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 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

TECHNICAL FIELD

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

BACKGROUND

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

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

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

SUMMARY

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

An “antagonist” of STING includes compounds that, at the protein level, directly bind or modify STING such that an activity of STING is decreased, e.g., by inhibition, blocking or dampening agonist-mediated responses, altered distribution, or otherwise. STING antagonists include chemical entities, which interfere or inhibit STING signaling.

In one aspect, compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are featured:

in which Z, Y¹, Y², Y³, X¹, X², R⁶, P¹, P², P³, P⁴, and P⁵ can be as defined anywhere herein.

In one aspect, compounds of Formula (II), or a pharmaceutically acceptable salt thereof, are featured:

in which X¹, X², R⁶, P¹, P², P³, P⁴, and P⁵ can be as defined anywhere herein.

In one aspect, compounds of Formula (III), or a pharmaceutically acceptable salt thereof, are featured:

in which R^1a, R^1b, R^1c, X¹, X², R⁶, P¹, P², P³, P⁴, and P⁵ can be as defined anywhere herein.

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

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

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

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

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

In another aspect, methods of suppressing STING-dependent type I interferon production in a subject in need thereof are featured that include administering to the subject an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Embodiments can include one or more of the following features.

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

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

The chemical entity can be administered in combination with one or more additional cancer therapies (e.g., surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof, e.g., chemotherapy that includes administering one or more (e.g., two, three, four, five, six, or more) additional chemotherapeutic agents. Non-limiting examples of additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g., azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti-helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

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

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

The chemical entity can be administered intratumorally.

The methods can further include identifying the subject.

Other embodiments include those described in the Detailed Description and/or in the claims.

Additional Definitions

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

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

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

“API” refers to an active pharmaceutical ingredient.

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

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

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

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

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

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

The term “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C_1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents.

Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.

The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo.

The term “alkoxy” refers to an —O-alkyl radical (e.g., —OCH₃).

The term “alkylene” refers to a divalent alkyl (e.g., —CH₂—).

The term “alkenyl” refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C_2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkenyl groups can either be unsubstituted or substituted with one or more substituents.

The term “alkynyl” refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C_2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups can either be unsubstituted or substituted with one or more substituents.

The term “aryl” refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, dihydro-1H-indenyl and the like.

The term “cycloalkyl” as used herein refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl includes: bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.2.0]octanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[2.6]nonanyl, spiro[4.5]decanyl, spiro[3.6]decanyl, spiro[5.5]undecanyl, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms.

The term “cycloalkenyl” as used herein means partially unsaturated cyclic hydrocarbon groups having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As partially unsaturated cyclic hydrocarbon groups, cycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the cycloalkenyl group is not fully saturated overall. Cycloalkenyl may include multiple fused and/or bridged and/or spirocyclic rings.

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

The term “heterocyclyl” refers to a mon-, bi-, tri-, or polycyclic saturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butanyl, 2-azabicyclo[2.1.0]pentanyl, 2-azabicyclo[1.1.1]pentanyl, 3-azabicyclo[3.1.0]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[3.2.0]heptanyl, octahydrocyclopenta[c]pyrrolyl, 3-azabicyclo[4.1.0]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 7-azabicyclo[4.2.0]octanyl, 2-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl, 2-oxabicyclo[1.1.0]butanyl, 2-oxabicyclo[2.1.0]pentanyl, 2-oxabicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.2.0]heptanyl, 3-oxabicyclo[4.1.0]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 7-oxabicyclo[4.2.0]octanyl, 2-oxabicyclo[2.2.2]octanyl, 3-oxabicyclo[3.2.1]octanyl, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentanyl, 4-azaspiro[2.5]octanyl, 1-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[4.4]nonanyl, 6-azaspiro[2.6]nonanyl, 1,7-diazaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl 2,5-diazaspiro[3.6]decanyl, 3-azaspiro[5.5]undecanyl, 2-oxaspiro[2.2]pentanyl, 4-oxaspiro[2.5]octanyl, 1-oxaspiro[3.5]nonanyl, 2-oxaspiro[3.5]nonanyl, 7-oxaspiro[3.5]nonanyl, 2-oxaspiro[4.4]nonanyl, 6-oxaspiro[2.6]nonanyl, 1,7-dioxaspiro[4.5]decanyl, 2,5-dioxaspiro[3.6]decanyl, 1-oxaspiro[5.5]undecanyl, 3-oxaspiro[5.5]undecanyl, 3-oxa-9-azaspiro[5.5]undecanyl and the like. The term “saturated” as used in this context means only single bonds present between constituent ring atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.

The term “heterocycloalkenyl” as used herein means partially unsaturated cyclic ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocycloalkenyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl. As partially unsaturated cyclic groups, heterocycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the heterocycloalkenyl group is not fully saturated overall. Heterocycloalkenyl may include multiple fused and/or bridged and/or spirocyclic rings.

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

As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself, e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.0] ring systems, in which 0 represents a zero atom bridge

(ii) a single ring atom (spiro-fused ring systems)

or (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths>0)

In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ¹³C and ¹⁴C.

In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety:

encompasses the tautomeric form containing the moiety:

Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

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

DETAILED DESCRIPTION

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

Formula I, II, and III Compounds

In one aspect, the disclosure features compounds of Formula (I):

or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

P¹, P², P³, P⁴, and P⁵ are each independently selected from the group consisting of: N, NH, NR^d, NR⁷, CH, CR^c, CR⁷, and C(═O), provided that 1-3, such as 1, of P², P³, and P⁴ is CR⁷ or NR⁷;

each occurrence of R⁷ is independently -(L^A)_a1-R⁸, wherein:

each L^A is independently selected from the group consisting of: C_1-3 alkylene optionally substituted with 1-4 R^a1; —O—; —NR^N; —S(O)_0-2; C(O); C(O)O; OC(O); NR^NC(O); C(O)NR^N; NR^NC(O)NR^N; NR^NC(O)O; and OC(O)NR^N;

a1 is 0, 1, 2, or 3; and

each occurrence of R⁸ is independently R^g or C_1-10 alkyl optionally substituted with 1-6 R^a1;

Z, Y¹, Y², and Y³ are independently selected from the group consisting of CR¹, C(═O), N, and NR²;

X¹ is selected from the group consisting of O, S, N, NR², and CR¹;

X² is selected from the group consisting of O, S, N, NR⁴, and CR⁵; provided that:

(1) when each one of Z, Y¹, and Y² is CR¹, then Y³ cannot be N; and

(2) when each one of Z, Y¹, Y², and Y³ is CR¹, then at least one R¹ is other than H;

each is independently a single bond or a double bond, provided that the five-membered ring comprising X¹ and X² is heteroaryl; the six-membered ring comprising Z, Y¹, Y², and Y³ is aryl or heteroaryl; and the six-membered ring comprising P¹, P², P³, P⁴, and P⁵ is aryl or heteroaryl;

each R¹ is independently selected from the group consisting of: H; R^c; R^g; and -(L¹)_b1-R^g;

each R² is independently selected from the group consisting of: H; R^d; R^g; and -(L²)_b2-R^g;

R⁴ is selected from the group consisting of: H and R^d;

R⁵ is selected from the group consisting of: H; R^c; and R^h;

R⁶ is selected from the group consisting of: H; R^d; and R^h;

each occurrence of R^a and R^a1 is independently selected from the group consisting of: —OH; -halo; —NR^eR^f; C_1-4 alkoxy; C_1-4 haloalkoxy; —C(═O)O(C_1-4 alkyl); —C(═O)(C_1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4 alkyl); and cyano;

each occurrence of R^c is independently selected from the group consisting of: halo; cyano; C_1-10 alkyl which is optionally substituted with 1-6 independently selected R^a; C_2-6 alkenyl; C_2-6 alkynyl; C_1-4 alkoxy optionally substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkoxy; —S(O)_1-2(C_1-4 alkyl); —S(O)(═NH)(C_1-4 alkyl); —NR^eR^f; —OH; —S(O)_1-2NR′R″; —C_1-4 thioalkoxy; —NO₂; —C(═O)(C_1-10 alkyl); —C(═O)O(C_1-4 alkyl); —C(═O)OH; —C(═O)NR′R″; and —SF₅;

each occurrence of R^d is independently selected from the group consisting of: C_1-6 alkyl optionally substituted with 1-3 independently selected R^a; —C(O)(C_1-4 alkyl); —C(O)O(C_1-4 alkyl); —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4 alkyl); —OH; and C_1-4 alkoxy;

each occurrence of R^e and R^f is independently selected from the group consisting of: H; C_1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, and Rⁱ; —C(O)(C_1-4 alkyl); —C(O)O(C_1-4 alkyl); —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4 alkyl); —OH; and C_1-4 alkoxy;

each occurrence of R^g is independently selected from the group consisting of:

• • C_3-12 cycloalkyl or C_3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_bg-R^h;
  • heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_bg-R^h;
  • heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R^c, R^h, and -(L^g)_bg-R^h; and
  • C_6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R^c, R^h, and -(L^g)_bg-R^h;

each occurrence of R^h is independently selected from the group consisting of:

• • C_3-12 cycloalkyl or C_3-12 cycloalkenyl, each of which is optionally substituted with 1-4 Rⁱ;
  • heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 Rⁱ;
  • heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rⁱ; and
  • C_6-10 aryl optionally substituted with 1-4 Rⁱ;

each occurrence of R¹ is independently selected from the group consisting of: C_1-6 alkyl; C_1-4 haloalkyl; C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-6 alkyl-O—C_1-6 alkyl-; C_1-4 haloalkyl-O—C_1-6 alkyl-; halo; cyano; —OH; —NR′R″; and C_3-6 cycloalkyl;

each occurrence of L¹, L², and L^g is independently selected from the group consisting of: —O—, —NH—, —NR^d, —S(O)_0-2, C(O), and C_1-3 alkylene optionally substituted with 1-3 R^a;

b1, b2, and bg are each independently 1, 2, or 3;

each occurrence of R′ and R″ is independently selected from the group consisting of: H; —OH; and C_1-4 alkyl; and

each occurrence of R^N is independently H or R^d;

provided that the six-membered ring including P¹, P², P³, P⁴, and P⁵ is other than:

In some embodiments of Formula (I), from 0-1 of Z, Y¹, Y², and Y³ is N or NR².

In some embodiments of Formula (I), it is provided that one or more of the compound provisions herein apply.

In another aspect, provided herein is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

P¹, P², P³, P⁴, and P⁵ are each independently selected from the group consisting of: N, NH, NR^d, NR⁷, CH, CR^c, CR⁷, and C(═O), provided that 1-3, such as 1, of P², P³, and P⁴ is CR⁷ or NR⁷;

• • each occurrence of R⁷ is independently -(L^A)_a1-R⁸, wherein:
  • each L^A is independently selected from the group consisting of: C_1-3 alkylene optionally substituted with 1-2 R^a1; —O—; —NR^N; —S(O)_0-2; C(O); C(O)O; OC(O); NR^NC(O); C(O)NR^N; NR^NC(O)NR^N; NR^NC(O)O; and OC(O)NR^N;

a1 is 0, 1, 2, or 3; and

each occurrence of R⁸ is independently R^g or C_1-10 alkyl optionally substituted with 1-6 R^a1;

X¹ is selected from the group consisting of O, S, N, NR², and CR¹;

X² is selected from the group consisting of O, S, N, NR⁴, and CR⁵;

each is independently a single bond or a double bond, provided that the five-membered ring comprising X¹ and X² is heteroaryl; and the six-membered ring comprising P¹, P², P³, P⁴, and P⁵ is aryl or heteroaryl;

R¹ is selected from the group consisting of: H; R^c; R^g; and -(L¹)_b1-R^g;

R² is selected from the group consisting of: H; R^d; R^g; and -(L²)_b2-R^g;

R⁴ is selected from the group consisting of: H and R^d;

R⁵ is selected from the group consisting of: H; R^c; and R^h;

R⁶ is selected from the group consisting of: H; R^d; and R^h, each occurrence of R^a and R^a1 is independently selected from the group consisting of: —OH; -halo; —NR^eR^f; C_1-4 alkoxy; C_1-4 haloalkoxy; —C(═O)O(C_1-4 alkyl); —C(═O)(C_1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4 alkyl); and cyano;

each occurrence of R^c is independently selected from the group consisting of: halo; cyano; C_1-10 alkyl which is optionally substituted with 1-6 independently selected R^a; C_2-6 alkenyl; C_2-6 alkynyl; C_1-4 alkoxy optionally substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkoxy; —S(O)_1-2(C_1-4 alkyl); —S(O)(═NH)(C_1-4 alkyl); —NR^eR^f; —OH; —S(O)_1-2NR′R″; —C_1-4 thioalkoxy; —NO₂; —C(═O)(C_1-10 alkyl); —C(═O)O(C_1-4 alkyl); —C(═O)OH; —C(═O)NR′R″; and —SF₅;

each occurrence of R^d is independently selected from the group consisting of: C_1-6 alkyl optionally substituted with 1-3 independently selected R^a; —C(O)(C_1-4 alkyl); —C(O)O(C_1-4 alkyl); —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4 alkyl); —OH; and C_1-4 alkoxy;

each occurrence of R^e and R^f is independently selected from the group consisting of: H; C_1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, and Rⁱ; —C(O)(C_1-4 alkyl); —C(O)O(C_1-4 alkyl); —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4 alkyl); —OH; and C_1-4 alkoxy;

each occurrence of R^g is independently selected from the group consisting of:

• • C_3-12 cycloalkyl or C_3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_bg-R^h;
  • heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_bg-R^h;
  • heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R^c, R^h, and -(L^g)_bg-R^h; and
  • C_6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R^c, R^h, and -(L^g)_bg-R^h;

each occurrence of R^h is independently selected from the group consisting of:

• • C_3-12 cycloalkyl or C_3-12 cycloalkenyl, each of which is optionally substituted with 1-4 Rⁱ;
  • heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 Rⁱ;
  • heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rⁱ; and
  • C_6-10 aryl optionally substituted with 1-4 Rⁱ;

each occurrence of R¹ is independently selected from the group consisting of: C_1-6 alkyl; C_1-4 haloalkyl; C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-6 alkyl-O—C_1-6 alkyl-; C_1-4 haloalkyl-O—C_1-6 alkyl-; halo; cyano; —OH; —NR′R″; and C_3-6 cycloalkyl;

each occurrence of L¹, L², and L⁹ is independently selected from the group consisting of: —O—, —NH—, —NR^d, —S(O)_0-2, C(O), and C_1-3 alkylene optionally substituted with 1-3 R^a;

b1, b2, and bg are each independently 1, 2, or 3;

each occurrence of R′ and R″ is independently selected from the group consisting of: H; —OH; and C_1-4 alkyl; and

each occurrence of R^N is independently H or R^d.

In some embodiments of Formula (II), it is provided that the ring including P¹, P², P³, P⁴, and P⁵ is other than:

(i) phenyl, pyridyl, or pyrimidinyl, each substituted with one substituent selected from the group consisting of: OMe; CH₂NH₂; CH₂NHC(O)OMe; CH₂NHC(O)OEt; CH₂NHC(O)Me; CH₂NHC(O)N(Me)₂; CH₂NHS(O)₂Me; methyl; tert-butyl; NHMe; morpholinyl; CH₂OH; 1,2,4-triazolyl; or trisubstituted pyrazolyl;

(ii) pyrimidinyl substituted with two substituents each independently selected from the group consisting of: methyl, ethyl, and pyrrolidinyl; and

In some embodiments of Formula (II), it is provided that one or more of the compound provisions herein apply.

In another aspect, provided herein is a compound of Formula (III)

or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

P¹, P², P³, P⁴, and P⁵ are each independently selected from the group consisting of: N, NH, NR^d, NR⁷, CH, CR^c, CR⁷, and C(═O), provided that 1-3, such as 1, of P², P³, and P⁴ is CR⁷ or NR⁷;

each occurrence of R⁷ is independently -(L^A)_a1-R⁸, wherein:

each L^A is independently selected from the group consisting of: C_1-3 alkylene optionally substituted with 1-2 R^a1; —O—; —NR^N; —S(O)_0-2; C(O); C(O)O; OC(O); NR^NC(O); C(O)NR^N; NR^NC(O)NR^N; NR^NC(O)O; and OC(O)NR^N;

a1 is 0, 1, 2, or 3; and

each occurrence of R⁸ is independently R^g or C_1-10 alkyl optionally substituted with 1-6 R^a1;

X¹ is selected from the group consisting of O, S, N, NR², and CR¹;

X² is selected from the group consisting of O, S, N, NR⁴, and CR⁵; provided that:

each is independently a single bond or a double bond, provided that the five-membered ring comprising X¹ and X² is heteroaryl; and the six-membered ring comprising P¹, P², P³, P⁴, and P⁵ is aryl or heteroaryl;

R¹, R^1a, R^1b, and R^1c are each independently selected from the group consisting of: H; R^c; R^g; and -(L¹)_b1-R^g;

each R² is independently selected from the group consisting of: H; R^d; R^g; and -(L²)_b2-R^g,

R⁴ is selected from the group consisting of: H and R^d;

R⁵ is selected from the group consisting of: H; R^c; and R^h;

R⁶ is selected from the group consisting of: H; R^d; and R^h, each occurrence of R^a and R^a1 is independently selected from the group consisting of: —OH; -halo; —NR^eR^f; C_1-4 alkoxy; C_1-4 haloalkoxy; —C(═O)O(C_1-4 alkyl); —C(═O)(C_1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4 alkyl); and cyano;

each occurrence of R^c is independently selected from the group consisting of: halo; cyano; C_1-10 alkyl which is optionally substituted with 1-6 independently selected R^a; C_2-6 alkenyl; C_2-6 alkynyl; C_1-4 alkoxy optionally substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkoxy; —S(O)_1-2(C_1-4 alkyl); —S(O)(═NH)(C_1-4 alkyl); —NR^eR^f; —OH; —S(O)_1-2NR′R″; —C_1-4 thioalkoxy; —NO₂; —C(═O)(C_1-10 alkyl); —C(═O)O(C_1-4 alkyl); —C(═O)OH; —C(═O)NR′R″; and —SF₅;

each occurrence of R^d is independently selected from the group consisting of: C_1-6 alkyl optionally substituted with 1-3 independently selected R^a; —C(O)(C_1-4 alkyl); —C(O)O(C_1-4 alkyl); —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4 alkyl); —OH; and C_1-4 alkoxy;

each occurrence of R^e and R^f is independently selected from the group consisting of: H; C_1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, and Rⁱ; —C(O)(C_1-4 alkyl); —C(O)O(C_1-4 alkyl); —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4 alkyl); —OH; and C_1-4 alkoxy;

each occurrence of R^g is independently selected from the group consisting of:

• • C_3-12 cycloalkyl or C_3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_bg-R^h;
  • heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_bg-R^h;
  • heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R^c, R^h, and -(L^g)_bg-R^h; and
  • C_6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R^c, R^h, and -(L^g)_bg-R^h;

each occurrence of R^h is independently selected from the group consisting of:

• • C_3-12 cycloalkyl or C_3-12 cycloalkenyl, each of which is optionally substituted with 1-4 Rⁱ;
  • heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 Rⁱ;
  • heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rⁱ; and
  • C_6-10 aryl optionally substituted with 1-4 Rⁱ;

each occurrence of Rⁱ is independently selected from the group consisting of: C_1-6 alkyl; C_1-4 haloalkyl; C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-6 alkyl-O—C_1-6 alkyl-; C_1-4 haloalkyl-O—C_1-6 alkyl-; halo; cyano; —OH; —NR′R″; and C_3-6 cycloalkyl;

each occurrence of L¹, L², and L^g is independently selected from the group consisting of: —O—, —NH—, —NR^d, —S(O)_0-2, C(O), and C_1-3 alkylene optionally substituted with 1-3 R^a;

b1, b2, and bg are each independently 1, 2, or 3;

each occurrence of R′ and R″ is independently selected from the group consisting of: H; —OH; and C_1-4 alkyl; and

each occurrence of R^N is independently H or R^d.

In some embodiments of Formula (III), it is provided that R^1a is other than monocyclic heterocyclyl of 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_bg-R^h.

In some embodiments of Formula (III), it is provided that the ring including P¹, P², P³, P⁴, and P⁵ is other than:

(ii) phenyl, pyridyl, pyridonyl, or pyridazinonyl substituted with one substituent selected from the group consisting of: OMe; methyl; trifluoromethyl; NHC(O)Me; NMe₂; CH₂CH₂-pyrrolindinyl; or

(iii) 3-fluoro-4-methoxyphenyl; 2-fluoro-5-methylphenyl; or dimethoxypyridyl.

In some embodiments of Formula (III), it is provided that one or more of the compound provisions herein apply.

The Variables Z, Y¹, Y², Y³, X¹, and X²

In some embodiments of Formula (I), each of Z, Y¹, Y², and Y³ is independently N or CR¹.

In some embodiments, the compound of Formula (I) is a compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein: R^1a, R^1b, R^1c, and R^1d are each an independently selected R¹.

In some embodiments of Formula (I), one of Z, Y¹, and Y² is N; and each remaining of Z, Y¹, Y², and Y³ is an independently selected CR¹.

In some embodiments, the compound of Formula (I) is selected from the group consisting of a compound of the following formulae:

or a pharmaceutically acceptable salt thereof, wherein: R^1a, R^1b, R^1c, and R^1d are each an independently selected R¹.

In certain of these embodiments, the compound of Formula (I) is a compound of Formula (Ib) or a pharmaceutically acceptable thereof.

In certain embodiments, the compound of Formula (I) is a compound of Formula (Ic) or a pharmaceutically acceptable thereof.

In certain embodiments, the compound of Formula (I) is a compound of Formula (Id) or a pharmaceutically acceptable thereof.

In some embodiments of Formulae (I), (II), or (III), X¹ is NR². In certain embodiments of Formulae (I), (II), or (III), X¹ is NH.

In some embodiments of Formulae (I), (II), or (III), X² is CR⁵. In certain embodiments of Formulae (I), (II), or (III), X² is CH.

In some embodiments of Formulae (I), (II), or (III), X¹ is NR²; and X² is CR⁵. In certain of these embodiments, X¹ is NH; and X² is CH.

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

or a pharmaceutically acceptable salt thereof, wherein: R^1a, R^1b, R^1c, and R^1d are each an independently selected R¹.

In some embodiments, the compound of Formula (I) is selected from the group consisting of a compound of the following formulae:

or a pharmaceutically acceptable salt thereof, wherein: R^1a, R^1b, R^1c, and R^1d are each an independently selected R¹.

In certain of these embodiments, the compound of Formula (I) is a compound of Formula (Ib-1), or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is a compound of Formula (Ic-1), or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is a compound of Formula (Id-1), or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II) is a compound of Formula

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (III) is compound of a compound of Formula (III-1):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formulae (Ia-1), (Ib-1), (Ic-1), (I-d1), (II-1), or (III-1), R² is H. In some embodiments of Formulae (Ia-1), (Ib-1), (Ic-1), (I-d1), (II-1), or (III-1), R⁵ is H. In certain of these embodiments, R² is H; and R⁵ is H.

The Variables R¹, R^1a, R^1b, R^1c, and R^1d.

In some embodiments of Formula (I), from 1-2 R¹ is independently selected from the group consisting of R^c1 and R^g1; and each remaining R¹ is H, wherein R^c1 is an independently selected R^c; and R^g1 is an independently selected R^g.

In certain of these embodiments, two occurrences of R¹ are independently selected from the group consisting of: R^c1 and R¹; and each remaining R¹ is H. In certain embodiments, two occurrences of R¹ are independently selected R^c1; and each remaining R¹ is H. In certain embodiments, one occurrence of R¹ is selected from the group consisting of: R^c1 and R^g1; and each remaining R¹ is H. In certain embodiments, one occurrence of R¹ is R^c1; and each remaining R¹ is H. In certain embodiments, one occurrence of R¹ is R^g1; and each remaining R¹ is H. In certain embodiments, one occurrence of R¹ is R^c1; one occurrence of R¹ is R^g1; and each remaining R¹ is H.

In certain embodiments, each R^c1 is an independently selected halo, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkoxy, or C_1-3 alkyl substituted with from 1-6 independently selected halo, such as wherein R^c1 is —F, —Cl, or —CN. As non-limiting examples of the foregoing embodiments, each R^c1 is independently —F or —Cl, such as —F.

In certain embodiments, each R^g1 is independently selected from the group consisting of:

• • heteroaryl of 5-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of R^c, R^h, and -(L^g)_bg-R^h; and
  • C_6-10 aryl optionally substituted with from 1-4 substituents independently selected from the group consisting of R^c, R^h, and -(L^A)_bg-R^h.

In certain of the foregoing embodiments, each R^g1 is independently selected from the group consisting of:

• • heteroaryl of 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is optionally substituted with from 1-4 R^c; and
  • C₆ aryl optionally substituted with from 1-4 R^c.

In certain embodiments, each R^g1 is independently heteroaryl of 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is optionally substituted with from 1-4 R^c. As non-limiting examples of the foregoing embodiments, each R^g1 can be pyrazolyl that is optionally substituted with from 1-2 R^c, such from 1-2 independently selected C_1-6 (e.g., C_1-3) alkyl which is optionally substituted with from 1-6 independently selected R^a (e.g., unsubstituted C_1-6 (e.g., C_1-3) alkyl). For example, R^g1 can be

and optionally R^c is C_1-6 (e.g., C_1-3) alkyl which is optionally substituted with from 1-6 independently selected R^a.

In certain embodiments, each R^g1 is independently selected from the group consisting of:

• • heteroaryl of 5-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is substituted with one occurrence of R^h1 or -(L^g)_bg-R^h1 (such as R^h1 or —CH₂-R^h1) and further optionally substituted with from 1-2 R^c; and
  • C_6-10 aryl that is substituted with one occurrence of R^h1 or -(L^g)_bg-R^h1 (such as R^h1 or —CH₂—R^h1) and further optionally substituted with from 1-2 R^c, wherein R^h1 is an independently selected R^h.

In certain of these embodiments, each R^g1 is heteroaryl of 5-6 (such as 5) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is substituted with one occurrence of R^h1 or -(L^g)_bg-R^h1 (such as R^h1 or —CH₂—R^h1) and further optionally substituted with from 1-2 R^c, wherein R^h1 is an independently selected R^h. As non-limiting examples of the foregoing embodiments, each R^g1 is pyrazolyl that is substituted with R^h1 or -(L^g)_bg-R^h1 (such as R^h1 or —CH₂R^h1) and further optionally substituted with from 1-2 R^c. For example, each R^g1 can be

each of which is optionally substituted with R^c.

In certain embodiments, R^h1 is selected from the group consisting of:

• • heteroaryl of 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rⁱ; and
  • C₆ aryl optionally substituted with from 1-4 Rⁱ, such as: wherein R^g1 is phenyl optionally substituted with from 1-4 Rⁱ.

In certain of these embodiments, R^h1 is selected from the group consisting of:

• • heteroaryl of 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-2 Rⁱ; and
  • C₆ aryl optionally substituted with from 1-2 Rⁱ, such as wherein R^g1 is phenyl optionally substituted with from 1-4 Rⁱ.

In some embodiments of Formulae (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), (III), or, (III-1), R^1a H.

In some embodiments of Formulae (Ia), (Ib), (Id), (Ia-1), (Ib-1), (Id-1), (III), or, (III-1), R^1b is H.

In some embodiments of Formulae (Ia), (Ib), (Id), (Ia-1), (Ib-1), (Id-1), (III), or, (III-1), R^1b is halo, such as —F or —Cl (e.g., —F).

In some embodiments of Formulae (Ia), (Ib), (Id), (Ia-1), (Ib-1), (Id-1), (III), or, (III-1), R^1b is heteroaryl of 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is optionally substituted with from 1-2 R^c. As non-limiting examples of the foregoing embodiments, R^1b can be pyrazolyl that is optionally substituted with from 1-2 R^c, such as each R^c is an independently selected C_1-6 (e.g., C_1-3) alkyl which is optionally substituted with from 1-6 independently selected R^a (e.g., unsubstituted).

In some embodiments of Formulae (Ia), (Ib), (Id), (Ia-1), (Ib-1), (Id-1), (III), or, (III-1), R^1b is heteroaryl of 5-6 (such as 5) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is substituted with one occurrence of R^h1 or -(L^g)_bg-R^h1 (such as R^h1 or —CH₂—R^h1) and further optionally substituted with from 1-2 R^c, wherein R^h1 is an independently selected R^h. As non-limiting examples of the foregoing embodiments, R^1l can be pyrazolyl that is substituted with R^h1 or -(L^g)_bg-R^h1 (such as R^h1 or —CH₂R^h1) and further optionally substituted with from 1-2 R^c, such as wherein R^1l is

each of which is optionally substituted with R^c.

In some embodiments of Formulae (Ia), (Ic), (Id), (Ia-1), (Ic-1), (Id-1), (III), or, (III-1), R^1c is H.

In some embodiments of Formulae (Ia), (Ic), (Id), (Ia-1), (Ic-1), (Id-1), (III), or, (III-1), R^1c is halo, such as —F or —Cl.

In some embodiments of Formulae (Ia), (Ib), (Ic), (Id), (Ia-1), (Ib-1), (Ic-1), or (Id-1), R^1d is H. In some embodiments of Formulae (Ia), (Ib), (Ic), (Id), (Ia-1), (Ib-1), (Ic-1), or (Id-1), R^1d is halo, such as —F or —Cl (e.g., —F).

In some embodiments of Formulae (Ia), (Ib), (Ic), (Id), (Ia-1), (Ib-1), (Ic-1), (Id-1), (III), or (III-1), R″ and R^1d when present are H; and R^1b and R^1c when present are independently selected halo, such as —F or —Cl, such as —F; such as: wherein R^1b and R^1c when present are —F; or wherein R^1b when present is —F, and R^1c when present is —Cl; or wherein R^1b when present is —Cl, and R^1c when present is —F.

In some embodiments of Formulae (Ia), (Ib), (Ic), (Id), (Ia-1), (Ib-1), (Ic-1), (Id-1), (III), or (III-1), R^1a and R^1d when present are H; one of R^1b and R^1c when present is H; and the other one of R^1b and R^1c when present is halo, such as —F or —Cl, such as —F; such as: wherein R^1b when present is H, and R^1c when present is —F; or wherein R^1b when present is H, and R^1c when present is —Cl; or wherein R^1b when present is —F, and R^1c when present is H; or wherein R^1b when present is —Cl, and R^1c when present is H.

In some embodiments of Formulae (Ia), (Ib), (Ic), (Id), (Ia-1), (Ib-1), (Ic-1), (Id-1), (III), or (III-1), R^1a and R^1d when present are H; R^1c when present is halo or H, such as —F, —Cl, or H; and R^1b when present is heteroaryl of 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is optionally substituted with from 1-4 R^c.

In some embodiments of Formulae (Ia), (Ib), (Ic), (Id), (Ia-1), (Ib-1), (Ic-1), (Id-1), (III), or (III-1), R^1a and R^1d when present are H; R^1c when present is halo or H, such as —F, —Cl, or H; and R^1b when present is heteroaryl of 5-6 (such as 5) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is substituted with one occurrence of R^h1 or -(L^g)_bg-R^h1 (such as R^h1 or —CH₂—R^h1) and further optionally substituted with from 1-2 R^c, wherein R^h1 is an independently selected R^h.

In some embodiments of Formulae (Ia) or (Ia-1), R^1a and R^1d are H; and R^1b and R^1c are independently selected halo, such as —F or —Cl, such as —F; such as: wherein R^1b and R^1c are —F; or wherein R^1b is —F, and R^1c is —Cl; or wherein R^1b is —Cl, and R^1c is —F.

In some embodiments of Formulae (Ia) or (Ia-1), R^1a and R^1d are H; one of R^1b and R^1c is H; and the other one of R^1b and R^1c is halo, such as —F or —Cl, such as —F; such as: wherein R^1b is H, and R^1c is —F; or wherein R^1b is H, and R^1c is —Cl; or wherein R^1b is —F, and R^1c is H; or wherein R^1b is —Cl, and R^1c is H.

In some embodiments of Formulae (Ia) or (Ia-1), R^1a and R^1d are H; R^1c is halo or H, such as —F, —Cl, or H; and R^1b is heteroaryl of 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is optionally substituted with from 1-4 R^c.

In some embodiments of Formulae (Ia) or (Ia-1), R^1a and R^1d are H; R^1c is halo or H, such as —F, —Cl, or H; and R^1b is heteroaryl of 5-6 (such as 5) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is substituted with one occurrence of R^h1 or -(L^g)_bg-R^h1 (such as R^h1 or —CH₂—R^h1) and further optionally substituted with from 1-2 R^c, wherein R^h1 is an independently selected R^h.

The Variable R⁶

In some embodiments, R⁶ is H.

The Variables P¹, P², P³, P⁴, and P⁵

In some embodiments, P¹ and P⁵ are independently CH or CR^c; and P², P³, and P⁴ are independently CH, CR^c, or CR⁷.

In some embodiments, one of P¹, P², P³, P⁴, and P⁵ is N. In some embodiments, two of P¹, P², P³, P⁴, and P⁵ are N.

In some embodiments, one of P², P³, and P⁴ is CR⁷.

In certain embodiments, P³ is CR⁷. In certain of these embodiments, P⁴ is N. In certain other embodiments, P⁴ is CH or CR^c. In certain of the foregoing embodiments, P¹ is N. In certain other embodiments, P¹ is CH or CR^c. In certain embodiments, P² and P⁵ are independently CH or CR^c.

In certain embodiments, P³ is CR⁷; P¹, P², P⁴, and P⁵ are independently CH or CR^c.

In certain embodiments, the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

In certain embodiments, P³ is CR⁷; P⁴ is N; and P¹, P², and P⁵ are independently CH or CR^c.

In certain embodiments, the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

In certain embodiments, P³ is CR⁷; P⁴ and P¹ are N; and P² and P⁵ are independently CH or CR^c.

In certain embodiments, the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

In some embodiments, P⁴ is CR⁷. In certain embodiments, P³ is N. In certain other embodiments, P³ is CH or CR^c. In certain embodiments, P¹, P², and P⁵ are independently CH or CR^c.

In certain embodiments, P⁴ is CR⁷; P³ is CH or CR^c; and P¹, P², and P⁵ are independently CH or CR^c.

In certain embodiments, the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

In certain embodiments, P⁴ is CR⁷; P³ is N; and P¹, P², and P⁵ are independently CH or CR^c.

In certain embodiments, the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

In certain embodiments, the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c.

In certain embodiments, each occurrence of R^c7 is independently selected from the group consisting of halo; cyano; C_1-3 alkyl; C_1-4 alkoxy; C_1-4 haloalkoxy; and C_1-3 alkyl substituted with from 1-6 independently selected halo, such as —F.

The Variables L^A, a1, and R⁸

In some embodiments, a1 is 0. In some embodiments, a1 is 1. In some embodiments, a1 is 2. In some embodiments, a1 is 3.

In some embodiments, L^A is —O—, —NH—, or —CH₂—, such as wherein L^A is —O—. In certain embodiment (when a1 is 1), L^A is —O—, —NH—, or —CH₂—, such as wherein L^A is —O—. In certain embodiments, a1 is 1; and L^A is —O—.

In certain embodiments, a1 is 2; and -(L^A)_a1- is -L^A1-L^A2, wherein L^A1 and L^A2 are independently selected L^A; and L^A2 is the point of attachment to R⁸. In certain of these embodiments, L^A1 is —O—; and L^A2 is C_1-3 alkylene optionally substituted with from 1-2 R^a1, such as wherein L^A1 is —O—; and L^A2 is CH₂.

In certain embodiments, a1 is 3; and -(L^A)_a1- is -L^A1-L^A2-L^A3, wherein L^A1 L^A2 and L^A3 are independently selected L^A; and L^A3 is the point of attachment to R⁸. In certain of these embodiments, L^A1 and L^A3 are each independently C_1-3 alkylene optionally substituted with from 1-2 R^a1. In certain embodiments, L^A2 is NR^NC(O)O or OC(O)NR^N.

In some embodiments, R⁸ is C_1-10 alkyl optionally substituted with 1-4 R^a1.

In certain embodiments, R⁸ is C_1-10 alkyl, such as C_1-7 alkyl, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl, such as ethyl or isopropyl.

In certain embodiments, R⁸ is C_1-10 alkyl substituted with 1-6 R^a1, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6 R^a1. In certain embodiments, R^a1 is selected from the group consisting of: halo, such as —F; —OH; C_1-4 alkoxy; and C_1-4 haloalkoxy.

In certain embodiments, R⁸ is C_1-10 alkyl substituted with 1-6 independently selected halo, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6 independently selected halo. As non-limiting examples of the foregoing embodiments, R⁸ is C_1-10 alkyl substituted with 1-6-F, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6-F, such as

In certain embodiments, R⁸ is C_1-10 alkyl substituted with —OH, C_1-4 alkoxy, or C_1-4 haloalkoxy, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6 independently selected C_1-4 alkoxy, such as

In some embodiments, R⁸ is R^g.

In certain embodiments, R⁸ is selected from the group consisting of:

• • C_3-8 cycloalkyl or C_3-8 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_bg-R^h; and
  • heterocyclyl or heterocycloalkenyl of 4-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_bg-R^h.

In certain embodiments, R⁸ is selected from the group consisting of:

• • C_3-8 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and
  • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

In certain embodiments, R⁸ is selected from the group consisting of:

• • C_3-8 cycloalkyl substituted with from 1-2 (such as 2) independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c; and
  • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is substituted with from 1-2 (such as 2) independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c.

As non-limiting examples of the foregoing embodiments, R⁸ can be selected from the group consisting of piperidinyl, pyrrolidinyl, azetidinyl, azaspiro[3.3]heptanyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is substituted with 2-F and further optionally substituted with from 1-2 R^c, such as

As another non-limiting example, R⁸ can be optionally substituted 3-azabicyclo[3.1.0]hexane, e.g.:

In certain embodiments, R⁸ is selected from the group consisting of:

• • C_3-8 cycloalkyl such as cyclopropyl, cyclohexyl, cyclobutyl, or cyclopentyl;
  • C_3-8 cycloalkyl substituted with a substituent selected from the group consisting of: C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-4 alkoxy substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkyl; and C_1-6 alkyl substituted from 1-6 independently selected halo, C_1-4 alkoxy, or C_1-4 haloalkoxy, wherein the cycloalkyl is further optionally substituted with from 1-2 R^c;
  • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, such as:

and

• • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is substituted with a substituent selected from the group consisting of: C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-4 alkoxy substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkyl; and C_1-6 alkyl substituted from 1-6 independently selected halo, C_1-4 alkoxy, or C_1-4 haloalkoxy, wherein the heterocyclyl is further optionally substituted with from 1-2 R^c, such as

In certain embodiments, R⁸ is C_3-8 cycloalkyl such as cyclopropyl, cyclohexyl, cyclobutyl, or cyclopentyl;

In certain embodiments, R⁸ is C_3-8 cycloalkyl substituted with a substituent selected from the group consisting of: C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-4 alkoxy substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkyl; and C_1-6 alkyl substituted from 1-6 independently selected halo, C_1-4 alkoxy, or C_1-4 haloalkoxy, wherein the cycloalkyl is further optionally substituted with from 1-2 R^c;

In certain embodiments, R⁸ is heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, such as:

In certain embodiments, R⁸ is heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is substituted with a substituent selected from the group consisting of: C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-4 alkoxy substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkyl; and C_1-6 alkyl substituted from 1-6 independently selected halo, C_1-4 alkoxy, or C_1-4 haloalkoxy, wherein the heterocyclyl is further optionally substituted with from 1-2 R^c, such as

In certain embodiments, R⁸ is selected from the group consisting of:

• • heteroaryl of 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c; and
  • C_6-10 aryl, such as phenyl, optionally substituted with from 1-4 R^c.

In certain embodiments, a1 is 0; and R⁸ is selected from the group consisting of:

• • C_3-8 cycloalkyl substituted with from 1-2 (such as 2) independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c; and
  • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is substituted with from 1-2 (such as 2) independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c.

As non-limiting examples of the foregoing embodiments, R⁸ is selected from the group consisting of piperidinyl, pyrrolidinyl, azetidinyl, azaspiro[3.3]heptanyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is substituted with 2-F and further optionally substituted with from 1-2 R^c, such as

As another non-limiting example, R⁸ can be optionally substituted 3-azabicyclo[3.1.0]hexane, e.g.:

In certain embodiments, a1 is 0; and R⁸ is C_1-10 alkyl substituted with 1-6 independently selected halo, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6 independently selected halo. As non-limiting examples of the foregoing embodiments, R⁸ can be C_1-10 alkyl substituted with 1-6-F, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6-F, such as

In certain embodiments, a1 is 1; L^A is —O— or —NH—; and R⁸ is C_1-10 alkyl substituted with 1-6 independently selected halo, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6 independently selected halo. In certain of these embodiments, R⁸ is C_1-10 alkyl substituted with 1-6-F, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6-F, such as

In certain embodiments, L^A is —O—.

In certain embodiments, a1 is 1; L^A is —O—, —NH—, or —CH₂—; and R⁸ is selected from the group consisting of:

• • C_3-8 cycloalkyl substituted with from 1-2 (such as 2) independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c; and
  • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), 0, and S(O)_0-2, and wherein the heterocyclyl is substituted with from 1-2 (such as 2) independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c.

In certain of these embodiments, R⁸ is C_3-8 cycloalkyl substituted with from 1-2 (such as 2) independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c, such as cyclobutyl, cyclopentyl, and cyclohexyl, each of which is substituted with 2-F and further optionally substituted with from 1-2 R^c, such as

In certain of the foregoing embodiments, L^A is —O—.

Non-Limiting Combinations

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

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (Ia-1-1), the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

In some embodiments of Formula (Ia-1-1), the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

In some embodiments of Formula (Ia-1-1), the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

In some embodiments, the compound of Formula (I) is a compound of Formula (Ia-1-2):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (Ia-1-2), the

moiety has formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

In some embodiments of Formula (Ia-1-2), the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R^1a and R^1d are H; and R^1b and R^1c are independently selected halo, such as —F or —Cl, such as —F; such as: wherein R^1b and R^1c are —F; or wherein R^1b is —F, and R^1c is —Cl; or wherein R^1b is —Cl, and R^1c is —F.

In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R^1a and R^1d are H; one of R^1b and R^1c is H; and the other one of R^1b and R^1c is halo, such as —F or —Cl, such as —F; such as: wherein R^1b is H, and R^1c is —F; or wherein R^1b is H, and R^1c is —Cl; or wherein R^1b is —F, and R^1c is H; or wherein R^1b is —Cl, and R^1c is H.

In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R^1a and R^1d are H; R^1c is halo or H, such as —F, —Cl, or H; and R^1b is selected from the group consisting of: heteroaryl of 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is optionally substituted with from 1-4 R^c; and heteroaryl of 5-6 (such as 5) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is substituted with one occurrence of R^h1 or -(L^g)b-R^h1 and further optionally substituted with from 1-2 R^c, wherein R^h1 is an independently selected R^h.

In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R² is H. In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R⁵ is H. In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R⁶ is H. In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R² is H; R⁵ is H; and R⁶ is H.

In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R⁷ is —R⁸; and R⁸ is selected from the group consisting of:

• • C_3-8 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and
  • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R⁷ is —R⁸; and R⁸ is selected from the group consisting of:

• • C_3-8 cycloalkyl substituted with from 1-2 independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c; and
  • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is substituted with from 1-2 independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c, such as:

wherein R⁸ is selected from the group consisting of piperidinyl, pyrrolidinyl, azetidinyl, azaspiro[3.3]heptanyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is substituted with 2-F and further optionally substituted with from 1-2 R^c. As non-limiting examples of the foregoing embodiments, R⁸ can be

As another non-limiting example, R⁸ can be optionally substituted 3-azabicyclo[3.1.0]hexane, e.g.:

In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R⁷ is —R⁸; and R⁸ is C_3-8 cycloalkyl substituted with from 1-2 independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c. As non-limiting examples of the foregoing embodiments, R⁸ can be cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with 2-F and further optionally substituted with from 1-2 R^e. For example, R⁸ can be:

In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R⁷ is —R⁸; and R⁸ is heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is substituted with from 1-2 independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c. As non-limiting examples of the foregoing embodiments, R⁸ can be selected from the group consisting of piperidinyl, pyrrolidinyl, azetidinyl, azaspiro[3.3]heptanyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is substituted with 2-F and further optionally substituted with from 1-2 R^c. For example, R⁸ can be

As another non-limiting example, R⁸ can be optionally substituted 3-azabicyclo[3.1.0]hexane, e.g.:

In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R⁷ is —R⁸; and R⁸ is selected from the group consisting of:

• • C_3-8 cycloalkyl such as cyclopropyl, cyclohexyl, cyclobutyl, or cyclopentyl;
  • C_3-8 cycloalkyl substituted with a substituent selected from the group consisting of: C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-4 alkoxy substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkyl; and C_1-6 alkyl substituted from 1-6 independently selected halo, C_1-4 alkoxy, or C_1-4 haloalkoxy, wherein the cycloalkyl is further optionally substituted with from 1-2 R^c;
  • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, such as:

and

• • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is substituted with a substituent selected from the group consisting of: C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-4 alkoxy substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkyl; and C_1-6 alkyl substituted from 1-6 independently selected halo, C_1-4 alkoxy, or C_1-4 haloalkoxy, wherein the heterocyclyl is further optionally substituted with from 1-2 R^c, such as

In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R⁷ is —R⁸; and R⁸ is C_3-8 cycloalkyl such as cyclopropyl, cyclohexyl, cyclobutyl, or cyclopentyl.

In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R⁷ is —R⁸; and R⁸ is C_3-8 cycloalkyl substituted with a substituent selected from the group consisting of: C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-4 alkoxy substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkyl; and C_1-6 alkyl substituted from 1-6 independently selected halo, C_1-4 alkoxy, or C_1-4 haloalkoxy, wherein the cycloalkyl is further optionally substituted with from 1-2 R^c.

In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R⁷ is —R⁸; and R⁸ is heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, such as:

In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R⁷ is —R⁸; and R⁸ is heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is substituted with a substituent selected from the group consisting of: C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-4 alkoxy substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkyl; and C_1-6 alkyl substituted from 1-6 independently selected halo, C_1-4 alkoxy, or C_1-4 haloalkoxy, wherein the heterocyclyl is further optionally substituted with from 1-2 R^c. As non-limiting examples of the foregoing embodiments, R⁸ can be

In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R⁷ is —R⁸; and R⁸ is optionally substituted 3-azabicyclo[3.1.0]hexane, e.g.:

In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R⁷ is —R⁸; and R⁸ is selected from the group consisting of C_1-10 alkyl substituted with 1-6 R^a1 (such as from 1-6 independently selected halo), such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6 R^a1 (such as from 1-6 independently selected halo), such as C_1-10 alkyl substituted with 1-6-F, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6-F, such as

In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R⁷ is —OR⁸; and R⁸ is selected from the group consisting of C_1-10 alkyl substituted with 1-6 R^a1 (such as from 1-6 independently selected halo), such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6 R^a1 (such as from 1-6 independently selected halo), such as C_1-10 alkyl substituted with 1-6-F, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6-F, such as

In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), R⁷ is —OR⁸; and R⁸ is C_3-8 cycloalkyl substituted with from 1-2 (such as 2) independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c, such as cyclobutyl, cyclopentyl, and cyclohexyl, each of which is substituted with 2-F and further optionally substituted with from 1-2 R^c, such as

In certain embodiments of Formulae (Ia-1-1) or (I-a-1-2), each occurrence of R⁷ is independently selected from the group consisting of halo; cyano; C_1-3 alkyl; C_1-4 alkoxy; C_1-4 haloalkoxy; and C_1-3 alkyl substituted with from 1-6 independently selected halo.

In certain of these embodiments, each occurrence of R⁷ is independently selected from the group consisting of halo, such as —F and —Cl; cyano; C_1-3 alkyl, such as methyl; C_1-4 alkoxy, such as methoxy; C_1-4 haloalkoxy such as —OCF₃; and C_1-3 alkyl substituted with from 1-6-F, such as —CF₃.

In certain embodiments, the compound is a compound of Formula (Ia-1-1) wherein:

P¹ and P⁵ are each independently CH;

P² and P⁴ are each independently selected from the group consisting of: N, CH, and CR^c;

R^1a and R^1d are each independently H;

R^1b, R^1c are each independently selected from: H; and R^c;

R², R⁵, R⁶ are each independently H;

R⁷ is -(L^A)_a1-R⁸, wherein:

L^A is —O—, when present;

a1 is 0 or 1;

R⁸ is independently R^g or C_1-10 alkyl optionally substituted with 1-6 R^a1;

wherein each occurrence of R^c is independently selected from the group consisting of: halo; cyano; C_1-10 alkyl which is optionally substituted with 1-6 independently selected R^a;

wherein each occurrence of R^a and R^a1 is independently selected from the group consisting of: -halo.

wherein R^g is independently selected from the group consisting of:

• • C_3-12 cycloalkyl, optionally substituted with 1-4 substituents independently selected from the group consisting of R^c; and
  • heterocyclyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), O, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of R^c.

Compound Provisions

In some embodiments of one or more formulae herein, the compound is other than the compounds disclosed in PCT/US2020/013786 (e.g., in Table C1), filed on Jan. 16, 2020, which is incorporated herein by reference in its entirety.

In some embodiments, the compound of Formula (I) is other than a compound selected from the group consisting of compounds 1, 2, 13, 21, 52, 54, 81, 83, 84, 85, 86, 87, 88, 89, 90, 92, 93, 94, 95, 96, 99, 102, 106, 108, 110, 112, 114, 115, 117, 120, 123, 141, 142, 143, 152, and 154 as delineated in Table C1 of PCT/US2020/013786, filed on Jan. 16, 2020, which is incorporated herein by reference in its entirety.

In some embodiments, the compound of Formula (II) is other than a compound selected from the group consisting of compounds 10, 11, 29, and 14 as delineated in Table C₁ of PCT/US2020/013786, filed on Jan. 16, 2020, which is incorporated herein by reference in its entirety.

In some embodiments, the compound of Formula (III) is other than a compound selected from the group consisting of compounds 12, 135, and 136 as delineated in Table C₁ of PCT/US2020/013786, filed on Jan. 16, 2020, which is incorporated herein by reference in its entirety.

In some embodiments of the compound of Formula (I), it is provided that one or both of (a) and (b) apply:

(a) when Z and Y³ are CH; Y¹ and Y² are CF; and the

moiety is

wherein P² is CH or N, then R⁷ is other than:

and

(b) the

moiety is other than:

In some embodiments of Formula (I), it is provided that Z and Y³ are CH; Y¹ and Y² are CF; one of P² and P³ is CR⁷; and each remaining one of P¹, P², P³, P⁴, and P⁵ is other than CR⁷, then R⁷ is other than:

In some embodiments of Formula (I), it is provided that when Z and Y³ are CH; and Y¹ and Y² are CF, then at least one of P¹, P², P³, P⁴, and P⁵ is CR^c, NR⁷, NR^d, or C(═O).

In some embodiments of Formula (I), it is provided that when Z and Y³ are CH; Y and Y² are CF; and P³ is CR⁷, then at least one of P¹, P², P⁴, and P⁵ is CR^c, NR⁷, NR^d, or C(═O).

In some embodiments of Formula (I), it is provided that the compound is other than a chemical entity disclosed in Chemical Biology and Drug Design, 2015, 86, 731-745, which is incorporated herein by reference.

In some embodiments of Formula (I), it is provided that the six-membered ring including P¹, P², P³, P⁴, and P⁵ is other than:

In some embodiments of the compound of Formula (II), the

moiety is other than:

In some embodiments of Formula (II), when the

and R⁸ is unsubstituted C_2-4 alkyl or CF₃, then a1 is 1, 2, or 3.

In some embodiments of Formula (II), it is provided that the ring including P¹, P², P³, P⁴, and P⁵ is other than:

• • (i) phenyl, pyridyl, or pyrimidinyl, each substituted with one substituent selected from the group consisting of: OMe; CH₂NH₂; CH₂NHC(O)OMe; CH₂NHC(O)OEt; CH₂NHC(O)Me; CH₂NHC(O)N(Me)₂; CH₂NHS(O)₂Me; methyl; tert-butyl; NHMe; morpholinyl; CH₂OH; 1,2,4-triazolyl; or trisubstituted pyrazolyl;
  • (ii) pyrimidinyl substituted with two substituents each independently selected from the group consisting of: methyl, ethyl, and pyrrolidinyl; or

In some embodiments of the compound of Formula (III), the

moiety is other than:

In some embodiments of Formula (III), it is provided that the ring including P¹, P², P³, P⁴, and P⁵ is other than:

• • (ii) phenyl, pyridyl, pyridonyl, or pyridazinonyl substituted with one substituent selected from the group consisting of: OMe; methyl; trifluoromethyl; NHC(O)Me; NMe₂; CH₂CH₂-pyrrolindinyl; or
  • (iii) 3-fluoro-4-methoxyphenyl; 2-fluoro-5-methylphenyl; or dimethoxypyridyl.

In some embodiments of Formula (III), R″ is other than monocyclic heterocyclyl of 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_bg-R^h; and Non-Limiting Exemplary Compounds

In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table C1 or a pharmaceutically acceptable salt thereof.

TABLE C1
# Structure
101
  5-chloro-N-(5,6-difluoro-1H-
  indol-3-yl)-6-(6,6-difluoro-2-
  azaspiro[3.3]heptan-2-
  yl)nicotinamide
102
  5-chloro-6-(4,4-difluoropiperidin-1-
  yl)-N-(5-(1-isopropyl-1H-pyrazol-4-
  yl)-1H-indol-3-yl)nicotinamide
103
  N-(5,6-difluoro-1H-indol-3-yl)-
  6-((3-methoxypropyl)amino)-5-
  methylnicotinamide
104
  N-(6-cyano-1H-indol-3-yl)-3-fluoro-
  4-(4,4,4-trifluorobutoxy)benzamide
105
  N-(5,6-difluoro-1H-indol-3-yl)-
  6-oxo-5-(4-
  (trifluoromethyl)benzyl)-1,6-
  dihydropyridazine-3-
  carboxamide
106
  N-(5,6-difluoro-1H-indol-3-yl)-2-
  (difluoromethoxy)isonicotinamide
107
  5-cyano-N-(5,6-difluoro-1H-
  indol-3-yl)-6-(4,4-
  difluoropiperidin-1-
  yl)nicotinamide
108
  N-(5,6-difluoro-1H-indol-3-yl)-4-
  (3,3-difluorocyclobutyl)benzamide
109
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-(3,3-
  difluorocyclobutoxy)benzamide
110
  N-(5,6-difluoro-1H-indol-3-yl)-4-(2-
  (trifluoromethoxy)ethyl)benzamide
111
  3-fluoro-N-(7-fluoro-1H-
  pyrrolo[3,2-c]pyridin-3-yl)-4-
  (4,4,4-
  trifluorobutoxy)benzamide
112
  N-(5,6-difluoro-1H-indol-3-yl)-3-
  methoxy-4-
  (trifluoromethyl)benzamide
113
  N-(5,6-difluoro-1H-indol-3-yl)-
  2-isopropoxyisonicotinamide
114
  3-chloro-N-(5,6-difluoro-1H-indol-3-
  yl)-4-(trifluoromethoxy)benzamide
115
  N-(5,6-difluoro-1H-indol-3-yl)-
  3,5-difluoro-4-(2,2,2-
  trifluoroethoxy)benzamide
116
  N-(5,6-difluoro-1H-indol-3-yl)-4-
  (difluoromethoxy)benzamide
117
  N-(5,6-difluoro-1H-indol-3-yl)-
  3-(1,1,2,2-
  tetrafluoroethoxy)benzamide
118
  N-(5,6-difluoro-1H-indol-3-yl)-4-
  (pyridin-3-yloxy)benzamide
119
  N-(5,6-difluoro-1H-indol-3-yl)-
  3-methyl-5-
  (trifluoromethoxy)benzamide
120
  3-cyano-N-(5,6-difluoro-1H-indol-3-
  yl)-4-isopropoxybenzamide
121
  N-(5,6-difluoro-1H-indol-3-yl)-
  3-(difluoromethoxy)benzamide
122
  2-chloro-N-(5,6-difluoro-1H-indol-3-
  yl)-4-(2,2,2-
  trifluoroethoxy)benzamide
123
  pyridin-3-ylmethyl (4-((5,6-
  difluoro-1H-indol-3-
  yl)carbamoyl)benzyl)carbamate
124
  N-(5,6-difluoro-1H-indol-3-yl)-6-
  ((tetahydro-2H-pyran-4-
  yl)oxy)picolinamide
125
  N-(5,6-difluoro-1H-indol-3-yl)-
  3-(trifluoromethoxy)benzamide
126
  N-(5,6-difluoro-1H-indol-3-yl)-4-
  isopropoxy-3-
  (trifluoromethyl)benzamide
127
  3-(cyclopropylmethoxy)-N-
  (5,6-difluoro-1H-indol-3-yl)-4-
  (difluoromethoxy)benzamide
128
  N-(5,6-difluoro-1H-indol-3-yl)-4-
  isopropoxybenzamide
129
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-(2-(piperidin-1-
  yl)ethoxy)benzamide
130
  4-(cyclopropylmethoxy)-N-(5,6-
  difluoro-1H-indol-3-yl)benzamide
131
  3-(benzyloxy)-N-(5,6-difluoro-
  1H-indol-3-yl)benzamide
132
  4-butoxy-N-(5,6-difluoro-1H-indol-
  3-yl)benzamide
133
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-((5-(trifluoromethyl)pyridin-
  2-yl)oxy)benzamide
134
  N-(5,6-difluoro-1H-indol-3-yl)-3-
  fluoro-4-(2,2,2-
  trifluoroethoxy)benzamide
135
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-(trifluoromethoxy)benzamide
136
  4-(benzyloxy)-N-(5,6-difluoro-1H-
  indol-3-yl)benzamide
137
  5-chloro-N-(5,6-difluoro-1H-
  indol-3-yl)-6-(3,3-
  difluoroazetidin-1-
  yl)nicotinamide
138
  N-(5,6-difluoro-1H-indol-3-yl)-6-
  (4,4,4-trifluorobutoxy)nicotinamide
139
  N-(5,6-difluoro-1H-indol-3-yl)-
  5-(4,4,4-
  trifluorobutoxy)picolinamide
140
  N-(5,6-difluoro-1H-indol-3-yl)-5-
  fluoro-6-(3,3,3-
  trifluoropropoxy)nicotinamide
141
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-(3,3,3-
  trifluoropropoxy)benzamide
142
  N-(5,6-difluoro-1H-indol-3-yl)-3-
  fluoro-4-(4,4,4-
  trifluorobutoxy)benzamide
143
  3-fluoro-N-(5-methoxy-1H-
  pyrrolo[3,2-b]pyridin-3-yl)-4-
  (4,4,4-
  trifluorobutoxy)benzamide
144
  3-fluoro-N-(5-fluoro-1H-pyrrolo[2,3-
  b]pyridin-3-yl)-4-(4,4,4-
  trifluorobutoxy)benzamide
145
  N-(5-cyano-1H-indol-3-yl)-3-
  fluoro-4-(4,4,4-
  trifluorobutoxy)benzamide
146
  3-fluoro-N-(5-fluoro-1H-indol-3-yl)-
  4-(4,4,4-trifluorobutoxy)benzamide
147
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-ethoxybenzamide
148
  N-(5,6-difluoro-1H-indol-3-yl)-5-
  (4,4,4-trifluorobutoxy)pyrazine-2-
  carboxamide
149
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-(3,3-difluorocyclobutoxy)-3-
  fluorobenzamide
150
  3-cyano-N-(5,6-difluoro-1H-indol-3-
  yl)-4-(4,4,4-
  trifluorobutoxy)benzamide
151
  3-chloro-N-(5,6-difluoro-1H-
  indol-3-yl)-4-(4,4,4-
  trifluorobutoxy)benzamide
152
  N-(5,6-difluoro-1H-indol-3-yl)-4-
  (2,2,2-trifluoroethoxy)benzamide
153
  N-(5-chloro-1H-indol-3-yl)-3-
  fluoro-4-(4,4,4-
  trifluorobutoxy)benzamide
154
  N-(5,6-difluoro-1H-indol-3-yl)-6-
  (4,4-difluoropiperidin-1-yl)-5-
  fluoronicotinamide
155
  N-(5,6-difluoro-1H-indol-3-yl)-
  3-methyl-4-(4,4,4-
  trifluorobutoxy)benzamide
156
  5-chloro-N-(5,6-difluoro-1H-indol-3-
  yl)-6-(4,4-difluoropiperidin-1-
  yl)nicotinamide
157
  N-(5,6-difluoro-1H-indol-3-yl)-
  6-(2-
  methoxyethoxy)nicotinamide
158
  N-(5,6-difluoro-1H-indol-3-yl)-4-
  (4,4-difluorocyclohexyl)benzamide
159
  N-(5,6-difluoro-1H-indol-3-yl)-
  6-(4,4-difluoropiperidin-1-
  yl)nicotinamide
160
  N-(5,6-difluoro-1H-indol-3-yl)-3-
  fluoro-4-(3,3,3-
  trifluoropropoxy)benzamide
161
  N-(5,6-difluoro-1H-indol-3-yl)-
  3-fluoro-4-(3,3,3-
  trifluoropropoxy)benzamide
162
  N-(5-(1-(4-(methoxymethyl)phenyl)-
  1H-pyrazol-4-yl)-1H-indol-3-yl)-4-
  (4,4,4-trifluorobutoxy)benzamide
163
  5-chloro-N-(5,6-difluoro-1H-
  indol-3-yl)-6-(4-(2-
  methoxyethyl)piperidin-1-
  yl)nicotinamide
164
  N-(5,6-difluoro-1H-indol-3-yl)-2-
  ((4,4,4-
  trifluorobutyl)amino)pyrimidine-4-
  carboxamide
165
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-(3,3-difluorocyclobutoxy)-3-
  methylbenzamide
166
  3-chloro-N-(5,6-difluoro-1H-indol-3-
  yl)-4-(4,4-
  difluorocyclohexyl)benzamide
168
  4-(cyclopentyloxy)-N-(5,6-difluoro-
  1H-indol-3-yl)benzamide
169
  N-(5,6-difluoro-1H-indol-3-yl)-
  3-((4,4,4-
  trifluorobutyl)amino)benzamide
170
  4-chloro-N-(5,6-difluoro-1H-indol-3-
  yl)-3-(4,4,4-
  trifluorobutoxy)benzamide
171
  N-(5,6-difluoro-1H-indol-3-yl)-
  3-(4,4,4-
  trifluorobutoxy)benzamide
172
  N-(5,6-difluoro-1H-indol-3-yl)-4-
  methyl-3-(4,4,4-
  trifluorobutoxy)benzamide
173
  N-(5,6-difluoro-1H-indol-3-yl)-
  6-methyl-5-(2,2,2-
  trifluoroethoxy)pyrazine-2-
  carboxamide
174
  N-(5,6-difluoro-1H-indol-3-yl)-4-
  (2,2-difluoroethoxy)benzamide
175
  N-(5,6-difluoro-1H-indol-3-yl)-
  2-(4,4-difluoropiperidin-1-yl)-
  6-methylisonicotinamide
176
  N-(5,6-difluoro-1H-indol-3-yl)-3-
  fluoro-4-(3,3,3-
  trifluoropropyl)benzamide
179
  3-(cyclohexyloxy)-N-(5,6-
  difluoro-1H-indol-3-
  yl)benzamide
180
  N-(5-(1-isopropyl-1H-pyrazol-4-yl)-
  1H-indol-3-yl)-4-(4,4,4-
  trifluorobutoxy)benzamide
181
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-((3,3-difluoroazetidin-1-
  yl)methyl)-3-fluorobenzamide
182
  N-(5,6-difluoro-1H-indol-3-yl)-5-(4-
  (trifluoromethoxy)piperidin-1-
  yl)pyrazine-2-carboxamide
183
  N-(5,6-difluoro-1H-indol-3-yl)-
  6-(3-methoxy-3-methylazetidin-
  1-yl)-5-methylnicotinamide
184
  (R)-N-(5,6-difluoro-1H-indol-3-yl)-
  6-(3-(2-methoxyethoxy)pyrrolidin-1-
  yl)-5-methylnicotinamide
185
  (R)-N-(5,6-difluoro-1H-indol-3-
  yl)-3-fluoro-4-(3-(2-
  methoxyethoxy)pyrrolidin-1-
  yl)benzamide
186
  2-cyclohexyl-N-(5,6-difluoro-1H-
  indol-3-yl)-6-methylisonicotinamide
187
  4-(4,4-difluoro-1-
  hydroxycyclohexyl)-N-(5,6-
  difluoro-1H-indol-3-
  yl)benzamide
188
  3-cyano-N-(5,6-difluoro-1H-indol-3-
  yl)-4-(4,4-difluoropiperidin-1-
  yl)benzamide
189
  5-chloro-N-(5,6-difluoro-1H-
  indol-3-yl)-6-(3-
  (trifluoromethyl)pyrrolidin-1-
  yl)nicotinamide
190
  5-chloro-6-(4,4-difluoropiperidin-1-
  yl)-N-(6-fluoro-1H-indol-3-
  yl)nicotinamide
191
  N-(5,6-difluoro-1H-indol-3-yl)-
  5-methyl-6-((4,4,4-
  trifluorobutyl)amino)nicotinamide
192
  3-fluoro-N-(6-fluoro-1H-indol-3-yl)-
  4-(4,4,4-trifluorobutoxy)benzamide
193
  N-(5,6-difluoro-1H-indol-3-yl)-
  2-oxo-1-(4-
  (trifluoromethyl)benzyl)-1,2-
  dihydropyrimidine-4-
  carboxamide
194
  N-(5,6-difluoro-1H-indol-3-yl)-3-(2-
  methoxyethoxy)benzamide
195
  3-chloro-4-
  (cyclopropylmethoxy)-N-(5,6-
  difluoro-1H-indol-3-
  yl)benzamide
196
  4-(cyclohexyloxy)-N-(5,6-difluoro-
  1H-indol-3-yl)benzamide
197
  N-(5,6-difluoro-1H-indol-3-yl)-
  6-
  (trifluoromethoxy)nicotinamide
198
  N-(5,6-difluoro-1H-indol-3-yl)-3-
  ethoxy-2,4-difluorobenzamide
199
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-ethoxy-5,6-
  difluorobenzamide
200
  N-(5-(1-(3-(methoxymethyl)phenyl)-
  1H-pyrazol-4-yl)-1H-indol-3-yl)-4-
  (4,4,4-trifluorobutoxy)benzamide
201
  N-(5-(1-(3-cyclopropylphenyl)-
  1H-pyrazol-4-yl)-1H-indol-3-
  yl)-4-(4,4,4-
  trifluorobutoxy)benzamide
202
  N-(5,6-difluoro-1H-indol-3-yl)-6-
  ((4,4,4-
  trifluorobutyl)amino)picolinamide
203
  N-(5,6-difluoro-1H-indol-3-yl)-
  2-((4,4,4-
  trifluorobutyl)amino)isonicotinamide
204
  N-(7-fluoro-5-(1-isopropyl-1H-
  pyrazol-4-yl)-1H-indol-3-yl)-4-
  (4,4,4-trifluorobutoxy)benzamide
205
  N-(5-cyano-7-fluoro-1H-indol-
  3-yl)-4-(4,4,4-
  trifluorobutoxy)benzamide
206
  (R)-N-(5,6-difluoro-1H-indol-3-yl)-
  3-methyl-4-(3-(2-
  (trifluoromethoxy)ethoxy)pyrrolidin-
  1-yl)benzamide
207
  N-(5,6-difluoro-1H-indol-3-yl)-
  5-methyl-6-(6-oxa-2-
  azaspiro[3.4]octan-2-
  yl)nicotinamide
208
  N-(5,6-difluoro-1H-indol-3-yl)-5-
  (3,3-difluorocyclobutoxy)-6-
  methylpyrazine-1-carboxamide
209
  5-chloro-N-(5,6-difluoro-1H-
  indol-3-yl)-6-((5-hydroxy-4,4-
  dimethylpentyl)amino)nicotinamide
210
  N-(5,6-difluoro-1H-indol-3-yl)-4-
  (4,4-difluorocyclohexyl)-3,5-
  dimethylbenzamide
211
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-(4,4-difluoropiperidin-1-yl)-
  3,5-dimethylbenzamide
212
  N-(5,6-difluoro-1H-indol-3-yl)-5-
  (4,4-difluoropiperidin-1-yl)-6-
  methylnicotinamide
213
  4-(1-cyano-4,4-
  difluorocyclohexyl)-N-(5,6-
  difluoro-1H-indol-3-
  yl)benzamide
214
  N-(5,6-difluoro-1H-indol-3-yl)-6-((2-
  methoxyethyl)amino)-5-
  methylnicotinamide
215
  N-(5,6-difluoro-1H-indol-3-yl)-
  5-methyl-6-((4,4,4-
  trifluorobutyl)amino)nicotinamide
216
  N-(5,6-difluoro-1H-indol-3-yl)-6-
  (3,3-difluorocyclobutyl)nicotinamide
217
  N-(5,6-difluoro-1H-indol-3-yl)-
  1-(4,4-difluorocyclohexyl)-2-
  oxo-1,2-dihydropyrimidine-4-
  carboxamide
218
  N-(5,6-difluoro-1H-indol-3-yl)-6-(4-
  methyl-1-(2,2,2-
  trifluoroethyl)piperidin-4-
  yl)nicotinamide
219
  N-(5,6-difluoro-1H-indol-3-yl)-
  6-(1,1-difluoro-6-
  azaspiro[2.5]octan-6-yl)-5-
  fluoronicotinamide
220
  6-(4,4-difluoro-1-methylcyclohexyl)-
  N-(5,6-difluoro-1H-indol-3-yl)-5-
  fluoronicotinamide
221
  N-(5,6-difluoro-1H-indol-3-yl)-
  5-fluoro-6-(6-(2,2,2-
  trifluoroethoxy)-2-
  azaspiro[3.3]heptan-2-
  yl)nicotinamide
222
  N-(5,6-difluoro-1H-indol-3-yl)-5-
  fluoro-6-(6-(2,2,2-
  trifluoroethoxy)spiro[3.3]heptan-2-
  yl)nicotinamide
223
  N-(5,6-difluoro-1H-indol-3-yl)-
  5-fluoro-6-((1R,5S,6r)-6-
  ((2,2,2-trifluoroethoxy)methyl)-
  3-azabicyclo[3.1.0]hexan-3-
  yl)nicotinamide
224
  N-(5-chloro-1H-indol-3-yl)-5-fluoro-
  6-((1R,5S,6r)-6-((2,2,2-
  trifluoroethoxy)methyl)-3-
  azabicyclo[3.1.0]hexan-3-
  yl)nicotinamide
225
  N-(5-chloro-1H-indol-3-yl)-3-
  fluoro-4-((1R,5S,6r)-6-((2,2,2-
  trifluoroethoxy)methyl)-3-
  azabicyclo[3.1.0]hexan-3-
  yl)benzamide
226
  N-(5,6-difluoro-1H-indol-3-yl)-6-(2-
  methoxyethoxy)-5-
  methylnicotinamide
227
  N-(5,6-difluoro-1H-indol-3-yl)-
  3-fluoro-4-((1R,5S,6r)-6-
  ((2,2,2-tifluoroethoxy)methyl)-
  3-azabicyclo[3.1.0]hexan-3-
  yl)benzamide
228
  N-(5,6-difluoro-1H-indol-3-yl)-6-(2-
  hydroxybutyl)nicotinamide
229
  N-(5-chloro-1H-indol-3-yl)-4-
  ((1-(2,2,2-
  trifluoroethyl)piperidin-4-
  yl)methyl)benzamide
230
  N-(5-chloro-1H-indol-3-yl)-4-((1-
  (2,2,2-trifluoroethyl)piperidin-4-
  yl)oxy)benzamide
231
  N-(5,6-difluoro-1H-indol-3-yl)-
  6-(2-ethoxyethoxy)-4-
  methylnicotinamide
232
  N-(5,6-difluoro-1H-indol-3-yl)-3-(2-
  methoxyethoxy)-4-
  (trifluoromethyl)benzamide
233
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-((3,3-
  difluorocyclobutyl)(hydroxy)
  methyl)benzamide
234
  3-(5-cyclopropyl-1,2,4-oxadiazol-3-
  yl)-N-(5,6-difluoro-1H-indol-3-
  yl)benzamide
235
  N-(5,6-difluoro-1H-indol-3-yl)-
  2-(2,2,2-trifluoro-1-
  hydroxyethyl)isonicotinamide
236
  N-(5,6-difluoro-1H-indol-3-yl)-3-((2-
  methoxyethyl)amino)-4-
  (trifluoromethyl)benzamide
237
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-((6,6-difluoro-2-
  azaspiro[3.3]heptan-2-
  yl)methyl)-3-fluorobenzamide
238
  N-(5,6-difluoro-1H-indol-3-yl)-2-((2-
  methoxyethyl)amino)isonicotinamide
239
  5-chloro-N-(5,6-difluoro-1H-
  indol-3-yl)-6-((3,3,3-
  trifluoropropyl)amino)nicotinamide
240
  5-chloro-N-(5,6-difluoro-1H-indol-3-
  yl)-6-(3,3-
  difluorocyclobutyl)nicotinamide
241
  N-(5,6-difluoro-1H-indol-3-yl)-
  2-(1-
  hydroxypropyl)isonicotinamide
242
  N-(5,6-difluoro-1H-indol-3-yl)-5-
  fluoro-6-((3,3,3-
  trifluoropropyl)amino)nicotinamide
243
  N-(5,6-difluoro-1H-indol-3-yl)-
  6-methyl-5-((4,4,4-
  trifluorobutyl)amino)nicotinamide
244
  (S)-N-(5,6-difluoro-1H-indol-3-yl)-4-
  (1-(3,3-difluoroazetidin-1-yl)ethyl)-
  3-fluorobenzamide
245
  (R)-N-(5,6-difluoro-1H-indol-3-
  yl)-4-(1-(3,3-difluoroazetidin-1-
  yl)ethyl)-3-fluorobenzamide
246
  N-(5,6-difluoro-1H-indol-3-yl)-6-((1-
  (2,2,2-trifluoroethyl)azetidin-3-
  yl)oxy)nicotinamide
247
  N-(5,6-difluoro-1H-indol-3-yl)-
  2-((3,3-
  difluorocyclobutyl)amino)isonicotinamide
248
  N-(5,6-difluoro-1H-indol-3-yl)-4-(4-
  hydroxytetrahydro-2H-pyran-4-
  yl)benzamide
249
  tert-butyl 4-(4-((5,6-difluoro-
  1H-indol-3-
  yl)carbamoyl)phenoxy)piperidine-1-
  carboxylate
250
  6-(4,4-difluoro-1-
  hydroxycyclohexyl)-N-(5,6-difluoro-
  1H-indol-3-yl)nicotinamide
251
  3-(4,4-difluoro-1-
  hydroxycyclohexyl)-N-(5,6-
  difluoro-1H-indol-3-
  yl)benzamide
252
  3-chloro-N-(5,6-difluoro-1H-indol-3-
  yl)-2-(3,3-difluoroazetidin-1-
  yl)isonicotinamide
253
  N-(5,6-difluoro-1H-indol-3-yl)-
  2-(3,3-difluoroazetidin-1-yl)-3-
  methylisonicotinamide
254
  5-chloro-N-(5,6-difluoro-1H-indol-3-
  yl)-6-((4,4-difluoropiperidin-1-
  yl)methyl)nicotinamide
255
  5-chloro-N-(5,6-difluoro-1H-
  indol-3-yl)-6-((3,3-
  difluoroazetidin-1-
  yl)methyl)nicotinamide
256
  N-(5,6-difluoro-1H-indol-3-yl)-5-
  (4,4-difluoropiperidin-1-yl)-6-
  methylnicotinamide
257
  N-(5,6-difluoro-1H-indol-3-yl)-
  2-((3,3-difluoroazetidin-1-
  yl)methyl)isonicotinamide
258
  4-(4,4-difluoro-1-
  hydroxycyclohexyl)-N-(5,6-difluoro-
  1H-indol-3-yl)-3-fluorobenzamide
259
  N-(5-chloro-6-fluoro-1H-indol-
  3-yl)-4-(4,4-difluoro-1-
  hydroxycyclohexyl)benzamide
260
  N-(5,6-difluoro-1H-indol-3-yl)-3-
  fluoro-4-((3-fluoroazetidin-1-
  yl)methyl)benzamide
261
  N-(5,6-difluoro-1H-indol-3-yl)-
  2-ethyl-2,3-dihydro-1H-indene-
  5-carboxamide
262
  N-(5,6-difluoro-1H-indol-3-yl)-3-
  fluoro-4-(2-
  (trifluoromethoxy)ethoxy)benzamide
263
  N-(5,6-difluoro-1H-indol-3-yl)-
  2-phenoxyisonicotinamide
264
  N-(5,6-difluoro-1H-indol-3-yl)-6-
  methoxy-5-
  (trifluoromethyl)nicotinamide
265
  N-(5,6-difluoro-1H-indol-3-yl)-
  6-isopropoxynicotinamide
266
  4-(5-cyclopropyl-1,2,4-oxadiazol-3-
  yl)-N-(5,6-difluoro-1H-indol-3-
  yl)benzamide
267
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-(5-isopropyl-1,2,4-oxadiazol-
  3-yl)benzamide
268
  N-(5,6-difluoro-1H-indol-3-yl)-4-
  (1,1,2,2-tetrafluoroethoxy)benzamide
269
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-(oxetan-3-yloxy)benzamide
270
  N-(5,6-difluoro-1H-indol-3-yl)-5-
  (difluoromethoxy)picolinamide
271
  N-(5-chloro-1H-indol-3-yl)-5-
  cyano-6-(3,3-difluoroazetidin-
  1-yl)nicotinamide
272
  N-(5-chloro-1H-indol-3-yl)-6-(3,3-
  difluoroazetidin-1-yl)-4-
  methylnicotinamide
273
  N-(5,6-difluoro-1H-indol-3-yl)-
  6-((3,3-difluoroazetidin-1-
  yl)methyl)nicotinamide
274
  N-(5,6-difluoro-1H-indol-3-yl)-3-(5-
  methyl-1,2,4-oxadiazol-3-
  yl)benzamide
275
  N-(5,6-difluoro-1H-indol-3-yl)-
  3-(1-hydroxyethyl)-5-
  (trifluoromethyl)benzamide
276
  N-(5,6-difluoro-1H-indol-3-yl)-3-(1-
  hydroxyethyl)-4-
  (trifluoromethyl)benzamide
277
  N-(5,6-difluoro-1H-indol-3-yl)-
  6-((4,4,4-
  trifluorobutyl)amino)picolinamide
278
  N-(5,6-difluoro-1H-indol-3-yl)-4-
  (4,4-difluorocyclohexyl)-3,5-
  dimethylbenzamide
279
  N-(5,6-difluoro-1H-indol-3-yl)-
  3-(2-hydroxyethyl)-5-
  (trifluoromethyl)benzamide
280
  N-(5,6-difluoro-1H-indol-3-yl)-3-(2-
  hydroxyethyl)-4-
  (trifluoromethyl)benzamide
209
  5-chloro-N-(5,6-difluoro-1H-
  indol-3-yl)-6-((5-hydroxy-4,4-
  dimethylpentyl)amino)nicotinamide
201
  N-(5-(1-(3-cyclopropylphenyl)-1H-
  pyrazol-4-yl)-1H-indol-3-yl)-4-
  (4,4,4-trifluorobutoxy)benzamide
213
  4-(1-cyano-4,4-
  difluorocyclohexyl)-N-(5,6-
  difluoro-1H-indol-3-
  yl)benzamide
216
  N-(5,6-difluoro-1H-indol-3-yl)-6-
  (3,3-difluorocyclobutyl)nicotinamide
200
  N-(5-(1-(3-
  (methoxymethyl)phenyl)-1H-
  pyrazol-4-yl)-1H-indol-3-yl)-4-
  (4,4,4-
  trifluorobutoxy)benzamide
204
  N-(7-fluoro-5-(1-isopropyl-1H-
  pyrazol-4-yl)-1H-indol-3-yl)-4-
  (4,4,4-trifluorobutoxy)benzamide
203
  N-(5,6-difluoro-1H-indol-3-yl)-
  2-((4,4,4-
  trifluorobutyl)amino)isonicotinamide
208
  N-(5,6-difluoro-1H-indol-3-yl)-5-
  (3,3-difluorocyclobutoxy)-6-
  methylpyrazine-2-carboxamide
207
  N-(5,6-difluoro-1H-indol-3-yl)-
  5-methyl-6-(6-oxa-2-
  azaspiro[3.4]octan-2-
  yl)nicotinamide
162
  N-(5-(1-(4-(methoxymethyl)phenyl)-
  1H-pyrazol-4-yl)-1H-indol-3-yl)-4-
  (4,4,4-trifluorobutoxy)benzamide
163
  5-chloro-N-(5,6-difluoro-1H-
  indol-3-yl)-6-(4-(2-
  methoxyethyl)piperidin-1-
  yl)nicotinamide
164
  N-(5,6-difluoro-1H-indol-3-yl)-2-
  ((4,4,4-
  trifluorobutyl)amino)pyrimidine-4-
  carboxamide
165
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-(3,3-difluorocyclobutoxy)-3-
  methylbenzamide
166
  3-chloro-N-(5,6-difluoro-1H-indol-3-
  yl)-4-(4,4-
  difluorocyclohexyl)benzamide
168
  4-(cyclopentyloxy)-N-(5,6-
  difluoro-1H-indol-3-
  yl)benzamide
169
  N-(5,6-difluoro-1H-indol-3-yl)-3-
  ((4,4,4-
  trifluorobutyl)amino)benzamide
170
  4-chloro-N-(5,6-difluoro-1H-
  indol-3-yl)-3-(4,4,4-
  trifluorobutoxy)benzamide
171
  N-(5,6-difluoro-1H-indol-3-yl)-3-
  (4,4,4-trifluorobutoxy)benzamide
172
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-methyl-3-(4,4,4-
  trifluorobutoxy)benzamide
173
  N-(5,6-difluoro-1H-indol-3-yl)-6-
  methyl-5-(2,2,2-
  trifluoroethoxy)pyrazine-2-
  carboxamide
174
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-(2,2-
  difluoroethoxy)benzamide
175
  N-(5,6-difluoro-1H-indol-3-yl)-2-
  (4,4-difluoropiperidin-1-yl)-6-
  methylisonicotinamide
176
  N-(5,6-difluoro-1H-indol-3-yl)-
  3-fluoro-4-(3,3,3-
  trifluoropropyl)benzamide
179
  3-(cyclohexyloxy)-N-(5,6-difluoro-
  1H-indol-3-yl)benzamide
180
  N-(5-(1-isopropyl-1H-pyrazol-
  4-yl)-1H-indol-3-yl)-4-(4,4,4-
  trifluorobutoxy)benzamide
181
  N-(5,6-difluoro-1H-indol-3-yl)-4-
  ((3,3-difluoroazetidin-1-yl)methyl)-
  3-fluorobenzamide
182
  N-(5,6-difluoro-1H-indol-3-yl)-
  5-(4-
  (trifluoromethoxy)piperidin-1-
  yl)pyrazine-2-carboxamide
183
  N-(5,6-difluoro-1H-indol-3-yl)-6-(3-
  methoxy-3-methylazetidin-1-yl)-5-
  methylnicotinamide
184
  (R)-N-(5,6-difluoro-1H-indol-3-
  yl)-6-(3-(2-
  methoxyethoxy)pyrrolidin-1-
  yl)-5-methylnicotinamide
185
  (R)-N-(5,6-difluoro-1H-indol-3-yl)-
  3-fluoro-4-(3-(2-
  methoxyethoxy)pyrrolidin-1-
  yl)benzamide
186
  2-cyclohexyl-N-(5,6-difluoro-
  1H-indol-3-yl)-6-
  methylisonicotinamide
187
  4-(4,4-difluoro-1-
  hydroxycyclohexyl)-N-(5,6-difluoro-
  1H-indol-3-yl)benzamide
188
  3-cyano-N-(5,6-difluoro-1H-
  indol-3-yl)-4-(4,4-
  difluoropiperidin-1-
  yl)benzamide
189
  5-chloro-N-(5,6-difluoro-1H-indol-3-
  yl)-6-(3-(trifluoromethyl)pyrrolidin-
  1-yl)nicotinamide
190
  5-chloro-6-(4,4-
  difluoropiperidin-1-yl)-N-(6-
  fluoro-1H-indol-3-
  yl)nicotinamide
191
  N-(5,6-difluoro-1H-indol-3-yl)-5-
  methyl-6-((4,4,4-
  trifluorobutyl)amino)nicotinamide
192
  3-fluoro-N-(6-fluoro-1H-indol-
  3-yl)-4-(4,4,4-
  trifluorobutoxy)benzamide
194
  N-(5,6-difluoro-1H-indol-3-yl)-3-(2-
  methoxyethoxy)benzamide
195
  3-chloro-4-
  (cyclopropylmethoxy)-N-(5,6-
  difluoro-1H-indol-3-
  yl)benzamide
196
  4-(cyclohexyloxy)-N-(5,6-difluoro-
  1H-indol-3-yl)benzamide
197
  N-(5,6-difluoro-1H-indol-3-yl)-
  6-
  (trifluoromethoxy)nicotinamide
198
  N-(5,6-difluoro-1H-indol-3-yl)-3-
  ethoxy-2,4-difluorobenzamide
199
  N-(5,6-difluoro-1H-indol-3-yl)-
  4-ethoxy-2,6-
  difluorobenzamide
101
  5-chloro-N-(5,6-difluoro-1H-indol-3-
  yl)-6-(6,6-difluoro-2-
  azaspiro[3.3]heptan-2-
  yl)nicotinamide

Pharmaceutical Compositions and Administration

General

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

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

Routes of Administration and Composition Components

In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral).

Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.

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

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

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

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

Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM), lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.

In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.

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

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

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

In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP/NF standard is usually sufficient.

In certain embodiments, solid oral dosage forms can further include one or more components that chemically and/or structurally predispose the composition for delivery of the chemical entity to the stomach or the lower GI; e.g., the ascending colon and/or transverse colon and/or distal colon and/or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K. J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

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

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

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

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

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

Dosages

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

In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about 0.01 mg/Kg to about 100 mg/Kg; from about 0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0.1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 10 mg/Kg).

Regimens

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

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

Methods of Treatment

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

Indications

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

In some embodiments, the condition, disease or disorder is a neurological disorder, which includes disorders that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Non-limiting examples of neurological disorders include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; age-related macular degeneration; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers' disease; alternating hemiplegia; Alzheimer's disease; Vascular dementia; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Anronl-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telegiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet's disease; Bell's palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger's disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome; causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy; chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorders; Cushing's syndrome; cytomegalic inclusion body disease; cytomegalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier's syndrome; Dejerine-Klumke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb's palsy; essential tremor; Fabry's disease; Fahr's syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich's ataxia; fronto-temporal dementia and other “tauopathies”; Gaucher's disease; Gerstmann's syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1-associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (also neurological manifestations of AIDS); holoprosencephaly; Huntington's disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile phytanic acid storage disease; infantile refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh's disease; Lennox-Gustaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; Lissencephaly; locked-in syndrome; Lou Gehrig's disease (i.e., motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; Lyme disease-neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neuron disease; Moyamoya disease; mucopolysaccharidoses; milti-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; p muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O'Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson's disease; paramyotonia congenital; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick's disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; post-polio syndrome; postherpetic neuralgia; postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (types I and II); Rasmussen's encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye's syndrome; Saint Vitus dance; Sandhoff disease; Schilder's disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjögren's syndrome; sleep apnea; Soto's syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; Stiff-Person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subcortical arteriosclerotic encephalopathy; Sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; Tic Douloureux; Todd's paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau disease; Wallenberg's syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wildon's disease; amyotrophe lateral sclerosis and Zellweger syndrome.

In some embodiments, the condition, disease or disorder is STING-associated conditions, e.g., type I interferonopathies (e.g., STING-associated vasculopathy with onset in infancy (SAVI)), Aicardi-Goutières Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis. In certain embodiments, the condition, disease or disorder is an autoimmune disease (e.g., a cytosolic DNA-triggered autoinflammatory disease). Non-limiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel diseases (IBDs) comprising Crohn disease (CD) and ulcerative colitis (UC), which are chronic inflammatory conditions with polygenic susceptibility. In certain embodiments, the condition is an inflammatory bowel disease. In certain embodiments, the condition is Crohn's disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated by one or more alloimmune diseases (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In certain of these embodiments, the condition is alloimmune disease (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis or intestinal mucositis).

In some embodiments, modulation of the immune system by STING provides for the treatment of diseases, including diseases caused by foreign agents. Exemplary infections by foreign agents which may be treated and/or prevented by the method of the present invention include an infection by a bacterium (e.g., a Gram-positive or Gram-negative bacterium), an infection by a fungus, an infection by a parasite, and an infection by a virus. In one embodiment of the present invention, the infection is a bacterial infection (e.g., infection by E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella spp., Staphylococcus aureus, Streptococcus spp., or vancomycin-resistant enterococcus), or sepsis. In another embodiment, the infection is a fungal infection (e.g. infection by a mould, a yeast, or a higher fungus). In still another embodiment, the infection is a parasitic infection (e.g., infection by a single-celled or multicellular parasite, including Giardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, and Toxoplasma gondiz).

In yet another embodiment, the infection is a viral infection (e.g., infection by a virus associated with AIDS, avian flu, chickenpox, cold sores, common cold, gastroenteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, and lower or upper respiratory tract infection (e.g., respiratory syncytial virus)).

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

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

In some embodiments, the condition, disease or disorder is age-related macular degeneration.

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

In some embodiments, the condition, disease or disorder is uveitis, which is inflammation of the uvea (e.g., anterior uveitis, e.g., iridocyclitis or iritis; intermediate uveitis (also known as pars planitis); posterior uveitis; or chorioretinitis, e.g., pan-uveitis).

In some embodiments, the condition, disease or disorder is selected from the group consisting of a cancer, a neurological disorder, an autoimmune disease, hepatitis B, uvetitis, a cardiovascular disease, age-related macular degeneration, and mucositis.

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

Combination Therapy

This disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

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

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

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

In some embodiments, the one or more additional cancer therapies is chemotherapy, which can include administering one or more additional chemotherapeutic agents.

In certain embodiments, the additional chemotherapeutic agent is an immunomodulatory moiety, e.g., an immune checkpoint inhibitor. In certain of these embodiments, the immune checkpoint inhibitor targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155; e.g., CTLA-4 or PD1 or PD-L1). See, e.g., Postow, M. J. Clin. Oncol. 2015, 33, 1.

In certain of these embodiments, the immune checkpoint inhibitor is selected from the group consisting of: Urelumab, PF-05082566, MEDI6469, TRX518, Varlilumab, CP-870893, Pembrolizumab (PD1), Nivolumab (PD1), Atezolizumab (formerly MPDL3280A) (PDL1), MEDI4736 (PD-L1), Avelumab (PD-L1), PDR001 (PD1), BMS-986016, MGA271, Lirilumab, IPH2201, Emactuzumab, INCB024360, Galunisertib, Ulocuplumab, BKT140, Bavituximab, CC-90002, Bevacizumab, and MNRP1685A, and MGA271.

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

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

In certain embodiments, the additional chemotherapeutic agent is a plant alkaloid and/or terpenoid. These alkaloids are derived from plants and block cell division by, in general, preventing microtubule function. In an embodiment, a plant alkaloid and/or terpenoid is a vinca alkaloid, a podophyllotoxin and/or a taxane. Vinca alkaloids, in general, bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules, generally during the M phase of the cell cycle. In an embodiment, a vinca alkaloid is derived, without limitation, from the Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). In an embodiment, a vinca alkaloid includes, without limitation, Vincristine, Vinblastine, Vinorelbine and/or Vindesine. In an embodiment, a taxane includes, but is not limited, to Taxol, Paclitaxel and/or Docetaxel. In a further embodiment a plant alkaloid or terpernoid is a synthetic, semisynthetic or derivative. In a further embodiment, a podophyllotoxin is, without limitation, an etoposide and/or teniposide. In an embodiment, a taxane is, without limitation, docetaxel and/or ortataxel. [021] In an embodiment, a cancer therapeutic is a topoisomerase. Topoisomerases are essential enzymes that maintain the topology of DNA. Inhibition of type I or type II topoisomerases interferes with both transcription and replication of DNA by upsetting proper DNA supercoiling. In a further embodiment, a topoisomerase is, without limitation, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In an embodiment a type I topoisomerase inhibitor is, without limitation, a camptothecin. In another embodiment, a camptothecin is, without limitation, exatecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67) and/or ST 1481. In an embodiment, a type II topoisomerase inhibitor is, without limitation, epipodophyllotoxin. In a further embodiment an epipodophyllotoxin is, without limitation, an amsacrine, etoposid, etoposide phosphate and/or teniposide. In a further embodiment a topoisomerase is a synthetic, semisynthetic or derivative, including those found in nature such as, without limitation, epipodophyllotoxins, substances naturally occurring in the root of American Mayapple (Podophyllum peltatum).

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

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

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

In certain embodiments, the additional chemotherapeutic agent is selected from abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyureataxanes, ifosfamide, liarozole, lonidamine, lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxanes, nilutamide, onapristone, paclitaxel, prednimustine, procarbazine, RPR109881, stramustine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine.

In certain embodiments, the additional chemotherapeutic agent is platinum, cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, azathioprine, mercaptopurine, vincristine, vinblastine, vinorelbine, vindesine, etoposide and teniposide, paclitaxel, docetaxel, irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, teniposide, 5-fluorouracil, leucovorin, methotrexate, gemcitabine, taxane, leucovorin, mitomycin C, tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide and doxorubicin. Additional agents include inhibitors of mTOR (mammalian target of rapamycin), including but not limited to rapamycin, everolimus, temsirolimus and deforolimus.

In still other embodiments, the additional chemotherapeutic agent can be selected from those delineated in U.S. Pat. No. 7,927,613, which is incorporated herein by reference in its entirety.

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

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

Non-limiting examples of additional therapeutic agents and/or regimens for treating lupus include steroids, topical immunomodulators (e.g., tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel®)), thalidomide (Thalomid®), non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarial drugs (e.g., Hydroxychloroquine (Plaquenil)), corticosteroids (e.g, prednisone) and immunomodulators (e.g., evobrutinib, iberdomide, voclosporin, cenerimod, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®, Gengraf®), and mycophenolate mofetil) baricitinb, iguratimod, filogotinib, GS-9876, rapamycin, and PF-06650833), and biologics (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDIO700, obinutuzumab, vobarilizumab, lulizumab, atacicept, PF-06823859, and lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirolizumab, edratide, IFN-α-kinoid, OMS721, RC18, RSLV-132, theralizumab, XmAb5871, and ustekinumab (Stelara®)). For example, non-limiting treatments for systemic lupus erythematosus include non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarial drugs (e.g., Hydroxychloroquine (Plaquenil)), corticosteroids (e.g, prednisone) and immunomodulators (e.g., iberdomide, voclosporin, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®, Gengraf®), and mycophenolate mofetil, baricitinb, filogotinib, and PF-06650833), and biologics (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDIO700, vobarilizumab, lulizumab, atacicept, PF-06823859, lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirolizumab, edratide, IFN-α-kinoid, RC18, RSLV-132, theralizumab, XmAb5871, and ustekinumab (Stelara®)). As another example, non-limiting examples of treatments for cutaneous lupus include steroids, immunomodulators (e.g., tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel®)), GS-9876, filogotinib, and thalidomide (Thalomid®). Agents and regimens for treating drug-induced and/or neonatal lupus can also be administered.

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

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

Non-limiting examples of additional therapeutic agents and/or regimens for treating IBDs include 6-mercaptopurine, AbGn-168H, ABX464, ABT-494, adalimumab, AJM300, alicaforsen, AMG139, anrukinzumab, apremilast, ATR-107 (PF0530900), autologous CD34-selected peripheral blood stem cells transplant, azathioprine, bertilimumab, BI 655066, BMS-936557, certolizumab pegol (Cimzia®), cobitolimod, corticosteroids (e.g., prednisone, Methylprednisolone, prednisone), CP-690,550, CT-P13, cyclosporine, DIMS0150, E6007, E6011, etrasimod, etrolizumab, fecal microbial transplantation, figlotinib, fingolimod, firategrast (SB-683699) (formerly T-0047), GED0301, GLPG0634, GLPG0974, guselkumab, golimumab, GSK1399686, HMPL-004 (Andrographis paniculata extract), IMU-838, infliximab, Interleukin 2 (IL-2), Janus kinase (JAK) inhibitors, laquinimod, masitinib (AB1010), matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, mirikizumab (LY3074828), natalizumab, NNC 0142-0000-0002, NNC0114-0006, ozanimod, peficitinib (JNJ-54781532), PF-00547659, PF-04236921, PF-06687234, QAX576, RHB-104, rifaximin, risankizumab, RPC1063, SB012, SHP647, sulfasalazine, TD-1473, thalidomide, tildrakizumab (MK 3222), TJ301, TNF-Kinoid®, tofacitinib, tralokinumab, TRK-170, upadacitinib, ustekinumab, UTTR1147A, V565, vatelizumab, VB-201, vedolizumab, and vidofludimus.

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

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

Non-limiting examples of additional therapeutic agents and/or regimens for treating Crohn's Disease (CD) include adalimumab, autologous CD34-selected peripheral blood stem cells transplant, 6-mercaptopurine, azathioprine, certolizumab pegol (Cimzia®), corticosteroids (e.g., prednisone), etrolizumab, E6011, fecal microbial transplantation, figlotinib, guselkumab, infliximab, IL-2, JAK inhibitors, matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, natalizumab, ozanimod, RHB-104, rifaximin, risankizumab, SHP647, sulfasalazine, thalidomide, upadacitinib, V565, and vedolizumab.

Non-limiting examples of additional therapeutic agents and/or regimens for treating UC include AbGn-168H, ABT-494, ABX464, apremilast, PF-00547659, PF-06687234, 6-mercaptopurine, adalimumab, azathioprine, bertilimumab, brazikumab (MEDI2070), cobitolimod, certolizumab pegol (Cimzia®), CP-690,550, corticosteroids (e.g., multimax budesonide, Methylprednisolone), cyclosporine, E6007, etrasimod, etrolizumab, fecal microbial transplantation, figlotinib, guselkumab, golimumab, IL-2, JNIU-838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitors (e.g., GS-5745), mesalamine, mesalamine, mirikizumab (LY3074828), RPC1063, risankizumab (BI 6555066), SHP647, sulfasalazine, TD-1473, TJ301, tildrakizumab (MK 3222), tofacitinib, tofacitinib, ustekinumab, UTTR1147A, and vedolizumab.

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

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

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

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

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

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

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

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

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

Non-limiting examples of additional therapeutic agents and/or regimens for treating alloimmune disease include intrauterine platelet transfusions, intravenous immunoglobin, maternal steroids, abatacept, alemtuzumab, alpha1-antitrypsin, AMG592, antithymocyte globulin, barcitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

Non-limiting examples of additional therapeutic agents and/or regimens for treating multiple sclerosis (MS) include alemtuzumab (Lemtrada®), ALKS 8700, amiloride, ATX-MS-1467, azathioprine, baclofen (Lioresal®), beta interferons (e.g., IFN-β-1a, IFN-β-1b), cladribine, corticosteroids (e.g., methylprednisolone), daclizumab, dimethyl fumarate (Tecfidera®), fingolimod (Gilenya®), fluoxetine, glatiramer acetate (Copaxone®), hydroxychloroquine, ibudilast, idebenone, laquinimod, lipoic acid, losartan, masitinib, MD1003 (biotin), mitoxantrone, montelukast, natalizumab (Tysabri®), NeuroVax™, ocrelizumab, ofatumumab, pioglitazone, and RPC1063.

Non-limiting examples of additional therapeutic agents and/or regimens for treating graft-vs-host disease include abatacept, alemtuzumab, alpha1-antitrypsin, AMG592, antithymocyte globulin, barcitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

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

Non-limiting examples of additional therapeutic agents and/or regimens for treating chronic graft vs. host disease include abatacept, alemtuzumab, AMG592, antithymocyte globulin, basiliximab, bortezomib, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, mycophenolate mofetil, pentostatin, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

Non-limiting examples of additional therapeutic agents and/or regimens for treating celiac disease include AMG 714, AMY01, Aspergillus niger prolyl endoprotease, BL-7010, CALY-002, GBR 830, Hu-Mik-Beta-1, IMGX003, KumaMax, Larazotide Acetate, Nexvan2®, pancrelipase, TIMP-GLIA, vedolizumab, and ZED1227.

Non-limiting examples of additional therapeutic agents and/or regimens for treating psoriasis include topical corticosteroids, topical crisaborole/AN2728, topical SNA-120, topical SAN021, topical tapinarof, topical tocafinib, topical IDP-118, topical M518101, topical calcipotriene and betamethasone dipropionate (e.g., MC2-01 cream and Taclonex®), topical P-3073, topical LEO 90100 (Enstilar®), topical betamethasone dipropriate (Sernivo®), halobetasol propionate (Ultravate®), vitamin D analogues (e.g., calcipotriene (Dovonex®) and calcitriol (Vectical®)), anthralin (e.g., Dritho-scalp® and Dritho-crème®), topical retinoids (e.g., tazarotene (e.g., Tazorac® and Avage®)), calcineurin inhibitors (e.g., tacrolimus (Prograf®) and pimecrolimus (Elidel®)), salicylic acid, coal tar, moisturizers, phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrow band UVB phototherapy, Goeckerman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), retinoids (e.g., acitretin (Soriatane®)), methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), Apo805K1, baricitinib, FP187, KD025, prurisol, VTP-43742, XP23829, ZPL-389, CF101 (piclidenoson), LAS41008, VPD-737 (serlopitant), upadacitinib (ABT-494), aprmilast, tofacitibin, cyclosporine (Neoral®, Sandimmune®, Gengraf®), biologics (e.g., etanercept (Enbrel®), entanercept-szzs (Elrezi®), infliximab (Remicade®), adalimumab (Humira®), adalimumab-adbm (Cyltezo®), ustekinumab (Stelara®), golimumab (Simponi®), apremilast (Otezla®), secukinumab (Cosentyx®), certolixumab pegol, secukinumab, tildrakizumab-asmn, infliximab-dyyb, abatacept, ixekizumab (Taltz®), ABP 710, BCD-057, BI695501, bimekizumab (UCB4940), CHS-1420, GP2017, guselkumab (CNTO 1959), HD203, M923, MSB11022, Mirikizumab (LY3074828), PF-06410293, PF-06438179, risankizumab (BI655066), SB2, SB4, SB5, siliq (brodalumab), namilumab (MT203, tildrakizumab (MK-3222), and ixekizumab (Taltz®)), thioguanine, and hydroxyurea (e.g., Droxia® and Hydrea®).

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

Non-limiting examples of additional therapeutic agents and/or regimens for treating uveitis include corticosteroids (e.g., intravitreal triamcinolone acetonide injectable suspensions), antibiotics, antivirals (e.g., acyclovir), dexamethasone, immunomodulators (e.g., tacrolimus, leflunomide, cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral®, Sandimmune®, Gengraf®), chlorambucil, azathioprine, methotrexate, and mycophenolate mofetil), biologics (e.g., infliximab (Remicade®), adalimumab (Humira®), etanercept (Enbrel®), golimumab (Simponi®), certolizumab (Cimzia®), rituximab (Rituxan®), abatacept (Orencia®), basiliximab (Simulect®), anakinra (Kineret®), canakinumab (Ilaris®), gevokixumab (XOMA052), tocilizumab (Actemra®), alemtuzumab (Campath®), efalizumab (Raptiva®), LFG316, sirolimus (Santen®), abatacept, sarilumab (Kevzara®), and daclizumab (Zenapax®)), cytotoxic drugs, surgical implant (e.g., fluocinolone insert), and vitrectomy.

on-limiting examples of additional therapeutic agents and/or regimens for treating mucositis include AG013, SGX942 (dusquetide), amifostine (Ethyol®), cryotherapy, cepacol lonzenges, capsaicin lozenges, mucoadhesives (e.g., MuGard®) oral diphenhydramine (e.g., Benadry® elixir), oral bioadherents (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), caphosol, Chamomilla recutita mouthwash, edible grape plant exosome, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., Peridex® or Periogard®), topical pain relievers (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and Ulcerease® (0.6% phenol)), corticosteroids (e.g., prednisone), pain killers (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor; Kepivance®), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble β-1,3/1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, granules comprising Vaccinium myrtillus extract, macleaya cordata alkaloids and Echinacea angustifolia extract (e.g., SAMITAL®), and gastrointestinal cocktail (an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid)). For example, non-limiting examples of treatments for oral mucositis include AG013, amifostine (Ethyol®), cryotherapy, cepacol lonzenges, mucoadhesives (e.g., MuGard®) oral diphenhydramine (e.g., Benadry® elixir), oral bioadherents (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), caphosol, Chamomilla recutita mouthwash, edible grape plant exosome, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., Peridex® or Periogard®), topical pain relievers (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and Ulcerease® (0.6% phenol)), corticosteroids (e.g., prednisone), pain killers (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor; Kepivance®), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble β-1,3/1,6 glucan, P²⁷⁶, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, and gastrointestinal cocktail (an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid)). As another example, non-limiting examples of treatments for esophageal mucositis include xylocaine (e.g., gel viscous Xylocaine 2%). As another example, treatments for intestinal mucositis, treatments to modify intestinal mucositis, and treatments for intestinal mucositis signs and symptoms include gastrointestinal cocktail (an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid)).

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

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

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

Patient Selection

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

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

Compound Preparation

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

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

To further illustrate the foregoing, the following non-limiting, exemplary synthetic schemes are included. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the invention as described, and claimed herein. The reader will recognize that the skilled artisan, provided with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples.

EXAMPLES

Abbreviations
Ac = acetyl                      LC-MS = liquid
                                 chromatography-mass
                                 spectrometry
ACN = acetonitrile               Me = methyl
Bu = butyl                       NMR = nuclear magnetic
                                 resonance
DAST = diethylaminosulphur trifluoride NMM = N-
                                 methylmorpholine
DBH = 1,3-dibromo-5,5-dimethylhydantoin PyBOP = Benzotriazole-1-
                                 yl-
                                 oxytripyrrolidinophosphonium
                                 hexafluorophosphate
DCM = dichloromethane            RT = retention time
DIAD = Diisopropylazodicarboxylate TEA = triethylamine
DIEA = N,N-diisopropylethylamine THF = tetrahydrofuran
DMF = N,N-dimethylformamide      T3P = 2,4,6-tripropyl-2,4,6-
                                 trioxo-1,3,5,2,4,6-
                                 trioxatriphosphorinane
DMSO = dimethyl sulfoxide        TEA = triethylamine
DPPA = diphenyl azidophosphate   HATU = N-
                                 [(Dimethylamino)-1H-1,2,3-
                                 triazolo-[4,5-b]pyridin-1-
                                 ylmethylene]-N-
                                 methylmethanaminium
                                 hexafluorophosphate N-
                                 oxide
Dppf = bis(diphenylphosphino)ferrocene HPLC = high-performance
                                 liquid chromatography
FA = formic acid                 LCMS = liquid
                                 chromatography-mass
                                 spectrometry
HATU = 2-(7-azaenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium DIEA = N-ethyl-N-
hexafluorophosphate              isopropylpropan-2-amine
HPLC = high performance liquid chromatography TFA = trifluoroacetic acid
AIBN = azodiisobutyronitrile; azobisisobutyronitrile Speedvac = Savant
BINAP = (±)-2,2′-Bis(diphenylphosphino)-1,1′-BINAPhthyl SC250EXP SpeedVac
BrettPhos = dicyclohexyl[3,6-dimethoxy-2′,4′,6′-tris(1-methylethyl)[1,1′- Concentrator
biphenyl]-2-yl]phosphine         Boc20 = di-tert-butyl
DCC = N,N′-dicyclohexylcarbodiimide pyrocarbornate
DMAP = Dimethylaminopyridine     BzCl = benzoyl chloride
Et = ethyl                       DCE = dichloroethane
                                 EDC = 1-Ethyl-3-(3-
                                 dimethylaminopropyl)
                                 carbodiimide hydrochloride
                                 HOBt = 1-
                                 Hydroxybenzotriazole
Ir[dF(CF3)ppy]2(dtbpy)PF6 = Iridium(1+), [4,4′-bis(1,1-dimethylethyl)- LDA = lithium
2,2′-bipyridine-κN1,κN1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2- diisopropylamide
pyridinyl-κN]phenyl-κC]-, (OC-6-33)-, hexafluorophosphate(1-) (1:1) NBS = N-
MsCl = methanesulfonyl chloride  Bromosuccinimide
PPh3 = triphenylphosphine        RuPhos = 2-
Selectfluor = 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane dicyclohexylphosphino-
bis(tetrafluoroborate)           2′,6′-diisopropoxy-1,1′-
TBDPSCl = tert-butylchlorodiphenylsilane biphenyl
TMS = tetramethylsilane          TBAF =
                                 Tetrabutylammonium
                                 fluoride
                                 Tf =
                                 trifluoromethanesulfonyl
                                 XPhos = (2-(2,4,6-
                                 triisopropylphenethyl)phenyl)
                                 dicyclohexylphosphine

Materials and Methods

The LC-MS was recorded using one of the following methods.

LCMS Method A: Kinetex EVO C18 100A, 30 *3 mm, 0.5 μL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH₄HCO₃ and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.0 min, hold at 95% MPB for 0.3 min, 95% MPB to 10% in 0.1 min.

LCMS Method B: XBridge Shield RP18, 50 *4.6 mm, 0.5 μL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.04% NH₄OH and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.79 min, 95% MPB to 10% in 0.06 min, then equilibration to 10% MPB for 0.15 min.

LCMS Method C: Shim-pack XR-ODS, 50 *3 mm, 0.3 μL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.05 TFA and Mobile Phase B (MPB): Acetonitrile/0.05% TFA. Elution 5% MPB to 100% in 1.10 min, hold at 100% MPB for 0.60 min, 100% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.25 min.

LCMS Method D: Kinetex 2.6 μm EVO C18 100A, 50 *3 mm, 0.6 μL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH₄HCO₃ and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 1.20 min, hold at 95% MPB for 0.50 min, 95% MPB to 10% in 0.05 min, then equilibration to 10% MPB for 0.10 min.

LCMS Method E: EVO C18, 50 *3 mm, 0.1 μL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH₄HCO₃ and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.60 min, 95% MPB to 10% in 0.15 min, then equilibration to 10% MPB for 0.25 min.

LCMS Method F: Titank C18, 50 *3 mm, 0.5 μL injection, 1.5 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH₄HCO₃ and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 1.80 min, hold at 95% MPB for 0.80 min, 95% MPB to 10% in 0.15 min, then equilibration to 10% MPB for 0.25 min.

LCMS Method G: XBridge BEH C18, 50 *3 mm, 4.0 μL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH₄HCO₃ and Mobile Phase B (MPB): Acetonitrile. Elution 5% MPB to 95% in 2.00 min, hold at 95% MPB for 0.70 min, 95% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.25 min.

LCMS Method H: XBridge BEH C18, 50 *3 mm, 4.0 μL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH₄HCO₃ and Mobile Phase B (MPB): Acetonitrile. Elution 5% MPB to 95% in 2.00 min, hold at 95% MPB for 0.70 min, 95% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.25 min.

LCMS Method I: HALOC18, 30 *3 mm, 0.5 μL injection, 1.5 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.05% TFA and Mobile Phase B (MPB): Acetonitrile/0.05% TFA. Elution 5% MPB to 100% in 1.20 min, hold at 100% MPB for 0.60 min, 100% MPB to 5% in 0.02 min, then equilibration to 5% MPB for 0.18 min.

Method BA

Instrument: Agilent LCMS system equipped with DAD and ELSD detector

Ion mode: Positive

Column: Waters X-Bridge C18, 50*2.1 mm*5 m or equivalent

Mobile Phase: A: H₂O (0.04% TFA); B: CH₃CN (0.02% TFA)

Gradient: 4.5 min gradient method, actual method would depend on clogP of compound.

Flow Rate: 0.6 mL/min or 0.8 mL/min

Column Temp: 40° C. or 50° C.

UV: 220 nm

Method BB

Instrument: Agilent LCMS system equipped with DAD and ELSD detector

Ion mode: Positive

Column: Waters X-Bridge ShieldRP18, 50*2.1 mm*5 m or equivalent

Mobile Phase:A: H₂O (0.05% NH₄₀H) or 10 mM ammonia bicarbonate; B: CH₃CN

Gradient: 4.5 min gradient method; actual method would depend on the clogP of the compound.

Flow Rate: 0.6 mL/min or 0.8 mL/min

Column Temp: 40° C.

UV: 220 nm

LCMS Method A-1: Kinetex EVO C18 100A, 30*3 mm, 0.5 μL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH₄HCO₃ and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.30 min, 95% MPB to 10% in 0.10 min.

LCMS Method B-1: Xselect CSH C18, 50*3 mm, 1.0 μL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.1% FA and Mobile Phase B (MPB): Acetonitrile/0.1% FA. Elution 5% MPB to 100% in 2.00 min, hold at 100% MPB for 0.70 min, 100% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.15 min.

LCMS Method C-1: XBridge Shield RP18, 50*4.6 mm, 0.5 μL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.04% NH₃·H₂O and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.79 min, 95% MPB to 10% in 0.06 min, then equilibration to 10% MPB for 0.15 min.

LCMS Method D-1: Shim-pack Scepter C18-120, 33*3 mm, 0.5 μL injection, 1.5 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH₄HCO₃ and Mobile Phase B (MPB): Acetonitrile. Elution 50% MPB to 95% in 2.00 min, hold at 95% MPB for 0.60 min, 95% MPB to 10% in 0.05 min, then equilibration to 10% MPB for 0.25 min.

LCMS Method E-1: kinetex 2.6 μm EVO, 50*3 mm, 0.5 μL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH₄HCO₃ and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.70 min, 95% MPB to 10% in 0.05 min, then equilibration to 10% MPB for 0.25 min.

LCMS Method F-1: HALOC18, 30*3 mm, 0.5 μL injection, 1.5 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.05% TFA and Mobile Phase B (MPB): Acetonitrile/0.05% TFA. Elution 5% MPB to 100% in 1.20 min, hold at 100% MPB for 0.60 min, 100% MPB to 5% in 0.02 min, then equilibration to 5% MPB for 0.18 min.

LCMS Method G-1: HALOC18, 30*3 mm, 0.5 μL 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 0.18 min.

LCMS Method H-1: HPH-C18, 50*3 mm, 0.5 μL injection, 1.5 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.04% NH₄₀H and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95 u % in 2.00 min, hold at 95% MPB for 0.70 min, 95% MPB to 10% in 0.05 min, then equilibration to 10% MPB for 0.25 min.

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.

Prep. HPLC Condition

Instrument:

1. GILSON 281 and Shimadzu LCMS 2010A

2. GILSON 215 and Shimadzu LC-20AP

3. GILSON 215

Mobile Phase:

A: NH₄OH/H₂O=0.05% v/v; B: ACN

A: FA/H₂O=0.225% v/v; B: ACN

Column

Xtimate C18 150*25 mm*5 μm

Flow rate: 25 mL/min or 30 mL/min

Monitor wavelength: 220&254 nm

Gradient: actual method would depend on clog P of compound

Detector: MS Trigger or UV

PREPARATIVE EXAMPLES

Synthesis of Intermediate 1 (5-chloro-6-[6,6-difluoro-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylic acid)

Step 1: methyl 5-chloro-6-[6,6-difluoro-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylate

6,6-Difluoro-2-azaspiro[3.3]heptane (200.0 mg, 1.5 mmol, 1.0 equiv.) and methyl 6-bromo-5-chloropyridine-3-carboxylate(376.3 mg, 1.5 mmol, 1.0 equiv.) were dissolved in ACN (5 mL), then Cs₂CO₃ (978.9 mg, 3.0 mmol, 2.0 equiv.) was added. The reaction mixture was stirred overnight at 80° C. After filtration and washing the solids with MeOH, the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give methyl 5-chloro-6-[6,6-difluoro-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylate (180.0 mg) as a white solid. LCMS Method A: [M+H]⁺=303.

Step 2: 5-chloro-6-[6,6-difluoro-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylic acid

Methyl 5-chloro-6-[6,6-difluoro-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylate (180.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and water (2 mL), then NaOH (47.6 mg, 1.2 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 2 hours at 80° C. and then concentrated under vacuum. The residue was diluted with water and adjusted to pH 5 with aqueous HCl (6 M). The resulting solid was collected by filtration and washed with water, then dried to give 5-chloro-6-[6,6-difluoro-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylic acid (150.0 mg) as a white solid. LCMS Method A: [M−H]⁻=287.

The following intermediates were prepared using the same method described for Intermediate 1.

	Starting	Starting
Intermediate	material A	material B	Structure	LCMS data
Intermediate 2				Method A: MS-ESI: 275 [M − H]−
Intermediate 3				Method A: MS-ESI: 266 [M − H]−
Intermediate 4				Method A: MS-ESI: 225 [M + H]+
Intermediate 5				Method A: MS-ESI: 261 [M + H]+
Intermediate 6				Method E MS-ESI: 249 [M + H]+
Intermediate 7				Method A: MS-ESI: 243 [M + H]+
Intermediate 8				Method A: MS-ESI: 299 [M + H]+
Intermediate 9				Method A: MS-ESI: 250 [M + H]+
Intermediate 10				Method A: MS-ESI: 246 [M + H]+
Intermediate 11				Method A: MS-ESI: 238 [M + H]+
Intermediate 12				Method B: MS-ESI: 237 [M + H]+
Intermediate 13				Method B: MS-ESI: 281 [M + H]+
Intermediate 14				Method B: MS-ESI: 284 [M + H]+
Intermediate 15				Method A: MS-ESI: 267 [M + H]+
Intermediate 16				Method A: MS-ESI: 295 [M + H]+
Intermediate 17				Method A: MS-ESI: 263 [M + H]+

Synthesis of Intermediate 18 (6-(4,4,4-trifluorobutoxy)pyridine-3-carboxylic acid)

Methyl 6-fluoropyridine-3-carboxylate (500.0 mg, 3.2 mmol, 1.0 equiv.) was dissolved in THE (20 mL), then t-BuOK (723.3 mg, 6.4 mmol, 2.0 equiv.) and 4,4,4-trifluoro-1-butanol (1.0 g, 8.0 mmol, 2.5 equiv.) were added. The resulting solution was stirred for 16 hours at ambient temperature and then concentrated under vacuum. The residue was diluted with water and washed with ethyl acetate. The aqueous layer was adjusted to pH 2 with aqueous HCl (3 M). The resulting solids were collected by filtration and dried to give 6-(4,4,4-trifluorobutoxy)pyridine-3-carboxylic acid (610 mg) as a white solid. LCMS Method F: [M−H]⁺=248.

The following intermediates were prepared using the same method described for Intermediate 18.

	Starting	Starting
Intermediate	material A	material B	Structure	LCMS data
Intermediate 19				Method A: MS-ESI: 254 [M + H]+

Synthesis of Intermediate 20 (5-(4,4,4-trifluorobutoxy)pyrazine-2-carboxylic acid)

Step 1: methyl 5-(4,4,4-trifluorobutoxy) pyrazine-2-carboxylate

Methyl 5-bromopyrazine-2-carboxylate (5.0 g, 23.0 mmol, 1.0 equiv.) was dissolved in THF (100 mL), then (4,4,4-trifluorobutoxy) sodium (6.9 g, 46.1 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 4 hours at ambient temperature, then adjusted to pH 3 with aqueous HCl (1 mol/L). The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give methyl 5-(4,4,4-trifluorobutoxy) pyrazine-2-carboxylate (800 mg) as a white solid. LCMS Method A: [M+H]⁺=265.

Step 2: 5-(4,4,4-trifluorobutoxy) pyrazine-2-carboxylic acid

Methyl 5-(4,4,4-trifluorobutoxy) pyrazine-2-carboxylate (500.0 mg, 1.9 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (151.4 mg, 3.8 mmol, 2.0 equiv.) wad added. The reaction mixture was heated to 80° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water and adjusted to pH 5 with aqueous HCl (6 M). The resulting solid was collected by filtration, washed with water, then dried to give 5-(4,4,4-trifluorobutoxy) pyrazine-2-carboxylic acid (300 mg) as a yellow solid. LCMS Method A: [M−H]=287.

The following intermediates were prepared using the same method described for Intermediate 20.

	Starting	Starting
Intermediate	material A	material B	Structure	LCMS data
Intermediate 21				Method B: MS-ESI: 237 [M + H]+

Synthesis of Intermediate 22 (6-(2-methoxyethoxy)nicotinic acid)

Step 1: methyl 6-(2-methoxyethoxy)pyridine-3-carboxylate

2-Methoxyethanol (422.7 mg, 5.6 mmol, 1.5 equiv.) was dissolved in THE (20 mL) and cooled to 0° C., then NaH (60% wt in mineral oil, 296.2 mg, 7.4 mmol, 2.0 equiv.) was added at 0° C. After 30 min at 0° C., methyl 6-bromopyridine-3-carboxylate (800.0 mg, 3.7 mmol, 1.0 equiv.) was added at 0° C. The resulting solution was stirred overnight at ambient temperature and then quenched by the addition of ice water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give methyl 6-(2-methoxyethoxy)pyridine-3-carboxylate (300 mg) as a yellow solid. LCMS Method A: [M+H]⁺=212.

Step 2: 6-(2-methoxyethoxy)pyridine-3-carboxylic acid

Methyl 6-(2-methoxyethoxy)pyridine-3-carboxylate (300.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then LiOH (68.0 mg, 2.8 mmol, 2.0 equiv.) was added. The resulting solution was stirred overnight at ambient temperature. The residue was diluted with water and adjusted to pH 5 with aqueous HCl (6 M). The resulting solid was collected by filtration, washed with water, then dried to give 6-(2-methoxyethoxy)pyridine-3-carboxylic acid (120 mg) as a white solid. LCMS Method A: [M−H]⁺=196.

Synthesis of Intermediate 23 (3-methyl-4-(4,4,4-trifluorobutoxy) benzoic acid

Step 1: methyl 3-methyl-4-(4,4,4-trifluorobutoxy) benzoate

Methyl 4-hydroxy-3-methylbenzoate (500.0 mg, 3.0 mmol, 1.0 equiv.) was dissolved in THF (20 mL), then 4,4,4-trifluoro-1-butanol (385.4 mg, 3.0 mmol, 1.0 equiv.) and PPh₃ (1183.8 mg, 4.5 mmol, 1.5 equiv.) were added and the reaction mixture was cooled to 0° C. This was followed by the addition of DIAD (912.6 mg, 4.5 mmol, 1.5 equiv.), maintaining the reaction mixture at 0° C. After 6 hours at 0° C., the reaction mixture diluted with 20 mL of ethyl acetate. The resulting solution was washed with brine, and the organic layer dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give methyl 3-methyl-4-(4,4,4-trifluorobutoxy) benzoate (300 mg) as a white solid. LCMS Method A: [M+H]⁺=277.

Step 2: 3-methyl-4-(4,4,4-trifluorobutoxy) benzoic acid

Methyl 3-methyl-4-(4,4,4-trifluorobutoxy) benzoate (300.0 mg, 1.1 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (86.9 mg, 2.2 mmol, 2.0 equiv.) was added. The resulting solution was stirred for 2 hours at 80° C. and then concentrated under vacuum. The residue was diluted with water, then adjusted to pH 5 with aqueous HCl (6 M). The resulting solid was collected by filtration and washed with water, then dried to give 3-methyl-4-(4,4,4-trifluorobutoxy) benzoic acid (160 mg) as a white solid. LCMS Method A: [M+H]⁺=263.

The following intermediates were prepared using the same method described for Intermediate 23.

	Starting	Starting		LCMS
Intermediate	material A	material B	Structure	data
Intermediate 24				Method A: MS-ESI: 250 [M + H]+
Intermediate 25				Method A: MS-ESI: 227 [M − H]−
Intermediate 26				Method E: MS-ESI: 245 [M − H]−
Intermediate 27				Method G: MS-ESI: 272 [M − H]−
Intermediate 28				Method G: MS-ESI: 281 [M − H]−
Intermediate 29				Method A: MS-ESI: 233 [M − H]−
Intermediate 30				Method A: MS-ESI: 265 [M − H]−
Intermediate 31				Method G: MS-ESI: 251 [M − H]−
Intermediate 32				Method H: MS-ESI: 251 [M − H]−
Intermediate 33				Method A: MS-ESI: 251 [M − H]−
Intermediate 34				Method A: MS-ESI: 251 [M − H]−
Intermediate 35				Method A: MS-ESI: 251 [M − H]−
Intermediate 36				Method B: MS-ESI: 251 [M − H]−

Synthesis of Intermediate 37 (6-oxo-5-(4-(trifluoromethyl)benzyl)-1,6-dihydropyridazine-3-carboxylic acid)

6-Oxo-4,5-dihydro-1H-pyridazine-3-carboxylic acid (1.0 g, 7.0 mmol, 1.0 equiv.) was dissolved in MeOH (20 mL), then KOH (789.6 mg, 14.0 mmol, 2.0 equiv.) and 4-(trifluoromethyl)benzaldehyde (1.4 g, 8.4 mmol, 1.2 equiv.) were added. The resulting solution was stirred for 2 hours at 80° C. and concentrated under vacuum. The residue was diluted with water, then adjusted to pH 2 with aqueous HCl (6 M). The resulting solid was collected by filtration and washed with water, then dried to give 6-oxo-5-[[4-(trifluoromethyl)phenyl]methyl]-1H-pyridazine-3-carboxylic acid (2.0 g, 95.3%) as an off-white solid. LCMS Method A: [M+H]⁺=299.

Synthesis of Intermediate 38 (4-(3,3-difluorocyclobutyl)benzoic acid)

Step 1: 1-bromo-4-(3,3-difluorocyclobutyl)benzene

3-(4-Bromophenyl)cyclobutan-1-one (1.0 g, 4.4 mmol, 1.0 equiv.) was dissolved in DCM (20 mL), then DAST (716.1 mg, 4.4 mmol, 1.0 equiv.) was added at 0° C. The resulting mixture was stirred for 2 hours at 40° C. and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give 1-bromo-4-(3,3-difluorocyclobutyl)benzene (800 mg) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.46 (d, 2H), 7.12 (d, 2H), 3.90-3.80 (m, 1H), 3.06-2.95 (m, 2H), 2.68-2.59 (m, 2H).

Step 2: 4-(3,3-difluorocyclobutyl)benzoic acid

1-Bromo-4-(3,3-difluorocyclobutyl)benzene (500.0 mg, 2.0 mmol, 1.0 equiv.) was dissolved in THE (20 mL) under an atmosphere of nitrogen, cooled to −78° C., then a solution of n-BuLi in hexane (2.5 M, 1.2 mL, 3.0 mmol, 1.5 equiv.) was added dropwise, maintaining the temperature at −78° C. After 30 min at −78° C., dry-ice (2.0 g, 45.4 mmol, 22.5 equiv.) was added in portions. The resulting solution was stirred for an additional 30 min at −40° C. and then quenched by the addition of 1 M aqueous HCl. The resulting mixture was concentrated under vacuum. The resulting solid was collected by filtration and purified by Flash-Prep-HPLC with the following conditions: Column, C18; mobile phase, ACN/H₂O increasing from 20% to 60% within 40 min; Detector, 254 nm. This resulted into 4-(3,3-difluorocyclobutyl)benzoic acid (320 mg) as a yellow solid. LCMS Method A: [M−H]⁻=211.

Synthesis of Intermediate 39 (4-(2-(trifluoromethoxy)ethyl)benzoic acid)

Step 1: O-(4-bromophenethyl)S-methyl carbonodithioate

2-(4-Bromophenyl)ethan-1-ol (5.0 g, 24.9 mmol, 1.0 equiv.) and imidazole (170.0 mg, 2.5 mmol, 0.1 equiv.) were dissolved in THE (100 mL), then NaH (60% wt in mineral oil, 2.5 g, 62.5 mmol, 2.1 equiv.) was added at 0° C. After 30 min at 0° C., CS₂ (3.8 mL, 63.0 mmol, 2.5 equiv.) was added dropwise. The mixture was stirred for 30 min at ambient temperature, then MeI (3.9 mL, 92.6 mmol, 2.5 equiv.) was added. After an additional 30 min, the reaction was quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give crude O-(4-bromophenethyl)-S-methyl carbonodithioate (7.4 g) as a yellow oil.

Step 2: 1-bromo-4-(2-(trifluoromethoxy)ethyl)benzene

DBH (14.8 g, 51.7 mmol, 3.0 equiv.) was dissolved in DCM (100 mL) and cooled to −78° C. Then HF-Pyridine (70% wt., 17.5 mL, 673.8 mmol, 39.2 equiv.) was added dropwise, maintaining the reaction mixture at −78° C. To the mixture, a solution of O-(4-bromophenethyl)-S-methyl carbonodithioate (5.0 g, 17.2 mmol, 1.0 equiv.) in DCM (10 mL) was added dropwise at −78° C. The resulting solution was stirred for 30 min at 0° C. and then quenched by the addition of ice-water. The reaction mixture was adjusted to pH 10 with saturated aqueous NaHCO₃, then extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether to give 1-bromo-4-(2-(trifluoromethoxy)ethyl)benzene (3.4 g) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆): 7.52 (d, 2H), 7.27 (d, 2H), 4.29 (t, 2H), 2.96 (t, 2H).

Step 3: 4-(2-(trifluoromethoxy)ethyl)benzoic acid

1-Bromo-4-(2-(trifluoromethoxy)ethyl)benzene (2.0 g, 7.4 mmol, 1.0 equiv.) was dissolved in THE (20 mL) under an atmosphere of nitrogen and cooled to 78° C., then a solution of n-BuLi in hexane (2.5 M, 4.5 mL, 11.3 mmol, 1.5 equiv.) was added dropwise, maintaining the reaction mixture at −78° C. After 30 min at −78° C., dry ice (10.0 g, 227.3 mmol, 30.6 equiv.) was added to above solution. The resulting solution was stirred for 30 min at −40° C. and then quenched by the addition of saturated aqueous NH₄Cl. The reaction mixture was adjusted to pH 2 with aqueous HCl (6 M), then extracted with ethyl acetate. The organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum to give 4-(2-(trifluoromethoxy)ethyl)benzoic acid (1.5 g) as a yellow solid. LCMS Method A: [M−H]⁻=233.

Synthesis of Intermediate 40 (4-(4,4-difluorocyclohexyl)benzoic acid)

Step 1: ethyl 4-(4,4-difluorocyclohex-1-en-1-yl)benzoate

Ethyl 4-bromobenzoate (2.0 g, 8.7 mmol, 1.0 equiv.) was dissolved in dioxane (20 mL) and water (2 mL), then 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.3 g, 9.6 mmol, 1.1 equiv.), Cs₂CO₃ (8.5 g, 26.2 mmol, 3.0 equiv.) and XPhos Pd G3 (739.0 mg, 0.9 mmol, 0.1 equiv.) were added. The reaction mixture was heated to 90° C. overnight, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give ethyl 4-(4,4-difluorocyclohex-1-en-1-yl)benzoate (1.9 g) as a yellow solid. LCMS Method A: [M+H]⁺=267.

Step 2: ethyl 4-(4,4-difluorocyclohexyl)benzoate

Ethyl 4-(4,4-difluorocyclohex-1-en-1-yl)benzoate (1.9 g, 7.1 mmol, 1.0 equiv.) was dissolved in MeOH (30 mL), then Pd/C (10% wt., 200.0 mg) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred overnight at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum to give ethyl 4-(4,4-difluorocyclohexyl)benzoate (1.6 g) as a yellow oil. LCMS Method A: [M+H]⁺=269.

Step 3: 4-(4,4-difluorocyclohexyl)benzoic acid

Ethyl 4-(4,4-difluorocyclohexyl)benzoate (1.5 g, 5.6 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL) and H₂O (10 mL), then NaOH (447.2 mg, 11.2 mmol, 2.0 equiv.) was added. The resulting solution heated for 3 hours at 80° C. and concentrated under vacuum. The residue was diluted with water then adjusted to pH 6 with aqueous HCl (1 M). The resulting solids were collected by filtration and dried to give 4-(4,4-difluorocyclohexyl)benzoic acid (1.0 g) as a white solid. LCMS Method A: [M−H]⁻=239.

The following intermediates were prepared using the same method described for Intermediate 40.

	Starting	Starting
Intermediate	material A	material B	Structure	LCMS data
Intermediate 41				Method A: MS-ESI: 275 [M + H]+
Intermediate 42				Method A: MS-ESI: 218 [M − H]−

Synthesis of Intermediate 43 (5,6-difluoro-1H-indol-3-amine hydrogen chloride)

Step 1: 5,6-difluoro-3-nitro-1H-indole

5,6-Difluoro-1H-indole (25.0 g, 163.3 mmol, 1.0 equiv.) was dissolved in in ACN (300 mL) and cooled to 0° C., then AgNO₃ (33.3 g, 195.9 mmol, 1.2 equiv.) was added under 0° C., the resulting mixture was stirred for 15 min, then benzoyl chloride (27.5 g, 195.9 mmol, 1.2 equiv.) was added batchwise, maintaining the reaction mixture at 0° C. After an additional 3 hours at 0° C. the reaction mixture was quenched by the addition of ice-water. The reaction mixture was adjusted to pH 8 with aqueous NaHCO₃, then extracted with DCM and the organic layers concentrated under vacuum. The residue was purified by flash column chromatography on silica gel column, eluting with ethyl acetate/petroleum ether (2:1) to give 5,6-difluoro-3-nitro-1H-indole (24 g) as a brown solid. LCMS Method A: [M+H]⁺=199.

Step 2: tert-butyl N-(5,6-difluoro-1H-indol-3-yl)carbamate

5,6-Difluoro-3-nitro-1H-indole (24.0 g, 121.1 mmol, 1.0 equiv.) was dissolved in MeOH (300 mL), then Pd/C (10% wt., 2.4 g) and (Boc)₂O (39.7 g, 181.7 mmol, 1.5 equiv.) were added under nitrogen. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred overnight at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel column, eluting with ethyl acetate/petroleum ether (1:4) to give tert-butyl N-(5,6-difluoro-1H-indol-3-yl)carbamate (22 g) as a yellow solid. LCMS Method E: [M+H]⁺=269.

Step 3: 5,6-difluoro-1H-indol-3-amine hydrochloride

tert-Butyl N-(5,6-difluoro-1H-indol-3-yl)carbamate (17.0 g, 63.4 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4N, 200 mL). The resulting mixture was stirred for 30 min at ambient temperature and then concentrated under vacuum to give 5,6-difluoro-1H-indol-3-amine hydrochloride (12 g) as a yellow crude solid. LCMS Method E: [M+H]⁺=169.

The following intermediates were prepared using the same method described for Intermediate 43.

Intermediate	Starting material	Structure	LCMS data
Intermediate 44			Method B: MS-ESI: 158 [M + H]+
Intermediate 45			Method B: MS-ESI: 164 [M + H]+
Intermediate 46			Method B: MS-ESI: 152 [M + H]+
Intermediate 47			Method B: MS-ESI: 151 [M + H]+
Intermediate 58			Method B: MS-ESI: 151 [M + H]+

Synthesis of Intermediate 48 (5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine hydrogen chloride)

Step 1: 5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl azide

5-Fluoro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (1.0 g, 5.6 mmol, 1.0 equiv.) and DPPA (3.0 g, 11.1 mmol, 2.0 equiv.) were dissolved in THE (10 mL), TEA (1.6 mL, 11.1 mmol, 2.0 equiv.) was added. The resulting mixture was stirred for overnight at ambient temperature and concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give 5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl azide (900 mg) as a white solid. LCMS Method G: [M+H]⁺=206.

Step 2: tert-butyl N-[5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl]carbamate

5-Fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl azide (300.0 mg, 1.5 mmol, 1.0 equiv.) was added in t-BuOH (8 mL). The resulting mixture was stirred for overnight at 100° C. and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel column, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl N-[5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl]carbamate (350 mg) as a yellow solid. LCMS Method G: [M+H]⁺=251.

Step 3: 5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine hydrogen chloride

tert-Butyl N-[5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl]carbamate (300.0 mg) was dissolved in HCl/1,4-dioxane (4 M, 10.0 mL). The resulting solution was stirred for overnight at 4 hours at ambient temperature and then concentrated under vacuum to give crude 5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine hydrogen chloride (350 mg) as a yellow solid. LCMS Method G: [M+H]⁺=151.

The following intermediates were prepared using the same method described for Intermediate 48.

Intermediate	Starting material	Structure	LCMS data
Intermediate 49			Method G: MS-ESI: 158 [M + H]+
Intermediate 50			Method G: MS-ESI: 167 [M + H]+

Synthesis of Intermediate 51 (5-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-amine hydrogen chloride)

Step 1: 5-bromo-1H-indole-3-carbonyl azide

5-Bromo-1H-indole-3-carboxylic acid (1.0 g, 4.2 mmol, 1.0 equiv.) was dissolved in THF (10 mL), DPPA (2.3 g, 8.3 mmol, 2.0 equiv.) and TEA (1.8 mL, 12.5 mmol, 3.0 equiv.) were added. The resulting solution was stirred for overnight at ambient temperature and then concentrated under vacuum. The residue was diluted with MeOH and the isolated solids were collected by filtration to give 5-bromo-1H-indole-3-carbonyl azide (900 mg) as a white solid. LCMS Method G: [M+H]⁺=265.

Step 2: tert-butyl N-(5-bromo-1H-indol-3-yl)carbamate

5-Bromo-1H-indole-3-carbonyl azide (900.0 mg, 3.4 mmol, 1.0 equiv.) was dissolved in t-BuOH (6 mL). The resulting solution was stirred for overnight at 80° C. and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl N-(5-bromo-1H-indol-3-yl)carbamate (910 mg) as a yellow solid. LCMS Method G: [M+H]⁺=311.

Step 3: tert-butyl N-[5-(1-isopropylpyrazol-4-yl)-1H-indol-3-yl]carbamate

tert-Butyl N-(5-bromo-1H-indol-3-yl)carbamate (500.0 mg, 1.6 mmol, 1.0 equiv.) was dissolved in dioxane (6 mL) and water (0.6 mL), then 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (417.3 mg, 1.8 mmol, 1.1 equiv.), Xphos Pd G3 (136.0 mg, 0.2 mmol, 0.1 equiv.) and Cs₂CO₃ (1.0 g, 3.2 mmol, 2.0 equiv.) were added. The solution heated overnight at 100° C., then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and the organic layers concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl N-[5-(1-isopropylpyrazol-4-yl)-1H-indol-3-yl]carbamate (400 mg) as a white solid. LCMS Method G: [M+H]⁺=341.

Step 4: 5-(1-isopropylpyrazol-4-yl)-1H-indol-3-amine hydrogen chloride

tert-butyl N-[5-(1-isopropylpyrazol-4-yl)-1H-indol-3-yl]carbamate (400.0 mg, 1.2 mmol, 1.0 equiv.) was dissolved in HCl in 1,4-dioxane (4 M, 8 mL). The resulting solution was stirred for 4 hours at ambient temperature and then concentrated under vacuum to give crude 5-(1-isopropylpyrazol-4-yl)-1H-indol-3-amine hydrogen chloride (400 mg) as a grey solid. LCMS Method G: [M+H]⁺=241.

Synthesis of Intermediate 52 (3-((4,4,4-trifluorobutyl)amino)benzoic acid)

Step 1: methyl 3-[(4,4,4-trifluorobutyl)amino]benzoate

Methyl 3-bromobenzoate (300.0 mg, 1.4 mmol, 1.0 equiv.) and 4,4,4-trifluorobutan-1-amine (177.3 mg, 1.4 mmol, 1.0 equiv.) were dissolved in 1,4-dioxane (5 mL), then Cs₂CO₃ (1.4 g, 4.2 mmol, 3.0 equiv.) and XPhos Pd G3 (118.1 mg, 0.1 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 100° C. overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give methyl 3-[(4,4,4-trifluorobutyl)amino]benzoate (250 mg) as a yellow solid. LCMS Method G: [M+H]⁺=262.

Step 2: 3-[(4,4,4-trifluorobutyl)amino]benzoic acid

Methyl 3-[(4,4,4-trifluorobutyl)amino]benzoate (250.0 mg, 1.0 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and water (2 mL), then NaOH (76.6 mg, 1.9 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water then adjusted to pH 6 with aqueous HCl (1 M). The resulting solids were collected by filtration, washed with water and dried to give 3-[(4,4,4-trifluorobutyl)amino]benzoic acid (200 mg) as a white solid. LCMS Method A: [M−H]⁻=246.

The following intermediates were prepared using the same method described for Intermediate 52.

	Starting		LCMS
Intermediate	material	Structure	data
Intermediate 53			Method E: MS-ESI: 257 [M + H]+

Synthesis of Intermediate 54 (4-(2,2-difluoroethoxy)benzoic acid)

Step 1: ethyl 4-(2,2-difluoroethoxy)benzoate

Ethylparaben (1.0 g, 6.0 mmol, 1.0 equiv.) and 2-bromo-1,1-difluoroethane (872.3 mg, 6.0 mmol, 1.0 equiv.) were dissolved in DMF (8 mL), then K₂CO₃ (2.5 g, 18.1 mmol, 3.0 equiv.) was added in portions. The reaction mixture was heated to 80° C. overnight. After filtration and washing the solids with MeOH, the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1: 10-1:3) to give ethyl 4-(2,2-difluoroethoxy)benzoate (700 mg) as a white solid.

Step 2: 4-(2,2-difluoroethoxy)benzoic acid

Ethyl 4-(2,2-difluoroethoxy)benzoate (700.0 mg, 3.0 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and water (2 mL), then LiOH (145.6 mg, 6.1 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water then adjusted to pH 6 with aqueous HCl (1 M). The resulting solids were collected by filtration, washed with water and dried to give 4-(2,2-difluoroethoxy)benzoic acid (350 mg) as a white solid. LCMS Method A: [M+H]⁺=203.

Synthesis of Intermediate 55 (3-fluoro-4-(3,3,3-trifluoropropyl)benzoic acid)

Step 1: methyl 3-fluoro-4-[(1Z)-3,3,3-trifluoroprop-1-en-1-yl]benzoate

Methyl 4-bromo-3-fluorobenzoate (1.0 g, 4.3 mmol, 1.0 equiv.) and 3,3,3-trifluoro-1-propene (0.8 g, 8.6 mmol, 2.0 equiv.) were dissolved in DMF (15 mL), then Pd(OAc)₂ (96.3 mg, 0.4 mmol, 0.1 equiv.) and NaOAc (0.7 g, 8.6 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen. The resulting mixture was heated to 100° C. overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give methyl 3-fluoro-4-[(1Z)-3,3,3-trifluoroprop-1-en-1-yl]benzoate (400 mg) as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.88-7.85 (m, 1H), 7.78-7.76 (m, 1H), 7.72-7.70 (m, 1H), 7.28-7.26 (m, 1H), 6.52-6.48 (m, 1H), 3.96 (s, 3H),

Step 2: methyl 3-fluoro-4-(3,3,3-trifluoropropyl)benzoate

Methyl 3-fluoro-4-[(1Z)-3,3,3-trifluoroprop-1-en-1-yl]benzoate (400.0 mg, 1.6 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL), then Pd/C (10% wt., 51.5 mg) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred overnight at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give methyl 3-fluoro-4-(3,3,3-trifluoropropyl)benzoate (100 mg) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.73-7.69 (m, 2H), 7.55-7.52 (m, 1H), 3.92 (s, 3H), 2.96-2.94 (m, 2H), 2.46-2.41 (m, 2H).

Step 3: 3-fluoro-4-(3,3,3-trifluoropropyl)benzoic acid

Methyl 3-fluoro-4-(3,3,3-trifluoropropyl)benzoate (100.0 mg, 0.4 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and water (2 mL), then LiOH (19.1 mg, 0.8 mmol, 2.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature and concentrated under vacuum. The residue was diluted with water then adjusted to pH 5 with aqueous HCl (6 M). The resulting solids were collected by filtration, washed with water and dried to give 3-fluoro-4-(3,3,3-trifluoropropyl)benzoic acid (50 mg) as a white solid. LCMS Method A: [M−H]⁻=235.

Synthesis of Intermediate 56 (4-(4,4-difluoro-1-hydroxycyclohexyl)benzoic acid)

Step 1: methyl 4-(4,4-difluoro-1-hydroxycyclohexyl)benzoate

Methyl 4-iodobenzoate (500.0 mg, 1.9 mmol, 1.0 equiv.) was dissolved in THE (15 mL) and cooled to −40° C., then i-PrMgCl—LiCl (1.3 M in THF, 2.2 mL, 2.9 mmol, 1.5 equiv.) was added dropwise, maintaining the mixture at −40° C. while under an atmosphere of nitrogen. After stirring for 1 hour at −40° C., 4-difluorocyclohexan-1-one (383.9 mg, 2.9 mmol, 1.5 equiv.) was added. The resulting mixture was stirred overnight at ambient temperature and then quenched by the addition of saturated aqueous NH₄Cl. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give methyl 4-(4,4-difluoro-1-hydroxycyclohexyl)benzoate (350 mg) as a colorless oil. LCMS Method A: [M+H]⁺=271.

Step 2: 4-(4,4-difluoro-1-hydroxycyclohexyl)benzoic acid

Methyl 4-(4,4-difluoro-1-hydroxycyclohexyl)benzoate (300.0 mg, 1.1 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (22 mg, 5.5 mmol, 5.0 equiv.) was added. The resulting mixture was stirred for 2 hours at ambient temperature, the concentrated under vacuum. The residue was diluted with water then adjusted to pH 6 with aqueous HCl (2 M). The resulting solids were collected by filtration, then purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (94:6) to give 4-(4,4-difluoro-1-hydroxycyclohexyl)benzoic acid (200 mg) as a white solid. LCMS Method A: [M−H]⁺=255.

Synthesis of Intermediate 57 (2-oxo-1-(4-(trifluoromethyl)benzyl)-1,2-dihydropyrimidine-4-carboxylic acid)

Step 1: Methyl 2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]pyrimidine-4-carboxylate

Methyl 2-oxo-1H-pyrimidine-4-carboxylate (500.0 mg, 3.2 mmol, 1.0 equiv.) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (775.5 mg, 3.2 mmol, 1.0 equiv.) were dissolved in DMSO (30 mL), then DIEA (2.7 mL, 16.2 mmol, 5.0 equiv.) was added. The reaction mixture was heated to 100° C. for 16 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give methyl 2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]pyrimidine-4-carboxylate (556 mg) as a yellow solid. LCMS Method G: [M+H]⁺=313.

Step 2: 2-oxo-1-(4-(trifluoromethyl)benzyl)-1,2-dihydropyrimidine-4-carboxylic acid

2-Oxo-1-[[4-(trifluoromethyl)phenyl]methyl]pyrimidine-4-carboxylate (556.0 mg, 1.8 mmol, 1.0 equiv.) was dissolved in MeOH (15 mL) and water (5 mL), then NaOH (142.4 mg, 3.6 mmol, 2.0 equiv.) was added. The resulting mixture was stirred for 2 hours at ambient temperature, and then concentrated under vacuum. The residue was diluted with water then adjusted to pH 5 with aqueous HCl (6 M). The resulting solids were collected by filtration, washed with water and dried to give 2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]pyrimidine-4-carboxylic acid (334 mg) as a yellow solid. LCMS Method E: [M+H]⁺=299.

Synthesis of Intermediate 43 (5,6-difluoro-1H-indol-3-amine hydrogen chloride)

Step 1: 5,6-difluoro-3-nitro-1H-indole

5,6-Difluoro-1H-indole (25.0 g, 163.3 mmol, 1.0 equiv.) was dissolved in in ACN (300 mL) and cooled to 0° C., then AgNO₃ (33.3 g, 195.9 mmol, 1.2 equiv.) was added. The resulting mixture was stirred for 15 min, then benzoyl chloride (27.5 g, 195.9 mmol, 1.2 equiv.) was added batchwise, maintaining the reaction mixture at 0° C. After an additional 3 hours at 0° C. the reaction mixture was quenched by the addition of ice-water. The reaction mixture was adjusted to pH 8 with saturated aqueous NaHCO₃, then extracted with DCM and the organic layers concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (2:1) to give 5,6-difluoro-3-nitro-1H-indole (24 g) as a brown solid. LCMS Method A-1: [M+H]⁺=199.

Step 2: tert-butyl N-(5,6-difluoro-1H-indol-3-yl)carbamate

5,6-Difluoro-3-nitro-1H-indole (24.0 g, 121.1 mmol, 1.0 equiv.) was dissolved in MeOH (300 mL), then Pd/C (2.4 g, wt 10%) and (Boc)₂O (39.7 g, 181.7 mmol, 1.5 equiv.) were added under nitrogen. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred overnight at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give tert-butyl N-(5,6-difluoro-1H-indol-3-yl)carbamate (22.0 g) as a yellow solid. LCMS Method C-1: [M+H]⁺=269.

Step 3: 5,6-difluoro-1H-indol-3-amine hydrochloride

tert-Butyl N-(5,6-difluoro-1H-indol-3-yl)carbamate (17.0 g, 63.4 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4N, 200 mL). The resulting mixture was stirred for 30 min at ambient temperature then concentrated under vacuum to give 5,6-difluoro-1H-indol-3-amine hydrochloride (12.0 g) as a yellow solid. LCMS Method C-1: [M+H]⁺=169.

The following intermediates were prepared using the same method described for Intermediate 43.

Intermediate	Starting material	Structure	LCMS data
Intermediate 60			Method A-1: MS-ESI: 185 [M + H]+

Synthesis of Intermediate 61 (5-bromo-1H-indol-3-amine hydrogen chloride)

Step 1: 5-bromo-1H-indole-3-carbonyl azide

5-Bromo-1H-indole-3-carboxylic acid (30.0 g, 124.9 mmol, 1.0 equiv.) was dissolved in THE (150 mL), then TEA (26.1 mL, 187.4 mmol, 1.5 equiv.) and DPPA (37.8 g, 137.4 mmol, 1.1 equiv.) were added. The reaction mixture was stirred for 12 hours at ambient temperature, then quenched by the addition of water and stirred for an additional 10 min. The precipitated solid was collected by filtration and dried under vacuum to give 5-bromo-1H-indole-3-carbonyl azide (33.6 g) as an off-white solid. LCMS Method B-1: [M−H]⁻=263.

Step 2: tert-butyl (5-bromo-1H-indol-3-yl)carbamate

5-Bromo-1H-indole-3-carbonyl azide (33.6 g, 126.7 mmol, 1.0 equiv.) was dissolved in t-BuOH (300 mL). The reaction mixture was heated to 80° C. for 12 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give tert-butyl (5-bromo-1H-indol-3-yl)carbamate (22.1 g) as a white solid. LCMS Method A-1: [M+H]⁺=311.

Step 3: 5-bromo-1H-indol-3-amine hydrochloride

tert-Butyl (5-bromo-1H-indol-3-yl)carbamate (20.0 g, 64.2 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4 M, 150 mL). The reaction mixture was stirred for 2 hours at ambient temperature then concentrated under vacuum to give 5-bromo-1H-indol-3-amine hydrochloride (18.7 g) as a brown solid. LCMS Method A-1: [M+H]⁺=211.

The following intermediates were prepared using the same method described for Intermediate 61.

Intermediate	Starting material	Structure	LCMS data
Intermediate 50			Method A-1: MS-ESI: 167 [M + H]+
Intermediate 58			Method A-1: MS-ESI: 151 [M + H]+

Synthesis of Intermediate 51 (5-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-amine hydrogen chloride)

Step 1: tert-butyl N-[5-(1-isopropylpyrazol-4-yl)-1H-indol-3-yl]carbamate

tert-Butyl N-(5-bromo-1H-indol-3-yl)carbamate (500.0 mg, 1.6 mmol, 1.0 equiv.) and 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (417.3 mg, 1.8 mmol, 1.1 equiv.) were dissolved in 1,4-dioxane (6 mL) and water (0.6 mL). Then Xphos Pd G3 (136.0 mg, 0.2 mmol, 0.1 equiv.) and Cs₂CO₃ (2.1 g, 6.4 mmol, 4.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 100° C. overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl N-[5-(1-isopropylpyrazol-4-yl)-1H-indol-3-yl]carbamate (390.0 mg) as a white solid. LCMS Method C-1: [M+H]⁺=341.

Step 2: 5-(1-isopropylpyrazol-4-yl)-1H-indol-3-amine hydrochloride

tert-Butyl N-[5-(1-isopropylpyrazol-4-yl)-1H-indol-3-yl]carbamate (385 mg, 1.1 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4 M, 8 mL). The reaction mixture was stirred for 4 hours at ambient temperature, then concentrated under vacuum to give 5-(1-isopropylpyrazol-4-yl)-1H-indol-3-amine hydrochloride (410.0 mg) as a grey solid. LCMS Method A-1: [M+H]⁺=241.

Synthesis of Intermediate 62 (7-fluoro-5-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-amine hydrogen chloride)

Step 1: 5-bromo-7-fluoro-3-nitro-1H-indole

5-Bromo-7-fluoro-1H-indole (3.0 g, 14.0 mmol, 1.0 equiv.) was dissolved in in ACN (50 mL) and cooled to 0° C., then AgNO₃ (3.6 g, 21.0 mmol, 1.5 equiv.) was added. The resulting mixture was stirred for 15 min, then benzoyl chloride (3.0 g, 21.0 mmol, 1.5 equiv.) was added batchwise, maintaining the reaction mixture at 0° C. After an additional 3 hours at 0° C. the reaction mixture was quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/petroleum ether (1:10) to give 5-bromo-7-fluoro-3-nitro-1H-indole (2.1 g) as a brown solid. LCMS Method A-1: [M+H]⁺=259.

Step 2: tert-butyl N-(5-bromo-7-fluoro-1H-indol-3-yl)carbamate

5-Bromo-7-fluoro-3-nitro-1H-indole (2.0 g, 7.7 mmol, 1.0 equiv.) and (Boc)₂₀ (2.0 g, 9.3 mmol, 1.2 equiv.) were dissolved in MeOH (40 mL) and cooled to 0° C. Then NaBH₄ (0.6 g, 15.4 mmol, 2.0 equiv.) and NiCl₂ (2.0 g, 15.4 mmol, 2.0 equiv.) were added in portions, maintaining the solution at 0° C. The reaction mixture was stirred for 0.5 hours at 0° C. and then then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give tert-butyl N-(5-bromo-7-fluoro-1H-indol-3-yl)carbamate (300.0 mg) as a brown solid. LCMS Method A-1: [M+H]⁺=329.

Steps 3-4: 7-fluoro-5-(1-isopropylpyrazol-4-yl)-1H-indol-3-amine hydrochloride

The title compound was prepared using the same methods described for Intermediate 51, Steps 1-2. LCMS Method A-1: [M+H]⁺=259.

Synthesis of Intermediate 63 (6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoronicotinic acid)

Step 1: 4,4-difluoro-1-methylcyclohexan-1-ol

4,4-difluorocyclohexan-1-one (10.0 g, 74.6 mmol, 1.0 equiv.) was dissolved in Et₂O (100.0 mL) and cooled to 0° C., then MeMgBr (3 M in THF, 80.0 mL, 240 mmol, 3.0 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for 2 hours at 0° C., then quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give 4,4-difluoro-1-methylcyclohexan-1-ol (9.5 g) as a yellow solid. LCMS Method A-1: [M+H]⁺=151.

Step 2: 4,4-difluoro-1-methylcyclohexyl methyl oxalate

4,4-Difluoro-1-methylcyclohexan-1-ol (10.0 g, 66.6 mmol, 1.0 equiv.) and DMAP (0.8 g, 6.7 mmol, 0.1 equiv.) were dissolved in DCM (200 mL), then TEA (18.7 mL, 133.2 mmol, 2.0 equiv.) was added. This was followed by the dropwise addition of methyl oxalochloridate (6.1 mL, 67.3 mmol, 1.0 equiv.). The reaction mixture was stirred for 1 hour at ambient temperature, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:20) to give 4,4-difluoro-1-methylcyclohexyl methyl oxalate (11.2 g) as a yellow oil. LCMS Method A-1: [M+H]⁺=237.

Step 3: cesium 2-((4,4-difluoro-1-methylcyclohexyl)oxy)-2-oxoacetate

4,4-Difluoro-1-methylcyclohexyl methyl oxalate (5.0 g, 21.2 mmol, 1.0 equiv.) was dissolved in THF (50 mL) and water (50 mL), then CsOH (3.2 g, 20.9 mmol, 1.0 equiv.) was added. The reaction mixture was stirred for 1 hour at ambient temperature then concentrated under vacuum to give cesium 2-((4,4-difluoro-1-methylcyclohexyl)oxy)-2-oxoacetate (5.2 g) as a white solid. LCMS Method A-1: [M+H]⁺=272.

Step 4: methyl 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylate

Cesium 2-((4,4-difluoro-1-methylcyclohexyl)oxy)-2-oxoacetate (5.0 g, 14.1 mmol, 1.0 equiv.) was dissolved in DMSO (30 mL), then (NH₄)₂S₂O₈ (2.3 g, 9.9 mmol, 0.7 equiv.), Ir[dF(CF₃)ppy]₂(dtbpy)PFe (1.6 g, 1.4 mmol, 0.1 equiv.) and methyl 5-fluoropyridine-3-carboxylate (1.8 g, 11.3 mmol, 0.8 equiv.) were added. The resulting solution was irradiated with the Royal Blue (450 nm) LED light for 3 hours with stirring at 1000 rpm, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give methyl 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylate (2.5 g) as a yellow oil. LCMS Method A-1: [M+H]⁺=272.

Step 5: 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylic acid

Methyl 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylate (2.5 g, 8.7 mmol, 1.0 equiv.) was dissolved in MeOH (25 mL) and water (25 mL), then NaOH (1.0 g, 26.0 mmol, 3.0 equiv.) was added. The reaction mixture was heated to 80° C. for 1 hour, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC using the following conditions: Column, C18 silica gel; mobile phase, ACN/H₂O=0% increasing to ACN/H₂O=100% within 30 min; Detector, 254 nm. This resulted in 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylic acid (2.1 g) as a yellow oil. LCMS Method C-1: [M+H]⁺=274 Synthesis of intermediate 64 (6-(4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)nicotinic acid)

Steps 1-3: methyl 6-(1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl)nicotinate

The title compound was prepared using the same methods described for Intermediate 63, steps 2-4. LCMS Method A-1: [M+H]⁺=335.

Step 4: methyl 6-(4-methylpiperidin-4-yl)nicotinate hydrochloride

Methyl 6-[1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl]pyridine-3-carboxylate (3.6 g, 10.8 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4 M, 20 mL). The reaction mixture was stirred for 30 min at ambient temperature, then concentrated under vacuum to give methyl 6-(4-methylpiperidin-4-yl)nicotinate hydrochloride (3.0 g) as a yellow solid that was used in next step directly without further purification. LCMS Method A-1: [M+H]⁺=235.

Step 5: methyl 6-(4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)nicotinate

Methyl 6-(4-methylpiperidin-4-yl)pyridine-3-carboxylate (3.0 g, 12.8 mmol, 1.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.6 g, 15.4 mmol, 1.2 equiv.) were dissolved in ACN (100 mL), then TEA (5.4 mL, 38.4 mmol, 3.0 equiv.) was added. The reaction mixture was stirred for 4 hours at ambient temperature, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give methyl 6-[4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl]pyridine-3-carboxylate (2.6 g) as a colorless oil. LCMS Method A-1: [M+H]⁺=317.

Step 6: 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylic acid

Methyl 6-[4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl]pyridine-3-carboxylate (2.6 g, 8.2 mmol, 1.0 equiv.) was dissolved in MeOH (100 mL) and water (40 mL), then NaOH (0.5 g, 12.2 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 1 hour at ambient temperature then concentrated under vacuum. The residue was diluted with water, adjusted to pH 6 with aqueous HCl (4 M), extracted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give 6-[4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl]pyridine-3-carboxylic acid (2.3 g) as an off-white solid. LCMS Method C-1: [M+H]⁺=303.

Synthesis of Intermediate 65 (4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)benzoic acid)

Step 1: methyl 4-[[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy]benzoate

Methyl 4-hydroxybenzoate (500.0 mg, 3.3 mmol, 1.0 equiv.) and 1-(2,2,2-trifluoroethyl)piperidin-4-ol (662.2 mg, 3.6 mmol, 1.1 equiv.) were dissolved in THE (10 mL) and cooled to 0° C., then Ph₃P (1.3 g, 4.9 mmol, 1.5 equiv.) was added. This was followed by the dropwise addition of DIAD (996.8 mg, 4.9 mmol, 1.5 equiv.) at 0° C. The reaction mixture was stirred overnight at ambient temperature then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give methyl 4-[[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy]benzoate (200.0 mg) as a white solid. LCMS Method A-1: [M+H]⁺=318.

Step 2: 4-[[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy]benzoic acid

Methyl 4-[[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy]benzoate (200.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in MeOH (3 mL) and water (3 mL), then LiOH (30.2 mg, 1.3 mmol, 2.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature then concentrated under vacuum. The residue was diluted with water then adjusted to pH 5 with conc. HCl. The resulting solution was extracted with dichloromethane then concentrated under vacuum. The residue was purified by Flash-Prep-HPLC using the following conditions: Column, C18 silica gel; mobile phase, H₂O/ACN, 10% ACN increasing to 90% within 30 min; Detector, 254 nm. This gave 4-[[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy]benzoic acid (110.0 mg) as a white solid. LCMS Method B-1: [M−H]⁻=302.

The following intermediates in were prepared using the same method described for Intermediate 65.

Inter-	Starting	Starting		LCMS
mediate	material A	material B	Structure	data
Inter- mediate 66				Method B-1: MS-ESI: 267 [M − H]−
Inter- mediate 32				Method B-1: MS-ESI: 247 [M − H]−
Inter- mediate 33				Method B-1: MS-ESI: 241 [M − H]−
Inter- mediate 34				Method B-1: MS-ESI: 281 [M − H]−
Inter- mediate 35				Method B-1: MS-ESI: 247 [M − H]−
Inter- mediate 36				Method B-1: MS-ESI: 261 [M − H]−
Inter- mediate 30				Method B-1: MS-ESI: 265 [M − H]−

Synthesis of Intermediate 67 (exo-6-((2,2,2-trifluoroethoxy)methyl)-3-azabicyclo[3.1.0]hexane)

Step 1: (exo-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl)methyl methanesulfonate

[exo-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl] methanol (2.5 g, 12.3 mmol, 1.0 equiv.) and TEA (2.6 mL, 18.4 mmol, 1.5 equiv.) were dissolved in DCM (30 mL), then the solution was cooled to 0° C. and MsCl (1.4 mL, 18.4 mmol, 1.5 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for 3 hours at 0° C., then quenched by the addition of water. The resulting solution was extracted with dichloromethane, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give [exo-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl methanesulfonate (2.5 g) as a yellow oil. LCMS Method C-1: [M+H]⁺=282.

Step 2: exo-3-benzyl-6-((2,2,2-trifluoroethoxy)methyl)-3-azabicyclo[3.1.0]hexane

Trifluoroethanol (0.7 mL, 8.9 mmol, 1.0 equiv.) was dissolved in DMF (30 mL) and the reaction mixture was cooled to 0° C., then NaH (60% in oil, 0.4 g, 8.9 mmol, 1.0 equiv.) was added, maintaining the solution at 0° C. After 15 min at 0° C., [exo-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl methanesulfonate (2.5 g, 8.9 mmol, 1.0 equiv.) was added at 0° C. The reaction mixture was stirred for 1 hour at ambient temperature, then quenched by the addition of ice-water. The reaction mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give exo-3-benzyl-6-[(2,2,2-trifluoroethoxy)methyl]-3-azabicyclo[3.1.0]hexane (600.0 mg) as a yellow oil. LCMS Method A-1: [M+H]⁺=286.

Step 3: exo-6-((2,2,2-trifluoroethoxy)methyl)-3-azabicyclo[3.1.0]hexane

Exo-3-benzyl-6-[(2,2,2-trifluoroethoxy)methyl]-3-azabicyclo[3.1.0]hexane (600.0 mg, 2.1 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL) and acetic acid (0.5 mL), then Pd/C (10% wt., 100.0 mg) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 2 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum to give exo-6-[(2,2,2-trifluoroethoxy)methyl]-3-azabicyclo[3.1.0]hexane (350.0 mg) as a yellow solid. LCMS Method A-1: [M+H]⁺=196.

Synthesis of Intermediate 68 (5-((tert-butyldiphenylsilyl)oxy)-4,4-dimethylpentan-1-amine)

Step 1: 5-ethoxy-2,2-dimethyl-5-oxopentanoic acid sodium salt

3,3-Dimethyloxane-2,6-dione (3.0 g, 21.1 mmol, 1.0 equiv.) was dissolved in EtOH (30 mL), then EtONa (2.2 g, 31.7 mmol, 1.5 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature and concentrated under vacuum. The residue was suspended in Et₂O and the solid was collected by filtration, then washed with Et₂O and dried under vacuum to give 5-ethoxy-2,2-dimethyl-5-oxopentanoic acid sodium salt (2.4 g) as a white solid. LCMS Method B-1: [M−H]⁻=187.

Step 2: ethyl 5-hydroxy-4,4-dimethylpentanoate

5-Ethoxy-2,2-dimethyl-5-oxopentanoic acid sodium salt (2.0 g, 10.6 mmol, 1.0 equiv.) and 1-chloroethyl 2-methylpropanoate (2.4 g, 15.9 mmol, 1.5 equiv.) were dissolved in THE (20 mL) and DMF (4 mL). The reaction mixture was stirred for 2 hours at ambient temperature. This was followed by the addition of a solution of NaBH₄ (804.0 mg, 21.3 mmol, 2.0 equiv.) in MeOH. The resulting mixture was stirred for an additional 1 hour at ambient temperature, then quenched by the addition of saturated aqueous NH₄Cl. The resulting solution was extracted with ethyl acetate and concentrated under vacuum to give ethyl 5-hydroxy-4,4-dimethylpentanoate (1.2 g) as a yellow oil. LCMS Method C-1: [M+H]⁺=175.

Step 3: ethyl 5-[(tert-butyldiphenylsilyl)oxy]-4,4-dimethylpentanoate

Ethyl 5-hydroxy-4,4-dimethylpentanoate (1.5 g, 8.6 mmol, 1.0 equiv.) and TBDPSCl (4.7 g, 17.2 mmol, 2.0 equiv.) were dissolved in THE (15 mL), then imidazole (1.2 g, 17.2 mmol, 2.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give ethyl 5-[(tert-butyldiphenylsilyl)oxy]-4,4-dimethylpentanoate (1.2 g) as a yellow solid. LCMS Method C-1: [M+H]⁺=413.

Step 4: 5-[(tert-butyldiphenylsilyl)oxy]-4,4-dimethylpentan-1-ol

Ethyl 5-[(tert-butyldiphenylsilyl)oxy]-4,4-dimethylpentanoate (1.0 g, 2.4 mmol, 1.0 equiv.) was dissolved in THE (10 mL) and cooled to 0° C., then LiAlH₄ (184.0 mg, 4.8 mmol, 2.0 equiv.) was added, maintaining the solution at 0° C. The reaction mixture was stirred overnight at ambient temperature, then cooled to 0° C. and quenched by the addition of saturated aqueous NH₄Cl. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give 5-[(tert-butyldiphenylsilyl)oxy]-4,4-dimethylpentan-1-ol (850.0 mg) as a yellow oil. LCMS Method C-1: [M+H]⁺=371.

Step 5: 2-[5-[(tert-butyldiphenylsilyl)oxy]-4,4-dimethylpentyl]isoindole-1,3-dione

5-[(tert-Butyldiphenylsilyl)oxy]-4,4-dimethylpentan-1-ol (700.0 mg, 1.9 mmol, 1.0 equiv.) and phthalimide (277.9 mg, 1.9 mmol, 1.0 equiv.) were dissolved in THE (10 mL) and cooled to 0° C., then PPh₃ (743.1 mg, 2.8 mmol, 1.5 equiv.) was added. This was followed by the dropwise addition of DIAD (572.9 mg, 2.8 mmol, 1.5 equiv.) at 0° C. The reaction mixture was stirred overnight at ambient temperature, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give 2-[5-[(tert-butyldiphenylsilyl)oxy]-4,4-dimethylpentyl]isoindole-1,3-dione (500.0 mg) as a yellow oil. LCMS Method C-1: [M+H]⁺=500.

Step 6: 5-((tert-butyldiphenylsilyl)oxy)-4,4-dimethylpentan-1-amine

2-[5-[(tert-Butyldiphenylsilyl)oxy]-4,4-dimethylpentyl]isoindole-1,3-dione (700.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in EtOH (10 mL), then hydrazine (224.4 mg, 7.0 mmol, 5.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature. The solid was removed by filtration and the filtrate was concentrated under vacuum to give 5-((tert-butyldiphenylsilyl)oxy)-4,4-dimethylpentan-1-amine (510.0 mg) as a yellow solid. LCMS Method C-1: [M+H]⁺=370.

Synthesis of Intermediate 69 (6-(1,1-difluoro-6-azaspiro[2.5]octan-6-yl)-5-fluoronicotinic acid)

Step 1: methyl 6-[1,1-difluoro-6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate

Methyl 6-bromo-5-fluoropyridine-3-carboxylate (400.0 mg, 1.7 mmol, 1.0 equiv.) and 1,1-difluoro-6-azaspiro[2.5]octane (251.5 mg, 1.7 mmol, 1.0 equiv.) were dissolved in ACN (40 ml), then Cs₂CO₃ (1.1 g, 3.4 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 90° C. overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give methyl 6-[1,1-difluoro-6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate (350.0 mg) as a pale yellow solid. LCMS Method A-1: [M+H]⁺=301.

Step 2: 6-[1,1-difluoro-6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylic acid

Methyl 6-[1,1-difluoro-6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate (290.0 mg, 1.0 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and water (2 mL), then LiOH (115.6 mg, 4.8 mmol, 5.0 equiv.) was added. The reaction mixture was stirred for 3 hours at ambient temperature, then concentrated under vacuum. The residue was diluted with water, then adjusted to pH 7 with aqueous HCl (6M). The resulting solution was extracted with ethyl acetate, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give 6-[1,1-difluoro-6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylic acid (210.0 mg) as an off-white solid. LCMS Method C-1: [M+H]⁺=287.

The following intermediates were prepared using the same method described for Intermediate 69.

Inter-	Starting	Starting
mediate	material A	material B	Structure
Inter- mediate 70
Inter- mediate 71
Inter- mediate 72
Inter- mediate 73
Inter- mediate 74
Inter- mediate 75
Inter- mediate 76
Inter- mediate 8
Inter- mediate 9
Inter- mediate 77
Inter- mediate 12
Inter- mediate 13
Inter- mediate 15
Inter- mediate 16
Inter- mediate 2
Inter- mediate 17
Inter- mediate 1
		Inter-	LCMS
		mediate	data
		Inter-	Method A-1:
		mediate	MS-ESI: 335
		70	[M + H]+
		Inter-	Method A-1:
		mediate	MS-ESI: 334
		71	[M + H]+
		Inter-	Method C-1:
		mediate	MS-ESI: 269
		72	[M + H]+
		Inter-	Method C-1:
		mediate	MS-ESI: 253
		73	[M + H]+
		Inter-	Method A-1:
		mediate	MS-ESI: 240
		74	[M + H]+
		Inter-	Method A-1:
		mediate	MS-ESI: 229
		75	[M + H]+
		Inter-	Method A-1:
		mediate	MS-ESI: 249
		76	[M + H]+
		Inter-	Method C-1:
		mediate	MS-ESI: 299
		8	[M + H]+
		Inter-	Method A-1:
		mediate	MS-ESI: 250
		9	[M + H]+
		Inter-	Method A-1:
		mediate	MS-ESI: 292
		77	[M + H]+
		Inter-	Method A-1:
		mediate	MS-ESI: 237
		12	[M + H]+
		Inter-	Method A-1:
		mediate	MS-ESI: 281
		13	[M + H]+
		Inter-	Method B-1:
		mediate	MS-ESI: 265
		15	[M − H]−
		Inter-	Method A-1:
		mediate	MS-ESI: 295
		16	[M + H]+
		Inter-	Method A-1:
		mediate	MS-ESI: 277
		2	[M + H]+
		Inter-	Method A-1:
		mediate	MS-ESI: 263
		17	[M + H]+
		Inter-	Method A-1:
		mediate	MS-ESI: 289
		1	[M + H]+

Synthesis of Intermediate 78 (4-(4,4-difluorocyclohexyl)-3,5-dimethylbenzoic acid)

Step 1: methyl 4-(4,4-difluorocyclohex-1-en-1-yl)-3,5-dimethylbenzoate

Methyl 4-bromo-3,5-dimethylbenzoate (500 mg, 2.1 mmol, 1.0 equiv.) and 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 4.1 mmol, 2.0 equiv.) were dissolved in 1,4-dioxane (10 mL) and water (1 mL), then Cs₂CO₃ (1.4 g, 4.3 mmol, 2.0 equiv.) and Pd(dppf)Cl₂ (153.7 mg, 0.2 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The resulting solution was heated to 90° C. for 16 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give methyl 4-(4,4-difluorocyclohex-1-en-1-yl)-3,5-dimethylbenzoate (410.0 mg) as a white solid. LCMS Method A-1: [M+H]⁺=281.

Step 2: methyl 4-(4,4-difluorocyclohexyl)-3,5-dimethylbenzoate

Methyl 4-(4,4-difluorocyclohex-1-en-1-yl)-3,5-dimethylbenzoate (380.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in DCM (15 mL), then PtO₂ (20.0 mg, 0.1 mmol, 0.06 equiv.) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred for 18 hours at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give methyl 4-(4,4-difluorocyclohexyl)-3,5-dimethylbenzoate (232.0 mg) as a white solid. LCMS Method C-1: [M+H]⁺=283.

Step 3: 4-(4,4-difluorocyclohexyl)-3,5-dimethylbenzoic acid

Methyl 4-(4,4-difluorocyclohexyl)-3,5-dimethylbenzoate (232.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (1 mL), then NaOH (32.9 mg, 0.8 mmol, 1.0 equiv.) was added. The reaction was heated to 50° C. for 16 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, then adjusted to pH 5 with aqueous HCl (4 M). The precipitated solids were collected by filtration, washed with water and dried under vacuum to give 4-(4,4-difluorocyclohexyl)-3,5-dimethylbenzoic acid (130.0 mg) as a white solid. LCMS Method B-1: [M−H]⁻=267.

The following intermediates were prepared using the same method described for Intermediate 78.

	Starting	Starting
Intermediate	material A	material B	Structure	LCMS data
Intermediate 41				Method B-1: MS-ESI: 273 [M − H]−
Intermediate 55*				Method B-1: MS-ESI: 235 [M − H]−
Intermediate 42				Method B-1: MS-ESI: 218 [M − H]−

Synthesis of Intermediate 79 (5-fluoro-6-(6-(2,2,2-trifluoroethoxy)-2-azaspiro[3.3]heptan-2-yl)nicotinic acid)

Step 1: 2-azaspiro[3.3]heptan-6-ol hydrochloride

tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (1.6 g, 7.5 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4 M, 20 mL). The reaction mixture was stirred overnight at ambient temperature, then concentrated under vacuum to give 2-azaspiro[3.3]heptan-6-ol hydrochloride (1.0 g) as a yellow oil. LCMS Method A-1: [M+H]⁺=114.

Step 2: methyl 5-fluoro-6-[6-hydroxy-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylate

Methyl 6-bromo-5-fluoropyridine-3-carboxylate (2.1 g, 8.8 mmol, 1.0 equiv.) and 2-azaspiro[3.3]heptan-6-ol hydrochloride (1.0 g, 8.8 mmol, 1.0 equiv.) were dissolved in ACN (20 mL), then K₂CO₃ (3.7 g, 26.5 mmol, 3.0 equiv.) was added. The reaction mixture was heated to 80° C. overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC using the following conditions: Column, C18 silica gel; mobile phase, H₂O/ACN; 10% ACN increasing to 90% within 30 min; Detector, 254 nm. This gave methyl 5-fluoro-6-[6-hydroxy-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylate (500.0 mg) as a yellow solid. LCMS Method A-1: [M+H]⁺=267.

Step 3: methyl 5-fluoro-6-[6-(methanesulfonyloxy)-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylate

Methyl 5-fluoro-6-[6-hydroxy-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylate (500.0 mg, 1.9 mmol, 1.0 equiv.) and TEA (0.5 mL, 2.0 equiv.) were dissolved in DCM (10 mL), then MsCl (215.1 mg, 1.9 mmol, 1.0 equiv.) was added. The reaction was stirred for 2 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give methyl 5-fluoro-6-[6-(methanesulfonyloxy)-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylate (510.0 mg) as a white solid. LCMS Method A-1: [M+H]⁺=345.

Step 4: methyl 5-fluoro-6-[6-(methanesulfonyloxy)-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylate

Methyl 5-fluoro-6-[6-(methanesulfonyloxy)-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylate (250.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in DMF (5 mL), then (2,2,2-trifluoroethoxy)sodium (265.8 mg, 2.2 mmol, 3.0 equiv.) was added. The reaction mixture was heated to 80° C. overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC using the following conditions: Column, C18 silica gel; mobile phase, H₂O/ACN, 10% ACN increasing to 90% within 30 min; Detector, 254 nm. This gave 5-fluoro-6-[6-(2,2,2-trifluoroethoxy)-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylic acid (52.0 mg) as a brown solid. LCMS Method A-1: [M+H]⁺=335.

Synthesis of Intermediate 80 (4-((2-methoxyethyl)amino)-3-(trifluoromethyl)benzoic acid)

Step 1: methyl 4-[(2-methoxyethyl)amino]-3-(trifluoromethyl)benzoate

Methyl 4-bromo-3-(trifluoromethyl)benzoate (500.0 mg, 1.8 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (10 mL), then Cs₂CO₃ (1.7 g, 5.3 mmol, 3.0 equiv.), 2-methoxyethan-1-amine (159.2 mg, 2.1 mmol, 1.2 equiv.) and XPhos Pd G3 (149.5 mg, 0.2 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 80° C. overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give methyl 4-[(2-methoxyethyl)amino]-3-(trifluoromethyl)benzoate (205.0 mg) as a yellow solid. LCMS Method A-1: [M+H]⁺=278.

Step 2: 4-[(2-methoxyethyl)amino]-3-(trifluoromethyl)benzoic acid

Methyl 4-[(2-methoxyethyl)amino]-3-(trifluoromethyl)benzoate (200.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in MeOH (3 mL) and water (7 mL), then NaOH (57.7 mg, 1.4 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, adjusted to pH 6 with aqueous HCl (1 M). The resulting solution was extracted with ethyl acetate, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give 4-[(2-methoxyethyl)amino]-3-(trifluoromethyl)benzoic acid (150.0 mg) as a white solid. LCMS Method B-1: [M−H]⁻=262.

The following intermediates were prepared using the same method described for Intermediate 80, using one of the three catalyst conditions for Step 1:_A: Pd₂(dba)₃, Binap and Cs₂CO₃; B: XPhos Pd G₃, Cs₂CO₃; C: RuPhos Palladacycle Gen.2, Cs₂CO₃

Inter-
me-	Starting	Starting
diate	material A	material B	Structure
Inter- me- diate 81
Inter- me- diate 82
Inter- me- diate 83
Inter- me- diate 84
Inter- me- diate 85
Inter- me- diate 86
Inter- me- diate 87
Inter- me- diate 88
Inter- me- diate 52
Inter- me- diate 53
Inter- me- diate 14
Inter- me- diate 89
	Inter-
	me-	Catalyst	LCMS
	diate	Condition	data
	Inter-	A	Method A-1:
	me-		MS-ESI:
	diate		197 [M + H]+
	81
	Inter-	B	Method A-1:
	me-		MS-ESI:
	diate		263 [M + H]+
	82
	Inter-	B	Method C-1:
	me-		MS-ESI:
	diate		249 [M + H]+
	83
	Inter-	B	Method C-1:
	me-		MS-ESI:
	diate		229 [M + H]+
	84
	Inter-	B	Method A-1:
	me-		MS-ESI:
	diate		229 [M + H]+
	85
	Inter-	C	Method A-1:
	me-		MS-ESI:
	diate		257 [M + H]+
	86
	Inter-	B	Method A-1:
	me-		MS-ESI:
	diate		249 [M + H]+
	87
	Inter-	B	Method C-1:
	me-		MS-ESI:
	diate		249 [M + H]+
	88
	Inter-	B	Method B-1:
	me-		MS-ESI:
	diate		246 [M − H]−
	52
	Inter-	C	Method A-1:
	me-		MS-ESI:
	diate		257 [M + H]+
	53
	Inter-	B	Method A-1:
	me-		MS-ESI:
	diate		284 [M + H]+
	14
	Inter-	B	Method A-1:
	me-		MS-ESI:
	diate		525 [M + H]+
	89

Synthesis of Intermediate 90 (6-(2-methoxyethoxy)-5-methylnicotinic acid)

Step 1: methyl 6-(2-ethoxyethoxy)-5-methylpyridine-3-carboxylate

6-Chloro-5-methylpyridine-3-carboxylic acid (1.0 g, 5.8 mmol, 1.0 equiv.) and 2-methoxyethanol (665.2 mg, 8.7 mmol, 1.5 equiv.) were dissolved in toluene (20 mL). Then BrettPhos (3.1 g, 5.8 mmol, 1.0 equiv.), Cs₂CO₃ (3.8 g, 11.7 mmol, 2.0 equiv.) and BrettPhos Pd G3 (528.3 mg, 0.6 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred overnight at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give methyl 6-(2-ethoxyethoxy)-5-methylpyridine-3-carboxylate (570.0 mg) as a white solid. LCMS Method A-1: [M+H]⁺=226.

Step 2: 6-(2-methoxyethoxy)-5-methylpyridine-3-carboxylic acid

Methyl 6-(2-methoxyethoxy)-5-methylpyridine-3-carboxylate (570.0 mg, 2.5 mmol, 1.0 equiv.) was dissolved in MeOH (3 mL) and water (3 mL), then LiOH (242.4 mg, 10.1 mmol, 4.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature, then concentrated under vacuum. The residue was diluted with water, then adjusted to pH 3 with conc. HCl. The resulting solution was extracted with dichloromethane and concentrated under vacuum. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN/water, 10% ACN increasing to 100% gradient in 20 min; detector, UV 254 nm. This gave 6-(2-methoxyethoxy)-5-methylpyridine-3-carboxylic acid (375.0 mg) as a white solid. LCMS Method C-1: [M+H]⁺=212.

The following intermediates were prepared using the same method described for Intermediate 90.

	Starting	Starting
Intermediate	material A	material B	Structure	LCMS data
Intermediate 91				Method C-1: MS-ESI: 226 [M + H]+

Synthesis of intermediate 92 (5-(3,3-difluorocyclobutoxy)-6-methylpyrazine-2-carboxylic acid)

Step 1: methyl 5-(3,3-difluorocyclobutoxy)-6-methylpyrazine-2-carboxylate

3,3-Difluorocyclobutan-1-ol (200.0 mg, 1.9 mmol, 1.0 equiv.) was dissolved in THE (20 mL) and cooled to 0° C., then NaH (60% in oil, 111.0 mg, 2.8 mmol, 1.5 equiv.) was added, maintaining the solution at 0° C. After 15 min at 0° C., methyl 5-chloro-6-methylpyrazine-2-carboxylate (345.3 mg, 1.9 mmol, 1.0 equiv.) was added. The reaction mixture was stirred for 16 hours at ambient temperature, then quenched by the addition of saturated aqueous NaHCO₃. The resulting solution was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give methyl 5-(3,3-difluorocyclobutoxy)-6-methylpyrazine-2-carboxylate (150.0 mg) as a white solid. LCMS Method A-1: [M+H]⁺=259.

Step 2: 5-(3,3-difluorocyclobutoxy)-6-methylpyrazine-2-carboxylic acid

Methyl 5-(3,3-difluorocyclobutoxy)-6-methylpyrazine-2-carboxylate (150.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and water (2 mL), then NaOH (46.5 mg, 1.2 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80° C. for 30 min, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, then adjusted to pH 5 with aqueous HCl (6M). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 5-(3,3-difluorocyclobutoxy)-6-methylpyrazine-2-carboxylic acid (105.0 mg) as a white solid. LCMS Method A-1: [M+H]⁺=245.

The following intermediates were prepared using the same method described for Intermediate 92.

	Starting	Starting
Intermediate	material A	material B	Structure	LCMS data
Intermediate 21				Method C-1: MS-ESI: 237 [M + H]+

Synthesis of Intermediate 93 (6-((1-(2,2,2-trifluoroethyl)azetidin-3-yl)oxy)nicotinic acid)

Step 1: methyl 6-[[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy]pyridine-3-carboxylate

tert-butyl 3-hydroxyazetidine-1-carboxylate (1.0 g, 5.8 mmol, 1.0 equiv.) was dissolved in THE (10 mL) and cooled to 0° C., then NaH (60% in mineral oil, 230.9 mg, 5.8 mmol, 1.0 equiv.) was added, maintaining the solution at 0° C. After 30 min at 0° C., methyl 6-bromopyridine-3-carboxylate (1.2 g, 5.8 mmol, 1.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give methyl 6-[[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy]pyridine-3-carboxylate (750.0 mg) as a light yellow oil. LCMS Method A-1: [M+H]⁺=309.

Step 2: methyl 6-(azetidin-3-yloxy)pyridine-3-carboxylate hydrochloride

Methyl 6-[[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy]pyridine-3-carboxylate (2.0 g, 6.5 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4 M, 15 mL). The reaction mixture was stirred for 3 hours at ambient temperature. The precipitated solids were collected by filtration and washed with 1,4-dioxane to give methyl 6-(azetidin-3-yloxy)pyridine-3-carboxylate hydrochloride (1.5 g) as a white solid. LCMS Method A-1: [M+H]⁺=209.

Step 3: methyl 6-[[1-(2,2,2-trifluoroethyl)azetidin-3-yl]oxy]pyridine-3-carboxylate

Methyl 6-(azetidin-3-yloxy)pyridine-3-carboxylate (1.5 g, 7.2 mmol, 1.0 equiv.) and TEA (5.0 mL, 36.0 mmol, 5.0 equiv.) were dissolved in ACN (10 mL) and cooled to 0° C., then 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.3 g, 14.4 mmol, 2.0 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred overnight at ambient temperature, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give methyl 6-[[1-(2,2,2-trifluoroethyl)azetidin-3-yl]oxy]pyridine-3-carboxylate (210.0 mg) as a white solid. LCMS Method A-1: [M+H]⁺=291.

Step 4: 6-[[1-(2,2,2-trifluoroethyl)azetidin-3-yl]oxy]pyridine-3-carboxylic acid

Methyl 6-[[1-(2,2,2-trifluoroethyl)azetidin-3-yl]oxy]pyridine-3-carboxylate (200.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (55.1 mg, 1.4 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 60° C. overnight, then cooled to ambient temperature and concentrated under vacuum. The residue was dissolved in water, then adjusted to pH 6 with aqueous HCl (2 M). The resulting solution was extracted with ethyl acetate and concentrated under vacuum to give 6-[[1-(2,2,2-trifluoroethyl)azetidin-3-yl]oxy]pyridine-3-carboxylic acid (180.0 mg) as a white solid. LCMS Method A-1: [M+H]⁺=277.

Synthesis of Intermediate 94 (3-(2-methoxyethoxy)-4-(trifluoromethyl)benzoic acid)

Step 1: methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)benzoate

Methyl 3-bromo-4-(trifluoromethyl)benzoate (1.0 g, 3.5 mmol, 1.0 equiv.) was dissolved in DMSO (20 mL), then bis(pinacolato)diboron (1.8 g, 7.0 mmol, 2.0 equiv.), AcOK (1.0 g, 10.6 mmol, 3.0 equiv.) and Pd(dppf)Cl₂ (258.5 mg, 0.4 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 80° C. overnight, then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)benzoate (0.9 g) as a yellow oil. LCMS Method A-1: [M+H]⁺=331.

Step 2: methyl 4-hydroxy-3-(trifluoromethyl)benzoate

Methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzoate (1.0 g, 3.0 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (10 mL), then H₂O₂ (30% in water, 2 mL) and AcOH (0.5 mL) were added. The reaction mixture was stirred overnight at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give methyl 4-hydroxy-3-(trifluoromethyl)benzoate (400.0 mg) as a yellow oil. LCMS Method A-1: [M−H]⁻=219.

Step 3: methyl 3-(2-methoxyethoxy)-4-(trifluoromethyl)benzoate

Methyl 4-hydroxy-3-(trifluoromethyl)benzoate (400.0 mg, 1.8 mmol, 1.0 equiv.) was dissolved in DMF (10 mL), then Cs₂CO₃ (1.8 g, 5.5 mmol, 3.0 equiv.) and 2-bromoethyl methyl ether (378.8 mg, 2.7 mmol, 1.5 equiv.) were added. The reaction mixture was heated to 60° C. for 4 hours, then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with brine and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give methyl 3-(2-methoxyethoxy)-4-(trifluoromethyl)benzoate (310.0 mg) as yellow oil. LCMS Method A-1: [M+H]⁺=279.

Step 4: 3-(2-methoxyethoxy)-4-(trifluoromethyl)benzoic acid

Methyl 3-(2-methoxyethoxy)-4-(trifluoromethyl)benzoate (300.0 mg, 1.1 mmol, 1.0 equiv.) was dissolved in MeOH (3 mL) and water (7 mL), then NaOH (86.3 mg, 2.2 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, adjusted to pH 4 with aqueous HCl (1 M). The resulting solution was extracted with ethyl acetate and concentrated under vacuum to give 3-(2-methoxyethoxy)-4-(trifluoromethyl)benzoic acid (200.0 mg) as a white solid. LCMS Method B-1: [M−H]⁻=263.

Synthesis of Intermediate 54 (4-(2,2-difluoroethoxy)benzoic acid)

Step 1: ethyl 4-(2,2-difluoroethoxy)benzoate

Ethyl 4-hydroxybenzoate (1.0 g, 6.0 mmol, 1.0 equiv.) and 2-bromo-1,1-difluoroethane (872.3 mg, 5.3 mmol, 1.0 equiv.) were dissolved in DMF (8 mL), then K₂CO₃ (2.5 g, 18.1 mmol, 3.0 equiv.) was added. The reaction mixture was heated to 80° C. overnight, then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:20) to give ethyl 4-(2,2-difluoroethoxy)benzoate (710.0 mg) as a white solid. LCMS Method A-1: [M−H]⁻=229.

Step 2: 4-(2,2-difluoroethoxy)benzoic acid

Methyl 4-(2,2-difluoroethoxy)benzoate (700.0 mg, 3.0 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and water (6 mL), then LiOH (145.6 mg, 6.0 mmol, 2.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature, then concentrated under vacuum. The residue was diluted with water, then adjusted to pH 6 with aqueous HCl (4 M). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 4-(2,2-difluoroethoxy)benzoic acid (350.0 mg) as a white solid. LCMS Method A-1: [M−H]⁻=201.

Synthesis of Intermediate 95 (5-bromo-6-(3,3-difluorocyclobutyl)nicotinic acid)

Step 1: methyl 5-bromo-6-(3,3-difluorocyclobutyl)nicotinate

Methyl 5-bromonicotinate (1.0 g, 4.6 mmol, 1.0 equiv.) and 3,3-difluorocyclobutane-1-carboxylic acid (1.3 g, 9.3 mmol, 2.0 equiv.) were dissolved in DCE (24 mL) and water (20 mL), then Selectfluor (3.3 g, 9.3 mmol, 2.0 equiv.) and TFA (0.35 mL, 4.6 mmol, 1.0 equiv.) were added. This was followed by the addition of aqueous AgNO₃ (31.5 mg in 2.4 mL of water, 0.2 mmol, 0.04 equiv.). The reaction mixture was heated to 50° C. overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give methyl 5-bromo-6-(3,3-difluorocyclobutyl)nicotinate (270.0 mg) as a yellow solid. LCMS Method A-1: [M+H]⁺=306.

Step 2: 5-bromo-6-(3,3-difluorocyclobutyl)pyridine-3-carboxylic acid

Methyl 5-bromo-6-(3,3-difluorocyclobutyl)pyridine-3-carboxylate (270.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (2 mL), then NaOH (70.4 mg, 1.8 mmol, 2.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature and concentrated under vacuum. The residue was diluted with water, then adjusted to pH 6 with aqueous HCl (1M). The resulting solution was extracted with ethyl acetate and concentrated under vacuum to give 5-bromo-6-(3,3-difluorocyclobutyl)pyridine-3-carboxylic acid (210.0 mg) as a white solid. LCMS Method C-1: [M+H]⁺=292.

The following intermediates were prepared using the same method described for Intermediate 95.

	Starting
Intermediate	material	Structure	LCMS data
Intermediate 96			Method A-1: MS-ESI: 248 [M + H]+

Synthesis of Intermediate 97 (5-fluoro-6-(6-(2,2,2-trifluoroethoxy)spiro[3.3]heptan-2-yl)nicotinic acid)

Step 1: methyl 5-fluoro-6-[6-oxospiro[3.3]heptan-2-yl]pyridine-3-carboxylate

Methyl 5-fluoropyridine-3-carboxylate (1.0 g, 6.4 mmol, 1.0 equiv.) and 6-oxospiro[3.3]heptane-2-carboxylic acid (1.5 g, 9.7 mmol, 1.5 equiv.) were dissolved in DCE (15 mL) and water (5 mL), then Selectfluor (4.6 g, 12.9 mmol, 2.0 equiv.) and TFA (0.1 mL, 1.3 mmol, 0.2 equiv.) were added. This was followed by the addition of AgNO₃ (109.5 mg, 0.6 mmol, 0.1 equiv.). The reaction mixture was heated to 50° C. for 16 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with dichloromethane, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give methyl 5-fluoro-6-[6-oxospiro[3.3]heptan-2-yl]pyridine-3-carboxylate (150.0 mg) as a white solid. LCMS Method A-1: [M+H]⁺=264.

Step 2: methyl 5-fluoro-6-[6-hydroxyspiro[3.3]heptan-2-yl]pyridine-3-carboxylate

Methyl 5-fluoro-6-[6-oxospiro[3.3]heptan-2-yl]pyridine-3-carboxylate (600.0 mg, 2.3 mmol, 1.0 equiv.) was dissolved in THE (10 mL), then NaBH₄ (172.5 mg, 4.6 mmol, 2.0 equiv.) was added. The reaction mixture was stirred for 2 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give methyl 5-fluoro-6-[6-hydroxyspiro[3.3]heptan-2-yl]pyridine-3-carboxylate (450.0 mg) as a white solid. LCMS Method C-1: [M+H]⁺=266.

Step 3: methyl 5-fluoro-6-(6-((methylsulfonyl)oxy)spiro[3.3]heptan-2-yl)nicotinate

Methyl 5-fluoro-6-[6-hydroxyspiro[3.3]heptan-2-yl]pyridine-3-carboxylate (450.0 mg, 1.7 mmol, 1.0 equiv.) and TEA (0.7 mL, 5.1 mmol, 3.0 equiv.) were dissolved in DCM (10 mL), then MsCl (291.5 mg, 2.5 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 2 hours at ambient temperature then diluted with DCM. The resulting solution was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give methyl 5-fluoro-6-(6-((methylsulfonyl)oxy)spiro[3.3]heptan-2-yl)nicotinate (450.0 mg) as a white solid. LCMS Method A-1: [M+H]⁺=344.

Step 4: 5-fluoro-6-[6-(2,2,2-trifluoroethoxy)spiro[3.3]heptan-2-yl]pyridine-3-carboxylic acid

2,2,2-Trifluoroethan-1-ol (240.0 mg, 2.4 mmol, 2.0 equiv.) was dissolved in DMF (5 mL) and cooled to 0° C., then NaH (60% in mineral oil, 94.3 mg, 2.4 mmol, 2.0 equiv.) was added, maintaining the solution at 0° C. After 30 min at 0° C., methyl 5-fluoro-6-(6-((methylsulfonyl)oxy)spiro[3.3]heptan-2-yl)nicotinate (400.0 mg, 1.2 mmol, 1.0 equiv.) was added. The reaction mixture was stirred heated to 90° C. for 24 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give 5-fluoro-6-[6-(2,2,2-trifluoroethoxy)spiro[3.3]heptan-2-yl]pyridine-3-carboxylic acid (200.0 mg) as a white solid. LCMS Method A-1: [M+H]⁺=334.

Synthesis of Intermediate 98 (methyl 4-(1-bromoethyl)-3-fluorobenzoate)

Step 1: methyl 3-fluoro-4-(1-hydroxyethyl)benzoate

Methyl 3-fluoro-4-formylbenzoate (8.0 g, 43.9 mmol, 1.0 equiv.) was dissolved in THF (20 mL) and cooled to −40° C., then MeMgBr (3M in Et₂O) (16.1 mL, 48.3 mmol, 1.1 equiv.) was added dropwise, maintaining the solution at −40° C. under an atmosphere of nitrogen. The reaction mixture was stirred overnight at ambient temperature and then quenched by the addition of saturated aqueous NH₄Cl. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give methyl 3-fluoro-4-(1-hydroxyethyl)benzoate (2.5 g) as a white solid. LCMS Method B-1: [M−H]⁻=197.

Step 2: methyl 4-(1-bromoethyl)-3-fluorobenzoate

Methyl 3-fluoro-4-(1-hydroxyethyl)benzoate (2.5 g, 12.6 mmol, 1.0 equiv.) was dissolved in DCM (50 mL) and cooled to 0° C., then PBr₃ (6.8 g, 25.2 mmol, 2.0 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for 3 hours at ambient temperature then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give methyl 4-(1-bromoethyl)-3-fluorobenzoate (1.1 g) as a pale yellow oil.

Synthesis of Intermediate 99 (methyl 6-(bromomethyl)-5-chloronicotinate)

Step 1: methyl 5-chloro-6-methylpyridine-3-carboxylate

Methyl 5,6-dichloropyridine-3-carboxylate (2.0 g, 9.7 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (20 mL), then K₂CO₃ (2.7 g, 19.4 mmol, 2.0 equiv.), methylboronic acid (0.6 g, 9.7 mmol, 1.0 equiv.) and Pd(dppf)C₁₂ (0.4 g, 0.5 mmol, 0.05 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 80° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give methyl 5-chloro-6-methylpyridine-3-carboxylate (1.3 g) as a yellow solid. LCMS Method A-1: [M+H]⁺=186.

Step 2: methyl 6-(bromomethyl)-5-chloropyridine-3-carboxylate

Methyl 5-chloro-6-methylpyridine-3-carboxylate (600.0 mg, 3.2 mmol, 1.0 equiv.) was dissolved in CCl₄ (10 mL), then NBS (1.7 g, 9.7 mmol, 3.0 equiv.) and AIBN (53.1 mg, 0.3 mmol, 0.1 equiv.) were added. The reaction mixture was heated to 80° C. for 5 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give methyl 6-(bromomethyl)-5-chloropyridine-3-carboxylate (300.0 mg) as a yellow solid. LCMS Method A-1: [M+H]⁺=264.

Synthesis of Intermediate 100 (4-(1-(3,3-difluoroazetidin-1-yl)ethyl)-3-fluorobenzoic acid)

Step 1: methyl 4-[1-(3,3-difluoroazetidin-1-yl)ethyl]-3-fluorobenzoate

Methyl 4-(1-bromoethyl)-3-fluorobenzoate (1.1 g, 4.2 mmol, 1.0 equiv.) was dissolved in DMF (20 mL), then K₂CO₃ (2.3 g, 16.9 mmol, 4.0 equiv.) and 3,3-difluoroazetidine hydrochloride (818.6 mg, 6.3 mmol, 1.5 equiv.) were added. The reaction mixture was heated to 80° C. overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give methyl 4-[1-(3,3-difluoroazetidin-1-yl)ethyl]-3-fluorobenzoate (810.0 mg) as a yellow solid. LCMS Method A-1: [M+H]⁺=274.

Step 2: 4-[1-(3,3-difluoroazetidin-1-yl)ethyl]-3-fluorobenzoic acid

Methyl 4-[1-(3,3-difluoroazetidin-1-yl)ethyl]-3-fluorobenzoate (800.0 mg, 2.9 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL) and water (10 mL), then LiOH (140.2 mg, 5.9 mmol, 2.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature then concentrated under vacuum. The residue was diluted with water, adjusted to pH 4 with conc. HCl, extracted with ethyl acetate, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC using the following conditions: Column, C18 silica gel; mobile phase, H₂O/ACN, 10% ACN increasing to 90% within 30 min; Detector, 254 nm. This gave 4-[1-(3,3-difluoroazetidin-1-yl)ethyl]-3-fluorobenzoic acid (620.0 mg) as a colorless oil. LCMS Method A-1: [M−H]⁻=258.

The following intermediates were prepared using the same method described for Intermediate 100.

	Starting	Starting
Intermediate	material A	material B	Structure	LCMS data
Intermediate 101				Method C-1: MS-ESI: 291 [M + H]+
Intermediate 102				Method A-1: MS-ESI: 263 [M + H]+
Intermediate 103				Method A-1: MS-ESI: 229 [M + H]+
Intermediate 104				Method B-1: MS-ESI: 226 [M − H]−
Intermediate  10				Method B-1: MS-ESI: 244 [M − H]−
Intermediate 105				Method C-1: MS-ESI: 229 [M + H]+

Synthesis of intermediate 106 (4-((6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)methyl)-3-fluorobenzoic acid)

Step 1: methyl 4-([6,6-difluoro-2-azaspiro[3.3]heptan-2-yl]methyl)-3-fluorobenzoate

Methyl 3-fluoro-4-formylbenzoate (1.0 g, 5.5 mmol, 1.0 equiv.) and 6,6-difluoro-2-azaspiro[3.3]heptane (877.1 mg, 6.6 mmol, 1.2 equiv.) were dissolved in MeOH (20 mL). After 2 hours, NaBH₃CN (690.0 mg, 11.0 mmol, 2.0 equiv.) was added portion wise. The reaction mixture was stirred overnight at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give methyl 4-([6,6-difluoro-2-azaspiro[3.3]heptan-2-yl]methyl)-3-fluorobenzoate (410.0 mg) as a yellow solid. LCMS Method A-1: [M+H]⁺=300.

Step 2: 4-([6,6-difluoro-2-azaspiro[3.3]heptan-2-yl]methyl)-3-fluorobenzoic acid

Methyl 4-([6,6-difluoro-2-azaspiro[3.3]heptan-2-yl]methyl)-3-fluorobenzoate (400.0 mg, 1.3 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL) and water (10 mL), then LiOH (128.0 mg, 5.3 mmol, 4.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature then concentrated under vacuum. The residue was diluted with water, adjusted to pH 5 with conc. HCl, extracted with dichloromethane and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC using the following conditions: Column, C18 silica gel; mobile phase, H₂O/ACN, 10% ACN increasing to 90% within 30 min; Detector, 254 nm. This gave 4-([6,6-difluoro-2-azaspiro[3.3]heptan-2-yl]methyl)-3-fluorobenzoic acid (211.0 mg) as a yellow solid. LCMS Method B-1: [M−H]⁻=284.

Synthesis of Intermediate 107 (2-(2,2,2-trifluoro-1-hydroxyethyl)isonicotinic acid)

Step 1: methyl 2-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-4-carboxylate

Methyl 2-formylpyridine-4-carboxylate (400.0 mg, 2.4 mmol, 1.0 equiv.) and trifluoromethyltrimethylsilane (344.4 mg, 2.4 mmol, 1.0 equiv.) were dissolved in THF (5 mL) and cooled to −50° C., then TBAF (1M in THF, 4.8 mL, 4.8 mmol, 2.0 equiv.) was added dropwise, maintaining the solution at −50° C. The reaction mixture was stirred for 30 min at ambient temperature then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give methyl 2-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-4-carboxylate (215.0 mg) as a pale yellow solid. LCMS Method A-1: [M+H]⁺=236.

Step 2: 2-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-4-carboxylic acid

Methyl 2-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-4-carboxylate (200.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (68.0 mg, 1.7 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, then adjusted to pH 5 with aqueous HCl (6M). The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC using the following conditions: Column, C18 silica gel; mobile phase, A: water with 0.1% TFA; B: ACN, (20% Phase B up to 60% in 10 min); Detector, UV 254 nm. This gave 2-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-4-carboxylic acid (150.0 mg) as a pale yellow oil. LCMS Method A-1: [M+H]⁺=222.

Synthesis of Intermediate 108 (2-(1-hydroxypropyl)isonicotinic acid)

Step 1: methyl 2-(1-hydroxypropyl)pyridine-4-carboxylate

Methyl 2-formylpyridine-4-carboxylate (500.0 mg, 3.0 mmol, 1.0 equiv.) was dissolved in THF (20 mL) and cooled to 0° C., then EtMgBr (1M in THF, 6.1 mL, 6.1 mmol, 2.0 equiv.) was added dropwise under an atmosphere of nitrogen, maintaining the solution at 0° C. The reaction mixture was stirred for 3 hours at ambient temperature then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give methyl 2-(1-hydroxypropyl)pyridine-4-carboxylate (220.0 mg) as yellow oil. LCMS Method A-1: [M+H]⁺=196.

Step 2: 2-(1-hydroxypropyl)pyridine-4-carboxylic acid

Methyl 2-(1-hydroxypropyl)pyridine-4-carboxylate (300.0 mg, 1.5 mmol, 1.0 equiv.) was dissolved in MeOH (3 mL) and water (7 mL), then NaOH (122.9 mg, 3.1 mmol, 2.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature then concentrated under vacuum. The residue was diluted with water, then adjusted to pH 6 with aqueous HCl (lM). The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give 2-(1-hydroxypropyl)pyridine-4-carboxylic acid (150.0 mg) as a yellow solid. LCMS Method A-1: [M+H]⁺=182.

Synthesis of Intermediate 109 (4-(4-hydroxytetrahydro-2H-pyran-4-yl)benzoic acid)

Step 1: methyl 4-(4-hydroxyoxan-4-yl)benzoate

Methyl 4-iodobenzoate (4.0 g, 15.3 mmol, 1.0 equiv.) was dissolved in THF (60 mL) and cooled to −50° C., then i-PrMgCl (1M in THF, 15.3 mL, 15.3 mmol, 1.0 equiv.) was added dropwise under an atmosphere of nitrogen, maintaining the solution at −50° C. The reaction mixture was stirred for 1 hour at −50° C., then a solution of tetrahydro-4H-pyran-4-one (1.5 g, 15.3 mmol, 1.0 equiv.) in THE (10 mL) was added dropwise at −50° C. The reaction mixture was stirred overnight at ambient temperature and then quenched by the addition of saturated aqueous NH₄Cl at 0° C. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give methyl 4-(4-hydroxyoxan-4-yl)benzoate (520.0 mg) as a yellow solid. LCMS Method A-1: [M−H]⁻=235.

Step 2: 4-(4-hydroxyoxan-4-yl)benzoic acid

Methyl 4-(4-hydroxyoxan-4-yl)benzoate (500.0 mg, 2.1 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL) and water (10 mL), then LiOH (101.4 mg, 4.2 mmol, 2.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature then concentrated under vacuum. The residue was diluted with water, then adjusted to pH 5 with concentrated HCl. The resulting solids were collected by filtration, washed with water and dried under vacuum to give 4-(4-hydroxyoxan-4-yl)benzoic acid (350.0 mg) as a white solid. LCMS Method B-1: [M−H]⁻=221.

The following intermediates were prepared using the same method described for Intermediate 109.

	Starting	Starting
Intermediate	material A	material B	Structure	LCMS data
Intermediate 110				Method B-1: MS-ESI: 256 [M − H]−
Intermediate 111				Method B-1: MS-ESI: 255 [M − H]−
Intermediate  56				Method B-1: MS-ESI: 255 [M − H]−
Intermediate 112				Method B-1: MS-ESI: 273 [M − H]−

Synthesis of Intermediate 113 (4-((3,3-difluorocyclobutyl)(hydroxy)methyl)benzoic acid)

Step 1: 3,3-difluorocyclobutane-1-carbaldehyde

(3,3-Difluorocyclobutyl) methanol (2.0 g, 16.4 mmol, 1.0 equiv.) was dissolved in DCM (10 mL), then Dess-Martin reagent (10.4 g, 24.6 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 2 hours at ambient temperature then quenched by the addition of aqueous Na₂S₂O₃. After stirring for 10 min at ambient temperature, the resulting solution was extracted with ether, washed with saturated aqueous NaHCO₃, dried over anhydrous MgSO₄ and concentrated under vacuum at 0° C. to give 3,3-difluorocyclobutane-1-carbaldehyde (610.0 mg) as a yellow oil. LCMS Method A-1: [M+H]⁺=121.

Steps 2-3: 4-[(3,3-difluorocyclobutyl)(hydroxy)methyl]benzoic acid

The title compound was prepared using the same methods described for Intermediate 109, Steps 1-2. LCMS Method A-1: [M−H] 241.

Synthesis of Intermediate 114 (6-(2-hydroxybutyl)nicotinic acid)

Step 1: 5-bromo-6-methylpyridine-3-carboxylic acid

Ethyl 5-bromo-6-methylpyridine-3-carboxylate (800.0 mg, 3.3 mmol, 1.0 equiv.) was dissolved in MeOH (8 mL) and water (8 mL), then NaOH (262.2 mg, 6.6 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, adjusted to pH 6 with conc. HCl, extracted with ethyl acetate and concentrated under vacuum to give 5-bromo-6-methylpyridine-3-carboxylic acid (675.0 mg) as a white solid. LCMS Method A-1: [M+H]⁺=216.

Step 2: 6-(2-hydroxybutyl)pyridine-3-carboxylic acid

5-Bromo-6-methylpyridine-3-carboxylic acid (300.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in THE (8 mL) and cooled to −78° C., then n-BuLi (2.5 M in hexane, 1.4 mL, 3.5 mmol, 2.5 equiv.) was added dropwise under an atmosphere of nitrogen, maintaining the reaction temperature at −78° C. After 1 hour at −78° C., propionaldehyde (80.7 mg, 1.4 mmol, 1.0 equiv.) was added. The reaction mixture was stirred for 1 hour at ambient temperature, then quenched by the addition of saturated aqueous NH₄Cl. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by reverse flash-HPLC using the following conditions: column, C18 silica gel; mobile phase, A: water with 0.1% TFA, B: ACN, 10% ACN to 50% gradient in 30 min; detector, UV 254 nm. This gave 6-(2-hydroxybutyl)pyridine-3-carboxylic acid (70.0 mg) as a white solid. LCMS Method B-1: [M−H]⁻=194.

Synthesis of Intermediate 115 (2-ethyl-2,3-dihydro-1H-indene-5-carboxylic acid)

Step 1: ethyl 2-[(4-bromophenyl)methyl]butanoate

Ethyl butyrate (14.3 g, 109.8 mmol, 1.0 equiv.) was dissolved in THE (150 mL) and cooled to −78° C., then LDA (2.0 M in THF, 54.9 mL, 109.8 mmol, 1.0 equiv.) was added dropwise under an atmosphere of nitrogen, maintaining the solution at −78° C. After 30 min at −78° C., a solution of 1-bromo-4-(bromomethyl)benzene (27.5 g, 109.8 mmol, 1.0 equiv.) in THE (100 mL) was added at −78° C. The reaction mixture was stirred for 12 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give ethyl 2-[(4-bromophenyl)methyl]butanoate (20.0 g) as a yellow oil.

Step 2: 2-[(4-bromophenyl)methyl]butanoic acid

Ethyl 2-[(4-bromophenyl)methyl]butanoate (20.0 g, 70.1 mmol, 1.0 equiv.) was dissolved in EtOH (100 mL), then a solution of NaOH in water (10% wt., 100.0 mL, 250.0 mmol, 3.6 equiv.) was added. The reaction mixture was heated to 80° C. for 3 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, adjusted to pH 5 with aqueous HCl (4 M). The resulting solids were collected by filtration and dried under vacuum to give 2-[(4-bromophenyl)methyl]butanoic acid (12.0 g) as a yellow solid. LCMS Method B-1: [M−H]⁻=255.

Step 3: 6-bromo-2-ethyl-2,3-dihydroinden-1-one

2-[(4-Bromophenyl)methyl]butanoic acid (18.0 g, 70.0 mmol, 1.0 equiv.) was dissolved in SOCl₂ (50 mL). The reaction mixture was heated to reflux for 3 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was dissolved in DCM (120 mL) and cooled to 0° C., then AlCl₃ (10.0 g, 75.0 mmol, 1.1 equiv.) was added in portions. The resulting solution was stirred for addition 5 hours at 50° C., then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give 6-bromo-2-ethyl-2,3-dihydroinden-1-one (14.0 g) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J=5.6 Hz, 1H), 7.71-7.68 (m, 1H), 7.41-7.35 (m, 1H), 3.32-3.26 (m, 1H), 2.81-2.76 (m, 1H), 2.71-2.64 (m, 1H), 2.03-1.93 (m, 1H), 1.59-1.54 (m, 1H), 1.02 (t, J=7.2 Hz, 3H).

Step 4: 5-bromo-2-ethyl-2,3-dihydro-1H-indene

6-Bromo-2-ethyl-2,3-dihydroinden-1-one (14.0 g, 58.6 mmol, 1.0 equiv.) was dissolved in Et₃SiH (23 mL) and TFA (40 mL). The reaction mixture was stirred for 12 hours at ambient temperature then quenched by the addition of water. The resulting solution was adjusted to pH 7-8 with Na₂CO₃ powder, then extracted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give 5-bromo-2-ethyl-2,3-dihydro-1H-indene (1.1 g) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 7.25-7.24 (m, 1H), 7.20-7.16 (m, 1H), 6.98 (d, J=8.0 Hz, 1H), 2.98-2.89 (m, 2H), 2.54-2.42 (m, 2H), 2.36-2.27 (m, 1H), 1.49-1.45 (m, 2H), 0.90 (t, J=7.2 Hz, 3H).

Step 5: methyl 2-ethyl-2,3-dihydro-1H-indene-5-carboxylate

5-Bromo-2-ethyl-2,3-dihydro-1H-indene (500.0 mg, 2.2 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and DMF (1 mL), then TEA (3.0 mL, 21.5 mmol, 10.0 equiv.) and Pd(dppf)Cl₂·CH₂Cl₂ (506.6 mg, 0.6 mmol, 0.3 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 100° C. overnight under an atmosphere of CO (20 atm). The mixture was cooled to ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give methyl 2-ethyl-2,3-dihydro-1H-indene-5-carboxylate (305.0 mg) as a yellow oil. LCMS Method A-1: [M+H]⁺=205.

Step 6: 2-ethyl-2,3-dihydro-1H-indene-5-carboxylic acid

Methyl 2-ethyl-2,3-dihydro-1H-indene-5-carboxylate (300.0 mg, 1.5 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (117.5 mg, 2.9 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, adjusted to pH 6 with aqueous HCl (1M). The solids were collected by filtration and dried under vacuum to give 2-ethyl-2,3-dihydro-1H-indene-5-carboxylic acid (210.0 mg) as a white solid. LCMS Method B-1: [M−H]⁻=189.

Synthesis of Intermediate 116 (4-(1-cyano-4,4-difluorocyclohexyl)benzoic acid)

Step 1: 1-(4-bromophenyl)-4,4-difluorocyclohexane-1-carbonitrile

1-(4-Bromophenyl)-4-oxocyclohexane-1-carbonitrile (700.0 mg, 2.5 mmol, 1.0 equiv.) was dissolved in DCM (20 mL) and cooled to 0° C., then DAST (610.0 mg, 3.8 mmol, 1.5 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for 15 hours at 40° C., then cooled to 0° C. and quenched by the addition ice-water. The resulting solution was extracted with dichloromethane then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (2:3) to give 1-(4-bromophenyl)-4,4-difluorocyclohexane-1-carbonitrile (670.0 mg) as a white solid.

Step 2: 4-(1-cyano-4,4-difluorocyclohexyl)benzoic acid

1-(4-Bromophenyl)-4,4-difluorocyclohexane-1-carbonitrile (550.0 mg, 1.8 mmol, 1.0 equiv.) was dissolved in THE (20 mL) and cooled to −78° C., then n-BuLi (2.5M in THF, 0.8 mL, 2.0 mmol, 1.1 equiv.) was added dropwise, maintaining the solution at -78° C. After 30 min at −78° C., dry-ice (2.0 g, 45.4 mmol, 24.8 equiv.) was added at −78° C. The reaction mixture was stirred for an additional 1 hour at −30° C. to −40° C., then quenched by the addition of water. The resulting solution was adjusted to pH 4 with aqueous HCl (1 M), extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (9:1) to give 4-(1-cyano-4,4-difluorocyclohexyl)benzoic acid (550.0 mg) as a white solid. LCMS Method B-1: [M−H]⁻=264.

Synthesis of Intermediate 117 (3-(2-hydroxyethyl)-4-(trifluoromethyl)benzoic acid) and intermediate 118 (3-(1-hydroxyethyl)-4-(trifluoromethyl)benzoic acid)

Step 1: methyl 3-ethenyl-4-(trifluoromethyl)benzoate

Methyl 3-bromo-4-(trifluoromethyl)benzoate (2.0 g, 7.1 mmol, 1.0 equiv.) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 g, 8.6 mmol, 1.2 equiv.) were dissolved in 1,4-dioxane (30 mL) and water (5 mL), then Cs₂CO₃ (4.6 g, 14.2 mmol, 2.0 equiv.) and Pd(dppf)Cl₂ (1.0 g, 1.4 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 90° C. for 15 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give methyl 3-ethenyl-4-(trifluoromethyl)benzoate (1.4 g) as a yellow solid. LCMS Method A-1: [M+H]⁺=231.

Step 2: methyl 3-(2-hydroxyethyl)-4-(trifluoromethyl)benzoate and methyl 3-(1-hydroxyethyl)-4-(trifluoromethyl)benzoate

Methyl 3-ethenyl-4-(trifluoromethyl)benzoate (1.3 g, 5.5 mmol, 1.0 equiv.) was dissolved in THE (40 mL) and cooled to 0° C., then BH₃-Me₂S (10 M in THF, 2.1 mL, 21.0 mmol, 4.0 equiv.) was added dropwise, maintaining the solution at 0° C. The reaction mixture was stirred for 2 hours at ambient temperature then cooled back down to 0° C. To the mixture was added aqueous NaOH (30% wt., 3.4 mL, 26.1 mmol, 4.7 equiv.) and aqueous H₂O₂ (30% wt., 1.4 g, 12.6 mmol, 2.3 equiv.) dropwise at 0° C. The resulting mixture was stirred for an additional 2 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give mixture of methyl 3-(2-hydroxyethyl)-4-(trifluoromethyl)benzoate (127A) and methyl 3-(1-hydroxyethyl)-4-(trifluoromethyl)benzoate (127B) (1.4 g) as yellow crude oil. LCMS Method C-1: [M+H]⁺=249.

Step 3: 3-(2-hydroxyethyl)-4-(trifluoromethyl)benzoic acid and 3-(1-hydroxyethyl)-4-(trifluoromethyl)benzoic acid

The mixture of methyl 3-(2-hydroxyethyl)-4-(trifluoromethyl)benzoate and methyl 3-(1-hydroxyethyl)-4-(trifluoromethyl)benzoate (1.3 g, 5.1 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL) and water (1 mL), then LiOH (486.3 mg, 20.3 mmol, 4.0 equiv.) was added. The reaction mixture was stirred for 4 hours at ambient temperature then concentrated under vacuum. The residue was diluted with water, then adjusted to pH 4 with aqueous HCl (1 M). The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:9) to give the mixture of 3-(2-hydroxyethyl)-4-(trifluoromethyl)benzoic acid (intermediate 117) and 3-(1-hydroxyethyl)-4-(trifluoromethyl)benzoic acid (intermediate 118) (710.0 mg) as a white solid. LCMS Method B-1: [M−H]⁻=233.

The following intermediates were prepared using the same method described for Intermediates 117/118.

	Starting
Intermediate	material	Structure	LCMS data
Intermediate 119			Method B-1: MS-ESI: 233 [M − H]−
Intermediate 120			Method B-1: MS-ESI: 233 [M − H]−

Synthesis of Intermediate 121 (4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)benzoic acid)

Step 1: tert-butyl 4-[[4-(methoxycarbonyl)phenyl]methylidene]piperidine-1-carboxylate

Methyl 4-[(diethoxyphosphoryl)methyl]benzoate (1.0 g, 3.5 mmol, 1.0 equiv.) was dissolved in THE (10 mL) and cooled to 0° C., then NaH (60% in mineral oil, 139.7 mg, 3.5 mmol, 1.0 equiv.) was added, maintaining the solution at 0° C. After 30 min at 0° C., tert-butyl 4-oxopiperidine-1-carboxylate (703.0 mg, 3.5 mmol, 1.0 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give tert-butyl 4-[[4-(methoxycarbonyl)phenyl]methylidene]piperidine-1-carboxylate (550.0 mg) as a yellow oil. LCMS Method A-1: [M+H]⁺=332.

Step 2: tert-butyl 4-[[4-(methoxycarbonyl)phenyl]methyl]piperidine-1-carboxylate

tert-Butyl 4-[[4-(methoxycarbonyl)phenyl]methylidene]piperidine-1-carboxylate (500.0 mg, 1.5 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL), then Pd/C (10% wt., 160.6 mg) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), then stirred overnight at ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum to give tert-butyl 4-[[4-(methoxycarbonyl)phenyl]methyl]piperidine-1-carboxylate (480.0 mg) as a pale yellow oil. LCMS Method A-1: [M+H]⁺=334.

Step 3: methyl 4-(piperidin-4-ylmethyl)benzoate hydrochloride

tert-Butyl 4-[[4-(methoxycarbonyl)phenyl]methyl]piperidine-1-carboxylate (500.0 mg, 1.5 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4 M, 15 mL). The reaction mixture was stirred for 2 hours at ambient temperature and concentrated under vacuum to give methyl 4-(piperidin-4-ylmethyl)benzoate hydrochloride (450.0 mg) as a yellow solid. LCMS Method A-1: [M+H]⁺=234.

Step 4: methyl 4-[[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl]benzoate

Methyl 4-(piperidin-4-ylmethyl)benzoate hydrochloride (400.0 mg, 1.7 mmol, 1.0 equiv.) and TEA (0.7 mL, 5.1 mmol, 3.0 equiv.) were dissolved in ACN (5 mL) and cooled to 0° C., then 2,2,2-trifluoroethyl trifluoromethanesulfonate (596.9 mg, 2.6 mmol, 1.5 equiv.) was added, maintaining the solution at 0° C. The reaction mixture was stirred overnight at ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give methyl 4-[[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl]benzoate (350.0 mg) as a yellow oil. LCMS Method A-1: [M+H]⁺=316.

Step 5: 4-[[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl]benzoic acid

Methyl 4-[[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl]benzoate (350.0 mg, 1.1 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (88.8 mg, 2.2 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 60° C. for 3 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, then adjusted to pH 6 with aqueous HCl (4 M). The resulting solution was extracted with ethyl acetate then concentrated under vacuum. The residue was purified by Flash-Prep-HPLC using the following conditions: Column, C18 silica gel; mobile phase Water (0.1% TFA) and ACN (10% Phase B up to 50% in 10 min); Detector, UV 254 nm. This gave 4-[[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl]benzoic acid (320.0 mg) as a white solid. LCMS Method A-1: [M−H]⁻=300.

Synthesis of Intermediate 122 (3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzoic acid)

Step 1: methyl 3-(N-hydroxycarbamimidoyl)benzoate

Methyl 3-cyanobenzoate (1.0 g, 6.2 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL), then K₂CO₃ (1.3 g, 9.3 mmol, 1.5 equiv.) and NH₂OH·HCl (862.4 mg, 12.4 mmol, 2.0 equiv.) were added. The reaction mixture was heated to 80° C. for 3 hours, then cooled to ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum to give methyl 3-(N-hydroxycarbamimidoyl)benzoate (1.1 g) as a white oil. LCMS Method A-1: [M+H]⁺=195.

Step 2: methyl 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzoate

Methyl 3-(N-hydroxycarbamimidoyl)benzoate (900.0 mg, 4.6 mmol, 1.0 equiv.) was dissolved in pyridine (100 mL), then cyclopropanecarbonyl chloride (484.5 mg, 4.6 mmol, 1.0 equiv.) was added. The reaction mixture was heated to 100° C. overnight, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC using the following conditions: Column, C18 silica gel; mobile phase, ACN/H₂O, 10% ACN increasing to 90% within 30 min; Detector, 254 nm. This gave methyl 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzoate (523 mg) as a yellow oil. LCMS Method A-1: [M+H]⁺=245.

Step 3: 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzoic acid

Methyl 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzoate (500.0 mg, 2.0 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (163.8 mg, 4.1 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 80° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC using the following conditions: Column, C18 silica gel; mobile phase, ACN/H₂O, 10% ACN increasing to 100% within 40 min; Detector, 254 nm. This gave 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzoic acid (315.0 mg) as a white solid. LCMS Method A-1: [M+H]⁺=231.

Synthesis of Intermediate 123 (3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzoic acid)

Step 1: 4-bromo-1-[3-(methoxymethyl)phenyl]pyrazole

3-(Methoxymethyl)phenylboronic acid (500.0 mg, 3.0 mmol, 1.0 equiv.) and 4-bromopyrazole (487.0 mg, 3.3 mmol, 1.1 equiv.) were dissolved in DCM (20 mL), then Cu(AcO)₂ (656.6 mg, 3.6 mmol, 1.2 equiv.) and pyridine (0.5 mL, 6.0 mmol, 2.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was stirred overnight at ambient temperature then diluted with ethyl acetate. The resulting solution was washed with brine and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give 4-bromo-1-[3-(methoxymethyl)phenyl]pyrazole (420.0 mg) as a white solid. LCMS Method A-1: [M+H]⁺=267.

Step 2: 1-[3-(methoxymethyl)phenyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole

4-Bromo-1-[3-(methoxymethyl)phenyl]pyrazole (400.0 mg, 1.5 mmol, 1.0 equiv.) and bis(pinacolato)diboron (760.5 mg, 3.0 mmol, 2.0 equiv.) were dissolved in DMSO (10 mL), then AcOK (440.9 mg, 4.5 mmol, 3.0 equiv.) and Pd(dppf)C₁₂ (109.6 mg, 0.15 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 80° C. overnight, then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with brine and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give 1-[3-(methoxymethyl)phenyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (312.0 mg) as a white solid. LCMS Method C-1: [M+H]⁺=315.

The following intermediates were prepared using the same method described for Intermediate 123.

	Starting
Intermediate	material	Structure	LCMS data
Intermediate 124			Method C-1: MS-ESI: 315 [M + H]+

Synthesis of Intermediate 125 (1-(3-cyclopropylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)

Step 1: 4-bromo-1-(3-cyclopropylphenyl)pyrazole

1-Bromo-3-cyclopropylbenzene (1.0 g, 5.1 mmol, 1.0 equiv.) and 4-bromopyrazole (894.9 mg, 6.1 mmol, 1.2 equiv.) were dissolved in DMSO (20 mL), then K₂CO₃ (2.1 g, 15.2 mmol, 3.0 equiv.), quinolin-8-ol (73.7 mg, 0.5 mmol, 0.1 equiv.) and CuI (96.6 mg, 0.5 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 110° C., then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with brine and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give 4-bromo-1-(3-cyclopropylphenyl)pyrazole (410.0 mg) as a white solid. LCMS Method A-1: [M+H]⁺=263.

Step 2: 1-(3-cyclopropylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole

4-Bromo-1-(3-cyclopropylphenyl)pyrazole (800.0 mg, 3.0 mmol, 1.0 equiv.) and bis(pinacolato)diboron (926.4 mg, 3.6 mmol, 1.2 equiv.) were dissolved in DMSO (10 mL), then AcOK (895.1 mg, 9.1 mmol, 3.0 equiv.) and Pd(dppf)Cl₂ (222.5 mg, 0.3 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 80° C. overnight, then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with brine and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give 1-(3-cyclopropylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (305.0 mg) as a white solid. LCMS Method A-1: [M+H]⁺=311.

Example 1: 5-chloro-N-(5,6-difluoro-1H-indol-3-yl)-6-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)nicotinamide (Compound 101)

5-Chloro-6-[6,6-difluoro-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylic acid (150.0 mg, 0.5 mmol, 1.0 equiv.) and HATU (296.4 mg, 0.8 mmol, 1.5 equiv.) were dissolved in DMF (4.0 mL), then 5,6-difluoro-1H-indol-3-amine hydrogen chloride (164.1 mg, 0.8 mmol, 1.5 equiv.) and DIEA (0.3 mL, 2.1 mmol, 4.0 equiv.) were added. The reaction mixture was stirred for 2 hours at ambient temperature and then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18 OBD Column, 19*150 mm, 5 m 10 nm; mobile phase, Water (0.1% FA) and ACN (5000 Phase B up to 64% o in 10 min); Detector, UV 254 nm. This resulted in 5-chloro-N-(5,6-difluoro-1H-indol-3-yl)-6-[6, 6-difluoro-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxamide (59.9 mg, 26.3%) as a white solid. LCMS Method C: [M+H]⁺=439. ¹H NMR (400 MHz, DMSO-d₆): δ 11.09 (s, 1H), 10.01 (s, 1H), 8.70 (s, 1H), 8.22 (s, 1H), 7.91-7.86 (m, 1H), 7.84 (s, 1H), 7.40-7.35 (m, 1H), 4.39 (s, 4H), 2.93-2.87 (in, 4H).

The following analogs were prepared using the same method described for Example 1.

		Starting
	Compound	materials		LCMS
Example	#	Used	Structure	data
Example  2	107	Intermediate 43/ Intermediate 3		Method F: MS-ESI: 418 [M + H]+.
Example  3	148	Intermediate 43/ Intermediate 20		Method C: MS-ESI: 401 [M + H]+.
Example  4	154	Intermediate 43/ Intermediate 5		Method C: MS-ESI: 411 [M + H]+.
Example  5	137	Intermediate 43/ Intermediate 6		Method C: MS-ESI: 399 [M + H]+.
Example  6	109	Intermediate 43/ Intermediate 25		Method B: MS-ESI: 379 [M + H]+.
Example  7	155	Intermediate 43/ Intermediate 23		Method C: MS-ESI: 413 [M + H]+.
Example  8	150	Intermediate 43/. Intermediate 27		Method C: MS-ESI: 424 [M + H]+.
Example  9	151	Intermediate 43/ Intermediate 28		Method C: MS-ESI: 433 [M + H]+.
Example 10	153	Intermediate 50/ Intermediate 30		Method F: MS-ESI: 415 [M + H]+.
Example 11	156	Intermediate 43/ Intermediate 2		Method C: MS-ESI: 427 [M + H]+.
Example 12	158	Intermediate 43/ Intermediate 40		Method C: MS-ESI: 391 [M + H]+.
Example 13	159	Intermediate 43/ Intermediate 7		Method C: MS-ESI: 393 [M + H]+.
Example 14	163	Intermediate 43/ Intermediate 8		Method I: MS-ESI: 449 [M + H]+.
Example 15	164	Intermediate 43/ Intermediate 9		Method I: MS-ESI: 400 [M + H]+.
Example 16	165	Intermediate 43/ Intermediate 33		Method I: MS-ESI: 393 [M + H]+.
Example 17	166	Intermediate 43/ Intermediate 41		Method A: MS-ESI: 425 [M + H]+.
Example 18	169	Intermediate 43/ Intermediate 52		Method C: MS-ESI: 398 [M + H]+.
Example 19	170	Intermediate 43/ Intermediate 34		Method C: MS-ESI: 433 [M + H]+.
Example 20	171	Intermediate 43/ Intermediate 35		Method C: MS-ESI: 399 [M + H]+.
Example 21	172	Intermediate 43/ Intermediate 36		Method C: MS-ESI: 413 [M + H]+.
Example 22	173	Intermediate 43/ Intermediate 21		Method A: MS-ESI: 387 [M + H]+.
Example 23	176	Intermediate 43/ Intermediate 55		Method C: MS-ESI: 387 [M + H]+.
Example 24	180	Intermediate 51/ Intermediate 32		Method C: MS-ESI: 471 [M + H]+.
Example 25	181	Intermediate 43/ Intermediate 10		Method C: MS-ESI: 396 [M + H]+.
Example 26	182	Intermediate 43/ Intermediate 11		Method C: MS-ESI: 442 [M + H]+.
Example 27	183	Intermediate 43/ Intermediate 12		Method C: MS-ESI: 387 [M + H]+.
Example 28	184	Intermediate 43/ Intermediate 13		Method C: MS-ESI: 431 [M + H]+.
Example 29	185	Intermediate 43/ Intermediate 14		Method C: MS-ESI: 434 [M + H]+.
Example 30	186	Intermediate 43/ Intermediate 42		Method C: MS-ESI: 370 [M + H]+.

Example 31: 4-(4,4-difluoro-1-hydroxycyclohexyl)-N-(5,6-difluoro-1H-indol-3-yl)benzamide (Compound 187)

4-(4,4-Difluoro-1-hydroxycyclohexyl)benzoic acid (220.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in THE (10.0 mL), then 5,6-difluoro-1H-indol-3-amine hydrogen chloride (175.9 mg, 0.9 mmol, 1.0 equiv.), TEA (0.4 mL, 2.6 mmol, 3.0 equiv.) and T₃P (409.8 mg, 1.3 mmol, 1.5 equiv.) were added. The reaction mixture was stirred for 2 hours at ambient temperature and quenched by the addition of MeOH. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C18, 30*250*5 m; Mobile Phase A: Water (10 mM NH₄HCO₃+0.1% NH₄OH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40 B to 50 B in 10 min; 254/210 nm; RT1: 9.67. This resulted in 4-(4,4-difluoro-1-hydroxycyclohexyl)-N-(5,6-difluoro-1H-indol-3-yl)benzamide (117.6 mg) as a white solid. LCMS Method E: [M+H]⁺=499. ¹H NMR (400 MHz, DMSO-d₆): δ 10.08 (s, 1H), 10.15 (s, 1H), 7.97-7.88 (m, 4H), 7.65 (d, 2H), 7.40-7.35 (m, 1H), 5.37 (s, 1H), 2.34-2.18 (m, 2H), 2.05-1.99 (m, 4H), 1.81-1.78 (m, 2H).

The following analogs were prepared using the same method described for Example 31.

	Compound	Starting		LCMS
Example	#	materials	Structure	data
Example 32	103	Intermediate 43/ Intermediate 4		Method F: MS- ESI 375 [M + H]+.
Example 33	104	Intermediate 44/ Intermediate 30		Method C: MS- ESI: 406 [M + H]+.
Example 34	105	Intermediate 43/ Intermediate 37		Method C: MS- ESI: 449 [M + H]+.
Example 35	138	Intermediate 43/ Intermediate 18		Method F: MS- ESI: 400 [M + H]+.
Example 36	139	Intermediate 43/ Intermediate 24		Method F: MS- ESI: 400 [M + H]+.
Example 37	140	Intermediate 43/ Intermediate 19		Method C: MS- ESI: 404 [M + H]+.
Example 38	108	Intermediate 43/ Intermediate 38		Method F : MS- ESI: 363 [M + H]+.
Example 39	149	Intermediate 43/ Intermediate 26		Method C: MS- ESI: 397 [M + H]+.
Example 40	110	Intermediate 43/ Intermediate 39		Method F: MS- ESI: 385 [M + H]+.
Example 41	141	Intermediate 43/ Intermediate 29		Method F: MS- ESI: 385 [M + H]+.
Example 42	142	Intermediate 43/ Intermediate 30		Method C: MS- ESI: 417 [M + H]+.
Example 43	152	Intermediate 43/ 4-(2,2,2- trifluoro- ethoxy) benzoic acid		Method C: MS- ESI: 371 [M + H]+.
Example 44	143	Intermediate 45/ Intermediate 30		Method C: MS- ESI: 412 [M + H]+.
Example 45	144	Intermediate 48/ Intermediate 30		Method C: MS- ESI: 400 [M + H]+.
Example 46	145	Intermediate 49/ Intermediate 30		Method C: MS- ESI: 406 [M + H]+.
Example 47	111	Intermediate 46/ Intermediate 30		Method C: MS- ESI: 400 [M + H]+.
Example 48	146	Intermediate 47/ Intermediate 30		Method C: MS- ESI: 399 [M + H]+.
Example 49	157	Intermediate 43/ Intermediate 22		Method C: MS- ESI: 348 [M + H]+.
Example 50	160	Intermediate 43/ Intermediate 31		Method E: MS- ESI: 403 [M + H]+.
Example 51	102	Intermediate 51/ Intermediate 2		Method C: MS- ESI: 499 [M + H]+.
Example 52	174	Intermediate 43/ Intermediate 54		Method A: MS- ESI: 353 [M + H]+.
Example 53	175	Intermediate 43/ Intermediate 53		Method A: MS- ESI: 407 [M + H]+.
Example 54	188	Intermediate 43/ Intermediate 15		Method C: MS- ESI: 417 [M + H]+.
Example 55	189	Intermediate 43/ Intermediate 16		Method C: MS- ESI: 445 [M + H]+.
Example 56	190	Intermediate 58/ Intermediate 2		Method C: MS- ESI: 409 [M + H]+.
Example 57	191	Intermediate 43/ Intermediate 17		Method E: MS- ESI: 413 [M + H]+.
Example 58	192	Intermediate 58/ Intermediate 30		Method C: MS- ESI: 399 [M + H]+.

Example 59: N-(5,6-difluoro-1H-indol-3-yl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]pyrimidine-4-carboxamide (Compound 193)

2-Oxo-1-[[4-(trifluoromethyl)phenyl]methyl]pyrimidine-4-carboxylic acid (100 mg, 0.3 mmol, 1.0 equiv.) and 5,6-difluoro-1H-indol-3-amine hydrogen chloride (68.5 mg, 0.3 mmol, 1.0 equiv.) were dissolved in DMF (15 mL), then PyBOP (174.5 mg, 0.3 mmol, 1.0 equiv.) and NMM (0.2 mL, 1.7 mmol, 5.0 equiv.) were added. The reaction mixture was stirred for 16 hours at ambient temperature and then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30×150 mm 5 m; Mobile Phase A: Water (10 mM NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 57% B to 57% B in 14 min; 254 nm; RT1:13.13 min. This resulted in N-(5,6-difluoro-1H-indol-3-yl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]pyrimidine-4-carboxamide (32.9 mg) as a pale solid. LCMS Method E: [M+H]⁺=449. ¹H NMR (400 MHz, DMSO-d₆): δ 11.21 (s, 1H), 10.65 (s, 1H), 8.67 (d, 1H), 7.87-7.82 (m, 2H), 7.78-7.76 (m, 2H), 7.58 (d, 2H), 7.41-7.37 (m, 1H), 7.08 (d, 1H), 5.28 (s, 2H).

Example 60: N-(5-(1-(4-(methoxymethyl)phenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-4-(4,4,4-trifluorobutoxy)benzamide (Compound 162)

Compound 40 was prepared using the same method desired for Example 1

N-(5-bromo-1H-indol-3-yl)-4-(4,4,4-trifluorobutoxy)benzamide (200.0 mg, 0.5 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (5 mL) and water (0.5 mL), then 1-[4-(methoxymethyl)phenyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (142.4 mg, 0.5 mmol, 1.0 equiv.), XPhos Pd G3 (38.4 mg, 0.05 mmol, 0.1 equiv.) and Cs₂CO₃ (443.4 mg, 1.4 mmol, 3.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 80° C. overnight, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column, YMC-Actus Triart C18, 20*250 mm, 5 m, 12 nm; Mobile Phase A: Water (10 mM NH₄HCO₃+0.1% NH₄OH), Mobile Phase B: ACN; (40% Phase B up to 70% in 10 min); Detector, UV 254 nm. This resulted in N-(5-[1-[4-(methoxymethyl)phenyl]pyrazol-4-yl]-1H-indol-3-yl)-4-(4,4,4-trifluorobutoxy)benzamide (77.4 mg) as a white solid. LCMS Method H: [M+H]⁺=549.

¹H NMR (400 MHz, DMSO-d₆): δ 10.94 (s, 1H), 9.99 (s, 1H), 8.87 (d, 1H), 8.19-8.16 (m, 2H), 8.06 (d, 2H), 7.90 (d, 2H), 7.79 (s, 1H), 7.52-7.40 (m, 4H), 7.10 (d, 2H), 4.46 (s, 2H), 4.16 (t, 2H), 3.28 (s, 3H), 2.48-2.41 (m, 2H), 2.03-1.96 (m, 2H).

Example 61: Synthesis of N-(5,6-difluoro-1H-indol-3-yl)-4-ethoxybenzamide (Compound 147)

Synthesis of N-(5,6-difluoro-1H-indol-3-yl)-4-ethoxybenzamide

5,6-difluoro-1H-indol-3-amine (29.2 mg, 0.174 mmol, 1.0 equiv.) and 4-ethoxybenzoic acid (37.5 mg, 0.226 mmol, 1.3 equiv.) were dissolved in DMF (1.0 mL). Then a solution of TEA (96 μl, 0.696 mmol, 4.0 equiv.) and HATU (69.5 mg, 0.183 mmol, 1.05 equiv.) dissolved in 1 mL DMF was added. The reaction mixture was stirred at 30° C. for 16 hours. The reaction mixture was concentrated by Speedvac. The residue was purified by prep HPLC to give N-(5,6-difluoro-1H-indol-3-yl)-4-ethoxybenzamide (30.2 mg, 0.095 mmol). MS-ESI, 317.0 [M+H⁺].

¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.04 (br s, 1H) 9.98 (s, 1H) 7.97 (d, 2H) 7.92-7.84 (m, 2H) 7.36 (dd, 1H) 7.04 (d, 2H) 4.12 (q, 2H) 1.36 (t, 3H)

Example 62: Synthesis of N-(5,6-difluoro-1H-indol-3-yl)-4-isopropoxybenzamide (Compound 128)

Synthesis of N-(5,6-difluoro-1H-indol-3-yl)-4-isopropoxybenzamide

5,6-difluoro-1H-indol-3-amine (28.1 mg, 0.167 mmol, 1.0 equiv.) and 4-isopropoxybenzoic acid (39.1 mg, 0.217 mmol, 1.3 equiv.) were dissolved in DMF (1.0 mL). Then a solution of DIEA (116 μl, 0.668 mmol, 4.0 equiv.) and HATU (66.5 mg, 0.175 mmol, 1.05 equiv.) dissolved in 1 mL DMF was added. The reaction mixture was stirred at 30° C. for 16 hours. The reaction mixture was concentrated by Speedvac. The residue was purified by prep HPLC to give N-(5,6-difluoro-1H-indol-3-yl)-4-isopropoxybenzamide (15.1 mg, 0.046 mmol). MS-ESI, 331.1 [M+H⁺].

¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.05 (br s, 1H), 9.98 (s, 1H), 7.96 (d, 2H), 7.92-7.83 (m, 2H), 7.36 (dd, 1H), 7.03 (d, 2H), 4.74 (dt, 1H), 1.30 (d, 6H)

The following compounds were prepared using the method above.

				LC-MS,
				MS-ESI,—
				[M + H+].
Exam-	Compound		IUPAC	Methods BA
ple #	#	Structure	Name	or BB
63	113		N-(5,6- difluoro-1H- indol-3-yl)- 2-(propan-2- yloxy) pyridine-4- carboxamide	332.1
64	121		N-(5,6- difluoro-1H- indol-3-yl)- 3- (difluoro- methoxy) benzamide	339
65	116		N-(5,6- difluoro-1H- indol-3-yl)- 4- (difluoro- methoxy) benzamide	339.1
66	106		N-(5,6- difluoro-1H- indol-3-yl)- 2- (difluoro- methoxy) pyridine-4- carboxamide	340.1
67	130		4- (cyclopropyl methoxy)-N- (5,6- difluoro-1H- indol-3- yl)benzamide	343.1
68	132		4-butoxy-N- (5,6- difluoro-1H- indol-3- yl)benzamide	345.1
69	120		3-cyano-N- (5,6- difluoro-1H- indol-3-yl)- 4-(propan-2- yloxy)benza- mide	356.1
70	135		N-(5,6- difluoro-1H- indol-3-yl)- 4- (trifluoro- methoxy) benzamide	357.1
71	125		N-(5,6- difluoro-1H- indol-3-yl)- 3- (trifluoro- methoxy) benzamide	357.1
72	118		N-(5,6- difluoro-1H- indol-3-yl)- 4-(pyridin-3- yloxy)benza- mide	366.1
73	112		N-(5,6- difluoro-1H- indol-3-yl)- 3-methoxy- 4- (trifluoro- methyl) benzamide	371
74	119		N-(5,6- difluoro-1H- indol-3-yl)- 3-methyl-5- (trifluoro- methoxy) benzamide	371.1
75	124		N-(5,6- difluoro-1H- indol-3-yl)- 6-(oxan-4- yloxy) pyridine-2- carboxamide	374.2
76	131		3- (benzyloxy)- N-(5,6- difluoro-1H- indol-3- yl)benzamide	379.1
77	136		4- (benzyloxy)- N-(5,6- difluoro-1H- indol-3- yl)benzamide	379.1
78	117		N-(5,6- difluoro-1H- indol-3-yl)- 3-(1,1,2,2- tetrafluoro- ethoxy) benzamide	389
79	134		N-(5,6- difluoro-1H- indol-3-yl)- 3-fluoro-4- (2,2,2- trifluoro- ethoxy) benzamide	389.1
80	114		3-chloro-N- (5,6- difluoro-1H- indol-3-yl)- 4- (trifluoro- methoxy) benzamide	391
81	126		N-(5,6- difluoro-1H- indol-3-yl)- 4-(propan-2- yloxy)-3- (trifluoro- methyl) benzamide	399.1
82	122		2-chloro-N- (5,6- difluoro-1H- indol-3-yl)- 4-(2,2,2- trifluoro- ethoxy) benzamide	405.1
83	115		N-(5,6- difluoro-1H- indol-3-yl)- 3,5-difluoro- 4-(2,2,2- trifluoro- ethoxy) benzamide	407
84	127		3- (cyclopropyl methoxy)-N- (5,6- difluoro-1H- indol-3-yl)- 4- (difluoro- methoxy) benzamide	409.1
85	133		N-(5,6- difluoro-1H- indol-3-yl)- 4-{[5- (trifluoro- methyl) pyridin-2- yl]oxy} benzamide	434.1
86	129		N-(5,6- difluoro-1H- indol-3-yl)- 4-[2- (piperidin-1- yl)ethoxy] benzamide	400
87	123		(pyridin-3- yl)methyl N- ({4-[(5,6- difluoro-1H- indol-3-yl) carbamoyl] phenyl} methyl) carbamate	437.2

Example 88: N-(5,6-difluoro-1H-indol-3-yl)-4-(5-isopropyl-1,2,4-oxadiazol-3-yl)benzamide (Compound 267)

5,6-difluoro-1H-indol-3-amine (23.4 mg, 0.14 mmol, 1.0 equiv.) and 4-(5-isopropyl-1,2,4-oxadiazol-3-yl)benzoic acid (41.8 mg, 0.18 mmol, 1.3 equiv.) were dissolved in DMF (1.0 mL). Then a solution of DIEA (97 μl, 0.56 mmol, 4.0 equiv.) and HATU (55.5 mg, 0.15 mmol, 1.05 equiv.) dissolved in 1 mL of DMF was added. The reaction mixture was stirred at 30° C. for 16 hours. The reaction mixture was concentrated by Speedvac. The residue was purified by prep HPLC to give N-(5,6-difluoro-1H-indol-3-yl)-4-(5-isopropyl-1,2,4-oxadiazol-3-yl)benzamide. MS-ESI, 383.2 [M+H⁺].

¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (br s, H), 10.38 (s, 1H), 8.21-8.11 (m, 4H), 7.96-7.85 (m, 2H), 7.39 (dd, J=11.0, 7.0 Hz, 1H), 3.43-3.39 (m, 1H), 1.41 (d, J=7.0 Hz, 6H).

The following compounds were prepared using the method for Example 88 above.

				LC-MS
Example	Compound			MS-ESI
#	No.	Structure	IUPAC Name	[M + H+].
89	270		N-(5,6-difluoro- 1H-indol-3-yl)- 5- (difluoromethoxy) pyridine-2- carboxamide	340.1
90	269		N-(5,6-difluoro- 1H-indol-3-yl)- 4-(oxetan-3- yloxy)benzamide	345.1
91	199		N-(5,6-difluoro- 1H-indol-3-yl)- 4-ethoxy-2,6- difluorobenzamide	353.1
92	198		N-(5,6-difluoro- 1H-indol-3-yl)- 3-ethoxy-2,4- difluorobenzamide	353.1
93	168		4- (cyclopentyloxy)- N-(5,6-difluoro- 1H-indol-3- yl)benzamide	357.1
94	197		N-(5,6-difluoro- 1H-indol-3-yl)- 6- (trifluoromethoxy) pyridine-3- carboxamide	358.1
95	196		4- (cyclohexyloxy)- N-(5,6-difluoro- 1H-indol-3- yl)benzamide	371.2
96	179		3- (cyclohexyloxy)- N-(5,6-difluoro- 1H-indol-3- yl)benzamide	371.2
97	195		3-chloro-4- (cyclopropyl- methoxy)-N-(5,6- difluoro-1H- indol-3- yl)benzamide	377.1
98	249		tert-butyl 4-{4- [(5,6-difluoro- 1H-indol-3- yl)carbamoyl] phenoxy} piperidine-1- carboxylate	416.1
99	194		N-(5,6-difluoro- 1H-indol-3-yl)- 3-(2- methoxyethoxy) benzamide	347.1
100	268		N-(5,6-difluoro- 1H-indol-3-yl)- 4-(1,1,2,2- tetrafluoroethoxy) benzamide	389.1
101	274		N-(5,6-difluoro- 1H-indol-3-yl)- 3-(5-methyl- 1,2,4-oxadiazol- 3-yl)benzamide	355.1
102	266		4-(5- cyclopropyl- 1,2,4-oxadiazol- 3-yl)-N-(5,6- difluoro-1H- indol-3- yl)benzamide	381.1
103	265		N-(5,6-difluoro- 1H-indol-3-yl)- 6-(propan-2- yloxy)pyridine- 3-carboxamide	332.1
104	264		N-(5,6-difluoro- 1H-indol-3-yl)- 6-methoxy-5- (trifluoromethyl) pyridine-3- carboxamide	372.1
105	263		N-(5,6-difluoro- 1H-indol-3-yl)- 2- phenoxypyridine- 4-carboxamide	366.1

Example 106: N-(5,6-difluoro-1H-indol-3-yl)-5-fluoro-6-((1R,5S,6r)-6-((2,2,2-trifluoroethoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)nicotinamide (Compound 223)

5-Fluoro-6-[(1R,5S,6R)-6-[(2,2,2-trifluoroethoxy)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]pyridine-3-carboxylic acid (200.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in DMF (10 mL), then EDC (172.1 mg, 0.9 mmol, 1.5 equiv.), HOBt (121.3 mg, 0.9 mmol, 1.5 equiv.) and 5,6-difluoro-1H-indol-3-amine hydrochloride (183.8 mg, 0.9 mmol, 1.5 equiv.) were added. This was followed by the addition of DIEA (0.3 mL, 1.8 mmol, 3.0 equiv.). The reaction mixture was stirred for 4 hours at ambient temperature and then diluted with ethyl acetate. The resulting solution was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by Prep-HPLC using the following conditions: Column, XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; mobile phase, Water (10 mM NH₄HCO₃) and ACN (40% Phase B up to 70% in 7 min); Detector, UV 254 nm. This resulted in N-(5,6-difluoro-1H-indol-3-yl)-5-fluoro-6-((1R,5S,6r)-6-((2,2,2-trifluoroethoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)nicotinamide (64.1 mg) as a white solid. LCMS Method E-1: [M+H]⁺=485. ¹H NMR (400 MHz, DMSO-d₆): δ 11.07 (s, 1H), 9.93 (s, 1H), 8.60 (s, 1H), 8.00-7.95 (m, 1H), 7.91-7.84 (m, 2H), 7.39-7.35 (m, 1H), 4.11-4.04 (m, 2H), 3.97-3.94 (m, 2H), 3.68-3.65 (m, 2H), 3.54 (d, J=6.8 Hz, 2H), 1.70 (s, 2H), 1.04-1.00 (m, 1H).

The following analogs were prepared using the same method described for Example 106.

		Starting
	Compound	materials
Example	#	Used	Structure	LCMS data
Example 107	221	Intermediate 43/ Intermediate 79		Method F-1: MS-ESI: 485 [M + H]+.
Example 108	224	Intermediate 50/ Intermediate 70		Method F-1: MS-ESI: 483 [M + H]+.
Example 109	227	Intermediate 1 Intermediate 71		Method D-1: MS-ESI: 484 [M + H]+.

Example 110: N-(5,6-difluoro-1H-indol-3-yl)-6-(4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)nicotinamide (Compound 218)

6-[4-Methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl]pyridine-3-carboxylic acid (100.0 mg, 0.3 mmol, 1.0 equiv.) and 5,6-difluoro-1H-indol-3-amine hydrochloride (81.2 mg, 0.4 mmol, 1.2 equiv.) were dissolved in DMF (5 mL), then HATU (150.9 mg, 0.4 mmol, 1.2 equiv.) and DIEA (0.1 mL, 0.7 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for 2 hours at ambient temperature then concentrated under vacuum. The residue was purified by Prep-HPLC using the following conditions: Column, Xselect CSH F-Phenyl OBD column, 19*250, 5 μm; mobile phase A, Water (10 mM NH₄HCO3); mobile phase B, ACN; 5400 Phase B up to 6900 in 7 min; Detector, UV 254 nm. This resulted in N-(5,6-difluoro-1H-indol-3-yl)-6-[4-methyl-1H-(2,2,2-trifluoroethyl)piperidin-4-yl]pyridine-3-carboxamide (50.0 mg) as an off-white solid. LCMS Method H-1: [M+H]+=453. ¹H NMR (400 MHz, DMSO-d₆): δ 11.12 (s, 1H), 10.34 (s, 1H), 9.09 (d, J=1.6 Hz, 1H), 8.28-8.25 (in, 1H), 7.94-7.89 (m, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.41-7.37 (in, 1H), 3.14-3.06 (m, 2H), 2.77-2.73 (m, 2H), 2.46-2.43 (m, 2H), 2.36-2.32 (m, 2H), 1.77-1.71 (m, 2H), 1.22 (s, 3H).

The following analogs were prepared using the same method described for Example 110.

	Compound	Starting materials
Example	#	Used	Structure	LCMS data
Example 111	219	Intermediate 43/ Intermediate 69		Method F-1: MS-ESI: 437 [M + H]+.
Example 112	220	Intermediate 43/ Intermediate 63		Method D-1: MS-ESI: 424 [M + H]+.
Example 113	222	Intermediate 43/ Intermediate 97		Method F-1: MS-ESI: 484 [M + H]+.
Example 114	225	Intermediate 50/ Intermediate 71		Method F-1: MS-ESI: 482 [M + H]+.
Example 115	226	Intermediate 43/ Intermediate 90		Method F-1: MS-ESI: 362 [M + H]+.
Example 116	228	Intermediate 43/ Intermediate 114		Method F-1: MS-ESI: 346 [M + H]+.
Example 117	229	Intermediate 50/ Intermediate 121		Method E-1: MS-ESI: 450 [M + H]+.
Example 118	230	Intermediate 50/ Intermediate 65		Method F-1: MS-ESI: 452 [M + H]+.
Example 119	231	Intermediate 43/ Intermediate 91		Method E-1: MS-ESI: 376 [M + H]+.
Example 120	232	Intermediate 43/ Intermediate 94		Method E-1: MS-ESI: 415 [M + H]+.
Example 121	233	Intermediate 43/ Intermediate 113		Method F-1: MS-ESI: 393 [M + H]+.
Example 122	234	Intermediate 43/ Intermediate 122		Method D-1: MS-ESI: 381 [M + H]+.
Example 123	235	Intermediate 43/ Intermediate 107		Method E-1: MS-ESI: 372 [M + H]+.
Example 124	236	Intermediate 43/ Intermediate 80		Method D-1: MS-ESI: 414 [M + H]+.
Example 125	237	Intermediate 43/ Intermediate 106		Method F-1: MS-ESI: 436 [M + H]+.
Example 126	238	Intermediate 43/ Intermediate 81		Method E-1: MS-ESI: 347 [M + H]+.
Example 127	239	Intermediate 43/ Intermediate 72		Method E-1: MS-ESI: 419 [M + H]+.
Example 128	240	Intermediate 43/ Intermediate 96		Method G-1: MS-ESI: 398 [M + H]+.
Example 129	241	Intermediate 43/ Intermediate 108		Method F-1: MS-ESI: 332 [M + H]+.
Example 130	243	Intermediate 43/ Intermediate 82		Method G-1: MS-ESI: 413 [M + H]+.
Example 131	246	Intermediate 43/ Intermediate 93		Method E-1: MS-ESI: 427 [M + H]+.
Example 132	247	Intermediate 43/ Intermediate 84		Method F-1: MS-ESI: 379 [M + H]+.
Example 133	248	Intermediate 43/ Intermediate 109		Method F-1: MS-ESI: 373 [M + H]+.
Example 134	250	Intermediate 43/ Intermediate 110		Method G-1: MS-ESI: 408 [M + H]+.
Example 135	251	Intermediate 43/ Intermediate 111		Method G-1: MS-ESI: 407 [M + H]+.
Example 136	252	Intermediate 43/ Intermediate 83		Method E-1: MS-ESI: 399 [M + H]+.
Example 137	253	Intermediate 43/ Intermediate 85		Method E-1: MS-ESI: 379 [M + H]+.
Example 138	254	Intermediate 43/ Intermediate 101		Method G-1: MS-ESI: 441 [M + H]+.
Example 139	255	Intermediate 43/ Intermediate 102		Method G-1: MS-ESI: 413 [M + H]+.
Example 140	256	Intermediate 43/ Intermediate 86		Method E-1: MS-ESI: 407 [M + H]+.
Example 141	257	Intermediate 43/ Intermediate 103		Method F-1: MS-ESI: 379 [M + H]+.
Example 142	259	Intermediate 60/ Intermediate 56		Method G-1: MS-ESI: 423 [M + H]+.
Example 143	260	Intermediate 43/ Intermediate 104		Method E-1: MS-ESI: 378 [M + H]+.
Example 144	258	Intermediate 43/ Intermediate 112		Method G-1: MS-ESI: 425 [M + H]+.
Example 145	261	Intermediate 43/ Intermediate 115		Method E-1: MS-ESI: 341 [M + H]+.
Example 146	262	Intermediate 43/ Intermediate 66		Method G-1: MS-ESI: 419 [M + H]+.
Example 147	271	Intermediate 43/ Intermediate 74		Method E-1: MS-ESI: 388 [M + H]+.
Example 148	272	Intermediate 50/ Intermediate 75		Method E-1: MS-ESI: 377 [M + H]+.
Example 149	273	Intermediate 43/ Intermediate 105		Method G-1: MS-ESI: 379 [M + H]+.
Example 150	280	Intermediate 43/ Intermediate 117		Method E-1: MS-ESI: 385 [M + H]+.
Example 151	276	Intermediate 43/ Intermediate 118		Method E-1: MS-ESI: 385 [M + H]+.
Example 152	279	Intermediate 43/ Intermediate 119		Method E-1: MS-ESI: 385 [M + H]+.
Example 153	275	Intermediate 43/ Intermediate 120		Method E-1: MS-ESI: 385 [M + H]+.
Example 154	204	Intermediate 62/ Intermediate 67		Method F-1: MS-ESI: 489 [M + H]+.
Example 155	203	Intermediate 43/ Intermediate 87		Method F-1: MS-ESI: 399 [M + H]+.
Example 156	277	Intermediate 43/ Intermediate 88		Method E-1: MS-ESI: 399 [M + H]+.
Example 157	208	Intermediate 43/ Intermediate 92		Method G-1: MS-ESI: 395 [M + H]+.
Example 158	207	Intermediate 43/ Intermediate 76		Method G-1: MS-ESI: 399 [M + H]+.
Example 159	278	Intermediate 43/ Intermediate 78		Method E-1: MS-ESI: 419 [M + H]+.
Example 14	163	Intermediate 43/ Intermediate 8		Method F-1: MS-ESI: 449 [M + H]+.
Example 15	164	Intermediate 43/ Intermediate 9		Method F-1: MS-ESI: 400 [M + H]+.
Example 16	165	Intermediate 43/ Intermediate 33		Method F-1: MS-ESI: 393 [M + H]+.
Example 17	166	Intermediate 43/ Intermediate 41		Method G-1: MS-ESI: 425 [M + H]+.
Example 18	169	Intermediate 43/ Intermediate 52		Method C-1: MS-ESI: 398 [M + H]+.
Example 19	170	Intermediate 43/ Intermediate 74		Method C-1: MS-ESI: 433 [M + H]+.
Example 20	171	Intermediate 43/ Intermediate 35		Method C-1: MS-ESI: 399 [M + H]+.
Example 21	172	Intermediate 43/ Intermediate 36		Method C-1: MS-ESI: 413 [M + H]+.
Example 22	173	Intermediate 43/ Intermediate 21		Method G-1: MS-ESI: 387 [M + H]+.
Example 23	176	Intermediate 43/ Intermediate 55		Method C-1: MS-ESI: 387 [M + H]+.
Example 25	181	Intermediate 43/ Intermediate 10		Method C-1: MS-ESI: 396 [M + H]+.
Example 26	182	Intermediate 43/ Intermediate 83		Method C-1: MS-ESI: 442 [M + H]+.
Example 27	183	Intermediate 43/ Intermediate 12		Method C-1: MS-ESI: 387 [M + H]+.
Example 28	184	Intermediate 43/ Intermediate 13		Method C-1: MS-ESI: 431 [M + H]+.
Example 29	185	Intermediate 43/ Intermediate 14		Method C-1: MS-ESI: 434 [M + H]+.
Example 30	186	Intermediate 43/ Intermediate 42		Method C-1: MS-ESI: 370 [M + H]+.
Example 55	189	Intermediate 43/ Intermediate 16		Method C-1: MS-ESI: 445 [M + H]+.
Example 1	101	Intermediate 43/ Intermediate 1		Method C-1: MS-ESI: 439 [M + H]+.
Example 24	180	Intermediate 51/ Intermediate 67		Method C-1: MS-ESI: 471 [M + H]+.
Example 53	175	Intermediate 43/ Intermediate 53		Method G-1: MS-ESI: 407 [M + H]+.
Example 31	187	Intermediate 43/ Intermediate 56		Method A-1: MS-ESI: 407 [M + H]+.
Example 54	188	Intermediate 43/ Intermediate 15		Method C-1: MS-ESI: 417 [M + H]+.
Example 56	190	Intermediate 58/ Intermediate 2		Method C-1: MS-ESI: 409 [M + H]+.
Example 58	192	Intermediate 58/ Intermediate 30		Method C-1: MS-ESI: 399 [M + H]+.
Example 57	191	Intermediate 43/ Intermediate 17		Method A-1: MS-ESI: 413 [M + H]+.
Example 161	213 2	Intermediate 43/ Intermediate 116		Method E-1: MS-ESI: 416 [M + H]+.

Example 160: N-(5,6-difluoro-1H-indol-3-yl)-4-(2,2-difluoroethoxy)benzamide (Compound 174)

4-(2,2-Difluoroethoxy)benzoic acid (300.0 mg, 1.5 mmol, 1.0 equiv.) and 5,6-difluoro-1H-indol-3-amine hydrochloride (303.6 mg, 1.5 mmol, 1.0 equiv.) were dissolved in DMF (4 mL), then T₃P (wt. 50% in ethyl acetate, 1.5 mL, 2.2 mmol, 1.5 equiv.) and TEA (0.8 mL, 5.9 mmol, 4.0 equiv.) were added. The reaction mixture was stirred overnight at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by Prep-HPLC using the following conditions: Column, Xselect CSH OBD Column 30*150 mm 5 μm; mobile phase A: Water (0.1% FA); mobile phase B: ACN (35% Phase B up to 62% in 7 min); Detector, UV 254 nm. This resulted in N-(5,6-difluoro-1H-indol-3-yl)-4-(2,2-difluoroethoxy)benzamide (109.0 mg) as a pink solid. LCMS Method G-1: [M+H]⁺=353. ¹H NMR (400 MHz, DMSO-d₆): δ 11.06 (s, 1H), 10.04 (s, 1H), 8.02 (d, J=8.8 Hz, 2H), 7.92-7.86 (m, 2H), 7.39-7.35 (m, 1H), 7.16 (d, J=8.8 Hz, 2H), 6.60-6.30 (m, 1H) 4.48-4.40 (m, 2H).

The following analogs were prepared using the same method described for Example 160.

Example 162: N-(5,6-difluoro-1H-indol-3-yl)-5-fluoro-6-((3,3,3-trifluoropropyl)amino)nicotinamide (Compound 242)

5-Fluoro-6-[(3,3,3-trifluoropropyl)amino]pyridine-3-carboxylic acid (500.0 mg, 2.0 mmol, 1.0 equiv.) and DCC (613.7 mg, 3.0 mmol, 1.5 equiv.) were dissolved in DCM (15 mL), then DMAP (726.7 mg, 5.9 mmol, 3.0 equiv.) and 5,6-difluoro-1H-indol-3-amine hydrochloride (608.5 mg, 3.0 mmol, 1.5 equiv.) were added. The reaction mixture was stirred overnight at ambient temperature then diluted with ethyl acetate. The resulting solution was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give the crude product, that was further purified by Prep-HPLC using the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mM NH₄HCO₃+0.1% NH₄OH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 65% B in 7 min; Wave Length: 220 nm; RT1: 6.33 min. This resulted in N-(5,6-difluoro-1H-indol-3-yl)-5-fluoro-6-[(3,3,3-trifluoropropyl)amino]pyridine-3-carboxamide (106.9 mg) as an off-white solid. LCMS Method E-1: [M+H]⁺=403. ¹H NMR (400 MHz, DMSO-d₆): δ 11.07 (s, 1H), 9.94 (s, 1H), 8.60 (s, 1H), 7.95-7.84 (m, 3H), 7.48-7.47 (m, 1H), 7.40-7.35 (m, 1H), 3.71-3.66 (m, 2H), 2.67-2.58 (m, 2H).

Example 163: 5-chloro-N-(5,6-difluoro-1H-indol-3-yl)-6-((5-hydroxy-4,4-dimethylpentyl)amino)nicotinamide (Compound 209)

Step 1: 6-((5-((tert-butyldiphenylsilyl)oxy)-4,4-dimethylpentyl)amino)-5-chloro-N-(5,6-difluoro-1H-indol-3-yl)nicotinamide

The title compound was prepared using the same methods described for Example 160. LCMS: Method A-1, [M+H]⁺=675.

Step 2: 5-chloro-N-(5,6-difluoro-1H-indol-3-yl)-6-[(5-hydroxy-4,4-dimethylpentyl)amino]pyridine-3-carboxamide

6-([5-[(tert-Butyldiphenylsilyl)oxy]-4,4-dimethylpentyl]amino)-5-chloro-N-(5,6-difluoro-1H-indol-3-yl)pyridine-3-carboxamide (80.0 mg, 0.1 mmol, 1.o equiv.) was dissolved in aqueous HBr (4 mL, 50% wt.). The reaction mixture was heated to 60° C. overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by Prep-HPLC using the following conditions: Column, XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; mobile phase A: Water (10 mM NH₄HCO_3+0.1% NH₄₀H), mobile phase B: ACN (30% Phase B up to 60% in 7 min); Detector, UV254 nm. This resulted in 5-chloro-N-(5,6-difluoro-1H-indol-3-yl)-6-[(5-hydroxy-4,4-dimethylpentyl)amino]pyridine-3-carboxamide (12.0 mg) as a white solid. LCMS Method F-1: [M+H]⁺=387. ¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 9.91 (s, 1H), 8.67 (d, J=2.0 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.92-7.88 (m, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.39-7.34 (m, 1H), 7.11 (t, J=5.6 Hz, 1H), 4.46 (brs, 1H), 3.43-3.40 (m, 2H), 3.10 (s, 2H), 1.59-1.55 (m, 2H), 1.25-1.22 (m, 2H), 0.79 (s, 6H).

Example 164: N-(5,6-difluoro-1H-indol-3-yl)-6-(3,3-difluorocyclobutyl)nicotinamide (Compound 216)

Step 1: 5-bromo-N-(5,6-difluoro-1H-indol-3-yl)-6-(3,3-difluorocyclobutyl)nicotinamide

The title compound was prepared using the same methods described for Example 160. LCMS: Method A-1, [M+H]⁺=442.

Step 2: N-(5,6-difluoro-1H-indol-3-yl)-6-(3,3-difluorocyclobutyl)pyridine-3-carboxamide

5-Bromo-N-(5,6-difluoro-1H-indol-3-yl)-6-(3,3-difluorocyclobutyl)pyridine-3-carboxamide (200.0 mg, 0.5 mmol, 1.0 equiv.) and HCOONH₄ (114.1 mg, 1.8 mmol, 4.0 equiv.) were dissolved MeOH (5 mL), then Pd/C (10% wt., 5.0 mg) was added. The reaction mixture was heated to 60° C. for 2 hours, then cooled to ambient temperature. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by Prep-HPLC using the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mM NH₄HCO₃+0.1% NH₄OH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 38 B to 54 B in 7 min; 220 nm; RT1: 6.38 min. This resulted in N-(5,6-difluoro-1H-indol-3-yl)-6-(3,3-difluorocyclobutyl)pyridine-3-carboxamide (50.9 mg) as a white solid. LCMS Method E-1: [M+H]⁺=364. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 10.34 (s, 1H), 9.14 (d, J=2.0 Hz, 1H), 8.30-8.27 (m, 1H), 7.93-7.88 (m, 2H), 7.54 (d, J=8.0 Hz, 1H), 7.41-7.37 (m, 1H), 3.68-3.63 (m, 1H), 3.02-2.90 (m, 4H).

Example 165: N-(5-(1-(4-(methoxymethyl)phenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-4-(4,4,4-trifluorobutoxy)benzamide (Compound 162)

Step 1: N-(5-bromo-1H-indol-3-yl)-4-(4,4,4-trifluorobutyl)benzamide

The title compound was prepared using the same methods described for Example 110. LCMS: Method A-1, [M+H]⁺=425.

Step 2: N-(5-[1-[4-(methoxymethyl)phenyl]pyrazol-4-yl]-1H-indol-3-yl)-4-(4,4,4-trifluorobutoxy)benzamide

N-(5-bromo-1H-indol-3-yl)-4-(4,4,4-trifluorobutoxy)benzamide (200.0 mg, 0.5 mmol, 1.0 equiv.) and 1-[4-(methoxymethyl)phenyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (142.4 mg, 0.5 mmol, 1.0 equiv.) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL). Then XPhos Pd G3 (38.4 mg, 0.05 mmol, 0.1 equiv.) and Cs₂CO₃ (443.0 mg, 1.4 mmol, 3.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 80° C. overnight under nitrogen, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by Prep-HPLC using the following conditions: Column, YMC-Actus Triart C18, 20*250 mm, 5 μm; mobile phase A, Water (0.05% TFA); mobile phase B: ACN (40% Phase B up to 70% o in 10 min); Detector, UV254 nm. This resulted in N-(5-[1-[4-(methoxymethyl)phenyl]pyrazol-4-yl]-1H-indol-3-yl)-4-(4,4,4-trifluorobutoxy)benzamide (77.4 mg) as a white solid.

LCMS Method F-1: [M+H]⁺=549. ¹H NMR (400 MHz, DMSO-d₆) δ 10.94 (s, 1H), 9.99 (s, 1H), 8.87 (s, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.4 Hz, 2H), 7.90 (d, J=8.4 Hz, 2H), 7.79 (d, J=2.0 Hz, 1H), 7.52-7.40 (m, 4H), 7.10 (d, J=8.8 Hz, 2H), 4.46 (s, 2H), 4.16 (t, J=6.0 Hz, 2H), 3.33 (s, 3H), 2.51-2.44 (m, 2H), 2.03-1.96 (in, 2H).

The following analogs were prepared using the same method described for Example

	Com-	Starting materials
Example	pound #	Used	Structure	LCMS data
Example 166	201	Intermediate 125		Method F-1: MS-ESI: 545 [M + H]+.
Example 167	200	Intermediate 123		Method E-1: MS-ESI: 549 [M + H]+.

165.

Example 168/169: (R or S)—N-(5,6-difluoro-1H-indol-3-yl)-4-(1-(3,3-difluoroazetidin-1-yl)-1l3-ethyl)-3-fluorobenzamide; Compound 245 (front peak, absolute stereochemistry unconfirmed) and (R or S)—N-(5,6-difluoro-1H-indol-3-yl)-4-(1-(3,3-difluoroazetidin-1-yl)-1l3-ethyl)-3-fluorobenzamide; Compound 244 (second peak, absolute stereochemistry unconfirmed)]

Step 1: N-(5,6-difluoro-1H-indol-3-yl)-4-(1-(3,3-difluoroazetidin-1-yl)ethyl)-3-fluorobenzamide

The title compound was prepared using the same methods described for Example 110. LCMS: Method A-1, [M+H]⁺=410.

Step 2: (R or S)—N-(5,6-difluoro-1H-indol-3-yl)-4-(1-(3,3-difluoroazetidin-1-yl)-1l3-ethyl)-3-fluorobenzamide; Compound 245 (front peak, absolute stereochemistry unconfirmed) and (R or S)—N-(5,6-difluoro-1H-indol-3-yl)-4-(1-(3,3-difluoroazetidin-1-yl)-1l3-ethyl)-3-fluorobenzamide; Compound 244 (second peak, absolute stereochemistry unconfirmed)

The racemic N-(5,6-difluoro-1H-indol-3-yl)-4-(1-(3,3-difluoroazetidin-1-yl)ethyl)-3-fluorobenzamide (400.0 mg) was separated by Prep-Chiral-HPLC using the following conditions: Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.2% DEA)—HPLC, Mobile Phase B: EtOH:DCM (1:1)—HPLC; Flow rate: 20 mL/min; Gradient: 15 B to 15 B in 18 min; 220/254 nm; RT1: 13.418 min; RT2: 15.766 min. This gave Compound 245 (front peak, 107.0 mg) as a white solid and Compound 244 (second peak, 112.0 mg) as a white solid.

Compound 245: (R or S)—N-(5,6-difluoro-1H-indol-3-yl)-4-(1-(3,3-difluoroazetidin-1-yl)-1l3-ethyl)-3-fluorobenzamide; LCMS Method F-1: [M+H]⁺=410. ¹H NMR (400 MHz, DMSO-d₆): δ 11.12 (s, 1H), 10.23 (s, 1H), 7.92-7.77 (m, 4H), 7.65-7.61 (m, 1H), 7.41-7.36 (m, 1H), 3.94-3.92 (m, 1H), 3.65-3.56 (m, 4H), 1.23 (d, J=6.6 Hz, 3H).

Compound 244: (R or S)—N-(5,6-difluoro-1H-indol-3-yl)-4-(1-(3,3-difluoroazetidin-1-yl)-1l3-ethyl)-3-fluorobenzamide; LCMS Method F-1: [M+H]⁺=410. ¹H NMR (400 MHz, DMSO-d₆): δ 11.11 (s, 1H), 10.23 (s, 1H), 7.92-7.77 (m, 4H), 7.65-7.61 (m, 1H), 7.41-7.36 (m, 1H), 3.94-3.92 (m, 1H), 3.65-3.56 (m, 4H), 1.23 (d, J=6.6 Hz, 3H).

Biological Assays

STING pathway activation by the compounds described herein was measured using THP1-Dual™ cells (KO-IFNAR2).

THP1-Dual™ KO-IFNAR2 Cells (obtained from invivogen) were maintained in RPMI, 10% FCS, 5 ml P/S, 2 mM L-glut, 10 mM Hepes, and 1 mM sodium pyruvate. Compounds were spotted in empty 384 well tissue culture plates (Greiner 781182) by Echo for a final concentration of 0.0017-100 μM. Cells were plated into the TC plates at 40 μL per well, 2×10E6 cells/mL. For activation with STING ligand, 2′3′cGAMP (MW 718.38, obtained from Invivogen), was prepared in Optimem media.

The following solutions were prepared for each 1×384 plate:

• • Solution A: 2 mL Optimem with one of the following stimuli:
    • 60 μL of 10 mM 2′3′cGAMP→150 μM stock
  • Solution B: 2 mL Optimem with 60 μL Lipofectamine 2000→Incubate 5 min at RT

2 mL of solution A and 2 ml Solution B was mixed and incubated for 20 min at room temperature (RT). 20 μL of transfection solution (A+B) was added on top of the plated cells, with a final 2′3′cGAMP concentration of 15 μM. The plates were then centrifuged immediately at 340 g for 1 minute, after which they were incubated at 37° C., 5% CO₂,>98% humidity for 24 h. Luciferase reporter activity was then measured. EC₅₀ values were calculated by using standard methods known in the art.

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

Luciferase reporter activity was then measured. EC₅₀ values were calculated by using standard methods known in the art.

Table BA shows the activity of compounds in STING reporter assay: <0.008 μM=“++++++”; ≥0.008 and ≤0.04 μM=“+++++”; ≥0.04 and <0.2 μM=“++++”; ≥0.2 and <1 μM=“+++”; ≥1 and <5 μM=“++”; ≥5 and <100 μM=“+”.

	TABLE BA
		hSTING		hSTING
	Compound #	EC50	Compound #	EC50
	101	+++	151	+++
	102	+++	152	+++
	103	+	153	+++
	104	++	154	+++
	105	+++	155	++++
	106	+++	156	+++
	107	+++	157	+++
	108	+++	158	++++
	109	+++	159	++++
	110	++++	160	++++
	111	++	161	++++
	112	+++	162	++++
	113	+++	163	++++
	114	+++	164	++
	115	+++	165	++++
	116	+++	166	+++
	117	+++	168	+++
	118	+++	169	+++
	119	+++	170	+++
	120	+++	171	+++
	121	++	172	+++
	122	+++	173	++
	123	++	174	+++
	124	+	175	+
	125	+++	176	+++
	126	+++	179	+++
	127	+++	180	+++
	128	+++	181	+++
	129	++	182	++++
	130	+++	183	++
	131	++	184	++
	132	+++	185	+++
	133	+++	186	++
	134	+++	187	+++
	135	+++	188	+++
	136	+++	189	+++
	137	+++	190	+++
	138	+++	191	+++
	139	+++	192	+++
	140	+++	193	++
	141	+++	194	+++
	142	+++	195	+++
	143	++	196	+++
	144	++	197	+++
	145	+++	198	+++
	146	++++	199	+++
	147	+++	250	++
	148	+++	251	++
	149	+++	252	++
	150	++++	253	++
	218	+++	254	+++
	219	++++	255	++
	220	++++	256	++
	221	++++	257	+
	222	+++	258	+++
	223	++++	259	+++
	224	++++	260	+++
	225	++++	261	+++
	226	+++	262	+++
	227	++++	263	+++
	228	++	264	+ +
	229	++++	265	+++
	230	++++	266	+++
	231	+++	267	+++
	232	+++	268	+++
	233	+++	269	++
	234	+++	270	+
	235	+	271	+++
	236	+++	272	+++
	237	+++	273	+
	238	+	274	+++
	239	+++	275	++
	240	+++	276	+++
	241	+	277	+
	242	+++	278	++
	243	+++	279	++
	244	+++	280	+++
	245	+++
	246	+++
	247	+++
	248	+
	249	+++
	209	+++
	201	+++
	213	+++
	216	+++
	200	+++
	204	+++
	203	+++
	208	+++
	207	++

Numbered Clauses

The compounds, compositions, methods, and other subject matter described herein are further described in the following numbered clauses:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

P¹, P², P³, P⁴, and P⁵ are each independently selected from the group consisting of: N, NH, NR^d, NR⁷, CH, CR^c, CR⁷, and C(═O), provided that 1-3, such as 1, of P², P³, and P⁴ is CR⁷ or NR⁷;

each occurrence of R⁷ is independently -(L^A)_a1-R⁸, wherein:

each L^A is independently selected from the group consisting of: C_1-3 alkylene optionally substituted with 1-4 R^a1; —O—; —NR^N; —S(O)_0-2; C(O); C(O)O; OC(O); NR^NC(O); C(O)NR^N; NR^NC(O)NR^N; NR^NC(O)O; and OC(O)NR^N;

a1 is 0, 1, 2, or 3; and

each occurrence of R⁸ is independently R^g or C_1-10 alkyl optionally substituted with 1-6 R^a1;

Z, Y¹, Y², and Y³ are independently selected from the group consisting of CR¹, C(═O), N, and NR²;

X¹ is selected from the group consisting of O, S, N, NR², and CR¹;

X² is selected from the group consisting of O, S, N, NR⁴, and CR⁵; provided that:

(1) 0-1 of Z, Y¹, Y², and Y³ is N or NR²;

(2) when each one of Z, Y¹, and Y² is CR¹, then Y³ cannot be N; and

(3) when each one of Z Y, Y², and Y³ is CR¹, then at least one R¹ is other than H;

each is independently a single bond or a double bond, provided that the five-membered ring comprising X¹ and X² is heteroaryl; the six-membered ring comprising Z, Y¹, Y², and Y³ is aryl or heteroaryl; and the six-membered ring comprising P¹, P², P³, P⁴, and P⁵ is aryl or heteroaryl;

each R¹ is independently selected from the group consisting of: H; R^c; R^g; and -(L¹)_b1-R^g,

each R² is independently selected from the group consisting of: H; R^d; R^g; and -(L²)_b2-R^g,

R⁴ is selected from the group consisting of: H and R^d;

R⁵ is selected from the group consisting of: H; R^c; and R^h;

R⁶ is selected from the group consisting of: H; R^d; and R^h;

each occurrence of R^a and R^a1 is independently selected from the group consisting of: —OH; -halo; —NR^eR^f; C_1-4 alkoxy; C_1-4 haloalkoxy; —C(═O)O(C_1-4 alkyl); —C(═O)(C_1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4 alkyl); and cyano;

each occurrence of R^c is independently selected from the group consisting of: halo; cyano; C_1-10 alkyl which is optionally substituted with 1-6 independently selected R^a; C_2-6 alkenyl; C_2-6 alkynyl; C_1-4 alkoxy optionally substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkoxy; —S(O)_1-2(C_1-4 alkyl); —S(O)(═NH)(C_1-4 alkyl); —NR^eR^f; —OH; —S(O)_1-2NR′R″; —C_1-4 thioalkoxy; —NO₂; —C(═O)(C_1-10 alkyl); —C(═O)O(C_1-4 alkyl); —C(═O)OH; —C(═O)NR′R″; and —SF₅;

each occurrence of R^d is independently selected from the group consisting of: C_1-6 alkyl optionally substituted with 1-3 independently selected R^a; —C(O)(C_1-4 alkyl); —C(O)O(C_1-4 alkyl); —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4 alkyl); —OH; and C_1-4 alkoxy;

each occurrence of R^e and R^f is independently selected from the group consisting of: H; C_1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, and Rⁱ; —C(O)(C_1-4 alkyl); —C(O)O(C_1-4 alkyl); —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4 alkyl); —OH; and C_1-4 alkoxy;

each occurrence of R^g is independently selected from the group consisting of:

• • C_3-12 cycloalkyl or C_3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_bg-R^h;
  • heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_bg-R^h;
  • heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R^c, R^h, and -(L^g)_bg-R^h and
  • C_6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R^c, R^h, and -(L^g)_bg-R^h;

each occurrence of R^h is independently selected from the group consisting of:

• • C_3-12 cycloalkyl or C_3-12 cycloalkenyl, each of which is optionally substituted with 1-4 Rⁱ;
  • heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 Rⁱ;
  • heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rⁱ; and
  • C_6-10 aryl optionally substituted with 1-4 Rⁱ;

each occurrence of R¹ is independently selected from the group consisting of: C_1-6 alkyl; C_1-4 haloalkyl; C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-6 alkyl-O—C_1-6 alkyl-; C_1-4 haloalkyl-O—C_1-6 alkyl-; halo; cyano; —OH; —NR′R″; and C_3-6 cycloalkyl;

each occurrence of L¹, L², and L^g is independently selected from the group consisting of: —O—, —NH—, —NR^d, —S(O)_0-2, C(O), and C_1-3 alkylene optionally substituted with 1-3 R^a;

b1, b2, and bg are each independently 1, 2, or 3;

each occurrence of R′ and R″ is independently selected from the group consisting of: H; —OH; and C_1-4 alkyl; and

each occurrence of R^N is independently H or R^d;

provided that the six-membered ring including P¹, P², P³, P⁴, and P⁵ is other than:

2. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

P¹, P², P³, P⁴, and P⁵ are each independently selected from the group consisting of: N, NH, NR^d, NR⁷, CH, CR^c, CR⁷, and C(═O), provided that 1-3, such as 1, of P², P³, and P⁴ is CR⁷ or NR⁷;

each occurrence of R⁷ is independently -(L^A)_a1-R⁸, wherein:

each L^A is independently selected from the group consisting of: C_1-3 alkylene optionally substituted with 1-2 R^a1; —O—; —NR^N; —S(O)_0-2; C(O); C(O)O; OC(O); NR^NC(O); C(O)NR^N; NR^NC(O)NR^N; NR^NC(O)O; and OC(O)NR^N; a1 is 0, 1, 2, or 3; and

each occurrence of R⁸ is independently R^g or C_1-10 alkyl optionally substituted with 1-6 R^a1;

X¹ is selected from the group consisting of O, S, N, NR², and CR¹;

X² is selected from the group consisting of O, S, N, NR⁴, and CR⁵;

each is independently a single bond or a double bond, provided that the five-membered ring comprising X¹ and X² is heteroaryl; and the six-membered ring comprising P¹, P², P³, P⁴, and P⁵ is aryl or heteroaryl;

R¹ is selected from the group consisting of: H; R^c; R^g; and -(L¹)_bi-R^g;

R² is selected from the group consisting of: H; R^d; R^g; and -(L²)_b2-R^g;

R⁴ is selected from the group consisting of: H and R^d,

R⁵ is selected from the group consisting of: H; R^c; and R^h;

R⁶ is selected from the group consisting of: H; R^d; and R^h;

each occurrence of R^a and R^a1 is independently selected from the group consisting of: —OH; -halo; —NR^eR^f; C_1-4 alkoxy; C_1-4 haloalkoxy; —C(═O)O(C_1-4 alkyl); —C(═O)(C_1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4 alkyl); and cyano;

each occurrence of R^c is independently selected from the group consisting of: halo; cyano; C_1-10 alkyl which is optionally substituted with 1-6 independently selected R^a; C_2-6 alkenyl; C_2-6 alkynyl; C_1-4 alkoxy optionally substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkoxy; —S(O)_1-2(C_1-4 alkyl); —S(O)(═NH)(C_1-4 alkyl); —NR^eR^f; —OH; —S(O)_1-2NR′R″; —C_1-4 thioalkoxy; —NO₂; —C(═O)(C_1-10 alkyl); —C(═O)O(C_1-4 alkyl); —C(═O)OH; —C(═O)NR′R″; and —SF₅;

each occurrence of R^d is independently selected from the group consisting of: C_1-6 alkyl optionally substituted with 1-3 independently selected R^a; —C(O)(C_1-4 alkyl); —C(O)O(C_1-4 alkyl); —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4 alkyl); —OH; and C_1-4 alkoxy;

each occurrence of R^e and R^f is independently selected from the group consisting of: H; C_1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, and Rⁱ; —C(O)(C_1-4 alkyl); —C(O)O(C_1-4 alkyl); —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4 alkyl); —OH; and C_1-4 alkoxy;

each occurrence of R^g is independently selected from the group consisting of:

• • C_3-12 cycloalkyl or C_3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_bg-R^h;
  • heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_bg-R^h;
  • heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R^c, R^h, and -(L^g)_bg-R^h and
  • C_6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R^c, R^h, and -(L^g)_bg-R^h;

each occurrence of R^h is independently selected from the group consisting of:

• • C_3-12 cycloalkyl or C_3-12 cycloalkenyl, each of which is optionally substituted with 1-4 Rⁱ;
  • heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 Rⁱ;
  • heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rⁱ; and
  • C_6-10 aryl optionally substituted with 1-4 Rⁱ;

each occurrence of R¹ is independently selected from the group consisting of: C_1-6 alkyl; C_1-4 haloalkyl; C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-6 alkyl-O—C_1-6 alkyl-; C_1-4 haloalkyl-O—C_1-6 alkyl-; halo; cyano; —OH; —NR′R″; and C_3-6 cycloalkyl;

each occurrence of L¹, L², and L⁹ is independently selected from the group consisting of: —O—, —NH—, —NR^d, —S(O)_0-2, C(O), and C_1-3 alkylene optionally substituted with 1-3 R^a;

b1, b2, and bg are each independently 1, 2, or 3;

each occurrence of R′ and R″ is independently selected from the group consisting of: H; —OH; and C_1-4 alkyl; and

each occurrence of R^N is independently H or R^d;

provided that the ring including P¹, P², P³, P⁴, and P⁵ is other than:

(iv) phenyl, pyridyl, or pyrimidinyl, each substituted with one substituent selected from the group consisting of: OMe; CH₂NH₂; CH₂NHC(O)OMe; CH₂NHC(O)OEt; CH₂NHC(O)Me; CH₂NHC(O)N(Me)₂; CH₂NHS(O)₂Me; methyl; tert-butyl; NHMe; morpholinyl; CH₂OH; 1,2,4-triazolyl; or trisubstituted pyrazolyl;

(v) pyrimidinyl substituted with two substituents each independently selected from the group consisting of: methyl, ethyl, and pyrrolidinyl; and

3. A compound of Formula (III)

or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

P¹, P², P³, P⁴, and P⁵ are each independently selected from the group consisting of: N, NH, NR^d, NR⁷, CH, CR^c, CR⁷, and C(═O), provided that 1-3, such as 1, of P², P³, and P⁴ is CR⁷ or NR⁷;

each occurrence of R⁷ is independently -(L^A)_a1-R⁸, wherein:

each L^A is independently selected from the group consisting of: C_1-3 alkylene optionally substituted with 1-2 R^a1; —O—; —NR^N; —S(O)_0-2; C(O); C(O)O; OC(O); NR^NC(O); C(O)NR^N; NR^NC(O)NR^N; NR^NC(O)O; and OC(O)NR^N;

a1 is 0, 1, 2, or 3; and

each occurrence of R⁸ is independently R^g or C_1-10 alkyl optionally substituted with 1-6 R^a1;

X¹ is selected from the group consisting of O, S, N, NR², and CR¹;

X² is selected from the group consisting of O, S, N, NR⁴, and CR⁵; provided that:

each is independently a single bond or a double bond, provided that the five-membered ring comprising X¹ and X² is heteroaryl; and the six-membered ring comprising P¹, P², P³, P⁴, and P⁵ is aryl or heteroaryl;

R¹, R^1a, R^1b, and R^1c are each independently selected from the group consisting of: H; R^c; R^g; and -(L¹)_b1-R^g;

each R² is independently selected from the group consisting of: H; R^d; R^g; and -(L²)_b2-R^g,

R⁴ is selected from the group consisting of: H and R^d;

R⁵ is selected from the group consisting of: H; R^c; and R^h;

R⁶ is selected from the group consisting of: H; R^d; and R^h;

each occurrence of R^a and R^a1 is independently selected from the group consisting of: —OH; -halo; —NR^eR^f; C_1-4 alkoxy; C_1-4 haloalkoxy; —C(═O)O(C_1-4 alkyl); —C(═O)(C_1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4 alkyl); and cyano;

each occurrence of R^c is independently selected from the group consisting of: halo; cyano; C_1-10 alkyl which is optionally substituted with 1-6 independently selected R^a; C_2-6 alkenyl; C_2-6 alkynyl; C_1-4 alkoxy optionally substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkoxy; —S(O)_1-2(C_1-4 alkyl); —S(O)(═NH)(C_1-4 alkyl); —NR^eR^f; —OH; —S(O)_1-2NR′R″; —Cl-4 thioalkoxy; —NO₂; —C(═O)(C_1-10 alkyl); —C(═O)O(C_1-4 alkyl); —C(═O)OH; —C(═O)NR′R″; and —SF₅;

each occurrence of R^d is independently selected from the group consisting of: C_1-6 alkyl optionally substituted with 1-3 independently selected R^a; —C(O)(C_1-4 alkyl); —C(O)O(C_1-4 alkyl); —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4 alkyl); —OH; and C_1-4 alkoxy;

each occurrence of R^e and R is independently selected from the group consisting of: H; C_1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, and Rⁱ; —C(O)(C_1-4 alkyl); —C(O)O(C_1-4 alkyl); —CONR′R″; —S(O)_1-2NR′R″; —S(O)_1-2(C_1-4 alkyl); —OH; and C_1-4 alkoxy;

each occurrence of R^g is independently selected from the group consisting of:

• • C_3-12 cycloalkyl or C_3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_bg-R^h;
  • heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_bg-R^h;
  • heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R^c, R^h, and -(L^g)_bg-R^h; and
  • C_6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R^c, R^h, and -(L^g)_bg-R^h;

each occurrence of R^h is independently selected from the group consisting of:

• • C_3-12 cycloalkyl or C_3-12 cycloalkenyl, each of which is optionally substituted with 1-4 Rⁱ;
  • heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 Rⁱ;
  • heteroaryl of 5-12 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rⁱ; and
  • C_6-10 aryl optionally substituted with 1-4 Rⁱ;

each occurrence of Rⁱ is independently selected from the group consisting of: C_1-6 alkyl; C_1-4 haloalkyl; C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-6 alkyl-O—C_1-6 alkyl-; C_1-4 haloalkyl-O—C_1-6 alkyl-; halo; cyano; —OH; —NR′R″; and C_3-6 cycloalkyl;

each occurrence of L¹, L², and L⁹ is independently selected from the group consisting of: —O—, —NH—, —NR^d, —S(O)_0-2, C(O), and C_1-3 alkylene optionally substituted with 1-3 R^a;

b1, b2, and bg are each independently 1, 2, or 3;

each occurrence of R′ and R″ is independently selected from the group consisting of: H; —OH; and C_1-4 alkyl; and each occurrence of R^N is independently H or R^d;

provided that the ring including P¹, P², P³, P⁴, and P⁵ is other than:

(v) phenyl, pyridyl, pyridonyl, or pyridazinonyl substituted with one substituent selected from the group consisting of: OMe; methyl; trifluoromethyl; NHC(O)Me; NMe₂; CH₂CH₂-pyrrolindinyl; or

(vi) 3-fluoro-4-methoxyphenyl; 2-fluoro-5-methylphenyl; or dimethoxypyridyl; and

R^1a is other than monocyclic heterocyclyl of 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_bg-R^h.

4. The compound of clause 1, wherein each of Z, Y¹, Y², and Y³ is independently N or CR¹.

5. The compound of clauses 1 or 4, wherein the compound is a compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein: R^1a, R^1b, R^1c, and R^1d are each an independently selected R¹.

6. The compound of clauses 1 or 4, wherein one of Z, Y¹, and Y² is N; and each remaining of Z, Y¹, Y², and Y³ is an independently selected CR¹.

7. The compound of any one of clauses 1, 4, or 6, wherein the compound is selected from the group consisting of a compound of the following formulae:

or a pharmaceutically acceptable salt thereof, wherein. R^1a, R^1b, R^1c, and R^1d are each an independently selected R¹.

8. The compound of any one of clauses 1-7, wherein X¹ is NR².

9. The compound of any one of clauses 1-8, wherein X¹ is NH.

10. The compound of any one of clauses 1-9, wherein X² is CR⁵.

11. The compound of any one of clauses 1-10, wherein X² is CH.

12. The compound of any one of clauses 1-7, wherein X¹ is NR²; and X² is CR.

13. The compound of any one of clauses 1-7 or 12, wherein X¹ is NH; and X² is CH.

14. The compound of clause 1, wherein the compound is a compound of Formula (Ia-1):

or a pharmaceutically acceptable salt thereof, wherein: R^1a, R^1b, R^1c, and R^1d are each an independently selected Rⁱ.

15. The compound of clause 1, wherein the compound is selected from the group consisting of a compound of the following formulae:

or a pharmaceutically acceptable salt thereof, wherein R^1a, R^1b, R^1c, and R^1d are each an independently selected R¹.

16. The compound of clause 2, wherein the compound is a compound of Formula (II-1):

or a pharmaceutically acceptable salt thereof.

17. The compound of clause 3, wherein the compound of a compound of Formula (III-1):

or a pharmaceutically acceptable salt thereof.

18. The compound of any one of clauses 14-17, wherein R² is H.

19. The compound of any one of clauses 14-18, wherein R⁵ is H.

20. The compound of any one of clauses 1 or 4-15, wherein from 1-2 R¹ is independently selected from the group consisting of: R^c1 and R^g1; and each remaining R¹ is H, wherein R^c1 is an independently selected R^c; and R^g1 is an independently selected R^g.

21. The compound of clause 20, wherein two occurrences of R¹ are independently selected from the group consisting of: R^c1 and R^g1; and each remaining Rⁱ is H.

22. The compound of clauses 20 or 21, wherein two occurrences of R¹ are independently selected R^c1; and each remaining R¹ is H.

23. The compound of clause 20, wherein one occurrence of R¹ is selected from the group consisting of: R^c1 and R^g1; and each remaining R¹ is H.

24. The compound of clauses 20 or 23, wherein one occurrence of R¹ is R¹; and each remaining R¹ is H.

25. The compound of clauses 20 or 23, wherein one occurrence of R¹ is R^g1; and each remaining R¹ is H.

26. The compound of clause 20, wherein one occurrence of R¹ is R¹; one occurrence of R¹ is R^g1; and each remaining R¹ is H.

27. The compound of any one of clauses 20-26, wherein each R^c1 is an independently selected halo, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkoxy, or C_1-3 alkyl substituted with from 1-6 independently selected halo, such as wherein R^c1 is —F, —Cl, or —CN.

28. The compound of clause 27, wherein each R^c1 is independently —F or —Cl, such as —F.

29. The compound of any one of clauses 20-28, wherein each R^g1 is independently selected from the group consisting of:

• • heteroaryl of 5-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of R^c, R^h, and -(L^g)_bg-R^h; and
  • C_6-10 aryl optionally substituted with from 1-4 substituents independently selected from the group consisting of R^c, R^h, and -(L^A)_bg-R^h.

30. The compound of clause 29, wherein each R^g1 is independently selected from the group consisting of:

• • heteroaryl of 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is optionally substituted with from 1-4 R^c; and
  • C₆ aryl optionally substituted with from 1-4 R^c

31. The compound of clauses 29 or 30, wherein each R^g1 is independently heteroaryl of 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is optionally substituted with from 1-4 R^c.

32. The compound of clause 31, wherein each R^g1 is pyrazolyl that is optionally substituted with from 1-2 R^c, such from 1-2 independently selected C_1-6 (e.g., C_1-3) alkyl which is optionally substituted with from 1-6 independently selected R^a (e.g., unsubstituted C_1-6 (e.g., C_1-3) alkyl).

33. The compound of clause 32, wherein R^g1 is

and optionally R^c is C_1-6 (e.g., C_1-3) alkyl which is optionally substituted with from 1-6 independently selected R^a.

34. The compound of clause 29, wherein each R^g1 is independently selected from the group consisting of:

• • heteroaryl of 5-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is substituted with one occurrence of R^h1 or -(L^g)_bg-R^h1 (such as R^h1 or —CH₂—R^h1) and further optionally substituted with from 1-2 R^c; and
  • C_6-10 aryl that is substituted with one occurrence of R^h1 or -(L^g)_bg-R^h1 (such as R^h1 or —CH₂—R^h1) and further optionally substituted with from 1-2 R^c, wherein R^h1 is an independently selected R^h.

35. The compound of clause 34, wherein each R^g1 is heteroaryl of 5-6 (such as 5) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is substituted with one occurrence of R^h1 or -(L^g)_bg-R^h1 (such as R^h1 or —CH₂—R^h1) and further optionally substituted with from 1-2 R^c, wherein R^h1 is an independently selected R^h.

36. The compound of clause 35, wherein each R^g1 is pyrazolyl that is substituted with R^h1 or -(L^A)_bg-R^h1 (such as R^h1 or —CH₂R^h1) and further optionally substituted with from 1-2 R^c.

37. The compound of clause 36, wherein each R^g1 is

each of which is optionally substituted with R^c.

38. The compound of any one of clauses 34-37, wherein R^h1 is selected from the group consisting of:

• • heteroaryl of 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rⁱ; and
  • C₆ aryl optionally substituted with from 1-4 Rⁱ, such as: wherein R^g1 is phenyl optionally substituted with from 1-4 Rⁱ.

39. The compound of clause 38, wherein R^h1 is selected from the group consisting of:

• • heteroaryl of 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, 20 each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-2 Rⁱ; and
  • C₆ aryl optionally substituted with from 1-2 Rⁱ, such as wherein R^g1 is phenyl optionally substituted with from 1-4 Rⁱ.

40. The compound of any one of clauses 3, 5, 7, 14-15, or 17, wherein R″ H.

41. The compound of any one of clauses 3, 5, 7, 14-15, 17, or 40, wherein R^1b is H.

42. The compound of any one of clauses 3, 5, 7, 14-15, 17, or 40, wherein R^1b is halo, such as —F or —Cl (e.g., —F).

43. The compound of any one of clauses 3, 5, 7, 14-15, 17, or 40, wherein R^1b is heteroaryl of 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is optionally substituted with from 1-2 R^c.

44. The compound of clause 43, wherein R^1b is pyrazolyl that is optionally substituted with from 1-2 R^c, such as each R^c is an independently selected C_1-6 (e.g., C_1-3) alkyl which is optionally substituted with from 1-6 independently selected R^a (e.g., unsubstituted).

45. The compound of any one of clauses 3, 5, 7, 14-15, 17, or 40, wherein R^1b is heteroaryl of 5-6 (such as 5) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is substituted with one occurrence of R^h1 or -(L^g)_bg-R^h1 (such as R^h1 or —CH₂—R^h1) and further optionally substituted with from 1-2 R^c, wherein R^h1 is an independently selected R^h.

46. The compound of clause 45, wherein R^1b is pyrazolyl that is substituted with R^h1 or -(L^g)_bg-R^h1 (such as R^h1 or —CH₂R^h1) and further optionally substituted with from 1-2 R^c, such as wherein R^1b is

each of which is optionally substituted with R^c.

47. The compound of any one of clauses 3, 5, 7, 14-15, 17, or 40-46, wherein R^1c is H.

48. The compound of any one of clauses 3, 5, 7, 14-15, 17, or 40-46, wherein R^1c is halo, such as —F or —Cl.

49. The compound of any one of clauses 3, 5, 7, 14-15, 17, or 40-48, wherein R^1d is H.

50. The compound of any one of clauses 3, 5, 7, 14-15, 17, or 40-49, wherein R^1d is halo, such as —F or —Cl (e.g., —F).

51. The compound of any one of clauses 3, 5, 7, 14-15, or 17, wherein R^1a and R^1d are H; and R^1b and R^1c are independently selected halo, such as —F or —Cl, such as —F; such as: wherein R^1b and R^1c are —F; or wherein R^1b is —F, and R^1c is —Cl; or wherein R^1b is —Cl, and R^1c is —F.

52. The compound of any one of clauses 3, 5, 7, 14-15, or 17, wherein R^1a and R^1d are H; one of R^1b and R^1c is H; and the other one of R^1b and R^1c is halo, such as —F or —Cl, such as —F; such as: wherein R^1b is H, and R^1c is —F; or wherein R^1b is H, and R^1c is —Cl; or wherein R^1b is —F, and R^1c is H; or wherein R^1b is —Cl, and R^1c is H.

53. The compound of any one of clauses 3, 5, 7, 14-15, or 17, wherein R^1a and R^1d are H; R^1c is halo or H, such as —F, —Cl, or H; and R^1b is heteroaryl of 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is optionally substituted with from 1-4 R^c.

54. The compound of any one of clauses 3, 5, 7, 14-15, or 17, wherein R^1a and R^1d are H; R^1c is halo or H, such as —F, —Cl, or H; and R^1b is heteroaryl of 5-6 (such as 5) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is substituted with one occurrence of R^h1 or -(L^g)_bg-R^h1 (such as R^h1 or —CH₂—R^h1) and further optionally substituted with from 1-2 R^c, wherein R^h1 is an independently selected R^h.

55. The compound of any one of clauses 1-54, wherein R⁶ is H.

56. The compound of any one of clauses 1-55, wherein P¹ and P⁵ are independently CH or CR^c; and P², P³, and P⁴ are independently CH, CR^c, or CR⁷.

57. The compound of any one of clauses 1-55, wherein one of P¹, P², P³, P⁴, and P⁵ is N.

58. The compound of any one of clauses 1-55, wherein two of P¹, P², P³, P⁴, and P⁵ are N.

59. The compound of any one of clauses 1-58, wherein one of P², P³, and P⁴ is CR⁷.

60. The compound of any one of clauses 1-59, wherein P³ is CR⁷.

61. The compound of clause 60, wherein P⁴ is N.

62. The compound of clause 60, wherein P⁴ is CH or CR^c.

63. The compound of any one of clauses 60-62, wherein P¹ is N.

64. The compound of any one of clauses 60-62, wherein P¹ is CH or CR^c.

65. The compound of any one of clauses 60-64, wherein P² and P⁵ are independently CH or CR^c.

66. The compound of any one of clauses 1-55, wherein P³ is CR⁷; P¹, P², P⁴, and P⁵ are independently CH or CR^c.

67. The compound ofany one of clauses 1-55 or 66, wherein the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

68. The compound of any one of clauses 1-55, wherein P³ is CR⁷; P⁴ is N; and P¹, P², and P⁵ are independently CH or CR^c.

69. The compound of clause 68, wherein the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

70. The compound of any one of clauses 1-55, wherein P³ is CR⁷; P⁴ and P¹ are N; and P² and P⁵ are independently CH or CR^c.

71. The compound of clause 70, wherein the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

72. The compound of any one of clauses 1-59, wherein P⁴ is CR⁷.

73. The compound of clause 72, wherein P³ is N.

74. The compound of clause 72, wherein P³ is CH or CR^c.

75. The compound of any one of clauses 72-74, wherein P¹, P², and P⁵ are independently CH or CR^c.

76. The compound of any one of clauses 1-55, wherein P⁴ is CR⁷; P³ is CH or CR^c; and P¹, P², and P⁵ are independently CH or CR^c.

77. The compound of clause 76, wherein the P¹: moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

78. The compound of any one of clauses 1-55, wherein P⁴ is CR⁷; P³ is N; and P¹, P², and P⁵ are independently CH or CR^c.

79. The compound of clause 78, wherein the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

80. The compound of any one of clauses 1-55, wherein the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c.

81. The compound of any one of clauses 67-80, wherein each occurrence of R⁷ is independently selected from the group consisting of halo; cyano; C_1-3 alkyl; C_1-4 alkoxy; C_1-4 haloalkoxy; and C_1-3 alkyl substituted with from 1-6 independently selected halo, such as —F.

82. The compound of any one of clauses 1-81, wherein a1 is 0.

83. The compound of any one of clauses 1-81, wherein a1 is 1.

84. The compound of any one of clauses 1-81 or 83, wherein L^A is —O—, —NH— or —CH₂—, such as wherein L^A is —O—.

85. The compound of any one of clauses 1-81, wherein a1 is 2; and -(L^A)_a1- is -L^A1-L^A2, wherein L^A1 and L^A2 are independently selected L^A; and L^A2 is the point of attachment to R⁸.

86. The compound of clause 85, wherein L^A1 is —O—; and L^A2 is C_1-3 alkylene optionally substituted with from 1-2 R^a1, such as wherein L^A1 is —O—; and L^A2 is CH₂.

87. The compound of any one of clauses 1-81, wherein a1 is 3; and -(L^A)_a1- is -L^A1-L^A2-L^A3, wherein L^A1, L^A2, and L^A3 are independently selected L^A; and L^A3 is the point of attachment to R⁸.

88. The compound of clause 87, wherein L^A1 and L^A3 are each independently C_1-3 alkylene optionally substituted with from 1-2 R^a1;

89. The compound of clauses 87 or 88, wherein L^A2 is NR^NC(O)O or OC(O)NR^N.

90. The compound of any one of clauses 1-89, wherein R⁸ is C_1-10 alkyl optionally substituted with 1-4 R^a1;

91. The compound of any one of clauses 1-90, wherein R⁸ is C_1-10 alkyl, such as C_1-7 alkyl, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl, such as ethyl or isopropyl.

92. The compound of any one of clauses 1-89, wherein R⁸ is C_1-10 alkyl substituted with 1-6 R^a1, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6 R^a1.

93. The compound of clause 92, wherein each R^a1 is selected from the group consisting of: halo, such as —F; —OH; C_1-4 alkoxy; and C_1-4 haloalkoxy.

94. The compound of any one of clauses 1-90 or 92, wherein R⁸ is C_1-10 alkyl substituted with 1-6 independently selected halo, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6 independently selected halo.

95. The compound of clause 94, wherein R⁸ is C_1-10 alkyl substituted with 1-6-F, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6-F, such as

96. The compound of any one of clauses 1-90 or 92-93, wherein R⁸ is C_1-10 alkyl substituted with —OH, C_1-4 alkoxy, or C_1-4 haloalkoxy, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6 independently selected C_1-4 alkoxy, such as

97. The compound of any one of clauses 1-89, wherein R⁸ is R^g.

98. The compound of any one of clauses 1-89 or 97, wherein R⁸ is selected from the group consisting of:

• • C_3-8 cycloalkyl or C_3-8 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_bg-R^h; and
  • heterocyclyl or heterocycloalkenyl of 4-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R^c, R^h, and -(L^g)_hg-R^h.

99. The compound of any one of clauses 1-89 or 97-98, wherein R⁸ is selected from the group consisting of.

• • C_3-8 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and
  • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

100. The compound of any one of clauses 1-89 or 97-99, wherein R⁸ is selected from the group consisting of.

• • C_3-8 cycloalkyl substituted with from 1-2 (such as 2) independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c; and
  • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is substituted with from 1-2 (such as 2) independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c.

101. The compound of any one of clauses 1-89 or 97-100, wherein R⁸ is selected from the group consisting of piperidinyl, pyrrolidinyl, azetidinyl, azaspiro[3.3]heptanyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is substituted with 2-F and further optionally substituted with from 1-2 R^c, such as

102. The compound of any one of clauses 1-89 or 98-99, wherein R⁸ is selected from the group consisting of:

• • C_3-8 cycloalkyl such as cyclopropyl, cyclohexyl, cyclobutyl, or cyclopentyl;
  • C_3-8 cycloalkyl substituted with a substituent selected from the group consisting of: C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-4 alkoxy substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkyl; and C_1-6 alkyl substituted from 1-6 independently selected halo, C_1-4 alkoxy, or C_1-4 haloalkoxy, wherein the cycloalkyl is further optionally substituted with from 1-2 R^c;
  • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, such as:

and

• • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is substituted with a substituent selected from the group consisting of: C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-4 alkoxy substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkyl; and C_1-6 alkyl substituted from 1-6 independently selected halo, C_1-4 alkoxy, or C_1-4 haloalkoxy, wherein the heterocyclyl is further optionally substituted with from 1-2 R^c, such as

103. The compound of any one of clauses 1-89, wherein R⁸ is selected from the group consisting of:

• • heteroaryl of 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c; and
  • C_6-10 aryl, such as phenyl, optionally substituted with from 1-4 R^c.

104. The compound of any one of clauses 1-81, wherein a1 is 0; and R⁸ is selected from the group consisting of:

• • C_3-8 cycloalkyl substituted with from 1-2 (such as 2) independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c; and
  • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is substituted with from 1-2 (such as 2) independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c.

105. The compound of clause 104, wherein R⁸ is selected from the group consisting of piperidinyl, pyrrolidinyl, azetidinyl, azaspiro[3.3]heptanyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is substituted with 2-F and further optionally substituted with from 1-2 R^c, such as

106. The compound of any one of clauses 1-81, wherein a1 is 0; and R⁸ is C_1-10 alkyl substituted with 1-6 independently selected halo, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6 independently selected halo.

107. The compound of clause 106, wherein R⁸ is C_1-10 alkyl substituted with 1-6-F, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6-F, such as

108. The compound of any one of clauses 1-81, wherein a1 is 1; L^A is —O— or —NH—; and R⁸ is C_1-10 alkyl substituted with 1-6 independently selected halo, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6 independently selected halo.

109. The compound of clause 108, wherein R⁸ is C_1-10 alkyl substituted with 1-6-F, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6-F, such as

110. The compound of clauses 108 or 109, wherein L^A is —O—.

111. The compound of any one of clauses 1-80, wherein a1 is 1; L^A is —O—, —NH— or —CH₂—; and R⁸ is selected from the group consisting of:

• • C_3-8 cycloalkyl substituted with from 1-2 (such as 2) independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c; and
  • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), 0, and S(O)_0-2, and wherein the heterocyclyl is substituted with from 1-2 (such as 2) independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c.

112. The compound of clause 111, wherein R⁸ is C_3-8 cycloalkyl substituted with from 1-2 (such as 2) independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c, such as cyclobutyl, cyclopentyl, and cyclohexyl, each of which is substituted with 2-F and further optionally substituted with from 1-2 R^c, such as

113. The compound of clauses 111-112, wherein L^A is —O—.

114. The compound of clause 1, wherein the compound is a compound of Formula (Ia-1-1):

• • or a pharmaceutically acceptable salt thereof.

115. The compound of clause 114, wherein the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

116. The compound of clause 114, wherein the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

117. The compound of clause 114, wherein the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

118. The compound of clause 1, wherein the compound is a compound of Formula (Ia-1-2):

or a pharmaceutically acceptable salt thereof.

119. The compound of clause 118, wherein the

moiety has formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

120. The compound of clause 118, wherein the

moiety has the formula:

wherein n7 is 0, 1, or 2; and each R^c7 is an independently selected R^c, such as:

121. The compound of any one of clauses 114-120, wherein R^1a and R^1d are H; and R^1b and R^1c are independently selected halo, such as —F or —Cl, such as —F; such as: wherein R^1b and R^1c are —F; or wherein R^1b is —F, and R^1c is —Cl; or wherein R^1b is —Cl, and R¹ is —F.

122. The compound of any one of clauses 114-120, wherein R^1a and R^1d are H; one of R^1b and R^1c is H; and the other one of R^1b and R^1c is halo, such as —F or —Cl, such as —F; such as: wherein R^1b is H, and R^1c is —F; or wherein R^1b is H, and R^1c is —Cl; or wherein R^1b is —F, and R^1c is H; or wherein R^1b is —Cl, and R^1c is H.

123. The compound of any one of clauses 114-120, wherein R^1a and R^1d are H; R^1c is halo or H, such as —F, —Cl, or H; and R^1b is selected from the group consisting of:

heteroaryl of 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is optionally substituted with from 1-4 R^c; and

heteroaryl of 5-6 (such as 5) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is substituted with one occurrence of R^h1 or -(L^g)b-R^h1 and further optionally substituted with from 1-2 R^c, wherein R^h1 is an independently selected R^h.

124. The compound of any one of clauses 114-123, wherein R² is H; R⁵ is H; and R⁶ is H.

125. The compound of any one of clauses 114-124, wherein R⁷ is —R⁸; and R⁸ is selected from the group consisting of:

• • C_3-8 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and
  • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

126. The compound of any one of clauses 114-125, wherein R⁷ is —R⁸; and R⁸ is selected from the group consisting of:

• • C_3-8 cycloalkyl substituted with from 1-2 independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c; and
  • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is substituted with from 1-2 independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c, such as:

wherein R⁸ is selected from the group consisting of piperidinyl, pyrrolidinyl, azetidinyl, azaspiro[3.3]heptanyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is substituted with 2-F and further optionally substituted with from 1-2 R^c, such as

127. The compound of any one of clauses 114-125, wherein R⁷ is —R⁸; and R⁸ is selected from the group consisting of:

• • C_3-8 cycloalkyl such as cyclopropyl, cyclohexyl, cyclobutyl, or cyclopentyl;
  • C_3-8 cycloalkyl substituted with a substituent selected from the group consisting of: C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-4 alkoxy substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkyl; and C_1-6 alkyl substituted from 1-6 independently selected halo, C_1-4 alkoxy, or C_1-4 haloalkoxy, wherein the cycloalkyl is further optionally substituted with from 1-2 R^c;
  • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, such as:

and

• • heterocyclyl of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is substituted with a substituent selected from the group consisting of: C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-4 alkoxy substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkyl; and C_1-6 alkyl substituted from 1-6 independently selected halo, C_1-4 alkoxy, or C_1-4 haloalkoxy, wherein the heterocyclyl is further optionally substituted with from 1-2 R^c, such as

128. The compound of any one of clauses 114-125, wherein R⁷ is —R⁸; and R⁸ is selected from the group consisting of C_1-10 alkyl substituted with 1-6 R^a1 (such as from 1-6 independently selected halo), such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6 R^a1 (such as from 1-6 independently selected halo), such as C_1-10 alkyl substituted with 1-6-F, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6-F, such as

129. The compound of any one of clauses 114-125, wherein R⁷ is —OR⁸; and R⁸ is selected from the group consisting of C_1-10 alkyl substituted with 1-6 R^a1 (such as from 1-6 independently selected halo), such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6 R^a1 (such as from 1-6 independently selected halo), such as C_1-10 alkyl substituted with 1-6-F, such as C₁, C₂, C₃, C₄, C₅, C₆, or C₇ alkyl substituted with from 1-6-F, such as

130. The compound of any one of clauses 114-125, wherein R⁷ is —OR⁸; and R⁸ is C_3-8 cycloalkyl substituted with from 1-2 (such as 2) independently selected halo (such as —F) and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c, such as cyclobutyl, cyclopentyl, and cyclohexyl, each of which is substituted with 2-F and further optionally substituted with from 1-2 R^c, such as

131. The compound of any one of clauses 114-130, wherein each occurrence of R^c7 is independently selected from the group consisting of halo; cyano; C_1-3 alkyl; C_1-4 alkoxy; C_1-4 haloalkoxy; and C_1-3 alkyl substituted with from 1-6 independently selected halo.

132. The compound of clause 131, wherein each occurrence of R^c7 is independently selected from the group consisting of halo, such as —F and —Cl; cyano; C_1-3 alkyl, such as methyl; C_1-4 alkoxy, such as methoxy; C_1-4 haloalkoxy such as —OCF₃; and C_1-3 alkyl substituted with from 1-6-F, such as —CF₃.

133. The compound of clause 1, wherein the compound is selected from the group consisting of the compounds delineated in Table C1, and a pharmaceutically acceptable salt thereof.

134. A pharmaceutical composition comprising a compound of clauses 1-133 and one or more pharmaceutically acceptable excipients.

135. 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 1-133; or a pharmaceutical composition as defined in clause 134.

136. The method of clause 135, wherein the inhibiting comprises antagonizing STING.

137. The method of any one of clauses 135-136, which is carried out in vitro.

138. The method of clause 137, wherein the method comprises contacting a sample comprising one or more cells comprising STING with the compound.

139. The method of clause 137 or 138, wherein the one or more cells are one or more cancer cells.

140. The method of clause 138 or 139 wherein the sample further comprises one or more cancer cells, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma.

141. The method of clause 135 or 136, which is carried out in vivo.

142. The method of clause 141, 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.

143. The method of clause 142, wherein the subject is a human.

144. The method of clause 143, wherein the disease is cancer.

145. The method of clause 144, 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.

146. The method of clause 144 or 145, wherein the cancer is a refractory cancer.

147. The method of clause 142, wherein the compound is administered in combination with one or more additional cancer therapies.

148. The method of clause 147, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

149. The method of clause 148, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.

150. The method of clause 149, wherein the one or more additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g., azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti-helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48 CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

151. The method of any one of clauses 142-150, wherein the compound is administered intratumorally.

152. A method of treating cancer, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of clauses 1-133, or a pharmaceutical composition as defined in clause 134.

153. The method of clause 152, 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.

154. The method of clause 152 or 153, wherein the cancer is a refractory cancer.

155. The method of clause 152, wherein the compound is administered in combination with one or more additional cancer therapies.

156. The method of clause 155, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

157. The method of clause 156, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.

158. The method of clause 157, wherein the one or more additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g., azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti-helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

159. The method of any one of clauses 152-158, wherein the compound is administered intratumorally.

160. 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 1-133, or a pharmaceutical composition as defined in clause 134.

161. The method of clause 160, wherein the subject has cancer.

162. The method of clause 161, wherein the subject has undergone and/or is undergoing and/or will undergo one or more cancer therapies.

163. The method of clause 161, 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.

164. The method of clause any one of clauses 161-163, wherein the cancer is a refractory cancer.

165. The method of clause 160, wherein the immune response is an innate immune response.

166. The method of clause 165, wherein the at least one or more cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

167. The method of clause 166, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.

168. The method of clause 167, wherein the one or more additional chemotherapeutic agents is selected from alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g., azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti-helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM -LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

169. 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 1-133, or a pharmaceutical composition as defined in clause 134.

170. 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 1-133, or a pharmaceutical composition as defined in clause 134.

171. A method of treatment comprising administering to a subject a compound as defined in any one of clauses 1-133, or a pharmaceutical composition as defined in clause 134, 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.

172. The method of any one of clauses 169-171, wherein the disease is cancer.

173. The method of clause 172, 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.

174. The method of clause 172 or 173, wherein the cancer is a refractory cancer.

175. The method of any one of clauses 172-174, wherein the compound is administered in combination with one or more additional cancer therapies.

176. The method of clause 175, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

177. The method of clause 176, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.

178. The method of clause 177, wherein the one or more additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g., azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti-helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM -LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

179. The method of any one of clauses 169-178, wherein the compound is administered intratumorally.

180. 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 1-133, or a pharmaceutical composition as defined in clause 134.

181. The method of clause 180, wherein the disease, disorder, or condition is selected from type I interferonopathies, Aicardi-Goutières Syndrome (AGS), genetic forms of lupus, inflammation-associated disorders, and rheumatoid arthritis.

182. The method of clause 181, wherein the disease, disorder, or condition is a type I interferonopathy (e.g., STING-associated vasculopathy with onset in infancy (SAVI)).

183. The method of clause 182, wherein the type I interferonopathy is STING-associated vasculopathy with onset in infancy (SAVI)).

184. The method of clause 181, wherein the disease, disorder, or condition is Aicardi-Goutières Syndrome (AGS).

185. The method of clause 181, wherein the disease, disorder, or condition is a genetic form of lupus.

186. The method of clause 181, wherein the disease, disorder, or condition is inflammation-associated disorder.

187. The method of clause 186, wherein the inflammation-associated disorder is systemic lupus erythematosus.

188. The method of any one of clauses 135-187, wherein the method further comprises identifying the subject.

189. A combination comprising a compounds defined in any one of clauses 1 to 133 or a pharmaceutically acceptable salt or tautomer thereof, and one or more therapeutically active agents.

190. A compound defined in any one of clauses 1 to 133 or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 134, for use as a medicament.

191. A compound defined in any one of clauses 1 to 133 or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 134, for use in the treatment of a disease, condition or disorder modulated by STING inhibition.

192. A compound defined in any one of clauses 1 to 133 or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition defined in clause 134, for use in the treatment of a disease mentioned in any one of clauses 135 to 188.

193. Use of a compound defined in any one of clauses 1 to 133 or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 134, in the manufacture of a medicament for the treatment of a disease mentioned in in any one of clauses 135 to 188.

Claims

1. A compound of Formula (I):

2. A compound of Formula (II):

3. A compound of Formula (III)

4. The compound of claim 1, wherein the compound is a compound of Formula (Ia):

5. The compound of claim 1, wherein one of Z, Y1, and Y2 is N; and each remaining of Z, Y1, Y2, and Y3 is an independently selected CR1.

6. The compound of any one of claims 1-5, wherein X1 is NR2; and X2 is CR5, optionally wherein X1 is NH; and X2 is CH.

7. The compound of any one of claims 1-6, wherein 1-2 R1 is independently selected from the group consisting of: Rc1 and Rg1; and each remaining R1 is H, wherein Rc1 is an independently selected Rc; and Rg1 is an independently selected Rg.

8. The compound of claim 7, wherein each R1 is independently selected from the group consisting of: halo, cyano, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkoxy, and C1-3 alkyl substituted with 1-6 independently selected halo, such as wherein each Rc1 is independently —F, —Cl, or —CN, such as wherein each R1 is independently —F or —Cl, such as —F; and each Rg1 is independently heteroaryl of 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 Rc.

9. The compound of claim 4, wherein R1a and R1d are H; and R1b and R1c are independently selected halo, such as —F or —Cl, such as —F; such as: wherein R1b and R1c are —F; or wherein R1b is —F, and R1c is —Cl; or wherein R1b is —Cl, and R1c is —F; or wherein R1a and R1d are H; one of R1b and R1c is H; and the other one of R1b and R1c is halo, such as —F or —Cl, such as —F; such as: wherein R1b is H, and R1c is —F; or wherein R1b is H, and R1c is —Cl; or wherein R1b is —F, and R1c is H; or wherein R1b is —Cl, and R1c is H; orwherein R1a and R1d are H; R1c is halo or H, such as —F, —Cl, or H; and R1b is heteroaryl of 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 Rc; orwherein R1a and R1d are H; R1c is halo or H, such as —F, —Cl, or H; and R1b is heteroaryl of 5-6, such as 5, ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is substituted with one occurrence of Rh or -(Lg)bg-Rh, such as Rh or —CH2-Rh, and further optionally substituted with 1-2 Rc.

10. The compound of any one of claims 1-9, wherein P1 and P5 are independently CH or CRc; and P2, P3, and P4 are independently CH, CRc, or CR7, such as: wherein one of P2, P3, and P4 is CR7; such as: wherein P3 is CR7, such as: wherein the

11. The compound of any one of claims 1-9, wherein one or two, such as one, of P1, P2, P3, P4, and P5 is N; such as: wherein P3 is CR7; P4 is N; and P1, P2, and P5 are independently CH or CRc, such as wherein the

12. The compound of any one of claims 1-11, wherein a1 is 0; or wherein a1 is 1, and optionally LA is —O—, —NH—, or —CH2—, such as wherein LA is —O—; orwherein a1 is 2; and -(LA)a1- is -LA1-LA2, wherein LA1 and LA2 are independently selected LA; and LA2 is the point of attachment to R8, optionally LA1 is —O—, and LA2 is C1-3 alkylene optionally substituted with 1-2 Ra1; orwherein a1 is 3; and -(LA)a1- is -LA1-LA2-LA3, wherein LA1, LA2, and LA3 are independently selected LA; and LA3 is the point of attachment to R8, optionally LA1 and LA3 are each independently C1-3 alkylene optionally substituted with 1-2 Ra1, and LA2 is NRNC(O)O or OC(O)NRN.

13. The compound of any one of claims 1-12, wherein R8 is C1-10 alkyl optionally substituted with 1-4 Ra1, such as wherein R8 is C1-10 alkyl, such as C2, C3, C4, C5, C6, or C7 alkyl, substituted with 1-6 independently selected halo, such as F; or wherein R8 is Rg, such as:wherein R8 is selected from the group consisting of: C3-8 cycloalkyl or C3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc, Rh, and -(Lg)bg-Rh; andheterocyclyl or heterocycloalkenyl of 4-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rc, Rh, and -(Lg)bg-Rh, such as:wherein R8 is selected from the group consisting of: C3-8 cycloalkyl which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; andheterocyclyl of 4-8 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.

14. The compound of claim 1, wherein the compound is a compound of Formula (Ia-1-1):

15. The compound of claim 1, wherein the compound is selected from the group consisting of the compounds delineated in Table C1, and a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound of claims 1-15 and one or more pharmaceutically acceptable excipients.

17. A method for inhibiting STING activity, the method comprising contacting STING with a compound as claimed in any one of claims 1-15, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition as claimed in claim 16.

18. 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 1-15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 16.

19. A method of treatment of disease, disorder, or condition associated with STING, such as a disease, disorder, or condition, in which increased STING signaling, such as excessive STING signaling, contributes to the pathology and/or symptoms and/or progression of the disease, such as cancer, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 16.