Compounds and compositions for treating conditions associated with sting activity

Abstract

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

Description

[0001] Compounds and Compositions for Treating Conditions Associated with STING Activity

[0002] TECHNICAL FIELD

[0003] This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and / or hydrate, and / or cocrystal, and / or drag combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as veH as methods of using and making the same.

[0004] BACKGROUND

[0005] STING, also known as transmembrane protein 173 (TMEM173) and MPYS / MITA / ERIS, is a protein that in humans is encoded by the TMEM173 gene. STING has been shown to play a role in innate immunity. STING induces type I interferon production when cells are infected with intracellular pathogens, such as viruses, mycobacteria and intracellular parasites. Type I interferon, mediated by STING, protects infected cells and nearby cells from local infection in an autocrine and paracrine manner.

[0006] The STING pathway is pivotal in mediating the recognition of cytosolic DNA. In this context, STING, a transmembrane protein localized to the endoplasmic reticulum (ER), acts as a second messenger receptor for 2', 3' cyclic GMP-AMP (hereafter cGAMP), which is produced by cGAS after dsDNA binding. In addition, STING can also function as a primary' pattern recognition receptor for bacterial cyclic dinucleotides (CDNs) and small molecule agonists. The recognition of endogenous or prokaryotic CDNs proceeds through the carboxy-terminal domain of STING, which faces mto the cytosol and creates a V-shaped binding pocket formed by a STING homodimer. Ligand-induced activation of STING triggers its re-localization to the Golgi, a process essential to promote the interaction of STING with TBK1 . This protein complex, in turn, signals through the transcription factors IRF-3 to induce type I interferons (IFNs) and other co-regulated antiviral factors. In addition, STING was shown to trigger NF-KB and MAP kinase activation. Following the initiation of signal transduction, STING is rapidly degraded, a step considered important in terminating the inflammatory response.

[0007] Excessive activation of STING is associated with a subset of monogenic autoinflammatory conditions, the so-called type 1 interferonopathies. Examples ofthese diseases include a clinical syndrome referred to as STING-associated vasculopathy with onset in infancy (SAVI), which is caused by gain-of-function mutations in TMEM173 (the gene name of STING). Moreover, STING is implicated in die pathogenesis of Aicardi-Goutieres Syndrome (AGS) and genetic forms of lupus. As opposed to SAVI, it is the dysregulation of nucleic acid metabolism that underlies continuous innate immune activation in AGS. Apart from these genetic disorders, emerging evidence points to a more general pathogenic role for STING in a range of inflammation-associated disorders such as systemic lupus erythematosus, rheumatoid arthritis and cancer. Thus, small molecule-based pharmacological interventions into the STING signaling pathway hold significant potential for the treatment of a wide spectrum of diseases

[0008] SUMMARY

[0009] This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and / or hydrate, and / or cocrystal, and / or drugcombination, and / or stereoisomers (e.g., enantiomers and diastereomers) of the compound)) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.

[0010] An "antagonist" of STING includes compounds that, at the protein level, directly bind or modify STING such that an activity of STING is decreased, e.g., by inhibition, blocking or dampening agonist-mediated responses, altered distribution, or otherwise. STING antagonists include chemical entities, which interfere or inhibit STING signaling. In one aspect, compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are featured: or a pharmaceutically acceptable salt thereof, wherein:

[0011] L is a bond or -O-;

[0012] R1is halo or C1-C4 alkyl;

[0013] R2is selected from the group consisting of:

[0014] « C1-C6 alkyl optionally substituted with 1-6 independently selected Ra;

[0015] • 5 membered heteroaryl optionally substituted with 1 Rb;

[0016] ® C3-C7 cycloalkyl, which is optionally substituted with 1-4 independently selected Rc; and

[0017] ® C4-C7 cycloalkenyl, which is optionally substituted with 1-4 independently selected Rc;

[0018] R31, R32, and R33are each, independently, halo or H;

[0019] R33is H or F; each occurrence of R3is, independently, -OH or halo;

[0020] Rbis selected from the group consisting of C1-C6 alkyl optionally substituted with 1-4 independently selected RM; C3-C5 cycloalkyl optionally substituted with 1-2 independently selelcted halo; and -SO2N(C1-C4 alkyl)2; each occurrence of R£is, independently, -OH or C1-C4 alkyl optionally substituted with 1-4 substituents independently selected from -OH and halo; and

[0021] RMis -OH, halo, or C3-C5 cycloalkyl optionally substituted with 1-2 halo.

[0022] In one aspect, pharmaceutical compositions are featured that include a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same) and one or more pharmaceutically acceptable excipients.

[0023] In one aspect, methods for inhibiting (e.g., antagonizing) STING activity are featured that include contacting STING with a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same). Methods include in vitro methods, e.g., contacting a sample that includes one or more cells comprising STING (e.g., innate immune cells, e.g., mast cells, macrophages, dendritic cells (DCs), and natural killer cells) with the chemical entity. Methods can also include in vivo methods; e.g., administering the chemical entity to a subject (e.g., a human) having a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and / or symptoms and / or progression of the disease.

[0024] In one aspect, methods of treating a condition, disease or disorder ameliorated by antagonizing STING are featured, e.g., treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). Hie methods include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).

[0025] In another aspect, methods of treating cancer are featured that include administering to a subject in need of such treatment an effective amount of a chemical entity’ described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).

[0026] In a further aspect, methods of treating other STING-associated conditions are featured, e.g., type I interferonopathies (e.g., STING-associated vasculopathywith onset in infancy (SAVI)), Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis. The methods include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).

[0027] In another aspect, methods of suppressing STING-dependent type I interferon production in a subject in need thereof are featured that include administering to the subject an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same). In a further aspect, methods of treating a disease in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the disease are featured. The m ethods include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).

[0028] In another aspect, methods of treatm ent are featured that include administering an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same) to a subject; wherein the subject has (or is predisposed to have) a disease in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the disease.

[0029] In a further aspect, methods of treatment that include administering to a subject a chemical entity described herein (e.g,, a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same), wherein tire chemical entity is administered in an amount effective to treat a disease in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the disease, thereby treating the disease.

[0030] In another aspect, there is provided is a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein, for use in the treatment of a disease, condition or disorder modulated by STING inhibition.

[0031] In another aspect, there is provided a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for use in the treatment of a condition, disease or disorder associated with increased (e.g,, excessive) STING activation. hi another aspect, there is provided a compound, or a pharmaceutically acceptable salt or tautomer thereof, described herein for use in the treatment of cancer.

[0032] In another aspect, there is provided a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for use in the treatment of cancer selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non- small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma.

[0033] In another aspect, there is provided a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for use in the treatment of type I interferonopathies.

[0034] In another aspect, there is provided a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for use in the treatment of type I interferonopathies selected from STING-associated vasculopathywith onset in infancy (SA VI)), Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis.

[0035] In another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein in the manufacture of a medicament for the treatment of a condition, disease or disorder associated with increased (e.g., excessive) STING activation.

[0036] In another aspect, there is provided tire use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein in the manufacture of a medicament for the treatment of cancer.

[0037] In another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein in the manufacture of a medicament for the treatment of cancer selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm’s tumor, or hepatocellular carcinoma. In another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein in the m anufacture of a medicament for the treatment of type I interferonopathies.

[0038] In another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for use in the manufacture of a medicament for the treatment of type I interferonopathies selected from STING-associated vasculopathywith onset in infancy (SA VI)), Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, and inflammation -associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis.

[0039] In another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein, for the treatment of a disease, condition or disorder modulated by STING inhibition.

[0040] In another aspect, there is provided tire use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for the treatment of a condition, disease or disorder associated with increased (e.g, excessive) STING activation.

[0041] In another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for the treatment of cancer.

[0042] In another aspect, there is provided tire use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for the treatment of cancer selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma.

[0043] In another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for the treatment of type I interferonopathies. In another aspect, there is provided the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein for the treatment of type I interferonopathies selected from STING -assoc iated vascul opathy with onset in infancy (SA VI)), Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis.

[0044] Embodiments can include one or more of the following features.

[0045] The chemical entity can be administered in combination with one or more additional therapeutic agents and / or regimens. For examples, methods can further include administering one or more (e.g., two, three, four, five, six, or more) additional agents.

[0046] The chemical entity can be administered in combination with one or more additional therapeutic agents and / or regimens that are useful for treating other STING- associated conditions, e.g., type I interferonopathies (e.g., STTNG-associated vasculopathy with onset in infancy (SAVT)), Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, and inflammation -associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis.

[0047] The chemical entity can be administered in combination with one or more additional cancer therapies (e.g., surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof; e.g., chemotherapy that includes administering one or more (e.g., two, three, four, five, six, or more) additional chemotherapeutic agents. Non-limiting examples of additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and / or oxaliplatin); an anti -metabolite (e.g., azathioprine and / or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and / or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and / or Vindesine Taxol, Pacllitaxel and / or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and / or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and / or topotecan;. amsacrine, etoposide, etoposide phosphate and / or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracy clines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and / or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelm, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basilixhnab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and / or Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory' agent; an anti -helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1 - PD-L1, PD-1 - PD-L2, interleukin 2 (IL-2), indoleamine 2,3 -dioxygenase (IDO), IL- 10, transforming growth factor-P (TGFP), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9 - TIM3, Phosphatidylserine - TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II - LAG3, 4 1BB-4 IBB ligand, 0X40-0X40 ligand, GITR, GITR ligand - GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25- TL 1 A, 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, TIG IT 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, Neuropilm, CD 160, CD30, and CD155 (e.g, CTLA-4 or PD1 or PD-L1).

[0048] The subject can have cancer; e.g, the subject has undergone and / or is undergoing and / or will undergo one or more cancer therapies.

[0049] Non-limiting examples of cancer include melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma. In certain embodiments, the cancer can be a refractory7cancer.

[0050] The chemical entity can be administered intratumorally.

[0051] The methods can further include identifying the subject.

[0052] Other embodiments include those described in the Detailed Description and / or m the claims.

[0053] Additional Definitions

[0054] To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry7, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary7skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.

[0055] As used herein, the term ‘"STING” is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous STING molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0056] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on tire general health of the subject being treated.

[0057] “API” refers to an active pharmaceutical ingredient.

[0058] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entity being administered which will relieve to some extent one or more of the symptoms of the di sease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.

[0059] The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically-accep table material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed:, Lippincott. Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6 th ed.,' Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed. ; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed. ,' Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0060] The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylamme, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof -with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

[0061] The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary', and topical administration.

[0062] The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.

[0063] The terms “treat,” “treating,” and “treatment,” in the context of treating a disease or disorder, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof. "lire “treatment of cancer”, refers to one or more of the following effects: (1) inhibition, to some extent, of tumor growth, including, (i) slowing down and (ii) complete growth arrest; (2) reduction in the number of tumor cells; (3) maintaining tumor size; (4) reduction in tumor size; (5) inhibition, including (i) reduction, (ii) slowing down or (lii) complete prevention, of tumor cell infiltration into peripheral organs; (6) inhibition, including (i) reduction, (ii) slowing down or (iii) complete prevention, of metastasis; (7) enhancement of anti-tumor immune response, which may result in (i) maintaining tumor size, (ii) reducing tumor size, (iii) slow'ing the growth of a tumor, (iv) reducing, slowing or preventing invasion and / or (8) relief, to some extent, of the severity or number of one or more symptoms associated with the disorder.

[0064] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0065] The term "alkyl" refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci- -o indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, rio-propyl, tert-butyl, n- hexyl. Hie term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0066] The term "alkenyl" refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon -carbon double bonds. "lire alkenyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkenyl groups can either be unsubstituted or substituted with one or more substituents.

[0067] The term "cycloalkyl" as used herein refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl includes: bicyclofl.1.0]butanyl, bicyclo[2.1 ,0]pentanyl, bicyclofl .1. l]pentanyl, bicyclo [3. l.OJhexanyl, bicyclo [2.1. l]hexanyl, bicyclo [3.2.OJheptanyl , bicyclo[4.1 .OJheptanyl, bicyclo[2.2. IJheptanyl, bicyclo[3.1 . IJheptanyl, bicyclo [4.2.0] octanyl , bicyclo [3.2.1] octanyl, bicyclo [2.2.2] octanyl, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2 ,2]pentanyl, spiro[2.5]octanyl, spiro[3 ,5]nonanyl, spiro[3 ,5]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[2.6Jnonanyl, spiro[4.5]decanyl, spiro[3.6]decanyl, spiro[5.5]undecanyl, and the like. The term “'saturated” as used in this context means only single bonds present between constituent carbon atoms. The term "cycloalkenyl" as used herein means partially unsaturated cyclic hydrocarbon groups having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As partially unsaturated cyclic hydrocarbon groups, cycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the cycloalkenyl group is not fully saturated overall. Cycloalkenyl may include multiple fused and / or bridged and / or spirocyclic rings.

[0068] The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in tire system is aromatic, and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyndazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, mdazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-t / ]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4- / ?]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-ft]pyridinyl, tetrazolyl, chromanyl, 2,3- dihydrobenzo[6][ 1,4] dioxinyl, benzo[<7][l ,3]dioxolyl, 2,3 -dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[ / ?][l,4]oxathiinyl, isoindolinyl, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0069] As used herein, when a ring is described as being ‘‘aromatic”, it means said ring has a continuous, delocalized n-electron system. Typically, the number of out of plane 7i-electrons corresponds to the Hiickel rale (4n+2). Examples of such rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

[0070] For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein) con taining a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms

[0071] (e.g., [x.x.O] ring systems, in which 0 represents a zero atom

[0072] )); (ii) a single ring atom (spiro-fused ring systems) (e.g., ), or (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths

[0073] In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include!’C and!4C.

[0074] In addition, tire compounds generically or specifically disclosed herein are intended to include all tautomeric forms. As used herein, the term “tautomer” is used to designate 2 molecules with the same molecular formula but different connectivity, which can interconvert in a rapid equilibrium . Thus, by way of example, a compound y . y, py y py y y be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms. Other heteroaryl group exists in various tautomeric forms. Another representative example is a pyrazolyl group:

[0075] In addition, any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)~, (S)- or (R.S)~ configuration. In certain embodiments, each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)~ or (5)- configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trans- (£)- form.

[0076] Accordingly, as used herein a compound of the present invention can be in the form of one of the possible stereoisomers, retainers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.

[0077] Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0078] Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g. , by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,<9 -p-tohioyl tartaric acid, mandelic acid, malic acid or camphor- 10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent. Compounds of the invention, i.e. compounds of formula (I) that contain groups capable of acting as donors and / or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (1) with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed. Hence the invention further provides co-crystals comprising a compound of formula (I).

[0079] As used herein, the phrase “optionally substituted” when used in conjunction with a structural moiety (e.g., alkyl) is intended to encompass both the unsubstituted structural moiety (i.e., none of the substitutable hydrogen atoms are replaced with one or more non-hydrogen substituents) and substituted structural moieties substituted with the indicated range of non-hydrogen substituents. For example, “ C1-C4 alkyl optionally substituted with 1-4 Ra” is intended to encompass both unsubstituted C1-C4 alkyl and Ci-C* alkyl substituted with 1-4 R3.

[0080] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0081] DETAILED DESCRIPTION

[0082] This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and / or hydrate, and / or cocrystal, and / or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.

[0083] Formula I Compounds

[0084] In one aspect, this disclosure features compounds having Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0085] L is a bond or -O-;

[0086] R1is halo or C1-C4 alkyl;

[0087] R2is selected from the group consisting of:

[0088] • C1-C6 alkyl optionally substituted with 1-6 independently selected Ra;

[0089] ® 5 membered heteroaryl optionally substituted with 1 Rb;

[0090] ® C3-C7 cycloalkyl, which is optionally substituted with 1-4 independently selected Rc; and

[0091] ® C4-C7 cycloalkenyl, which is optionally substituted with 1-4 independently selected Rc;

[0092] R3i, R32, and R33are each, independently, halo or H;

[0093] R34is H or F; each occurrence of Rais, independently, -OH or halo;

[0094] Rbis selected from the group consisting of CI-C6 alkyl optionally substituted with 1-4 independently selected Rbl; C3-C5 cycloalkyl optionally substituted with 1-2 independently selelcted halo; and -SO2N(C1-C4 alkyllr; each occurrence of Rcis, independently, -OH or C1-C4 alkyl optionally substituted with 1 -4 substituents independently selected from -OH and halo; and

[0095] Rbsis -OH, halo, or C3-C5 cycloalkyl optionally substituted with 1-2 halo.

[0096] In some embodiments, L is a bond.

[0097] In some embodiments, L is -O-.

[0098] In some embodiments, R1is C1-C4 alkyl, e.g., C2-C4 alkyl, C1-C2 alkyl,

[0099] In certain embodiments, R1is C1-C2 alkyl.

[0100] For example, R1can be CH?.

[0101] In some embodiments, R1is halo, e.g., Cl. hr some embodiments, R2is C1-C6 alkyl optionally substituted with 1-6 independently selected Ra. In certain embodiments, R2is C2-C5 alkyl optionally substituted with 1 -6 independently selected R3.

[0102] In certain embodiments, R2is C2-C4 alkyl optionally substituted with 1-6 independently selected R3.

[0103] In certain embodiments, R2is C2-C3 alkyl optionally substituted with 1-6 independently selected

[0104] In some embodiments, R2is C 1 -C6 alkyl that is substituted with 1-6 substituents independently selected from the group consisting of -OH and F,

[0105] In certain embodiments, R2is C2-C5 alkyl that is substituted with 1-6 substituents independently selected from the group consisting of -OH and F.

[0106] In certain embodiments, R2is C2-C4 alkyl that is substituted with 1-6 substituents independently selected from the group consisting of -OH and F.

[0107] In certain embodiments, R2is C2-C3 alkyl that is substituted with 1-6 substituents independently selected from the group consi sting of -OH and F.

[0108] In some embodiments, R2is C1 -C6 alkyl that is substituted with 1 -6 independently selected R3.

[0109] In certain embodiments, R2is C2-C5 alkyl that is substituted with 1-6 independently selected R3.

[0110] In certain embodiments, R2is C2-C4 alkyl that is substituted with 1-6 independently selected R3.

[0111] In certain embodiments, R2is C2-C3 alkyl that is substituted with 1-6 independently selected R3.

[0112] In some embodiments, R2is C1-C6 alkyl that is substituted with 1-6 substituents independently selected from tire group consisting of -OH and F.

[0113] In certain embodiments, R2is C2-C5 alkyl that is substituted with 1-6 substituents independently selected from the group consisting of -OH and F,

[0114] In certain embodiments, R2is C2-C4 alkyl that is substituted with 1-6 substituents independently selected from the group consisting of -OH and F.

[0115] In certain embodiments, R2is C2-C3 alkyl that is substituted with 1-6 substituents independently selected from the group consisting of -OH and F.

[0116] In some embodiments, R2is 5 membered heteroaryl optionally substituted with

[0117] 1 Rb.

[0118] In certain embodiments, R2is 5 membered heteroaryl substituted with 1 Rb.

[0119] In certain embodiments, the 5 membered heteroaryl is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyi, orthiatriazolyl.

[0120] In certain embodiments, the 5 membered heteroaryl imidazolyl, pyrazolyl, or thiazolyl.

[0121] In certain embodiments, R2is C3-C7 (e.g., C3-C6) cycloalkyl optionally substituted with 1-4 independently selected R£.

[0122] In certain embodiments, R2is C5-C6 cycloalkyl substituted with 1-2 independently selected R£.

[0123] In certain embodiments,

[0124] In some embodiments, R2is C4-C7 (e.g., C4-C6) cycloalkenyl substituted with

[0125] 1-2 independently selected Rc.

[0126] In certain embodiments, R2is C5-C6 cycloalkenyl substituted with 1-2 independently selected Rc. For example, R2can be In some embodiments, one or two of R31, R32, and R33are an independently selected halo, and the others are hydrogen.

[0127] In certain embodiments, one or two of R31, R32, and R33are independently fluoro or chloro, and the others are hydrogen.

[0128] In certain embodiments, R31is H; and R32and R33are an independently selected halo.

[0129] In certain embodiments, R31is H; and R32and R33are independently fluoro or chloro.

[0130] In certain embodiments, R31is H; R32is F, and R33is Cl or F.

[0131] In certain embodiments, R31is I I. R32is F, and R33is I I

[0132] In some embodiments, Rbis alkyl optionally substituted with 1-4 Rbl. hi certain embodiments, Rbis alkyl substituted with 1-4 Rbl.

[0133] In certain embodiments, Rbis alkyl substituted with 1 Rbl.

[0134] In some of the foregoing embodiments, Rbl, or each occurrence of Rbl, is independently selected from the group consisting of -OH and halo.

[0135] In certain of these embodiments, Rbl, or each occurrence of Rbl, is independently selected from the group consisting of -OH and F.

[0136] For example, Rbcan

[0137] In some of the foregoing embodiments, Rbl, or each occurrence of Rbl, is C3-

[0138] C5 cycloalkyl optionally substituted with 1 -2 halo.

[0139] For example, Rbcan

[0140] In some of the foregoing embodiments, Rbis -S()2N(C1-C4 alkyl) / . hi some of the foregoing embodiments, R£is -OH.

[0141] In some of the foregoing embodiments, Rcis Cl -C4 alkyl optionally substituted with 1-4 substituents independently selected from -OH and halo.

[0142] In certain of these embodiments, R£is C1-C4 alkyl optionally substituted with 1-4 substituents independently selected from -OH and fluoro. In certain of these embodiments, Rcis C1-C4 alkyl that is substituted with 1-4 substituents independently selected from -OH and halo.

[0143] In certain of these embodiments, Rcis C1-C4 alkyl that is substituted with 1-4 substituents independently selected from -OH and fluoro.

[0144] In certain of these embodiments, Rcis C1-C4 alkyl substituted with -OH.

[0145] For example, Rccan .

[0146] As another example, Rccan

[0147] OH

[0148] In still another example, Rccan be

[0149] As another example, Rccan be CH3.

[0150] In some embodiments, R34is H.

[0151] In some embodiments, the compound has formula (II): wherein R32is H or F.

[0152] In certain embodiments of formula (II), L is a bond.

[0153] In certain embodiments of formula (II), R2is C3-C6 cycloalkyl optionally substituted with 1-4 independently selected Rc.

[0154] In certain embodiments of formula (II), R2is C5-C6 cycloalkyl optionally substituted with 1-4 independently selected Rc.

[0155] In certain embodiments of formula (II), R2is C3-C6 cycloalkyl that is substituted with 1-4 independently selected Rc.

[0156] In certain embodiments of formula (IT), R2is C5-C6 cycloalkyl that is substituted with 1-4 independently selected Rc.

[0157] In certain embodiments of formula (II), R2is C6 cycloalkyl that is substituted with 1-4 independently selected Rc.

[0158] In certain embodiments of formula (II), R2is C6 cycloalkyl that is substituted with 1 Rc, In certain embodiments of formula (II). R2is

[0159] In certain embodiments of formula (II), Rcis C1-C4 alkyl optionally substituted with hydroxyl or halo.

[0160] In certain embodiments of formula (II), Rcis C1-C2 alkyl optionally substituted with hydroxyl or halo.

[0161] In certain embodiments of formula (II), Rcis C 1-C2 alkyl optionally substituted with hydroxyl.

[0162] In certain embodiments of formula (II), R£is C1-C4 alkyl that is substituted with hydroxyl or halo.

[0163] In certain embodiments of formula (II), Rcis C 1 -C2 alkyl that is substituted with hydroxyl or halo. hi certain embodiments of formula (11), Rcis C1-C2 alkyl that is substituted with hydroxyl. hi certain embodiments of formula (II), R£

[0164] In certain embodiments of formula (II), R2is 5 membered heteroaryl substituted with 1 Rb.

[0165] In certain embodiments of formula (II), the 5 membered heteroaryl is imidazolyl, pyrazolyl, or thiazolyl. hi certain embodiments of formula (11), R2is hi certain embodiments of formula (11), R2is C1-C6 alkyl optionally substituted with 1-6 independently selected Ra.

[0166] In certain embodiments of formula (II), R2is C1-C6 alkyl substituted with 1 -6 independently selected R3.

[0167] In certain embodiments of formula (11), R2is C1-C6 alkyl substituted with 1-6 substituents independently selected from the group consisting of -OH and F. In certain embodiments of formula (II), R2is selected from the group consisting Limiting Exemplary Compounds

[0168] In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table Cl or a pharmaceutically acceptable salt thereof.

[0169] Table Cl

[0170]

[0171] Pharmaceutical Compositions and Administration

[0172] General

[0173] In some embodiments, a chemical entity (e.g., a compound that inhibits (e.g., antagonizes) STING, or a pharmaceutically acceptable salt, and / or hydrate, and / or cocrystaL and / or drug combination thereof) is administered as a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein. In some embodiments, tire chemical entities can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium -chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as a-, p, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-P-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery7of compounds described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from nontoxic excipient may' be prepared. The contemplated compositions may' contain 0.001 %- 100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, m a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22ndEdition (Pharmaceutical Press, London, UK. 2012).

[0174] Routes of Administration and Composition Components

[0175] In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any' accepted route of administration. Acceptable routes of admini stration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracistemal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, mtrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory7(inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral). Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.

[0176] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi .

[0177] The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0178] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze -drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0179] Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential ofHPMA Copolymer-Based Drug Delivery Systems” Neoplasia. 2006, 10, 788-795.

[0180] Pharmacologically acceptable excipients usable m the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty' acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sw'eet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p- oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM) , lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate. hi certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository' wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.

[0181] In other embodiments, the compounds described herein or a pharmaceutical composition thereof are suitable for local delivery' to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).

[0182] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and / or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example. carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. hi one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g. , in propylene carbonate, vegetable oils, PEG S, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drag; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

[0183] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly usefill for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0184] In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP / NF standard is usually sufficient. In certain embodiments, solid oral dosage forms can further include one or more components that chemically and / or structurally predispose the composition for delivery' of the chemical entity to the stomach or the lower GI; e.g, the ascending colon and / or transverse colon and / or distal colon and / or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, KJ, et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

[0185] Examples include upper-GI targeting techniques, e.g.. Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

[0186] Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric / pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid -methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure- controlled colon delivery capsule, and Pulsincap.

[0187] Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g, Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g, Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g. Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0188] Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically’ water-washable, and contain an oil phase, an emulsifier and tin aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non-sensitizing.

[0189] In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGAJ-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0190] Dosages

[0191] The dosages may be varied depending on the requirement of the patient, the severity of the condition being treating and the particular compound being employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.

[0192] In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg / Kg to about 500 mg / Kg (e.g., from about 0.01 mg / Kg to about 100 mg / Kg; from about 0.01 mg / Kg to about 10 mg / Kg; from about 0.01 mg / Kg to about 1 mg / Kg; from from about 0.01 mg / Kg to about 0. 1 mg / Kg; from about 0. 1 mg / Kg to about 100 mg / Kg; from about 0. 1 mg / Kg to about 10 mg / Kg).

[0193] Regimens

[0194] The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

[0195] In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks. 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 1 1 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 1 1 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0196] Methods of Treatment

[0197] In some embodiments, methods for treating a subject having condition, disease or disorder in which increased (e.g., excessive)STING activity (e.g., , e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease or disorder (e.g., immune disorders, cancer) are provided.

[0198] Indications

[0199] In some embodiments, the condition, disease or disorder is cancer. Nonlimiting examples of cancer include melanoma, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include breast cancer, colon cancer, rectal cancer, colorectal cancer, kidney or renal cancer, clear cell cancer lung cancer including small-cell lung cancer, non- small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, squamous cell cancer (e.g. epithelial squamous cell cancer), cervical cancer, ovarian cancer, prostate cancer, prostatic neoplasms, liver cancer, bladder cancer, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, gastrointestinal stromal tumor, pancreatic cancer, head and neck cancer, glioblastoma, retinoblastoma, astrocytoma, thecomas, arrhenoblastomas, hepatoma, hematologic malignancies including non-Hodgkins lymphoma (NHL), multiple myeloma, myelodysplasia disorders, myeloproliferative disorders, chronic myelogenous leukemia, and acute hematologic malignancies, endometrial or uterine carcinoma, endometriosis, endometrial stromal sarcoma, fibrosarcomas, choriocarcinoma, salivary' gland carcinoma, vulval cancer, thyroid cancer, esophageal carcinomas, hepatic carcinoma, anal carcinoma, penile carcinoma, nasopharyngeal carcinoma, laryngeal carcinomas, Kaposi’s sarcoma, mast cell sarcoma, ovarian sarcoma, uterine sarcoma, melanoma, malignant mesothelioma, skin carcinomas, Schwannoma, oligodendroglioma, neuroblastomas, neuroectodermal tumor, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcomas, Ewing Sarcoma, peripheral primitive neuroectodermal tumor, urinary tract carcinomas, thyroid carcinomas, Wilm's tumor, as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs’ syndrome. In some cases, the cancer is melanoma.

[0200] In some embodiments, the condition, disease or disorder is a neurological disorder, which includes disorders that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Non-limiting examples of neurological disorders include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; age-related macular degeneration; agenesis of the corpus callosum; agnosia; Arcardi syndrome; Alexander disease; Alpers' disease; alternating hemiplegia; Alzheimer's disease; Vascular dementia; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Anronl-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telegiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet's disease; Bell's palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger's disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome; causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy; chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt- Jakob disease; cumulative trauma disorders; Cushing's syndrome; cytomegalic inclusion body disease; cytomegalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier's syndrome; Dejerine-Klumke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb's palsy; essential tremor; Fabry's disease; Fahr's syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich's ataxia; fronto-temporal dementia and other “tauopathies”; Gaucher's disease; Gerstmarm's syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1 -associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (also neurological manifestations of AIDS); holoprosencephaly; Huntington's disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile phytanic acid storage disease; infantile refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease Kinsboume syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg- Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffiier syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh's disease; Lennox-Gustaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; Lissencephaly; locked-in syndrome; Lou Gehrig's disease (i.e., motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; Lyme disease — -neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini -strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neuron disease; Moyamoya disease; mucopolysaccharidoses; milti -infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; p muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O'Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson's disease; paramyotonia congenital; paraneoplastic diseases; paroxysmal atacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick's disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; post-polio syndrome; postherpetic neuralgia; postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (types I and II); Rasmussen's encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye's syndrome; Saint Vitus dance; Sandhoff disease; Schilder's disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren's syndrome; sleep apnea; Soto's syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; Stiff-Person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subcortical arteriosclerotic encephalopathy; Sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; Tic Douloureux; Todd's paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury'; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi -infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau disease; Wallenberg's syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wildon's disease; amyotrophe lateral sclerosis and Zellweger syndrome. hi some embodiments, the condition, disease or disorder is STING-associated conditions, e.g., type I interferonopathies (e.g., STING-associated vasculopathywith onset in infancy (SAVI)), Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis. In certain embodiments, the condition, disease or disorder is an autoimmune disease (e.g., a cytosolic DNA-triggered autoinflammatory disease). Nonlimiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel diseases (IBDs) comprising Crohn disease (CD) and ulcerative colitis (UC), which are chronic inflammatory conditions with polygenic susceptibility. In certain embodiments, the condition is an inflammatory' bowel disease. In certain embodiments, the condition is Crohn’s disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated by one or more alloimmune diseases (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis, hi certain of these embodiments, the condition is alloimmune disease (such as graft-vs- host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis or intestinal mucositis). In some embodiments, modulation of the immune system by STING provides for the treatment of diseases, including diseases caused by foreign agents. Exemplary' infections by foreign agents which may be treated and / or prevented by the method of the present invention include an infection by a bacterium (e.g., a Gram-positive or Gram-negative bacterium), an infection by a fungus, an infection by a parasite, and an infection by a virus. In one embodiment of the present invention, tire infection is a bacterial infection (e.g., infection by E. coll, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella spp., Staphylococcus aureus, Streptococcus spp., or vancomycin-resistant enterococcus), or sepsis. In another embodiment, the infection is a fungal infection (e.g. infection by a mould, a yeast, or a higher fungus). In still another embodiment, the infection is a parasitic infection (e.g., infection by a single-celled or multicellular parasite, including Giardia duodenalis, Cryptosporidium parvurn, Cyclospora cayetanensis, and Toxoplasma gondiz). In yet another embodiment, the infection is a viral infection (e.g., infection by a virus associated with AIDS, avian flu, chickenpox, cold sores, common cold, gastroenteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, lower or upper respiratory tract infection (e.g., respiratory syncytial virus), Ebola, Zika, and SARS-CoV-2 (C0VID19)).

[0201] In some embodiments, the condition, disease or disorder is hepatits B (see, e.g., WO 2015 / 061294).

[0202] In some embodiments, the condition, disease or disorder is selected from cardiovascular diseases (including e.g,, myocardial infarction).

[0203] In some embodiemnts, the condition, disease or disorder is age-related macular degeneration.

[0204] In some embodiments, the condition, disease or disorder is mucositis, also known as stomatitits, which can occur as a result of chemotherapy or radiation therapy, either alone or in combination as well as damage caused by exposure to radiation outside of the context of radiation therapy.

[0205] In some embodiments, the condition, disease or disorder is uveitis, which is inflammation of the uvea (e.g., anterior uveitis, e.g., iridocyclitis or iritis; intermediate uveitis (also known as pars planitis); posterior uveitis; or chorioretinitis, e.g., panuveitis) . In some embodiments, the condition, disease or disorder is selected from the group consisting of a cancer, a neurological disorder, an autoimmune disease, hepatitis B, uvetitis, a cardiovascular disease, age-related macular degeneration, and mucositis.

[0206] In some embodiments, the condition, disease or disorder is selected from the group consisting of Familial Chilblain Lupus, RVCL (autosomal dominant retinal vasculopathy with cerebral leukodystrophy), lupus nephritis (LN), Sjogren's Syndrome (SS), lung inflammation, acute lung inflammation, idiopathic pulmonary fibrosis, liver and renal fibrosis, nonalcoholic steatohepatitis (NASH), cirrhosis, endomyocardial fibrosis, acute and chronic kidney injury, APOL1 -associated podocytopathy, acute pancreatitis, chronic obstructive pulmonary disease (COPD), senescence, and aging.

[0207] Still other examples can include those indications discussed herein and below in contemplated combination therapy regimens.

[0208] Combination therapy

[0209] This disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

[0210] In some embodiments, the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more therapeutic regimens) in combination with administration of the compounds described herein.

[0211] In certain embodiments, the methods described herein can further include administering one or more additional cancer therapies.

[0212] The one or more additional cancer therapies can include, without limitation, surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine, hepatitis B vaccine, Oncophage, Provenge) and gene therapy, as well as combinations thereof. Immunotherapy, including, without limitation, adoptive cell therapy, the derivation of stem cells and / or dendritic cells, blood transfusions, lavages, and / or other treatments, including, without limitation, freezing a tumor.

[0213] In some embodiments, the one or more additional cancer therapies is chemotherapy, which can include administering one or more additional chemotherapeutic agents. In certain embodiments, the additional chemotherapeutic agent is an immunomodulatory moiety, e.g., an immune checkpoint inhibitor. In certain of these embodiments, the immune checkpoint inhibitor targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1 - PD-Ll, PD-1 - PD-L2, interleukin 2 (IL 2), indoleamine 2,3 -dioxygenase (IDO), H. 10, transforming growth factor-P (TGFp), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9 - TIM3, Phosphatidylserine - TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II - LAG3, 4 1BB-4 IBB ligand, 0X40-0X40 ligand, GITR, GITR ligand - GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM - B TLA, HVEM - CD160, HVEM - LIGHT, HVEM-BTLA-CD 160, CD80, CD80 - PDL-1, PDL2 - CD80, CD244, CD48 - CD244, CD244, ICOS, ICOS-ICOS ligand, B7 H3, B7 TI4, 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, STRPA-CD47, VEGF, Neuropilin, GDI 60, CD30, and CD155; e.g., CTLA-4 or PD1 or PD-Ll). See, e.g., Postow, M. J. Clin. Oncol. 2015, 33, 1.

[0214] In certain of these embodiments, the immune checkpoint inhibitor is selected from the group consisting of: Urelumab, PF- 05082566, MEDI6469, TRX518, Varliluniab, CP 870893, Pembrolizuniab (PD1), Nivolumab (PD1), Atezolizumab (formerly MPDL3280A) (PDL1), MEDI4736 (PD-Ll), Avelumab (PD-Ll), PDR001 (PD1), BMS 986016, MGA271, Lirilumab, IPFI2201 , Emactuzuniab, INCB024360, Galunisertib, Ulocuplumab, BKT140, Bavituximab, CC 90002, Bevacizumab, and MNRPI685A, and MGA271.

[0215] In certain embodiments, the additional chemotherapeutic agent is an alkylating agent. Alkylating agents are so named because of their ability to alkylate many nucleophilic functional groups under conditions present in cells, including, but not limited to cancer cells. In a further embodiment, an alkylating agent includes, but is not limited to, Cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and / or oxaliplatin. In an embodiment, alkylating agents can function by impairing cell function by forming covalent bonds with the amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules or they can work by modifying a cell's DNA. In a further embodiment an alkylating agent is a synthetic, semisynthetic or derivative.

[0216] In certain embodiments, the additional chemotherapeutic agent is an antimetabolite. Anti-metabolites masquerade as purines or pyrimidines, the building -blocks of DNA and in general, prevent these substances from becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Anti-metabolites can also affect RNA synthesis. In an embodiment, an antimetabolite includes, but is not limited to azathioprine and / or mercaptopurine. In a further embodiment an anti-metabolite is a synthetic, semisynthetic or derivative.

[0217] In certain embodiments, the additional chemotherapeutic agent is a plant alkaloid and / or terpenoid. These alkaloids are derived from plants and block cell division by, in general, preventing microtubule function. In an embodiment, a plant alkaloid and / or terpenoid is a vinca alkaloid, a podophyl lotoxin and / or a taxane. Vinca alkaloids, in general, bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules, generally during the M phase of the cell cycle. In an embodiment, a vinca alkaloid is derived, without limitation, from the Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). In an embodiment, a vinca alkaloid includes, without limitation, Vincristine, Vinblastine, Vinorelbine and / or Vindesine. In an embodiment, a taxane includes, but is not limited, to Taxol, Paclitaxel and / or Docetaxel. In a further embodiment a plant alkaloid or terpemoid is a synthetic, semisynthetic or derivative. In a further embodiment, a podophyllotoxin is, without limitation, an etoposide and / or teniposide. In an embodiment, a taxane is, without limitation, docetaxel and / or ortataxel.

[0021] In an embodiment, a cancer therapeutic is a topoisomerase. Topoisomerases are essential enzymes that maintain the topology of DNA. Inhibition of type I or type II topoisomerases interferes with both transcription and replication of DNA by upsetting proper DNA supercoiling. In a further embodiment, a topoisomerase is, without limitation, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In an embodiment a type I topoisomerase inhibitor is, without limitation, a camptothecin. In another embodiment, a camptothecin is, without limitation, exatecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67) and / or ST 1481 . In an embodiment, a type II topoisomerase inhibitor is, without limitation, epipodophyllotoxin. In a further embodiment an epipodophyl lotoxin is, without limitation, an amsacrine, etoposid, etoposide phosphate and / or teniposide. In a further embodiment a topoisomerase is a synthetic, semisynthetic or derivative, including those found in nature such as, without limitation, epipodophyllotoxins, substances naturally occurring in the root of American Mayapple (Podophyllum peltatum).

[0218] In certain embodiments, the additional chemotherapeutic agent is a stilbenoid. In a further embodiment, a stilbenoid includes, but is not limited to. Resveratrol, Piceatannol, Pinosylvin, Pterostilbene, Alpha-Viniferin, Ampelopsin A, Ampelopsin E, Diptoindonesin C, Diptoindonesin F, Epsilon- Vinferin, Flexuosol A, Gnetin H, Hemsleyanol D, Hopeaphenol, Trans-Diptoindonesin B, Astringin, Piceid and Diptoindonesin A. In a further embodiment a stilbenoid is a synthetic, semisynthetic or derivative.

[0219] In certain embodiments, the additional chemotherapeutic agent is a cytotoxic antibiotic. In an embodiment, a cytotoxic antibiotic is, without limitation, an actinomycin, an anthracenedione, an anthracycline, thalidomide, di chloroacetic acid, nicotinic acid, 2-deoxyglucose and / or chlofazimine. In an embodiment, an actinomycin is, without limitation, actinomycin D, bacitracin, colistin (polymyxin E) and / or polymyxin B. In another embodiment, an antracenedione is, without limitation, mitoxantrone and / or pixantrone. In a further embodiment, an anthracycline is, without limitation, bleomycin, doxorubicin (Adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, mitomycin, plicamycin and / or valrubicin. In a further embodiment a cytotoxic antibiotic is a synthetic, semisynthetic or derivative.

[0220] In certain embodiments, the additional chemotherapeutic agent is selected from endostatin, angiogenin, angiostatin, chemokines, angioarrestin, angiostatin (plasminogen fragment), basement-membrane collagen-derived anti-angiogenic factors (tumstatin, canstatin, or arrestin), anti-angiogenic antithrombin III, signal transduction inhibitors, cartilage-derived inhibitor (CDI), CD59 complement fragment, fibronectin fragment, gro-beta, heparinases, heparin hexasaccharide fragment, human chorionic gonadotropin (hCG), interferon alpha / beta / gamma, interferon inducible protein (IP- 10), interleukin- 12, kringle 5 (plasminogen fragment), metalloproteinase inhibitors (TIMPs), 2-methoxyestradiol, placental ribonuclease inhibitor, plasminogen activator inhibitor, platelet factor-4 (PF4), prolactin 16 kD fragment, proliferin-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin- 1 (TSP-1), transforming growth factor-beta (TGF-p), vasculostatin, vasostatin (calreticulin fragment) and the like.

[0221] In certain embodiments, the additional chemotherapeutic agent is selected from abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4- methoxyphenyl)benzene sulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N- methyl-L-valyl-L-proly- 1 -Lproline-t-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3',4'-didehydro-4'-deoxy-8'-norvin-caleukoblastine, docetaxel, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyureataxanes, ifosfamide, liarozole, lomdamine, lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxanes, nilutamide, onapristone, paclitaxel, prednimustine, procarbazine, RPR109881, stramustine phosphate, tamoxifen, tasonermm, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine.

[0222] In certain embodiments, the additional chemotherapeutic agent is platinum, cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, azathioprine, mercaptopurine, vincristine, vinblastine, vinorelbine, vindesine, etoposide and teniposide, paclitaxel, docetaxel, irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, teniposide, 5-fluorouracil, leucovorin, methotrexate, gemcitabine, taxane, leucovorin, mitomycin C, tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide and doxorubicin. Additional agents include inhibitors of mTOR (mammalian target of rapamycin), including but not limited to rapamycin, everolimus, temsirolimus and deforolimus. hi still other embodiments, the additional chemotherapeutic agent can be selected from those delineated in U.S. Patent 7,927,613, which is incorporated herein by reference in its entirety.

[0223] In some embodiments, the additional therapeutic agent and / or regimen are those that can be used for treating other STTNG-associated conditions, e.g., type I interferonopathies (e.g., STING-associated vasculopathywith onset in infancy (SAVI)), Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, and inflammation- associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis and the like.

[0224] Non-limiting examples of additional therapeutic agents and / or regimens for treating rheumatoid arthritis include non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g, prednisone), disease-modifying antirheumatic drugs (DMARDs; e.g., methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), leflunomide (Arava®), hydroxychloroquine (Plaquenil), PF- 06650833, iguratimod, tofacitinib (Xeljanz®), ABBV-599, evobrutinib, and sulfasalazine (Azulfidine®)), and biologies (e.g., abatacept (Orencia®), adalimumab (Humira®), anakinra (Kineret®), certolizumab (Cimzia®), etanercept (Enbrel®), golimumab (Simponi®), infliximab (Remicade®), rituximab (Rituxan®), tocilizumab (Actemra®), vobarilizumab, sarilumab (Kevzara®), secukinumab, ABP 501, CHS- 0214, ABC-3373, and tocilizumab (ACTEMRA®)).

[0225] Non-limiting examples of additional therapeutic agents and / or regimens for treating lupus include steroids, topical immunomodulators (e.g., tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel®)), thalidomide (Thalomid®), nonsteroidal anti-inflammatory drags (NSAIDs; e.g., ibuprofen and naproxen), antimalarial drugs (e.g.. Hydroxychloroquine (Plaquenil)), corticosteroids (e.g, prednisone) and immunomodulators (e.g., evobrutinib, iberdomide, voclosporin, cenerimod, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®, Gengraf®), and mycophenolate mofet.il) baricitinb, iguratimod, filogotinib, GS-9876, rapamycin, and PF-06650833), and biologies (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDI0700, obinutuzumab, vobarilizumab, lulizumab, atacicept, PF-06823859, and lupizor, rituximab, BT063, BI655064, BITB059, aldesleukin (Proleukin®), dapirolizumab, edratide, IFN-a-kinoid, OMS721, RC18, RSLV-132, theralizurnab, XmAb5871, and ustekmumab (Stelara®)). For example, non-limiting treatments for systemic lupus erythematosus include non-steroidal anti-inflammatory' drags (NSAIDs; e.g., ibuprofen and naproxen), antimalarial drugs (e.g., Hydroxychloroquine (Plaquenil)), corticosteroids (e.g, prednisone) and immunomodulators (e.g., iberdomide, voclosporin, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®, Gengraf®), and mycophenolate mofetil, baricitinb, filogotinib, and PF-06650833), and biologies (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDI0700, vobarilizumab, lulizumab, atacicept, PF-06823859, lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirolizumab, edratide, IFN-a-kinoid, RC18, RSLV-132, theralizumab, XmAb5871, and ustekinumab (Stelara®)). As another example, non-limiting examples of treatments for cutaneous lupus include steroids, immunomodulators (e.g., tacrolimus ointment (Protopic®) and pimecrolimus cream (Elide!®)), GS-9876, filogotinib, and thalidomide (Thalomid®). Agents and regimens for treating drug-induced and / or neonatal lupus can also be administered.

[0226] Non-limiting examples of additional therapeutic agents and / or regimens for treating STING-associated vasculopathy with onset in infancy (SA VI) include JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).

[0227] Non-limiting examples of additional therapeutic agents and / or regimens for treating Aicardi-Goutieres Syndrome (AGS) include physiotherapy, treatment for respiratory7complications, anticonvulsant therapies for seizures, tube-feeding, nucleoside reverse transcriptase inhibitors (e.g., emtricitabine (e.g., Emtriva®), tenofovir (e.g., Viread®), emtricitabine / tenofovir (e.g., Truvada®), zidovudine, lamivudine, and abacavir), and JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).

[0228] Non-limiting examples of additional therapeutic agents and / or regimens for treating IBDs include 6-mercaptopurine, AbGn-168H, ABX464, ABT-494, adalimumab, AJM300, alicaforsen, AMG139, anrukinzumab, apremilast, ATR-107 (PF0530900), autologous CD34-selected peripheral blood stem cells transplant, azathioprine, bertilimumab, Bl 655066, BMS-936557, certolizumab pegol (Cimzia®), cobitolimod, corticosteroids (e.g., prednisone, Methylprednisolone, prednisone), CP- 690,550, CT-P13, cyclosporine, DIMS0150, E6007, E6011, etrasimod, etrolizumab, fecal microbial transplantation, figlotinib, fingolimod, firategrast (SB-683699) (formerly T-0047), GED0301, GLPG0634, GLPG0974, guselkumab, golimumab, GSK1399686, HMPL-004 (Andrographis paniculata extract), IMU-838, infliximab, Interleukin 2 (IL-2), Janus kinase (JAK) inhibitors, laquinimod, masitinib (AB 1010), matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, mirikizumab (LY3074828), natalizumab, NNC 0142-0000- 0002, NNC0114-0006, ozanimod, peficitinib (JNJ-54781532), PF-00547659, PF- 04236921, PF-06687234, QAX576, RHB-104, rifaximin, risankizumab, RPC1063, SB012, SHP647, sulfasalazine, TD-1473, thalidomide, tildrakizumab (MK 3222), TJ301, TNF-Kinoid®, tofacitinib, tralokinumab, TRK-170, upadacitinib, ustekinumab, UTTR 1 147A, V565, vatelizumab, VB-201, vedolizumab, and vidofludimus.

[0229] Non-limiting examples of additional therapeutic agents and / or regimens for treating irritable bowel syndrome include alosetron, bile acid sequesterants (e.g., cholestyramine, colestipol, colesevelam), chloride channel activators (e.g., lubiprostone), coated peppermint oil capsules, desipramine, dicyclomine, ebastine, eluxadoline, famesoid X receptor agonist (e.g., obeticholic acid), fecal microbiota transplantation, fluoxetine, gabapentin, guanylate cyclase-C agonists (e.g., linaclotide, plecanatide), ibodutant, imipramine, JCM-16021, loperamide, lubiprostone, nortriptyline, ondansetron, opioids, paroxetine, pinaverium, polyethylene glycol, pregabalin, probiotics, ramosetron, rifaximin, and tanpanor.

[0230] Non-limiting examples of additional therapeutic agents and / or regimens for treating scleroderma include non-steroidal anti-inflammatory' drags (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g, prednisone), immunomodulators (e.g., azathioprine, methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral®, Sandimmune®, Gengraf®), antithymocyte globulin, mycophenolate mofetil, intravenous immunoglobulin, rituximab, sirolimus, and alefacept), calcium channel blockers (e.g., nifedipine), alpha blockers, serotonin receptor antagonists, angiotensin IT receptor inhibitors, statins, local nitrates, iloprost, phosphodiesterase 5 inhibitors (e.g., sildenafil), bosentan, tetracycline antibiotics, endothelin receptor antagonists, prostanoids, and tyrosine kinase inhibitors (e.g., imatinib, nilotinib and dasatinib).

[0231] Non-limiting examples of additional therapeutic agents and / or regimens for treating Crohn’s Disease (CD) include adalimumab, autologous CD34-selected peripheral blood stem cells transplant, 6-mercaptopurine, azathioprine, certolizumab pegol (Cimzia®), corticosteroids (e.g., prednisone), etrolizumab, E6011, fecal microbial transplantation, figlotinib, guselkumab, infliximab, IL-2, JAK inhibitors, matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, natalizumab, ozanimod, RHB-104, rifaximin, risankizumab, SHP647, sulfasalazine, thalidomide, upadacitinib, V565, and vedolizumab. Non-limiting examples of additional therapeutic agents and / or regimens for treating UC include AbGn-168H, ABT-494, ABX464, apremilast, PF-00547659, PF- 06687234, 6-mercaptopurine, adalimumab, azathioprine, bertilimumab, brazikumab (MEDI2070), cobitolimod, certolizumab pegol (Cimzia®), CP-690, 550, corticosteroids (e.g., multimax budesonide, Methylprednisolone), cyclosporine, E6007, etrasimod, etrolizumab, fecal microbial transplantation, figlotinib, guselkumab, golimumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitors (e.g., GS-5745), mesalamine, mesalamine, mirikizumab (LY3074828), RPC1063, risankizumab (BI 6555066), SHP647, sulfasalazine, TD-1473, TJ301, tildrakizumab (MK 3222), tofacitinib, tofacitinib, ustekinumab, UTTR1147A, and vedolizumab.

[0232] Non-limiting examples of additional therapeutic agents and / or regimens for treating autoimmune colitis include corticosteroids (e.g., budesonide, prednisone, prednisolone, Beclometasone dipropionate), diphenoxy late / atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[0233] Non-limiting examples of additional therapeutic agents and / or regimens for treating iatrogenic autoimmune colitis include corticosteroids (e.g., budesonide, prednisone, prednisolone, Beclometasone dipropionate), diphenoxylate / atropine, infliximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[0234] Non-limiting examples of additional therapeutic agents and / or regimens for treating colitis induced by one or more chemotherapeutics agents include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), diphenoxylate / atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[0235] Non-limiting examples of additional therapeutic agents and / or regimens for treating colitis induced by treatment with adoptive cell therapy include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), diphenoxylate / atropine, infliximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[0236] Non-limiting examples of additional therapeutic agents and / or regimens for treating colitis associated with one or more alloimmune diseases include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), sulfasalazine, and eicopentaenoic acid.

[0237] Non-limiting examples of additional therapeutic agents and / or regimens for treating radaiation enteritis include teduglutide, amifostine, angiotensin-converting enzyme (ACE) inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril), probiotics, selenium supplementation, statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatm), sucralfate, and vitamin E.

[0238] Non-limiting examples of additional therapeutic agents and / or regimens for treating collagenous colitis include 6-mercaptopurine, azathaioprine, bismuth subsalicate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.

[0239] Non-limiting examples of additional therapeutic agents and / or regimens for treating lyphocytic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), loperamide, mesalamine, methotrexate, and sulfasalazine .

[0240] Non-limiting examples of additional therapeutic agents and / or regimens for treating microscopic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), fecal microbial transplantation, loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.

[0241] Non-limiting examples of additional therapeutic agents and / or regimens for treating alloimmune disease include intrauterine platelet transfusions, intravenous immunoglobin, maternal steroids, abatacept, alemtuzumab, alpha 1 “antitrypsin, AMG592, antithymocyte globulin, barcitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib. Non-limiting examples of additional therapeutic agents and / or regimens for treating multiple sclerosis (MS) include alemtuzumab (Lemtrada®), ALKS 8700, amiloride, ATX-MS-1467, azathioprine, baclofen (Lioresal®), beta interferons (e.g., IFN-P-la, IFN-p-lb), cladribine, corticosteroids (e.g., methylprednisolone), daclizumab, dimethyl fumarate (Tecfidera®), fingolimod (Gilenya®), fluoxetine, glatiramer acetate (Copaxone®), hydroxychloroquine, ibudilast, idebenone, laquinimod, lipoic acid, losartan, masitinib, MD1003 (biotin), mitoxantrone, montelukast, natalizumab (Tysabri®), NeuroVax™, ocrelizumab, ofatumumab, pioglitazone, and RPC 1063.

[0242] Non-limiting examples of additional therapeutic agents and / or regimens for treating graft-vs-host disease include abatacept, alemtuzumab, alphal -antitrypsin, AMG592, antithymocyte globulin, barcitinib, basilixirnab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[0243] Non-limiting examples of additional therapeutic agents and / or regimens for treating acute graft-vs-host disease include alemtuzumab, alpha- 1 antitrypsin, antithymocyte globulin, basilixirnab, brentuximab, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, ibrutinib, infliximab, itacitinib, LBH589, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, photopheresis, ruxolitinib, sirolimus, tacrolimus, and tocilizumab.

[0244] Non-limiting examples of additional therapeutic agents and / or regimens for treating chronic graft vs. host disease include abatacept, alemtuzumab, AMG592, antithymocyte globulin, basilixirnab, bortezomib, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, mycophenolate mofetil, pentostatin, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib. Non-limiting examples of additional therapeutic agents and / or regimens for treating celiac disease include AMG 714, AMY01, Aspergillus mger prolyl endoprotease, BL-7010, CALY-002, GBR 830, Hu-Mik-Beta-1, IMGX003, KumaMax, Larazotide Acetate, Nexvan2®, pancrehpase, TIMP-GLIA, vedolizumab, and ZED 1227.

[0245] Non-limiting examples of additional therapeutic agents and / or regimens for treating psoriasis include topical corticosteroids, topical crisaborole / AN2728, topical SNA- 120, topical SAN021 , topical tapinarof, topical tocafmib, topical IDP- 1 18, topical M518101, topical calcipotriene and betamethasone dipropionate (e.g., MC2-01 cream and Taclonex®), topical P-3073, topical LEO 90100 (Enstilar®), topical betamethasone dipropriate (Semivo®), halobetasol propionate (Ultravate®), vitamin D analogues (e.g., calcipotriene (Dovonex®) and calcitriol (Vectical®)), anthralin (e.g., Dntho-scalp® and Dritho-creme®), topical retinoids (e.g., tazarotene (e.g., Tazorac® and Avage®)), calcineurin inhibitors (e.g., tacrolimus (Prograf®) and pimecrolimus (Elide!®)), salicylic acid, coal tar, moisturizers, phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrow band UVB phototherapy, Goeckerman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), retinoids (e.g., acitretin (Soriatane®)), methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), Apo805Kl, baricitimb, FP187, KD025, prurisol, VTP-43742, XP23829, ZPL-389, CF101 (piclidenoson), LAS41008, VPD-737 (serlopitant), upadacitinib (ABT-494), aprmilast, tofacitibin, cyclosporine (Neoral®, Sandimmune®, Gengraf®), biologies (e.g., etanercept (Enbrel®), entanercept-szzs (Elrezi®), infliximab (Remicade®), adalimumab (Humira®), adalimumab-adbm (Cyltezo®), ustekinumab (Stelara®), golimumab (Simponi®), apremilast (Otezla®), secukinumab (Cosentyx®), certolixumab pegol, secukinumab, tildrakizumab-asmn, infliximab-dyyb, abatacept, ixekizumab (Taltz®), ABP 710, BCD-057, BI695501, bimekizumab (UCB4940), CHS-1420, GP2017, guselkumab (CNTO 1959), HD203, M923, MSB11022, Mirikizumab (LY3074828), PF-06410293, PF-06438179, risankizumab (BI655066), SB2, SB4, SB5, siliq (brodalumab), namilumab (MT203, tildrakizumab (MK-3222), and ixekizumab (Taltz®)), thioguanine, and hydroxyurea (e.g., Droxia® and Hydrea®).

[0246] Non-limiting examples of additional therapeutic agents and / or regimens for treating cutaneous T-cell lymphoma include phototherapy (e.g., exposure to sunlight. UVB phototherapy, narrow band UVB phototherapy, Goeckerman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), extracorporeal photopheresis, radiation therapy (e.g., spot radiation and total skin body electron beam therapy), stem cell transplant, corticosteroids, imiquimod, bexarotene gel, topical bis -chloroethyl - nitrourea, mechlorethamine gel, vorinostat (Zolinza®), romidepsin (Istodax®), pralatrexate (Folotyn®) biologies (e.g., alemtuzumab (Campath®), brentuximab vedotin (SGN-35), mogamulizumab, and IPH4102).

[0247] Non-limiting examples of additional therapeutic agents and / or regimens for treating uveitis include corticosteroids (e.g., intravitreal triamcinolone acetonide injectable suspensions), antibiotics, antivirals (e.g., acyclovir), dexamethasone, immunomodulators (e.g., tacrolimus, leflunomide, cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral®, Sandimmune®, Gengraf®), chlorambucil, azathioprine, methotrexate, and mycophenolate mofetil), biologies (e.g., infliximab (Remicade®), adalimumab (Humira®), etanercept (Enbrel®), golimumab (Simponi®), certolizumab (Cimzia®), rituximab (Rituxan®), abatacept (Orencia®), basiliximab (Simulect®), anakinra (Kineret®), canakinumab (Haris®), gevokixumab (XOMA052), tocilizumab (Actemra®), alemtuzumab (Campath®), efalizumab (Raptiva®), LFG316, sirolimus (Santen®), abatacept, sarilumab (Kevzara®), and daclizumab (Zenapax®)), cytotoxic drags, surgical implant (e.g., fluocinolone insert), and vitrectomy. on-limiting examples of additional therapeutic agents and / or regimens for treating mucositis include AG013, SGX942 (dusquetide), amifostine (Ethyol®), cryotherapy, cepacol lonzenges, capsaicin lozenges, mucoadhesives (e.g., MuGard®) oral diphenhydramine (e.g., Benadry® elixir), oral bioadherents (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), caphosol, chamomiHa recutita mouthwash, edible grape plant exosome, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., Peridex® or Periogard®), topical pain relievers (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and Ulcerease® (0.6% phenol)), corticosteroids (e.g., prednisone), pain killers (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor; Kepivance®), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble p-1,3 / 1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, granules comprising vaccmium myrtillus extract, macleaya cordata alkaloids and echinacea angustifolia extract (e.g., SAMITAL®), and gastrointestinal cocktail (an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid)). For example, non-limiting examples of treatments for oral mucositis include AGO 13, amifostine (Ethyol®), cryotherapy, cepacol lonzenges, mucoadhesives (e.g., MuGard®) oral diphenhydramine (e.g., Benadry® elixir), oral bioadherents (e.g., polyvinylpyrrolidone -sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g,, Oral Balance®), caphosol, chamomilla recutita mouthwash, edible grape plant exosome, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., Peridex® or Periogard®), topical pain relievers (e.g., lidocaine, benzocaine, dyclonine hydrochloride, x ylocaine (e.g., viscous xylocaine 2%), and Ulcerease® (0.6% phenol)), corticosteroids (e.g., prednisone), pain killers (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor; Kepivance®), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble P-1 ,3 / 1,6 glucan, P276, LP-0004-09, CR-3294, ALD- 518, IZN-6N4, quercetin, and gastrointestinal cocktail (an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid)). As another example, non-limiting examples of treatments for esophageal mucositis include xylocaine (e.g., gel viscous Xylocaine 2%). As another example, treatments for intestinal mucositis, treatments to modify intestinal mucositis, and treatments for intestinal mucositis signs and symptoms include gastrointestinal cocktail (an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid)).

[0248] In certain embodiments, the second therapeutic agent or regimen is administered to the subject prior to contacting -with or administering the chemical entity (e.g., about one hour prior, or about 6 hours prior, or about 12 hours prior, or about 24 hours prior, or about 48 hours prior, or about 1 week prior, or about 1 month prior).

[0249] In other embodiments, the second therapeutic agent or regimen is administered to the subject at about the same time as contacting with or administering the chemical entity. By way of example, the second therapeutic agent or regimen and the chemical entity are provided to the subject simultaneously in the same dosage form. As another example, the second therapeutic agent or regimen and the chemical entity are provided to the subject concurrently in separate dosage forms.

[0250] In still other embodiments, the second therapeutic agent or regimen is administered to the subject after contacting with or administering the chemical entity (e.g., about one hour after, or about 6 hours after, or about 12 hours after, or about 24 hours after, or about 48 hours after, or about 1 week after, or about 1 month after).

[0251] Patient Selection

[0252] In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of such treatment (e.g., by way of biopsy, endoscopy, or other conventional method known in the art). In certain embodiments, the STING protein can serve as a biomarker for certain types of cancer, e.g., colon cancer and prostate cancer. In other embodiments, identifying a subject can include assaying the patient’s tumor microenvironment for the absence of T-cells and / or presence of exhausted T-cells, e.g., patients having one or more cold tumors. Such patients can include those that are resistant to treatment with checkpoint inhibitors. In certain embodiments, such patients can be treated with a chemical entity herein, e.g., to recruit T-cells into the tumor, and in some cases, further treated with one or more checkpoint inhibitors, e.g,, once the T-cells become exhausted.

[0253] In some embodiments, the chemical entities, methods, and compositions described herein can be administered to certain treatment-resistant patient populations (e.g., patients resistant to checkpoint inhibitors; e.g,, patients having one or more cold tumors, e.g., tumors lacking T-cells or exhausted T-cells).

[0254] Compound Preparation

[0255] As can be appreciated by the skilled artisan, methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Synthetic chemistry' transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L, Paquete, ed,, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available. The skilled artisan will also recognize that conditions and reagents described herein that can be interchanged with alternative art-recognized equivalents. For example, in many reactions, triethylamine can be interchanged with other bases, such as non-nucleophilic bases (e.g. diisopropylamine, 1,8- diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene).

[0256] The skilled artisan will recognize a variety of analytical methods that can be used to characterize the compounds described herein, including, for example, 1HNMR, heteronuclear NMR, mass spectrometry’, liquid chromatography, and infrared spectroscopy. The foregoing list is a subset of characterization methods available to a skilled artisan and is not intended to be limiting.

[0257] 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 die purview of one skilled in die art and are considered to fail within the scope of the invention as described, and claimed herein. The reader will recognize that the skilled artisan, provided with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples.

[0258] Examples

[0259] Chemical Examples

[0260] The following abbreviations have the indicated meanings:

[0261] Ac = acetyl

[0262] ACN = acetonitrile

[0263] BoCzO = di-rtTt-butyl pyrocarbomate

[0264] BretPhos:= 2-Dicyclohexjdphosphino-2',4',6'-tri-i-propyl-3,6-diMethoxy- 1,1' -biphenyl

[0265] BrettPhos Pd G3 == Methanesulfonato2-Dicyclohexylphosphino-3,6- dimethoxy-2'-4' -6'-tri-i-propyl-l,T-bipheny)(2'-amino-l,r-biphenyl-2- yl)palladium(II)

[0266] Bu = butyl CMBP = cyanomethylenetributyl-phosphorane

[0267] DAST = Diethylaminosulphur trifluoride

[0268] DCE = dichloroethane

[0269] DCM = dichloromethane

[0270] DIEA == A^A-diisopropylethylamine

[0271] DMAP = 4-dimethylaminopyridine

[0272] DME = Methoxymethane

[0273] DMF = AiA-dimethylformamide

[0274] DMF-DMA = JV^-dimethylformamide dimethyl acetal

[0275] DMSO:::dimethyl sulfoxide

[0276] Dppf = bis(diphenylphosphino)ferrocene

[0277] EPhos =:Methanesulfonato{Dicyclohexyl[3-( l-methylethoxy)“2',4;6'-tris(l - methylethyl)- 1 , l'-biphenyl-2-yl]phosphine } (2'-methylamino- 1 , l'-biphenyl-2-yl)

[0278] EPhos Pd G4 =‘- Methanesulfonato{Dicyclohexyl[3-(l-methylethoxy)-2',4',6'- tri s( 1 -methylethyl)" 1 , 1 '-biphenyl -2-yl]phosphine } (2'-methylamino- 1 , 1 '-biphenyl-2- yl)palladium(II)

[0279] Et:= ethyl

[0280] Ethyl Acetate = EtOAc

[0281] FA = formic acid

[0282] HATU = 2-(7-Azabenzotriazol- 1 -yl)-A, N, N’, 7V-tetramethyluronium hexafluorophosphate

[0283] HPLC = high performance liquid chromatography

[0284] IBX = 2-Iodoxybenzoic acid

[0285] LAH = Lithium aluminum hydride

[0286] LC-MS:=:liquid chromatography -- mass spectrometry

[0287] LiHMDS = Lithium bis(trimethylsilyl)amide m-CPBA:=:3 “Chloroperoxybenzoic acid Me = methyl

[0288] MszO = Methanesulfonic anhydride

[0289] NCS == A-Chlorosuccinimide

[0290] NMR = nuclear magnetic resonance

[0291] Pd(dtbpf)Ch = 1, 1'-Bis (di-t-butylphosphino)ferrocene palladium dichloride

[0292] PMDETA =N,N,N’ ,N" ,N” -Pentamethyldiethylenetriamine

[0293] PPI13 = triphenylphosphine

[0294] PTS A = P-toluene sulfonic acid

[0295] Py = pyridine

[0296] Rockphos = 2-Di-teit-butj'lphosphino-3-Metiioxy-6-Methyl-2',4',6'- triisopropyl- 1 , 1 ’-biphenyl

[0297] Rockphos Pd G3 = Methanesulfonato(2-(di-t-butylphosphino)-3-methoxy-6- methyl-2',4',6’-tri-i-propyl- 1 , 1 '-biphenyl)(2'-amino- 1 , l'-biphenyl-2-yl)palladium(II)

[0298] Select-F:= 1 -Chloromethyl-4-fluoro- 1 ,4-diazoniabicyclo [2.2 ,2]octane bis(tetrafluoroborate)

[0299] TB AF = Tetrabutylammonium fluoride

[0300] TBS = t-Butyldimethylsilane

[0301] TEA:= trimethylamine

[0302] Tf = trifluoromethanesulfonyl

[0303] TFA = trifluoroacetic acid

[0304] TFAA = Trifluoroacetic anhydride

[0305] THF = tetrahydrofuran

[0306] TMS = Trimethylsilyl

[0307] TosMIC = Tosylmethyl isocyanide

[0308] Ts:::tosyl

[0309] Materials and Methods LCMS Method A: Kinetex EVO C18 100 A, 30*3mm, 0.5 uL injection, 1.2 mL / min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water / 5mM NH4HCO3 and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.30 min, 95% MPB to 10% in 0.10 min.

[0310] LCMS Method B: Xselect CSH C18, 50*3mm, 1.0 pL injection, 1.2 mL / min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water / 0.1% FA and Mobile Phase B (MPB): Acetonitrile / 0.1% FA. Elution 5% MPB to 100% in 2.00 min, hold at 100% MPB for 0.70 min, 100% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.15 min.

[0311] LCMS Method C: HALOCI 8. 30*3mm, 0.5 pL injection, 1.5 mL / min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water / 0.05% TFA and Mobile Phase B (MPB): Acetonitrile / 0.05% TFA. Elution 5% MPB to 100% in 1.20 min, hold at 100% MPB for 0.60 min, 100% MPB to 5% in 0.02 min, then equilibration to 5% MPB for 0.18 min.

[0312] LCMS Method D: Luna Omega PS Cl 8, 33* 3mm, 0.5 pL injection, 1.5 mL / min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water / 0.1% FA and Mobile Phase B (MPB): Acetonitrile / 0.1% FA. Elution 5% MPB to 100% in 1 .20 min, hold at 100% MPB for 0.60 min, 100% MPB to 5% in 0.02 min, then equilibration to 5% MPB for 0.25 min.

[0313] NMR was recorded on BRUKER NMR 300.03 Mz, DUL-C-H, ULTRASHIELD™ 300, AVANCE II 300 B-ACS™ 120 or BRUKER NMR 400.13 Mz, BBFO, ULTRASHIELD™ 400, AVANCE III 400, B-ACS™ 120.

[0314] Intermediate 1. (3-fluoro-lH-indoI-6-amine hydrochloride) intermediate 1

[0315] Step 1: 2,2,2-trifluoro-l-(6-nitro-l / f-indol-3-yI) ethanone 6-Nitro-lH-indole (660.0 g, 4.0 mol, 1.0 equiv.) was dissolved in DMF (19.8 L), then TFAA (1711.1 g, 8.1 mol, 2.0 equiv.) was added dropwise at 5-10 °C under N2 atmosphere. The resulting mixture was stirred for 15 hours at 80 °C under Nj atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with waler (13.2 L). After filtration, filter cake was washed with water (13.2 L) and then dried under vacuum for 24 hours at 40 °C. This resulted in 2,2,2-trifluoro-l-(6-nitro-lH-indol-3-yl) ethanone (1089.5 g) as a light-yellow7solid. LCMS Method A: [M+H]+= 259.0.

[0316] Step 2: 6-nitro-lIJ-indoie-3-carboxyfic acid

[0317] 2,2,2-Trifluoro-l -(6-nitro-lH-indol-3-yl)ethanone (1089.5 g, 3.7 mol, 1.0 equiv.) was dissolved in 4 M aq. NaOH (18.5 L) at room temperature. The resulting mixture was stirred for 15 hours at 60 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (17.0 L). The aqueous layer was adjusted to pH 1 with cone. HC1 at 5 °C. The precipitated solids were collected by filtration and washed with water and then dried under vacuum for 24 hours at 40 °C. This resulted m 6-nitro-l / / -indole-3-carboxylic acid (573.5 g) as a light brown solid. LCMS Method A: [M-H]" = 205.0.

[0318] Step 3: 3-fluoro-6-Hitro-177-indoIe

[0319] 6-Nitro-127-indole-3-carboxylic acid (573.5 g, 2.7 mol, 1.0 equiv.) and Selectfluor (1911.6 g, 5.4 mol, 2.0 equiv.) were dissolved in DCE (17.2 L) and H2O (8.6 L), then LieCOg (797.4 g, 10.8 mol, 4.0 equiv.) was added in five portions over 1 hour at 5-10 °C under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 25 °C under nitrogen atmosphere. The resulting mixture was diluted with water (10.0 L). The resulting mixture was extracted with DCM, washed with brine, dried over anhydrous NaeSOr. After filtration, the filtrate was concentrated under vacuum. Crude product (42.3.1 g) was slurried with petroleum ether / EtOAc (3: 1, 2.8 L) for 2 hours. After filtration, filter cake was washed with petroleum ether and then dried under vacuum for 2 hours at 40 °C. This resulted in 3-fluoro-6-nitro-177-indole (297.3 g) as a yellow solid. LCMS Method A: [M+H]+== 181.0.

[0320] Step 4: 3-fluoro-n7“iiido>L6-amine hydrochloride 3-Fluoro-6-nitro-lH-indole (297.3 g, 1.3 mol, 1.0 equiv.) was dissolved in EtOAc (11.8 L), 10% wet Pd / C (20% w / w, 59.4 g) was added under nitrogen atmosphere. The resulting mixture was degassed and back filled with hydrogen. The mixture was hydrogenated at 25 °C for 15 hours under hydrogen atmosphere, filtered through a celite pad. To above filtrate was added 4 M hydrochloric acid solution in EtOAc (5.2 L) dropwise over 30 min at 25 °C. The resulting mixture was stirred for 3 hours at 25 °C. After filtration, filter cake was washed with EtOAc and then dried under vacuum for 16 hours at 40 °C. This resulted in 3-fluoro-177-indol-6-amine hydrochloride (151.0 g) as a black solid. LCMS Method A: [M+H]+151.1.

[0321] Intermediate 2. (4-chIoro-lH-indol-6-amine)

[0322] Step 1: [(E)-2-(2-chloro-4,6-dinitrophenyl)ethenyl] dimethylamine l-Chloro-2-methyl-3, 5 -dinitrobenzene (2.0 g, 9.2 mmol, 1.0 equiv.) was dissolved in DMF (30 mb), then DMF-DMA (4 / 4 g, 36.9 mmol, 4.0 equiv.) was added. The reaction mixture was stirred for 4 hours at 80 °C, then cooled to room temperature and concentrated under vacuum. The residue was diluted with water, extracted with EtOAc, washed with brine, dried over anhydrous Na?.SO4 and concentrated under vacuum . This resulted in [(E)-2-(2-chloro-4,6- dinitrophenyl)ethenyl]dimethylamine (1.8 g) as a white solid. LCMS Method A:

[0323] Step 2: 4-chloro-1H-mdol-6-ainine

[0324] [(E)-2-(2-chloro-4,6-dinitrophenyl)ethenyl]dimethylamine (1.8 g, 6.6 mmol, 1.0 equiv.) was dissolved in ACN (20 mb), then Pt / C (2.6 g, 13.3 mmol, 2.0 equiv.) was added under an atmosphere of nitrogen. The resulting solution was degassed and back fdled with hydrogen for three times. The reaction mixture was stirred overnight at room temperature under hydrogen, lire reaction mixture w'as filtered through Celite and the collected filtrate was concentrated under vacuum. This resulted in 4-chloro- 177- indol-6-amine (700.0 mg) as a white solid. LCMS Method A: [M+H]+ :=:167.0.

[0325] Intermediate 3. ([(3-fluoro-lH-indol-6-yl)sulfanyI]formonitrile) intermediate 3 3-Fluoro-177-indol-6-aminium hydrochloride (119.0 g, 638.0 mmol, 1.0 equiv.) was dissolved in DCM (2.4 L), then TEA (96.8 g, 957.0 mmol, 1.5 equiv.) and l-(2- oxopyridine-l-carbothioyl)pyridin-2-one (148.1 g, 638.0 mmol, 1.0 equiv.) were added. The reaction mixture was stirred for 1.5 hours at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (10: 1) to afford [(3 -fluoro- 177- indol-6-yl)sulfanyl]fomionitrile (72.0 g) as a brown solid. 1HNMR (400 MHz, DMSO- d6) δ 6.66-6.62 (m, 1H), 6.43-6.41 (m, 1H), 6.37-6.36 (m, 1H), 6.28-6.25 (m, 1H).

[0326] The intermediate in Table 1 was prepared using tire same method described for Intermediate 3. Table 1 Intermediate 5. (4-chIoro-3-fIuoro-6-isothiocyanato-lH-indoIe)

[0327] Intermediate 5

[0328] Step 1: l-(4-chloro-lH-indoI-3-yl)-2,2,2-trifluoroethanone

[0329] 4-Chloro-HZ-indole (500.0 g, 3.3 mol, 1.0 equiv.) was dissolved in DMF (3.5 L), then TFAA (831 .3 g, 3.9 mol, 1 .2 equiv.) was added dropwise at 10°C over 30 min under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere and then quenched by the addition of water. The precipitated solids were collected by filtration and washed with water, then dried under oven vacuum at 45 °C for 24 hours. This resulted in 1 -(4-chloro-177-indol-3-yl)- 2,2,2-trifluoroethanone (683.0 g) as a light yellow solid. LCMS Method A: [M+H]+= 248.0.

[0330] Step 2: l-(4-chIoro-6-nitro-1H “indo>l-3-yI)-2,2,2-trifluoroethanone l-(4-Chloro-lH-indol-3-yl)-2,2,2-trifluoroethanone (683.0 g, 2.7 mol, 1.0 equiv.) was dissolved in AcOH (10.2 L), H2SO4 (68.3 mL, 1.3 mol, 0.46 equiv.) was added dropwise at 15 °C under nitrogen atmosphere. Uris was followed by the addition of a solution of HNO3 (869.0 g, 13.8 mol, 5.0 equiv.) in AcOH (3.41 L) dropwise over 1 hour at 15 °C. The resulting mixture was stirred overnight at room temperature and then quenched by the addition of 10% aq. NaCl (13.7 L) at room temperture. Tire resulting mixture was extracted with EtOAc, washed aq. NaHCOi and brine, then dried over anhydrous NaiSOr and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (10: 1) to afford l-(4-chloro-6-nitro-lZZ-indol-3-yl)-2,2,2-trifluoroethanone (220.0 g) as a yellow solid. LCMS Method A: [M+H]+= 293.0.

[0331] Step 3: 4-chloro-6-nitro-lJjT-indoIe-3-carboxylic acid l-(4-Chloro-6-nitro-12 / -indol-3-yl)-2,2,2-trifluoroethanone (220.0 g, 751.8 mmol, 1.0 equiv.) was dissolved in 4 M aq. NaOH (601.4 g, 15.0 mol, 20.0 equiv.). The resulting mixture was stirred overnight at 65 °C under nitrogen atmosphere. Tire mixture was allowed to cool down to room temperature and washed with MeTHF. lire water phase was adjusted to pH 1 -2 wuth cone. HCl at 0 °C. The precipitated solids were collected by filtration, washed with water and dried under vacuum at 45 °C for 6 hours to afford 4-chloro-6-nitro-17 / -indole-3-carboxylic acid (157.0 g) as a brown solid. LCMS Method B: [M-H]' == 238.9.

[0332] Step 4: 4-chloro-3-fluoro-6-nitro-LH-indole

[0333] 4-Chloro-6-nitro-l / 7-indole-3-carboxylic acid (157.0 g, 652.5 mmol, 1.0 equiv.) was dissolved in THF (4.7 L) and water (2.4 L), then selectfluor (462.3 g, 1.3 mol, 2.0 equiv.) was added. Tills was followed by the addition of LizCOj (192.8 g, 2.6 mol, 4.0 equiv.) in five portions over 30 min at 10 °C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was w<ashed with THF. The resulting solution was diluted with water, extracted with EtOAc, washed with brine, dried over anhydrous NarSCL and concentrated under vacuum. The residue w'as purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (12: 1) to afford 4-chloro-3-fluoro-6-nitro-177-indole (76.9 g) as a yellow solid. LCMS Method A: [M-H]' = 213.0.

[0334] Step 5: 4-chloro-3-fluoro-177-indoI-6-amine hydrochloride

[0335] 4-Chloro-3-fluoro-6-nitro-177-indole (76.9 g, 358.3 mmol, 1.0 equiv.) was dissolved in EtOH (1.2 L) and water (0.3 L), then NH4CI (95.8 g, 1.8 mol, 5.0 equiv.) was added. After stirred for 10 min at 50 °C under nitrogen atmosphere, Fe powder (100.0 g, 1.8 mol, 5.0 equiv.) was added in five portions over 1 hour at 50 °C. The resulting mixture was stirred for additional 3 hours at 50 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, lire resulting mixture was filtered and the filter cake was washed with EtOH. The filtrate was concentrated under vacuum. The residue was dilute with water, extracted with EtOAc, washed with 10% aq. NaCl, dried over anhydrous Na2SO4. To the organic layers was added 4 M^ HC1 in EtOAc (769 mL) dropwise over 30 min at 10 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at room temperature under nitrogen atmosphere and then concentrated to about 600 mL (8 V) under vacuum. The precipitated solids were collected by filtration to afford 4-chloro-3-fluoro-lH-indol-6-amine hydrochloride (63.5 g) as a brown solid. LCMS Method A: [M+H]1= 185.0. 'HNMR (300 MHz, DMSO-cfe) δ 11.66 (s, IH), 10.44 (s, 2H), 7.54 (dt, J = 15.0, 2.3 Hz, 2H), 7.13 (d, J= 1.6 Hz, IH).

[0336] Intermediate 6. (3,4-difluoro-6-isothiocyanato-lH-indole)

[0337] Intermediate 6

[0338] Step 1: 6-bromO”3,4-difliioro-l / ir-indo>ie

[0339] 6-Bromo-4-fluoro-lH-indole (2.0 g, 9.3 mmol, 1.0 equiv.) was dissolved in ACN (16 mL) and Pyridine (8 mL), Selectfluor (3.9 g, 1 1.2 mmol, 1.2 equiv.) was added at 0°C. The resulting mixture was stirred for 16 h at room temperature and then quenched by the addition of water. The resulting mixture was extracted with EtOAc, w’ashed with brine and dried over anhydrous NaiSCh. After filtration, the filtrate wras concentrated under reduced pressure to afford 6-bromo-3,4-difluoro-177-indole (2.1 g, 96.86%) as a yellow^ solid. The crude product wns used in the next step directly without further purification. LCMS Method A: [M+H]+= 230.0.

[0340] Step 2: tert-butyl 6-bromo-3,4-difluoroindole-l-carboxylate

[0341] 6-Bromo-3,4-difluoro-l / / -indole (2.1 g, 9.1 mmol, 1.0 equiv.) was dissolved in DCM (15 mL), TEA (1.8 g, 18.1 mmol, 2.0 equiv.), DMAP (111.0 mg, 0.9 mmol, 0.1 equiv.) and Boc?.O (2.96 g, 13.6 mmol, 1.5 equiv.) were added at room temperature. The reaction mixture was stirred for 5 h at room temperature and then concentrated under vacuum. Tire residue w'as purified by silica gel column chromatography, eluting with petroleum ether to afford tert-butyl 6-bromo-3,4-difluoroindole-l -carboxylate (2.0 g, 66.53%) as a yellow solid. LCMS Method A: [M+H]1= 330.0.

[0342] Step 3: tert-butyl 6-bromo-3,4-difluoroindole-l-carboxylate tert-Butyl 6-bromo-3,4-difluoroindole-l-carboxylate (2.0 g, 6.0 mmol, 1.0 equiv.) and tert-butyl carbamate (1.05 g, 9.0 mmol, 1.5 equiv.) were dissolved in 1,4- dioxane (20 mL), CS2CO3 (3.9 g, 12.0 mmol, 2.0 equiv.), BretPhos (323.0 mg, 0.6 mmol, 0.1 equiv.) and BretPhos Pd G3 (546.0 mg, 0.6 mmol, 0.1 equiv.) were added under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 100°C under nitrogen atmosphere and then cooled to room temperature. Tire resulting mixture was filtered; the filter cake was washed with EtOAc. The combined filtrate was concentrated under reduced pressure. The residue was purified by re versed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 50% to 80% gradient in 30 min; detector, UV 254 ran. This resulted in tert-butyl 6-[(tert-butoxycarbonyl)amino]-3,4-difluoroindole-l -carboxylate (600 mg, 27.0%) as an off-white solid. LCMS Method B: [M~H]~ = 367.0.

[0343] Step 4: 3,4-difluoro-LH-iiidoI-6-amme hydrochloride tert-Butyl 6-[(tert-butoxycarbonyl)amino]-3,4-difluoroindole-l-carboxylate (600.0 mg, 1.6 mmol, 1.0 equiv.) w?as dissolved in EtOAc (12 mL), HC1 (gas) in 1,4- dioxane (4N, 3 mL) was added. The resulting mixture was stirred for 5 h at room temperature and then diluted with CH2CI2 (40 mL). The solid was collected by filtration and washed with EtOAc. This resulted in 3,4-difluoro-lH-indol-6-amine hydrochloride (220 mg, 80.33%) as a brown solid. LCMS Method A: [M+H]+= 169.0.

[0344] Step 5: 3,4-difluoro-6-isothiocyanato-lfl-indole

[0345] 3,4-Difluoro-lH-indol-6-amine hydrochloride (1.0 g, 5.9 mmol, 1.0 equiv.) and l-(2-oxopyridine-l-carbothioyl) pyridin-2-one (1.4 g, 5.9 mmol, 1.0 equiv.) were dissolved in DCM (10 mL), TEA (0.9 g, 8.9 mmol, 1.5 equiv.) was added dropwise. The resulting mixture was stirred for overnight at room temperature and then quenched by the addition of water. The resulting mixture was extracted with EtOAc, washed with brine, dried over anhydrous NarSOr and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (5: 1) to afford 3,4-difluoro-6-isothiocyanato-LF / -indole (450 mg, 36.0%) as a brown solid. LCMS Method B: [M-H]' = 209.1.

[0346] The intermediate in Table 2 was prepared using the same method described for

[0347] Intermediate 6.

[0348] Intermediate 8. (4-chloro-5-fluoro-6-isothiocyanato-lH-indok)

[0349] In termed tete 8

[0350] Step 1: 4-chIoro-5-fluoro-l-(triisopropyisiIyl)-Lfi-indole 4-Chloro-5-fl uoro- 1 H-indole (400.0 mg, 2.4 mmol, 1.0 equiv.) was dissolved in

[0351] DMF (6.0 mL), NaH (60% wt%, 188.7 mg, 4.7 mmol, 2.0 equiv.) was added in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0°C, then chlorotriisopropyl silane (682.2 mg, 3.5 mmol, 1.5 equiv.) was added dropwise at 0°C. The resulting mixture was stirred for additional 1 h at room temperature and then quenched by the addition of ice-water. The resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous NaiSOv After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (5: 1) to afford 4-chloro-5-fluoro- 1 -(triisopropylsilyl)- 177-indole (740 mg, 96.25%) as a colorless oil. LCMS Method A: i M H | ' 326.2.

[0352] Step 2: 4-chloro-5-fluoro-l~(triisopropyIsilyi)-lJ7-indoIe-6-carboxylic acid

[0353] 2,2,6,6-Tetramethylpiperidme (641 .4 mg, 4.5 mmol, 2.0 equiv.) and PMDTA (787.0 mg, 4.5 mmol, 2.0 equiv.) were dissolved in THF (5 mL) and cooled to -78°C, n-BuLi (2.5 M in hexanes, 1.8 mL, 4.5 mmol, 2.0 equiv.) was dissolved dropwise at - 78°C under nitrogen atmosphere. After stirred for 30 min at -78°C, a solution of 4- chloro-5 -fluoro- 1 -(triisopropylsilyl)- IH-indole (740.0 mg, 2.3 mmol, 1.0 equiv.) in THF (5 mL) was added dropwise under nitrogen atmosphere. The resulting mixture was stirred for additional 2. h at -78°C under nitrogen atmosphere. That was followed by the addition of CCh gas at -60 °C for 30 min. Tire mixture was warmed to room temperature and stirred for additional 16 h. The reaction was quenched by the addition of ice -water, then extracted with EtOAc, washed with aqueous citric acid (1.0 M) and brine (5x20 mL), dried over anhydrous Na.2.SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 4-chloro-5-fluoro-l-(triisopropylsilyl)-lH-indole-6- carboxylic acid (1.1 g, 78.58%) as an off-white solid. LCMS Method A: [M+H]+=

[0354] 370.1.

[0355] Step 3: 4~chloro-5-fluoro-L^-indole-6-carbonyl azide

[0356] 4-Chloro-5 -fluoro- 1 -(triisopropylsilyl)- l / f-indole-6-carboxy lie acid (1.1 g, 3.0 mmol, 1.0 equiv.) was dissolved in THF (15.0 mL), TEA (601.8 mg, 5.9 mmol, 2.0 equiv.) and DPPA (1.2 g, 4.5 mmol, 1.5 equiv.) were added. The resulting mixture was stirred for overnight at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1: 1) to afford 4-chloro-5-fluoro-177-indole-6-carbonyl azide (240 mg, 33.83%) as a light brown oil. LCMS Method A: | M 1 1 i 239.1.

[0357] Step 4: tert-butyl (4-chloro-5-fluoro-lH-indol-6-yl)carbamate

[0358] 4-Chloro-5-fiuoro-127-indole-6-carbonyl azide (240.0 mg, 1.0 mmol, 1.0 equiv.) was dissolved in t-BuOH (5.0 mL) at room temperature. The resulting mixture was stirred for 2 h at 90°C, then cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (5: 1) to afford tert-butyl (4-chloro-5 -fluoro- lH-indol-6- yl)carbamate (205.1 mg, 69.84%) as an off-white solid. LCMS Method A: [M+H]+=

[0359] 285.1 .

[0360] Step 5: 4-chloro-5-fluoro-lJf-indoI-6-amine TFA salt terr-Butyl (4-chloro-5 -fluoro- 1 H-indol-6-yl)carbamate (200.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in DCM (5 mL) and TFA (1 mL). The resulting mixture was stirred for 1 h at room temperature and then concentrated under vacuum. This resulted in 4-chloro-5-fluoro-l / / -indol-6-amine TFA salt (120 mg, 92.54%) as a brown oil. LCMS Method A: [M+H]+= 185.1. Step 6: 4-chloro-5-fluoro-6-isothiocyanato-17f-indole

[0361] 4-Chloro-5-fiuoro-127-indol-6-amine (120.0 mg, 0.7 mmol, 1.0 equiv.) and 1- (2-oxopyridine-l -carbothioyl) pyridin-2-one (151.0 mg, 0.7 mmol, 1.0 equiv.) were dissolved in DCM (4.0 mL), TEA (98.7 mg, 1.0 mmol, 1.5 equiv) was added dropwise. The resulting mixture was stirred for 1 h at room temperature and then quenched by the addition of water. The resulting mixture was extracted with DCM, washed with brine, dried over anhydrous NazSOi and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc ( 1: 1) to afford 4-chloro-5-fluoro-6-isothiocyanato-JH-indole (85 mg, 57.69%) as a brown yellow solid. LCMS Method B : [M-Hj" = 225.1.

[0362] The intermediate in Table 3 was prepared using the same method described for Intermediate 8.

[0363] T able 3

[0364] Intermediate 10. (3-chIoro-6-isothiocyanato-lH-indole)

[0365] SCN

[0366] Intermediate 10

[0367] Step 1: 3-chloro-6-nitro-UJ-indole

[0368] 6-Nitro-lH-indole (1 .0 g, 6.2 mmol, 1 .0 equiv.) was dissolved in ACN (25 mL), thenNCS (1.3 g, 9.3 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for overnight at room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (5: 1). Tills resulted In 3-chloro-6-nitro-lH-indole (1 g, 82.48%) as a white solid. LCMS Method A: | M • H i == 197.0.

[0369] Step 2: 3-chloro-lH-indoI-6-amine

[0370] 3-Chloro-6-nitro-lH-indole (800.0 mg, 4.1 mmol, 1.0 equiv.) was dissolved in ACN (15 mL), then Pt / C (79.4 mg, 0.4 mmol, 0.1 equiv.) was added. The reaction mixture was degassed and back filled with hydrogen. The mixture was hydrogenated at room temperature for overnight under hydrogen atmosphere using a hydrogen balloon. The resulting mixture was filtered through a Celite pad and the combined filtrated was concentrated under reduced pressure. This resulted in 3-chloro-lH-indoi-6-amine (500 mg, 73.75%) as a white solid. LCMS Method A: [M+H]+= 167.0.

[0371] Step 3: 3-chloro-6-isothiocyanato-l ff-indole

[0372] 3-Chloro-lH-indoi-6-amine (450.0 mg, 2.7 mmol, 1.0 equiv.) was dissolved in THF (15 mL), then TEA (546.6 mg, 5.4 mmol, 2.0 equiv.) and thiophosgene (465.8 mg, 4.1 mmol, 1.5 equiv.) were added. The reaction mixture was stirred for 3 h at room temperature and then concentrated under reduced pressure to afford the crude 3-chloro- 6-isothiocyanato-lH-indole (300 mg, 53.23%) as a white solid. The crude product -was used in the next step directly without further purification. LCMS Method A: [M+H]+== 209.0.

[0373] Intermediate 11. (4-chIoro-7-fluoro-6-isothiocyanato-lH-indo>le)

[0374] Step 1: 6-bromo-4-chloro-7-fluoro-l / / -indo!e l-Bromo-5-chloro-2-fluoro-3-nitrobenzene (10.0 g, 39.3 mmol, 1.0 equiv.) was dissolved in THF (10 mL) and cooled to -5°C, bromo(ethenyl)magnesium (IM in THF, 196.5 mL, 196.5 mmol, 5.0 equiv.) was added dropwise at -5°C under nitrogen atmosphere. Hie resulting mixture was stirred for 2 h at -5°C under nitrogen atmosphere and then quenched by the addition of sat. NH4CI (aq.) at -5°C. The resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1 : 1) to afford 6-bromo-4-chloro-7-fluoro-177-indole (830 mg, 8.50%) as a yellow solid. LCMS Method B: i M-H f 246.1.

[0375] Step 2: tert-butyl 6-bromo-4-chloro-7-fIuoroindole-l-carboxykte

[0376] 6-Bromo-4-chloro-7-fluoro-177-indole (830.0 mg, 3.3 mmol, 1.0 equiv.) and BociO (1093.5 mg, 5.0 mmol, 1.5 equiv.) were dissolved in DCM (50 mL), then TEA (676.0 mg, 6.7 mmol, 2.0 equiv.) and DMAP (40.8 mg, 0.3 mmol, 0.1 equiv.) were added in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature and then quenched by the addition of water, lire resulting mixture was extracted with DCM, washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (10: 1) to afford tert-butyl 6-bromo-4-chloro-7 -fluoroindole- 1 -carboxylate (820 mg, 70.42%) as a yellow solid. LCMS Method A: [M+H]+= 348.1.

[0377] Step 3: tert-butyl 6-((tert-butoxycarbonyI) amino)-4-ch!oro-7-fluoro-lH-indole-l- carboxylate tert-Butyl 6-bromo-4-chloro-7-fluoro-lH-indole-l-carboxylate ( 1.0 g, 2.9 mmol, 1.0 equiv.) and tert-butyl carbamate (302.5 mg, 2.6 mmol, 0.9 equiv.) were dissolved in 1,4-dioxane (10 mL), then EPhos (153.4 mg, 0.3 mmol, 0.1 equiv.), EPhos Pd G4 (263.5 mg, 0.3 mmol, 0.1 equiv.) and CS2CO3 (1.87 g, 5.7 mmol, 2.0 equiv.) were added under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80°C, then cooled to room temperature and quenched by the addition of water. The resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous NaaSO*. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (5: 1) to afford tert-butyl 6-((tert-butoxycarbonyl) amino)-4- chloro-7-fluoro-lH-indole-l~carboxylate (760 mg, 68.84%) as a yellow oil. LCMS Method A: | M • H i ' 385.0. Step 4: 4-chloro-7-fluoro-lH~indoI-6~amine hydrochloride terf-Butyl 6-((rert-butoxycarbonyl) amino)-4-chloro-7-fluoro- 1 H-indole- 1 - carboxylate (760.0 mg, 2.0 mmol, 1.0 equiv.) was dissolved in MeOH (13 mL), HC1 (g) in MeOH (32 mL, 4 mol / L) was added drop wise at room temperature. 'lire resulting mixture was stirred for 2 h at 50°C, then cooled to room temperature and concentrated under vacuum. This resulted in 4-chloro-7-fluoro-l / 7-indol-6-amine hydrochloride (300 mg, 82.3%) as a brown solid. LCMS Method A: | M H | ' 185.0.

[0378] Step 5: 4-chIoro-7-fluoro~6-isothiocyanato-lI / -indole

[0379] 4-Chloro-7-fluoro-12f-indol-6-amine hydrochloride (900.0 mg, 4.9 mmol, 1.0 equiv.) and l,T-thiocarbonylbis (pyridin-2(lH)-one) (1132.4 mg, 4.9 mmol, 1.0 equiv.) were dissolved in DCM (10 mL), TEA (740.0 mg, 7.3 mmol, 1.5 equiv.) was added dropwise at room temperature. The resulting mixture was stirred for 2 h at room temperature and then quenched by the addition of water. The resulting mixture was extracted with DCM, washed with brine, dried over anhydrous NajSCh and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1: 1) to afford 4-chloro-7-fluoro- 6-isothiocyanato-177-indole (430 mg, 38.91%) as a yellow7oil. LCMS Method A: [M+H]+= 227.0.

[0380] Intermediate 12. (3,4,5-trifluoro-6-isothiocyanato-lH-indole) intermediate 12

[0381] 4,5-Difluoro-6-isothiocyanato-177-indole (90.0 mg, 0.4 mmol, 1.0 equiv.) and Li2C0j (63.3 mg, 0.9 mmol, 2.0 equiv.) were dissolved in THF (1 .0 mL) and ITO (0.5 mL), Selectfluor (606.7 mg, 1.7 mmol, 4.0 equiv.) was added in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0°C and then quenched by the addition of water. The resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous NaiSOi. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether / EtOAc = 3: 1) to afford 3,4,5-trifluoro-6-isothiocyanato-177-indole (55 mg, 32.09%) as an off- white solid. [M-i-H]+- 229.0.

[0382] Intermediate 13. (6-(3-hydroxy-3-methylbutyl)-3-methylquinoline 1-oxide) intermediate 13

[0383] Step 1: 6-bromo-3-methylquinoline

[0384] 2-Amino-5-bromobenzaldehyde (50.0 g, 249.9 mmol, 1.0 equiv.) was dissolved in EtOH (500 mL), propionaldehyde (17.4 g, 299.9 mmol, 1.2 equiv.) was added at room temperature. That was followed by the addition of KOH (28.1 g, 499.9 mmol, 2.0 equiv., powder) in portions at 0°C. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere, then cooled to room temperature and concentrated under vacuum. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCri. After filtration, the filtrate was concentrated under reduced pressure. The residue was slurryin EtOAc (30 mL) and dried under vacuum. This resulted in 6-bromo-3- methylquinoline (32 g, 57.6%) as a yellow' solid. LCMS Method A: [M+H]+ := 222.1.

[0385] Step 2: methyl (E)-3-(3-methylquinolin-6-yI) acrylate

[0386] 6-Bromo-3 -methylquinoline (2.0 g, 9.0 mmol, 1.0 equiv.) and methyl acrylate (1.2 g, 13.5 mmol, 1.5 equiv.) were dissolved in DMF (20 mL), K2CO3 (2.5 g, 18.0 mmol, 2.0 equiv.) and Pd(PPh3)2C12 (0.63 g, 0.9 mmol, 0.1 equiv.) were added under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 100°C, then cooled to room temperature and quenched by tire addition of water, lire resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous Naj-SOv After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1: 1) to afford methyl (E)-3-(3-methylquinolin-6-yl) acrylate (1.6 g, 78.18%) as a yellow solid. LCMS Method A: [M+H]+= 228.1 . Step 3: methyl 3-(3-methylquinolin-6-yl) propanoate

[0387] Methyl (E)-3 -(3 -methyl quinolin-6-yl) acrylate (1 .6 g, 8.8 mmol, 1 .0 equiv.) was dissolved in MeOH (20 mL), Pd / C (0.47 g, 4.4 mmol, 0.5 equiv.) was added. The mixture was hydrogenated at room temperature for 2 h under hydrogen atmosphere using a hydrogen balloon. The resulting mixture was filtered through a Celite pad and the combined filtrated was concentrated under reduced pressure. This resulted in methyl 3-(3-methylquinolin-6-yl) propanoate (1.5 g, 94.16%) as a yellow' solid. LCMS Method A: [M+H]+= 230.1.

[0388] Step 4: 2-methyl-4-(3-methylquinolin-6-yl) butan-2-ol

[0389] Methyl 3-(3-methylquinolin-6-yl) propanoate (600.0 mg, 2.6 mmol, 1.0 equiv.) was dissolved in THF (10 mL) and cooled to 0°C. Then MeMgBr (3M in THF, 4.36 mL, 13.1 mmol, 5.0 equiv.) was added dropwise at 0°C. The resulting mixture was stirred for additional 2 h at 0°C and then quenched by the addition of ice-water. The resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous NaaSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1: 1) to afford 2-methyl-4-(3-methylquinolin-6-yl) butan-2-ol (320 mg, 53.32%) as a yellow' solid. LCMS Method A: [MH-H] ’ = 230.2.

[0390] Step 5: 6-(3-hydroxy-3-methyIbutyl)-3-methyIquinoline 1-oxide

[0391] 2-Methyl-4-(3-methylquinolin-6-yl) butan-2-ol (500.0 mg, 2.2 mmol, 1.0 equiv.) in DCM (5 mL) was added m-CPBA (885.2 mg, 4.4 mmol, 2.0 equiv.) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature and then quenched by the addition of water, lire resulting solution was extracted with DCM, washed w'ith brine and dried over anhydrous NaaSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with tire following conditions: column, Cl 8 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 30 min; detector, UV 254 nm. This resulted in 6-(3-hydroxy-3-methylbutyl)-3-methylqumoline 1 -oxide (200 mg, 37.39%) as a yellow' solid. LCMS Method A: [M+H]1== 246. 1 . Intermediate 14. 3-methyI-6-(4,4,4-trifluoro-3-hydroxybutyl)qumolme 1 -oxide

[0392] Step 1 : (E)-l,l,l-trif]uoro-4-(3-methylquinolin-6-yl)but-3-en-2-one

[0393] Tetrabutylazanium acetate (66.3 mg, 0.2 mmol, 0.1 equiv.) and methyl (E)-3- (3-methylquinolin-6-yl)acrylate (500.0 mg, 2.2 mmol, 1.0 equiv.) were dissolved in toluene (7 mL), then TMSCF-j (469.2 mg, 3.3 mmol, 1.5 equiv.) was added dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature and then quenched by the addition of water. The resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous NazSCfi. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, ACN in Water ( lOmmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (E)- 1,1,1 -trifluoro-4-(3- methylquinolin-6-yl)but-3-en-2-one (140 mg, 23.9%) as a crude brown solid. LCMS Method A: [M+H]+= 266.1.

[0394] Step 2: 1,1 ,l-trifluoro-4-(3~methylquinolin-6-yl)butan-2-one

[0395] (E)- 1,1,1 -Trifluoro-4-(3 -methylquinolin-6-yl)but-3 -en-2-one ( 120.0 mg, 0.4 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL), Pd / C (12.0 mg, 0.1 mmol, 0.2 equiv.) was added under nitrogen atmosphere. The mixture wras hydrogenated at room temperature for 1 h under hydrogen atmosphere using a hydrogen balloon. The resulting mixture was filtered through a Celite pad and the filtrate cake was washed with MeOH. The combined filtrated was concentrated under reduced pressure to afford 1,1,1- trifluoro-4-(3-methylquinolin-6-yl)butan-2-one (130 mg, crude) as a yellow solid. LCMS Method A: [ M + H ] = 269. 1 .

[0396] Step 3: l,l,l-trifluoro-4-(3-methylquinoIin-6-yI)butan-2-ol 1.1.1-Trifluoro-4-(3-methylquinolin-6-yl)butan-2-one (200.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL), then a solution of LiBH:in THF (2M, 0.75 mL, 1 .4 mmol, 2.0 equiv.) was added dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature and then quenched by the addition of ice-water. The resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous NazSCU. After filtration, the filtrate w'as concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1 : 1) to afford 1 ,1, 1-trifluoro-4-(3-methylquinolin- 6-yl)butan-2-ol (90 mg, 44.6%) as a yellow solid. LCMS Method A: [M-i-H]+= 270.1.

[0397] Step 4: 3-methyl-6-(4,454-trifluoro-3-hydroxybutyl)quinoline 1-oxide

[0398] 1.1.1-Trifluoro-4-(3-methylquinolin-6-yl)butan-2-ol (90.0 mg, 0.3 mmol, 1.0 equiv.) was dissolved in DCM (3 mL), then m-CPBA (86.5 mg, 0.5 mmol, 1.5 equiv.) was added. The resulting mixture was stirred for 1 h at room temperature and then quenched by the addition of w aler. Tire resulting mixture was adjusted to pH 10 with NaOH (aq.). The resulting mixture was extracted with DCM, washed with brine, dried over anhydrous NTtSCL and concentrated under reduced pressure. This resulted in 3- methyl-6-(4,4,4-trifluoro-3-hydroxybutyl)quinoline 1-oxide (130 mg, crude) as a yellow crude solid. LCMS Method A: [M+H]+= 286.1.

[0399] Intermediate 15. (3-methyl-6-(3,3,3-trifIuoro-2-hydroxypropyl)quinoline 1-oxide)

[0400] Step 1: 6-|(E)-2-ethoxyethenyi]-3-methyiquinoiine

[0401] 6-Bromo-3-methylquinoline (5.0 g, 22.5 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (50 mL) and H2O (10 mL), 2-[(E)-2-ethoxyethenyl]-4,4,5,5~tetramethyl~

[0402] 1,3,2-dioxaborolane (8.9 g, 45.0 mmol, 2.0 equiv.), K3PO4 (9.5 g, 45.0 mmol, 2.0 equiv.) and PdCdppfjCh.CTLCL (1.8 g, 2.2 mmol, 0.1 equiv.) were added at room temperature under nitrogen atmosphere. "lire reaction mixture was stirred for 12 h at 90°C under nitrogen atmosphere, then cooled to room temperature and quenched by the addition of water. Tire resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous NaiSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (3: 1). This resulted in 6- [(E)-2 -ethoxyethenyl] -3- methylquinoline (3.5 g, 72.8%) as a while solid. LCMS Method A: [M+H]+= 214.1.

[0403] Step 2: 2-(3-methyIquinolin-6-yl)acetaldehyde

[0404] 6~[(E)-2-ethoxyethenyl]-3~methylquinoline (2.0 g, 9.3 mmol, 1.0 equiv.) was dissolved in THF ( 10 mL), hydrogen chloride (4 mL, 6N) was added at room temperature. The reaction mixture was stirred for 12 h at room temperature. The resulting mixture was diluted with water and adjusted to pH 8 with NaHCCh (aq.). The resulting mixture was extracted with EtOAc, washed with water and dried over anhydrous NtfeSCL. After filtration, the filtrate w'as concentrated under reduced pressure to afford crude 2-(3-methylquinolin-6-yl)acetaldehyde (1.5 g, 86.3%) as a white solid, that was used in the next step directly without further purification. LCMS Method A: [M+H]+= 186.1.

[0405] Step 3: l,l,l-trinuoro-3-(3-methylquinolin-6-yI)propan-2-ol

[0406] 2-(3-Methylquinolin-6-yl)acetaldehyde (1.5 g, 8.0 mmol, 1.0 equiv.) was dissolved in DMF (10 mL), TMSCF3 (2.3 g, 16.1 mmol, 2.0 equiv.) and K2CO3 (2.2 g, 16.1 mmol, 2.0 equiv.) were added at 0°C. The reaction mixture wras stirred for 1 h at 80°C, then cooled to room temperature and quenched by the addition of water. The resulting mixture was extracted with EtOAc, washed with water and dried over anhydrous NarSOi. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8; mobile phase, ACN in Water (0.1 % FA), 0% to 100% gradient in 15 min; detector, UV 254 nm. This resulted in l,l,l-trifluoro-3-(3- methylquinolin-6-yl)propan-2~ol (240 mg, 11.6%) as a white solid. LCMS Method A: [M+H]+= 256.1.

[0407] Step 4: 3-methyl-6-(3,3,3-trifluoro-2-hydroxypropyl)quinoline l-oxide l,l,l-Trifluoro-3-(3-methylquinolin-6-yl)propan-2-ol (240.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in DCM (8 mL), m-CPBA (412.8 mg, 1.8 mmol, 2.0 equiv.) wras added at room temperature. The reaction mixture was stirred for 2 h at room temperature and then quenched by the addition of aqueous NaOH (2N). The resulting mixture was extracted with EtOAc, washed with water and dried over anhydrous NaiSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (20: 1). This resulted in 3-methyl-6-(3,3,3-trifluoro-2-hydroxypropyl)quinoline 1 -oxide (100 mg, 39.2%) as a white solid. LCMS Method A: [M+H]+= 272.1 .

[0408] Intermediate 16. (3-chloro-6-(3-hydroxy-3-methyIbutyl)quinoIine 1-oxide) intermediate 16

[0409] Step 1: methyl (2E)-3-(3-chIoroquinoiin-6-yDprop-2-enoate

[0410] 6-Bromo-3 -chloroquinoline (1.0 g, 4.1 mmol, 1.0 equiv.) and methyl acrylate (0.5 g, 6. 1 mmol, 1 .5 equiv.) were dissolved in DMF (10 mL), then K2CO3 (1.1 g, 8,2 mmol, 2.0 equiv.) and Pd(PPh3)2Ch (0.2 g, 0.4 mmol, 0.1 equiv.) were added at room temperature under nitrogen atmosphere. ITe resulting mixture was stirred for 3 h at 100c,C, then cooled to room temperature and quenched by the addition of water. The resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous NivSOj. After filtration, tire filtrate was concentrated under reduced pressure. The residue was purified by’ silica gel column chromatography, eluting with petroleum ether / EtOAc (2: 1) to afford methyl (2E)-3-(3-chloroquinolin-6-yl)prop-2- enoate (700 mg, 68.5%) as a yellow solid. LCMS Method A: [M+H]]= 248.0.

[0411] Step 2: methyl 3-(3-chIoroquinoIin-6-y!)propanoate

[0412] Methyl (2E)-3-(3-chloroquinolin-6-yl)prop-2-enoate (200.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in EtOAc (15 mL), Raney Ni (60 mg) was added under nitrogen atmosphere. The m ixture was degassed and back filled wath hydrogen. The m ixture was hydrogenated at room temperature for overnight under hydrogen atmosphere using a hydrogen balloon. The resulting mixture was filtered through a Celite pad and the filtrate cake was washed with MeOH. 'the combined filtrate w'as concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C 18; mobile phase, MeCN in Water (0. 1% FA), 30% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in methyl 3-(3~ chloroquinolin-6-yl)propanoate (100 mg, 33.0%) as a yellow oil. LCMS Method A: i M H | 250.1.

[0413] Step 3: 4-(3-chIoroquim)Iin-6-yI)-2-methylbutan-2-o!

[0414] Methyl 3-(3-chloroquinolin-6-yl)propanoate (100.0 mg, 0.4 mmol, 1.0 equiv.) was dissolved in THF (5 mL), MeMgBr (3M in THF, 0.67 ml, 2.0 mmol, 5.0 equiv.) was added dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature and then quenched by the addition of NH4CI (aq.). The resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous NaiSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 20% to 40% gradient in 20 min; detector, UV 254 nm. This resulted in 4-(3- chloroquinolin-6-yl)-2-methylbutan-2-ol (90 mg, 89.9%) as a yellow' oil. LCMS Method A: [M+H]+= 250.1 .

[0415] Step 4: 3-chIoro-6-(3-hydroxy-3-methylbutyl)quinoIine 1-oxide

[0416] 4-(3-Chloroquinolin-6-yl)-2-methylbutan-2-ol (130.0 mg, 0.5 mmol, 1.0 equiv.) was dissolved in DCM (3 mL), then m-CPBA (317.0 mg, 1 .5 mmol, 3.0 equiv.) was added at room temperature. The resulting mixture was stirred for 2 h at room temperature and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous NazSCL. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-chloro-6-(3- hydroxy-3 -methylbutyl) quinolin-l-ium-l-olate (100 mg, 72.2%) as an orange solid. LCMS Method A: [M+H]+= 266.1.

[0417] Intermediate 17. (3-chloro-7-(trifluoromethoxy)quinoline 1-oxide)

[0418] Step 1: [2ramino-4-(triflnoromethoxy)phenyl] methanol

[0419] 2-Bromo-5-(trifluoromethoxy)aniline (6.0 g, 23.4 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (15 mL), then (tributylstannyl)methanol (11.3 g, 35.2 mmol, 1.5 equiv.). Butyl di-l-adamantylphosphine (2.1 g, 4.7 mmol, 0.2 equiv.) and (Chloro[(diadamantan- l-yl)(n-butyl)phosphino] [2-aminao- 1 , 1 -biphenyl-2- ylJpalladium(II) (782.8 mg, 0.15 equiv.) were added in portions under nitrogen atmosphere. The resulting mixture was stirred for overnight at 100°C, then cooled to room temperature and filtrated. The filter cake was washed with DCM and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (5: 1) to afford [2-amino-4-(trifluoromethoxy)phenyl]methanol (2.5 g, 51.50%) as a light yellow oil. LCMS Method A: [M+Hf = 208.1.

[0420] Step 2: 2-amino-4-(trifluoromethoxy)benzaldehyde

[0421] [2-Amino-4-(trifluoromethoxy)phenyl]methanol (1.0 g, 4.8 mmol, 1.0 equiv.) was dissolved in DCM (15 mL), then MnCh (4.2 g, 48.3 mmol, 10.0 equiv.) was added in portions at room temperature. The resulting mixture was stirred for overnight at room temperature. The resulting mixture was filtered and the filter cake was washed with DCM. The combined filtrate was concentrated under reduced pressure. Tire residue -was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (5: 1) to afford 2-amino-4-(trifluoromethoxy)benzaidehyde (1.0 g) as a white solid. LCMS Method A: [M+H]+= 206.0.

[0422] Step 3: 3~chloro-7-(trifluoromethoxy)quinoline

[0423] 2-Amino-4-(trifluoromethoxy)benzaldehyde (1.0 g, 4.9 mmol, 1.0 equiv.) and 2-chloro-l ,l-diethoxyethane (1 .5 g, 9.8 mmol, 2.0 equiv.) were dissolved in toluene (15 ml), then p-Toluenesulfonic acid (83.9 mg, 0.5 mmol, 0.1 equiv.) was added. The resulting mixture was stirred for overnight at 110°C, then cooled to room temperature and concentrated under vacuum. The residue was diluted with water, extracted with DCM, washed with brine and dried over anhydrous NhfeSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (5: 1) to afford 3-chloro-7- (trifluoromethoxy)quinoline (1 .5 g, cnide) as a white solid. LCMS Method A: [M+H] ' == 248.0.

[0424] Step 4: 3-chloro-7-(trifluoromethoxy)quinoline 1-oxide

[0425] 3-Chloro-7-(trifluoromethoxy)quinoline (1.5 g, 6.1 mmol, 1.0 equiv.) was dissolved in DCM (15 mL), then m-CPBA (2.1 g, 12.1 mmol, 2.0 equiv.) was added. Tire resulting mixture was stirred for overnight at room temperature and then quenched by the addition of sat. sodium sulfite (aq.) (30 mL) at 0°C. The resulting mixture was adjusted pH 8 with sat. sodium bicarbonate (aq.). The resulting solution was extracted with DCM, washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue -was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (5: 1) to afford 3-chloro- 7-(trifluoromethoxy)quinoline 1-oxide (500 mg, 31.31%) as a white solid. LCMS Method A: [M+H]+= 264.0.

[0426] Intermediate 18. (3-methyl-6-(l-(2,2,2-trifluoroethyl)-lH-pyrazoI-4-yI)quinoline 1-oxide) intermediate 13

[0427] Step 1: 3-methyl-6- [l-(2, 2, 2-trifluoroethyI)pyrazoI-4-yl] quinoline

[0428] 6-Bromo-3-methylquinoline (10.0 g, 45.0 mmol, 1.0 equiv.) and 4-(4, 4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 -(2,2,2-trifluoroethyl)pyrazoIe (12.4 g, 45.0 mmol, 1.0 equiv.) were dissolved in 1,4-dioxane (100 mL) and H2O (10 mL), then CS2CO3 (29.3 g, 90.0 mmol, 2.0 equiv.) and PdldppfjCh.ClLCh (3.6 g, 4.5 mmol, 0.1 equiv.) were added under nitrogen atmosphere. The reaction mixture was stirred for 3 h at 100°C, then cooled to room temperature and concentrated under vacuum. The residue was diluted with water, then extracted with EtOAc, washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (3: 1). This resulted in 3 -methyl -6- [1 -(2,2,2- trifluoroethyl)pyrazol-4-yl]quinoline (10.2 g, 77.7%) as a white solid. LCMS Method A: i M H | ' 292.1.

[0429] Step 2: 3-methyl-6-(l-(2,2,2-trifluoroethyI)-lH-pyrazoI-4-yl)quinoIine 1-oxide

[0430] 3-Methyl-6-[l-(2,2,2-trifluoroethyl)pyrazol-4-yl]quinoline (10.0 g, 34.3 mmol, 1.0 equiv.) was dissolved in DCM (25 mL), then m-CPBA (12.6 g, 51.4 mmol, 1.5 equiv.) was added at room temperature. The reaction mixture was stirred for 4 h at room temperature and then quenched by the addition of water. Hie resulting solution was adjusted to pH 8 with aqueous NaOH (2M). The resulting mixture was extracted with EtOAc, washed with water and dried over anhydrous Na2§04. After filtration, the filtrate was concentrated under reduced pressure. Tills resulted in 3 -methyl -6-(l -(2,2,2- trifluoroethyI)-lH-pyrazol-4-yI)quinoline 1-oxide (7.6 g, 72.0%) as a white solid. LCMS Method A: | M H i == 308.1.

[0431] "lire intermediate in Table 4 was prepared using the same method described for Intermediate 18.

[0432] Table 4 Intermediate 20. (7-fluoro-3-methyl-6-(l-(2,2,2-trifIuoroethyl)-lH-pyrazol-4- yl)quinoline 1-oxide)

[0433] Step 1: (2-amino-5-bromo-4-fluorophenyi)methanol

[0434] 2-Amino-5-bromo-4-fluorobenzoic acid (5.0 g, 21.4 mmol, 1.0 equiv.) was dissolved in THF (80 mL) and cooled to 0°C. ill L-XkoS (IM, 53.4 mL, 53.4 mmol, 2.5 equiv.) was added under nitrogen atmosphere. The reaction mixture was stirred for overnight at 65°C, then cooled to 0°C quenched by the addition of MeOH. Hie reaction was diluted water, then extracted with EtOAc, washed with brine and dried over anhydrous NazSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10: 1) to afford (2-amino-5-bromo-4-fluorophenyl)methanol (4.06 g, 43.18%) as a yellow solid. LCMS Method A: [M+H]+== 220.1.

[0435] Step 2: 2-amino-5-bromo-4-fluorobenzaldehyde

[0436] (2-Amino-5-bromo-4-fluorophenyI)methanol (3.0 g, 13.6 mmol, 1.0 equiv.) was dissolved in DCM (60 mL), MnOj (11.9 g, 136.3 mmol, 10.0 equiv.) was added. The reaction mixture was stirred for 4 h at room temperature under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with DCM. The combined filtrate was concentrated under reduced pressure. Hus resulted in 2-amino-5-bromo-4-fluorobenzaldehyde (2.6 g, 87.47%) as a yellow solid. LCMS Method A: [MH< == 218.0.

[0437] Step 3: 6-bromo-7-fluoro-3-methyi quinoline

[0438] 2-Ammo-5-bromo-4-fluorobenzaldehyde (3.3 g, 15.1 mmol, 1.0 equiv.) and propionaldehyde (1.8 g, 30.3 mmol, 2.0 equiv.) was dissolved in EtOH (50 mL) and cooled 0°C. Then KOH (0.25 g, 4.5 mmol, 0.3 equiv.) was added in portions under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 80°C, then cooled to room temperature and quenched by the addition of water. The resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous NaiSCE. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1 : 1) to afford 6-bromo-7-fluoro-3-methylquinoline (2.9 g, 79.81%) as a yellow solid. LCMS Method A: | M H i === 240.1.

[0439] Step 4: 7-fluoro-3-methyl-6-(l-(2,2,2-trifluoroethyI)-l / / -pyrazol-4-yi)quinoiine

[0440] 6-Bromo-7-fluoro-3-methylquinoline (2.0 g, 8.3 mmol, 1.0 equiv.) and 4- (4,4,5 ,5 -tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 -(2, 2, 2 -tri fluoroethyl)- 1 H-pyrazole (3.4 g, 12.4 mmol, 1.5 equiv.) were dissolved in 1,4-dioxane (20 mb) and H2O (2 mL), then Pd(dppf)C12.CH2C12 (0.6 g, 0.8 mmol, 0.1 equiv.) and CS2CO3 (5.4 g, 16.6 mmol, 2.0 equiv.) were added under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80°C, then cooled to room temperature and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1: 1) to afford 7-fhioro-3-methyl-6-(l-(2,2,2-trifluoroethyl)- 177-pyrazol-4-yl)quinoline (1.5 g, 58.2%) as a white solid, LCMS Method A: [M+H]+== 310.1.

[0441] Step 5: 7-fluoro-3-methyl-6-(l-(2,2,2-trifluoroethyl)-l / / -pyrazol-4-yi)quinoiine 1-oxide

[0442] 7-Fluoro-3-methyl-6-(l-(2,2,2-trifluoroethyi)-177-pyrazol-4-yi)quinolme (1.5 g, 4.8 mmol, 1,0 equiv.) was dissolved in DCM (15 mL), then m-CPBA (1,0 g, 5.8 mmol, 1.2 equiv.) was added. The reaction mixture was stirred for 2 h at room temperature and then quenched by the addition of water. The resulting mixture was adjusted to pH 8 with saturated NaHCCh (aq.). The resulting solution was extracted with DCM, washed with brine and dried over anhydrous NaaSCU. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 7-fluoro-3-methyl-6- (l-(2,2,2-trifluoroethyl)-17 / -pyrazol-4-yl)quinoline 1-oxide (1.2 g, 76.0%) as a brown solid. LCMS Method A: [M+H]+= 326.2. The intermediate in Table 5 was prepared using the same method described for Intermediate 20.

[0443] Table 5 Intermediate 22. (6-(4-((tert-butyldimethyIsilyl)oxy)cyclohexyl)-3- methylquinoline 1 -oxide) intermediate 22

[0444] Step 1 : 6-(4-((fert-buty IdimethyIsiIyl)oxy)cyclohex-l-en-l-yl)-3-methylquinoline

[0445] 6-Bromo-3-methylquinoline (3.0 g, 13.5 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (30 mL) and H2O (6 mL). then CS2CO3 (8802.5 mg, 27.0 mmol, 2.0 equiv.), tert-butyldimethyl{[4-(4,4,5,5-tetramethyl4,3,2-dioxaborolan-2-yl)cyclohex-3-en-l- yl]oxy}silane (4570.8 mg, 13.5 mmol, 1.0 equiv.) and Pd(dppf)Ch (988.4 mg, 1.3 mmol, 0.1 equiv.) were added under nitrogen atmosphere. The reaction mixture was stirred for 3 h at 90°C, then cooled to room temperature and quenched by the addition of water. The resulting solution was extracted with of EtOAc, -washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc / petroleum ether (1:3) to give 6-{4-[(tert- butyldimethylsilyl)oxy]cyclohex-l-en-l-yl}-3-methylquinoline (4.5 g, 94.2%) as a yellow solid. LCMS Method A: [ M i l l = 354.2. Step 2: 6-(4-((ten~butyidimethyIsiiyl)oxy)cycIohexyl)-3-methyIquinoline

[0446] 6-{4-[(terr-Butyldimethylsilyl)oxy]cyclohex-l -en-l -yl}-3-methylquinoline

[0447] (4.5 g, 12.7 mmol, 1.0 equiv.) was dissolved in MeOH (50 mL), Pd / C (900 mg, 10% wet) was added under nitrogen atmosphere. The mixture was degassed and back filled with hydrogen. The mixture was hydrogenated at room temperature for 2, h under hydrogen atmosphere using a hydrogen balloon. Hie resulting mixture was filtered through a Celite pad and the filtrate cake w'as washed with MeOH. The combined filtrate was concentrated under reduced pressure to afford 6-{4-[(tert- butyldimethylsilyl)oxy]cyclohexy]}-3-methylquinoline (4.0 g, 88.3%) as a yellow green oil. LCMS Method A: | M 1 1 i ' = 356.2.

[0448] Step 3: 6-(4-((terf-butyldimethyIsilyI)oxy)cyclohexyl)-3-methyIquinoline 1-oxide

[0449] 6-{4-[(terr-Butyldimethylsilyl)oxy]cyclohexyl}-3-methylquinoline (4.0 g, 11.2 mmol, 1.0 equiv.) was dissolved in DCM (50 mL), m-CPBA (4.5 g, 22.4 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 3 h at room temperature and then quenched by the addition of water. The resulting solution was adjusted to pH 8 with aqueous NaOH (2N). The resulting mixture was extracted with DCM, washed with water and dried over anhydrous NkoSOv After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10: 1) to afford 6-(4-((terr- butyldimethylsilyl)oxy)cyclohexyl)-3-methylquinoline 1-oxide (4.0 g, 95.6%) as a brown solid. LCMS Method A: | M H i == 372.2.

[0450] Intermediate 23. (3-methyl-6-(2-(2,2,2-trifluoroethyl)thiazol-4-yl)quinoline 1 oxide) Step 1 : 3-methyI-6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborohm-2-yl)quinofine

[0451] 6-Bromo-3 -methyl quinoline (5.0 g, 22.5 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (100 mL), then AcOK (4.42 g, 45.0 mmol, 2.0 equiv.), PdfdppflCh.CHzCh (1.8 g, 2.2 mmol, 0.1 equiv.) and bis(pinacolato) diboron (11.4 g, 45.0 mmol, 2.0 equiv.) were added under nitrogen atmosphere. The reaction mixture was stirred for 4 h at 100°C, then cooled to room temperature and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1:1) to afford 3-methyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline (5.0 g, 82.5%) as a yellow solid. LCMS Method A: [M+H]+= 270.2.

[0452] Step 2: l~(4-bromothiazol-2-yi)-2,2,2-trifluoroethan-l~ol

[0453] 4-Bromo-l,3-thiazole-2-carbaldehyde (2.0 g, 10.4 mmol, 1.0 equiv.) was dissolved in DME (20 mL), then trifluoromethyltrimethylsilane (1.4 g, 10.4 mmol, 1.0 equiv.) and CsF (1.5 g, 10.4 mmol, 1.0 equiv.) were added. Tire reaction mixture was stirred for 4 h at room temperature and then concentrated under reduced pressure. Tire residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, ACN in Water (0.1% FA), 10% to 100% gradient in 10 min; detector, UV 254 nm. This resulted in l-(4-bromothiazol-2-yl)- 2,2,2-trifluoroethan-l-oI (1.2 g, 43.9%) as a yellow solid. LCMS Method A: [M+H]+ :=:262.0.

[0454] Step 3: 2,2,2-trifluoro-l-(4~(3-methyIquinolin-6-yl)thiazol-2~yI)ethan~l-ol

[0455] 3-Methyl~6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (1.0 g, 3.7 mmol, 1 .0 equiv.) was dissolved in 1,4-dioxane (10 mL) and H2O (2 mL), then CS2CO3 (2.4 g, 7.4 mmol, 2.0 equiv.), PdfdppflCh.CHzCb. (0.3 g, 0.3 mmol, 0.1 equiv.) and 1- (4-bromo-l,3-thiazol-2-yl)-2,2,2-trifiuoroethanol (0.9 g, 3.7 mmol, 1.0 equiv.) were added under nitrogen atmosphere. The reaction mixture was stirred for 2 h at 90 °C, then cooled to room temperature and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous NacSCL. After filtration, the filtrate was concentrated under reduced pressure. Tire residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1: 1) to afford 2,2,2-trifluoro-l-[4-(3-methylquinolin-6-yl)-l,3-thiazol-2- yljethanol (1.0 g, 82.9%) as a yellow solid. LCMS Method A: [M+H]+= 325.1.

[0456] Step 4: 2,2,2-trifluoro-l-(4-(3-methylquinolin-6-yl)thiazoI-2-yl)ethyl m eth anesulf on ate

[0457] 2.2.2-Trifiuoro-l-[4-(3-methylquinolin-6-yl)-l,3-thiazol-2-yl]ethanol (1.0 g, 3.0 mmol, 1.0 equiv.) and TEA (0.6 g, 6.1 mmol, 2.0 equiv.) were dissolved in DCM (10 mL), then and methanesulfonic anhydride (0.8 g, 4.6 mmol, 1.5 equiv.) was added under nitrogen atmosphere. The reaction mixture was stirred for 2 h at room temperature and then quenched by the addition of water. The resulting mixture was extracted with DCM, washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 2,2,2- trifluoro-l -[4-(3 -methylquinolin-6-yl)-l,3-thiazol-2-yl]ethyl methanesulfonate (1 .2 g, 96.7%) as a yellow' solid. LCMS Method A: j M • H | ' - 403.0.

[0458] Step 5: 4-(3-methyIquinolin-6-yl)-2-(2,2,2-trifluoroethyl)thiazoIe

[0459] 2.2.2-Trifiuoro-l-[4-(3-methylquinolin-6-yl)-l,3-thiazol-2-yl]ethyl methanesulfonate (1.1 g, 2.7 mmol, 1.0 equiv.) was dissolved in MeOH (12 mL), Pd / C (220 mg, 20% wd) was added under nitrogen atmosphere. The mixture was degassed and back filled with hydrogen. The mixture was hydrogenated at room temperature for 2 h under hydrogen atmosphere using a hydrogen balloon. The resulting mixture was filtered through a Celite pad and the filtrate cake w'as washed with MeOH. The combined filtrate was concentrated under reduced pressure. This resulted in 3-methyl- 6-[2-(2,2,2-trifluoroethyl)-l ,3-thiazol-4- yl]quinohne (800.0 mg, 94.9%) as a yellow solid. LCMS Method A: | M H i ' == 309.1.

[0460] Step 6: 3-methyl-6-(2-(2,2,2-trifliioroethyl)thiazol-4-yI)quinoline 1-oxide

[0461] 3-Methyl-6-[2-(2,2,2-trifluoroethyl)-l,3-thiazol-4-yl]quinoline (800.0 mg, 2.5 mmol, 1.0 equiv.) was dissolved in DCM (10 mL), then m-CPBA (2.1 g, 10.3 mmol, 4.0 equiv.) was added. The reaction mixture was stirred for 2 h at room temperature and the quenched by the addition of water. Tire resulting mixture was adjusted to pH 8 with aqueous NaOH (2N). The solution was extracted with DCM, washed with brine and dried over anhydrous NasSOv After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10: 1) to afford 3-methyl-6-(2-(2,2,2-trifluoroethyl)thiazol- 4-yl)quinoline 1-oxide (300.0 mg, 35.6%) as a yellow solid. LCMS Method A: [M+H]+

[0462] = 325.1.

[0463] Intermediate 24. (3-methyI-6-(2-(2,2,2-trifluoro-l-hydroxyethyl)thiazoI-4- yDquinoline 1-oxide)

[0464] Step 1: 3-methyI-6-(2-(2,2,2-trifluoro-l-hydroxyethyl)thiazol-4-yl)quinoline 1- oxide

[0465] 2,2,2-Trifluoro-l -[4-(3-methylquinolm-6-yl)-l ,3-thiazol-2-yl]ethanol (900.0 mg, 2.7 mmol, 1.0 equiv.) was dissolved in DCM (15.0 mL), then m-CPBA (1126.7 mg, 5.5 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 2 h at 50°C, then cooled to room temperature and quenched by the addition of water. The resulting mixture was adjusted to pH 8 with aqueous NaOH (2N). The solution was extracted with DCM, washed with brine and dried over anhydrous NazSOv After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10: 1) to afford 3-methyl-6-(2- (2,2,2-trifluoro-l -hydroxy ethyl)thiazol-4-yl)quinoline 1-oxide (800.0 mg, 84.7%) as a yellow7solid. LCMS Method A: [M+H]+= 341.1 . Intermediate 25. (6-(4-hydroxy-2-methykyclohexyl)-3-methylquinoiine 1 -oxide)

[0466] Step 1: 9-methyl-l,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate

[0467] 7-Methyl-l,4-dioxaspiro[4.5]decan-8-one (5.0 g, 29.4 mmol, 1.0 equiv.) was dissolved in THF (15 mL) and cooed to -78°C. LiHMDS (IM in THF, 58.8 mL, 58.8 mmol, 2.0 equiv.) was added dropwise under nitrogen atmosphere. The reaction mixture w as stirred for 20 min at -78°C. That was followed by the addition of a solution of 1,1 ,1-trifluoro-jV-phenyl-A^rifluoromethanesulfonylmethanesulfonamide (21.0 g, 58.8 mmol, 2.0 equiv.) in THF (20 mL) dropwise. The resulting mixture was stirred for overnight at room temperature and quenched by the addition of ice-water. The resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous NaiSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 30% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in 9-methyl-l,4- dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (9.6 g, crude) as a yellow^ oil. I .(MS Method A: | M- H i ' 303.1.

[0468] Step 2: 3-methyl-6-(9-methyl-l,4-dioxaspiro[4.5]dec-7-en-8-yl)quinoline

[0469] 9-Methyl-l,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (1.5 g, 5.6 mmol, 1.0 equiv.) and 3-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinoline (1.7 g, 5.6 mmol, 1.0 equiv.) were dissolved in 1,4-dioxane (10 mL) and H2O (1 mL), CS2CO3 (860.0 mg, 1 1.2 mmol, 2.0 equiv.) and Pd(dppf)CI2 (415.2 mg, 0.6 mmol, 0. 1 equiv.) wrere added in portions under nitrogen atmosphere, lire reaction mixture was stirred for 2 h at 80°C, then cooled to room temperature and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous NaiSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue wras purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 40% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3-methyl-6-(9-methyl-l,4-dioxaspiro[4.5]dec-7-en-8-yl)quinoline (1.6 g, 96.31 %) as a yellow oil. LCMS Method A: [M+H]+= 296.1.

[0470] Step 3: 3-methyl-6~(7-methyi-l,4-dioxaspiro[4.5]decan-8-yi)quinofine

[0471] 3-Methyl-6-(9-methyl-l,4-dioxaspiro[4.5]dec-7-en-8-yl)quinoline (1.6 g, 0.1 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL), Pd / C (80.0 mg, 0.01 mmol, 0.3 equiv.) was added in portions at room temperature. The mixture was hydrogenated at room temperature for 24 h under hydrogen atmosphere using a hydrogen balloon. The resulting mixture was filtered through a Celite pad and the filtrate cake was washed with MeOH. The combined filtrated was concentrated under reduced pressure. This resulted in 3-methyl-6-(7-methyl-l,4-dioxaspiro[4.5]decan-8-yl)quinoline (500 mg, 31.2%) as a yellow oil. LCMS Method A: [M+H]+= 298.2.

[0472] Step 4: 3-methyl-4~(3-methyiquinofin-6-yi)cydo>hexan-l-one

[0473] 3-Methyl-6-(7-methyl-l,4-dioxaspiro[4.5]decan-8-yl)quinoline (500.0 mg, 1.7 mmol, 1.0 equiv.) was dissolved in THF (7.5 mL), cone. HC1 (2.5 mL) was added dropwise. The reaction mixture was stirred for 1 h at room temperature and then adjusted to pH 7 with saturated K2CO3 (aq.). The resulting solution was diluted with 50.0 mL of water, then extracted with EtOAc, washed with brine and dried over anhydrous NazSOr. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-methyl-4-(3-methylquinolin-6-yl)cyclohexan-l-one (370 mg, 86.87%) as a yellow oil. LCMS Method A: [M H | 254.0.

[0474] Step 5: 3-methyl-4-(3-methylquinoIin-6-yI)cyclohexan-l-ol

[0475] 3-Methyl-4-(3-methylquinolin-6-yl)cyclohexan-l-one (300.0 mg, 1.2 mmol, 1.0 equiv.) was dissolved in MeOH (5.0 mL), NaBHj (89.6 mg, 2.4 mmol, 2.0 equiv.) was added in portions at room temperature. Tire resulting mixture was stirred for 2 h at room temperature and then quenched by the addition of ice-water. The resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous NazSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10: 1) to afford 3-methyl-4-(3-methylquinolin-6-yl)cyclohexan-l-ol (110 mg, 36.38%) as a yellow oil . LCMS Method A: [M+H]+= 256.1 .

[0476] Step 6: 6-(4-hydroxy-2-methyIcydohexyl)-3-methyIquinoline 1-oxide

[0477] 3-Methyl-4-(3-methylquinolin-6-yl)cyclohexan-l-ol (110.0 mg, 0.4 mmol, 1.0 equiv.) was dissolved in DCM (5 mL), m-CPBA (148.7 mg, 0.9 mmol, 2.0 equiv.) was added in portions at room temperature. Tire reaction mixture was stirred for 2 h at room temperature and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine and concentrated under reduced pressure. The residue was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10: 1) to afford 6-(4-hydroxy-2-methylcyclohexyl)-3- methylquinoline 1-oxide (100 mg, 85.55%) as a yellow solid. LCMS Method A: [M+H]+= 272.0.

[0478] Intermediate 26. (3-methyl-6-((l-(trifluoromethyl)-lH-pyrazol-4- yl)oxy)quinoline 1-oxide)

[0479] Step 1: l-(trifluoromethyl)-lH-pyrazoI-4-oI

[0480] 4-(4,4,5,5-Tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 -(trifluoromethyl)- 1H- pyrazole (1.0 g, 3.8 mmol, 1.0 equiv.) was dissolved in THF (10 mL) and H2O (1 mL), NaBO3(0.93 g, 1 1 .4 mmol, 3.0 equiv.) was added. The resulting mixture was stirred for 2 h at room temperature and then quenched by the addition of wzater. Hie resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous NaiSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (30: 1) to afford 1 -(trifluoromethyl)- l / f-pyrazol-4-ol (600 mg, crude) as a yellow oil. LCMS Method A: [M+H]+= 153.0. Step 2: 3-methyl-6-((l-(trifluoromethyl)-127-pyrazol-4-yl)oxy)quinoline l-(Trifluoromethyl)-177-pyrazol-4-ol (400.0 mg, 2.6 mmol, 1.0 equiv.) and 6- bromo-3-methylquinoline (292.0 mg, 1.3 mmol, 0.5 equiv.) were dissolved in toluene (4 mL), then Rockphos (246.5 mg, 0.5 mmol, 0.2 equiv.), Rockphos Pd G< (220.5 mg, 0.26 mmol, 0.1 equiv.) and CS2CO3 (1713.9 mg, 5.2 mmol, 2.0 equiv.) were added under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100°C, then cooled to room temperature and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous NazSCfi. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 30% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3 -methyl -6-((l- (trifluoromethyl)-l / 7-pyrazol-4-yl)oxy)quinoline (250 mg, 32.4%) as a yellow solid. L( MS Method A: [M+H]+== 294.1.

[0481] Step 3: 3-methyl-6-((l-(trifluoromethyl)-lH-pyrazoI-4-yl)oxy)quinoline 1-oxide

[0482] 3-Methyl-6-((l -( trifluoromethyl)- l / / -pyrazol-4-yl)oxy)quinoline (250.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in DCM (5 mL), m-CPBA (294.2 mg, 1.7 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 2 h at room temperature and then quenched by the addition of -water. The resulting mixture -was adjusted to pH 8 with saturated NaHCOs (aq.). The resulting solution was extracted with DCM, washed with brine and dried over anhydrous NazSCh. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-methyl-6-((l-(trifluoromethyl)- l / 7-pyrazoI-4-yI)oxy)quinoline 1-oxide (300 mg, crude) as an orange solid. LCMS Method A: | M • H i == 310.0.

[0483] Intermediate 27. (6-(l-(3,3-difluorocydobutyl)-lH-pyrazol“4-yl)“3- methylquinoline 1-oxide) Step 1 : 3-(4-bromo-17?-pyrazol-l-yl) cyclobutan-l-one

[0484] 3-Bromocyclobutan-l-one (3,4 g, 22.5 mmol, 1.1 equiv.) and 4-bromo-lH- pyrazole (3.0 g, 20.4 mmol, 1.0 equiv.) were dissolved in ACN (10 mL), K2CO3 (5.6 g, 40.8 mmol, 2.0 equiv.) was added in portions at room temperature. The resulting mixture was stirred for 2 h at 80°C, then cooled to room temperature and quenched by the addition of water. The resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous NazSO-i. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 40% to 50% gradient in 10 min; detector, UV 254 nm. This resulted m 3-(4-bromo-lH-pyrazol-l-yI) cyclobutan-l-one (1.2 g, 27.34%) as a yellow solid. LCMS Method A: [M+H]+= 216.1.

[0485] Step 2: 4-bromo-l-(3,3-difluorocycIobutyl)-liy-pyrazoIe

[0486] 3-(4-Bromo-117-pyrazol-l-yl) cyclobutan-l-one (1.2 g, 5.6 mmol, 1.0 equiv.) was dissolved in DCM (10 mL) and cooled to 0°C, Then DAST (1.8 g, 1 1.2 mmol, 2.0 equiv.) was added dropwise. Hie resulting mixture was stirred for overnight at 50°C, then cooled to 0°C and quenched by the addition of ice-water. The resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous NarSOv After filtration, the filtrate was concentrated under reduced pressure. This resulted in 4- bromo-l-(3,3-difluorocycIobutyl)-lH-pyrazole (1.5 g, crude) as a yellow solid. LCMS Method A: | M H i 238.0.

[0487] Step 3: 6-(l-(3,3-difluorocyclobutyl)-l / T-pyrazol-4-yl)-3-methyIquinoline

[0488] 4-Bromo-l -(3, 3 -difluorocyclobutyl)- 1 / 7-pyrazole (400.0 mg, 1.7 mmol, 1.0 equiv.) and 3-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) quinoline (454.2 mg, 1.7 mmol, 1.0 equiv.) were dissolved in 1,4-dioxane (5 mL) and H2O (0.5 mL), Pd(dppf)Cb (123.5 mg, 0.2 mmol, 0.1 equiv.) and CS2CO3 (1099.6 mg, 3.4 mmol, 2.0 equiv.) were added at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80°C, then cooled to room temperature and quenched by the addition of water. The resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elutmg with petroleum ether / EtOAc (1: 1) to afford 6-(l-(3,3-difluorocyclobuty4)-lH- pyrazol-4-yl)-3-methylquinoline (200 mg, 39.60%) as a white solid. LCMS Method A: i \l l l | 300.0.

[0489] Step 4: 6-(l-(3,3-difIuorocyclobutyl)-lf?-pyrazoI-4-yI)-3-methylquinoIine 1-oxide

[0490] 6-(l-(3,3-Difluorocyclobutyl)-117-pyrazol-4-yl)-3-mediylquinoline (200.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in DCM (3 mL), m-CPBA (230.6 mg, 1.3 mmol, 2.0 equiv.) was added at room temperature. Hie resulting mixture was stirred for 1 h at room temperature and then quenched by the addition of water. The resulting mixture was adjusted to pH 8 with saturated aqueous NaOH (2N). The resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous NazSOv After filtration, the filtrate was concentrated under reduced pressure. This resulted in 6-(l- (3,3-difluorocyclobutyl)-lH-pyrazol-4-yl)-3-methylquinoline 1-oxide (200 mg, 94.9%) as a brown solid. LCMS Method A: [M+H]+= 316.1.

[0491] Intermediate 28. (6-(l-((3,3-difIuorocyclobutyl)methyl)-lH-pyrazol-3-yl)-3- methylquinoline 1-oxide) and Intermediate 29. (6-(l-((3,3- difluorocydobutyl)methyl)-lH-pyrazol-5-yl)-3-methylquiiioline 1-oxide)

[0492] Step 1: l-[(3,3-difluorocyclobutyI)methyI]-4-(4,4,5,5-tetramethyl-l,3,2- dioxaboro!an-2-yI)pyrazole and l-((3,3-difluorocyclobutyI)methyl)-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaboro!an-2-yI) -pyrazole

[0493] 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2Zf-pyrazole (2.0 g, 10.3 mmol, 1.0 equiv.) and (3, 3 -difluorocyclobutyl (methanol (2.5 g, 20.6 mmol, 2.0 equiv.) were dissolved in Toluene (8 mL), then CMBP (2.4 g, 10.3 mmol, 1 .0 equiv.) was added dropwise at room temperature under nitrogen atmosphere, Tire resulting mixture was stirred for overnight at 100°C, then cooled to room temperature and quenched by the addition of water. The resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous NazSOv After filtration, the filtrate was concentrated under reduced pressure. This resulted in a mixture of l-[(3,3-difluorocyclobutyI)methyl]-4- (4,4,5 ,5 -tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyrazole and 1 - [( 3 ,3 - difluorocyclobutyl)methyl]-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (15 g, 1 :8) as a brown crude oil. The crude product was used in the next step directly without further purification. LCMS Method A: [ M i l l = 299.1 .

[0494] Step 2: 6-(l-((3,3-difluorocyclobutyI)methyl)-lJf-pyrazol-3-yl)-3- methylquinoline and 6-(l-((3,3-difluorocyclobutyl)methyI)-llf-pyrazoi-5-yI)-3- m ethylquinoline

[0495] A mixture of l-[(3,3-difluorocyclobutyl)methyl]-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazole and 1 -[(3,3-difluorocyclobutyl)methyl]-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (12 g, 40.2 mmol, 15.3 equiv.) was dissolved in 1,4-dioxane (20 mL) and H2O (2 mL), 6-bromo-3 -methylquinoline (581.0 mg, 2.6 mmol, 1.0 equiv.), Pd^ppQCh.CHzCh (0.4 g, 0.5 mmol, 0.2 equiv.) and CS2CO3 (1 .7 g, 5.2 mmol, 2.0 equiv.) were added at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80°C, then cooled to room temperature and quenched by the addition of water. The resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous Na2SOd. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C 18; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in a mixture of 6-(l-((3,3-difluorocyclobutyl)methyl)-177-pyrazol-3-yl)-3- methylquinoline and 6-(l-((3,3-difluorocyclobutyl)methyl)-l / / -pyrazol-5-yl)-3- methylquinoline (1.5 g, 1:8) as a brown oil. LCMS Method A: [M+H]+= 314.1. Step 3: 6-(l-((3,3-difluorocyclobutyI)methyl)-lH-pyrazol-3-yl)-3- methyiqumoline-l-ium-l-olate and 6-(l-((3,3-difiuorocydobutyI)methyl)-lH- pyrazoI-5-yl)-3-methylquinoline-l-ium-l-o!ate

[0496] A mixture of 6-( 1 -((3 ,3 -difluorocyclobutyl)methyl)- lH-pyrazol-3 -yl)-3 - methylquinoline and 6-(l-((3,3-difluorocyclobutyl)methyl)-177-pyrazol-5-yl)-3- methylquinoline (450.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in DCM (5 mL), then m-CPBA (291.5 mg, 1.4 mmol, 1.0 equiv.) was added at room temperature. The resulting mixture was stirred for 3 h and then quenched by the addition of water. The resulting mixture was adjusted to pH 8 with aqueous NaOH (2N), then extracted with DCM, washed with brine and dried over anhydrous NazSCh. After filtration, the filtrate was concentrated under reduced pressure. This resulted in a mixture of 6-(l-((3,3- difluorocyclobutyl)methyl)- 17 / -pyrazol-3-yl)-3-methylquinoline- 1 -ium- 1 -olate and 6- ( 1 “((3 ,3 -difluorocyclobutyl (methyl)- 1 / 7-pyrazol -5 -yl)-3 -methylquinoline- 1 -ium- 1 - olate (450 mg, 1:8) as a yellow oil. LCMS Method A: [M+H]+= 329.2.

[0497] Intermediate 30. (3-methyI-6-(4,4,4-trifluoro-3-hydroxy-3- methylbutyl)quinoline 1-oxide)

[0498] Step 1: 4-(3-methylquinolin-6-yi)butan-2-one

[0499] 6-Bromo-3 -methylquinoline (1.0 g, 4.5 mmol, 1.0 equiv.) and 3-buten-2-ol (357.1 mg, 4.9 mmol, 1.1 equiv.) were dissolved in DMA (5 mL), then 2-(di-tert- butylphosphanyl)-l-phenylindole (91.1 mg, 0.2 mmol, 0.06 equiv.), JV-cyclohexyl-A- methylcyclohexanamine (1.7 g, 8.7 mmol, 2.0 equiv.) and Pd(OAc)2 (20.2 mg, 0.09 mmol, 0.02 equiv.) were added under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 100°C, then cooled to room temperature and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous NazSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1 :2) to afford 4-(3-methylquinolin-6-yl)butan-2-one (0.9 g, 93.7%) as a yellow solid. LCMS Method A: i .M H | = 214.1.

[0500] Step 2: l,l,l-tr’fIuoro-2-methyI-4-(3-methylquinolin-6-yI)butan-2-oI

[0501] 4-(3-Methylquinolin-6-yl)butan-2-one (300.0 mg, 1.4 mmol, 1.0 equiv.) and trifluoromethyltrimethylsilane (400.0 mg, 2.8 mmol, 2.0 equiv.) were dissolved in DMF (6 ml) and cooled to 0°C, then K2CO3 (388.8 mg, 2.8 mmol, 2.0 equiv.) was added under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at 80°C, then cooled to room temperature and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous Na?.SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in aq. HC1 (4N) and stirred for 0.5 h at room temperature. The resulting mixture was diluted with water, then extracted with EtOAc, washed with brine and dried over anhydrous NazSOr. After filtration, the filtrate was concentrated under reduced pressure. Tills resulted in l,l,l-trifiuoro-2-methyl-4-(3-methylquinolin-6- yl)butan-2-ol (300 mg, 60.2%) as a yellow solid. The crude product was used in the next step directly without further purification. LCMS Method A: [M+H]+= 284.0.

[0502] Step 3: 3-methyl-6-(4,4,4-trifluorO“3~hydroxy-3~methylbutyl)quirioHne 1-oxide l,l,l-Trifluoro-2-methyl-4-(3-methylquinolin-6-yI)butan-2-ol (280.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in DCM ( 10 mL), then m-CPBA (364.2 mg, 1 .8 mmol, 2.0 equiv.) was added in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature and quenched by the addition of water. The resulting solution was extracted with DCM, washed with brine and dried over anhydrous Na?.SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-methyl-6-(4,4,4-trifiuoro-3-hydroxy-3-methylbuty4)quinoline 1-oxide (230 mg, 54.4%) as a brown solid. The crude product was used in the next step directly without further purification. LCMS Method A: [M+H]+= 300. 1. Intermediate 31. (3-methyI~6-(3,3,3"triflimro-2-hydroxy-2- methyipropoxy)quinoline 1-oxide)

[0503] Intermediate 31

[0504] Step 1: 3-methylquinolm-6-ol

[0505] 3-Methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)qainoline (3.5 g, 13.0 mmol, 1.0 equiv.) was dissolved in THF (35 mL) and H2O (4 mL), sodium perborate (2.1 g, 26.0 mmol, 2.0 equiv.) was added in portions at 0°C. The resulting mixture was stirred for 2 h at room temperature and then quenched by the addition of water. Hie resulting mixture was extracted with EtOAc, washed with water and dried over anhydrous NaiSOv After filtration, the filtrate wzas concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1: 1) to afford 3-methylquinolin-6-ol (2 g, 96.6%) as a yellow' solid. I. CMS Method A: | M 1 1 i 160.0.

[0506] Step 2: l-[(3-methylquinolin-6-yl)oxy]propan-2-one

[0507] 3-Methylquinolin-6-ol (300.0 mg, 1.8 mmol, 1.0 equiv.) was dissolved in ACN (10 mL), then K2CO3 (520.9 mg, 3.7 mmol, 2.0 equiv.), bromoacetone (387.2 mg, 2.8 mmol, 1.5 equiv.) were added at 0°C. The resulting mixture was stirred for overnight at 80°C, then cooled to room temperature and concentrated under vacuum. The residue was diluted with water, then extracted with EtOAc, washed with brine and dried over anhydrous NazSOv After filtration, the filtrate was concentrated under reduced pressure to afford crude l-[(3-methylquinolin-6-yl)oxy]propan-2-one (400 mg, 98.6%) as a brown solid. The crude product was used in the next step directly without further purification. LCMS Method A: [M+H]+= 216.1.

[0508] Step 3: l,l,l-trifluoro-2-methyI-3-[(3-methyIquinoIin-6-yI)oxy]propan-2-ol l-[(3-Methylquinohn-6-yl)oxy]propan-2-one (380.0 mg, 1.7 mmol, 1.0 equiv.) and trifluoromethyltrimethylsiiane (753.0 mg, 5.2 mmol, 3.0 equiv.) were dissolved in ACN (10 mL), then K2CO3 (488.0 mg, 3.5 mmol, 2.0 equiv.) was added at 0°C. The resulting mixture was stirred for 2 h at 80°C, then cooled to room temperature and concentrated under vacuum. The residue was diluted with water, then extracted with EtOAc, washed with brine and dried over anhydrous NaaSO*. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1: 1) to afford 1,1,1- trifluoro-2-methyl-3-[(3-methylquinolin-6-yl)oxy]propan-2-ol (300 mg, crude) as a yellow solid. LCMS Method A: [M+Hf = 286.1.

[0509] Step 4: 3-methyI-6-(3,3,3-trifhwro-2-hydroxy-2-methyIpropoxy)quinoIine 1- oxide

[0510] 1 ,1 ,l-Trifluoro-2-methyl-3-[(3-methylquinolin-6-yl)oxy]propan-2-ol (280.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in DCM (10 mL), m-CPBA (364.2 mg, 1.8 mmol, 2.0 equiv.) was added at room temperature. The mixture was stirred for 2 h at room temperature and then quenched by the addition of w ater. The resulting mixture was adjusted to pH 8 with aqueous NaOH (2N). The resulting solution was extracted with DCM, washed with brine and dried over anhydrous NazSOr. After filtration, the filtrate w?as concentrated under reduced pressure. This resulted in 3-methyl-6-(3,3,3- trifluoro-2-hydroxy-2-methylpropoxy)quinoline 1 -oxide (300 mg, 71.0%) as a brown oil. LCMS Method A: [M+H]+302.2.

[0511] Intermediate 32. (6-(3-hydroxy-3-methyIbutoxy)-3-methylquinoIine 1-oxide)

[0512] Step 1 : 2-methyl-4- |(3-methylquinoIin-6-yl)oxy]butan-2-oI

[0513] 3-MethyIquinolin-6-ol (300.0 mg, 1.8 mmol, 1.0 equiv.) and 4-bromo-2- methylbutan-2-ol (472.2 mg, 2.8 mmol, 1.5 equiv.) were dissolved in DMF (5 mL), CS2CO3 (1.2 g, 3.7 mmol, 2.0 equiv.) was added. The resulting mixture was stirred for 1 h at room temperature and then quenched by the addition of water. Tire resulting solution mixture was extracted with EtOAc, washed with brine and dried over anhydrous NazSOr. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 2-methyl-4-[(3-methylquinolin-6-yl)oxy]butan-2-ol (400 mg, 86.5%) as a yellow oil. LCMS Method A: [M+H]+= 246.1.

[0514] Step 2: 6-(3-hydroxy-3-methyIbutoxy)-3-methyIquinoIine 1-oxide

[0515] 2-Methyl-4-|(3-methylquinolin-6-yl)oxy]butan-2-oI (400.0 mg, 1.6 mmol, 1.0 equiv.) was dissolved in DCM (5 mL), m-CPBA (331.0 mg, 1.6 mmol, 1.0 equiv.) was added at room temperature. The resulting mixture was stirred for 1 h at room temperature and then quenched by the addition of water. The resulting mixture was adjusted to pH 8 with aqueous NaOH (2N). The resulting solution was extracted with DCM, washed with brine and dried over anhydrous NazSOr. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 6-(3 -hydroxy-3 - methylbutoxy) -3 -methylquinoline 1-oxide (395.6 mg, 93.8%) as an orange solid. LCMS Method A: [M+ 11 f = 262.0.

[0516] Intermediate 33. (6-(4-((3,3-difluorocyclobutyl)methyl)-lH-imidazol-l-yl)-3- methylquinoline 1-oxide)

[0517] Intermediate 33

[0518] Step 1 : 2-(3,3-difIuorocycIobutyI)-Ar-methoxy-Ar-methylacetamide

[0519] (3,3-Difluorocyclobutyl)acetic acid (4.0 g, 26.6 mmol, 1.0 equiv.), N,O- dimethylhydroxylamine (2.44 g, 39.9 mmol, 1.5 equiv.) were dissolved in DCM (80 mL), HATU (15.2 g, 39.9 mmol, 1.5 equiv.), DIEA (6.89 g, 53.2 mmol, 2.0 equiv.) were added. The resulting mixture was stirred for overnight at room temperature and then quenched by the addition of water. The resulting mixture was extracted with DCM, w’ashed with brine and dried over anhydrous NazSCL. After filtration, the filtrate wras concentrated under reduced pressure. The residue -was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (lOmmol / L NH4HCO3), 0% to 100% gradient in 15 min; detector, UV 254 nm. This resulted in 2-(3,3-difluorocyclobutyl)- / V-methoxy-A-methylacetamide (4.7 g, 91.3%) as a light yellow oil. LCMS Method A: [ M + H i == 194.0.

[0520] Step 2: 2-(3,3-difIuorocydobutyl)aceta!dehyde

[0521] 2-(3,3-Difluorocyclobutyl)-Ar-methoxy-JV-methylacetamide (3.0 g, 15.5 mmol, 1.0 equiv.) was dissolved in THF (60 mL) and cooled to -65°C. Red-Al (7.54 mL, 26.3 mmol, 1.7 equiv, 70%) was added dropwise at -65 °C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at -65 °C and then quenched by the addition of NazSCh.lOEhO. The resulting mixture was filtered and the filter cake was washed with THF. The combined filtrate was dried over anhydrous NaiSCh. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 2-(3,3- difluorocyclobutyl)acetaldehyde (2.8 g, crude) as a light yellow' oil. LCMS Method A: i M H | 135.0.

[0522] Step 3: 4-|(3,3-difluorocyclobutyI)methylJ-l / Z-imidazole

[0523] 2-(3,3-Difluorocyclobutyl)acetaldehyde (2.8 g, 20.8 mmol, 1.0 equiv.) was dissolved in MeOH (28 mL), TosMIC (6.1 g, 31.3 mmol, 1.5 equiv.) was added. The resulting mixture was stirred for 15 min at room temperature, then NFLlg) in MeOH (112.0 mL, 784.1 mmol, 37.5 equiv., 7N) was added dropwise. The resulting mixture was stirred for overnight at 80°C, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (lOmmol / L NH4HCO3), 10% to 50% gradient in 15 min; detector, UV 254 nm. This resulted in 4-[(3,3-difluorocyclobutyl)methyl]-12 / -imidazole (800 mg, 15.5%) as a light yellow7solid. Method A: [M+H]+= 173.0.

[0524] Step 4: 6-(4-((3,3-difluorocyclobutyl)methyl)-liy-imidazol-l-yl)-3- methylquinoline 1 -oxide

[0525] 4-[(3,3-Difiuorocyclobutyl)methyl]-lH-imidazole (650.0 mg, 3.7 mmol, 1.0 equiv.) and 6-bromo-3-methylquinoline 1 -oxide (898.8 mg, 3.7 mmol, 1.0 equiv.) were dissolved in 1,4-dioxane (8 mL), CS2CO3 (2.5 g, 7.5 mmol, 2.0 equiv.), EPhos (403.8 mg, 0.7 mmol, 0.2 equiv.) and EPhos Pd G4 (346.7 mg, 0.4 mmol, 0.1 equiv.) were added at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 100°C, then cooled to room temperature and quenched by the addition of water. The resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous NaiSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 10 min; detector, UV 254 nm. This resulted in 6-(4-((3,3- difluorocyclobutyl)methyl)-177-imidazol-l-yl)-3-methylquinoline 1 -oxide (280 mg, 22.5%) as a yellow solid. LCMS Method A: [M- H | = 330.1.

[0526] Intermediate 34. (6-(4-(l-hydroxyethyI)cyclohexyl)-3-methylquinoline 1-oxide)

[0527] Step 1 : ethyl 4-(3-methyIquinoIm~6-yl)cyclohex-3-ene-l-carboxyiate

[0528] 6-Bromo-3 -methyl quinoline (100.0 g, 450.3 mmol, 1 .0 equiv.) was dissolved in 1,4-dioxane (1 L) and FLO (200 mL), ethyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)cyclohex-3-ene-l -carboxylate (151.4 g, 540.3 mmol, 1.2 equiv.) and PdCI2(DTBPF) (29.4 g, 45.0 mmol, 0.1 equiv.) were added under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere and quenched by the addition of water, lire resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous Na^SCfi. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (5: 1) to afford ethyl 4- (3-methylquinolin-6-yl)cyclohex-3-ene-l-carboxylate (100 g, 75.19%) as an off-white solid. [M+HJ4= 296.1.

[0529] Step 2: ethyl 4-(3-methyIquinolin-6-yl) cyclohexane-l-carboxylate

[0530] Ethyl 4-(3-methylquinolm-6-yl) cyclohex-3-ene-l-carboxylate (31.0 g, 105.0 mmol, 1.0 equiv.) was dissolved in MeOH (400 mL), Pd / C (10%, 10.0 g) was added under nitrogen atmosphere. Tire mixture was hydrogenated at room temperature for 6 h under hydrogen atmosphere using a hydrogen balloon. The resulting mixture was filtered, then the filter cake was washed with MeOH. The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1 : 1) to afford ethyl 4-(3- methylquinolin-6-yl) cyclohexane -1 -carboxylate (30.5 g) as a colorless oil. LCMS Method A: [M+H]+= 298.1.

[0531] Step 3: (4-(3-m ethyl quinoIin-6-yl) cyclohexyl) methanol

[0532] Ethyl 4-(3-methylquinolin-6-yl) cyclohexane- 1 -carboxylate (30.0 g, 101.0 mmol, 1.0 equiv.) was dissolved in THF (300 mL) and cooled to 0°C, LAH (6.4 g, 168.1 mmol, 1.7 equiv.) was added at 0°C in batches under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 0°C and then quenched by the addition of Na2SO4-10H2O at 0°C. The resulting mixture was filtered, then the filter cake was washed -with EtOAc. The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1: 1) to afford (4-(3-methyIquinolin-6-yl) cyclohexyl) methanol (15.7 g, 67.7% over two steps) as a colorless oil. LCMS Method A: [M+H]+= 256.0.

[0533] Step 4: 4-(3-methylquinoIin-6-yI) cyclohexane-l-carbaldehyde

[0534] (4-(3-Methylquinolin-6-yl) cyclohexyl) methanol (5.2 g, 20.5 mmol, 1.0 equiv.) was dissolved in DCM (50 mL), IBX (23.0 g, 82.1 mmol, 4.0 equiv.) was added at room temperature. The resulting mixture was stirred for 16 h at 50°C, then cooled to room temperature and filtered through a Celite pad. The filter cake was washed with DCM and the combined filtrate was concentrated under reduced pressure. This resulted in 4- (3-methylquinolin-6-yl)cyclohex-3-ene-l-carbaldehyde (4.9 g, 94.2%) as a yellow oil. LCMS Method A: | M- H ]+= 252.0.

[0535] Step 5: l-(4-(3-methy!quinolin-6-yI) cyclohexyl) ethan-l-ol

[0536] 4-(3-Methylquinolin-6-yl) cyclohexane-l-carbaldehyde (6.4 g, 25.3 mmol, 1.0 equiv.) was dissolved in THF (80 mL) and cooled to 0°C, CH-jMgBr (3M in Et2O, 16.8 mL, 50.4 mmol, 2.0 equiv.) was added dropwise under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 0°C, and quenched by the addition of sat, NH4CI (aq.). The resulting solution was extracted with EtOAc, washed wuth brine and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1 : 1) to afford l-(4-(3- methylquinolin-6-yl) cyclohexyl) ethan-l-ol (1.5 g, 22.04%) as a white solid. LCMS Method A: | M H i 270.0.

[0537] Step 6: 6-(4-(l-hydroxyethyi) cyclohexyl)-3-methylquinoline 1-oxide l-(4-(3-Methylquinolin-6-yl) cyclohexyl) ethan-l-ol (1.5 g, 5.6 mmol, 1.0 equiv.) was dissolved in DCM (20 mb), m-CPBA (1.9 g, 1 1.1 mmol, 2.0 equiv.) was added, Tire reaction mixture was stirred for 2 h at room temperature and quenched by the addition of water. The resulting mixture was adjusted to pH 8 with aqueous NaOH, then extracted with EtOAc, washed with brine and dried over anhydrous NaiSOi. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 6-(4-(l- hydroxyethyl) cyclohexyl)-3-methylquinoline 1 -oxide (1.5 g, 94,39%) as a brown oil . LCMS Method A: | M H i ' == 286.1. == 432. 1 .

[0538] Intermediate 35. (3-methyl-6-(4-(2,2,2-trifluoro-l-hydroxyethyI)cyclohex-l-en- l-yl)quinoline 1-oxide)

[0539] Step 1 : 2,2,2-trifinoro-l-[4-(3-methyIquinofin-6~yl)cydohex-3~en-l-yI]ethanol

[0540] 4~(3-Methylquinolin-6-yl)cyclohex-3-ene-l-carbaldehyde (4.9 g, 19.4 mmol, 1.0 equiv.) and TMSCF3 (5.5 g, 38.9 mmol, 2.0 equiv.) were dissolved in DME (50 ml), CsF (11.8 g, 77.9 mmol, 4.0 equiv.) was added in portions at 0°C. The resulting mixture was stirred for 4 h at room temperature and the quenched by the addition of water, Tire resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous Na2§04. After filtration, the filtrate was concentrated under reduced pressure. The residue w'as shiny' in MeOH and the solid w'as collected by filtration. This resulted in 2,2,2-trifluoro-l -[4-(3-methylquinolin-6-yl)cyclohex-3-en-l -yl]ethanol (3 g. 47.8%) as a white solid. LCMS Method A: i M H i == 322.1.

[0541] Step 2: 3-methyl-6-(4-(2,2,2-trifluoro-l-hydroxyethyl)cyclohex-l-en-l- yl)quinoline 1-oxide

[0542] 2,2,2-Triliuoro- 1 -[4-(3 -methylquinolin-6-yl)cyclohex-3 ~en~ 1 -yl]ethanol (500.0 mg, 1.5 mmol, 1.0 equiv.) was dissolved in DCM (10 mL), m-CPBA (402.8 mg, 2.3 mmol, 1.5 equiv.) was added in portions at room temperature. Hie resulting mixture was stirred for 16 h at room temperature and then quenched by the addition of water. The resulting mixture was adjusted to pH 8 with aqueous NaOH (2N). The resulting solution was extracted with DCM, washed with brine and dried over anhydrous NazSO-u After filtration, the filtrate was concentrated under reduced pressure. The residue w'as purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 10 min; detector, UV 254 nm. This resulted in 3-methyl-6-[4-(2,2,2- trifluoro- l-hydroxyethyl)cyclohex- 1 -en-1 -yl] quinolin- 1 -ium- 1-olate (270 mg, 51.4%) as a yellow solid. LCMS Method A: [ M + 1 l | == 338.2.

[0543] Intermediate 36. (3-methyl-6-(l,l,l-trifluoro-2-hydroxypropan-2-yI)quinoline 1- oxide)

[0544] Step 1: l-(3-methyIquinoIin-6-yl)ethanone

[0545] 6-Bromo-3 -methylquinoline (1.0 g, 4.5 mmol, 1.0 equiv) and tributyl(l- ethoxyethenyl)stannane (487.8 mg, 1.4 mmol, 1.5 equiv.) were dissolved in 1,4- dioxane (10 mL), then Pd(PPli3)4 (0.5 g, 0.4 mmol, 0.1 equiv.) was added under nitrogen atmosphere. Tire resulting mixture was stirred for 16 h at 100°C and then cooled to room temperature. The resulting mixture was adjusted to pH 5 with HQ (gas) in 1,4- dioxane (4M). The resulting mixture was stirred for additional 0.5 h at room temperature and diluted with water. Tire resulting solution was adjusted to pH 8 with saturated NaiCCL (aq.). The resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous NarSOi. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1 : 1) to afford l-(3-methylquinolin-6-yl)ethanone (1.15 g, crude) as a yellow solid. LCMS Method A: i M H | 186.1.

[0546] Step 2: 144Arinuoro-2-(3-methyIquinolin-6-yl)propan-2~oI l-(3-Methylquinolin-6-yl)ethanone (1.1 g, 5.9 mmol, 1.0 equiv.) and TMSCFj (2.3 g, 17.8 mmol, 3.0 equiv.) were dissolved in DMF (20 mL), then K2CO3 (1.6 g, 1 1 .8 mmol, 2.0 equiv.) was added in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature and then quenched by the addition of water. The resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous NazSOr. After filtration, tire filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1 : 1 ) to afford 1,1 , l-trifluoro-2-(3-methylquinolin- 6-yl)propan-2-ol (1.0 g, 65.9%) as a brown solid. LCMS Method A: 1 M H i ' 256.1.

[0547] Step 3: 3-methyl-6-(l,l,l-trifluoro-2-hydroxypropan-2-yI)quinoIine 1-oxide l,l,l-Trifiuoro-2-(3-methylquinolin-6-yl)propan-2-ol (1.0 g, 3.9 mmol, 1.0 equiv.) w'as dissolved in DCM (20 mL), then m-CPBA (1.1 g, 5.8 mmol, 1.5 equiv.) was added in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature under air atmosphere and then quenched by the addition of aqueous NaOH (2N). The resulting mixture was extracted with DCM, washed with brine and dried over anhydrous NazSOr. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-methyl-6-( 1,1,1 -trifluoro-2-hydroxypropan-2- yllquinoline 1-oxide (950 mg, 89.4%) as a brown solid. The crude product was used in the next step directly without further purification. LCMS Method A: [M+H]+= 272.2. Intermediate 37. (6-bromo-N-(3-chloro-l H-mdoL6-yI)-3-methylquinoIin~2- amine)

[0548] Step 1: 6-bromo>-3-methylquinolin-l-ium-l-olate

[0549] 6-Bromo-3-methylquinoline (5.0 g, 22.5 mmol, 1.0 equiv.) was dissolved in DCM (80 mL), m-CPBA (5.8 g, 33.7 mmol, 1.5 equiv.) was added at room temperature. The resulting mixture was stirred for 3 h at room temperature and then quenched by the addition of water. The resulting mixture was adjusted to pH 8 with aqueous NaOH (2N). The resulting solution was extracted with DCM, washed with brine and dried over anhydrous NaiSOv After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10: 1) to afford 6-bromo-3-methylquinolin-l-ium-l-olate (4.8 g, 89.5%) as a brown solid. LCMS Method A: [ M- + 1 1 |=197.1.

[0550] Step 2: 6-bromo-A?'-(3-chloro-l / ir“indol-6-yI)-3-methylquinoIin"2-amine

[0551] 3-Chloro-6-isothiocyanato-12 / -indole (550 mg, 2.6 mmol, 1.0 equiv.) and 6- bromo-3 -methylquinolin- 1-ium-l-olate (627.5 mg, 2.6 mmol, 1.0 equiv.) were dissolve in DMF (10 mL), then AgBFi (1.0 g, 5.2 mmol, 2.0 equiv.) was added at room temperature. The reaction mixture was stirred for 4 h at room temperature and then quenched by the addition of water. Tire resulting mixture was extracted with EtOAc, washed with water and dried over anhydrous NazSOi. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1: 1). This resulted in 6-bromo- jV-(3-chloro-lH-indol-6-yl)-3-methyiquinolin-2-amine (450 mg, 44.1%) as a white solid. LCMS Method A: [M+H]+= 386.2.

[0552] The intermediate in Table 6 was prepared using the same method described for Intermediate 37.

[0553] Table 6

[0554] Intermediate 39. (2-chloro-6-(4-(cyclobutyImethyl)-lH-imidazol-l-yI)quinoline)

[0555] Step 1: l-(quinolin-6-yl)imidazo>le-4-carbaldehyde l / / -imidazole-4-carbaldehyde (5.5 g, 23.5 mmol, 1.5 equiv.) and 6- iodoquinoline (8.0 g, 15.6 mmol, 1.0 equiv.) were dissolved in DMF (80 mL), K3PO4 (3.2 g, 7.8 mmol, 0.5 equiv.), Cui (3.0 g, 7.8 mmol, 0.5 equiv.) and (1S,2S)-NI, N?- dimethylcyclohexane-l,2-diamine (2.2 g, 7.8 mmol, 0.5 equiv.) were added under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 150°C, then cooled to room temperature and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous NaiSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1:9) to afford l-(quinolin-6-yl)imidazole-4-carbaldehyde (5 g, 71.4%) as an off-white solid. LCMS Method A: | M I I F == 224.1.

[0556] Step 2: cydobutyl[l-(quinoIin-6-yl)imidazol-4-yl]methanoI l-(Quinolin-6-yl)imidazole-4-carbaldehyde (5.0 g, 6.7 mmol, 1.0 equiv.) was dissolved in THF (50 mL), bromo(cyclobutyl)magnesium (0.37 mol / L in THF, 180 mL, 67.1 mmol, 10.0 equiv.) was added dropwise at -5°C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at -5°C and then quenched by the addition of sat. NH4CI aqueous. The resulting mixture was extracted with DCM, washed with brine and dried over anhydrous NazSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (20: 1) to afford cyclobutyl [l-(quinolin-6-yl)imidazol -4- yljmethanol (3 g, 47.9%) as an off-white solid. LCMS Method A: [M+H]+= 280.0.

[0557] Step 3: 6-[4-(cyclobutyIidenemethyI)imidazol-l-yI]quinoline

[0558] Cyclobutyl [l-(quinolin-6-yl)imidazol-4-yl]methanol (3.0 g, 10.7 mmol, 1.0 equiv.) was dissolved in DMF (40 ml) and cooled to 0°C. POCh (8.2 g, 53.6 mmol, 5.0 equiv.) was added dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100°C, then cooled to room temperature and quenched by the addition of ice-water. The resulting mixture was adjusted to pH 8 with aqueous NaOH (2N). The resulting solution was extracted with DCM, washed with brine and dried over anhydrous N%SO.:. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (20: 1 ) to afford 6-[4-(cyclobutylidenemethyl)imidazol-l- yl]quinoline (2 g, 71.2%) as an off-white solid. LCMS Method A: [M + H]+ := 262.1.

[0559] Step 4: 6- [4-(cydobutylmethyI)imidazol-l-yI] quinoline

[0560] 6-[4-(Cyclobutylidenemethyl) imidazol-l-yl] quinoline (2.0 g, 7.6 mmol, 1.0 equiv.) was dissolved in MeOH (20 mL), Pd(OH)2 / C (100 mg, 10%wt) wzas added under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 2 h under hydrogen atmosphere using a hydrogen balloon. Tire resulting mixture was filtered through a Celite pad and the combined filtrated v, as concentrated under reduced pressure. This resulted in 6-[4-(cyclobutyImethyl) imidazol-l-yljquinoline (1.2 g, 59.5%) as a yellow solid. LCMS Method A: [M+H]+= 264.2.

[0561] Step 5: 6-(4-(cyclobutyImethyI)-l£T-imidazoI-l-yI)quinoline 1-oxide

[0562] 6-[4-(Cyclobutylmethyl) imidazol-l-yl] quinoline (1.2 g, 4.5 mmol, 1.0 equiv.) was dissolved in DCM (12 mL), m-CPBA (1.1 g, 6.8 mmol, 1.5 equiv.) was added at room temperature. The resulting mixture was stirred for 2 h at room temperature and then quenched by the addition of water. The resulting mixture was adjusted to pH 8 with aqueous NaOH (2N). The resulting solution was extracted with DCM, washed with brine and dried over anhydrous NaiSOi. After filtration, the flitrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10: 1) to afford 6-(4- (cyclobutylmethyl)-177-imidazol-l-yl)quinoline 1 -oxide (400 mg, 32.5%) as an off- white solid. LC MS Method A: [M+H]+== 280.0.

[0563] Step 6: 2-chloro-6-[4-(cyclobutylmethyl)imidazoI-l-yl] quinoline

[0564] 6-(4-(Cyclobutylmethyl)-177-imidazol-l-yl)quinoline 1 -oxide (400.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in DMF (4 mL), POCh (439.1 mg, 2.8 mmol, 2.0 equiv.) was added dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature and quenched by the addition of sat. NaHCO-j (aq.) at 0°C. The resulting mixture was diluted with water, then extracted with EtOAc, washed with brine and dried over anhydrous NaiSCfi. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8; mobile phase, MeCN in Water (0.1% FA), 10% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in 2-chloro-6-[4-(cyclobutylmethyI)imidazol-l-yI]quinoline (130 mg, 30.4%) as a yellow solid. LCMS Method A: [M+H]+= 298.0.

[0565] Example 1. 4-(2-((3-fIuoro-lf?-mdoI-6-yI)amino)-3-methylquinolin-6-yI)-2- methyIbiitan-2-oI (Compound 1)

[0566] Step 1: 6-(3-hydroxy-3-methyIbutyl)-3-methylquinoline 1-oxide

[0567] 2-Methyl-4-(3-methylquinohn-6-yl)butan-2-ol (330 mg, 1 .44 mmol, 1 .0 equiv.) was dissolved in DCM (5 mL), m-CPBA (496.6 mg, 2.88 mmol, 2.0 equiv.) was added in portions. The resulting mixture was stirred for 1 h at room temperature and then quenched by the addition of water. The resulting solution was adjusted to pH 7 with NaOH aqueous. The resulting mixture was extracted with EtOAc, washed with brine and dried over anhydrous NazSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 20% to 30% gradient in 10 min; detector, UV 254 nm. This resulted in 6-(3-hydroxy-3-methylbutj'l)-3-me±yiquinoline 1 -oxide (210 mg, 59.49%) as a yellow oil. LCMS Method A: [M+H]+= 246. 1 . Step 2: 4-(2-((3-fluoro-llf-mdoi-6-yI)amino)-3-methylquinolin-6-yI)-2- m ethyIbutan-2-ol

[0568] 6-(3-Hydroxy-3-methylbutyl)-3-methylquinoline 1 -oxide (Intermediate 13; 150 mg, 0.61 mmol, 1.0 equiv.) and 3-luoro-6-isothiocyanato-lH-indole (129.3 mg, 0.67 mmol, 1.1 equiv.) were dissolved in DMF (5 mL), then AgBF4 (59.5 mg, 0.31 mmol, 0.5 equiv.) w'as added. Hie resulting mixture was stirred for 1 h at room temperature and then quenched by the addition of water (20 mL). The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous NazSO-v After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0. 1% FA), 10% to 40% gradient in 20 min; detector, UV 254 nm. This resulted in 4-(2-((3-fluoro-lH-indol-6-yl)amino)-3- methylquinolm-6-yl)-2-methylbutan-2-ol (96.1 mg, 39.93%) as a yellow solid. LCMS Method D: [M+H]+= 378.2. 1HNMR (400 MHz, DMSO-<): 8 10.67 (s, 1H), 8.41 (s, 1H), 8.19 (s, 1H), 8.04-8.01 (m, I I I). 7.87-7.83 (m, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.46-7.38 (m, 4H), 7.18 (d, J= 2.4 Hz, TH), 4.28 (s, 2H), 2.75-2.71 (m, 2H), 2.45 (s,

[0569] 3H), 1.74-1.69 (m, 2H), 1.18 (s, 6H).

[0570] The analogs prepared in Table 7 were prepared using the same method described for Example 1.

[0571] Table 7

[0572] Example 2. (2R)-l,l,l-trifluoro-4-{2-[(3-fiuoro-lfl-indol-6-yi)amino]-3- methylquinolin-6-yI}~2-methyIbutan-2-oI (Compound 34) and (2S)-1,1,1- trifluoro-4-{2-[(3-fluoro-Lff-indoI-6-yI)amino]-3-methyIquinolin-6-yI}-2- methyibutan-2-oI (Compound 35)

[0573] *peak order assigned arbitrarily

[0574] 1,1 ,l-trifluoro-4-{2-[(3-fluoro-lH-indol-6-yl)amino]-3-methylquinolin-6-yl}- 2-methylbutan-2-ol was separated by Prep-chiral-HPLC with the following conditions: Column: JW-CHIRALPAK IF, 20*250mm, 5um; Mobile Phase A: EtOH-HPLC, Mobile Phase B: Hex(0.5% 2M NH3-MeOH)— HPLC; Flow rate: 20 mL / min; Gradient: 85% B to 85% B in 24min; Wave Length: 220 / 254 nm; RTJ(min): 11.37; RT2(min): 15.68; Sample Solvent: EtOH— HPLC; Injection Volume: 0.4 mL. The resulted in (2R)- 1,1,1 -trifluoro-4~ (2- [(3 -fluoro- 177-indol-6-yl)amino] -3 -methylqumolin-6-y 1 } -2- methylbutan-2-ol (front peak, assigned as Compound 34), 128.9 mg, 23.29%) as a yellow solid and (2S)-1 ,l,l-trifluoro-4-{2-[(3-fluoro-177-indol-6-yl)amino]-3- methylquinolin-6-yl}-2-methylbutan-2-ol (second peak, assigned as Compound 35), 116.6 mg, 21 .07%) as a yellow solid.

[0575] Compound 34: LCMS Method D: [M+H]+= 432.0. 1HNMR (400 MHz, DMSO-tZe) δ 12.74 (brs, 1H), 10.69 (brs, 1H), 8.43 (brs, 1H), 8.14 (brs, 1H), 7.86 (brs, 1H), 7.60 - 7.42 (m, 5H), 7.20 (brs, 2H), 5.94 (s, 1H), 2.84 - 2.79 (m, 2H), 2.45 (s, 3H), 1.94 - 1.87 (m, 2.H), 1.34 (s, 3H).

[0576] Compound 35: LCMS Method D: [M+H]4= 432.0.1HNMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.40 (s, 1H), 8.06 (s, 1H), 7.84 (s, 1H), 7.58 - 7.56 (m, 1H), 7.50 (s, 1H), 7.43 - 7.40 (m, 3H), 7.18 (t, J = 2.4 Hz, 2H), 5.94 (brs, 1H), 2.83 - 2.76

[0577] (m. 2H), 2.45 (s, 31 1). 1.98 - 1.87 (m, 2H), 1.34 (s, 3H).

[0578] The analogs prepared in Table 8 were prepared using the same method described for Example 2.

[0579] Table 8

[0580] Example 3. trans-4-(2~[(4-chloro-3-fluoro-lH-indoI-6~yl) amino]-3- methyIquinolin-6-ykydohexan-l-oI (Compound 40) and cis-4-(2-[(4-chloro-3- fluoro-lH-indoI-6-yl) amino]-3-methyIquinolin-6-ylcyclohexan-l-ol (Compound 41)

[0581] * peak order assigned arbitrarily

[0582] Step 1: 6-(4-((tert-butyldimethyIsilyl)oxy)cyclohexyI)-3-methyIquinoIine 1 -oxide

[0583] 6-{4-[(terr-butyldimethylsilyl)oxy]cyclohexyl}-3-methylquinoline (4.0 g, 11.2 mmol, 1.0 equiv.) was dissolved in DCM (50.0 mL), m-CPBA (4.5 g, 22.4 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 3 h at room temperature then quenched by the addition of water. The resulting solution was adjusted to pH 8 with NaOH aqueous. The resulting mixture was extracted with DCM, washed with water and dried over anhydrous NazSOv After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to afford 6-(4-((terr- butyldimethylsilyl)oxy)cyclohexyd)-3-methylquinoline 1-oxide (4.0 g, 95.6%) as a brown solid. LCMS Method A: | M H i == 372.1.

[0584] Step 2: frans-4-(2-[(4-chloro-3-fluoro-lH-indol-6-yl) amino]-3-methyIquinoIin-6- ylcyclohexan-l-ol and cis-4-(2-[(4-chIoro-3-fluoro-U / -indol-6-yl) amino]-3- methyiqiimoIin-6-ykydohexan-l-oI

[0585] 6-(4-((te / 7-Butyldimethylsilyl)oxy)cyclohexyl)-3-methylquinoline 1-oxide (1 .0 g, 2.7 mmol, 1.0 equiv.) and 4-chloro-3-fluoro-6-isothiocyanato-lH-indole (0.7 g, 2.7 mmol, 1.0 equiv.) were dissolved in DMF (10 mL), then AgBEj (1.3 g, 6.7 mmol, 2.5 equiv.) was added in portions. The resulting mixture was stirred for 16 h at room temperature and then quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous NaiSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8; mobile phase, MeCN m Water (0.1% FA), 0% to 100% gradient in 30 min: detector, UV 254 nm. The resulting crude product was further purified by Prep-HPLC with the following conditions: Column: X-Select Prep OBD Cl 8 Column, 30* 150 mm, 5pm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm / 220nm nm. That resulted in trara-4-(2-[(4-chloro-3-fluoro-17 / -indol-6-yl) amino]-3-methylquinolin-6- ylcyclohexan-l-ol (front peak, assigned as Compound 40), 102.9 mg, 7.7%) as a yellow solid and c / s-4-(2-[(4-chloro-3-fluoro-177-indol-6-yl) amino]-3-methylquinolin-6- ylcyclohexan-l-ol (second peak, assigned as Compound 41, 262.6 mg, 22.5%) as a yellow solid.

[0586] Compound 40: LCMS Method C: [M- H | = 424.2. NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.44 (s, 1H), 8.18 (d. . / 9.2 Hz, 2H), 7.85 (s, 1H), 7.61 - 7.57 (m, 2H), 7.49 - 7.45 (m, 2H), 7.29 (t, J= 2.4 Hz, 1H), 4.59 (brs, 1H), 3.51 - 3.47 (m, 1H), 2.57 - 2.51 (m, 1H), 2.44 (s, 3H), 1.97 - 1.94 (m, 2H), 1.87 - 1.84 (m, 2H), 1.59 - 1.54 (m, 2H), 1.35 - 1.27 (m, 2H). Compound 41 : LCMS Method C: i M H | = 424.2.5H NMR (400 MHz,

[0587] DMSCM 5) δ 11.00 (s, 1H), 8.45 (s, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.62 - 7.59 (m, 2H),

[0588] 7.50 - 7.45 (m, 2H), 7.29 (t, J= 2.4 Hz, 1H), 4.38 (s, 1H), 3.93 (s, 1H), 2.68 - 2.60 (m, TH), 2.44 (s, 3H), 1 .97 - 1 .88 (m, 2H), 1 .79 - 1 .77 (m, 2H), 1.61 - 1 .55 (m, 4H). Example 4A. (S)-l-((lr,4S)-4-(2-((3-fluoro-lH-indol-6-yi)amino)-3- methyIquinolin-6-yl)cycIohexyl)ethan-l-ol [Compound 26-a], (R)-l-((lr,4R)-4- (2-((3-fluoro-lH-indoL6-yI)amino)-3~methyIquinoIin-6-yI)cydohexyI)ethan-l-oI (Compound 26-b), (S)-l-((ls,4R)-4-(2-((3-fluoro-lH-indol-6-yI)amino)-3- methyiqumoIin-6-yI)cydohexyl)ethan-l-oi (Compound 26-c) and (R)-l-((ls,4S)- 4-(2-((3~fluoro-lH~indol-6-yI)amino)-3-methyIquinoIin-6-yI)cyclohexyI)ethan-l- ol (Compound 26~d)

[0589] The mixture of Compound 26 was separated by Prep-Chiral-HPLC with the following conditions: Column: JW-CH1RALPAK IE, 20*250mm, 5 pm; Mobile Phase A: EtOH-HPLC, Mobile Phase B: Hex(0.5% 2M NH3-MeOH)-HPLC; Flow rate: 20 mL / min; Gradient: 70% B to 70% B in 15min; Wave Length: 220 / 254 nm; RTl(min): 8.32; RT2(min): 9.23; RT3(mm): 10.72; RT4(min): 17.62; Sample Solvent: EtOH: DCM=1 : 1 — HPLC; Injection V olume: 1.0 m. This resulted in a mixture of the first peak and tlie second peak (170 mg) as a yellow^ solid, (S)-l-((ls,4R)-4-(2-((3-fluoro-lH- indol-6-yl)amino)-3-methylquinolin-6-yl)cyclohexyl)ethan-l-ol (third peak, assigned as Compound 26-c), 82.5 mg, 3.90%) as a white solid and (R)-l-((ls,4S)-4-(2-((3- fluoro- lH-indol-6-yl )amino)-3 -m ethylquinol in-6-yl)cycl ohexyl)ethan - 1 -ol (fourth peak, assigned as Compound 26-d), 90 mg, 4.10%) as a white solid. Then the mixture of the first peak and the second peak w'as further separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SJ 3*25 cm, 5um; Mobile Phase A: CO2, Mobile Phase B: MeOH(l%-2M-NH3-MeOH); Flow rate: 100 mL / min; Gradient: isocratic 46% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 14.47; RT2(min): 16.27; Sample Solvent: MEOH; Injection Volume: 1 m. That resulted in (S)-l-((lr,4S)-4-(2-((3-fluoro-lH-indol-6- yl)amino)-3-methylquinolin-6-yl)cyclohexyl)ethan-l-ol (first peak, assigned as Compound 26-a), 74.8 mg, 3.4%) as a yellow solid and (R)-l-((lr,4R)-4-(2-((3-fluoro- lH-indol-6-yl)amino)-3-methylquinolin-6-yl)cyclohexyl)ethan-l-ol (second peak, assigned as Compound 26-b), 65.8 mg, 3%) as a yellow solid.

[0590] Compound 26-a: LCMS Method D: [M+H]1= 418.2. 1H NMR (400 MHz, MeOD-d4) δ 8.07 (s, 1H), 7.82 (s, IH), 7.60 (d. . / 8.8 Hz, 1H), 7.49 - 7.46 (m, 2H), 7.42 - 7.39 (m, IH), 7.26 - 7.23 (m, IH), 6.97 (d, J= 2.8 Hz, 1 H), 3.59 - 3.54 (m, 1H), 2.64 - 2.60 (m, IH), 2.46 (s, 3H), 2.11- 2.08 (m, IH), 2.05 - 2.03 (m, 2H), 1.91 - 1 .87 (in. IH), 1.61 - 1.56 (m, 2H), 1.42 - 1.41 (m, IH), 1.34 - 1.29 (m, IH), 1.26 - 1.25 (m, IH), 1.21 (d, J = 6.4 Hz, 3H).

[0591] Compound 26-b: LCMS Method C: [M+H]+= 418.2.1H NMR (400 MHz, DMSO-d6) 6 10.67 (brs, IH), 8.40 (s, IH), 8.04 (s, IH), 7.83 (s, IH), 7.67 (s, IH), 7.55 (d, J= 8.8 Hz, IH), 7.47 - 7.42 (m, 3H), 7.18 (d. . / 2.8 Hz, IH), 4.33 (d. . / 4.8 Hz, IH), 3.43 - 3.40 (m, IH), 2.58 - 2.55 (m, IH), 2.44 (s, 3H), 2.00 - 1.91 (m, 3H), 1.79

[0592] - 1.76 (m, IH), 1.51 - 1.45 (m, 2H), 1.26 - 1.21 (m, 2H), 1.19 - 1.15 (m, 2H), 1.07 (s, J= 6.4 Hz, 3H).

[0593] Compound 26-c: LCMS Method C: i .M H| = 418.2. 1H NMR (400 MHz, MeOD-d4.-) 8 8.35 (s, IH), 8.03 (s, IH), 7.83 (s, IH), 7.65 - 7.60 (m, 3H), 7.54 - 7.51 (m, IH), 7.22 - 7.20 (m, IH), 7.09 (d,.7= 2.8 Hz, IH), 3.95 - 3.91 (m, IH), 2.85 - 2.83 (m, IH), 2.51 (s, 3H), 2.05 - 1.94 (m, 2H), 1.81 - 1.63 (rn, 7H), 1.23 (d, J= 6.4 Hz, 3H).

[0594] Compound 26-d: LCMS Method D: [M+Hp = 418.2. 1H NMR (400 MHz, MeOD-d4A 3 8.01 (s, IH), 7.88 (s, IH), 7.63 - 7.61 (m, IH), 7.53 - 7.50 (m, 2H), 7.48

[0595] - 7.45 (m, IH), 7.25 - 7.23 (m, IH), 7.00 (d.. / 2.8 Hz, IH), 3.96 - 3.92 (m, IH), 2.83

[0596] - 2.82 (m, IH), 2.48 (s, 3H), 2.05 - 1.95 (m, 2H), 1.84 - 1.63 (m, 7H), 1.23 (d, J= 6.4 Hz, 3H). Example 4B. (R)-l-((ls,4S)-4-(2-((3-fluoro-lH-indol-6-yl)amino)-3- methyiqumoIin-6-yI)cyclohexyl)ethan-l-oi (26-a)

[0597] Step 1: ethyl 4-(3-methylquinoIin-6-yl) cydohex-3-ene-l -carboxylate

[0598] To a stirred solution of 6-bromo-3-methylquinoline (20.0 g, 90.1 mmol, 1.0 equiv) and ethyl 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl) cyclohex-3-ene-l- carboxylate (37.9 g, 135.1 mmol, 1.5 equiv) in dioxane (250.0 mL) andH2O (50.0 mL) was added Pd(dppf)C12.CH2C12 (6.6 g, 9.0 mmol, 0.1 equiv) and Cs2CO3 (13.7 g, 180.1 mmol, 2.0 equiv) in portions at room temperature. The resulting mixture was stirred for overnight at 90 degrees C under nitrogen atmosphere. Tire mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (1: 1) to afford ethyl 4-(3 -methyl quinolin-6-yl) cyclohex-3 -ene-1 -carboxylate (31 g, crude) as a white solid. LCMS Method A: i Xl I I I =296.

[0599] Step 2: ethyl 4-(3-methylquinoIin-6-yl) cyclohexane- 1 -carboxylate

[0600] To a solution of ethyl 4-(3-methylquinolin-6-yl) cyclohex-3-ene-l -carboxylate (31.0 g, 105.0 mmol, 1.0 equiv) in 400.0 mL MeOH was added Pd / C (10%, 10.0 g) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 6 h under hydrogen atmosphere using a hydrogen balloon. The resulting mixture was filtered, then the filter cake was washed with MeOH (5x20 mL). Tire combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (1: 1) to afford ethyl 4-(3- methylquinolin-6-yl) cyclohexane-l-carboxylate (30.5 g) as a colorless oil. LCMS Method A: [M+H]+=298. Step 3: (4-(3-methylquinolin-6-yl) cyclohexyl) methanol

[0601] To a stirred solution of ethyl 4-(3-methylquinolin-6-yl) cyclohexane- 1- carboxylate (30.0 g, 101.0 mmol, 1.0 equiv) in THF (300.0 mL) was added LAH (6.4 g, 168.1 mmol, 1.7 equiv) at 0°C in batches. The resulting mixture was stirred for 2h at 0°C and then quenched by the addition of Na2SO4 10H2O at 0°C. Tire resulting mixture was filtered, then the filter cake was washed with EtOAc (5x20 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (1: 1) to afford (4-(3- methylquinolin-6-yl) cyclohexyl) methanol (15.7 g, 67.7% over three steps) as a colorless oil. LCMS Method A: [M+H]+=256.

[0602] Step 4: 4-(3-methylquinoIin-6-yI) cyclohexane-l-carbaldehyde

[0603] To a stirred solution of (4-(3 -methyl quinolin-6-yl) cyclohexyl) methanol (14.0 g, 54.8 mmol, 1.0 equiv) m DCM (140.0 mL) was added IBX (61.4 g, 219.3 mmol, 4.0 equiv) at room temperature. The resulting mixture was stirred for overnight at 50°C. The resulting mixture w'as cooled to room temperature and filtered, then the filter cake was washed with DCM (3 x 10 mL). The combined filtrate was concentrated under reduced pressure. This resulted in crude 4-(3-methylquinolin-6-yl) cyclohexane-l- carbaldehyde (23 g, ciude, 5% of int.4 and remained) as a white solid. LCMS Method A: [ M- + H == 254.

[0604] Step 5: (R)-l-((ls,4S)-4-(3-methyIqiiinoIin-6-yI)cyciohexyl)ethan-l-oI

[0605] To a stirred solution of 4-(3-methylquinolin-6-yl) cyclohexane-l-carbaldehyde (23.0 g, crude) in THF (250.0 mL) was added CH3MgBr (in 3M EtzO) (60.5 mL, 181.6 mmol, 2.0 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture w'as stirred for 2h at 0°C under nitrogen atmosphere. The reaction was quenched with sat. NH4CI (aq.) at 0°C. Tire resulting mixture was extracted with EtOAc (3 x 500.0 mL). The combined organic layers were washed with brine (5x20.0 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted w'ith petroleum ether / EtOAc (1: 1) to afford the etude product (8.4 g) as an off-white solid. The crude product was re- crystallized from ACN to afford 1 -(4-(3-methylquinolin-6-yl) cyclohexyl) ethan-l-ol (2.7 g, 96%) as a white solid. This mixture of two isomers (2.7 g) was separated by Prep-Chiral-HPLC with the following conditions (Column: JW-CHIRALPAK IE, 20*250mm, 5um; Mobile Phase A: EtOH—HPLC, Mobile Phase B: Hex(0.5% 2M NH3-MeOH)-HPLC; Flow rate: 20 mL / min; Gradient: 70% B to 70% B in 18min; Wave Length: 220 / 254 nm; two peaks collected: RTl(min): 7.88; RT2(min): 9.72; Sample Solvent: EtOH—HPLC; Injection Volume: 1.0 mL; Number Of Runs: 40) to afford (R)-l-((ls,4S)-4-(3-methylquinolin-6-yl)cyclohexyl)ethan-l-ol (930 mg, 3.80%, second peak) as a white solid and (S)-l-((ls,4R)-4-(3-methylquinolin-6- yl)cyciohexyl)ethan-l-ol(l g, 4%, first peak) as a white solid. LCMS Method A: [M+H]+=270.!H NM R (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.06 (s, 1H), 7.88 (d, J= 8.8 Hz, H I). 7.70 (s, H I). 7.62 - 7.59 (m, 1H), 4.31 (d, .7 6.4 Hz, H I). 3.79 - 3.74 (m, 1H), 2.84 - 2.82 (m, 1H), 2.51 (s, 3H), 1.95 - 1.86 (m, 2H), 1.79 - 1.74 (m, 1H), 1.70 - 1.59 (m, 4H), 1.57 - 1.42 (m, 2H), 1.09 (d, J = 6.0 Hz, 3H).

[0606] Step 6: 6-((ls,4s)-4-(dihydroxyniethyl)cycIohexyI)-3-methylquinoIine 1-oxide

[0607] To a stirred solution of (R)-l-((ls,4S)-4-(3-methylquinolin-6- yl)cyclohexyl)ethan-l-ol (P5-6108D, 930.0 mg, 3.5 mmol, 1.0 equiv) in DCM (10.0 mL) was added m-CPBA (1.2 g, 6.9 mmol, 2.0 equiv) at room temperature. Tire resulting mixture was stirred for 2h at room temperature. The resulting mixture was diluted with water (20.0 mL). The mixture was basified to pH 8 with NaOH (IM aq.). The resulting mixture was extracted with EtOAc (3 x 40.0 mL). The combined organic layers were washed with brine (5x20.0 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10: 1) to afford 6- ((ls,4s)-4-(dihydroxymethyl)cyclohexyl)-3-methylquinoline 1-oxide (I g, 100.80%) as a crude brown yellow oil. LCMS Method A: [M+H]+= 286.

[0608] Step 7. ((ls,4s)-4-(2-((3-fluoro-lH-indol-6-yl)amino)-3-methylquinolin-6-yl)cyclo hexyl)methanediol

[0609] To a stirred solution of 6-((ls,4s)-4-(dihydroxymethyl)cyclohexyl)-3- methylquinoline 1-oxide (1.0 g, 3.5 mmol, 1.0 equiv) and 3-fluoro-6-isothiocyanato- IH-indole (606.2 mg, 3.2 mmol, 0.9 equiv) in DMF (8.0 mL) was added AgBF4 (1.4 g, 7.0 mmol, 2.0 equiv) at room temperature. Hie resulting mixture was stirred for 2h at room temperature. "lire resulting mixture was diluted with water (40 mL). The precipitated solids were collected by filtration and washed with water (3x30 mL). The resulting solid was purified by silica gel column chromatography, eluted with CILCb / MeOH (3: 1) to afford the crude product (950 mg, 80% purity), which is in further purification. 1H NMR (400 MHz, Methanol-d4) δ 8.25 (s, 0.7 H, FA) 8.01 (t, J = 2.2 Hz, i l l). 7.88 (brs, i l l). 7.62 (d, J= 8.6 Hz, i l l). 7.59 - 7.56 (m, 21 1). 7.50 - 7.48 (m, 2H), 7.24 (dd, J= 8.4, 1 .6 Hz, 1H), 7.00 (d, J= 2.8 Hz, 1H), 3.92 - 3.89 (m, 1H), 2.85 - 2.82 (m, 1H), 2.48 (s, 3H), 2.03 - 1.92 (m, 2H), 1.82 - 1.52 (m, 7H), 1.21 (d, J = 6.0 Hz, 3H).

[0610] Example 5. (R)-2,2,2-trifluoro-l-((R)-4-(2-((3-fluoro-lH-indol-6-yi)amino)-3- methyIquinolin-6-yl)cycIohex-3-en-l-yI)ethan-l-ol (compound 31-a), (R)-2,2,2- trifluoro-l-((S)-4-(2-((3-fluoro-lH-indoI-6-yl)amino)-3-methyIquinolin-6- yl)cyclohex-3-en-l-yI)ethan-l-ol (Compound 31-b), (S)-2,2,2-trifluoro~l-((R)-4- (2-((3-fluoro-lH-indol-6-yl)amino)”3-methylquinolin-6-yl)cyclohex-3-en-l" yl)ethan-l-ol (Compound 31 -c) and (S)-2,2,2-trifIuoro-l-((S)-4-(2-((3-fluoro-lH- indol-6-yl)amino)-3-methylquinolin-6-yl)cyclohex-3-en-l-yI)ethan-l-ol (Compound 31-d)

[0611] * peak order assigned arbitrarily

[0612] The mixture Compound 31 was separated by Prep-HPLC with the following conditions: Column: JW-CH1RAL ART Cellulose-SB 3.0*25cm, 5 pin; Mobile Phase A: IPA: DCM I : 1-HPLC, Mobile Phase B: Hex(0.5% 2M NH3-MeOH)-HPLC; Flow7rate: 45 mL / min; Gradient: 70% B to 70% B in 20mm:. Wave Length: 220 / 254 nm; RTl(min): 14.21; RT2(min): 16.32; Sample Solvent: EtOH: DCM=1 : 1 — HPLC; Injection Volume: 0,5 mL. This resulted in a mixture of the first, second and third peaks and (S)-2,2,2-trifluoro-l-((S)-4-(2-((3-fluoro-l / f-indol-6-yl)amino)-3-methylquinolin- 6-yl)cyclohex-3-en-l-yl)ethan-l-ol (fourth peak, assigned as Compound 31 -d), 150 mg, 18.31 %) as a brown solid. Then the mixture of the first, second and third peaks was further separated by Prep-Chiral-HPLC with the following conditions: Column: JW- CHIRALPAK IG 3*25cm, Sum; Mobile Phase A: EtOH-HPLC, Mobile Phase B: Hex(0.5% 2M NHa-MeOH)— HPLC; Flow rate: 45 mL / min; Gradient: 80% B to 80% B in 20mm; Wave Length: 220 / 254 nm; RTl(min): 13,21 ; RT2(min): 15.53; Sample Solvent: EtOH: DCM=1: 1— HPLC; Injection Volume: 0.8 mL. This resulted in (R)- 2,2,2-trifluoro-l-((R)-4-(2-((3-fluoro-lH-indol-6-yl)amino)-3-methylquinolin-6- yl)cyclohex-3-en-l-yl)ethan-l-ol (first peak, assigned as Compound 31-a), 88.8 mg, 11.3%) as a brown solid and a mixture of the second and third peaks. The resulting mixture was further resolved by Prep-Chiral HPLC with the following conditions: Column: JW-CHIRAL ART Cellulose-SA 20*250mm, 5 pm; Mobile Phase A: IP A— HPLC, Mobile Phase B: Hex(0.5% 2M NHj-MeOH)— HPLC; Flow rate: 20 mL / min; Gradient: 75% B to 75% B in 18min; Wave Length: 220 / 254 nm; RTl(min): 22.62; RT2(min): 28.27; Sample Solvent: EtOH-HPLC; Injection Volume: 0.4 mL. This resulted in (R)-2,2,2-trifluoro-l-((S)-4-(2-((3-fluoro-12 / -indol-6-yl)amino)-3- methylquinoIin-6-yl)cycIohex-3-en-l-yl)ethan-l-ol (second peak, assigned as Compound 31-b), 69.5 mg, 8.6%] as a brown solid and (S)-2,2,2-trifluoro-l-((R)-4-(2- ((3-fluoro~lH-indol-6-yl)amino)-3-methylquinolin-6-yl)cyclohex-3-en-l-yl)ethan-l- ol (third peak, assigned as Compound 31-c), 68 mg, 8.5%) as a brown solid.

[0613] Compound 31-a: LCMS Method D: [MH-I]1= 470.1.JH NMR (400 MHz, DMSO-%) 5 10.67 (s, 1H), 8.39 (s, 1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.68 - 7.65 (m, 2H),

[0614] 7.55 (d, J= 8.4 Hz, 1H), 7.44 (s, 2H), 7.18 (t, J= 2.4 Hz, 1H), 6.24 (d, J= 6.8 Hz, 2H), 3.88 - 3.82 (m, 1H), 2.67 - 2.59 (m, 2H), 2.44 (s, 3H), 2.32 - 2,21 (m, 2H), 2, 15 - 2.12 (m, 1H), 1.95 - 1.89 (m, 1H), 1.56 - 1.50 (m, 1H).

[0615] Compound 31-b: LCMS Method D: [M+H]+= 470.1.1HNMR (400 MHz, DMSO-Jc) δ 10.68 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.70 - 7.65 (m, 2H),

[0616] 7.56 (d, .1 8.8 Hz, 1H), 7.45 (s, 2H), 7.19 (I. . / 2.4 Hz, 1H), 6.24 (d, . / 6.8 Hz, 2H), 3.88 - 3.83 (m, 1H), 2.63 - 2.59 (m, 21 1). 2.45 (s, 3H), 2.33 - 2.13 (m, 3H), 1.92 - 1.87 (m. 1H), 1.57 - 1.51 (m, i l l). Compound 31-c: LCMS Method D: [M+H]1= 470.1. NMR (400 MHz, DMSO-Ty) 5 10.68 (s, 1H), 8.41 (s, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.69 - 7.65 (m, 2H), 7.56 (d, 7 = 8.8 Hz, 1H), 7.45 (s, 2H), 7.19 (t, .7 = 2.4 Hz, 1H), 6.27 - 6.26 (m, 1H), 6.21 (d, J = 7.2 Hz, 1H), 4.00 - 3.95 (m, 1H), 2.68 - 2.58 (m, 2H), 2.45 (s, 3H), 2.33 (brs, 2H), 1.93 - 1.90 (m, 2H), 1.70 - 1.62 (m, 1H).

[0617] Compound 31-d: LCMS Method D: | M H i == 470.1.:H NMR (400 MHz, DMSO-%.) 5 10.67 (s, H I). 8.40 (s, i l l}. 8.10 (s, I M). 7.86 (s, H I). 7.69 - 7.64 On. 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.44 (s, 2H), 7.18 (t, J = 2.4 Hz, 1H), 6.27 - 6.26 (m, 1H), 6.21 (d, .J 7.2 Hz, 1H), 3.99 -- 3.94 (m, 1H), 2.67 -- 2.58 (m, 2H), 2.44 (s, 3H), 2.33 -- 2.28 (m, 2H), 1.97 - 1.89 (m, 2H), 1.67 - 1.62 (m, i l l).

[0618] Example 6. 4-(2-((4-chloro-3-fluoro-lfl-indoI-6-yl)amino)-3-methylquinolin-6- yli-A^^V-dimethyl-lTZ-pyrazole-l-suifonamide (Compound 42)

[0619] Step 11:: A-(4-chloro-3-fluoro-lH-indoI-6-yI)-3-methyl-6-(4,4,5,5-tetramethyl- l,3)2-dioxaborolan-2~yl)quinolin-2-amine

[0620] 6-Bromo-7V-(4-chloro-3-fluoro-lfl-indol-6-yl)-3-methylquinolin-2-amine

[0621] (350.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (10 mL), then bis(pinacolato)diboron (219.6 mg, 0.8 mmol, 1.0 equiv.), AcOK (169.7 mg, 1.7 mmol, 2.0 equiv.) and PdtdppflCh.CHiCb (70.4 mg, 0.08 mmol, 0.1 equiv.) were added under nitrogen atmosphere. The reaction mixture was stirred for 3 h at 80°C, then cooled to room temperature and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with water and dried over anhydrous NarSO-i. After filtration, the filtrate was concentrated under reduced pressure to afford 7V-(4-chloro-3- fluoro~177-indol-6-yi)-3-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinolin-2-amine (300 mg, 76.7%) as a white solid. LCMS Method A: | M • H i ' = 452.2.

[0622] Step 2: 4-bromo-A^-dimethylpyrazole-l-sulfonamide

[0623] 4-Bromopyrazole (6.0 g, 40.8 mmol, 1.0 equiv.) was dissolved in THF (150 mL), NaH (3.26 g, 81.6 mmol, 2.0 equiv., 60%) was added in portions at 0°C. After stirred for 30 min at room temperature, dimethylsulphamoyl-chloride (11,7 g, 81,6 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 3 h at room temperature and then quenched by the addition of water. The resulting mixture was extracted with EtOAc, washed with water and dried over anhydrous NajSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1: 1) to afford 4-bromo-AW-dimethylpyrazole-l-sulfonamide (8.0 g, 77.12%) as a white solid. LCMS Method A: [M+H]+= 254. 1 .

[0624] Step 3: 4-{2-[(4-chioro-3-fluoro-l / / -indol-6-yi)aminoJ-3-methyIquinoIm-6-yi}- A’, / V-dim ethyl py r az ole- 1 -su If onam i de

[0625] A-(4-Chloro-3-fluoro-l / / -indol-6-yl)-3-methyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinolin-2-amine (300.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (8 mL) and water (0.8 mL). Then 4-bromo-ACV-dimethylpyra.zole-l- sulfonamide (168.7 mg, 0.6 mmol, 1.0 equiv.), CS2CO3 (432.7 mg, 1.3 mmol, 2.0 equiv.) and Pd(dppf)C12.CH2C12 (54.1 mg, 0.06 mmol, 0.1 equiv.) were added under nitrogen atmosphere. The reaction mixture was stirred for 3 h at 100°C, then cooled to room temperature and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: Column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), to 100% gradient in 15 min; detector, UV 254 nm. The resulting crude product was purified by Prep-HPLC with the following conditions: Column: Xselect CSH PrepC 18 Column, 19*250 mm, 5um; Mobile Phase A: Water (lOmmol / L NH4HCO3), Mobile Phase B: ACN; Flow' rate: 25 mL / min; Gradient: 36% B to 46% B in 7min; Wave Length: 254nm / 220nm; RTl(min): 7. That resulted m 4-{2-[(4-chloro-3-fluoro-12 / -indol-6-yl)amino]-3-methylquinolin-6- yl}-M,ALdimethylpyrazole-l-sulfonamide (14.6 mg, 4.40%) as a white solid. LCMS Method D: | M 1 1 i == 499.0. 1HNMR (400 MHz, DMSO-d6) δ 11.03 (brs, IH), 8.80 - 8.79 (m, IH), 8.50 - 8.48 (m, 2H), 8.30 -- 8.29 (m, IH), 8.10 -- 8.09 (m, IH), 7.99 - 7.96 (m, 1H), 7.88 - 7.87 (m, IH), 7.69 - 7.67 (m, IH), 7.63 (d, J= 1.6 Hz, 1H), 7.33 (t, J= 2.4 Hz, IH), 2.91 (s, 6H), 2.48 (s, 3H). Example 7. At-(3-chloro-l£r-indol-6-yl)-6-{l-[(3,3-difluorocyclobutyl)methyl] pyrazoI-3-yI}-3-methyIquinoIin-2-amine (Compound 43)

[0626] Step 1: l-[(3,3-difluorocydobutyI)methyl]-3-(4,4,5,5-tetramethyi-l,392- dioxaborolan-2-yi)pyrazoIe

[0627] 3-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-177-pyrazole (300.0 mg, 1.5 mmol, 1.0 equiv.) and 3 -(bromomethyl)- 1,1 -difluorocyclobutane (286.0 mg, 1.5 mmol, 1.0 equiv.) were dissolved in DMF (5 mL), then K2CO3 (427.3 mg, 3.0 mmol, 2.0 equiv.) was added at room temperature. The reaction mixture was stirred for 12 h at 80°C, then cooled to room temperature and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with water and dried over anhydrous NaaSOv After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: Column, C18; mobile phase, MeCN in Water (lOmmol / L NH4HCO3), 0% to 100% gradient in 15 min; detector, UV 254 nm. This resulted in 1- [(3,3-difluorocyclobutyl)methyl]-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yllpyrazole (260 mg, 56.4%) as a white solid. LCMS Method A: [M+H]+= 299.2.

[0628] Step 2: A7-(3~chloro-17ir“indol~6-yl)~6-{l-[(3,3"difluoroi€ydobutyl)methyl]pyrazol- 3-yl}-3-methylquinolin-2-amine TEA salt

[0629] 6-Bromo-7V-(3-chloro-177-indol-6-yl)-3-methylquinolin-2-amine (200.0 mg, 0.5 mmol, 1.0 equiv.), l-[(3,3-difluorocyclobutyl)methyl]-3-(4,4,5,5-tetramethyl- l,3,2-dioxaboro!an-2-yl)pyrazole (154.2 mg, 0.5 mmol, 1.0 equiv.) were dissolved in 1,4-dioxane (5 mL) and water (1 mL), then CS2CO3 (337.0 mg, 1.0 mmol, 2.0 equiv.) and Pd(dppf)C12.CH2C12 (42.1 mg, 0.05 mmol, 0.1 equiv.) were added under nitrogen atmosphere. Tire reaction mixture was stirred for 3 h at 100°C, then cooled to room temperature and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with water and dried over anhydrous Na2§04. After filtration, the filtrate was concentrated under reduced pressure. Tire residue was purified by reversed- phase flash chromatography with the following conditions: Column, Cl 8; mobile phase, MeCN in Water (lOmmol / L NH4HCO3), 0% to 100% gradient in 15 min; detector, UV 254 run. The resulting crude product was further purified by Prep-HPLC with the following conditions: Column: SunFire Prep OBD C 18 Column, 19*250 mm, 5 pm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 25 mL / min mL / min; Gradient: 37% B to 47% B m 12 min; Wave Length: 254nm / 220nm; RTl(min): 8.21. This resulted in AL(3-chloro-lH-indol-6-yl)-6-{ l-[(3,3- difluorocyclobutyl)methyl]pyrazol-3-yl }-3-methylquinolin-2-amine TFA salt (43.4 mg, 13.9%) as a white solid. LCMS Method C: | V • H f == 478.2. 1H NMR (400 MHz. Methanol-^) δ 8.33 (s, 1H), 8.23 (d, J = 1.6 Hz, IB), 8.12 - 8.09 (m, 1H), 7.77 - 7.72 (m, 3H), 7.62 (d, J= 1 .6 Hz, 1H), 7.44 (s, 1H), 7.25 - 7.23 (m, 1H), 6.75 (d, J= 2.4 Hz, 1H), 4.31 (d. . / 6.8 Hz, 2H), 2.74 - 2.63 (m, 3H), 2.56 (s, 3H), 2.51 - 2.45 (m, 2H).

[0630] Example 8. 6-[4-(cyclobutyImethyl)imidazol-l-yl]-Ar-(3-fluoro-lZT-indol-6- yl)quinolin-2-amine (Compound 44)

[0631] 2-Chloro-6-[4-(cyclobutylmethyl)imidazol-l-yl]quinoline (120.0 mg, 0.4 mmol, 1.0 equiv.) and 3-fluoro-12 / -indol-6-amine (60.5 mg, 0.4 mmol, 1.0 equiv.) were dissolved in 1,4-dioxane (3 mL), then CS2CO3 (262.5 mg, 0.8 mmol, 2.0 equiv.), EPhos (43.1 mg, 0.1 mmol, 0.2 equiv.) and EPhos Pd G4 (37.1 mg, 0.1 mmol, 0.1 equiv.) were added under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere, then cooled to room temperature and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine and dried over anhydrous NazSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0. 1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The resulting crude product was further purified by prep-HPLC with the following conditions: Column: X-Select Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm / 220nm nm; RTl(min): 6.56. This resulted in 6-[4- (cyclobutylmethyl)im idazol - 1 -yl] -7V-(3-fl uoro- 177-indol-6-yl)quinolin -2 -amine (19,8 mg, 11.5%) as a brown yellow solid. LCMS Method D: [ M H ]+- 4 12. 1. 4 1 NMR (400 MHz, DMSO-%) 5 10.68 (s, IH), 9.49 (s, IH), 8.56 (s, 1H), 8.17 (s, IH), 8.05 (d, .7 = 9.2 Hz, IH), 7.96 (d, J = 2.8 Hz, IH), 7.89 - 7.86 (m, IH), 7.75 (d, .7 = 9.2 Hz, IH), 7.47 ... 7.44 (rn, 2H), 7.28 - 7.26 (m, IH), 7.19 - 7.18 (m, IH), 7.14 (d.. / 8.8 Hz, IH), 2.68 - 2.62 (m, 3H), 2.10 -- 2.06 (m, 2H), 1.89 - 1.84 (m, 2H), 1.75 - 1.72 (m, 2H).

[0632] Example 9. N-(4-chioro-lH-indoI-6-yI)-6-(l-((3,3-difluorocyclobutyI)methyI)-lH- pyrazoI-4-yl)-3-methylquinolin-2-amine (Compound 4)

[0633] Step 1: l-((3,3-difluorocydobutyI)methyl)-4-(4,4,5,5-tetramethyI-l,3»2- dioxaborolan-2- yl)-lH-pyrazole

[0634] To a stirred mixture of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (9 g, 46.382 mmol, 1 equiv) and 3 -(bromomethyl)- 1,1 -difluorocyclobutane (10.30 g, 55.658 mmol, 1.2 equiv) in DMF (100 mL) was added CS2CO3 (30.22 g, 92.764 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred for 3h at 80°C under air atmosphere. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (3 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Hie residue was purified by silica gel column chromatography, eluted with EtOAc / petroleuni ether (1:2) to afford l -[(3,3-difluorocyclobutyl)methyl]-4-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)pyrazole (12 g, 86.78%) as a yellow' solid. LCMS Method A: [M+H]+==299.

[0635] Step 2: 6-(l-((3,3-difluorocydobutyl)methyl)-lH-pyrazoI-4-yI)-3-methyIquinoIine l-[(3,3-difluorocyclobutyl)methyl]-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazole ( 11.8 g, 39.6 mmol, 1.1 equiv) was dissolved in H?.O (20.0 mL) and dioxane (100.0 mL), then CS2CO3 (23.4 g, 72,0 mmol, 2.0 equiv), Pd(dppf)C12 (2.6 g, 3.6 mmol, 0.1 equiv) and 6-bromo-3-methylquinoline (8.0 g, 36.0 mmol, 1.0 equiv) were added under nitrogen atmosphere. The reaction mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. Then reaction mixture was cooled to ambient temperature, then quenched byt the addition of water. Tire resulting solution was extracted with EtOAc (3x 500 ml), dried over anhydrous NaiSCL and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with EtOAc / petroleum ether (1:3) to give 6-{ l-[(3,3- difluorocyclobutyl)methyl]pyrazol-4-yl}-3-methylquinoline (10.0 g, 88.5%) as a yellow' solid. LCMS Method A: [M+H]+==314.

[0636] Step 3: 6-(l-((3,3-difluorocyclobutyI)methyl)-lH-pyrazoI-4-yl)-3- methylquinoline 1-oxide

[0637] 6- { 1 - [(3 ,3 -difluorocy clobutyl)methyl]pyrazol-4-yl } -3 -methylquinoline ( 10.0 g, 31.9 mmol, 1.0 equiv) was dissolved in DCM (100.0 mL), then m-CPBA (15.7 g, 63.8 mmol, 2.0 equiv, 70%) was added. The reaction mixture was stirred for 2 h at room temperature. Hie mixture was adjusted to pH 8 with aq. NaOH. The resulting solution was extracted with CH2CI2 (3x 500 mL), washed w'ith brine (3x 500 mL), dried over anhydrous NazSCh and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane / methanol (10: 1 ) to give 6- { 1 - [(3 ,3 -difluorocyclobutyl)methyl]pyrazol-4-yl} -3-me thylquinolin- 1 -him- 1 - olate (10.0 g, 95.1%) as a yellow' solid. LCMS Method A: [M+H]+=330.

[0638] Step 4: methyl 4-methyl-3,5-dinitrobenzoate

[0639] 4-methyl-3, 5 -dinitrobenzoic acid (5.0 g, 22.1 mmol, 1.0 equiv) was dissolved in MeOH (50.0 mL), SOCI2 (6.6 g, 30.0 mmol, 1 .3 equiv) was added dropwise at 0 degrees C. Tire resulting mixture was stirred for 2 h at 60 degrees C. After cooled to room temperature, the reaction mixture was concentrated m vacuum. Hus resulted in methyl 4-methyl-3, 5 -dinitrobenzoate (5 g, 94.2%) as a white solid.

[0640] Step 5: methyl 3-amino-4-methyL5-nitrobenzoate

[0641] Methyl 4-methyl-3,5-dinitrobenzoate (5.0 g, 20.8 mmol, 1.0 equiv) was dissolved in AcOH (50.0 mL), Fe (3.5 g, 62.5 mmol, 3.0 equiv) was added and the reaction mixture was stirred for 3 h at room temperature. The resulting mixture was diluted with water (200.0 mL). The resulting mixture was extracted with EtOAc (3 x 100.0 mL). The combined organic layers w?ere washed with brine (3x20.0 mL), dried over anhydrous NaiSCh. After filtration, the filtrate was concentrated under reduced pressure. Hie residue was purified by silica gel column chromatography, eluted with PE / EA (1: 1) to afford methyl methyl 3 -amino-4-methy 1-5 -nitrobenzoate (2.8 g, 63.99%) as a yellow solid. LCMS Method A: [M+H]+=211.

[0642] Step 6: methyl 3-chioro-4-methyl-5~nitrobenzo>ate

[0643] Methyl 3-amino-4-methyl-5-nitrobenzoate (2.8 g, 13.3 mmol, 1.0 equiv) was dissolved in ACN (30.0 mL), CuCI2 (2.7 g, 20.0 mmol, 1 .5 equiv) was added at room temperature. To the above mixture was added tBuONO (2.1 g, 20.0 mmol, 1.5 equiv) dropwise at room temperature. "lire resulting mixture was stirred for 1 h at 60 degrees C. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (60.0 mL).The resulting mixture was extracted with EtOAc (3 x 60.0 mL). The combined organic layers were washed with brine (3x 20.0 mL), dried over anhydrous Na2SO4. After filtration, tire filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5: 1) to afford methyl 3-chloro-4-methyl-5-nitrobenzoate (2.8 g, 91 .54%) as a white solid.

[0644] Step 7: methyl (E)-3-chloro-4-(2-(dimethyIamino)vinyl)-5-nitrobenzoate

[0645] Methyl 3-chloro-4-methyl-5-nitrobenzoate (2.8 g, 12.2 mmol, 1.0 equiv) was dissolved in DMF (30.0 mL), DMF-DMA (2.9 g, 24.4 mmol, 2.0 equiv) was added at room temperature. The resulting mixture was stirred for 1 h at 100 degrees C. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (60.0 mLj.The resulting mixture was extracted with EtOAc (2 x 60.0 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous NaaSO*. After filtration, the filtrate was concentrated under reduced pressure. This resulted in methyl methyl (E)-3-chloro-4-(2-(dimethylamino)vinyl)-5- nitrobenzoate (3 g, 86.41%) as a red oil. LCMS Method A: [M+H]+= 285. Step 8: methyl 4-chloro-lH-indole-6-carboxylate

[0646] Methyl (E)-3-chloro-4-(2-(dimethylamino)vinyl)-5-nitrobenzoate (3.0 g, 10.5 mmol, 1.0 equiv) was dissolved in MeOH (40.0 ml), Raney nickel (1.0 g, 11.7 mmol, 1. 1 equiv) was added and the resulting mixture was stirred for 4 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered; the filter cake was washed with MeOH (4 x 10.0 mL). The filtrate was concentrated under reduced pressure. "lire residue was purified by silica gel column chromatography, eluted with PE / EA (1 : 1) to afford methyl 4-chloro-l H-indole-6-carboxylate (1.8 g, 81 .49%) as an off-white solid. LCMS Method A: [M+H]+=2I0.

[0647] Step 9: 4-chloro-lII-indole-6-carboxylic acid

[0648] Methyl 4-chloro-lH-indole-6-carboxylate (1.8 g, 8.6 mmol, 1.0 equiv) was dissolved in MeOH (20.0 mL) and ITO (10.0 mL), NaOH (0.7 g, 17.2 mmol, 2.0 equiv) was added and the resulting mixture was stirred for 4 h at 40 degrees C. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water (20.0 mL). The residue was acidified to pH 4 with conc.HCl. The precipitated solids were collected by filtration and washed with water (4x5.0 mL). The resulting solid was dried under vacuum. This resulted in 4-chloro-l 1 I-indole-6-carboxy lie acid (1.6 g, 95.26%) as a white solid. LCMS Method A: | M • I l k I 96.

[0649] Step 10. 4-chloro-l H-indole-6-carbonyl azide

[0650] A solution of 4-chloro-lH-indole-6-carboxylic acid (50 g, 255.6 mmol, 1 equiv) in THF (400 mL) was treated with TEA (38.8 g, 383.4 mmol, 1.5 equiv) and DPPA (84.4 g, 275.2 mmol, 1.2 equiv). Hie resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction solution was pouring into water(500 mL).The precipitated solids were collected by filtration and -washed with water. "lire solid was dried in oven at 50 °C . To afford 4-chloro-lH-indole-6-carbonyl azide (60 g, 106.3%) as a yellow crude solid.

[0651] Step 11: tert-butyl N-(4-chloro-lH-indol-6-yl)carbamate 4-chloro- JH-indole-6-carbonyl azide (60 g, 271.9 mmol, 1 equiv) was dissolved in t-BuOH (500 mL). The resulting mixture was stirred for 5 h at 90 °C under nitrogen atmosphere. The resulting solution was cooled down to room temperature and concentrated under vacuum. This resulted in tert-butyl N-(4-chloro-lH-indol-6- yl)carbamate (70 g, 96.5%) as a yellow crude oil. Hie crude product was used in the next step directly without further purification.

[0652] Step 12: 4-chloro-lH-indoll-6-amine hydrogen chloride

[0653] To a stirred mixture of tert -butyl N-(4-chloro-lH-indol-6-yl)carbamate (70 g, 262.4 mmol, 1 equiv) in MeOH(80 mL), HC1(4N) in MeOH (80 mL) was added in portions at room temperature under air atmosphere. The resulting mixture was stirred for 16 h at room temperature under air atmosphere. The precipitated solids were collected by filtration. The filtrate was concentrated under reduced pressure, lire residue was slum’ in ACN. The solids were collected by filtration. This resulted in 4- chloro-lH-indol-6-amine hydrogen chloride (40 g, 75.5%) as a white solid.

[0654] Step 13: 4-chIoro~6-isothiocyanato~lH-indoIe

[0655] To a stirred solution of 4-chloro- lH-indol-6-amine hydrogen chloride (10 g, 49.5 mmol, 1 equiv) and TEA (10.0 g, 99.0 mmol, 2 equiv) in DCM (100 mL), l-(2- oxo~llambda4-pyridine-l-carbothioyl)~llambda4-pyridin-2-one (11.5 g, 49.5 mmol, 1 equiv) was added at room temperature under air atmosphere. The resulting mixture was stirred for 2h at room temperature under air atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSO*. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1: 1) to afford 4-chloro-6- isothiocyanato-lH-indole (5 g, 39.9%) as a yellow solid. LCMS: [M+H]+==209 / 210.

[0656] Step 14: N-(4-chioro-lH-indol-6-yI)-6-(l-((3,3-difluorocyclobutyl)methyi)-lH- pyrazoI-4-yl)-3- methyIquinolin-2-amine (Compound 4)

[0657] 6- { 1 - [(3,3 -difhiorocyclobutyl)methyl]pyrazol-4-yl } -3 -methylquinolin- 1 -ium- 1-olate (6.8 g, 20.6 mmol, 1.0 equiv) was dissolved in DMF (70.0 mL), then 4-chloro- 6-isothiocyaiiato-lH-indole (4.3 g, 20.6 mmol, 1.0 equiv) and AgBFi (4.0 g, 20.6 mmol, 2.0 equiv) were added. The reaction mixture was stirred for additional 2 h at room temperature and then quenched by the addition of hSO (500 mL). The resulting solution was extracted with EtOAc (3 x 500 mL), washed with brine (3x 500 mL), dried over anhydrous NaiSCL and concentrated under vacuum. Hie residue was purified by reversed-phase flash chromatography with tire following conditions: column, CT 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 20% to 60% gradient in 30 min; detector, UV 254 nm. Tire resulting crude product was further purified by trituration with ACN (20 mL) and dried. This resulted in N-(4-chloro-lH-indol-6-yl)-6-{l-[(3,3- difluorocyclobutyl)methyl] pyrazol-4-yl}-3-methylquinolin-2-amine (4.4 g, 44.6%) as a yellow solid. LCMS Method B: | M H | = 478. % NMR (400 MHz, DMSO~<*) 5 11.31 (s, 1H), 8.41 (s, 1H), 8.27 (s, lH), 8.17 (s, 1H), 7.96 (s, 1H), 7.84 (d, J- 2.0 Hz, 2H), 7.78 - 7.76 (m, 1H), 7.63 - 7.61 (m, 2H), 7.36 (1. . / 2.8 Hz, 1H), 6.40 (t, . / 2.4 Hz, 1H), 4.28 (d, J = 5.6 Hz, 2.H), 2.74 - 2.64 (m, 4H), 2.47 - 2.45 (m, 1H), 2.47 (s, 3H).

[0658] Biological Assays

[0659] STING pathway activation by the compounds described herein was measured using THPl-Dual™ cells (KO-IFNAR2).

[0660] THPl-Dual™ KO-IFNAR2 Cells (obtained from InvivoGen) were maintained in RPMI, 10% FCS, 5 ml P / S, 2mM L-glut, lOmM Hepes, and 1 mM sodium pyruvate. Compounds were spotted in empty 384 well tissue culture plates (Greiner 781182) by Echo for a final concentration of 0.0017 - 100 pM. Cells were plated into the TC plates at 40 pL per well, 2 i OE6 cells / mL. For activation with STING ligand, 2'3fcG AMP (MW 718.38, obtained from Invivogen), was prepared in Optimem media.

[0661] The following solutions were prepared for each 1 x384 plate: o Solution A: 2 mL Optimem with one of the following stimuli: a 150 pM stock o Solution B: 2 mL Optimem with 60 pL Lipofectamine 2000 Incubate 5 min at RT

[0662] 2 mL of solution A and 2 ml Solution B was mixed and incubated for 20 min at room temperature (RT). 20 pL of transfection solution (A+B) was added on top of the plated cells, with a final 2’3’cGAMP concentration of 15 p.M. The plates were then centrifuged immediately at 340 g for 1 minute, after which they were incubated at 37 °C, 5% COz, >98% humidity for 24h. Luciferase reporter activity was then measured. EC50 values were calculated by using standard methods known in the art.

[0663] 5

[0664] Luciferase reporter assay: 10 pL of supernatant from tire assay was transferred to white 384-plate with flat botom and squared weils. One pouch of QUANTI-Luc™ Plus was dissolved in 25 ml of water. 100 pL of QLC Stabilizer per 25 mL of QUANTI-Luc™ Plus solution was added. 50 pL of QUANTI-Luc™ w Plus / QLC solution per well was then added. Luminescence was measured on a Platereader (e.g., Spectramax I3X (Molecular Devices GF3637001 )).

[0665] Luciferase reporter activity was then measured. ECso values were calculated by using standard methods known in the art.

[0666] Table BA show's the activity’ of compounds in STING reporter assay: <0. 1 pM 15 not determined. Numbered Clauses

[0667] The compounds, compositions, methods, and other subject matter described herein are further described in the foilowing numbered clauses: or a pharmaceutically acceptable salt thereof, wherein:

[0668] L is a bond or -O-;

[0669] R1is halo or C1-C4 alkyl;

[0670] R2is selected from the group consisting of:

[0671] « C1-C6 alkyl optionally substituted with 1-6 independently selected R3;

[0672] • 5 membered heteroaryl optionally substituted with 1 Rb;

[0673] ® C3-C7 cycloalkyl, which is optionally substituted with 1-4 independently selected Rc; and

[0674] ® C4-C7 cycloalkenyl, which is optionally substituted with 1-4 independently selected Rc;

[0675] R31, R32, and R33are each, independently, halo or H;

[0676] R33is H or F; each occurrence of R3is, independently, -OH or halo;

[0677] Rbis selected from the group consisting of C1-C6 alkyl optionally substituted with 1-4 independently selected RM; C3-C5 cycloalkyl optionally substituted with 1-2 independently selelcted halo; and -SO2N(C1-C4 alkyl)2; each occurrence of R£is, independently, -OH or C1-C4 alkyl optionally substituted with 1-4 substituents independently selected from -OH and halo; and

[0678] RMis -OH, halo, or C3-C5 cycloalkyl optionally substituted with 1-2 halo.

[0679] 2. The compound of clause 1, wherein L is a bond.

[0680] 3. Tire compound of clause 1, wherein L is -O-, 4. The compound of any one of clauses 1-3, wherein R1is C1-C4 alkyl.

[0681] 5. Hie compound of any one of clauses 1 -4, wherein Rsis CH3.

[0682] 6. Hie compound of any one of clauses 1-3 and 5, wherein R1is halo.

[0683] 7. The compound of any one of clauses 1-6, wherein R2is C1-C6 alkyl optionally substituted with 1-6 independently selected Ra.

[0684] 8. The compound of any one of clauses 1-7, wherein R2is C1-C6 alkyl substituted with 1-6 independently selected Ra, optionally wherein R2is C1-C6 alkyl substituted with 1-6 substituents independently selected from the group consisting of - OH and F.

[0685] 9. The compound of tiny one of clauses 1-8, wherein R2is selected from

[0686] 10. The compound of any one of clauses 1-6, wherein R2is 5 membered heteroaryl optionally substituted with 1 Rb.

[0687] 11. The compound of any one of clauses 1-6 and 10, wherein R2is membered heteroaryl substituted with 1 Rb.

[0688] 12. The compound of any one of clauses 1-6 and 10-1 1, wherein the 5 membered heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl. 13. The compound of any one of clauses 1-6 and 10-12, wherein the 5 membered heteroaryl is imidazolyl, pyrazolyl, or thiazolyl.

[0689] 14. Hie compound of any one of clauses 1 -6 and 10-13, wherein R2is selected from the group consisting of

[0690] 15. The compound of any one of clauses 1-6, wherein R2is C3-C7 cycloalkyl optionally substituted with 1-4 independently selected Rc.

[0691] 16. The compound of any one of clauses 1-6, and 15 wherein R2is C5-C6 cycloalkyl substituted with 1-2 independently selected RT optionally wherein R2is C6 cycloalkyl substituted with 1-2 independently selected R£.

[0692] 17. The compound of any one of clauses 1-6, and 15-16 wherein R2is selected from the group consisting of

[0693] 18. The compound of clause 17, wherein R2is

[0694] 19. The compound of any one of clauses 1-6, wherein R2is C4-C7 cycloalkenyl substituted with 1-2, independently selected Rc.

[0695] 20. The compound of any one of clauses 1-6 and 19, wherein R2is C5-C6 cycloalkenyl substituted with 1-2 independently selected Rc, optionally wherein R2is l substituted with 1-2 independently selected Rc, optionally wherein R2 21. The compound of any one of clauses 1-20, wherein one or two of R31, R32, and R33are an independently selected halo, and the others are hydrogen; optionally wherein one or too of R31, R32, and R33are independently fluoro or chloro, and the others are hydrogen.

[0696] 22. The compound of any one of clauses 1-21, wherein R31is H; and R32and R33are an independently selected halo; optionally wherein R31is H; and R32and R33are independently fluoro or chloro.

[0697] 23. The compound of any one of clauses 1-22, wherein R31is H; R32is F, and R33is Cl or F.

[0698] 24. The compound of any one of clauses 1-22, wherein R31is H; R32is F, and R33is H.

[0699] 25. The compound of any one of clauses 1 -24, wherein Rbis alkyl optionally- substituted with 1-4 Rbl; optionally wherein Rbis alkyl substituted with 1-4 Rbl; optionally wherein Rbis alkyl substituted with 1 Rbl.

[0700] 26. The compound of any one of clauses 1-25, wherein Rbl, or each occurrence of Rbl, is independently selected from the group consisting of -OH and halo; optionally wherein Rbl, or each occurrence of Rbl, is independently selected from the group consisting of -OH and F.

[0701] 27. The compound of any one of clauses 1-26, wherein Rbis selected from

[0702] 28. The compound of any one of clauses 1-25, wherein Rbl, or each occurrence of Rbl, is C3-C5 cycloalkyl optionally substituted with 1-2 halo. 29. The compound of any one of clauses 1-25 and 28, wherein Ri!is

[0703] 30. The compound of any one of clauses 1-25, wherein Rbis -SO2N(C1-C4 alkyl)?..

[0704] 31. The compound of any one of clauses 1-30, wherein Rcis -OH.

[0705] 32. The compound of any one of clauses 1 -30, wherein Rcis C1-C4 alkyl optionally substituted with 1-4 substituents independently selected from -OH and halo; optionally wherein Rcis C1-C4 alkyl optionally substituted with 1-4 substituents independently selected from -OH and fluoro.

[0706] 33. The compound of any one of clauses 1-30 and 32, wherein Rcis C1-C4 alkyl that is substituted with 1-4 substituents independently selected from -OH and halo.

[0707] 34. The compound of any one of clauses 1-30 and 32-33, wherein Rcis Cl- C4 alkyl that is substituted with 1-4 substituents independently selected from -OH and fluoro.

[0708] 35. The compound of any one of clauses 1-30 and 32-34, wherein R£is Cl- C4 alkyl substituted with -OH.

[0709] 36. The compound of any one of clauses 1-30 and 32-35, wherein Rcis

[0710] 37. The compound of any one of clauses 1-30 and 32-35, wherein Reis 38. The compound of any one of clauses 1-30, wherein Rcis CHj.

[0711] 39. Hie compound of any one of clauses 1 -38, wherein Ruis H. wherein R’2is H or F.

[0712] 41. The compound of clause 40, wherein L is a bond.

[0713] 42. The compound of clause 40 or 41, wherein R2is C3-C6 cycloalkyl optionally substituted with 1-4 independently selected Rc.

[0714] 43. The compound of any one of clauses 40-42, wherein R2is C5-C6 cycloalkyl optionally substituted with 1 -4 independently selected Rc.

[0715] 44. The compound of any one of clauses 40-43, wherein R2is C6 cycloalkyl optionally substituted with 1-4 independently selected Rc. optionally wherein R2is C6 cycloalkyl that is optionally substituted with 1 Rc; optionally wherein R2is C6 cycloalkyl that is substituted with 1-4 independently selected optionally wherein R2is C6 cycloalkyl that is substituted with 1 Rc.

[0716] 45. The compound of any one of clauses 40-44, wherein R2is

[0717] 46. Tire compound of any one of clauses 40-45, wherein Rcis C1-C4 alkyl optionally substituted with 1-4 substituents independently selected from hydroxyl or halo; optionally wherein Rcis C1-C4 alkyl optionally substituted with 1-4 substituents independently selected from hydroxyl or fluoro.

[0718] 47. Tire compound of any one of clauses 40-46, wherein Rcis C1-C2 alkyl optionally substituted with 1-4 substituents independently selected from hydroxyl or halo, optionally wherein Rcis C1-C2 alkyl optionally substituted with hydroxyl.

[0719] OH

[0720] 48. The compound of any one of clauses 40-47, wherein Rcis

[0721] 49. The compound of clause 40 or 41, wherein R2is 5 membered heteroaryl substituted with 1 Rb, optionally wherein the 5 membered heteroaryl is imidazolyl, pyrazolyl, or thiazolyl, optionally wherein R2is selected from the group consisting of

[0722] 50. The compound of clause 40 or 41, wherein R2is C1-C6 alkyl optionally substituted with 1-6 independently selected Ra, optionally wherein R2is C1-C6 alkyl substituted with 1 -6 independently selected Ra, optionally wherein R2is C1 -C6 alkyl substituted with 1-6 substituents independently selected from the group consisting of --- OH and F.

[0723] 51. Hie compound of clause 50, wherein R2is selected from the group

[0724] 52. The compound of any one of clauses 40-51, wherein R32is F. 53. The compound of clause 1, wherein the compound is selected from the group consisting of compounds delineated in Table Cl, and a pharmaceutically acceptable salt thereof.

[0725] 54. A pharmaceutical composition comprising a compound of any one of clauses 1-53 and one or more pharmaceutically acceptable excipients.

[0726] 55. A method for inhibiting STING activity, the method comprising contacting STING with a compound or a pharmaceutically acceptable salt thereof as defined in any one of clauses 1-53; or a pharmaceutical composition as defined in clause 54.

[0727] 56. The method of clause 55, wherein the inhibiting comprises antagonizing STING.

[0728] 57. The method of tiny one of clauses 55-56, winch is carried out in vitro.

[0729] 58. The method of clause 57, wherein the method comprises contacting a sample comprising one or more cells comprising STING with the compound.

[0730] 59. The method of clause 58, wherein the one or more cells are one or more cancer cells.

[0731] 60. The method of clauses 58 or 59, wherein the sample further comprises one or more cancer cells, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma ceil neoplasms, Wilm's tumor, or hepatocellular carcinoma. 61. The method of clause 55 or 56, which is carried out in vivo.

[0732] 62. The method of clause 61, wherein the method comprises administering the compound to a subject having a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and / or symptoms and / or progression of the disease.

[0733] 63. The method of clause 62, wherein the subject is a human.

[0734] 64. The method of clauses 62 or 63, wherein the disease is cancer.

[0735] 65. The method of clause 64, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma.

[0736] 66. The method of clauses 64 or 65, wherein the cancer is a refractor}' cancer.

[0737] 67. The method of clause 62, wherein the compound is administered in combination with one or more additional cancer therapies.

[0738] 68. The method of clause 67, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

[0739] 69. The method of clause 68, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents. 70. The method of clause 69, wherein the one or more additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and / or oxaliplatin); an anti -metabolite (e.g., azathioprine and / or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and / or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and / or Vindesine Taxol, Pacllitaxel and / or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and / or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and / or topotecan;. amsacrine, etoposide, etoposide phosphate and / or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracy clines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and / or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and / or Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory7agent; an anti-helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1 - PD-L1, PD-1 - PD-L2, interleukin 2 (IL 2), indoleamine 2,3-dioxygenase (IDO), IL 10, transforming growth factor-P (TGFP), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9 - TIM3, Phosphatidylserine - TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II - LAG3, 4 1BB-4 1BB ligand, 0X40-0X40 ligand, GITR, GITR ligand - GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM- LIGHT- LTA, HVEM, HVEM - BTLA, HVEM - CD160, HVEM - LIGHT, HVEM-BTLA-CD160, CD80, CD80 - PDL-1, PDL2 - CD80, CD244, CD48 - CD244, CD244, ICOS, ICOS-ICOS ligand, B7 TI3, 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, Phosphatidyl serine - TIM3, SIRPA-CD47, VEGF, INeuropilin, CD160, CD30, and CD155 (e.g, CTLA-4 or PD1 or PD-L1).

[0740] 71. Tire method of any one of clauses 62-70, wherein the compound is administered intratumorally.

[0741] 72. A method of treating cancer, comprising adm inistering to a subject in need of such treatment an effective amount of a compound as defined in any one of clauses 1-53, or a pharmaceutical composition as defined in clause 54.

[0742] 73. The method of clause 72, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma.

[0743] 74. The method of clause 72 or 73, wherein the cancer is a refractory cancer.

[0744] 75. The method of clause 74, wherein the compound is administered in combination with one or more additional cancer therapies.

[0745] 76. The method of clause 75, wherein the one or more additional cancer therapies comprises surgery', radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

[0746] 77. The method of clause 76, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.

[0747] 78. The method of clause 77, wherein the one or more additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin. carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and / or oxaliplatin); an anti-metabolite (e.g., azathioprine and / or mercaptopurine); a terpenoid (e.g, a vinca alkaloid and / or a taxane; e.g.. Vincristine, Vinblastine, Vinorelbine and / or Vindesine Taxol, Pacllitaxel and / or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and / or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and / or topotecan;. amsacrine, etoposide, etoposide phosphate and / or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracy clines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and / or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutam ide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and / or Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti -helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1 - PD-L1, PD-1 - PD-L2, interleukin-2 (IL-2), indoleamine 2,3 -dioxygenase (IDO), IL- 10, transforming growth factor-P (TGFp), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9 - TIM3, Phosphatidylserine - TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II - LAG3, 4 1BB-4 1BB ligand, 0X40-0X40 ligand, GITR, GITR ligand - GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM - B TLA, HVEM - CD160, HVEM - LIGHT, HVEM-BTLA-CD 160, CD80, CD80 - PDL-1, PDL2 - CD80, CD244, CD48 - CD244, CD244, ICOS, ICOS-ICOS ligand, B7 H3, B7 1 14. 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-CXCLI2, Phosphatidylserine, TIM3, Phosphatidylserine - TIM3, SIRPA-CD47, VEGF, Neuropilin, CD 160, CD30, and CD155 (e.g, CTLA-4 or PD1 or PD-L1). 79. The method of any one of clauses 72-78, wherein the compound is administered intratumorally.

[0748] 80. A method of inducing an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as defined in any one of clauses 1-53, or a pharmaceutical composition as defined in clause 54.

[0749] 81. The method of clause 80, wherein the subject has cancer.

[0750] 82. The method of clause 81, wherein the subject has undergone and / or is undergoing and / or will undergo one or more cancer therapies.

[0751] 83. The method of clause 81, wherein the cancer selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma.

[0752] 84. The method of clause any one of clauses 80-83, wherein the cancer is a refractory cancer.

[0753] 85. The method of clause 80, wherein the immune response is an innate immune response.

[0754] 86. The method of clause 82, wherein the at least one or more cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof. 87. The method of clause 86, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.

[0755] 88. Tire method of clause 87, wherein the one or more additional chemotherapeutic agents is selected from alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and / or oxaliplatin); an anti -metabolite (e.g., azathioprine and / or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and / or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and / or Vindesine Taxol, Pacllitaxel and / or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and / or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and / or topotecan;. amsacrine, etoposide, etoposide phosphate and / or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and / or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Dachzumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and / or Trastuzumab); an anti -angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti -helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1 - PD-L1, PD-1 - PD-L2, interleukin 2 (IL 2), indoleamine 2, 3 -dioxygenase (IDO), IL- 10, transforming growth factor-p (TGFp), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9 - TIMS, Phosphatidylserine - TTM3, lymphocyte activation gene 3 protein (LAG3), MHC class II - LAG3, 4 1BB-4 IBB ligand, 0X40-0X40 ligand, GITR, GITR ligand - GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40- CD40 ligand, HVEM- LIGHT LTA, HVEM, HVEM - BTLA, HVEM - CD 160, HVEM - LIGHT, HVEM-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, T1G1T 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).

[0756] 89. A method of treatment of a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and / or symptoms and / or progression of the disease, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of clauses 1-53, or a pharmaceutical composition as defined in clause 54.

[0757] 90. A method of treatment comprising administering to a subject having a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and / or symptoms and / or progression of the disease an effective amount of a compound as defined in any one of clauses 1-53, or a pharmaceutical composition as defined in clause 54.

[0758] 91. A method of treatment comprising administering to a subject a compound as defined m any one of clauses 1-53, or a pharmaceutical composition as defined in clause 54, wherein the compound or composition is administered in an amount effective to treat a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and / or symptoms and / or progression of the disease, thereby treating the disease.

[0759] 92. Tire method of any one of clauses 89-91, wherein the disease is cancer.

[0760] 93. The method of clause 92, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma. myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma.

[0761] 94. Tire method of clause 92 or 93, wherein the cancer is a refractor}' cancer.

[0762] 95. The method of any one of clauses 91-94, wherein the compound is administered in combination with one or more additional cancer therapies.

[0763] 96. The method of clause 95, wherein the one or more additional cancer therapies comprises surgery', radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

[0764] 97. The method of clause 96, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.

[0765] 98. The method of clause 97, wherein the one or more additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and / or oxaliplatin); an anti -metabolite (e.g., azathioprine and / or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and / or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and / or Vindesine Taxol, Pacllitaxel and / or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and / or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and / or topotecan;. amsacrine, etoposide, etoposide phosphate and / or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracy clines, doxorubicin, dauiiorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and / or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab~CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and / or Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitor}' agent; an anti -helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1 - PD-L1, PD-1 - PD-L2, interleukin 2 (IL 2), indoleamine 2,3 -dioxygenase (IDO), IL 10, transforming growth factor-p (TGFp), T cell immunoglobulin and mucin 3 (TTM3 or HAVCR2), Galectin 9 - TIM3, Phosphatidylserine - TIMS, lymphocyte activation gene 3 protein (LAG3), MHC class II - LAG3, 4 IBB -4 IBB ligand, 0X40-0X40 ligand, GITR, GITR ligand - GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM- -LIGHT- -LTA, HVEM, H VI XI - BTLA, HVEM - CD 160, HVEM - LIGHT, HVEM-BTLA-CD160, CD80, CD80 - PDL-1, PDL2 - CD80, CD244, CD48 - CD244, CD244, ICOS, ICOS-ICOS ligand, B7 FI3, B7 H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, K I Rs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICE, 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 CD! 55 (e.g., CTLA-4 or PD1 or PD-L1).

[0766] 99. The method of any one of clauses 91-98, wherein the compound is administered intratumorally.

[0767] 100. A method of treatment of a disease, disorder, or condition associated with STING, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of clauses 1-53, or a pharmaceutical composition as defined in clause 54.

[0768] 101. The method of clause 100, wherein the disease, disorder, or condition is selected from type I interferonopathies, Aicardi-Goutieres Syndrome (AGS), genetic forms of lupus, inflammation-associated disorders, and rheumatoid arthritis.

[0769] 102. The method of clause 101, wherein the disease, disorder, or condition is a type I interferonopathy (e.g., STING-associated vasculopathywith onset in infancy (SAVI)). 103. The method of clause 102, wherein the type I interferonopathy is STTNG-associated vasculopathy with onset in infancy (SAVI)).

[0770] 104. The method of clause 101, wherein the disease, disorder, or condition is Aicardi-Goutieres Syndrome (AGS).

[0771] 105. The method of clause 101, wherein the disease, disorder, or condition is a genetic form of lupus.

[0772] 106. The method of cl ause 101, wherein the disease, disorder, or condition is inflammation-associated disorder.

[0773] 107. The method of clause 106, wherein the inflammation-associated disorder is systemic lupus erythematosus.

[0774] 108. The method of any one of clauses 55-107, wherein the method further comprises identifying the subject.

[0775] 109. A combination comprising a compounds defined in any one of clauses 1-53 or a pharmaceutically acceptable salt or tautomer thereof, and one or more therapeutically active agents.

[0776] 110. A compound defined in any one of clauses 1-53 or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 54, for use as a medicament.

[0777] 111. A...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:L is a bond or -O-;R1is halo or C1-C4 alkyl;R2is selected from the group consisting of:• C1-C6 alkyl optionally substituted with 1-6 independently selected Ra;® 5 membered heteroaryl optionally substituted with 1 Rb;® C3-C7 cycloalkyl, which is optionally substituted with 1-4 independently selected Rc; and® C4-C7 cycloalkenyl, which is optionally substituted with 1-4 independently selected Rc;R3i, R32, and R33are each, independently, halo or H;R34is H or F; each occurrence of Rais, independently, -OH or halo;Rbis selected from the group consisting of C1-C6 alkyl optionally substituted with 1-4 independently selected Rbl; C3-C5 cycloalkyl optionally substituted with 1-2 independently selelcted halo; and -SO2N(C1-C4 alkyl)i; each occurrence of Rcis, independently, -OH or C1-C4 alkyl optionally substituted with 1 -4 substituents independently selected from -OH and halo; andRbsis -OH, halo, or C3-C5 cycloalkyl optionally substituted with 1-2 halo.

2. The compound of claim 1, wherein L is a bond.

3. The compound of claim 1, wherein L is -O-.

4. Tire compound of any one of claims 1-3, wherein R1is C1-C4 alkyl.

5. The compound of any one of claims 1-4, wherein R1is CH-j.

6. Hie compound of any one of claims 1-3 and 5, wherein R1is halo,7. The compound of any one of claims 1-6, wherein R2is CT-C6 alkyl optionally substituted with 1-6 independently selected R3.

8. The compound of any one of claims 1-7, wherein R2is C1-C6 alkyl substituted with 1-6 independently selected Ra, optionally wherein R2is C1-C6 alkyl substituted with 1-6 substituents independently selected from the group consisting of- OH and F.

9. The compound of any one of claims 1-8, wherein R2is selected from the10. The compound of any one of claims 1-6, wherein R2is 5 membered heteroaryl optionally substituted with 1 Rb,11. The compound of any one of claims 1-6 and 10, wherein R2is 5 membered heteroaryl substituted with 1 Rb.

12. The compound of any one of claims 1-6 and 10-11, wherein the 5 membered heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl.

13. Tire compound of any one of claims 1-6 and 10-12, wherein the 5 membered heteroaryl is imidazolyl, pyrazolyl, or thiazolyl.

14. The compound of any one of claims 1-6 and 10-13, wherein R2is selected from the group consisting of15. Hie compound of any one of claims 1-6, wherein R2is C3-C7 cycloalkyl optionally substituted with 1-4 independently selected Rc.

16. The compound of any one of claims 1-6, and 15 wherein R2is C5-C6 cycloalkyl substituted with 1-2 independently selected R' : optionally wherein R2is C6 cycloalkyl substituted with 1-2 independently selected Rc.

17. Tire compound of any one of claims 1-6, and 15-16 wherein R2is selected from the group consisting of18. The compound of claim 17, wherein R2is19. The compound of any one of claims 1-6, wherein R2is C4-C7 cycloalkenyl substituted with 1-2 independently selected Rc.

20. The compound of any one of claims 1-6 and 19, wherein R2is C5-C6 cycloalkenyl substituted with 1-2 independently selected Rc, optionally wherein R2isC6 cycloalkenyl substituted with 1-2 independently selected Rc, optionally wherein R221. The compound of any one of claims 1-20, wherein one or two of R31,R32, and R33are an independently selected halo, and the others are hydrogen; optionallywherein one or two of R31, R32, and R33are independently fluoro or chloro, and the others are hydrogen.

22. Tire compound of any one of claims 1-21 , wherein R31is H; and R32and R33are an independently selected halo; optionally wherein R31is H; and R32and R33are independently fluoro or chloro.

23. The compound of any one of claims 1-22, wherein R31is H; R32is F, and R33is Cl or F.

24. The compound of any one of claims 1-22, wherein R31is H; R32is F, and R33is H.

25. The compound of any one of claims 1-24, wherein Rbis alkyl optionally substituted with 1-4 RM; optionally wherein Rbis alkyl substituted with 1-4 RM; optionally wherein Rbis alkyl substituted with 1 Rbl.

26. The compound of any one of claims 1-25, wherein Rbl, or each occurrence of Rbi, is independently selected from the group consisting of -OH and halo; optionally wherein Rbl, or each occurrence of Rbl, is independently selected from the group consisting of -OH and F.

27. The compound of any one of claims 1-26, wherein Rbis selected from28. The compound of any one of claims 1 -25, wherein Rbl, or each occurrence of Rbs, is C3-C5 cycloalkyl optionally substituted with 1-2 halo.

29. The compound of any one of claims 1-25 and 28, wherein Rbis30. The compound of any one of claims 1 -25, wherein Rbis -SO2N(C1-C4 alkyl)?..

31. The compound of any one of claims 1-30, wherein Rcis -OH32. The compound of any one of claims 1-30, wherein Rtis C1-C4 alkyl optionally substituted with 1-4 substituents independently selected from -OH and halo; optionally wherein Rcis C1-C4 alkyl optionally substituted with 1-4 substituents independently selected from -OH and fluoro.

33. The compound of any one of claims 1-30 and 32, wherein R' is C1-C4 alkyl that is substituted with 1-4 substituents independently selected from -OH and halo.

34. The compound of any one of claims 1-30 and 32-33, wherein Reis Cl- C4 alkyl that is substituted with 1-4 substituents independently selected from -OH and fluoro.

35. The compound of any one of claims 1-30 and 32-34, wherein R£is CT- C4 alkyl substituted with -OH.

36. The compound of any one of claims 1-30 and 32-35, wherein Rcis37. The compound of any one of claims 1-30 and 32-35, wherein Rcis38. The compound of tiny one of claims 1-30, wherein Rcis CH?. claims 1-38, wherein R3‘* is H.

40. The compound of claim 1, wherein the compound has formula (II):

41. The compound of claim 40, wherein L is a bond.

42. The compound of claim 40 or 41, wherein R2is C3-C6 cycloalkyl optionally substituted with 1-4 independently selected Rc.

43. The compound of any one of claims 40-42, wherein R2is C5-C6 cycloalkyl optionally substituted with 1 -4 independently selected R£.

44. The compound of any one of claims 40-43, wherein R2is C6 cycloalkyl optionally substituted with 1-4 independently selected R£. optionally wherein R2is C6 cycloalkyl that is optionally substituted with 1 R£; optionally wherein R2is C6 cycloalkyl that is substituted with 1 -4 independently selected R£, optionally wherein R2is C6 cycloalkyl that is substituted with 1 Rc.

45. The compound of any one of claims 40-44, wherein R2is46. The compound of any one of claims 40-45, wherein R£is C1-C4 alkyl optionally substituted w7ith 1-4 substituents independently selected from hydroxyl or halo; optionally wherein R' is C1-C4 alkyl optionally substituted with 1-4 substituents independently selected from hydroxyl or fluoro.

47. Tire compound of any one of claims 40-46, wherein Rcis C1-C2 alkyl optionally substituted with 1-4 substituents independently selected from hydroxyl or halo, optionally wherein R£is C1-C2 alkyl optionally substituted with hydroxyl.

48. The compound of any one of claims 40-47, wherein Rcis49. The compound of claim 40 or 41, wherein R2is 5 membered heteroaryl substituted with 1 Rb, optionally wherein the 5 membered heteroaryl is imidazolyl, pyrazolyl, or thiazolyl, optionally wherein R2is selected from the group consisting of50. The compound of claim 40 or 41, wherein R2is C1-C6 alkyl optionally substituted with 1-6 independently selected Ra, optionally wherein R2is C1-C6 alkyl substituted with 1-6 independently selected Ra, optionally wherein R2is C1-C6 alkyl substituted with 1-6 substituents independently selected from the group consisting of- OH and F.

51. The compound of claim 50, wherein R2is selected from the group52. The compound of any one of claims 40-51 , wherein R32is F.

53. The compound of claim 1, wherein the compound is selected from the group consisting of the compounds delineated in Table Cl or a pharmaceutically acceptable salt thereof.

54. A pharmaceutical composition comprising a compound of any one of claims 1-53, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

55. A method for inhibiting STING activity, the method comprising contacting STING with a compound as claimed in any one of claims 1-53, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition as claimed in claim 54.

56. A method of inducing an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as claimed in any one of claims 1-53, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition as claimed in claim 54.

57. A method of treatment of disease, disorder, or condition associated with STING, such as a disease, disorder, or condition, m which increased STING signaling, such as excessive STING signaling, contributes to the pathology and / or symptoms and / or progression of the disease, such as cancer, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-53, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 54.

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