoroacetanhydride (0.5 mmol) was dissolved in 2 mL of DCM and slowly added to the DCM layer. The solution was stirred for 30 min and the two layers were separated. The organic layer was washed with brine and dried over anhydrous Mg2SO4. The organic layer was rotary evaporated and used as is in the next step.

[1101] Synthesis of Intermediate 5 (5-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-amine)

[1102]

[1103] Step 1: 3-Chloro-2-(4,4-difluoropiperidin-l-yl)-5-nitropyridine

[1104] Dissolve 2,3-dichloro-5-nitropyridine (600.0 mg, 3.1 mmol, 1.0 equiv) in DMF (30 mL), add Cs2CO3(4.1 g, 12.4 mmol, 4.0 equiv) and 4,4-difluoropiperidine (375.1 mg, 3.1 mmol, 1.0 equiv). Stir the reaction mixture at 60 °C for 6 hours, then quench by the addition of water. Extract the resulting solution with ethyl acetate, wash with brine, dry over anhydrous sodium sulfate and concentrate in vacuo to give 3-chloro-2-(4,4-difluoropiperidin-l-yl)-5-nitropyridine (420 mg) as a yellow solid. LCMS Method C: [M+H] + = 278.

[1105] Step 2: 5-Chloro-6-(4,4-difluoropiperidin-l-yl)pyridin-3-amine

[1106] Dissolve 3-chloro-2-(4,4-difluoropiperidin-l-yl)-5-nitropyridine (3.4 g, 12.2 mmol, 1.0 equiv) in 40% HBr (10.0 mL), then add SnCl2(5.5 g, 29.0 mmol, 2.4 equiv). Stir the resulting solution at ambient temperature for 2 hours and adjust the pH to 8 with aqueous NaOH (1 mol / L). Extract the mixture with ethyl acetate, dry over anhydrous Na2SO4and concentrate in vacuo. Purify the residue by flash column chromatography on silica gel eluting with DCM / MeOH (10:1) to give 5-chloro-6-(4,4-difluoropiperidin-l-yl)pyridin-3-amine (2.8 g) as a brown solid. LCMS Method C: [M+H] + = 248.

[1107] The following intermediates were prepared using the same methods described for Intermediate 5.

[1108]

[1109]

[1110]

[1111]

[1112]

[1113]

[1114]

[1115]

[1116]

[1117]

[1118]

[1119] Synthesis of intermediate 43 (6-(4,4-difluorocyclohexyl)pyridin-3-amine)

[1120]

[1121] Step 1: 6-(4,4-difluorocyclohex-1-en-1-yl)pyridin-3-amine

[1122] 6-iodopyridin-3-amine (4.0 g, 18.2 mmol, 1.0 equiv) and 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.3 g, 21.8 mmol, 1.2 equiv) were dissolved in 1,4-dioxane (40 mL) and water (8 mL), then K2CO3 (7.5 g, 54.5 mmol, 3.0 equiv) and Pd(dppf)Cl2 (1.5 g, 1.8 mmol, 0.1 equiv) were added under nitrogen atmosphere. The reaction compound was heated at 90 °C for 12 h, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluted with ethyl acetate / petroleum ether (1:5) to give 6-(4,4-difluorocyclohex-1-en-1-yl)pyridin-3-amine (2.7 g) as a light yellow solid. LCMS Method D: [M+H] + = 211.

[1123] Step 2: 6-(4,4-difluorocyclohexyl)pyridin-3-amine

[1124] 6-(4,4-difluorocyclohex-1-en-1-yl)pyridin-3-amine (10.0 g, 47.6 mmol, 1.0 equiv) was dissolved in MeOH (40 mL), Pd / C (1.0 g, 9.5 mmol, 0.2 equiv) was added. The mixture was purged with nitrogen, placed under hydrogen (balloon) atmosphere, then stirred at ambient temperature for 2 h. The solids were removed by filtration, the filtrate was concentrated under vacuum to give 6-(4,4-difluorocyclohexyl)pyridin-3-amine (9.1 g) as an off-white solid. LCMS Method C: [M+H] + = 213.

[1125] The following intermediates were prepared using the same method as described for intermediate 43.

[1126]

[1127]

[1128]

[1129] Synthesis of intermediate 49 (6-(4,4-difluoropiperidin-l-yl)pyridin-3-amine)

[1130]

[1131] DAST (30.0 mL) at 0 °C. The resulting mixture was stirred at room temperature overnight, then quenched by the addition of aqueous NaHC03solution at 0 °C. The resulting mixture was extracted with DCM, dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with ethyl acetate / petroleum ether (1 :2) to give 4-bromo-l-(3,3-difluorocyclobutyl)-2-fluorobenzene (1.1 g) as a yellow oil. + = 215.

[1132] Synthesis of intermediate 50 (4-(3,3-difluorocyclobutyl)-3-fluoroaniline)

[1133]

[1134] Step 1 : 4-Bromo-l-(3,3-difluorocyclobutyl)-2-fluorobenzene

[1135] DAST (30.0 mL) at 0 °C. The resulting mixture was stirred at room temperature overnight, then quenched by the addition of aqueous NaHC03solution at 0 °C. The resulting mixture was extracted with DCM, dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with ethyl acetate / petroleum ether (1 :2) to give 4-bromo-l-(3,3-difluorocyclobutyl)-2-fluorobenzene (1.1 g) as a yellow oil. 1 HNMR (300 MHz, DMSO-d4): δ 7.53-7.49 (m, 1H), 7.43-7.34 (m, 2H), 3.52-3.46 (m, 1H), 3.07-2.94 (m, 2H), 2.84-2.66 (m, 2H).

[1136] Step 2: tert-Butyl (4-(3,3-difluorocyclobutyl)-3-fluorophenyl)carbamate DAST (30.0 mL) at 0 °C. The resulting mixture was stirred at room temperature overnight, then quenched by the addition of aqueous NaHC03solution at 0 °C. The resulting mixture was extracted with DCM, dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with ethyl acetate / petroleum ether (1 :2) to give 4-bromo-l-(3,3-difluorocyclobutyl)-2-fluorobenzene (1.1 g) as a yellow oil.

[1137] Dissolve 4-bromo-l-(3,3-difluorocyclobutyl)-2-fluorobenzene (1.1 g, 4.2 mmol, 1.0 equiv) and BocNH2(2.4 g, 20.7 mmol, 5.0 equiv) in toluene (11.0 mL). Under a nitrogen atmosphere, at room temperature, add Pd2(dba)3(0.4 g, 0.4 mmol, 0.1 equiv), XPhos (0.4 g, 0.8 mmol, 0.2 equiv), and t-BuOK (2.3 g, 20.7 mmol, 5.0 equiv). Stir the resulting mixture at 100 °C overnight, then quench by the addition of water. Extract the resulting solution with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate in vacuo. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:8) to give [4-(3,3-difluorocyclobutyl)-3-fluorophenyl]carbamic acid tert-butyl ester (1.0 g, 80.0%) as a white solid. LCMS Method A: [M+H] + = 302.

[1138] Step 3: 4-(3,3-difluorocyclobutyl)-3-fluoroaniline

[1139] Dissolve [4-(3,3-difluorocyclobutyl)-3-fluorophenyl]carbamic acid tert-butyl ester (1.2 g, 4.0 mmol, 1.0 equiv) in DCM (12.0 mL) and add TFA (3.0 mL) dropwise at 0 °C. Stir the resulting mixture at room temperature for 2 hours, then concentrate in vacuo. Dissolve the residue in DCM, wash the solution with saturated aqueous NaHCO3and brine, dry over anhydrous sodium sulfate, and concentrate in vacuo to give crude 4-(3,3-difluorocyclobutyl)-3-fluoroaniline (800 mg) as a red oil. LCMS Method A: [M+H] + = 202.

[1140] Synthesis of Intermediate 51 (5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-amine)

[1141]

[1142] Step 1: tert-Butyl 3,3-difluorocyclobutane-l-carboxylate

[1143] Dissolve 3,3-difluorocyclobutane carboxylic acid (1.0 g, 7.3 mmol, 1.0 equiv) in DCM (10 mL), add N,N-dimethylpyridin-4-amine (92.0 mg, 0.7 mmol, 0.1 equiv), 2-methylpropan-2-ol (1.1 g, 14.7 mmol, 2.0 equiv) and N,N'-dicyclohexyl (1.7 g, 8.1 mmol, 1.1 equiv) at 10 °C. Warm the reaction mixture to room temperature and stir for 18 hours. Filter off the solids, wash the filtrate with aqueous HC1 (2N), saturated aqueous NaHC03, brine, dry over anhydrous Na2S04, concentrate in vacuo to give crude tert-butyl 3,3-difluorocyclobutane-1-carboxylate (896.1 mg) as a colorless oil. 1 H NMR (400 MHz, CDC13): δ 2.83-2.78 (m, 5H), 1.47 (s, 9H).

[1144] Step 2: tert-Butyl 1-(3-chloropyridin-2-yl)-3,3-difluorocyclobutane-1-carboxylate

[1145] Dissolve 3-chloro-2-fluoropyridine (1.2 g, 10.4 mmol, 1.0 equiv) and tert-butyl 3,3-difluorocyclobutane-1-carboxylate (2.0 g, 10.4 mmol, 1.0 equiv) in toluene (60 mL). Subsequently, add NaHMDS (2 M in THF, 6.2 ml, 12.4 mmol, 1.2 equiv) dropwise over 10 minutes at 0 °C with stirring. Stir the resulting solution at 0 °C for 2 hours, then quench by the addition of saturated aqueous NH4C1. Extract the resulting solution with ethyl acetate, dry over anhydrous sodium sulfate and concentrate in vacuo. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1 :5) to give tert-butyl 1-(3-chloropyridin-2-yl)-3,3-difluorocyclobutane-1-carboxylate (1.6 g) as a colorless oil. LCMS Method D: [M+H] + = 304.

[1146] Step 3: 3-Chloro-2-(3,3-difluorocyclobutyl)pyridine

[1147] tert-Butyl 1-(3-chloropyridin-2-yl)-3,3-difluorocyclobutane-1-carboxylate (1.5 g, 5.2 mmol, 1.0 equiv) was dissolved in DCM (30 mL) and TFA (3 ml). The resulting solution was stirred at ambient temperature for 10 hours, then concentrated under vacuum. The residue was dissolved in toluene (30 mL) and stirred at 90 °C for 18 hours. After cooling to ambient temperature and quenching by the addition of water, the pH of the solution was adjusted to 7.5 with saturated aqueous Na2CO3solution. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with ethyl acetate / petroleum ether (1 :7) to give 3-chloro-2-(3,3-difluorocyclobutyl)pyridine (700 mg) as a colourless oil. LCMS Method D: [M+H] = 204. + = 204. 1 H NMR (400 MHz, DMSO-d6): δ 8.45-8.43 (m, 1H), 7.69-7.67 (m, 1H), 7.40-7.38 (m, 1H), 3.72-3.70 (m, 1H), 3.02-2.85 (m, 4H).

[1148] Step 4: 3-Chloro-2-(3,3-difluorocyclobutyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine

[1149] 3-Chloro-2-(3,3-difluorocyclobutyl)pyridine (700.0 mg, 3.7 mmol, 1.0 equiv) was dissolved in heptane (30 mL) under a nitrogen atmosphere, bis(pinacolato)diboron (1.1 g, 4.4 mmol, 1.2 equiv), 4,4-ditert-butyl-2,2-bipyridyl (1.0 g, 3.7 mmol, 1.0 equiv) and dimethylol diiridium (Ir-Ir)-cycloocta-1,5-diene (1:2) (495.8 mg, 0.7 mmol, 0.2 equiv) were added. The resulting solution was stirred at ambient temperature for 18 hours, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with ethyl acetate / petroleum ether (1 :5) to give 3-chloro-2-(3,3-difluorocyclobutyl)-5-(4,4,5,5)-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (300 mg) as a white solid. LCMS Method D: [M+H] = 330. + = 330.

[1150] Step 5: 5-Chloro-6-(3,3-difluorocyclobutyl)pyridin-3-ol

[1151] Dissolve 3-chloro-2-(3,3-difluorocyclobutyl)-5-(4,4,5,5)-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (300.0 mg, 0.9 mmol, 1.0 equiv) in MeOH (10 mL) and H2O (3 mL). Then add H2O2 (30%, 0.14 ml, 1.4 mmol, 1.5 equiv). Stir the resulting solution at ambient temperature for 30 minutes, then quench by the addition of saturated aqueous Na2S2O3 solution. Extract the resulting solution with ethyl acetate, dry over anhydrous sodium sulfate and concentrate in vacuo. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:2) to give 5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-ol (160 mg) as a white solid. LCMS Method D: [M+H] = 220. + = 220. 1 H NMR (400 MHz, CD3OD-d4): δ 8.0 (s, 1H), 6.97-6.93 (m, 1H), 3.69-3.58 (m, 1H), 3.01-2.78 (m, 4H).

[1152] Step 6: 5-Chloro-6-(3,3-difluorocyclobutyl)pyridin-3-yl trifluoromethanesulfonate

[1153] Dissolve 5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-ol (160.0 mg, 0.7 mmol, 1.0 equiv) in DCM (20 mL), add TEA (0.1 ml, 0.9 mmol, 1.2 equiv) and 1,1,1-trifluoro-N-phenyl-N-trifluoromethylsulfonamidosulfonamide (309.4 mg, 0.8 mmol, 1.1 equiv). Stir the resulting solution at ambient temperature for 30 minutes, then quench by the addition of water. Extract the solution with ethyl acetate, dry over anhydrous sodium sulfate and concentrate in vacuo. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:8) to give 5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-yl trifluoromethanesulfonate (220 mg) as a white solid. LCMS Method D: [M+H] = 352. + = 352.

[1154] Step 7: tert-Butyl (5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-yl)carbamate

[1155] Dissolve 5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-yl trifluoromethanesulfonate (220.0 mg, 0.6 mmol, 1.0 equiv) in 1,4-dioxane (30 mL). Then, under nitrogen atmosphere, add NH2Boc (230.3 mg, 1.9 mmol, 3.0 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (75.8 mg, 0.1 mmol, 0.2 equiv) and Pd2(dba)3 (120.1 mg, 0.1 mmol, 0.2 equiv). Stir the resulting solution at 90 °C under nitrogen atmosphere for 3 h, then concentrate under vacuum. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:9) to give tert-butyl (5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-yl)carbamate (120 mg) as a white solid. LCMS Method D: [M+H] + = 319.

[1156] Step 8: 5-Chloro-6-(3,3-difluorocyclobutyl)pyridin-3-amine

[1157] Dissolve tert-butyl (5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-yl)carbamate (120.0 mg, 0.3 mmol, 1.0 equiv) in DCM (10 mL) and TFA (2 ml). Stir the resulting solution at ambient temperature for 30 min, then dilute with water. Adjust the pH of the solution to 7.5 with saturated aqueous Na2CO3 solution and extract with ethyl acetate. Dry the organic layer over anhydrous sodium sulfate and concentrate under vacuum. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:3) to give 5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-amine (60 mg) as a white solid. LCMS Method D: [M+H] + = 219.

[1158] The following intermediates were synthesized using the method described for Intermediate 51.

[1159]

[1160]

[1161] Synthesis of Intermediate 52 (6-(4,4-difluoropiperidin-1-yl)-5-ethylpyridin-3-amine)

[1162]

[1163] Step 1: 6-(4,4-difluoropiperidin-1-yl)-5-vinylpyridin-3-amine

[1164] Dissolve 5-chloro-6-(4,4-difluoropiperidin-l-yl)pyridin-3-amine (3.0 g, 12.1 mmol, 1.0 equiv) and K3PO4(5.1 g, 24.2 mmol, 2.0 equiv) in 1,4-dioxane (60 mL) and water (6 mL), then add Xphos Pd G3 (1.0 g, 1.2 mmol, 0.1 equiv) and XPhos (577.4 mg, 1.2 mmol, 0.1 equiv) under a nitrogen atmosphere. Heat the resulting mixture to 90 °C overnight, then cool to ambient temperature and quench by the addition of water. Extract the resulting mixture with ethyl acetate, wash with brine, dry over anhydrous Na2SO4and concentrate in vacuo. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give 6-(4,4-difluoropiperidin-l-yl)-5-vinylpyridin-3-amine (5.1 g) as a yellow solid. LCMS Method D: [M+H] + = 240. 1 H NMR (300 MHz, DMSO-d6): δ 7.62 (d, 1H), 7.13 (d, 1H), 6.85-6.81 (m, 1H), 5.70-5.65 (m, 1H), 5.32-5.28 (m, 1H), 3.04-2.97 (m, 4H), 2.15-2.00 (m, 4H).

[1165] Step 2: 6-(4,4-difluoropiperidin-l-yl)-5-ethylpiperidin-3-amine

[1166] Dissolve 6-(4,4-difluoropiperidin-l-yl)-5-vinylpyridin-3-amine (1.2 g, 2.5 mmol, 1.0 equiv) in THF (12 mL), then add Pd / C (0.2 g, 2.5 mmol, 1.0 equiv). Purge the mixture with nitrogen, place under a hydrogen (balloon) atmosphere, then stir at ambient temperature overnight. Remove the solids by filtration and concentrate the filtrate in vacuo. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give 6-(4,4-difluoropiperidin-l-yl)-5-ethylpyridin-3-amine (860 mg) as a dark yellow solid. LCMS Method D: [M+H] + = 242. 1 H NMR (300 MHz, DMSO-d6): δ 7.52 (d, 1H), 6.84 (d, 1H), 2.96-2.91 (m, 5H), 2.56-2.54 (m, 2H), 2.07-2.01 (m, 4H), 1.14 (t, 3H).

[1167] Synthesis of intermediate 53 (2-(5-amino-2-(4,4-difluoropiperidin-1- yl)pyridin-3-yl)ethan-1-ol)

[1168]

[1169] 6-(4,4-difluoropiperidin-1-yl)-5-vinylpyridin-3-amine (2.0 g, 8.4 mmol, 1.0 equiv) was dissolved in THF (40 mL) and cooled to 0 °C, then BH3.THF (1 M, 16.7 mL, 16.7 mmol, 2.0 equiv) was added dropwise, keeping the solution at 0 °C. The resulting mixture was stirred at ambient temperature for 3 h. To the above mixture was added NaOH (5.0 g, 12.5 mmol, 1.5 equiv) and H2O2 (30%, 1.3 mL, 16.7 mmol, 2.0 equiv). The resulting mixture was stirred at ambient temperature for an additional 4 h and quenched by the addition of water. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography under the following conditions: column: C18; mobile phase A: water / 0.1% NH3HCO3, mobile phase B: ACN; flow rate: 100 mL / min; gradient: from 5% B to 35% B over 30 min; 254 nm. This resulted in 2-[5-amino-2-(4,4-difluoropiperidin-1-yl)pyridin-3-yl]ethanol (first peak, 740 mg) as a yellow solid and 1-[5-amino-2-(4,4-difluoropiperidin-1-yl)pyridin-3-yl]ethanol (second peak, 540 mg) as a yellow solid. LCMS Method A: [M+H] + = 258. 1 H NMR (400 MHz, DMSO-d6): δ 7.53 (d, 1H), 6.85 (d, 1H), 4.92 (s, 2H), 4.67 (t, 1H), 3.65-3.60 (m, 2H), 2.94 (t, 4H), 2.66 (t, 2H), 2.08-2.03 (m, 4H).

[1170] Synthesis of intermediate 54 ((5-amino-2-(4,4-difluorocyclohexyl)pyridin-3- yl)methanol)

[1171]

[1172] Step 1: methyl 2-(4,4-difluorocyclohex-1-en-1-yl)-5-nitronicotinate

[1173] Dioxane (30 mL) and water (5 mL) then K2CO3 (1.0 g, 7.2 mmol, 1.5 eq), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.4 g, 5.7 mmol, 1.2 eq) and Pd(dppf)Cl2 (0.7 g, 1.0 mmol, 0.2 eq) were added under nitrogen atmosphere. The resulting solution was heated to 90 °C for 2 h and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / pet. ether (1:6) to give methyl 2-(4,4-difluorocyclohex-1-en-1-yl)-5-nitropyridine-3-carboxylate (700 mg) as a white solid. LCMS Method A: [M+H] + = 299.

[1174] Step 2: Methyl 5-amino-2-(4,4-difluorocyclohexyl)nicotinate

[1175] Methyl 2-(4,4-difluorocyclohex-1-en-1-yl)-5-nitropyridine-3-carboxylate (700.0 mg, 2.3 mmol, 1.0 eq) was dissolved in MeOH (20 mL) then Pd / C (70.0 mg, 0.7 mmol, 0.3 eq) and AcOH (28.2 mg, 0.5 mmol, 0.2 eq) were added. The mixture was purged with nitrogen, placed under hydrogen (balloon) atmosphere then stirred at ambient temperature for 3 days. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / pet. ether (1:2) to give methyl 5-amino-2-(4,4-difluorocyclohexyl)pyridine-3-carboxylate (350 mg) as a white solid. LCMS Method C: [M+H] + = 271.

[1176] Step 3: (5-Amino-2-(4,4-difluorocyclohexyl)pyridin-3-yl)methanol

[1177] Methyl 5-amino-2-(4,4-difluorocyclohexyl)pyridine-3-carboxylate (300.0 mg, 1.1 mmol, 1.0 equiv) was dissolved in THF (20 mL) and cooled to 0 °C, then LiAlH4(189.6 mg, 5.0 mmol, 4.5 equiv) was added and the solution was maintained at 0 °C. The resulting solution was stirred at 0 °C for 10 min, then quenched by the addition of aqueous HC1 (1 M). The solution was adjusted to pH 7 with aqueous Na2C03solution. The resulting solution was extracted with dichloromethane and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1 : 1) to give [5-amino-2-(4,4-difluorocyclohexyl)pyridin-3-yl]methanol (200 mg) as a white solid. LCMS Method C: [M+H] + = 243.

[1178] Synthesis of intermediate 57 (5-amino-2-(4,4-difluoropiperidin-1-yl)nicotinonitrile)

[1179]

[1180] Methyl 5-amino-2-(4,4-difluorocyclohexyl)pyridine-3-carboxylate (300.0 mg, 1.1 mmol, 1.0 equiv) was dissolved in THF (20 mL) and cooled to 0 °C, then LiAlH4(189.6 mg, 5.0 mmol, 4.5 equiv) was added and the solution was maintained at 0 °C. The resulting solution was stirred at 0 °C for 10 min, then quenched by the addition of aqueous HC1 (1 M). The solution was adjusted to pH 7 with aqueous Na2C03solution. The resulting solution was extracted with dichloromethane and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1 : 1) to give [5-amino-2-(4,4-difluorocyclohexyl)pyridin-3-yl]methanol (200 mg) as a white solid. LCMS Method C: [M+H] + = 239. 1 H NMR (300 MHz, Methanol-d4): δ 8.15 (d, 1H), 7.25 (d, 1H), 3.21-3.05 (m, 1H), 2.26-1.80 (m, 8H).

[1181] The following intermediates were prepared using the method described for intermediate 57.

[1182]

[1183] Synthetic intermediate 58 (6-chloro-5-(4,4-difluoropiperidin-1-yl)pyrazin-2-amine)

[1184]

[1185] Step 1: Methyl 6-chloro-5-(4,4-difluoropiperidin-1-yl)pyrazine-2-carboxylate

[1186] 6-Chloro-5-fluoropyrazine-2-carboxylic acid ester (1.0 g, 5.2 mmol, 1.0 equivalent) and 4,4-difluoropiperidine (0.8 g, 6.3 mmol, 1.2 equivalent) were dissolved in DMF (20 mL), and then Cs₂CO₃ (5.1 g, 15.7 mmol, 3.0 equivalent) was added. The reaction mixture was heated to 50 °C and maintained for 3 hours, then cooled to ambient temperature and quenched by adding water. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (1:1) to give methyl 6-chloro-5-(4,4-difluoropiperidine-1-yl)pyrazine-2-carboxylic acid ester (1.5 g) as a yellow solid. LCMS method D: [M+H] + =292.

[1187] Step 2: 6-Chloro-5-(4,4-difluoropiperidin-1-yl)pyrazine-2-carboxylic acid

[1188] Methyl 6-chloro-5-(4,4-difluoropiperidin-1-yl)pyrazin-2-carboxylic acid (1.0 g, 3.4 mmol, 1.0 equivalent) was dissolved in MeOH (10 mL) and water (10 mL), and then NaOH (548.5 mg, 13.7 mmol, 4.0 equivalent) was added. The resulting mixture was stirred at ambient temperature for 2 hours and concentrated under vacuum. The residue was diluted with water, and the solution was adjusted to pH 2 with concentrated aqueous HCl. The solid was collected by filtration and dried to give 6-chloro-5-(4,4-difluoropiperidin-1-yl)pyrazin-2-carboxylic acid (950 mg) as a yellow solid. LCMS Method B: [MH] - =276.

[1189] Step 3: 6-Chloro-5-(4,4-difluoropiperidin-1-yl)pyrazine-2-carbonyl azide

[1190] DPPA (669.0 mg, 2.4 mmol, 1.5 equiv) and TEA (0.45 mL, 3.2 mmol, 2.0 equiv). The resulting mixture was stirred at ambient temperature for 3 hours and concentrated in vacuo to give 6-chloro-5-(4,4-difluoropiperidin-l-yl)pyrazine-2-carbonitrile (100 mg) as an off-white solid. LCMS Method C: [M+H] + = 303.

[1191] Step 4: tert-Butyl (6-chloro-5-(4,4-difluoropiperidin-l-yl)pyrazin-2- yl)carbamate

[1192] DPPA (669.0 mg, 2.4 mmol, 1.5 equiv) and TEA (0.45 mL, 3.2 mmol, 2.0 equiv). The resulting mixture was stirred at ambient temperature for 3 hours and concentrated in vacuo to give 6-chloro-5-(4,4-difluoropiperidin-l-yl)pyrazine-2-carbonitrile (100 mg) as an off-white solid. LCMS Method C: [M+H] + = 349.

[1193] Step 5: 6-Chloro-5-(4,4-difluoropiperidin-l-yl)pyrazin-2-amine

[1194] DPPA (669.0 mg, 2.4 mmol, 1.5 equiv) and TEA (0.45 mL, 3.2 mmol, 2.0 equiv). The resulting mixture was stirred at ambient temperature for 3 hours and concentrated in vacuo to give 6-chloro-5-(4,4-difluoropiperidin-l-yl)pyrazine-2-carbonitrile (100 mg) as an off-white solid. LCMS Method C: [M+H] + = 249.

[1195] The following intermediates were prepared using the methods described for Intermediate 58.

[1196]

[1197] Synthesis of Intermediate 60 (4-chloro-5-(4,4-difluorocyclohexyl)pyridin-2-amine)

[1198]

[1199] Step 1: Methyl 5-(4,4-difluorocyclohex-l-en-l-yl)-4-methoxypyridine-2- carboxylate

[1200] Methyl 5-bromo-4-hydroxypyridine-2-carboxylate (1.5 g, 6.5 mmol, 1.0 equiv) and 2-(4,4-difluorocyclohex-l-en-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (4.7 g, 19.4 mmol, 3.0 equiv) were dissolved in 1.4-dioxane (15 mL) and water (1.5 mL), followed by the addition of Pd(dppf)Cl2(0.5 g, 0.6 mmol, 0.1 equiv) and Na2CO3(2.1 g, 19.4 mmol, 3.0 equiv). The reaction mixture was heated to 70 °C overnight, then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with ethyl acetate / petroleum ether (1:1) to give methyl 5-(4,4-difluorocyclohex-l-en-l-yl)-4-hydroxypyridine-2-carboxylate (1.1 g) as a white solid. LCMS Method D: [M+H] + = 284.

[1201] Step 2: Methyl 5-(4,4-difluorocyclohexyl)-4-methoxypyridine-2-carboxylate

[1202] Methyl 5-(4,4-difluorocyclohex-l-en-l-yl)-4-methoxypyridine-2-carboxylate (6.0 g, 21.2 mmol, 1.0 equiv) was dissolved in ethyl acetate (60 mL), followed by the addition of Pd / C (10% wt., 1.2 g). The reaction mixture was purged with nitrogen, placed under an atmosphere of hydrogen (balloon), then stirred at ambient temperature overnight. The solids were removed by filtration, and the filtrate was concentrated in vacuo to give methyl 5-(4,4-difluorocyclohexyl)-4-methoxypyridine-2-carboxylate (5.3 g) as an off-white solid. LCMS Method D: [M+H] + = 286.

[1203] Step 3: Methyl 4-chloro-5-(4,4-difluorocyclohexyl)pyridine-2-carboxylate

[1204] Methyl 5-(4,4-difluorocyclohexyl)-4-methoxypyridine-2-carboxylate (0.8 g, 2.6 mmol, 1.0 equiv) was dissolved in toluene (30 mL) and DMF (1 mL) and cooled to 0 °C, then POCl3(1.1 mL, 13.1 mmol, 5.0 equiv) was added dropwise, keeping the temperature at 0 °C. The reaction mixture was heated to 90 °C overnight, then cooled to 0 °C and quenched by the addition of ice water. The mixture was adjusted to pH 8 with saturated aqueous NaHCO3solution, then extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluted with ethyl acetate / petroleum ether (1:3) to give methyl 4-chloro-5-(4,4-difluorocyclohexyl)pyridine-2-carboxylate (355.0 mg) as a white solid. LCMS Method D: [M+H] + = 290.

[1205] Step 4: 4-Chloro-5-(4,4-difluorocyclohexyl)pyridine carboxylic acid

[1206] Methyl 4-chloro-5-(4,4-difluorocyclohexyl)pyridine-2-carboxylate (2.0 g, 6.9 mmol, 1.0 equiv) was dissolved in MeOH (20 mL) and water (20 mL), then NaOH (1.1 g, 27.6 mmol, 4.0 equiv) was added. The reaction mixture was stirred at ambient temperature overnight and concentrated in vacuo. The residue was diluted with water, then the pH was adjusted to 5 with aqueous HC1 (6 M). The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4and concentrated in vacuo to give 4-chloro-5-(4,4-difluorocyclohexyl)pyridine-2-carboxylic acid (705.1 mg) as a white solid. LCMS Method D: [M-H] - = 274.

[1207] Step 5: 4-Chloro-5-(4,4-difluorocyclohexyl)pyridine carboxylic acid azide

[1208] 4-Chloro-5-(4,4-difluorocyclohexyl)pyridine-2-carboxylic acid (430.0 mg, 1.6 mmol, 1.0 equiv) and TEA (189 mg, 1.9 mmol, 1.2 equiv) were dissolved in toluene (6 mL), then DPPA (515.0 mg, 1.9 mmol, 1.2 equiv) was added. The reaction mixture was stirred at ambient temperature overnight and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4and concentrated in vacuo to give 4-chloro-5-(4,4-difluorocyclohexyl)pyridine-2-carbonyl azide (400.0 mg) as a light brown solid. LCMS Method D: [M+H] + = 301.

[1209] Step 6: tert-Butyl (4-chloro-5-(4,4-difluorocyclohexyl)pyridin-2- yl)carbamate

[1210] tert-Butyl (4-chloro-5-(4,4-difluorocyclohexyl)pyridin-2- yl)carbamate (380 mg) was obtained as a white solid by dissolving 4-chloro-5-(4,4- difluorocyclohexyl)pyridine-2-carboxylic acid azide (400.0 mg, 1.3 mmol, 1.0 equiv) in t-BuOH (4 mL). The solution was heated to 90 °C overnight. The precipitated solid was collected by filtration and washed with ethyl acetate. LCMS Method D: [M+H] + = 347.

[1211] Step 7: 4-Chloro-5-(4,4-difluorocyclohexyl)pyridin-2-amine

[1212] tert-Butyl (4-chloro-5-(4,4-difluorocyclohexyl)pyridin-2- yl)carbamate (380 mg) was obtained as a white solid by dissolving 4-chloro-5-(4,4- difluorocyclohexyl)pyridine-2-carboxylic acid azide (400.0 mg, 1.3 mmol, 1.0 equiv) in t-BuOH (4 mL). The solution was heated to 90 °C overnight. The precipitated solid was collected by filtration and washed with ethyl acetate. LCMS Method D: [M+H] + = 247.

[1213] Synthesis of Intermediate 61 (5,6-Dichloro-lH-indole-3-carboxylic acid)

[1214]

[1215] Step 1: 2,2,2-Trichloro-l-(5,6-dichloro-lH-indol-3-yl)ethan-l-one

[1216] Dissolve 5,6-dichloro-lH-indole (500.0 mg, 2.7 mmol, 1.0 equiv) and pyridine (0.4 mL, 5.0 mmol, 2.0 equiv) in DCM (20 mL) and then add trichloroacetyl chloride (736.3 mg, 4.0 mmol, 1.5 equiv) at ambient temperature. Heat the reaction mixture to 65 °C for 2 h and then concentrate in vacuo. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1 : 1) to give 2,2,2-trichloro-l-(5,6-dichloro-lH-indol-3-yl)ethanone (667.3 mg) as a yellow solid. LCMS Method A: [M+H] + = 330.

[1217] Step 2: 5,6-Dichloro-lH-indole-3-carboxylic acid

[1218] Dissolve 2,2,2-trichloro-l-(5,6-dichloro-lH-indol-3-yl)ethanone (1.0 g, 3.0 mmol, 1.0 equiv) in THF (10 mL) and then add NaOH (120.7 mg, 3.0 mmol, 1.0 equiv). Stir the reaction mixture at ambient temperature for 24 h and then concentrate in vacuo. Dilute the residue with water and then adjust the pH to 4 with aqueous HC1 (6 M). Extract the resulting mixture with Et20, wash with brine, dry over anhydrous Na2S04and concentrate in vacuo to give 5,6-dichloro-lH-indole-3-carboxylic acid (650 mg) as a pink solid. LCMS Method B: [M-H] - = 228.

[1219] The following intermediates were prepared using the methods described for Intermediate 61.

[1220]

[1221] Synthesis of Intermediate 65 (3-amino-lH-indol-5-ol)

[1222]

[1223] Step 1: 5-Hydroxy-lH-indole-3-carbonyl azide

[1224] Dissolve 5-hydroxy-lH-indole-3-carboxylic acid (1.0 g, 5.6 mmol, 1.0 equiv) in THF (40 mL), then add TEA (1.2 mL, 8.5 mmol, 1.5 equiv) and DPPA (2.0 g, 7.3 mmol, 1.3 equiv). Stir the reaction mixture at ambient temperature for 8 hours, then concentrate in vacuo to give crude 5-hydroxy-lH-indole-3-carbonyl azide (1.2 g) as a white solid. LCMS Method C: [M+H] + = 203.

[1225] Step 2: tert-Butyl (5-hydroxy-lH-indol-3-yl)carbamate

[1226] Dissolve 5-hydroxy-lH-indole-3-carbonyl azide (1.2 g, 5.9 mmol, 1.0 equiv) in t-BuOH (40 mL). Heat the resulting solution to 90 °C for 4 hours, then cool to ambient temperature and concentrate in vacuo. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1 :6) to give tert-butyl (5-hydroxy-lH-indol-3-yl)carbamate (1.0 g) as a white solid. LCMS Method C: [M+H] + = 249.

[1227] Step 3: 3-Amino-lH-indol-5-ol

[1228] Dissolve tert-butyl (5-hydroxy-lH-indol-3-yl)carbamate (300.0 mg, 1.2 mmol, 1.0 equiv) in DCM (6 mL) and TFA (2 ml). Stir the resulting solution at ambient temperature for 30 minutes, then concentrate in vacuo to give crude 3-amino-lH-indol-5-ol (420 mg) as a yellow solid. LCMS Method C: [M+H] + = 149.

[1229] Synthesis of Intermediate 66 (5-(Difluoromethyl)-lH-indol-3-amine)

[1230]

[1231] Step 1: 5-(Difluoromethyl)-lH-indole

[1232] 1H-indole-5-carboxaldehyde (15.0 g, 103.3 mmol, 1.0 equivalent) was dissolved in DCM (150 mL) and cooled to 0 °C. Then, DAST (83.3 g, 516.7 mmol, 5.0 equivalent) was added dropwise under a nitrogen atmosphere, maintaining the solution at 0 °C. The resulting mixture was stirred overnight at ambient temperature, then cooled to 0 °C and quenched by adding ice water. The resulting solution was adjusted to pH 7 with a saturated aqueous NaHCO3 solution. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (1:5) to give 5-(difluoromethyl)-1H-indole (0.6 g) as a yellow solid. LCMS method C: [M+H] + =168.

[1233] Step 2: 5-(difluoromethyl)-3-nitro-1H-indole

[1234] 5-(difluoromethyl)-1H-indole (5.8 g, 6.0 mmol, 1.0 equivalent) and AgNO3 (1.5 g, 9.0 mmol, 1.5 equivalent) were dissolved in MeCN (15 mL) and cooled to 0 °C. Benzoyl chloride (1.1 mL, 9.2 mmol, 1.5 equivalent) was added dropwise while maintaining the solution at 0 °C for 10 minutes. The reaction mixture was stirred at 0 °C for another 2 hours, then quenched by adding ice water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (1:8) to give 5-(difluoromethyl)-3-nitro-1H-indole (490 mg) as a yellow oil. LCMS method D: [M+H] + =213.

[1235] Step 3: (5-(difluoromethyl)-1H-indol-3-yl)tert-butyl carbamate

[1236] 5-(difluoromethyl)-3-nitro-1H-indole (480.0 mg, 0.9 mmol, 1.0 equivalent) was dissolved in MeOH (10 mL), followed by the addition of Pd / C (10% wt., 100.3 mg) and Boc₂O (411.5 mg, 1.9 mmol, 2.0 equivalent). The mixture was purged with nitrogen, placed under a hydrogen (balloon) atmosphere, and stirred overnight at ambient temperature. The solid was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (1:10) to give N-[5-(difluoromethyl)-1H-indole-3-yl]tert-butyl carbamate (320 mg), as a grayish-white solid. LCMS method C: [M+H] += 283.

[1237] Step 4: 5-(Difluoromethyl)-lH-indol-3-amine

[1238] tert-Butyl N-[5-(difluoromethyl)-lH-indol-3-yl]carbamate (320.0 mg, 0.5 mmol, 1.0 equiv) was dissolved in HCl (4 M in 1,4-dioxane, 5 mL). The resulting solution was stirred at ambient temperature for 1 hour and then concentrated in vacuo to give 5-(difluoromethyl)-lH-indol-3-amine hydrochloride (210 mg) as a yellow oil which was used directly in the next step without further purification. LCMS Method A: [M+H] + = 183.

[1239] Synthesis of Intermediate 67 (5-(methylsulfonyl)-lH-indole-3-carboxylic acid)

[1240]

[1241] 5-(methylsulfanyl)-lH-indole-3-carboxylic acid (400.0 mg, 1.9 mmol, 1.0 equiv) was dissolved in ACN (400 mL) and NaIO4(1.6 g, 7.7 mmol, 4.0 equiv) was added. The resulting solution was heated to 80 °C for 2 hours and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give 5-methanesulfonyl-lH-indole-3-carboxylic acid (300 mg) as an off-white solid. LCMS Method B: [M-H] - = 238.

[1242] Synthesis of Intermediate 68 (2-(lH-indol-5-yl)ethan-l-ol)

[1243]

[1244] Step 1: 5-vinyl-lH-indole

[1245] Methyltriphenylphosphonium bromide (14.8 g, 41.4 mmol, 2.0 equiv) and t-BuOK (4.6 g, 42.1 mmol, 2.0 equiv) were dissolved in THF (50 mL) and cooled to 0 °C before the dropwise addition of a solution of lH-indole-5-carbaldehyde (3.0 g, 20.7 mmol, 1.0 equiv) in THF (5 mL). The reaction mixture was stirred at ambient temperature for 2 hours and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:10) to give 5-vinyl-lH-indole (1.8 g) as an off-white solid. LCMS Method A: [M+H] + = 144.

[1246] Step 2: 2-(lH-indol-5-yl)ethan-l-ol

[1247] Dissolve 5-vinyl-lH-indole (1.0 g, 7.0 mmol, 1.0 equiv) in THF (40 mL) and cool to 0 °C, then add BH3-THF (1 M, 8.4 mL, 8.4 mmol, 1.2 equiv) dropwise. Stir the reaction mixture at 0 °C for 20 min, then add NaOH (1.1 g, 27.5 mmol, 4.0 equiv). Stir the resulting mixture at ambient temperature for 1 h, then quench by addition of sodium dithionite. Extract the resulting mixture with ethyl acetate, wash with brine, dry over anhydrous Na2SO4, and concentrate in vacuo to give 2-(lH-indol-5-yl)ethan-l-ol (650.1 mg) as a yellow solid. LCMS Method A: [M+H] + = 162.

[1248] Synthesis of Intermediate 69 (5-(methylthio)-lH-indole)

[1249]

[1250] Dissolve 5-iodo-lH-indole (15.0 g, 61.7 mmol, 1.0 equiv) in THF (200 mL) and cool to -78 °C, then add n-BuLi (2.5 M, 49.4 mL, 123.5 mmol, 2.0 equiv) in hexanes dropwise, maintaining the temperature at -78 °C. After 30 min at -78 °C, add dimethyl disulfide (11.6 g, 123.5 mmol, 2.0 equiv) dropwise at 78 °C. Stir the reaction mixture at ambient temperature for an additional 1 h, then quench by addition of aqueous NH4Cl. Extract the resulting mixture with ethyl acetate, wash with brine, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the residue by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN and water (0.5% TFA), 35% MeCN increasing to 70% over 30 min; detector, UV 254 nm. Obtain 5-(methylsulfanyl)-lH-indole (1.7 g) as a yellow solid. LCMS Method C: [M+H] + = 164.

[1251] Synthesis of Intermediate 70 (l-(4-ethylphenyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole)

[1252]

[1253] Step 1: 4-bromo-1-(4-ethylphenyl)-1H-pyrazole

[1254] Dissolve 4-ethylphenylboronic acid (10.0 g, 66.7 mmol, 1.0 equiv) and 4- bromopyrazole (9.8 g, 66.7 mmol, 1.0 equiv) in DCM (300.0 mL), then add Cu(OAc)2(24.2 g, 133.4 mmol, 2.0 equiv) and pyridine (2.1 mL, 26.7 mmol, 2.0 equiv) under nitrogen. Stir the reaction mixture at ambient temperature overnight and concentrate under vacuum. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:10) to give 4-bromo-1-(4-ethylphenyl)pyrazole (9.5 g) as a white solid. LCMS Method F: [M+H] + = 251.

[1255] Step 2: 1-(4-ethylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1256] Dissolve 4-bromo-1-(4-ethylphenyl)pyrazole (9.5 g, 37.8 mmol, 1.0 equiv) in dioxane (200.0 ml), then add bis(pinacolato)diboron (9.6 g, 37.8 mmol, 1.0 equiv), AcOK (7.4 g, 75.7 mmol, 2.0 equiv) and Pd(dppf)Cl2(5.5 g, 7.6 mmol, 0.2 equiv) under nitrogen. Heat the reaction mixture to 80 °C overnight, then cool to ambient temperature and concentrate under vacuum. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:4) to give 1-(4-ethylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.0 g) as a yellow solid. LCMS Method D: [M+H] + = 299.

[1257] Synthesis of Intermediate 106 (2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)pyridin-4-amine)

[1258]

[1259] Step 1: 4-amino-5,6-dihydro-2H-[2,3-bipyridin]-1-carboxylic acid tert-butyl ester

[1260] Dissolve 2-bromopyridine-4-amine (500.0 mg, 2.9 mmol, 1.0 equiv) and 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-l-carboxylic tert-butyl ester (1072.3 mg, 3.5 mmol, 1.2 equiv) in 1,4-dioxane / water (25 / 5 mL), add Cs2CO3(1883.2 mg, 5.8 mmol, 2.0 equiv) and Pd(dppf)Cl2(211.5 mg, 0.3 mmol, 0.1 equiv) under a nitrogen atmosphere. Heat the reaction mixture to 90 °C overnight under nitrogen, cool to ambient temperature and concentrate under vacuum. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give 4-amino-5,6-dihydro-2H-[2,3-bipyridine]-l-carboxylic tert-butyl ester (580.0 mg) as a brown solid. LCMS Method A: [M+H] + = 276.

[1261] Step 2: 1,2,5,6-Tetrahydro-[2,3-bipyridine]-4-amine

[1262] Dissolve 4-amino-5,6-dihydro-2H-[2,3-bipyridine]-l-carboxylic tert-butyl ester (605.0 mg, 2.2 mmol, 1.0 equiv) in HC1 (4 M in 1,4-dioxane, 10 mL). Stir the reaction mixture at ambient temperature for 2 hours and concentrate under vacuum. Dilute the residue with water, then adjust to pH 8 with saturated aqueous NaHC03. Extract the resulting solution with ethyl acetate and concentrate under vacuum. Purify the residue by flash column chromatography on silica gel eluting with DCM / MeOH (10:1) to give 1,2,5,6-tetrahydro-[2,3-bipyridine]-4-amine (332.2 mg) as a brownish yellow solid. LCMS Method D: [M+H] + = 176.

[1263] Step 3: 2-(Piperidin-3-yl)pyridin-4-amine

[1264] Dissolve 1,2,5,6-tetrahydro-[2,3-bipyridine]-4-amine (332.0 mg, 1.9 mmol, 1.0 equiv) in MeOH (10 mL), add Rh(PPh3)3Cl (175.3 mg, 0.2 mmol, 0.1 equiv). Purge the mixture with nitrogen, place under a hydrogen (balloon) atmosphere, then stir at 50 °C overnight. Filter off solids and concentrate the filtrate under vacuum. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:10) to give 2-(piperidin-3-yl)pyridin-4-amine (215.2 mg) as a brown solid. LCMS Method D: [M+H]+ = 178.

[1265] Step 4: 2-[l-(2,2,2-trifluoroethyl)piperidin-3-yl]pyridin-4-amine

[1266] Dissolve 2-(piperidin-3-yl)pyridin-4-amine (200.0 mg, 1.1 mmol, 1.0 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (314.3 mg, 1.4 mmol, 1.2 equiv) in ACN (10 mL) and add Cs2CO3 (1102.9 mg, 3.4 mmol, 3.0 equiv). Stir the reaction mixture at ambient temperature overnight. After removing the solids by filtration, concentrate the solution in vacuo. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give 2-[l-(2,2,2-trifluoroethyl)piperidin-3-yl]pyridin-4-amine (180.0 mg) as a brown solid. LCMS Method A: [M+H] + = 260.

[1267] The following intermediates were prepared using the method described for Intermediate 106.

[1268]

[1269] Synthesis of Intermediate 109 (3-chloro-4-(l-(2,2,2-trifluoroethyl)azetidin-3- yl)aniline hydrochloride)

[1270]

[1271]

[1272] Step 1: 3-(4-bromo-2-chlorophenyl)azetidine

[1273] Dissolve 3-(4-bromo-2-chlorophenyl)azetidine-1 -carboxylate tert-butyl ester (2.0 g, 5.8 mmol, 1.0 equiv) in HC1 (4 M in 1,4-dioxane, 10 mL). Stir the resulting solution at ambient temperature for 2 hours, then concentrate in vacuo to give 3-(4-bromo-2-chlorophenyl)azetidine hydrochloride (1.4 g) as a white solid. LCMS Method F: [M+H] + = 246.

[1274] Step 2: 3-(4-bromo-2-chlorophenyl)-l-(2,2,2-trifluoroethyl)azetidine

[1275] Dissolve 3-(4-bromo-2-chlorophenyl)azetidine hydrochloride (800.0 mg, 2.8 mmol, 1.0 equiv) and TEA (2.2 mL, 16.2 mmol, 5.0 equiv) in ACN (15 mL), add 2,2,2-trifluoroethyl trifluoromethanesulfonate (1129.8 mg, 4.9 mmol, 1.5 equiv). Heat the reaction mixture to 50 °C for 4 h, then cool to ambient temperature and concentrate under vacuum. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give 3-(4-bromo-2-chlorophenyl)-1-(2,2,2- trifluoroethyl)azetidine (789.2 mg) as a brown oil. LCMS Method D: [M+H]=328. +

[1276] Step 3: tert-Butyl (3-chloro-4-(1-(2,2,2-trifluoroethyl)azetidin-3- yl)phenyl)carbamate

[1277] Dissolve 3-(4-bromo-2-chlorophenyl)-1-(2,2,2-trifluoroethyl)azetidine (400.0 mg, 1.2 mmol, 1.0 equiv) in dioxane (10 mL), add BocNH2 (213.9 mg, 1.8 mmol, 1.5 equiv), Cs2CO3 (793.3 mg, 2.4 mmol, 2.0 equiv), Brettphos (65.4 mg, 0.1 mmol, 0.1 equiv) and Brettphos Pd G3 (110.4 mg, 0.1 mmol, 0.1 equiv) under a nitrogen atmosphere. Heat the reaction mixture to 50 °C for 4 h, then cool to ambient temperature and concentrate under vacuum. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give tert-butyl (3-chloro-4-(1-(2,2,2-trifluoroethyl)azetidin-3- yl)phenyl)carbamate (280.5 mg) as a brown oil. LCMS Method D: [M+H]=365. +

[1278] Step 4: 3-Chloro-4-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)aniline hydrochloride

[1279] ​​tert-Butyl (3-chloro-4-(l-(2,2,2-trifluoroethyl)azetidin-3-yl)phenyl)carbamate (200.0 mg, 0.5 mmol, 1.0 equiv) was dissolved in HC1 (4 M in 1,4-dioxane, 5 mL). The resulting solution was stirred at ambient temperature for 2 hours, then concentrated in vacuo to afford 3-chloro-4-(l-(2,2,2-trifluoroethyl)azetidin-3-yl)aniline HC1 salt (131.5 mg) as an off-white solid. LCMS Method A: [M+H] + = 265.

[1280] Synthesis of Intermediate 113 (l-(4,4-difluorocyclohexyl)pyrazol-4-amine)

[1281]

[1282] Step 1: l-(4,4-difluorocyclohexyl)-4-nitropyrazole

[1283] 4,4-Difluorocyclohexyl methanesulfonate (500.0 mg, 2.3 mmol, 1.0 equiv) was dissolved in DMF (10 mL), then 4-nitropyrazole (316.7 mg, 2.8 mmol, 1.2 equiv), Cs2CO3(1.5 g, 4.7 mmol, 2.0 equiv) were added. The reaction mixture was heated to 90 °C for 12 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with ethyl acetate / petroleum ether (1:10) to afford l-(4,4-difluorocyclohexyl)-4-nitropyrazole (420.0 mg) as an off-white solid. LCMS Method C: [M+H] + = 232.

[1284] Step 2: l-(4,4-difluorocyclohexyl)pyrazol-4-amine

[1285] l-(4,4-Difluorocyclohexyl)-4-nitropyrazole (400.0 mg, 1.7 mmol, 1.0 equiv) was dissolved in MeOH (10 mL), then Pd / C (184.1 mg, 10% wt.) was added. The reaction mixture was purged with nitrogen, placed under an atmosphere of hydrogen (balloon), then stirred at ambient temperature overnight. The solids were removed by filtration, the filtrate was concentrated in vacuo to afford l-(4,4-difluorocyclohexyl)pyrazol-4-amine (243.1 mg) as a yellow solid. LCMS Method C: [M+H] + = 202.

[1286] The following intermediates were prepared using the methods described for Intermediate 113.

[1287]

[1288] Synthesis of intermediate 116 (1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-amine)

[1289]

[1290] Step 1: 3-(4-nitropyrazol-1-yl)cyclobutan-1-one

[1291] Dissolve 4-nitropyrazole (1.0 g, 8.8 mmol, 1.0 equiv) and K2CO3(2.4 g, 17.7 mmol, 2.0 equiv) in ACN (20 mL), add 3-bromocyclobutan-1-one (5.3 g, 35.4 mmol, 4.0 equiv). Stir the reaction mixture at ambient temperature overnight, then remove the solids by filtration and concentrate the filtrate under vacuum. Purify the residue by flash column chromatography on a silica gel column eluting with ethyl acetate / petroleum ether (1:1) to give 3-(4-nitropyrazol-1-yl)cyclobutan-1-one (530.0 mg) as an off-white solid. LCMS Method D: [M+H] + = 182.

[1292] Step 2: 1-(3,3-difluorocyclobutyl)-4-nitropyrazole

[1293] Dissolve 3-(4-nitropyrazol-1-yl)cyclobutan-1-one (470.0 mg, 2.6 mmol, 1.0 equiv) in DCM (20 mL) and cool to 0 °C, add DAST (836.4 mg, 5.2 mmol, 2.0 equiv). Stir the reaction mixture at ambient temperature overnight and quench by the addition of ice water. Concentrate the resulting solution under vacuum, purify the residue by flash column chromatography on a silica gel column eluting with ethyl acetate / petroleum ether (1:1) to give 1-(3,3-difluorocyclobutyl)-4-nitropyrazole (420.0 mg) as a brown solid. LCMS Method A: [M+H] + = 204.

[1294] Step 3: 1-(3,3-difluorocyclobutyl)pyrazol-4-amine

[1295] Dissolve 1 -(3,3-difluorocyclobutyl)-4-nitropyrazole (400.0 mg, 2.0 mmol, 1.0 equiv) in MeOH (10 mL), add Pd / C (41.9 mg, 10% wt.). Purge the reaction mixture with nitrogen, place under an atmosphere of hydrogen (balloon) and then stir at ambient temperature overnight. Remove the solids by filtration and concentrate the filtrate in vacuo. Purify the residue by flash column chromatography on silica gel eluting with DCM / MeOH (12:1 ) to give 1 -(3,3-difluorocyclobutyl)pyrazol-4-amine (300.0 mg) as an off-white solid. LCMS method E: [M+H] + = 174.

[1296] Synthesis of intermediate 117 (1 -(1 -(3,3,3-trifluoropropyl)piperidin-4-yl)-1 H- pyrazol-4-amine)

[1297]

[1298] Step 1 : tert-Butyl 4-(4-nitro-1 H-pyrazol-1 -yl)piperidine-1 -carboxylate

[1299] Dissolve 4-nitropyrazole (1.0 g, 8.8 mmol, 1.0 equiv) and Cs2CO3(5.8 g, 17.7 mmol, 2.0 equiv) in DMF (20 mL), add tert-butyl 4-(methanesulfonyloxy)piperidine-1 - carboxylate (3.7 g, 13.3 mmol, 1.5 equiv). Heat the reaction mixture to 90 °C for 4 h, then cool to ambient temperature and quench by addition of water. Extract the resulting solution with ethyl acetate, wash with brine, dry over anhydrous sodium sulfate and concentrate in vacuo. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1 :1 ) to give tert-butyl 4-(4-nitro-1 H-pyrazol-1 -yl)piperidine-1 -carboxylate (1.5 g) as a white solid. LCMS method D: [M+H] + = 297.

[1300] Step 2: 4-(4-Nitro-1 H-pyrazol-1 -yl)piperidine

[1301] Dissolve tert-butyl 4-(4-nitropyrazol-1 -yl)piperidine-1 -carboxylate (1.5 g, 5.1 mmol, 1.0 equiv) in HCI (4 M in 1,4-dioxane, 15 mL). Stir the resulting solution at ambient temperature for 1 h and concentrate in vacuo to give 4-(4-nitro-1 H-pyrazol-1 -yl)piperidine hydrochloride (1.5 g) as a brown solid. LCMS method D: [M+H] + = 197.

[1302] Step 3: 4-(4-nitropyrazol-l-yl)-l-(3,3,3-trifluoropropyl)piperidine

[1303] Dissolve 4-(4-nitropyrazol-l-yl)piperidine hydrochloride (1.5 g, 7.6 mmol, 1.0 equiv) and l,l,l-trifluoro-3-iodopropane (5.1 g, 22.9 mmol, 3.0 equiv) in ACN (40 mL) and add Cs2CO3(12.5 g, 38.2 mmol, 5.0 equiv). Heat the reaction mixture to 50 °C, then cool to ambient temperature, filter off the solids and concentrate the solution in vacuo. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give 4-(4-nitropyrazol-l-yl)-l-(3,3,3- trifluoropropyl)piperidine (1.2 g) as a colorless oil. LCMS Method A: [M+H] + = 293.

[1304] Step 4: l-(l-(3,3,3-trifluoropropyl)piperidin-4-yl)-lH-pyrazol-4-amine

[1305] Dissolve 4-(4-nitropyrazol-l-yl)-l-(3,3,3-trifluoropropyl)piperidine (500.0 mg, 1.7 mmol, 1.0 equiv) in HBr (40%, 15 mL) and cool to 0 °C, then add SnCl2.2H2O (772.1 mg, 3.4 mmol, 2.0 equiv) and keep the solution at 0 °C. Stir the resulting solution at ambient temperature for 2 hours and concentrate in vacuo. Dilute the residue with water and adjust to pH 9 with aqueous NaOH (4 M). Extract the resulting mixture with ethyl acetate, wash with brine and concentrate in vacuo. Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:3) to give l-(l-(3,3,3-trifluoropropyl)piperidin-4-yl)-lH-pyrazol-4-amine (230.0 mg) as a white solid. LCMS Metho...

Claims

1. Compounds of Formula I: Or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein: X 1 It is NH; X 2 It is CH; Each It can be a single bond or a double bond independently, provided that: Includes X 1 and X 2 The 5-membered ring is a heteroaryl group; 6-membered ring It is of the Fang ethnic group; as well as Includes P 1 P 2 P 3 P 4 and P 5 The ring is from the Aromatic tribe; Part of it is: Where n2 is 0, 1, or 2; Where n2 is 0 or 1; Each R 7 Selected independently from: -R 8 and -L 3 -R 9 ; R 8 yes R 9 Is it cyclobutyl or -L 3 It is -C 1-4 Alkylene; Each occurrence of R 7 'Independently selected from: halogen; -OH; optionally selected by 1-2 independent R's a Replacement -C 1-4 Alkyl; -C 2-4 alkynyl group; -C 1-4 Halogenated alkyl; optionally with 1-2 independently selected R a Replacement -C 1-6 Alkoxy; -C 1-6 Halogenated alkoxy groups; and -C(=O)O(C 1-4 alkyl); W is C (=O); Q is selected from: NH or N(C) 1-6 alkyl); R 1a R 1b R 1c and R 1d Each group is independently selected from: H; halogen; cyano; optionally surrounded by 1-2 R groups. a Replacement C 1-6 Alkyl; C 1-4 Halogenated alkyl group; -S(O)2(C 1-4 alkyl); –OH; and -C 1-4 Thioalkoxy; R 6 It is H; Each occurrence of R a Independently selected from the following groups: –OH; -F; C 1-4 Alkoxy; and C 3-6 cycloalkyl; Each occurrence of R c Independently selected from the group consisting of: halogens; cyano groups; R groups optionally selected by 1-6 independently selected groups. a Optional substitution of C 1-10 Alkyl groups; and -C(=O)O(C 1-4 alkyl); and R d Selected from the following group: C 1-6 Alkyl groups, optionally substituted with 1 to 3 substituents, each independently selected from halogens.

2. The compound of claim 1, wherein, Partially has the following formula: Where n2 is 0 or 1.

3. The compound of claim 1, wherein, Partially has a formula Where n2 is 0 or 1.

4. The compound of claim 1, wherein, Partially has the following formula: Where n2 is 0, 1 or 2.

5. The compound of claim 1, wherein, Partially has a formula 6. The compound of claim 1, wherein, Partially has the following formula: Where n2 is 0, 1 or 2.

7. The compound of claim 1, wherein... Partially has the following formula: Where n2 is 0, 1 or 2.

8. The compound of claim 1, wherein, Partially has the following formula:

9. The compound of claim 1, wherein, Partially has the following formula: Where n2 is 0, 1 or 2.

10. The compound of claim 1, wherein, Partially has the following formula:

11. The compound of claim 1, wherein, R 7 It is R 8 .

12. The compound of claim 1, wherein, R 8 yes 13. The compound of claim 1, wherein, R 8 yes 14. The compound of claim 1, wherein, R 8 yes 15. The compound of claim 1, wherein, R 8 yes Each R 7 'It is a halogen on its own.' 16. The compound of claim 1, wherein, R 8 yes 17. The compound of claim 1, wherein, R 8 yes 18. The compound of claim 1, wherein, R 8 yes 19. The compound of claim 1, wherein, R 8 yes 20. The compound of claim 1, wherein, R 8 yes 21. The compound of claim 1, wherein, Each R 7 'Independently halogen or C 1-3 alkyl.

22. The compound of claim 1, wherein, Each R c It is an independently selected halogen.

23. The compound of claim 1, wherein, Q is NH.

24. The compound of claim 1, wherein R 1a R 1b R 1c and R 1d One or two of them are not H; the rest are R. 1a R 1b R 1c and R 1d Each is H.

25. The compound of claim 1, wherein R 1b and R 1c Neither of them is H; R 1a and R 1d Each is H.

26. The compound of claim 1, wherein R 1b and R 1c Each is independent and selected from halogens, R 1a and R 1d Each is H.

27. The compound of claim 1, wherein R 1b Not H; R 1a R 1c and R 1d Each is H.

28. The compound of claim 1, wherein R 1b Selected from: halogens; optionally covered by 1-2 Rs a Replacement C 1-6 Alkyl; C 1-4 Haloalkyl; –CN; C 1-4 Thioalkoxy groups; and S(O)2(C 1-4 Alkyl); R 1a R 1c and R 1d Each is H.

29. The compound of claim 1, wherein R 1b It is halogen; R 1a R 1c and R 1d Each is H.

30. The compound of claim 1, wherein the compound is of formula (I-1a), (I-2a), or (I-3a): Or its pharmaceutically acceptable salt, wherein: R 2 It is H; R 1a R 1b R 1c and R 1d Each group is independently selected from: H; halogen; cyano; optionally surrounded by 1-2 R groups. a Replacement C 1-6 Alkyl; and C 1-4 Halogenated alkyl groups; n2 is 0, 1, or 2; When it exists, each R c Independently selected from: halogen, cyano, and C 1-3 alkyl; R 8 Selected from: · and · 31. The compound of claim 30, wherein, R 8 Selected from:

32. The compound of claim 30, wherein, Each R 7 'Independently halogen or C 1-3 Alkyl groups, and R therein d C is optionally replaced by 1-3 independently selected halogens. 1-6 alkyl.

33. Compounds, selected from: Or its pharmaceutically acceptable salt.

34. A pharmaceutical composition comprising a compound as described in any one of claims 1-33 and one or more pharmaceutically acceptable excipients.

35. Use of the compound of any one of claims 1-33 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting STING activity.

36. Use of the pharmaceutical composition of claim 34 in the preparation of a medicament for inhibiting STING activity.

37. Use of the compound of any one of claims 1-33 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing an immune response.

38. Use of the pharmaceutical composition of claim 34 in the preparation of a medicament for inducing an immune response.

39. The use of any compound of claims 1-33 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases, conditions or symptoms associated with STING.

40. Use of the pharmaceutical composition of claim 34 in the preparation of a medicament for treating diseases, conditions, or symptoms associated with STING.

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