JP2023540672A - Compounds and compositions for treating conditions associated with STING activity - Google Patents

Abstract

The present disclosure describes chemical entities (e.g., compounds or pharmaceutically acceptable salts and/or hydrates and/or co-crystals of said compounds) that inhibit (e.g., antagonize) STING (Stimulator of Interferon Gene) and /or combination drugs). The chemical entity may, for example, increase (e.g., enhance) STING activation (e.g., STING signaling) and/or the pathology of a condition, disease, or disorder (e.g., cancer) in a subject (e.g., human). Useful for treating conditions, diseases, or disorders that contribute to the symptoms and/or progression. The disclosure also features compositions containing the chemical entities and methods of using and making the chemical entities.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63/052,117, filed July 15, 2020, which is incorporated herein by reference in its entirety.

TECHNICAL FIELD This disclosure relates to chemical entities (compounds or pharmaceutically acceptable salts and/or hydrates and/or co-crystals of said compounds) that inhibit (e.g., antagonize) STING (Stimulator of Interferon Gene). /or combination drugs). The chemical entity may, for example, be associated with an increase (e.g., enhancement) of STING activation (e.g., STING signaling) in a disease state and/or symptom of a condition, disease, or disorder (e.g., cancer) in a subject (e.g., human). and/or are useful for treating conditions, diseases, or disorders that contribute to the progression of the disease. The disclosure also features compositions containing the chemical entities and methods of using and making the chemical entities.

Background STING, also known as transmembrane protein 173 (TMEM173) and MPYS/MITA/ERIS, is a protein encoded by the TMEM173 gene in humans. 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 interferons mediated by STING protect infected cells and nearby cells from local infection in an autocrine and paracrine manner.

The STING pathway is central in mediating the recognition of cytosolic DNA. In this context, STING, an endoplasmic reticulum (ER)-localized transmembrane protein, is a second messenger of 2',3' cyclic GMP-AMP (hereafter cGAMP) produced by cGAS after dsDNA binding. Acts as a receptor. In addition, STING can also function as a major pattern recognition receptor for bacterial cyclic dinucleotides (CDNs) and small molecule agonists. Recognition of endogenous or prokaryotic CDNs proceeds through the carboxy-terminal domain of STING, which is oriented into the cytosol and creates a V-shaped binding pocket formed by STING homodimers. Ligand-induced activation of STING induces its relocalization to the Golgi, an essential process to promote STING's interaction with TBK1. This protein complex then signals through the transcription factor IRF-3, inducing type I interferon (IFN) and other coregulated antiviral factors. In addition, STING was shown to induce activation of NF-κB and MAP kinases. After initiation of signal transduction, STING is rapidly degraded, a step thought to be important in the termination of the inflammatory response.

Hyperactivation of STING is associated with a subset of monogenic autoinflammatory conditions, the so-called type I interferonoses. Examples of these diseases include a clinical syndrome called infantile-onset STING-associated vasculitis (SAVI), caused by gain-of-function mutations in TMEM173 (the gene name for STING). Furthermore, STING has been implicated in the pathogenesis of Ecardi-Gouthière syndrome (AGS) and inherited forms of lupus. In contrast to SAVI, dysregulation of nucleic acid metabolism underlies the continuous innate immune activation in AGS. Apart from these genetic disorders, emerging evidence points to a more general pathogenic role for STING in a wide range of inflammation-related disorders, such as systemic lupus erythematosus, rheumatoid arthritis, and cancer. Therefore, small molecule-based pharmacological intervention in the STING signaling pathway holds significant potential for the treatment of a wide range of diseases.

SUMMARY The present disclosure describes chemical entities (compounds or pharmaceutically acceptable salts and/or hydrates and/or co-crystals and/or co-crystals of said compounds) that inhibit (e.g., antagonize) STING (Stimulator of Interferon Gene). or drug combinations). The chemical entity may, for example, be associated with an increase (e.g., enhancement) of STING activation (e.g., STING signaling) in a disease state and/or symptom of a condition, disease, or disorder (e.g., cancer) in a subject (e.g., human). and/or are useful for treating conditions, diseases, or disorders that contribute to the progression of the disease. The disclosure also features compositions containing the chemical entities and methods of using and making the chemical entities.

An "antagonist" of STING directly binds to STING at the protein level such that the activity of STING is reduced, e.g., by inhibition, blocking or attenuating agonist-mediated responses, altering distribution, or otherwise. compounds that modify or modify the same. STING antagonists include chemical entities that interfere with or inhibit STING signaling.

の化合物、またはその薬学的に許容される塩が特徴とされ、式中、Z、Y¹、Y²、Y³、X¹、X²、R⁶、環B、L^A、a1、環C、およびR⁷は本明細書中のいずれかの箇所において定義される通りであり得る。 In one aspect, equation (I):

or a pharmaceutically acceptable salt thereof, where Z, Y ¹ , Y ² , Y ³ , X ¹ , X ² , R ⁶ , Ring B, L ^A , a1, Ring C , and R ⁷ can be as defined elsewhere herein.

In one aspect, a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or a composition containing the same); and one or more pharmaceutically acceptable excipients.

In one aspect, STING is a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or a composition containing the same). ), a method for inhibiting (eg, antagonizing) STING activity is featured. The method includes in vitro methods, e.g., by chemically including in vitro methods of contacting the target entity. Methods include in vivo methods, e.g., administering a chemical entity to a subject (e.g., a human) having a disease in which increased (e.g., enhanced) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease. Can further include in vivo methods of administering.

In one aspect, methods of treating a condition, disease, or disorder that is ameliorated by antagonizing STING, e.g., increasing (e.g., enhancing) STING activation (e.g., STING signaling) in a subject (e.g., human ) features a method of treating a condition, disease, or disorder that contributes to the pathology and/or symptoms and/or progression of a condition, disease, or disorder (e.g., cancer). The method comprises 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 compound thereof). or a composition containing the same.

In another aspect, a subject in need of such treatment is administered an effective amount of a chemical entity described herein (e.g., a compound generically or specifically described herein or a pharmaceutical agent thereof). The present invention features a method of treating cancer, the method comprising the step of administering a therapeutically acceptable salt or a composition containing the same.

In a further aspect, other STING-related conditions, such as type I interferonosis (e.g., infantile-onset STING-associated vasculitis (SAVI)), Ecardi-Gouthière syndrome (AGS), hereditary forms of lupus, and systemic lupus erythematosus and joint It features methods for treating inflammation-related disorders such as rheumatism. The method comprises 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 compound thereof). or a composition containing the same.

In another aspect, administering to a subject in need thereof an effective amount of a chemical entity described herein (e.g., a compound described herein generically or specifically or a pharmaceutically acceptable compound thereof). The present invention is characterized by a method for suppressing STING-dependent type I interferon production in a subject, comprising the step of administering a salt containing the same or a composition containing the same.

Further aspects feature methods of treating diseases in which increased (eg, enhanced) STING activation (eg, STING signaling) contributes to the pathology and/or symptoms and/or progression of the disease. The method comprises 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 compound thereof). or a composition containing the same.

In another aspect, the subject receives 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 in which the subject is concerned that increased (e.g., enhanced) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the disease. Having (or being predisposed to having) a disease, methods of treatment are featured.

In a further aspect, the method of treatment comprises administering to a subject a chemical entity described herein (e.g., a compound described herein generically or specifically or a pharmaceutically acceptable salt thereof or to treat a disease in which increased (e.g., enhancement) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the disease. The chemical entity is administered in an amount effective to treat the disease.

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

In another aspect, a compound described herein, or a pharmaceutically acceptable salt or compound thereof, for use in treating a condition, disease, or disorder associated with increased (e.g., enhanced) activation of STING. Variants are provided.

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

In another aspect, melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colon Rectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multifocal as described herein for use in the treatment of a cancer selected from the group consisting of myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms tumor, or primary hepatocellular carcinoma. A compound or a pharmaceutically acceptable salt or tautomer thereof is provided.

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

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

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

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

In another aspect, melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colon Rectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multifocal The present invention in the manufacture of a medicament for the treatment of a cancer selected from the group consisting of myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms tumor, or primary hepatocellular carcinoma. Uses of the described compounds or pharmaceutically acceptable salts or tautomers thereof are provided.

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

In another aspect, an I.I. Provided is the use of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, for use in the manufacture of a medicament for the treatment of type interferonosis.

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

In another aspect, a compound described herein or a pharmaceutically acceptable salt or tautomer thereof for treating a condition, disease, or disorder associated with increased (e.g., enhanced) activation of STING. Body use provided.

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

In another aspect, melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colon Rectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multifocal A compound or compound as described herein for treating a cancer selected from the group consisting of myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms tumor, or primary hepatocellular carcinoma. Use of pharmaceutically acceptable salts or tautomers thereof is provided.

In another aspect, there is provided the use of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, to treat type I interferonosis.

In another aspect, an I.I. Provided is the use of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, to treat type interferonosis.

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 example, the method can further include administering one or more (eg, 2, 3, 4, 5, 6, or more) additional agents.

The chemical entity may be associated with other STING-related conditions, such as type I interferonosis (e.g., infantile-onset STING-associated vasculitis (SAVI)), Ecardi-Gouthière syndrome (AGS), hereditary forms of lupus, and systemic lupus erythematosus and It can be administered in combination with one or more additional therapeutic agents and/or regimens useful for treating inflammation-related disorders such as rheumatoid arthritis.

The chemical entity may be associated with one or more additional cancer therapies (e.g., surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy, or combinations thereof, e.g., one or more Can be administered in combination with chemotherapy, including administering (e.g., 2, 3, 4, 5, 6, or more) additional chemotherapeutic agents. Non-limiting example of additional chemotherapeutic agents Examples include alkylating agents (e.g. cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, and/or oxaliplatin), antimetabolites (e.g. azathioprine and/or mercaptopurine), terpenoids (e.g. vinca alkaloids and/or taxanes, such as vincristine, vinblastine, vinorelbine, and/or vindesine; taxol, paclitaxel, and/or docetaxel); camptothecin, amsacrine, etoposide, etoposide phosphate, and/or teniposide), cytotoxic antibiotics (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin, and/or mitomycin) ), hormones (e.g., luteinizing hormone-releasing hormone agonists such as leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide, and/or nilutamide), antibodies (e.g., abciximab, adalimumab, alemtuzumab, atolizumab, basiliximab, Belimumab, bevacizumab, bretuximab vedotin, canakinumab, cetuximab, certolizumab pegol, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab - CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumumab (Panitumuab), ranibizumab, rituximab, tocilizumab, tositumomab, and/or trastuzumab), antiangiogenic agents, cytokines, thrombotic agents, antiproliferative substances, antihelminthic agents, and selected from immune checkpoint inhibitors that target immune checkpoint receptors, said immune checkpoint receptors being 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- Butyrophilin, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, selected from the group consisting of TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30, and CD155 (eg, CTLA-4 or PD1 or PD-L1).

The subject can have cancer, eg, the subject has received 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 cancer, bladder cancer, non-small cell lung cancer, small cell cancer. Lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, spinal cord formation abnormal syndromes, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms tumor, or primary hepatocellular carcinoma. In certain embodiments, the cancer can be a refractory cancer.

Chemical entities can be administered intratumorally.

The method can further include identifying the subject.

Other embodiments include those described in the detailed description and/or claims.

Additional Definitions A number of additional terms are defined below to facilitate understanding of the disclosure set forth herein. In general, the academic terminology used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly used in the art. Unless otherwise defined, all scientific and technical 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 patent, application, application publication, and other publication mentioned throughout this specification and the appendices is incorporated by reference in its entirety.

As used herein, the term "STING" refers to nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous STING It is meant to include, but not be limited to, molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

The term "acceptable" in reference to a formulation, composition, or component, as used herein, means that it does not have any lasting adverse effects on the general health of the subject being treated. do.

"API" refers to active pharmaceutical component.

The term "effective amount" or "therapeutically effective amount" as used herein refers to the chemical being administered that alleviates to some extent one or more of the symptoms of the disease or condition being treated. refers to a sufficient amount of physical entities. Results include reduction and/or alleviation of signs, symptoms, or causes of disease, or any other desired alteration of biological systems. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as disclosed herein required to provide a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case is determined using any suitable technique, such as dose escalation studies.

The term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. , or means a medium. In one aspect, each component is compatible with the other components of the pharmaceutical formulation and has no undue toxicity, irritation, allergic response, immunogenicity, or other concerns commensurate with a reasonable benefit/risk ratio. "Pharmaceutically acceptable" in the sense of being suitable for use in contact with human and animal tissues or organs without complications. For example, 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: See 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

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

The term "pharmaceutical composition" includes other chemical ingredients (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersants, suspending agents, etc. refers to a mixture of the compounds described herein with a thickening agent and/or a thickening agent. Pharmaceutical compositions facilitate administration of a compound to an organism. Multiple techniques exist in the art for administering compounds, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, 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. Not that it will be done. The terms "subject" and "patient" are used interchangeably herein in reference to a mammalian subject, eg, a human.

The terms "treat," "treating," and "therapy" in the context of the treatment of a disease or disorder refer to or slowing the progression, spread, or worsening of a disease, disorder, or condition or one or more symptoms thereof. is meant. "Treatment of cancer" refers to one or more of the following effects: (1) inhibition of tumor growth to any extent, including (i) slowing down and (ii) complete growth arrest; ) reduction in the number of tumor cells, (3) maintenance of tumor size, (4) reduction in tumor size, (5) to peripheral organs, including (i) reduction, (ii) slowing down, or (iii) complete prevention. (6) inhibition of metastasis, including (i) reduction, (ii) slowing, or (iii) complete prevention of tumor cell invasion; (7) maintenance of (i) tumor size; (ii) tumor size; (iii) slowing tumor growth; (iv) enhancing anti-tumor immune responses that may result in reducing, slowing, or preventing invasion; and/or (8) one associated with a disorder. or any reduction in the severity or number of symptoms.

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

The term "alkyl" refers to a saturated acyclic hydrocarbon group, which may be straight or branched, containing the specified number of carbon atoms. For example, C _1-10 indicates that the group may have 1 to 10 (inclusive) carbon atoms therein. An alkyl group may 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 that only single bonds are present between the constituent carbon atoms, and the only other valences available are hydrogen and/or other substituents as defined herein. means to be occupied.

The term "haloalkyl" refers to alkyl in which one or more hydrogen atoms are replaced with independently selected halo.

The term "alkoxy" refers to the group -O-alkyl (eg _-OCH3 ).

The term "alkylene" refers to divalent alkyl (eg, _-CH2- ).

The term "alkenyl" refers to an acyclic hydrocarbon chain, which may be straight or branched, 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 2 to 6 carbon atoms (inclusive) therein. An alkenyl group may be unsubstituted or substituted with one or more substituents.

The term "alkynyl" refers to an acyclic hydrocarbon chain, which may be straight or branched, having one or more carbon-carbon triple bonds. Alkynyl moieties contain the indicated number of carbon atoms. For example, C _2-6 indicates that the group may have 2 to 6 carbon atoms (inclusive) therein. An alkynyl group may be unsubstituted or substituted with one or more substituents.

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

The term "cycloalkyl" as used herein refers to, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, more preferably 3 to 12 ring carbons or 3 to 10 ring carbons. Refers to a cyclic saturated hydrocarbon group having a ring carbon or 3 to 6 ring carbons, and the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Cycloalkyl may contain multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyls include 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, etc. Cycloalkyl also includes spirocyclic rings (eg, spirocyclic bicycles in which the two rings are joined by only one carbon). Non-limiting examples of spirocyclic cycloalkyl 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, Examples include 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 that only single bonds are present between the constituent carbon atoms.

As used herein, the term "cycloalkenyl" has 3 to 20 ring carbons, preferably 3 to 16 ring carbons, more preferably 3 to 12 ring carbons or 3 to 10 ring carbons. Refers to a partially unsaturated cyclic hydrocarbon group having carbon or 3 to 6 ring carbons, and the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. As a partially unsaturated cyclic hydrocarbon group, a cycloalkenyl group is one in which one or more double bonds are present within the ring, no ring within the ring system is aromatic, and the cycloalkenyl group as a whole is It can have any degree of unsaturation as long as it is not completely saturated. Cycloalkenyls can contain multiple fused and/or bridged and/or spirocyclic rings.

As used herein, the term "heteroaryl" has 5 to 20 ring atoms, or 5, 6, 9, 10, or 14 ring atoms, arranged in a cyclic array. means a monocyclic, bicyclic, tricyclic or polycyclic group having 6, 10, or 14 shared pi electrons, at least one ring in the system is aromatic, and the system at least one ring in the ring contains one or more heteroatoms independently selected from the group consisting of N, O, and S (but need not be a ring containing a heteroatom, For example, tetrahydroisoquinolinyl, such as tetrahydroquinolinyl). A heteroaryl group may 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]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl , chromanyl, 2,3-dihydrobenzo[b][1,4]dioxynyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo Examples include [b][1,4]oxathiinyl and isoindolinyl. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

The term "heterocyclyl" contains 1 to 3 heteroatoms selected from O, N, or S if monocyclic, from 1 to 6 if bicyclic, or tricyclic or polycyclic. having 1 to 9 ring atoms (for example, carbon atoms and 1 to 3 carbon atoms and O, N, or S, respectively, in the case of a monocyclic, bicyclic, or tricyclic , 1 to 6, or 1 to 9 heteroatoms), monocyclic, bicyclic, tricyclic, or polycyclic saturated ring systems (e.g., 5 to 8 membered monocyclic, 8 ~12-membered bicyclic, or 11- to 14-membered tricyclic ring system), and 0, 1, 2, or 3 atoms of each ring may be substituted with a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl can contain multiple fused and bridged rings. Non-limiting examples of fused/bridged heterocyclyls include 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-oxa Bicyclo[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] Examples include octanyl, 2-oxabicyclo[2.2.2]octanyl, 3-oxabicyclo[3.2.1]octanyl, and the like. Heterocyclyl also includes spirocyclic rings (eg, spirocyclic bicycles in which the two rings are joined by only one carbon). 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- Examples include 9-azaspiro[5.5]undecanyl. The term "saturated" as used in this context means that only single bonds are present between the constituent ring atoms, and the only other valencies available are hydrogen and/or other substituents as defined herein. means to be occupied.

As used herein, the term "heterocycloalkenyl" contains 1 to 3 heteroatoms selected from O, N, or S if monocyclic, or from 1 to 6 heteroatoms if bicyclic. monocyclic, bicyclic, or tricyclic, having 3 to 16 ring atoms (e.g. carbon atoms and O, N, or S), or 1 to 9 if tricyclic or polycyclic; cyclic, with 1 to 3, 1 to 6, or 1 to 9 heteroatoms, respectively), partially unsaturated cyclic ring systems (e.g., 5 to 8 membered monocyclic, 8 to 12 membered 0, 1, 2, or 3 atoms of each ring may be substituted with a substituent. Examples of heterocycloalkenyl groups include, but are not limited to, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl. As a partially unsaturated cyclic group, a heterocycloalkenyl group is one in which one or more double bonds are present within the ring, no ring within the ring system is aromatic, and the heterocycloalkenyl group as a whole is It can have any degree of unsaturation as long as it is not completely saturated. Heterocycloalkenyl can contain multiple fused and/or bridged and/or spirocyclic rings.

When a ring is described herein as "aromatic," it is meant that the ring has a continuous delocalized pi-electron system. Typically, the number of out-of-plane π electrons corresponds to Huckel's law (4n+2). Examples of such rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

When a ring is described herein as "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (attributable to the ring itself), provided that the ring is not aromatic. In addition to a degree of unsaturation; for example, one or more double or triple bonds between the constituent ring atoms). Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

）、（ii）単一の環原子上に位置するもの（スピロ縮合環系）

、または（iii）連続する環原子のアレイ上に位置するもの（＞0の架橋長を有する架橋環系）

を包含すると理解される。 For the avoidance of doubt, unless otherwise specified, a sufficient number of rings to form a bicyclic or higher order ring system (e.g. tricyclic, polycyclic ring system) For rings and cyclic groups containing atoms (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc. as described herein), such rings and cyclic groups have fused rings. (e.g., [xx0] ring systems in which 0 represents no atom bridge) in which the point of fusion is located on (i) adjacent ring atoms

), (ii) located on a single ring atom (spirofused ring systems)

, or (iii) located on an array of consecutive ring atoms (bridged ring systems with a bridge length of >0)

is understood to include.

Additionally, the atoms that make up the compounds of this embodiment are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include atoms having the same number of atoms but different mass numbers. As general, non-limiting examples, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ^13C and ^14C .

を含有する化合物は、部分:

を含有する互変異型を包含する。同様に、ヒドロキシルで置換されていてもよいと記載されるピリジニルまたはピリミジニル部分は、ピリドンまたはピリミドン互変異型を包含する。 Additionally, compounds disclosed herein, either generically or specifically, are intended to include all tautomeric forms. So, as an example, part:

Compounds containing moiety:

It includes tautomeric forms containing. Similarly, a pyridinyl or pyrimidinyl moiety described as optionally substituted with hydroxyl includes pyridone or pyrimidone tautomers.

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 The present disclosure describes chemical entities (compounds or pharmaceutically acceptable salts and/or hydrates and/or co-crystals of said compounds) that inhibit (e.g., antagonize) STING (Stimulator of Interferon Gene). and/or prodrugs and/or tautomers and/or drug combinations). The chemical entity may, for example, be associated with an increase (e.g., enhancement) of STING activation (e.g., STING signaling) in a disease state and/or symptom of a condition, disease, or disorder (e.g., cancer) in a subject (e.g., human). and/or are useful for treating conditions, diseases, or disorders that contribute to the progression of the disease. The disclosure also features compositions containing the chemical entities and methods of using and making the chemical entities.

の化合物またはその薬学的に許容される塩もしくはその互変異性体が提供され、
式中、
Z、Y¹、Y²、およびY³は、CR¹、C（＝O）、N、およびNR²からなる群より独立して選択され、
X¹は、O、S、N、NR²、およびCR¹からなる群より選択され、
X²は、O、S、N、NR⁴、およびCR⁵からなる群より選択され、
各

は独立して単結合または二重結合であり、但し、X¹およびX²を含む5員環はヘテロアリールであり、Z、Y¹、Y²、およびY³を含む6員環はアリールまたはヘテロアリールであり、
各R¹は、H;R^c;R^g;および-（L¹）_b1-R^gからなる群より独立して選択され、
各R²は、H;R^d;R^g;および-（L²）_b2-R^gからなる群より独立して選択され、
R⁴は、HおよびR^dからなる群より選択され、
R⁵は、H;R^c;およびR^hからなる群より選択され、
R⁶は、H;R^d;およびR^hからなる群より選択され、
環Bは、環原子5個のヘテロアリーレンであって、環原子のうちの1～4個が、N、NH、N（R^d）、O、およびSからなる群よりそれぞれ独立して選択されるヘテロ原子であり、環Bのヘテロアリーレンが、オキソおよびR^cからなる群より独立して選択される1～2個の置換基で置換されていてもよく、但し、環Bが環炭素原子を介してC（＝O）NR⁶基に結合している、ヘテロアリーレンであり、
各L^Aは、1～2個のR^a1で置換されていてもよいC_1～3アルキレン;-O-;-NH-;-NR^d;-S（O）_0～2;およびC（O）からなる群より独立して選択され、
a1は、0、1、または2であり、
環Cは、
・オキソ、R^c、およびR^hからなる群より独立して選択される1～4個の置換基でそれぞれ置換されていてもよい、C_3～12シクロアルキレンまたはC_3～12シクロアルケニレン;
・環原子3～12個のヘテロシクリレンまたはヘテロシクロアルケニレンであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、前記ヘテロシクリレンまたはヘテロシクロアルケニレンが、オキソ、R^c、およびR^hからなる群より独立して選択される1～4個の置換基で置換されていてもよい、ヘテロシクリレンまたはヘテロシクロアルケニレン;
・環原子5～12個のヘテロアリーレンであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、前記ヘテロアリーレンが、R^cおよびR^hからなる群より独立して選択される1～4個の置換基で置換されていてもよい、ヘテロアリーレン;ならびに
・R^cおよびR^hからなる群より独立して選択される1～4個の置換基で置換されていてもよい、C_6～10アリーレン
からなる群より選択され、
R⁷は、R^gおよび-（L⁷）_b7-R^gからなる群より選択され、
R^aおよびR^a1の各出現は、-OH;-ハロ;-NR^eR^f;C_1～4アルコキシ;C_1～4ハロアルコキシ;-C（＝O）O（C_1～4アルキル）;-C（＝O）（C_1～4アルキル）;-C（＝O）OH;-CONR'R'';-S（O）_1～2NR'R'';-S（O）_1～2（C_1～4アルキル）;およびシアノからなる群より独立して選択され、
R^cの各出現は、ハロ;シアノ;1～6個の独立して選択されるR^aで置換されていてもよいC_1～10アルキル;C_2～6アルケニル;C_2～6アルキニル;C_1～4アルコキシ;C_1～4ハロアルコキシ;-S（O）_1～2（C_1～4アルキル）;-S（O）（＝NH）（C_1～4アルキル）;-NR^eR^f;-OH;-S（O）_1～2NR'R'';-C_1～4チオアルコキシ;-NO₂;-C（＝O）（C_1～10アルキル）;-C（＝O）O（C_1～4アルキル）;-C（＝O）OH;-C（＝O）NR'R'';および-SF₅からなる群より独立して選択され、
R^dの各出現は、1～3個の独立して選択されるR^aで置換されていてもよいC_1～6アルキル;-C（O）（C_1～4アルキル）;-C（O）O（C_1～4アルキル）;-CONR'R'';-S（O）_1～2NR'R'';-S（O）_1～2（C_1～4アルキル）;-OH;およびC_1～4アルコキシからなる群より独立して選択され、
R^eおよびR^fの各出現は、H;NR'R''、-OH、およびRⁱからなる群よりそれぞれ独立して選択される1～3個の置換基で置換されていてもよいC_1～6アルキル;-C（O）（C_1～4アルキル）;-C（O）O（C_1～4アルキル）;-CONR'R'';-S（O）_1～2NR'R'';-S（O）_1～2（C_1～4アルキル）;-OH;ならびにC_1～4アルコキシからなる群より独立して選択され、
R^gの各出現は、
・それぞれ、オキソ、R^c、R^h、および-（L^g）_bg-R^hからなる群より独立して選択される1～4個の置換基で置換されていてもよい、C_3～12シクロアルキルまたはC_3～12シクロアルケニル;
・環原子3～12個のヘテロシクリルまたはヘテロシクロアルケニルであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、前記ヘテロシクリルまたはヘテロシクロアルケニルが、オキソ、R^c、R^h、および-（L^g）_bg-R^hからなる群より独立して選択される1～4個の置換基で置換されていてもよい、ヘテロシクリルまたはヘテロシクロアルケニル;
・環原子5～12個のヘテロアリールであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、前記ヘテロアリールが、R^c、R^h、および-（L^g）_bg-R^hからなる群より独立して選択される1～4個の置換基で置換されていてもよい、ヘテロアリール;ならびに
・R^c、R^h、および-（L^g）_bg-R^hからなる群より独立して選択される1～4個の置換基で置換されていてもよい、C_6～10アリール
からなる群より独立して選択され、
R^hの各出現は、
・それぞれ1～4個のRⁱで置換されていてもよい、C_3～12シクロアルキルまたはC_3～12シクロアルケニル;
・環原子3～12個のヘテロシクリルまたはヘテロシクロアルケニルであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、前記ヘテロシクリルまたはヘテロシクロアルケニルが1～4個のRⁱで置換されていてもよい、ヘテロシクリルまたはヘテロシクロアルケニル;
・環原子5～12個のヘテロアリールであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、前記ヘテロアリールが1～4個のRⁱで置換されていてもよい、ヘテロアリール;ならびに
・1～4個のRⁱで置換されていてもよいC_6～10アリール
からなる群より独立して選択され、
Rⁱの各出現は、C_1～6アルキル;C_1～4ハロアルキル;C_1～4アルコキシ;C_1～4ハロアルコキシ;およびハロからなる群より独立して選択され、
L¹、L²、L⁷、およびL^gの各出現は、-O-、-NH-、-NR^d、-S（O）_0～2、C（O）、および、1～3個のR^aで置換されていてもよいC_1～3アルキレンからなる群より選択され、
b1、b2、b7、およびbgは、それぞれ独立して1、2、または3であり、かつ
R'およびR''の各出現は、H;-OH;およびC_1～4アルキルからなる群より独立して選択される。 In one aspect, compounds of formula I are herein defined as compounds of formula I:

or a pharmaceutically acceptable salt thereof or a tautomer thereof,
During the ceremony,
Z, Y ¹ , Y ² , and Y ³ are independently selected from the group consisting of CR ¹ , C(=O), N, and NR ² ;
X ¹ is selected from the group consisting of O, S, N, NR ² and CR ¹ ;
^X2 is selected from the group consisting of O, S, N, ^NR4 , and ^CR5 ;
each

are independently a single bond or a double bond, provided that the 5-membered ring containing X ¹ and X ² is heteroaryl, and the 6-membered ring containing Z, Y ¹ , Y ² , and Y ³ is aryl or is a heteroaryl,
each R ¹ is independently selected from the group consisting of H;R ^c ;R ^g ; and -(L ¹ ) _b1 -R ^g ;
each R ² is independently selected from the group consisting of H;R ^d ;R ^g ; and -(L ² ) _b2 -R ^g ;
R ⁴ is selected from the group consisting of H and R ^d ;
R ⁵ is selected from the group consisting of H; R ^c ; and R ^h ;
R ⁶ is selected from the group consisting of H; R ^d ; and R ^h ;
Ring B is a 5 ring atom heteroarylene in which 1 to 4 of the ring atoms are each independently selected from the group consisting of N, NH, N(R ^d ), O, and S. and the heteroarylene of ring B is optionally substituted with 1 to 2 substituents independently selected from the group consisting of oxo and R ^c , provided that ring B is a ring carbon atom is a heteroarylene bonded to the C(=O)NR ⁶ group through
^and _C ^{( O} _{_} ) are independently selected from the group consisting of
a1 is 0, 1, or 2;
Ring C is
- C _{3-12 cycloalkylene or C 3-12 cycloalkenylene} , each optionally substituted with 1 to 4 substituents independently selected from the group consisting of oxo, R ^c , and R ^h ;
・Heterocyclylene or heterocycloalkenylene with 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R ^d ), O, and S(O) _{0 to 2} , wherein said heterocyclylene or heterocycloalkenylene has 1 to 4 atoms independently selected from the group consisting of oxo, R ^c , and ^Rh heterocyclylene or heterocycloalkenylene, optionally substituted with substituents;
・Heteroarylene with 5 to 12 ring atoms, in which 1 to 3 ring atoms are from the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2} a heteroarylene, each independently selected heteroatom, wherein said heteroarylene is optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c and R ^h ; and - selected from the group consisting of C _6-10 arylene, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c and R ^h ,
R ⁷ is selected from the group consisting of R ^g and -(L ⁷ ) _b7 -R ^g ;
Each occurrence of R ^a and R ^a1 is -OH;-halo;-NR ^e R ^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) _1~2 NR'R'';-S(O) _{1~ 2} (C _1-4 alkyl); and cyano;
Each occurrence of R ^c represents halo; cyano; C _1-10 alkyl optionally substituted with 1 to 6 independently selected R ^a ; C _2-6 alkenyl; C _2-6 alkynyl; _1-4 alkoxy;C _1-4 haloalkoxy;-S(O) _1-2 (C _1-4 alkyl);-S(O)(=NH)(C _1-4 alkyl);-NR ^e R ^f ;-OH;-S(O) _1~2 NR'R'';-C _{1~4thioalkoxy} ;-NO ₂ ;-C(=O) (C _1~10 alkyl);-C(=O) independently selected from the group consisting of O(C _1-4 alkyl); -C(=O)OH; -C(=O)NR'R''; and -SF ₅ ;
Each occurrence of R ^d is C _1-6 alkyl, optionally substituted with 1 to 3 independently selected R ^a ;-C(O)(C _1-4 alkyl);-C(O )O(C _1-4 alkyl);-CONR'R'';-S(O) _1-2 NR'R'';-S(O) _1-2 (C _1-4 alkyl);-OH; and C _1-4 alkoxy;
Each ^occurrence of R ^e and R ^f is a C _1-6 alkyl;-C(O)(C _1-4 alkyl);-C(O)O(C _1-4 alkyl);-CONR'R'';-S(O) _1-2 NR'R '';-S(O) _1-2 (C _1-4 alkyl);-OH; and C _1-4 alkoxy;
Each occurrence of R ^g is
・C _3-12 , each optionally substituted with 1 to 4 substituents independently selected from the group consisting of oxo, R ^c , R ^h , and -(L ^g ) _bg -R ^h cycloalkyl or C _3-12 cycloalkenyl;
- Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R ^d ), O, and S(O) from _{0 to 2} wherein the heterocyclyl or heterocycloalkenyl is independently selected from the group consisting of oxo, R ^c , ^Rh , and -(L ^g ) _bg -R ^h heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents;
- Heteroaryl of 5 to 12 ring atoms, in which 1 to 3 ring atoms are from the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2} each independently selected heteroatom, and said heteroaryl has 1 to 4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h and 1 to 4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h ; independently selected from the group consisting of C _6-10 aryls, which may be
Each occurrence of R ^h is
- C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each optionally substituted with 1 to 4 R ⁱ ;
- Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R ^d ), O, and S(O) from _{0 to 2} a heteroatom each independently selected from the group consisting of heterocyclyl or heterocycloalkenyl, wherein said heterocyclyl or heterocycloalkenyl is optionally substituted with 1 to 4 R ⁱ ;
- Heteroaryl of 5 to 12 ring atoms, in which 1 to 3 ring atoms are from the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2} heteroaryl, each independently selected heteroatom, wherein said heteroaryl is optionally substituted with 1 to 4 R ⁱ ; and - optionally substituted with 1 to 4 R ⁱ independently selected from the group consisting of C _6-10 aryls,
each occurrence of R ⁱ is independently selected from the group consisting of C _1-6 alkyl; C _1-4 haloalkyl; C _1-4 alkoxy; C _1-4 haloalkoxy; and halo;
Each occurrence of L ¹ , L ² , L ⁷ , and L ^g represents -O-, -NH-, -NR ^d , -S(O) _0-2 , C(O), and 1-3 selected from the group consisting of C _1-3 alkylene optionally substituted with R ^a ,
b1, b2, b7, and bg are each independently 1, 2, or 3, and
Each occurrence of R' and R'' is independently selected from the group consisting of H;-OH; and C _1-4 alkyl.

Variable symbols Z, Y ¹ , Y ² , Y ³ , X ¹ , and X ²
In some embodiments, each of Z, Y ¹ , Y ² , and Y ³ is independently N or CR ¹ .

In some embodiments, each of Z, Y ¹ , Y ² , and Y ³ is independently selected CR ¹ .

の化合物またはその薬学的に許容される塩であり、式中、R^1a、R^1b、R^1c、およびR^1dはそれぞれ、独立して選択されるR¹である。 In certain embodiments, the compound has formula (Ia):

or a pharmaceutically acceptable salt thereof, where R ^1a , R ^1b , R ^1c , and R ^1d are each independently selected R ¹ .

In some embodiments, one to two (eg, one) of Z, Y ¹ , Y ² , and Y ³ are N, and the remaining of Z, Y ¹ , Y ² , and Y ³ Each is an independently selected CR ¹ .

の化合物またはその薬学的に許容される塩からなる群より選択され、式中、R^1a、R^1b、R^1c、およびR^1dはそれぞれ、独立して選択されるR¹である。 In some of these embodiments, the compound has the following formula:

or a pharmaceutically acceptable salt thereof, where R ^1a , R ^1b , R ^1c , and R ^1d are each independently selected R ¹ .

の化合物またはその薬学的に許容される塩であり、式中、R^1a、R^1b、およびR^1cはそれぞれ、独立して選択されるR¹である。 In certain embodiments, the compound has formula (Ib):

or a pharmaceutically acceptable salt thereof, where R ^1a , R ^1b , and R ^1c are each independently selected R ¹ .

の化合物またはその薬学的に許容される塩であり、式中、R^1a、R^1b、およびR^1dはそれぞれ、独立して選択されるR¹である。 In certain embodiments, the compound has formula (Ic):

or a pharmaceutically acceptable salt thereof, where R ^1a , R ^1b , and R ^1d are each independently selected R ¹ .

の化合物またはその薬学的に許容される塩であり、式中、R^1a、R^1c、およびR^1dはそれぞれ、独立して選択されるR¹である。 In certain embodiments, the compound has formula (Id):

or a pharmaceutically acceptable salt thereof, where R ^1a , R ^1c , and R ^1d are each independently selected R ¹ .

の化合物またはその薬学的に許容される塩であり、式中、R^1b、R^1c、およびR^1dはそれぞれ、独立して選択されるR¹である。 In certain embodiments, the compound has formula (Ie):

or a pharmaceutically acceptable salt thereof, where R ^1b , R ^1c , and R ^1d are each independently selected R ¹ .

In some embodiments, X ¹ is NR ² . In some of these embodiments, X ¹ is NH.

In some embodiments, ^X2 is ^CR5 . In some of these embodiments, X ² is CH.

In some embodiments, X ¹ is NR ² and X ² is CR ⁵ . In certain embodiments, X ¹ is NR ² and X ² is CH. In certain embodiments, X ¹ is NH and X ² is CR ² . In certain embodiments, X ¹ is NH and X ² is CH.

の化合物またはその薬学的に許容される塩であり、式中、R^1a、R^1b、R^1c、およびR^1dはそれぞれ、独立して選択されるR¹である。式（Ia-1）のある特定の態様において、R²はHである。式（Ia-1）のある特定の態様において、R⁵はHである。式（Ia-1）のある特定の態様において、R²はHであり、R⁵はHである。 In some embodiments, the compound has formula (Ia-1):

or a pharmaceutically acceptable salt thereof, where R ^1a , R ^1b , R ^1c , and R ^1d are each independently selected R ¹ . In certain embodiments of formula (Ia-1), ^R2 is H. In certain embodiments of formula (Ia-1), R ⁵ is H. In certain embodiments of formula (Ia-1), ^R2 is H and ^R5 is H.

の化合物またはその薬学的に許容される塩からなる群より選択され、式中、R^1a、R^1b、R^1c、およびR^1dはそれぞれ、独立して選択されるR¹である。 In some embodiments, the compound has the formula:

or a pharmaceutically acceptable salt thereof, where R ^1a , R ^1b , R ^1c , and R ^1d are each independently selected R ¹ .

の化合物またはその薬学的に許容される塩であり、式中、R^1a、R^1b、およびR^1cはそれぞれ、独立して選択されるR¹である。式（Ib-1）のある特定の態様において、R²はHである。式（Ib-1）のある特定の態様において、R⁵はHである。式（Ib-1）のある特定の態様において、R²はHであり、R⁵はHである。 In certain embodiments, the compound has formula (Ib-1):

or a pharmaceutically acceptable salt thereof, where R ^1a , R ^1b , and R ^1c are each independently selected R ¹ . In certain embodiments of formula (Ib-1), ^R2 is H. In certain embodiments of formula (Ib-1), R ⁵ is H. In certain embodiments of formula (Ib-1), ^R2 is H and ^R5 is H.

の化合物またはその薬学的に許容される塩であり、式中、R^1a、R^1b、およびR^1dはそれぞれ、独立して選択されるR¹である。式（Ic-1）のある特定の態様において、R²はHである。式（Ic-1）のある特定の態様において、R⁵はHである。式（Ic-1）のある特定の態様において、R²はHであり、R⁵はHである。 In certain embodiments, the compound has formula (Ic-1):

or a pharmaceutically acceptable salt thereof, where R ^1a , R ^1b , and R ^1d are each independently selected R ¹ . In certain embodiments of formula (Ic-1), ^R2 is H. In certain embodiments of formula (Ic-1), R ⁵ is H. In certain embodiments of formula (Ic-1), ^R2 is H and ^R5 is H.

の化合物またはその薬学的に許容される塩であり、式中、R^1a、R^1c、およびR^1dはそれぞれ、独立して選択されるR¹である。式（Id-1）のある特定の態様において、R²はHである。式（Id-1）のある特定の態様において、R⁵はHである。式（Id-1）のある特定の態様において、R²はHであり、R⁵はHである。 In certain embodiments, the compound has formula (Id-1):

or a pharmaceutically acceptable salt thereof, where R ^1a , R ^1c , and R ^1d are each independently selected R ¹ . In certain embodiments of formula (Id-1), ^R2 is H. In certain embodiments of formula (Id-1), R ⁵ is H. In certain embodiments of formula (Id-1), ^R2 is H and ^R5 is H.

の化合物またはその薬学的に許容される塩であり、式中、R^1b、R^1c、およびR^1dはそれぞれ、独立して選択されるR¹である。式（Ie-1）のある特定の態様において、R²はHである。式（Ie-1）のある特定の態様において、R⁵はHである。式（Ie-1）のある特定の態様において、R²はHであり、R⁵はHである。 In certain embodiments, the compound has formula (Ie-1):

or a pharmaceutically acceptable salt thereof, where R ^1b , R ^1c , and R ^1d are each independently selected R ¹ . In certain embodiments of formula (Ie-1), ^R2 is H. In certain embodiments of formula (Ie-1), R ⁵ is H. In certain embodiments of formula (Ie-1), ^R2 is H and ^R5 is H.

Variable symbol R ¹
In some embodiments, each R ¹ is H.

In some embodiments, 1-2 R ¹ are independently selected non-hydrogen substituents and each remaining R ¹ is H. In certain embodiments, 1 to 2 R ¹ are each independently selected from the group consisting of R ^c1 and R ^g1 and each remaining R ¹ is H and R ^c1 is independently selected. R ^c and R ^g1 are independently selected R ^g .

In some of these embodiments, two occurrences of R ¹ are independently selected from the group consisting of R ^c1 and R ^g1 and each remaining R ¹ is H.

For example, each of the two occurrences of R ¹ is an independently selected R ^c1 and each remaining R ¹ is H. In some of these embodiments, each R ^c1 is an independently selected halo, such as -F or -Cl.

Certain embodiments (1 to 2 R ¹ are independently selected from the group consisting of R ^c1 and R ^g1 , each remaining R ¹ is H, and R ^c1 is independently selected R ^c and R ^g1 is an independently selected R ^g ), one occurrence of R ¹ is selected from the group consisting of R ^c1 and R ^g1 , and each remaining R ¹ is H It is. In some of these embodiments, one occurrence of R ¹ is R ^c1 and each remaining R ¹ is H. In some of these embodiments, R ^c1 is halo, such as -F or -Cl, such as -F.

Certain embodiments (1 to 2 R ¹ are independently selected from the group consisting of R ^c1 and R ^g1 , each remaining R ¹ is H, and R ^c1 is independently selected R ^c and R ^g1 is an independently selected R ^g ), one occurrence of R ¹ is R ^g1 and each remaining R ¹ is H.

Certain embodiments (1 to 2 R ¹ are independently selected from the group consisting of R ^c1 and R ^g1 , each remaining R ¹ is H, and R ^c1 is independently selected R ^c and R ^g1 is an independently selected R ^g ), each R ^c1 is an independently selected halo, such as -F, -Cl, or -Br. In some of these embodiments, each R ^c1 is independently -F or -Cl, such as -F.

Certain embodiments (1 to 2 R ¹ are independently selected from the group consisting of R ^c1 and R ^g1 , each remaining R ¹ is H, and R ^c1 is independently selected R ^c and R ^g1 is an independently selected R ^g ), each R ^g1 is a heteroaryl of 5 to 10 ring atoms, and 1 to 3 ring atoms are N , N(H), N(R ^d ), O, and S, and the heteroaryl is R ^c , R ^h , and -(L ^g ) _bg heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of -R ^h ; and consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h independently selected from the group consisting of C _6-10 aryl optionally substituted with 1 to 4 substituents independently selected from the group.

In some of these embodiments, each R ^g1 is a heteroaryl of 5 to 6 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R ^d ), a heteroatom each independently selected from the group consisting of O, and S, wherein said heteroaryl is optionally substituted with 1 to 4 R ^c ; and 1 to 4 R ^c independently selected from the group consisting of C ₆ aryl optionally substituted with .

In some of the above embodiments, each R ^g1 is independently a 5 ring atom heteroaryl, wherein from 1 to 3 ring atoms are N, N(H), N(R ^d ) , O, and S, and the heteroaryl is optionally substituted with 1 to 4 R ^c . As a non-limiting example of the above embodiment, each R ^g1 is optionally substituted with 1 to 2 R ^c pyrazolyl, such as substituted with 1 to 6 independently selected R ^a It can be pyrazolyl optionally substituted with 1 to 2 independently selected C _1-6 (eg C _1-3 )alkyl which may be optionally substituted (eg unsubstituted).

In some embodiments, the compound has the formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Id), or (Id-1) and R ^1a is H.

In some embodiments, the compound has the formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Ie), or (Ie-1) and R ^1b is H.

In some embodiments, the compound has the formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Ie), or (Ie-1) and R ^1b is halo, such as -F or -Cl (eg -F).

In some embodiments, the compound has the formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Ie), or (Ie-1) and R ^1b is independently a 5 ring atom heteroaryl in which 1 to 3 ring atoms are N, N(H), N(R ^d ), O, and S and wherein the heteroaryl is optionally substituted with 1 to 2 R ^c . In some of these embodiments, R ^1b is pyrazolyl, optionally substituted with 1 to 2 R ^c , for example, each R ^c is substituted with 1 to 6 independently selected is an independently selected C _1-6 (eg, C _1-3 ) alkyl optionally substituted (eg, unsubstituted) with R ^a .

In some embodiments, the compound has the formula (Ia), (Ia-1), (Ib), (Ib-1), (Id), (Id-1), (Ie), or (Ie-1) and R ^1c is H.

In some embodiments, the compound has the formula (Ia), (Ia-1), (Ib), (Ib-1), (Id), (Id-1), (Ie), or (Ie-1) and R ^1c is halo, such as -F or -Cl (eg -F).

In some embodiments, the compound has the formula (Ia), (Ia-1), (Ic), (Ic-1), (Id), (Id-1), (Ie), or (Ie-1) and R ^1d is H.

In some embodiments, the compound has the formula (Ia), (Ia-1), (Ic), (Ic-1), (Id), (Id-1), (Ie), or (Ie-1) and R ^1d is halo, such as -F or -Cl (eg -F).

In some embodiments, the compound has formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Id), (Id-1), (Ie) or (Ie-1), when R ^1a and R 1d are present, R ^1a and R ^1d are H, and when R ^1b and ^{R 1c are} present, R ^1b and R ^1c is independently selected halo, such as -F or -Cl, such as -F.

In some embodiments, the compound has formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Id), (Id-1), (Ie) or (Ie-1), when R ^1a and R 1d are present, R ^1a and R ^1d are H, and when R ^1b and ^{R 1c are} present, R ^1b and R ^1c One of them is H and when R ^1b and R ^1c are present, the other of R ^1b and R ^1c is halo, eg -F or -Cl, eg -F.

In some embodiments, the compound has formula (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Id), (Id-1), (Ie), or (Ie-1), and when R ^1a and R ^1d are present, R ^1a and R ^1d are H, and when R ^1c is present, R ^1c is halo or H, e.g. -F, -Cl, or H, and when R ^1b is present, R ^1b is a 5 ring atom heteroaryl with 1 to 3 ring atoms containing N, N(H), N( R ^d ), O, and S, and the heteroaryl is optionally substituted with 1 to 4 R ^c .

Variable symbol R ⁶
In some embodiments, R ⁶ is H.

Variable symbol ring B
In some embodiments, Ring B is a 5 ring atom heteroarylene, wherein 1-3 of the ring atoms are each independently selected from the group consisting of N, NH, O, and S. A heteroarylene in which the heteroarylene of ring B is optionally substituted with 1 to 2 R ^cBs , each R ^cB being an independently selected R ^c .

In some embodiments, Ring B is a 5 ring atom heteroarylene, wherein 2-3 of the ring atoms are from the group consisting of N, NH, N(R ^d ), O, and S. Heteroarylene in ring B is optionally substituted with 1 to 2 R ^cB , each independently selected heteroatom, and each R ^cB is an independently selected R ^c It's Arilen.

In some embodiments, Ring B is a 5 ring atom heteroarylene, wherein 2-3 of the ring atoms are heteroatoms each independently selected from the group consisting of N and NH. , is a heteroarylene in which the heteroarylene of ring B is optionally substituted with 1-2 R ^cB , each R ^cB being an independently selected R ^c . As a non-limiting example of said embodiment, ring B is selected from the group consisting of imidazolylene, pyrazolylene, or triazorylene (eg 1,2,3-triazolylene) optionally substituted with one R ^cB .

In certain embodiments, ring B is imidazolylene optionally substituted with one R ^cB .

であり、ここで、aaは（L^A）_a1への接続点である。 In certain embodiments, ring B is optionally substituted with one R ^cB

, where aa is the connection point to (L ^A ) _a1 .

であり、ここで、aaは（L^A）_a1への接続点である。 In certain embodiments, ring B is optionally substituted with one R ^cB

, where aa is the connection point to (L ^A ) _a1 .

In certain embodiments, ring B is a triazorylene (eg, 1,2,3-triazolylene) optionally substituted with one R ^cB .

であり、ここで、aaは（L^A）_a1への接続点である。 In certain embodiments, ring B is optionally substituted with one R ^cB

, where aa is the connection point to (L ^A ) _a1 .

In certain embodiments, ring B is pyrazolylene optionally substituted with one R ^cB .

であり、ここで、aaは（L^A）_a1への接続点である。 In certain embodiments, each ring B is optionally substituted with one R ^cB

, where aa is the connection point to (L ^A ) _a1 .

であり、ここで、aaは（L^A）_a1への接続点である。 In certain embodiments, each ring B is optionally substituted with one R ^cB

, where aa is the connection point to (L ^A ) _a1 .

In certain embodiments, each R ^cB is independently a halo or with 1 to 3 independently selected R ^a (e.g., 1 to 3 independently selected halos). It is C _1-3 alkyl which may be substituted.

In some embodiments, ring B is selected from the group consisting of isoxazolylene, oxadiazolyl, oxazolyl, thiazolyl, isothiazolylene, or thiadiazolyl, optionally substituted with one R ^cB .

であり、ここで、aaは（L^A）_a1への接続点である。 In certain embodiments, each ring B is optionally substituted with one R ^cB

, where aa is the connection point to (L ^A ) _a1 .

であり、ここで、aaは（L^A）_a1への接続点である。 In certain embodiments, each ring B is optionally substituted with one R ^cB

, where aa is the connection point to (L ^A ) _a1 .

であり、ここで、aaは（L^A）_a1への接続点である。 In certain embodiments, each ring B is optionally substituted with one R ^cB

, where aa is the connection point to (L ^A ) _a1 .

であり、ここで、aaは（L^A）_a1への接続点である。 In certain embodiments, ring B is optionally substituted with one R ^cB

, where aa is the connection point to (L ^A ) _a1 .

であり、ここで、aaは（L^A）_a1への接続点である。 In certain embodiments, each ring B is optionally substituted with one R ^cB

, where aa is the connection point to (L ^A ) _a1 .

であり、ここで、aaは（L^A）_a1への接続点である。 In certain embodiments, each ring B is optionally substituted with one R ^cB

, where aa is the connection point to (L ^A ) _a1 .

In certain embodiments, each R ^cB is independently a halo or with 1 to 3 independently selected R ^a (e.g., 1 to 3 independently selected halos). It is C _1-3 alkyl which may be substituted.

Variable symbols a1 and L ^A
In some embodiments, a1 is 0. In some other embodiments, a1 is 1.

In some embodiments, L ^A is C _1-3 alkylene optionally substituted with 1-2 R ^a1 . In some of these embodiments, ^LA is _CH2 or CH(Me), such as _CH2 .

In some embodiments, a1 is 1 and L ^A is C _1-3 alkylene optionally substituted with 1-2 R ^a1 . In some of these embodiments, ^LA is _CH2 or CH(Me), such as _CH2 .

Variable symbol ring C
In some embodiments, ring C is
・Heteroarylene with 5 to 10 ring atoms, in which 1 to 3 ring atoms are from the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2} a heteroarylene, each independently selected heteroatom, wherein said heteroarylene is optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^cC and R ^hC ; and - selected from the group consisting of C _6-10 arylene, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^cC and R ^hC ,
Each R ^cC is an independently selected R ^c and each R ^hC is an independently selected R ^h .

In some of these embodiments, ring C is
- Heteroarylene of 5 to 6 (e.g. 6) ring atoms, in which 1 to 3 (e.g. 1 to 2) ring atoms are N, N(H), N(R ^d ), O, and S(O) is a heteroatom each independently selected from the group consisting of _{0 to 2} , and the heteroarylene is substituted with 1 to 4 substituents independently selected from the group consisting of R ^cC . C ₆ arylene, optionally substituted with 1 to 4 substituents independently selected from the group consisting of; and -R ^cC ;

Certain embodiments (ring C is a heteroarylene of 5 to 10 ring atoms, and 1 to 3 ring atoms are N, N(H), N(R ^d ), O, and S(O ) heteroatoms each independently selected from the group consisting of _{0 to 2} , and the heteroarylene is substituted with 1 to 4 substituents independently selected from the group consisting of R ^cC and R ^hC ; and C _6-10 arylene optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^cC and R ^hC ; where each R ^cC is an independently selected R ^c and each R ^hC is an independently selected R ^h ), then the ring C is
・Pyridylene optionally substituted with 1 to 3 (for example, 1) substituents independently selected from the group consisting of R ^cC ; and ・1 to 1 independently selected from the group consisting of R ^cC selected from the group consisting of C ₆ arylene optionally substituted with 4 (eg 1 to 2) substituents;

の基であり、式中、Q¹、Q²、Q³、およびQ⁴のそれぞれ1つは、N、CH、およびCR^cCからなる群より独立して選択され、bbはR⁷への接続点であり、各R^cCは独立して選択されるR^cである。 In certain embodiments, ring C is of the formula:

, where each one of Q ¹ , Q ² , Q ³ , and Q ⁴ is independently selected from the group consisting of N, CH, and CR ^cC , and bb is the connection to R ⁷ points, and each R ^cC is an independently selected R ^c .

In certain embodiments, each one of Q ¹ , Q ² , Q ³ , and Q ⁴ is independently CH or CR ^cC . In certain other embodiments, one to two ^{(eg, one) of Q 1 , Q 2 , Q 3 , and Q 4 are N} ; Each of the remaining ones is independently CH or CR ^cC .

In some of the embodiments, ^Q2 is CH. In certain embodiments, ^Q3 is CH. In certain embodiments, Q ⁴ is N. In certain embodiments, Q ¹ is CH. In certain other embodiments, Q ¹ is CR ^cC .

、例えば

である。 In certain embodiments, ring C is

,for example

It is.

In certain embodiments, each R ^cC is substituted with -halo and 1 to 6 independently selected R ^a (e.g., 1 to 6 independently selected halo, e.g., -F) independently selected from the group consisting of C _1-6 (eg, C _1-3 )alkyl, which may be

In certain embodiments, each R ^cC is independently halo, such as -Cl or -F, such as -F.

Variable symbol R ⁷
In some embodiments, R ⁷ is R ^g .

In some embodiments, R ⁷ is
・C 3-12 cycloalkyl optionally substituted with 1 to 4 substituents independently selected from _the group consisting of oxo, R ^c7 , R ^h7 , and -(L ^g ) _bg -R ^h7 ; and - Heterocyclyl of 4 to 12 ring atoms, in which 1 to 3 ring atoms are the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2} 1 to 4 heteroatoms independently selected from the group consisting of oxo, R ^c7 , R ^h7 , and -(L ^g ) _bg -R ^h7 . optionally substituted with substituents selected from the group consisting of heterocyclyl, where each R ^c7 is independently selected R ^c and R ^h7 is independently selected R ^h be done.

In some of these embodiments, R ⁷ is
・C 4-8 (e.g. C ⁴ _, C 5 , or _{C 6 )} optionally substituted with 1 to 4 substituents independently selected from the group consisting of oxo, R _c7 , and R ^h7 cycloalkyl; and heterocyclyl of 4 to 8 (e.g. 4, 5, or 6) ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R ^d ), O, and S(O) _{0 to 2} , and the heterocyclyl is 1 to 4 heteroatoms independently selected from the group consisting of oxo, R ^c7 , and R ^h7 is selected from the group consisting of heterocyclyl, optionally substituted with a substituent.

In some of the above embodiments, R ⁷ is
・C ₆ cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c7 ; and ・Heterocyclyl with 6 ring atoms, with 1 to 2 ( For example, one of _the ring atoms of the ^heterocyclyl is selected from the group consisting of heterocyclyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c7 .

の基であり、式中、X⁷は、CH、CR^c7、またはN、例えばCHまたはNである。ある特定の態様（R⁷が

である場合）では、2つのR^c7基が存在する。 In some of these embodiments, R ⁷ is of the formula:

in which X ⁷ is CH, CR ^c7 , or N, such as CH or N. Certain aspects (R ⁷

), there are two R ^c7 groups.

の基であり、式中、X⁷はNまたはCHであり、各R^c7は独立して選択されるR^cである。ある特定の態様において、R⁷は、X⁷がNまたはCHである

、例えば

である。 In certain embodiments, R ⁷ is of the formula:

where X ⁷ is N or CH and each R ^c7 is an independently selected R ^c . In certain embodiments, ^R7 is such that ^X7 is N or CH

,for example

It is.

In some of the above embodiments, R ⁷ is
・C ₄ cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c7 ; and ・Heterocyclyl with 4 ring atoms, with 1 to 2 ( For example, one of _the ring atoms of the ^heterocyclyl is selected from the group consisting of heterocyclyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c7 .

の基であり、式中、X⁷は、CH、CR^c7、またはN、例えばCHまたはNである。ある特定の態様（R⁷が

である場合）では、2つのR^c7基が存在する。 In some of these embodiments, R ⁷ is of the formula:

in which X ⁷ is CH, CR ^c7 , or N, such as CH or N. Certain aspects (R ⁷

), there are two R ^c7 groups.

の基であり、式中、X⁷はNまたはCHであり、各R^c7は独立して選択されるR^cである。ある特定の態様において、R⁷は、X⁷がNまたはCHである

、例えば

である。 In certain embodiments, R ⁷ is of the formula:

where X ⁷ is N or CH and each R ^c7 is an independently selected R ^c . In certain embodiments, ^R7 is such that ^X7 is N or CH

,for example

It is.

であることができる。 In certain embodiments, R ⁷ is tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octanyl, or 2-azabicyclo[2.2.1]heptanyl, each optionally substituted with 1-2 R ^c7 selected from the group consisting of. For example, R ⁷ is

can be.

In certain embodiments, each R ^c7 is optionally substituted with independently selected halo, or 1 to 6 R ^a (e.g., 1 to 6 independently selected halo). Good C _1-3 alkyl. In some of these embodiments, each R ^c7 is independently halo, such as -F.

In some embodiments, R ⁷ is
・C _{4-5 cycloalkyl, optionally substituted with 1 to 4} substituents independently selected from the group consisting of R ^c7 ; and ・Heterocyclyl of 5 to 6 ring atoms, wherein 1 ~2 (e.g. 1) 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 the heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c7 .

の基であり、式中、X⁷は、CH、CR^c7、またはN、例えばCHまたはNである。 In certain embodiments, R ⁷ is of the formula:

in which X ⁷ is CH, CR ^c7 , or N, such as CH or N.

の基であり、式中、R^dは、1～3個の独立して選択されるR^aで置換されていてもよいC_1～6アルキルからなる群より独立して選択される。 In certain embodiments, R ⁷ is of the formula:

wherein R ^d is independently selected from the group consisting of C _1-6 alkyl optionally substituted with 1 to 3 independently selected R ^a .

であることができる。 In certain embodiments, R ⁷ is tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octanyl, or 2-azabicyclo[2.2.1]heptanyl, each optionally substituted with 1-2 R ^c7 selected from the group consisting of. For example, R ⁷ is

can be.

の化合物またはその薬学的に許容される塩であり、
式中、
R^1a、R^1b、R^1c、およびR^1dのそれぞれ1つは、独立して選択されるR¹であり、
B⁴はCまたはNであり、
B¹、B²、およびB³は、それぞれ独立して、CH、CR^cB、NH、N（R^d）、N、O、またはSであり、
Q¹、Q²、Q³、およびQ⁴は、N、CH、およびCR^cCからなる群よりそれぞれ独立して選択され、
R^cBおよびR^cCの各出現は、独立して選択されるR^cであり、かつ
各

は独立して単結合または二重結合であり、但し、B¹～B⁴を含む環はヘテロアリールである。 Non-Limiting Combinations In some embodiments, the compound has formula (I-a1-1):

or a pharmaceutically acceptable salt thereof,
During the ceremony,
each one of R ^1a , R ^1b , R ^1c , and R ^1d is independently selected R ¹ ;
B ⁴ is C or N;
B ¹ , B ² , and B ³ are each independently CH, CR ^cB , NH, N(R ^d ), N, O, or S;
Q ¹ , Q ² , Q ³ , and Q ⁴ are each independently selected from the group consisting of N, CH, and CR ^cC ;
Each occurrence of R ^cB and R ^cC is an independently selected R ^c , and each

are independently a single bond or a double bond, provided that the ring containing B ¹ to B ⁴ is heteroaryl.

In some embodiments of formula (I-a1-1), R ^1a and R ^1d are H, and R ^1b and R ^1c are independently H or halo.

In some embodiments of formula (I-a1-1), R ^1a and R ^1d are H and R ^1b and R ^1c are independently selected halo, such as -F or -Cl, such as -F. be.

In some embodiments of formula (I-a1-1), each one of R ^1a , R ^1b , R ^1c , and R ^1d is H.

In some embodiments of formula (I-a1-1), R ^1a and R ^1d are H, R ^1c is halo or H, such as -F, -Cl, or H, and R ^1b is a ring atom 5 heteroaryls in which 1 to 3 ring atoms are each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S; , wherein the heteroaryl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c .

In some embodiments of formula (I-a1-1), ^R2 is H. In some embodiments of formula (I-a1-1), R ⁵ is H. In some embodiments of formula (I-a1-1), ^R2 is H and ^R5 is H.

In some embodiments of formula (I-a1-1), R ⁶ is H.

In some embodiments of formula (I-a1-1), ^R2 is H, ^R5 is H, and ^R6 is H.

In some embodiments of formula (I-a1-1), B ⁴ is N, B ¹ is N, B ³ is CH or CR ^cB , and B ² is CH or CR ^cB . In certain embodiments, B ⁴ is N, B ¹ is N, B ³ is CH, and B ² is CH. In certain embodiments, B ⁴ is N, B ¹ is N, B ³ is CH, and B ² is CR ^cB .

In some embodiments of formula (I-a1-1), B ⁴ is N, B ¹ is N, B ³ is CH or CR ^cB , and B ² is N. In certain embodiments, B ⁴ is N, B ¹ is N, B ³ is CH, and B ² is N.

In some embodiments of formula (I-a1-1), B ⁴ is N, B ¹ is CH or CR ^cB , B ³ is CH or CR ^cB , and B ² is N. In certain embodiments, B ⁴ is N, B ¹ is CH, B ³ is CH, and B ² is N.

In some embodiments of formula (I-a1-1), B ⁴ is N, B ¹ is CH or CR ^cB , B ³ is N, and B ² is CH or CR ^cB . In certain embodiments, B ⁴ is N, B ¹ is CH, B ³ is N, and B ² is CH.

In some embodiments of formula (I-a1-1), B ⁴ is C, B ¹ is N, B ³ is CR ^cB , and B ² is O. In certain embodiments, B ⁴ is C, B ¹ is N, B ³ is CH, and B ² is O. In other embodiments, ^B4 is C, ^B1 is O, ^B3 is CH, and ^B2 is N.

In some embodiments of formula (I-a1-1), a1 is 0. In some embodiments of formula (I-a1-1), a1 is 1. In some embodiments of formula (I-a1-1), L ^A is CH ₂ or CH(Me).

In some embodiments of formula (I-a1-1), Q ¹ and Q ³ are CH or CR ^cC (eg, CH). In some embodiments of formula (I-a1-1), ^Q4 is N and ^Q2 is CH or ^CRcC , such as ^CRcC .

であり、ここで、bbはR⁷への接続点である。 In some embodiments of formula (I-a1-1), the ring containing Q ¹ to Q ⁴ is

, where bb is the connection point to ^R7 .

In some embodiments of formula (I-a1-1), R ^cC is halo, such as -F or -Cl, such as -F.

In some embodiments of formula (I-a1-1), R ⁷ is
・C ₆ cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c7 ; and ・Heterocyclyl with 6 ring atoms, with 1 to 2 ( For example, one of _the ring atoms of the ^heterocyclyl may be substituted with 1 to 4 substituents independently selected from the group consisting of R ^c7 , where each R ^c7 is R ^c independently selected from heterocyclyl; selected from the group.

の基であり、式中、X⁷は、CH、CR⁷、またはN、例えばCHまたはNである。これらの態様のうちのいくつかでは、2つのR^c7基が存在する。 In some embodiments of formula (I-a1-1), R ⁷ is the following formula:

in which X ⁷ is CH, CR ⁷ or N, such as CH or N. In some of these embodiments, two R ^c7 groups are present.

の基であり、式中、X⁷はNまたはCHであり、各R^c7は独立して選択されるR^cである。これらの態様のうちのいくつかにおいて、R⁷は、X⁷がNまたはCHである

、例えば

である。 In some embodiments of formula (I-a1-1), R ⁷ is the following formula:

where X ⁷ is N or CH and each R ^c7 is an independently selected R ^c . In some of these embodiments, ^R7 is such that ^X7 is N or CH.

,for example

It is.

In some embodiments of formula (I-a1-1), R ⁷ is
・C ₄ cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c7 ; and ・Heterocyclyl with 4 ring atoms, with 1 to 2 ( For example, one of _the ring atoms of the ^heterocyclyl is selected from the group consisting of heterocyclyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c7 .

の基であり、式中、X⁷は、CH、CR^c7、またはN、例えばCHまたはNである。ある特定の態様（R⁷が

である場合）では、2つのR^c7基が存在する。 In some embodiments of formula (I-a1-1), R ⁷ is the following formula:

in which X ⁷ is CH, CR ^c7 , or N, such as CH or N. Certain aspects (R ⁷

), there are two R ^c7 groups.

の基であり、式中、X⁷はNまたはCHであり、各R^c7は独立して選択されるR^cである。ある特定の態様において、R⁷は、X⁷がNまたはCHである

、例えば

である。 In some embodiments of formula (I-a1-1), R ⁷ is the following formula:

where X ⁷ is N or CH and each R ^c7 is an independently selected R ^c . In certain embodiments, ^R7 is such that ^X7 is N or CH

,for example

It is.

であることができる。 In some embodiments of formula (I-a1-1), R ⁷ is tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octanyl, ^or selected from the group consisting of 2-azabicyclo[2.2.1]heptanyl; For example, R ⁷ is

can be.

In some embodiments of formula (I-a1-1), each R ^c7 is independently selected halo, or 1 to 6 R ^a (e.g., 1 to 6 independently selected C _1-3 alkyl optionally substituted with halo). In some of these embodiments, each R ^c7 is independently halo, such as -F.

は独立して単結合または二重結合であり、但し、B¹～B⁴を含む環はヘテロアリールであり、
R⁷は、X⁷がNまたはCHである

であり、
R^cの各出現は、ハロ;1～6個の独立して選択されるR^aで置換されていてもよいC_1～10アルキルからなる群より独立して選択され、
R^aの各出現は、-OH;-ハロ;C_1～4アルコキシ;C_1～4ハロアルコキシからなる群より独立して選択される。 In some embodiments, the compound is of formula (I-a1-1),
During the ceremony,
R ^1a and R ^1d are H;
R ^1b and R ^1c are each independently selected from H; and R ^c ;
R ² , R ⁵ , and R ⁶ are each independently H;
B ¹ is selected from CH and N,
B ² and B ⁴ are each independently N;
^B3 is CH;
Q ¹ is N, Q ² and Q ³ are each independently CH, Q ⁴ is CR ^c , and each

are independently a single bond or a double bond, provided that the ring containing B ¹ to B ⁴ is a heteroaryl,
^R7 is ^X7 is N or CH

and
each occurrence of R ^c is independently selected from the group consisting of halo; C _1-10 alkyl optionally substituted with 1 to 6 independently selected R ^a ;
Each occurrence of R ^a is independently selected from the group consisting of -OH; -halo; C _1-4 alkoxy; C _1-4 haloalkoxy.

の化合物またはその薬学的に許容される塩であり、
式中、
ZはNまたはCR^1aであり、Y¹はNまたはCR^1bであり、Y²はNまたはCR^1cであり、Y³はNまたはCR^1dであり、但し、Z、Y¹、Y²、およびY³のうちの1～2つ（例えば1つ）はNであり、
R^1a、R^1b、R^1c、およびR^1dのそれぞれ1つは、独立して選択されるR¹であり、
B⁴はCまたはNであり、
B¹、B²、およびB³は、それぞれ独立して、CH、CR^cB、NH、N（R^d）、N、O、またはSであり、
Q¹、Q²、Q³、およびQ⁴は、N、CH、およびCR^cCからなる群よりそれぞれ独立して選択され、
R^cBおよびR^cCの各出現は、独立して選択されるR^cであり、かつ
各

は独立して単結合または二重結合であり、但し、B¹～B⁴を含む環はヘテロアリールである。 In some embodiments, the compound has the formula (I-f1-1):

or a pharmaceutically acceptable salt thereof,
During the ceremony,
Z is N or CR ^1a , Y ¹ is N or CR ^1b , Y ² is N or CR ^1c , Y ³ is N or CR ^1d , provided that Z, Y ¹ , Y ² , and One or two (for example, one) of Y ³ are N,
each one of R ^1a , R ^1b , R ^1c , and R ^1d is independently selected R ¹ ;
B ⁴ is C or N,
B ¹ , B ² , and B ³ are each independently CH, CR ^cB , NH, N(R ^d ), N, O, or S;
Q ¹ , Q ² , Q ³ , and Q ⁴ are each independently selected from the group consisting of N, CH, and CR ^cC ;
Each occurrence of R ^cB and R ^cC is an independently selected R ^c , and each

are independently a single bond or a double bond, provided that the ring containing B ¹ to B ⁴ is heteroaryl.

In some embodiments of formula (I-f1-1), one of Z, Y ¹ , Y ² , and Y ³ is N.

の化合物またはその薬学的に許容される塩である。 In some embodiments of formula (I-f1-1), the compound has formula (I-b1-1):

or a pharmaceutically acceptable salt thereof.

の化合物またはその薬学的に許容される塩である。 In some embodiments of formula (I-f1-1), the compound has formula (I-c1-1):

or a pharmaceutically acceptable salt thereof.

の化合物またはその薬学的に許容される塩である。 In some embodiments of formula (I-f1-1), the compound has formula (I-d1-1):

or a pharmaceutically acceptable salt thereof.

の化合物またはその薬学的に許容される塩である。 In some embodiments of formula (I-f1-1), the compound has formula (I-d1-1):

or a pharmaceutically acceptable salt thereof.

In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , R ^1a and R ^1d are H, ^and when R ^1b and R ^1c are present, R ^1b and ^{R 1c are} independently H or halo.

In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , R ^1a and R ^1d are H, and when R ^1b and R ^1c are present, ^{R 1b and R 1c are} independently selected halo, such as -F or - Cl, for example -F.

In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , R ^1a , R ^1b , R ^1c , and R ^1d are present, each one of R ^1a , R ^1b , R ^1c , and R ^1d is H.

In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , R ^1a and R ^1d are H, and ^if R ^1c is present, ^{R 1c is} halo or H, such as -F, -Cl, or H, and R ^1b is If present, R ^1b is a 5 ring atom heteroaryl in which 1 to 3 ring atoms are each independently from the group consisting of N, N(H), N(R ^d ), O, and S. wherein the heteroaryl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c .

In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , R ^1d is an independently selected halo, such as -F ^or -Cl. In some of these embodiments, when R ^1a , R ^1b , and R ^1c are present, each one of R ^1a , R ^1b , and R ^1c is H.

In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , R ² is H. In some embodiments of formula (I-a1-1), R ⁵ is H. In some embodiments of formula (I-a1-1), ^R2 is H and ^R5 is H.

In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , R ⁶ is H.

In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , R ² is H, R ⁵ is H, and R ⁶ is H.

In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , B ⁴ is N, B ¹ is N, B ³ is CH or CR ^cB , B ² is CH or CR ^cB . In certain embodiments, B ⁴ is N, B ¹ is N, B ³ is CH, and B ² is CH. In certain embodiments, B ⁴ is N, B ¹ is N, B ³ is CH, and B ² is CR ^cB .

In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , B ⁴ is N, B ¹ is N, B ³ is CH or CR ^cB , and B ² is N. In certain embodiments, B ⁴ is N, B ¹ is N, B ³ is CH, and B ² is N.

In a part of formula (I-f1-1) (for example, formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)), B ⁴ is N, B ¹ is CH or CR ^cB , B ³ is CH or CR ^cB , B ² is N. In certain embodiments, B ⁴ is N, B ¹ is CH, B ³ is CH, and B ² is N.

In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , B ⁴ is N, B ¹ is CH or CR ^cB , B ³ is N, B ² is CH or CR ^cB . In certain embodiments, B ⁴ is N, B ¹ is CH, B ³ is N, and B ² is CH.

In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , a1 is 0. In some embodiments of formula (I-a1-1), a1 is 1. In some embodiments of formula (I-f1-1), L ^A is CH ₂ or CH(Me).

In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , Q ¹ and Q ³ are CH or CR ^cC (e.g. CH). In some embodiments of formula (I-f1-1), Q ⁴ is N and Q ² is CH or CR ^cC , such as CR ^cC .

であり、ここで、bbはR⁷への接続点である。 In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , the ring containing Q ¹ to Q ⁴ is

, where bb is the connection point to ^R7 .

In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , R ^cC is halo, eg -F or -Cl, eg -F.

In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , R ⁷ is
・C ₆ cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c7 ; and ・Heterocyclyl with 6 ring atoms, with 1 to 2 ( For example, one of _the ring atoms of the ^heterocyclyl may be substituted with 1 to 4 substituents independently selected from the group consisting of R ^c7 , wherein each R ^c7 is R ^c independently selected from heterocyclyl. selected from the group.

の基であり、式中、X⁷は、CH、CR⁷、またはN、例えばCHまたはNである。これらの態様のうちのいくつかでは、2つのR^c7基が存在する。 In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , R ⁷ is the following formula:

in which X ⁷ is CH, CR ⁷ or N, such as CH or N. In some of these embodiments, two R ^c7 groups are present.

の基であり、式中、X⁷はNまたはCHであり、各R^c7は独立して選択されるR^cである。これらの態様のうちのいくつかにおいて、R⁷は、X⁷がNまたはCHである

、例えば

である。 In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , R ⁷ is the following formula:

where X ⁷ is N or CH and each R ^c7 is an independently selected R ^c . In some of these embodiments, ^R7 is such that ^X7 is N or CH.

,for example

It is.

In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , R ⁷ is
・C ₄ cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c7 ; and ・Heterocyclyl with 4 ring atoms, with 1 to 2 ( For example, one of _the ring atoms of the ^heterocyclyl is selected from the group consisting of heterocyclyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c7 .

の基であり、式中、X⁷は、CH、CR^c7、またはN、例えばCHまたはNである。ある特定の態様（R⁷が

である場合）では、2つのR^c7基が存在する。 In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , R ⁷ is the following formula:

in which X ⁷ is CH, CR ^c7 , or N, such as CH or N. Certain aspects (R ⁷

), there are two R ^c7 groups.

の基であり、式中、X⁷はNまたはCHであり、各R^c7は独立して選択されるR^cである。ある特定の態様において、R⁷は、X⁷がNまたはCHである

、例えば

である。 In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , R ⁷ is the following formula:

where X ⁷ is N or CH and each R ^c7 is an independently selected R ^c . In certain embodiments, ^R7 is such that ^X7 is N or CH

,for example

It is.

であることができる。 In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , R ⁷ is selected from the group consisting of tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octanyl, or 2-azabicyclo[2.2.1]heptanyl, each optionally substituted with 1 to 2 R ^c7 be done. For example, R ⁷ is

can be.

In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , each R ^c7 is optionally substituted with independently selected halo or 1 to 6 R ^a (eg, 1 to 6 independently selected halo) C _1-3 It is an alkyl. In some of these embodiments, each R ^c7 is independently halo, such as -F.

In some embodiments of formula (I-f1-1) (e.g., formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)) , each R ^c7 is optionally substituted with independently selected halo or 1 to 6 R ^a (eg, 1 to 6 independently selected halo) C _1-3 It is an alkyl. In some of these embodiments, each R ^c7 is independently halo, such as -F.

Non-Limiting Exemplary Compounds In some embodiments, the compound is selected from the group consisting of the compounds shown in Table C1 or a pharmaceutically acceptable salt thereof.

Pharmaceutical Compositions and Administration Overview In some embodiments, a chemical entity, such as a compound that inhibits (e.g., antagonizes) STING, or a pharmaceutically acceptable salt thereof, and/or a hydrated (and/or co-crystals, and/or drug combinations) include a chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more pharmaceutically acceptable excipients as described herein. and multiple additional therapeutic agents.

In some embodiments, the chemical entity can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), such as d-alpha-tocopheryl succinate polyethylene glycol 1000, Tween, etc. Surfactants, poloxamers or other similar polymeric delivery matrices used in pharmaceutical dosage forms, serum proteins such as human serum albumin, buffer substances such as phosphate, Tris, glycine, sorbic acid, sorbic acid Potassium, 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, polyvinylpyrrolidone, Examples include, but are not limited to, cellulose-based materials, polyethylene glycols, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, and wool fat. Cyclodextrins, such as α, β, and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives, may also be used. Can be used to enhance the delivery of the compounds described herein. Dosage forms or compositions containing within the range of 0.005% to 100% of the chemical entities as described herein, with the remainder made up of non-toxic excipients, may be prepared. Envisioned compositions contain from 0.001% to 100%, in one aspect 0.1 to 95%, in another aspect 75 to 85%, and in a further aspect 20 to 80% of a chemical entity provided herein. You may. Actual methods of preparing such dosage forms will be known or apparent to those skilled in the art, see, eg, Remington: The Science and Practice of Pharmacy, ^22nd Edition (Pharmaceutical Press, London, UK. 2012).

Routes of Administration and Composition Components In some embodiments, the chemical entities described herein or pharmaceutical compositions thereof can be administered to a subject in need thereof by any approved route of administration. Acceptable routes of administration include buccal, cutaneous, intracervical, endosinusial, intratracheal, enteral, epidural, interstitial, intraabdominal, intraarterial, intrabronchial, intrasynovial, 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, intracanal, intratumoral, intrauterine, intravascular, intravenous, nasal, Nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral including, but not limited to, the urethra, and vagina. In certain embodiments, the preferred route of administration is parenteral (eg, intratumoral).

The compositions can be formulated for parenteral administration, eg, for injection via the intravenous, intramuscular, subcutaneous, or even intraperitoneal route. Typically, such compositions are prepared as injectables, either as liquid solutions or suspensions, with the addition of liquid prior to injection to prepare the solution or suspension. Solid forms suitable for the preparation can also be prepared and the preparations can also be emulsified. The preparation of such formulations is known to those skilled in the art in light of this disclosure.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions, formulations containing sesame oil, peanut oil, or aqueous propylene glycol, and for the extemporaneous preparation of sterile injectable solutions or dispersions. Sterile powders may be mentioned. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It should also be stable under the conditions of production and storage and must be protected against the contaminating action of microorganisms such as bacteria and fungi.

The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyols such as glycerol, propylene glycol, and liquid polyethylene glycol, suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. In many cases, it will be preferable to include isotonic agents, such as sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the composition of agents that delay 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 other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle that contains the basic dispersion medium and the required other ingredients from those enumerated above. For sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques, which remove the active ingredient and any additional additives from its previously sterile-filtered solution. yield a powder with the desired ingredients.

Intratumoral injection is discussed, for example, 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 that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (PEG ointments, etc.) ), glycerin, glycerinated gelatin, hydrogenated vegetable oil, poloxamer, mixtures of polyethylene glycol and fatty acid esters of polyethylene glycol of various molecular weights, Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, benzoic acid Sodium, anoxide SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, methyl sodium p-oxybenzoate, propyl sodium p-oxybenzoate, diethylamine, carbomer, carbopol, methyloxybenzoate, macrogolcetostearyl ether, cocoyl capri Rocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, Vitamins include, but are not limited to, any one or more of vitamins A and E, and potassium acetate.

In certain embodiments, suppositories contain the chemical entities described herein in a suitable non-irritating compound that is solid at ambient temperature but liquid at body temperature and thus dissolves in the rectum to release the active compound. excipients or carriers, such as cocoa butter, polyethylene glycols or suppository waxes. In other embodiments, the composition for rectal administration is in the form of an enema.

In other embodiments, the compounds described herein or pharmaceutical compositions thereof are suitable for local delivery to the gastrointestinal or GI tract via oral administration (eg, 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 may contain one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and/or a) fillers or fillers. , for example starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) Disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) Solution retarders, such as paraffin, f) Absorption enhancers, such as quaternary ammonium compounds, g) humectants, such as cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite clay, and i) lubricants, such as talc, calcium stearate, magnesium stearate. , solid polyethylene glycol, sodium lauryl sulfate, as well as mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain a buffering agent. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

In one aspect, the composition takes the form of a unit dosage form, such as a pill or tablet, such that the composition, along with the chemical entities provided herein, contains a diluent, e.g., lactose, sucrose, or It may also contain lubricants such as dicalcium phosphate, such as magnesium stearate, and binders such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, or cellulose derivatives. In another solid dosage form, the powder, marume, solution or suspension (e.g. in propylene carbonate, vegetable oil, PEG, poloxamer 124 or triglycerides) is encapsulated in capsules (gelatin or cellulose based capsules). Ru. A unit dosage form in which one or more chemical entities or additional active agents provided herein are physically separated, e.g., a capsule (or tablet in a capsule) having granules of each drug, two Layered tablets, two-compartment gel caps, etc. are also envisioned. Enteric coated or delayed release oral dosage forms are also envisioned.

Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents, or preservatives specifically 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 excipient is sterile and generally free of undesirable materials. These compositions can be sterilized by conventional, well-known sterilization techniques. Sterility is not required for excipients in various oral dosage forms such as tablets and capsules. USP/NF standards are usually sufficient.

In certain embodiments, the solid oral dosage form contains chemical and/or chemical agents for delivery of chemical entities to the stomach or lower GI, e.g., the ascending and/or transverse colon and/or the distal colon and/or the small intestine. Alternatively, the composition may further include one or more components that impart a structural predisposition to the composition. Exemplary formulation techniques are described, for example, in 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 technologies such as the Accordion Pill (Intec Pharma), floating capsules, and materials that can adhere to mucosal walls.

Other examples include lower GI targeting techniques. Several enteric/pH-responsive coatings and excipients are available to target various areas in the intestinal tract. These materials are typically polymers designed to dissolve or erode at specific pH ranges selected based on the GI region of desired drug release. These materials also function to protect acid-labile drugs from gastric fluids or to limit exposure if the active ingredient can be irritating to the upper GI (e.g., hydroxypropyl phthalate). Methylcellulose series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymer), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, pressure-controlled colonic delivery capsules, and Pulsincap.

Ophthalmic compositions contain viscogen (e.g. carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol), stabilizers (e.g. Pluronic (triblock copolymer), cyclodextrin), preservatives (e.g. benzalkonium chloride, ETDA). , SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride, Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex, Allergan, Inc.) Yes, but not limited to that.

External compositions can include ointments and creams. Ointments are semisolid preparations typically based on petrolatum or other petroleum derivatives. Creams containing the active agent of choice 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, sometimes referred to as the "inner" phase, generally contains petrolatum and an aliphatic alcohol, such as cetyl or stearyl alcohol, and the aqueous phase usually, but not necessarily, exceeds the oil phase in volume and is generally moist. Contains an agent. Emulsifiers in cream formulations are generally nonionic, anionic, cationic or amphoteric surfactants. Like other carriers or vehicles, ointment bases should be inert, stable, nonirritating and nonsensitizing.

In any of the foregoing embodiments, the pharmaceutical composition described herein comprises a lipid, an interbilayer crosslinked multilamellar vesicle, a biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particles supported lipid bilayers.

Dosage Dosage may vary depending on the needs of the patient, the severity of the condition being treated and the particular compound being used. Determination of the appropriate dosage for a particular situation can be determined by one of ordinary skill in the medical arts. The total daily dosage may be administered in divided doses or by means of providing continuous delivery throughout the day.

In some embodiments, the compounds described herein are about 0.001 mg/Kg to about 500 mg/Kg (e.g., about 0.001 mg/Kg to about 200 mg/Kg, about 0.01 mg/Kg to about 200 mg/Kg, Approximately 0.01mg/Kg to approximately 150mg/Kg, approximately 0.01mg/Kg to approximately 100mg/Kg, approximately 0.01mg/Kg to approximately 50mg/Kg, approximately 0.01mg/Kg to approximately 10mg/Kg, approximately 0.01mg/Kg to Approx. 5mg/Kg, approx. 0.01mg/Kg to approx. 1mg/Kg, approx. 0.01mg/Kg to approx. 0.5mg/Kg, approx. 0.01mg/Kg to approx. 0.1mg/Kg, approx. 0.1mg/Kg to approx. 200mg/Kg , about 0.1mg/Kg to about 150mg/Kg, about 0.1mg/Kg to about 100mg/Kg, about 0.1mg/Kg to about 50mg/Kg, about 0.1mg/Kg to about 10mg/Kg, about 0.1mg/Kg to about 5 mg/Kg, about 0.1 mg/Kg to about 1 mg/Kg, about 0.1 mg/Kg to about 0.5 mg/Kg).

Regimens The above dosages may be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or on a non-daily basis (e.g., every other day, every 2 days, every 3 days). It can be administered (daily, once a week, twice a week, once every two weeks, once a month).

In some embodiments, the period of administration of the compounds described herein is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days. Day, 12th, 13th, 14th, 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 further embodiments, the period during which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days. , 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In one aspect, the therapeutic compound is administered to an individual in one period followed by separate periods. In another aspect, the therapeutic compound is administered during a first period and a second period after the first period in which administration of the therapeutic compound is subsequently discontinued during the second period. and then in a fourth period after the third period when administration is discontinued. In one aspect of this embodiment, the period of administration of the therapeutic compound, followed by the period of cessation of administration, is repeated for a determined or undetermined period of time. In further embodiments, the period of administration is 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 further embodiments, the period during which administration is discontinued is 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, increasing (e.g., enhancing) STING activity (e.g., STING signaling) is associated with the pathology and/or symptoms and/or symptoms of a condition, disease, or disorder (e.g., immune disorder, cancer). Methods are provided for treating a subject having a condition, disease, or disorder that contributes to or contributes to the progression of the disease.

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 specific examples of such cancers include breast cancer, colon cancer, rectal cancer, colorectal cancer, kidney or renal cancer, clear cell cancer, small cell lung cancer, Lung cancer, including non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, squamous cell carcinoma (e.g. epithelial squamous cell carcinoma), cervical cancer, ovarian cancer, prostate cancer, prostate neoplasm , gastric or stomach cancers, including liver cancer, bladder cancer, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, gastrointestinal stromal tumors, pancreatic cancer, head and neck cancer. , glioblastoma, retinoblastoma, astrocytoma, capsular cell tumor, arenoblastoma, hepatoma, non-Hodgkin's lymphoma (NHL), multiple myeloma, myelodysplasia, myeloproliferative disorder, chronic myeloid Leukemia and hematological malignancies, including acute hematological malignancies, endometrial or uterine cancer, endometriosis, endometrial stromal sarcoma, fibrosarcoma, choriocarcinoma, salivary gland cancer, vulva Cancer, thyroid cancer, esophageal cancer, liver cancer, anal cancer, penile cancer, nasopharyngeal cancer, laryngeal cancer, Kaposi's sarcoma, mast cell sarcoma, ovarian sarcoma, uterine sarcoma, melanoma malignant mesothelioma, skin cancer, schwannoma, oligodendroglioma, neuroblastoma, neuroectodermal tumor, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcoma, Ewing sarcoma, peripheral tumor Differentiated neuroectodermal tumors, urinary tract cancer, thyroid carcinoma, Wilms tumor, as well as abnormal vascular proliferation associated with nevi, edema (e.g., associated with brain tumors), and Meigs Syndromes include. In some cases, the cancer is melanoma.

In some embodiments, the condition, disease, or disorder is a neurological disorder that includes the central nervous system (brain, brainstem, and cerebellum), peripheral nervous system (including cranial nerves), and autonomic nervous system (including the cranial nerves). (parts located in both the central and peripheral nervous systems) are included. Non-limiting examples of such neurological disorders include acquired epileptic aphasia, acute powdery encephalomyelitis, adrenoleukodystrophy, age-related macular degeneration, hypoplasia of the corpus callosum, agnosia, and aneurysms. syndrome, Alexander disease, Alpers disease, alternating hemiplegia, Alzheimer's disease, vascular dementia, amyotrophic lateral sclerosis, anencephaly, Angelman syndrome, angiomatosis, anoxia, aphasia, apraxia, Arachnoid cyst, 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, muscle atrophy, benign intracranial hypertension, Binswanger disease, blepharospasm, Bloch-Sulzberger syndrome, brachial plexus injury , brain abscess, brain injury, brain tumor (including glioblastoma multiforme), spinal cord tumor, Brown-Séquard syndrome, Canavan disease, carpal tunnel syndrome, burning pain, central pain syndrome, central pontine myelinolysis, head disorders, cerebral aneurysms, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, Charcot-Marie-Tooth disease, chemotherapy-induced neuropathy and neuropathic pain, Chiari malformation, chorea, chronic inflammatory demyelinating multiplex Neuropathy, chronic pain, chronic regional pain syndrome, Coffin-Lowry syndrome, coma including persistent vegetative state, congenital facial diplegia, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob Cumulative Traumatic Disorder, Cushing's Syndrome, Giant Cell Inclusion Body Disease, Cytomegalovirus Infection, Dancing Eyes-Dancing Feet Syndrome, Dandy-Walker Syndrome, Dawson's Disease, Demorcia Syndrome, Dejerine-Klumke Palsy, Dementia , dermatomyositis, diabetic neuropathy, diffuse sclerosis, autonomic imbalance, dysgraphia, dyslexia, dystonia, early infantile epileptic encephalopathy, empty cell syndrome, encephalitis, encephalocele, cerebral trigeminal angiomatosis, Epilepsy, Erb's palsy, essential tremor, Fabry disease, Fahr syndrome, syncope, familial spastic paralysis, febrile seizures, Fischer syndrome, Friedreich's ataxia, frontotemporal dementia and other "tauopathies", Gaucher disease , Gerstmann syndrome, giant cell arteritis, giant cell inclusion body disease, globoid cell leukodystrophy, Guillain-Barre syndrome, HTLV-1-associated myelopathy, Hallerholden-Spatz disease, head injury, headache, hemifacial spasm, hereditary Spastic paraplegia, hereditary ataxia polyneuritis, herpes zoster, herpes zoster, Hirayama syndrome, HIV-associated dementia and neuropathy (also a neurological manifestation of AIDS), holoprosencephaly, Huntington's disease and others Polyglutamine repeat disease, hydrocephalic anencephaly, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, ataxia pigmentosa, infantile phytanic acid storage disease, infantile Refsum disease, epilepsy, inflammation sexual myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsborne syndrome, Klippel-Feil syndrome, Krabbe disease, Kugelberg-Wellander disease, Kuru, Lafora disease, Lambert-Eaton myasthenia syndrome, Landau-Kleffner syndrome, lateral medullary (Wallenberg) syndrome, learning disabilities, Leigh 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, Melkerson-Rosenthal syndrome, Menieres disease, meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, migraine, Miller-Fisher syndrome, minor stroke, mitochondrial myopathy, Mobius syndrome, single limb Muscular atrophy, motor neuron disease, moyamoya disease, mucopolysaccharidoses, milti-infarct dementia, multifocal motor neuropathy, multiple sclerosis and other demyelinating disorders, orthostatic hypotension. multiple system atrophy, p muscular dystrophy, myasthenia gravis, myelinoclastic diffuse sclerosis, infantile myoclonic encephalopathy, myoclonus, myopathy, congenital muscular rigidity, narcolepsy , neurofibromatosis, neuroleptic malignant syndrome, neurological symptoms of AIDS, neurological sequelae of lupus, neurogenic myotonia, neuronal ceroid lipofuscinosis, neuronal migration disorder, Niemann-Pick disease, O'Sullivan- McLeod syndrome, occipital neuralgia, occult spinal dysraphism sequence, Otahara syndrome, olivopontocerebellar atrophy, opsoclonus-myoclonus, optic neuritis, orthostatic hypotension, overuse syndrome, paresthesia, Parkinson's disease , congenital paramyotonia, paraneoplastic disease, seizures, Paley-Romberg syndrome, Pelizaus-Merzbacher disease, periodic paralysis, peripheral neuropathy, painful neuropathy and neuropathic pain, persistent vegetative state , pervasive developmental disorder, photo-sneeze reflex, phytanic acid storage disease, Pick's disease, pinched nerve, pituitary tumor, polymyositis, porencephaly, post-polio syndrome, postherpetic neuralgia, post-infectious encephalomyelitis , orthostatic hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion disease, progressive hemifacial atrophy, progressive multifocal leukoencephalopathy, progressive sclerosing polyodystrophy, progressive supranuclear palsy, pseudotumor cerebri , Ramsay-Hunt syndrome (types I and II), Rasmussen encephalitis, reflex sympathetic dystrophy syndrome, Refsum disease, repetitive movement disorder, repetitive stress injury, restless leg syndrome, retrovirus-associated myelopathy, Rett syndrome , Reye's syndrome, chorea, Sandhoff's disease, Schilder's disease, schizencephaly, septo-optic dysplasia, shaken baby syndrome, herpes zoster, Shy-Drager syndrome, Sjögren's syndrome, sleep apnea, Sotos syndrome, spasticity, bifidism Spinal cord, spinal cord injury, spinal cord tumor, spinal muscular atrophy, stiff person syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical atherosclerotic encephalopathy, Sydenham chorea, syncope, syringomyelia, slow Pathogenic dyskinesia, Tay-Sachs disease, temporal arteritis, spinal cord tethering syndrome, Thomsen's disease, thoracic outlet syndrome, trigeminal neuralgia, Todd's palsy, Tourette's syndrome, transient ischemic attack, transmissible spongiform encephalopathy, transverse spinal cord inflammation, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paraplegia, tuberous sclerosis, vascular dementia (multiinfarct dementia), vasculitis including temporal arteritis, von Hippel-Lindau disease, These include Wallenberg syndrome, Werdnig-Hoffmann disease, West syndrome, whiplash syndrome, Williams syndrome, Wildon's disease, amyotrophic lateral sclerosis, and Zellweger syndrome.

In some embodiments, the condition, disease, or disorder is a STING-related condition, e.g., type I interferonosis (e.g., infantile-onset STING-associated vasculitis (SAVI)), Ecardi-Goutière syndrome (AGS), inherited lupus, and inflammation-related disorders such as systemic lupus erythematosus and rheumatoid arthritis. In certain embodiments, the condition, disease, or disorder is an autoimmune disease (eg, a cytosolic DNA-induced autoinflammatory disease). Non-limiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel diseases (including Crohn's disease (CD) and ulcerative colitis (UC), which are chronic inflammatory conditions with polygenic susceptibility). IBD). In certain embodiments, the condition is 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, adoptive cell therapy Colitis induced by treatment with, colitis associated with one or more alloimmune diseases (e.g., graft-versus-host disease, e.g., acute graft-versus-host disease and chronic graft-versus-host disease), radiation These are genital colitis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation colitis. In some of these embodiments, the condition is an alloimmune disease (e.g., graft-versus-host disease, e.g., acute graft-versus-host disease and chronic graft-versus-host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (eg, oral mucositis, esophageal mucositis, or intestinal mucositis).

In some embodiments, modulation of the immune system by STING provides treatment for diseases, including diseases caused by foreign agents. Exemplary infections caused by foreign agents that may be treated and/or prevented by the methods of the invention include infections caused by bacteria (e.g., gram-positive or gram-negative bacteria), infections caused by fungi, infections caused by parasites, and Examples include infectious diseases caused by viruses. In one aspect of the invention, the infection is a bacterial infection (e.g., E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella spp., Staphylococcus spp. infection with Staphylococcus aureus, Streptococcus spp., or vancomycin-resistant enterococcus), or sepsis. In another embodiment, the infection is a fungal infection (eg, an infection with mold, yeast, or higher fungi). In yet another aspect, the infection is caused by a parasitic infection (e.g., Giardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, and Toxoplasma gondii). infections caused by unicellular or multicellular parasites, including Toxoplasma gondiz). In yet another aspect, the infectious disease is a viral infection (e.g., AIDS, avian influenza, chickenpox, cold sores, common cold, gastroenteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS). , and infections caused by viruses associated with lower or upper respiratory tract infections (e.g., respiratory syncytial virus).

In some embodiments, the condition, disease, or disorder is hepatitis B (see, eg, WO 2015/061294).

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

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

In some aspects, the condition, disease, or disorder occurs as a result of damage caused by exposure to radiation outside the context of radiation therapy, as well as chemotherapy or radiation therapy, either alone or in combination. canker sores, also known as stomatitis.

In some embodiments, the condition, disease, or disorder is an inflammation of the uvea, such as uveitis (e.g., anterior uveitis, e.g., iridocyclitis or iritis, intermediate uveitis) (also known as pars planitis), posterior uveitis, or chorioretinitis (eg, panuveitis).

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

Still other examples may include the indications discussed below herein and in the envisioned combination therapy regimens.

Combination Therapy The present disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

In some embodiments, the methods described herein include administering one or more additional therapies (e.g., one or more additional therapeutic agents and/or The method may further include administering one or more therapeutic regimens).

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

One or more additional cancer therapies include surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine, hepatitis B vaccine, Oncophage, Provenge), and In addition to gene therapy, mention may be made of, but not limited to, combinations thereof. Immunotherapy includes, but is not limited to, other treatments including, but not limited to, adoptive cell therapy, stem cell and/or dendritic cell induction, blood transfusions, lavage, and/or tumor freezing. Not that it will be done.

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

In certain embodiments, the additional chemotherapeutic agent is an immunomodulatory moiety, such as an immune checkpoint inhibitor. In some of these embodiments, the immune checkpoint inhibitor targets an immune checkpoint receptor, and the immune checkpoint receptor is 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 cells 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- Contains BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, BTNL2 Butyrophilin, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, 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 some of these embodiments, the immune checkpoint inhibitor is urelumumab, PF-05082566, MEDI6469, TRX518, valilumab, CP-870893, pembrolizumab (PD1), nivolumab (PD1), atezolizumab (formerly MPDL3280A) (PDL1 ), MEDI4736 (PD-L1), Avelumab (PD-L1), PDR001 (PD1), BMS-986016, MGA271, Lililumab, IPH2201, Emactuzumab, INCB024360, Galunisertib, Urokupulumab, BKT140, Bavituximab, CC-90002, Bevacizumab, and selected from the group consisting of MNRP1685A, and MGA271.

In certain embodiments, the additional chemotherapeutic agent is an alkylating agent. Alkylating agents are so named for their ability to alkylate many nucleophilic functional groups under conditions present in cells, including but not limited to cancer cells. . In further embodiments, alkylating agents include, but are not limited to, cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, and/or oxaliplatin. In one aspect, alkylating agents can function by impairing cellular function by forming covalent bonds with amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules; Or they can work by modifying the DNA of cells. In further embodiments, the alkylating agent is synthetic, semi-synthetic or derivative.

In certain embodiments, the additional chemotherapeutic agent is an antimetabolite. Antimetabolites impersonate the building blocks of DNA, purines or pyrimidines, and generally prevent the incorporation of these substances into DNA during the "S" phase (of the cell cycle), allowing normal development and division. to be discontinued. Antimetabolites can also affect RNA synthesis. In one aspect, antimetabolites include, but are not limited to, azathioprine and/or mercaptopurine. In further embodiments, the antimetabolite is synthetic, semi-synthetic or derivative.

In certain embodiments, the additional chemotherapeutic agent is a plant alkaloid and/or terpenoid. These alkaloids are derived from plants and generally block cell division by preventing microtubule function. In one embodiment, the plant alkaloids and/or terpenoids are vinca alkaloids, podophyllotoxins and/or taxanes. Vinca alkaloids generally bind to specific sites on tubulin and inhibit tubulin assembly into microtubules, generally during the M phase of the cell cycle. In one aspect, the vinca alkaloid is derived from, but is not limited to, Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). In one aspect, vinca alkaloids include, but are not limited to, vincristine, vinblastine, vinorelbine and/or vindesine. In one aspect, taxanes include, but are not limited to, taxol, paclitaxel, and/or docetaxel. In further embodiments, the plant alkaloid or terpenoid is synthetic, semi-synthetic or derivative. In a further embodiment, the podophyllotoxin is, but is not limited to, etoposide and/or teniposide. In one embodiment, the taxane is, but is not limited to, docetaxel and/or ortataxel. [021] In one embodiment, the cancer therapeutic agent is a topoisomerase. Topoisomerases are essential enzymes that maintain the topology of DNA. Inhibition of type I or type II topoisomerases interferes with both DNA transcription and replication by disrupting proper DNA supercoiling. In further embodiments, the topoisomerase is, but is not limited to, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In one embodiment, the type I topoisomerase inhibitor is, but is not limited to, camptothecin. In another embodiment, the camptothecin is, but is not limited to, exatecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67) and/or ST 1481. In one embodiment, the type II topoisomerase inhibitor is, but is not limited to, epipodophyllotoxin. In further embodiments, the epipodophyllotoxin is, but is not limited to, amsacrine, etoposide, etoposide phosphate, and/or teniposide. In a further aspect, the topoisomerase is synthetic, semi-synthetic or derivative, such as epipodophyllotoxin, a substance naturally occurring in the roots of Mayapple (Podophyllum peltatum). These include, but are not limited to, those found in nature.

In certain embodiments, the additional chemotherapeutic agent is a stilbenoid. In further embodiments, the stilbenoids include resveratrol, piceatannol, pinosylvin, pterostilbene, alpha-viniferin, ampelopsin A, ampelopsin E, dyptinodonesin C, dyptinodonesin F, Epsilon-Vinferin, Examples include, but are not limited to, Flexuosol A, Gnetin H, Hemsleyanol D, Hopeaphenol, trans-diptoindonesin B, astringin, piceide and dyptoindonesin A. In further embodiments, the stilbenoid is synthetic, semi-synthetic or derivative.

In certain embodiments, the additional chemotherapeutic agent is a cytotoxic antibiotic. In one aspect, the cytotoxic antibiotic is, but is not limited to, actinomycin, anthracenedione, anthracycline, thalidomide, dichloroacetic acid, nicotinic acid, 2-deoxyglucose, and/or chlofazimine. In one embodiment, the actinomycin is, but is not limited to, actinomycin D, bacitracin, colistin (polymyxin E) and/or polymyxin B. In another embodiment, the anthracenedione is, but is not limited to, mitoxantrone and/or pixantrone. In further embodiments, the anthracycline is, but is not limited to, bleomycin, doxorubicin (Adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, mitomycin, plicamycin, and/or valrubicin. In further embodiments, the cytotoxic antibiotic is synthetic, semi-synthetic or derivative.

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

In certain embodiments, the additional chemotherapeutic agent is abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3- Fluoro-4-methoxyphenyl)benzenesulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-L proline-t-butyramide , cachectin, cemadin, chlorambucil, cyclophosphamide, 3',4'-didehydro-4'-deoxy-8'-norbin-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, mibobulin isethionate, rhizoxin, sertenef (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, taxanes, 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 yet other embodiments, the additional chemotherapeutic agent can be selected from those described in detail in US Pat. No. 7,927,613, which is incorporated herein by reference in its entirety.

In some embodiments, additional therapeutic agents and/or regimens may be used to treat other STING-related conditions, such as type I interferonism (e.g., infantile-onset STING-associated vasculitis (SAVI)), Ecardi-Gouthière syndrome (AGS) , inherited forms of lupus, and inflammation-related disorders such as systemic lupus erythematosus and rheumatoid arthritis.

Non-limiting examples of additional therapeutic agents and/or regimens to treat rheumatoid arthritis include nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., ibuprofen and naproxen), corticosteroids (e.g., prednisone), disease modifying Sexual 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®), bovalizumab, sarilumab (Kevzara®), secukinumab, ABP 501, CHS-0214, ABC-3373, and tocilizumab (ACTEMRA®) Trademark))).

Non-limiting examples of additional therapeutic agents and/or regimens to treat lupus include steroids, topical immunomodulators (e.g., tacrolimus ointment (Protopic®)) and pimecrolimus cream (Elidel®). (registered trademark)), thalidomide (Thalomid®), non-steroidal anti-inflammatory drugs (NSAIDs, e.g. ibuprofen and naproxen), antimalarials (e.g. hydroxychloroquine (Plaquenil)), corticosteroids (e.g. prednisone) ) and immunomodulators (e.g., evobrutinib, iberdomide, voclosporin, senelimod, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®, Gengraf®), and mycophenolate mofetil) baricitinib (baricitinb), iguratimod, filgotinib (filogotinib, GS-9876, rapamycin, and PF-06650833), and Biologics (e.g., Benlysta®, anifrolumab, prezalumab, MEDI0700, obinutuzumab, bovalizumab, lulizumab, atacicept, PF-06823859, and lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapilrolizumab, edratide, IFN-α-quinoid, OMS721, RC18, RSLV-132, seralizumab, XmAb5871, and ustekinumab (Stelara®). For example, non-limiting treatments for systemic lupus erythematosus include nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., ibuprofen and naproxen), antimalarials (e.g., hydroxychloroquine (Plaquenil)), corticosteroids (e.g., prednisone) and immunomodulators (e.g., iberdomide, voclosporin, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral , Sandimmune®, Gengraf®), and mycophenolate mofetil, baricitinib, filgotinib, and PF-06650833), and biologics (e.g., belimumab (Benlysta®), anifrolumab, presalumab, MEDI0700) , bovalizumab, lulizumab, atacicept, PF-06823859, lupuzol, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirolizumab, edratide, IFN-α-quinoid, RC18, RSLV-132, seralizumab, 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, filgotinib, 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 to treat infantile-onset STING-associated vasculitis (SAVI) include JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib) .

Non-limiting examples of additional therapeutic agents and/or regimens to treat Ecardi-Gouthière syndrome (AGS) include physical therapy, treatment for respiratory complications, anticonvulsant therapy for seizures, tube feeding, nucleosides. 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 (eg, tofacitinib, ruxolitinib, filgotinib, and baricitinib).

Non-limiting examples of additional therapeutic agents and/or regimens to treat IBD include 6-mercaptopurine, AbGn-168H, ABX464, ABT-494, adalimumab, AJM300, alicaforsen, AMG139, anlukinsumab, apremilast, ATR-107 (PF0530900), autologous CD34-selected peripheral blood stem cell transplantation, azathioprine, vertilimumab, BI 655066, BMS-936557, certolizumab pegol (Cimzia®), cobitolimod, corticosteroids (e.g., prednisone, methyl prednisolone, prednisone), CP-690,550, CT-P13, cyclosporine, DIMS0150, E6007, E6011, etrasimod, etrolizumab, fecal microbial transplant, filgotinib, fingolimod, filategrast (SB-683699) (formerly known as 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, Salide Mide, 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 to treat irritable bowel syndrome include alosetron, bile acid sequesterants (e.g., cholestyramine, colestipol, colesevelam), chloride channels activators (e.g., lubiprostone), coated peppermint oil capsules, desipramine, dicyclomine, ebastine, eluxadrine, farnesoid (e.g. linaclotide, plecanatide), ibodutant, imipramine, JCM-16021, loperamide, lubiprostone, nortriptyline, ondansetron, opioids, paroxetine, pinaverium, polyethylene glycol, pregabalin, probiotics, ramosetron, rifaximin, and tenapanol (tanpanor).

Non-limiting examples of additional therapeutic agents and/or regimens to treat scleroderma include nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., ibuprofen and naproxen), corticosteroids (e.g., prednisone), immunotherapy Modulators (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, topical nitrates, iloprost, phosphodiesterase 5 inhibitors (e.g., sildenafil), bosentan, These include tetracycline antibiotics, endothelin receptor antagonists, prostanoids, and tyrosine kinase inhibitors (eg, imatinib, nilotinib, and dasatinib).

Non-limiting examples of additional therapeutic agents and/or regimens to treat Crohn's disease (CD) include adalimumab, autologous CD34-selected peripheral blood stem cell transplantation, 6-mercaptopurine, azathioprine, certolizumab pegol ( Cimzia®), corticosteroids (e.g. prednisone), etrolizumab, E6011, fecal microbial transplantation, filgotinib, 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 to treat UC include AbGn-168H, ABT-494, ABX464, apremilast, PF-00547659, PF-06687234, 6-mercaptopurine, adalimumab, Azathioprine, vertilimumab, brazikumab (MEDI2070), cobitolimod, certolizumab pegol (Cimzia®), CP-690,550, corticosteroids (e.g. multimax budesonide, methylprednisolone), cyclosporine, E6007, etrasimod, etrolizumab, fecal microbial transplantation, filgotinib, guselkumab, golimumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitors (e.g., GS-5745), mesalamine, mesalamine, mirikizumab (LY3074828) ), RPC1063, risankizumab (BI 6555066), SHP647, sulfasalazine, TD-1473, TJ301, tildrakizumab (MK 3222), tofacitinib, tofacitinib, ustekinumab, UTTR1147A, and vedolizumab.

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

Non-limiting examples of additional therapeutic agents and/or regimens to treat iatrogenic autoimmune colitis include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), diphenoxy These include leto/atropine, infliximab, loperamide, TIP60 inhibitors (see, eg, US Patent Application Publication No. 2012/0202848), and vedolizumab.

Non-limiting examples of additional therapeutic agents and/or regimens to treat colitis induced by one or more chemotherapeutic agents include corticosteroids (e.g., budesonide, prednisone, prednisolone, dipropion). acid beclomethasone), diphenoxylate/atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, eg, US Patent Application Publication No. 2012/0202848), and vedolizumab.

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

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

Non-limiting examples of additional therapeutic agents and/or regimens to treat 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 supplements, statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin), sucralfate, and vitamins An example is E.

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

Non-limiting examples of additional therapeutic agents and/or regimens to treat lymphocytic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, cholestyramine, colestipol, corticosteroids ( Examples include budesonide, prednisone, prednisolone, beclomethasone dipropionate), loperamide, mesalamine, methotrexate, and sulfasalazine.

Non-limiting examples of additional therapeutic agents and/or regimens to treat microscopic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, Boswellia serrata extract, cholestyramine, colestipol, cortico These include steroids (eg, budesonide, prednisone, prednisolone, beclomethasone dipropionate), fecal microbial transplants, loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.

Non-limiting examples of additional therapeutic agents and/or regimens to treat alloimmune diseases 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, daclizumab, defibrotide ( defribrotide), denileukin diftitox, glasdegib, ibrutinib, IL-2, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, These include ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

Non-limiting examples of additional therapeutic agents and/or regimens to treat 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, These include montelukast, natalizumab (Tysabri®), NeuroVax®, ocrelizumab, ofatumumab, pioglitazone, and RPC1063.

Non-limiting examples of additional therapeutic agents and/or regimens to treat graft-versus-host disease include abatacept, alemtuzumab, alpha1-antitrypsin, AMG592, antithymocyte globulin, baricitinib, basiliximab, bortezomib, bren. Tuximab, cannabidiol, corticosteroids (e.g. methylprednisolone, prednisone), cyclosporine, daclizumab, defibrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, itacitinib, LBH589, maraviroc, These include mycophenolate mofetil, natalizumab, nemolizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

Non-limiting examples of additional therapeutic agents and/or regimens to treat acute graft-versus-host disease include alemtuzumab, alpha-1 antitrypsin, antithymocyte globulin, basiliximab, brentuximab, and corticosteroids. (e.g. methylprednisolone, prednisone), cyclosporine, daclizumab, defibrotide, denileukin diftitox, ibrutinib, infliximab, itacitinib, LBH589, mycophenolate mofetil, natalizumab, nemolizumab, pentostatin, photopheresis, ruxolitinib, sirolimus , tacrolimus, and tocilizumab.

Non-limiting examples of additional therapeutic agents and/or regimens to treat chronic graft-versus-host disease include abatacept, alemtuzumab, AMG592, antithymocyte globulin, basiliximab, bortezomib, corticosteroids (e.g., methyl prednisolone, prednisone), cyclosporine, daclizumab, 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 to treat 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 to treat psoriasis include topical corticosteroids, topical crisaborole/AN2728, topical SNA-120, topical SAN021, topical Tapinarov, 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 Dipropionate Betamethasone dipropriate (Sernivo®), halobetasol propionate (Ultravate®), vitamin D analogs (e.g. calcipotriene (Dovonex®)) and calcitriol (Vectical® ))), anthralin (e.g. Dritho-scalp® and Dritho-creme®), topical retinoids (e.g. tazarotene (e.g. Tazorac® and Avage®)), calcineurin inhibition substances (e.g. tacrolimus (Prograf®) and pimecrolimus (Elidel®)), salicylic acid, coal tar, humectants, phototherapy (e.g. sunlight exposure, UVB phototherapy, narrowband UVB phototherapy) , Geckelmann 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, 494), aprmilast, tofacitibin, cyclosporine (Neoral®, Sandimmune®, Gengraf®), biologics (e.g. etanercept (Enbrel®)), etanercept-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, Milikizumab (LY3074828), PF-06410293, PF -06438179, risankizumab (BI655066), SB2, SB4, SB5, siliq (brodalumab), namilumab (MT203, tildrakizumab (MK-3222), and ixekizumab (Taltz®)), thioguanine, and hydroxyurea ( Examples include Droxia (registered trademark) and Hydrea (registered trademark).

Non-limiting examples of additional therapeutic agents and/or regimens for treating cutaneous T-cell lymphoma include phototherapy (e.g., sunlight exposure, UVB phototherapy, narrowband UVB phototherapy, Geckelmann therapy, psoralen + ultraviolet A (PUVA) therapy, and excimer laser), extracorporeal photopheresis, radiation therapy (e.g., spot radiation and whole-body skin electron beam therapy), stem cell transplantation, corticosteroids, imiquimod, bexarotene gel, topical bis-chloroethyl-nitrourea. (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 to treat uveitis include corticosteroids (e.g., intravitreal triamcinolone acetonide injectable suspension), antibiotics, antivirals ( For example, 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 implants ( Examples include fluocinolone inserts), and vitrectomy.

Non-limiting examples of additional therapeutic agents and/or regimens to treat mucositis include AG013, SGX942 (dusquetide), amifostine (Ethyol®), cryotherapy, sepachol lozenges ( cepacol lonzenge), 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 exosomes, antiseptic mouthwashes (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, nepidermine, soluble β-1,3/1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518 , IZN-6N4, quercetin, granules containing vaccinium myrtillus extract, macleaya cordata alkaloids and echinacea angustifolia extract (e.g. SAMITAL®), and gastrointestinal cocktails (acid reducing agents such as aluminum and magnesium hydroxides (eg, Maalox), antifungals (eg, nystatin), and analgesics (eg, hurricane liquid)). For example, non-limiting examples of treatments for oral mucositis include AG013, amifostine (Ethyol®), cryotherapy, Sepacol lozenges, mucoadhesives (e.g., MuGard®), oral diphenhydramine (e.g. , Benadry® elixir), oral bioadhesives (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), cafozole, chamomilla Rectita mouthwash, edible grape plant exosomes, antiseptic mouthwashes (e.g., chlorhexidine gluconate (e.g., Peridex® or Periogard®)), topical pain relievers (e.g., lidocaine, benzocaine, dyclonine hydrochloride) salts, 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 (acid reducers, e.g., aluminum hydroxide and magnesium hydroxide (e.g., Maalox), antifungal agents (e.g., nystatin) ); As an example, treatments for intestinal mucositis, treatments to modify intestinal mucositis, and treatments for signs and symptoms of intestinal mucositis include gastrointestinal cocktails (acid-reducing agents, such as aluminum hydroxide and magnesium hydroxide ( Examples include Maalox), antifungals (eg, nystatin), and analgesics (eg, hurricane liquid).

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

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

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

Patient Selection In some embodiments, the methods described herein identify a subject (e.g., a patient) in need of such treatment (e.g., by biopsy, endoscopy, or other methods known in the art). (via other conventional methods). In certain embodiments, STING proteins can serve as biomarkers for certain types of cancer, such as colon cancer and prostate cancer. In other embodiments, identifying the subject includes assaying the patient's tumor microenvironment for the absence of T cells and/or the presence of exhausted T cells, e.g., a patient with one or more cold tumors. can be included. Such patients can include those who are refractory to treatment with checkpoint inhibitors. In certain embodiments, such patients can be treated with the chemical entities herein, e.g., to recruit T cells to tumors; in some cases, e.g. Once the cells are exhausted, they can be further treated with one or more checkpoint inhibitors.

In some embodiments, the chemical entities, methods, and compositions described herein are useful for certain treatment-resistant patient populations (e.g., patients resistant to checkpoint inhibitors, e.g., one or Patients with multiple cold tumors, eg, tumors lacking T cells or exhausted T cells).

Compound Preparation Methods to synthesize compounds of the formulas herein will be apparent to those skilled in the art, as can be appreciated by those skilled in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in the synthesis of the compounds described herein are known in the art, and see, for example, R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989. ); TW 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 the preparation of the compounds of the invention are known, made by known methods, or commercially available. Those skilled in the art will also recognize that the conditions and reagents described herein are interchangeable with art-recognized alternative equivalents. For example, in many reactions triethylamine is used as a non-nucleophilic base such as diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene. ) can be interchanged with other bases such as

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

To further illustrate the foregoing, the following non-limiting, exemplary synthetic schemes are included. Variations of these embodiments within the scope of the claims are within the purview of those skilled in the art, are considered to be within the scope of the invention as described, and are claimed in this application. The reader will recognize that one of ordinary skill in the art, given this disclosure and skill in the art, can make and use the invention without the exhaustive examples.

The following abbreviations have the meanings indicated below.
Ac=acetyl
ACN=acetonitrile
Boc ₂ O = di-tert-butylpyrocarbonate
Bu=butyl
DCM=dichloromethane
DIEA=N,N-diisopropylethylamine
DMF=N,N-dimethylformamide
DMSO = dimethyl sulfoxide
DPPA = diphenyl azidophosphate
Dppf = bis(diphenylphosphino)ferrocene
HATU=2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
HPLC = high performance liquid chromatography
LC-MS=liquid chromatography-mass spectrometry
Me=methyl
NMR = nuclear magnetic resonance
RT=retention time
TEA=triethylamine
THF=tetrahydrofuran
TMS=tetramethylsilane
T ₃ P=2,4,6-tripropyl-2,4,6-trioxo-1,3,5,2,4,6-trioxatriphosphorinane
XPhos = (2-(2,4,6-triisopropylphenethyl)phenyl)dicyclohexylphosphine
DCC=N,N'-dicyclohexylcarbodiimide
DCE=dichloroethane
DMAP=dimethylaminopyridine
Ir[dF(CF3)ppy]2(dtbpy)PF6=iridium(1+),[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-κN1,κN1']bis[3 ,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC]-,(OC-6-33)-,hexafluorophosphate (1-) (1:1)
NBS=N-bromosuccinimide
NCS=N-chlorosuccinimide
NMM=N-methylmorpholine
PyBOP = benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
Selectfluor = 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate)
TFA = trifluoroacetic acid
Ts=p-toluenesulfonyl
t-AmOH=tert-amyl alcohol
TES=triethylsilane
AcOH=acetic acid
SOCl ₂ = sulfur dichloride oxide
CHCl ₃ = chloroform
MTBE=2-methoxy-2-methylpropane
MgSO ₄ = magnesium sulfate anhydride
EtOH=ethanol
NaOH=sodium hydroxide
HCl=hydrochloric acid
EDCI=1-(3-dimethylaminopropyl)-3-ethyl
Py = pyridine
RuPhos Pd G3 = methanesulfonato(2-dicyclohexylphosphino-2,6-di-i-propoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II)
XPhos Pd G3 = methanesulfonato(2-dicyclohexylphosphino-2,4,6-tri-i-propyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II )
K ₃ PO ₄ = potassium phosphate
EtOAc = ethyl acetate
Na ₂ SO ₄ = Sodium sulfate
FA = formic acid
MeOH=methanol
SpeedVac = Savant SC250EXP SpeedVac concentrator

material and method
LC-MS was recorded using one of the following methods.

LCMS method A: Kinetex EVO C18 100A, 30*3mm, injection volume 0.5μL, flow rate 1.2mL/min, scan range 90-900amu, UV detection 254nm. Mobile phase A (MPA): water/ _{5mM NH4HCO3} and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.30 min, 95% MPB to 10% in 0.10 min.

LCMS method B: Xselect CSH C18, 50*3mm, injection volume 1.0μL, flow rate 1.2mL/min, scan range 90-900amu, UV detection 254nm. 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 equilibrate to 5% MPB for 0.15 min.

LCMS method C: XBridge Shield RP18, 50*4.6mm, injection volume 0.5μL, flow rate 1.2mL/min, scan range 90-900amu, UV detection 254nm. 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 equilibrate to 10% MPB for 0.15 min.

LCMS method D: Shim-pack XR-ODS, 50*3mm, injection volume 0.3μL, flow rate 1.2mL/min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water/0.05 TFA and mobile phase B (MPB): acetonitrile/0.05% TFA. Elution: 1.10 min from 5% MPB to 100%, hold at 100% MPB for 0.60 min, 100% MPB to 5% in 0.05 min, then equilibrate to 5% MPB for 0.25 min.

LCMS method E: XBridge BEH C18, 50*3mm, injection volume 4.0μL, flow rate 1.2mL/min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water/ _{5mM 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 equilibrate to 5% MPB for 0.25 min.

LCMS method F: Kinetex 2.6μm EVO C18 100A, 50*3mm, injection volume 0.6μL, flow rate 1.2mL/min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water/ _{5mM NH4HCO3} and mobile phase B (MPB): acetonitrile. Elution: 1.20 min from 10% MPB to 95%, hold at 95% MPB for 0.50 min, 0.05 min from 95% MPB to 10%, then equilibrate to 10% MPB for 0.10 min.

LCMS method G: kinetex 2.6μm EVO, 50*3mm, injection volume 0.5μL, flow rate 1.2mL/min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water/ _{5mM NH4HCO3} and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.70 min, 95% MPB to 10% in 0.05 min, then equilibrate to 10% MPB for 0.25 min.

LCMS method H: Titank C18, 50*3mm, injection volume 0.5μL, flow rate 1.5mL/min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water/ _{5mM 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 equilibrate to 10% MPB for 0.25 min.

LCMS method I: XBridge BEH C18, 50*3mm, injection volume 4.0μL, flow rate 1.2mL/min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water/ _{5mM 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 equilibrate to 5% MPB for 0.25 min.

LCMS method J: HALOC18, 30*3mm, injection volume 0.5μL, flow rate 1.5mL/min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water/0.05% TFA and mobile phase B (MPB): acetonitrile/0.05% TFA. Elution: 1.20 min from 5% MPB to 100%, hold at 100% MPB for 0.60 min, 0.02 min from 100% MPB to 5%, then equilibrate to 5% MPB for 0.18 min.

LCMS method K: Ascentis Express C18, 50*3mm, injection volume 0.5μL, flow rate 1.5mL/min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water/0.05% TFA and mobile phase B (MPB): acetonitrile/0.05% TFA. Elution: 5% MPB to 100% in 2.00 min, hold at 100% MPB for 0.70 min, 100% MPB to 5% in 0.05 min, then equilibrate to 5% MPB for 0.25 min.

The NMR is BRUKER NMR 300.03Mz, DUL-C-H, ULTRASHIELD(TM) 300, AVANCE II 300 B-ACS(TM) 120 or BRUKER NMR 400.13Mz, BBFO, ULTRASHIELD(TM) 400, AVANCE III 400, B-ACS( Trademark) recorded at 120.

Preparation Examples Preparation Scheme of Key Intermediate: The following scheme illustrates the preparation of the key intermediate.

Scheme 1: Synthesis of intermediate 1 (1-(6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)-1H-imidazole-4-carboxylic acid)

Step 1: 2-(4,4-difluoropiperidin-1-yl)-3-methyl-5-nitropyridine
2-chloro-3-methyl-5-nitropyridine (5.0 g, 28.9 mmol, 1.0 eq.) was dissolved in ACN (100 mL), then 4,4-difluoropiperidine (4.2 g, 34.7 mmol, 1.2 eq.) and _Cs2CO3 (18.8g, _57.9mmol , 2.0eq) were added. The resulting mixture was heated to 80° C. for 16 hours, then cooled to room temperature. 2-(4,4-difluoropiperidin-1-yl)-3-methyl-5-nitropyridine (6 g) was purified to a brown color by filtration and washing the solid with MeOH and then concentrating the filtrate under vacuum. Obtained as a solid. LCMS method B: [M+H] ⁺ =258.

Step 2: 6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-amine
2-(4,4-difluoropiperidin-1-yl)-3-methyl-5-nitropyridine (6.0 g, 23.3 mmol, 1.0 eq.) was dissolved in MeOH (50 mL) and then Pd/C (1.0 g , 10% wt.) was added. The mixture was sparged with nitrogen, placed under a hydrogen gas atmosphere (balloon), and then stirred at ambient temperature overnight. The solids were removed by filtration and the filtrate was concentrated under vacuum to give 6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-amine (4.8 g) as a brown oil. Obtained. LCMS method B: [M+H] ⁺ =228.

Steps 3-4: Ethyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl]imidazole-4-carboxylate
6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-amine (2.0 g, 8.8 mmol, 1.0 eq.) was dissolved in EtOH (20 mL) and AcOH (1 mL), then Ethyl 2-nitroacetate (1.1 g, 8.8 mmol, 1.0 eq.) was added. The reaction mixture was heated to 80° C. for 30 minutes, then cooled to ambient temperature. Triethoxymethane (6.5 g, 44.0 mmol, 5.0 eq.) was then added and the resulting solution was heated at 80° C. for 2 hours. After cooling to ambient temperature, AcOH (10 mL) and triethoxymethane (10 mL) were added, followed by Fe (0.3 g, 5.4 mmol, 1.0 eq) in portions. 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, 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-[6-(4,4-difluoropiperidin-1-yl)-5-methyl Ethyl pyridin-3-yl]imidazole-4-carboxylate (600 mg) was obtained as an off-white solid. Method A: [M+H] ⁺ =351.

Step 5: 1-[6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl]imidazole-4-carboxylic acid
Ethyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl]imidazole-4-carboxylate (500.0 mg, 1.4 mmol, 1.0 eq.) in MeOH/H ₂ O (5:1, 12 mL) and then added NaOH (85.6 mg, 2.1 mmol, 1.5 eq.). The resulting solution was heated to 50° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water and the solution was then adjusted to pH 2 with aqueous HCl (6M). The solid was collected by filtration and dried to give 1-[6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl]imidazole-4-carboxylic acid (300 mg). Obtained as an off-white solid. Method A: [M+H] ⁺ =323.

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

Scheme 2: Synthesis of intermediate 6 (1-((6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl)methyl)-1H-pyrazole-4-carboxylic acid)

Step 1: Ethyl 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]pyrazole-4-carboxylate
5-(Bromomethyl)-2-(4,4-difluorocyclohexyl)-3-fluoropyridine (500.0 mg, 1.6 mmol, 1.0 eq.) was dissolved in ACN (20 mL), then _K2CO3 ( _704.9 mg, 5.1 mmol, 3.0 eq.) and ethyl 1H-pyrazole-4-carboxylate (238.2 mg, 1.7 mmol, 1.0 eq.) were added. The reaction mixture was stirred at ambient temperature for 16 hours. 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 (1:1) to give 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridine-3 Ethyl -yl]methyl]pyrazole-4-carboxylate (300mg) was obtained as a white solid. LCMS method B: [M+H] ⁺ =368.

Step 2: 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]pyrazole-4-carboxylic acid
Ethyl 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]pyrazole-4-carboxylate (300.0 mg, 0.8 mmol, 1.0 eq.) was dissolved in MeOH (2 mL) and water. (2 mL) and then added NaOH (65.3 mg, 1.6 mmol, 2.0 eq.). The reaction mixture was heated to 80° C. for 1 hour, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water and then the solution was adjusted to pH 5 with aqueous HCl (6M). The solid was collected by filtration and dried to give 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]pyrazole-4-carboxylic acid (250 mg) as white. Obtained as a solid. LCMS method B: [M+H] ⁺ =340.

Scheme 3: Intermediates 7 and 8 (1-((6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl)methyl)-1H-imidazole-4-carboxylic acid and 1-((6 -(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl)methyl)-1H-imidazole-5-carboxylic acid)

化合物8BのLCMS、方法B:［M＋H］^＋＝368。

Step 1: Ethyl 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]imidazole-4-carboxylate and 3-[[6-(4,4-difluorocyclohexyl) )-5-fluoropyridin-3-yl]methyl]imidazole-4-carboxylic acid ethyl
5-(bromomethyl)-2-(4,4-difluorocyclohexyl)-3-fluoropyridine (800.0 mg, 2.6 mmol, 1.0 eq.) was dissolved in ACN (15 mL) and then K ₂ CO ₃ (1.1 g , 7.8 mmol, 3.0 eq.) and ethyl 1H-imidazole-4-carboxylate (363.8 mg, 2.6 mmol, 1.0 eq.) were added. The reaction mixture was heated to 80°C for 2 hours. After filtration and washing 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→1:1) to give 1-[[6-(4,4-difluorocyclohexyl)-5- Ethyl fluoropyridin-3-yl]methyl]imidazole-4-carboxylate (Compound 8A, 350 mg) as a pale yellow solid and also as 3-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridine- Ethyl 3-yl]methyl]imidazole-4-carboxylate (Compound 8B, 370 mg) was obtained as a white solid. LCMS of Compound 8A, Method B: [M+H] ⁺ =368.

LCMS of Compound 8B, Method B: [M+H] ⁺ =368.

Step 2: 1-((6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl)methyl)-1H-imidazole-4-carboxylic acid
Ethyl 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]imidazole-4-carboxylate (200.0 mg, 0.5 mmol, 1.0 eq.) was dissolved in MeOH (4 mL) and water. (4 mL) and then added NaOH (65.3 mg, 1.6 mmol, 3.0 eq.). The reaction mixture was stirred at 80° C. for 2 hours, then concentrated under vacuum. The residue was diluted with water and adjusted to pH 5 with aqueous HCl (6M). The resulting solid was collected by filtration and purified by Flash-Prep-HPLC with the following conditions: column, C18; mobile phase, ACN/H ₂ O, within 30 min. increase from 0% to 100%; detector, 254nm; This gave 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]imidazole-4-carboxylic acid (160 mg) as a white solid. LCMS method B: [M+H] ⁺ =340.

Step 3: 1-((6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl)methyl)-1H-imidazole-5-carboxylic acid Using the same method as described for Step 2 This gave 1-((6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl)methyl)-1H-imidazole-5-carboxylic acid (160 mg) as a white solid. LCMS method B: [M+H] ⁺ =340.

The following intermediates were prepared using the same method as described for intermediates 7 and 8.

Scheme 4: Synthesis of intermediate 10 (1-(6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl)-1H-pyrazole-4-carboxylic acid)

Step 1: 2-(4,4-difluorocyclohexyl)-3-fluoro-5-iodopyridine
6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-amine (400.0 mg, 1.7 mmol, 1.0 eq.) was dissolved in aqueous HCl (6 M, 10 mL) and cooled to 0 °C, then A solution of NaNO ₂ (179.8 mg, 2.6 mmol, 1.5 eq) in water (0.5 mL) was added dropwise while maintaining the reaction mixture at 0 °C. After 30 minutes at 0°C, KI (576.8 mg, 3.5 mmol, 2.0 eq) was added in portions while maintaining the temperature at 0°C. After the addition was complete, the solution was stirred at 0° C. for an additional 2 hours. After quenching with 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 2-(4,4-difluorocyclohexyl)-3-fluoro-5-iodopyridine (120 mg ) was obtained as a pale yellow solid. LCMS method A: [M+H] ⁺ = 342.

Step 2: Ethyl 1-(6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl)-1H-pyrazole-4-carboxylate
2-(4,4-difluorocyclohexyl)-3-fluoro-5-iodopyridine (500.0 mg, 1.5 mmol, 1.0 eq.) was dissolved in DMF (5 mL), then Cs ₂ CO ₃ (1.4 g, 4.4 mmol, 3.0 eq), ethyl 1H-pyrazole-4-carboxylate (246.5 mg, 1.8 mmol, 1.2 eq), _N1 , _N2 -dimethylcyclohexane-1,2-diamine (0.1 mL, 0.7 mmol, 0.5 eq) and CuI (57.3 mg, 0.3 mmol, 0.2 eq.) were added. The resulting solution was heated to 80° C. for 8 hours, then cooled to ambient temperature and quenched by 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 1-[6-(4,4-difluorocyclohexyl)-5-fluoropyridine-3- Ethyl]pyrazole-4-carboxylate (120 mg) was obtained as a pale yellow solid. LCMS method A: [M+H] ⁺ =354.

Step 3: 1-(6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl)-1H-pyrazole-4-carboxylic acid
Ethyl 1-[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]pyrazole-4-carboxylate (110.0 mg, 0.3 mmol, 1.0 eq.) was dissolved in MeOH (5 mL) and then An aqueous NaOH solution (2 mL, 2M) was added to the solution. The reaction mixture was stirred at ambient temperature for 2 hours, then diluted with 5 mL of water. The solution was adjusted to pH 5 with aqueous HCl (2M) and concentrated under vacuum. The crude product was purified by flash preparative HPLC under the following conditions: column, silica gel; mobile phase, ACN/water, increasing from 0% to 70% within 25 min. This gave 1-[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]pyrazole-4-carboxylic acid (70 mg) as a pale yellow solid. LCMS method A: [M+H] ⁺ =326.

Scheme 5: Synthesis of intermediate 11 (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 eq.) was dissolved in ACN (300 mL) and cooled to 0 °C, then _AgNO3 (33.3 g, 195.9 mmol, 1.2 eq.) added. The resulting mixture was stirred for 15 minutes, then benzoyl chloride (27.5 g, 195.9 mmol, 1.2 eq.) was added in one portion while maintaining the reaction mixture at 0.degree. 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 layer was 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. Obtained. 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 eq.) was dissolved in MeOH (300 mL), then Pd/C (2.4 g, wt 10%) and (Boc) ₂ O (39.7g, 181.7mmol, 1.5eq) was added under nitrogen. The mixture was sparged with nitrogen, placed under a hydrogen gas atmosphere (balloon), and then stirred at ambient temperature overnight. 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 N-(5,6-difluoro-1H-indol-3-yl)carbamic acid tert- Butyl (22g) was obtained as a yellow solid. LCMS method C: [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 eq.) was dissolved in HCl/1,4-dioxane (4N, 200 mL). The resulting mixture was stirred at ambient temperature for 30 min and then concentrated under vacuum to give 5,6-difluoro-1H-indol-3-amine hydrochloride (12 g) as a yellow solid. Ta. LCMS method C: [M+H] ⁺ = 169.

Using the same method as described for Intermediate 11, the intermediates in the table below were prepared.

Scheme 6: Synthesis of intermediate 14 (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 eq.) and DPPA (3.0 g, 11.1 mmol, 2.0 eq.) dissolved in THF (10.0 mL) Then TEA (1.6 mL, 11.1 mmol, 2.0 eq.) was added. The resulting mixture was stirred at ambient temperature overnight and concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate, dried over anhydrous _Na SO and concentrated _under vacuum to give 5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl azide. (900 mg) was obtained as a white solid. LCMS method E: [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 eq.) was added to t-BuOH (8.0 mL). The resulting mixture was stirred at 100° C. overnight, then concentrated under vacuum. The residue was purified by flash column chromatography on a silica gel column, eluting with ethyl acetate/petroleum ether (1:1) to give N-[5-fluoro-1H-pyrrolo[2,3-b]pyridine-3 tert-butyl]carbamate (350 mg) was obtained as a yellow solid. LCMS method E: [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 (4M, 10.0 mL). The resulting solution was stirred at ambient temperature for 4 hours and then concentrated under vacuum to obtain crude 5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine hydrogen chloride (350 mg ) was obtained as a yellow solid. LCMS method E: [M+H] ⁺ = 151.

Scheme 7: Synthesis of intermediate 15 (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 eq.) was dissolved in THF (10.0 mL), then DPPA (2.3 g, 8.3 mmol, 2.0 eq.) and TEA (1.8 mL , 12.5 mmol, 3.0 eq) was added. The resulting solution was stirred at ambient temperature overnight, then concentrated under vacuum. The residue was diluted with MeOH and the isolated solid was collected by filtration to give 5-bromo-1H-indole-3-carbonyl azide (900 mg) as a white solid. LCMS method E: [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 eq.) was dissolved in t-BuOH (6 mL). The resulting solution was heated at 80° C. overnight, 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 tert-butyl N-(5-bromo-1H-indol-3-yl)carbamate ( 910 mg) was obtained as a yellow solid. LCMS method E: [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 1,4-dioxane (6 mL) and water (0.6 mL) and then to 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (417.3 mg, 1.8 mmol, 1.1 eq.), Xphos Pd G3 (136.0 mg, 0.2 _mmol , 0.1 eq.) and _Cs2CO3 (1.0 g, 3.2 mmol, 2.0 eq.) were added under nitrogen atmosphere. The solution was heated at 100° C. overnight and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and the organic layer 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 N-[5-(1-isopropylpyrazol-4-yl)-1H-indole-3 tert-butyl]carbamate (400 mg) was obtained as a white solid. LCMS method E: [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 eq.) in HCl ( 4M, 8.0mL). The resulting solution was stirred at ambient temperature for 4 hours and then concentrated under vacuum to obtain crude 5-(1-isopropylpyrazol-4-yl)-1H-indol-3-amine hydrogen chloride ( 400 mg) as a gray solid. LCMS method E: [M+H] ⁺ =241.

The following intermediates were prepared using the same method as described for Intermediate 15.

Scheme 8: Synthesis of intermediate 18 (6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-amine)

Step 1: 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridin-3-amine
6-Bromo-5-fluoropyridin-3-amine (500.0 mg, 2.6 mmol, 1.00 eq.) was dissolved in 1,4-dioxane (10 mL) and water ( ₁ mL), then _K2CO3 (1.1 g, 7.9 mmol, 3.0 eq), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (766.8 mg, 3.1 mmol, 1.2 eq.) and Pd(dppf) _Cl2 (383.1 mg, 0.5 mmol, 0.2 eq.) were added under nitrogen atmosphere. The reaction mixture was heated to 90° 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 (1:2) to give 6-(4,4-difluorocyclohex-1-en-1-yl)-5. -Fluoropyridin-3-amine (420mg) was obtained as an off-white solid. LCMS method C: [M+H] ⁺ =229.

Step 2: 6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-amine
6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridin-3-amine (400.0 mg, 1.8 mmol, 1.0 eq.) was dissolved in MeOH (20 mL) and then Pd /C (93.3 mg, 0.9 mmol, 0.5 eq.) was added. The reaction mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), and then stirred at ambient temperature for 2 hours. The solids were removed by filtration and the filtrate was concentrated under vacuum to give 6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-amine (300 mg) as an off-white solid. LCMS method C: [M+H] ⁺ =231.

Scheme 9: Synthesis of intermediate 19 (6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-amine)

Step 1: 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-nitropyridine
2-Chloro-3-fluoro-5-nitropyridine (10.0 g, 56.6 mmol, 1.0 eq.) was dissolved in DMF (150 mL), then Cs ₂ CO ₃ (37.3 g, 114.5 mmol, 2.0 eq.) and 4, 4-difluoropiperidine (9.8g, 81.0mmol, 1.4eq) was added. The reaction mixture was heated to 90° C. for 15 hours, then cooled to ambient temperature and quenched by the addition of water. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5- Nitropyridine (13.3g) was obtained as a yellow solid. LCMS method D: [M+H] ⁺ =262.

Step 2: 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-amine
2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-nitropyridine (13.2 g, 50.5 mmol, 1.0 eq.) was dissolved in MeOH (100 mL) and then Pd/C (2.0 g , 18.8 mmol, 0.4 eq) was added. The reaction mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), and then stirred at ambient temperature for 15 hours. 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 dichloromethane/methanol (97:3) to give 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-amine. (11.4g) was obtained as a yellow solid. LCMS method D: [M+H] ⁺ =232.

Scheme 10: Synthesis of intermediate 20 (5-(bromomethyl)-2-(4,4-difluorocyclohexyl)-3-fluoropyridine)

Step 1: Methyl 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridine-3-carboxylate
Methyl 6-bromo-5-fluoropyridine-3-carboxylate (2.0 g, 8.5 mmol, 1.0 eq.) was dissolved in 1,4-dioxane (2 mL) and water (2 mL), then dissolved in Cs ₂ CO ₃ (5.6 g, 17.1 mmol, 2.0 eq), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 g , 8.5 mmol, _1.0 eq.) and Pd( _dppf ) _Cl2CH2Cl2 (1.4 g, 1.7 mmol, 0.2 eq.) were added under nitrogen atmosphere. The reaction mixture was heated at 90° C. overnight, 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-(4,4-difluorocyclohex-1-en-1-yl)-5. Methyl -fluoropyridine-3-carboxylate (2.2g) was obtained as a yellow solid. LCMS method A: [M+H] ⁺ =272.

Step 2: Methyl 6-(4,4-difluorocyclohexyl)-5-fluoropyridine-3-carboxylate
Methyl 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridine-3-carboxylate (2.0 g, 7.4 mmol, 1.0 eq.) was dissolved in DCM (80 mL) and then _PtO2 (837.2 mg, 3.7 mmol, 0.5 eq.) was added to the solution. The mixture was sparged with nitrogen, placed under a hydrogen gas atmosphere (balloon), and then stirred at ambient temperature overnight. The solids were removed by filtration and the filtrate was concentrated under vacuum to give methyl 6-(4,4-difluorocyclohexyl)-5-fluoropyridine-3-carboxylate (2 g) as an off-white oil. Ta. LCMS method I: [M+H] ⁺ =274.

Step 3: [6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methanol
Methyl 6-(4,4-difluorocyclohexyl)-5-fluoropyridine-3-carboxylate (2.0 g, 7.3 mmol, 1.0 eq.) was dissolved in THF (20 mL) and cooled to 0 °C, then _LiAlH4 (0.6g, 14.6mmol, 2.0eq) was added portionwise. The resulting solution was stirred at 0° C. for 30 min, then quenched by the addition of Na ₂ SO ₄ .10H ₂ O. After removing the solids by filtration, the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (10:1) to give [6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methanol ( 1.1 g) was obtained as a white solid. LCMS method B: [M+H] ⁺ =246.

Step 4: 5-(bromomethyl)-2-(4,4-difluorocyclohexyl)-3-fluoropyridine [6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methanol (1.0 g, 4.1 mmol, 1.0 eq.) was dissolved in DCM (10 mL) and cooled to 0.degree. C., then _PBr3 (0.4 mL, 4.1 mmol, 1.0 eq.) was added while maintaining the mixture at 0.degree. The reaction mixture was stirred at 0° C. for 1 h, then quenched by the addition of saturated aqueous NaHCO ₃ . Extracting the resulting solution with ethyl acetate and concentrating under vacuum yielded 5-(bromomethyl)-2-(4,4-difluorocyclohexyl)-3-fluoropyridine (800 mg) as a white solid. obtained as. LCMS method A: [M+H] ⁺ =308.

Scheme 1B: Synthesis of intermediate 1B (5,6-difluoro-1H-indol-3-amine hydrogen chloride)

Step 1: 5,6-difluoro-3-nitro-1H-indole
5,6-difluoro-1H-indole (25.0 g, 163.3 mmol, 1.0 eq.) was dissolved in ACN (300 mL) and cooled to 0 °C, then AgNO ₃ (33.3 g, 195.9 mmol, 1.2 eq.) added. The resulting mixture was stirred for 15 minutes, then benzoyl chloride (27.5 g, 195.9 mmol, 1.2 eq.) was added batchwise while maintaining the reaction mixture at 0.degree. 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 layer was 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. Obtained. 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 eq.) was dissolved in MeOH (300 mL), then Pd/C (2.4 g, wt 10%) and (Boc) ₂ O (39.7g, 181.7mmol, 1.5eq) was added under nitrogen. The mixture was sparged with nitrogen, placed under a hydrogen gas atmosphere (balloon), and then stirred at ambient temperature overnight. 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 N-(5,6-difluoro-1H-indol-3-yl)carbamic acid tert- Butyl (22.0g) was obtained as a yellow solid. LCMS method C: [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 eq.) was dissolved in HCl/1,4-dioxane (4N, 200 mL). The resulting mixture was stirred at ambient temperature for 30 minutes and then concentrated under vacuum to give 5,6-difluoro-1H-indol-3-amine hydrochloride (12.0 g) as a yellow solid. Obtained. LCMS method C: [M+H] ⁺ = 169.

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

Scheme 2B: Synthesis of intermediate 6B (6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-amine)

Step 1: 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridin-3-amine
6-Bromo-5-fluoropyridin-3-amine (500.0 mg, 2.6 mmol, 1.00 eq.) was dissolved in 1,4-dioxane (10 mL) and water ( ₁ mL), then _K2CO3 (1.1 g, 7.9 mmol, 3.0 eq), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (766.8 mg, 3.1 mmol, 1.2 eq.) and Pd(dppf) _Cl2 (383.1 mg, 0.5 mmol, 0.2 eq.) were added under nitrogen atmosphere. The reaction mixture was heated to 90° 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 (1:2) to give 6-(4,4-difluorocyclohex-1-en-1-yl)-5. -Fluoropyridin-3-amine (420mg) was obtained as an off-white solid. LCMS method C: [M+H] ⁺ =229.

Step 2: 6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-amine
6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridin-3-amine (400.0 mg, 1.8 mmol, 1.0 eq.) was dissolved in MeOH (20 mL) and then Pd /C (10% wt., 93.3 mg) was added. The reaction mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), and then stirred at ambient temperature for 2 hours. The solids were removed by filtration and the filtrate was concentrated under vacuum to give 6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-amine (300 mg) as an off-white solid. LCMS method C: [M+H] ⁺ =231.

The following intermediates were prepared using the same method as described for Intermediate 6B.

Scheme 3B: Synthesis of intermediate 12B (6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-amine)

Step 1: 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-nitropyridine
2-Chloro-3-fluoro-5-nitropyridine (10.0 g, 56.6 mmol, 1.0 eq.) was dissolved in DMF (150 mL), then Cs ₂ CO ₃ (37.3 g, 114.5 mmol, 2.0 eq.) and 4, 4-difluoropiperidine (9.8g, 81.0mmol, 1.4eq) was added. The reaction mixture was heated to 90° C. for 15 hours, then cooled to ambient temperature and quenched by the addition of water. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5- Nitropyridine (13.3g) was obtained as a yellow solid. LCMS method D: [M+H] ⁺ =262.

Step 2: 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-amine
2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-nitropyridine (13.2 g, 50.5 mmol, 1.0 eq.) was dissolved in MeOH (100 mL) and then Pd/C (10% wt., 2.0g) was added. The reaction mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), and then stirred at ambient temperature for 15 hours. 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 dichloromethane/methanol (97:3) to give 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-amine. (11.4g) was obtained as a yellow solid. LCMS method D: [M+H] ⁺ =232.

The following intermediates were prepared using the same method as described for Intermediate 12B.

Scheme 4B: Synthesis of intermediate 21B (5-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-amine)

Step 1: 3-chloro-2-(4,4-difluoropiperidin-1-yl)-5-nitropyridine
2-bromo-3-chloro-5-nitropyridine (10.0 g, 42.1 mmol, 1.0 eq.) and 4,4-difluoropiperidine (5.6 g, 46.3 mmol, 1.1 eq.) were dissolved in DMF (100 mL) and then _{Cs2CO3 (} 27.4g, 84.2mmol, 2.0eq) was added. The reaction mixture was heated to 90° C. overnight, then cooled to ambient temperature and quenched by the addition of water. 3-chloro-2-( _{4,4 -} difluoropiperidine- 1-yl)-5-nitropyridine (9.5g) was obtained as a brown solid. LCMS method A: [M+H] ⁺ =278.

Step 2: 5-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-amine
3-chloro-2-(4,4-difluoropiperidin-1-yl)-5-nitropyridine (9.0 g, 32.4 mmol, 1.0 eq.) was dissolved in EtOH (90 mL), then _SnCl2 (30.7 g, 162.1 mmol, 5.0 eq.) was added portionwise. The reaction mixture was heated to 60° C. overnight, then cooled to ambient temperature and quenched by the addition of water. 5 _- chloro- _6- (4,4- Difluoropiperidin-1-yl)pyridin-3-amine (7.1 g) was obtained as a black solid. LCMS method E: [M+H] ⁺ =248.

The following intermediates were prepared using the same method as described for Intermediate 21B.

Scheme 5B: Synthesis of intermediate 23B (2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-4-amine)

Step 1: 1-(4-nitropyridin-2-yl)-4-(2,2,2-trifluoroethyl)piperazine
2-chloro-4-nitropyridine (2.0 g, 12.6 mmol, 1.0 eq.) and 1-(2,2,2-trifluoroethyl)piperazine (2.5 g, 15.1 mmol, 1.2 eq.) were dissolved in 1,4-dioxane ( Cs ₂ CO ₃ (12.3 g, 37.8 mmol, 3.0 eq.) and XPhos Pd G3 (1.1 g, 1.3 mmol, 0.1 eq.) were then added under nitrogen atmosphere. The reaction mixture was heated to 80° C. for 12 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ 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 1-(4-nitropyridin-2-yl)-4-(2,2,2 -trifluoroethyl)piperazine (1.2g) was obtained as a yellow solid. LCMS method A: [M+H] ⁺ =291.

Step 2: 2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-4-amine
1-(4-nitropyridin-2-yl)-4-(2,2,2-trifluoroethyl)piperazine (1.0 g, 3.4 mmol, 1.0 eq.) was dissolved in MeOH (15 mL) and then Pd/ C (10% wt., 36.7 mg) was added under nitrogen atmosphere. The mixture was sparged with nitrogen, placed under a hydrogen gas atmosphere (balloon), and then stirred at ambient temperature overnight. The solids were removed by filtration and the filtrate was concentrated under vacuum to give crude 2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-4-amine (560.0 mg). was obtained as a brown solid, which was used in the next step without further purification. LCMS method E: [M+H] ⁺ =261.

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

Scheme 6B: Synthesis of intermediate 25B (6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-amine)

Step 1: 4,4-difluoro-1-methylcyclohexan-1-ol
4,4-Difluorocyclohexan-1-one (10.0 g, 74.6 mmol, 1.0 eq.) was dissolved in _Et2O (100.0 mL) and cooled to 0 °C, then while maintaining the solution at 0 °C. MeMgBr (3M in THF, 80.0 mL, 240 mmol, 3.0 eq.) was added dropwise. The reaction mixture was stirred at 0° C. for 2 hours and then quenched by the addition of ice water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over _anhydrous Na SO and concentrated under vacuum to give 4,4-difluoro- ₁ -methylcyclohexan-1-ol. (9.5g) was obtained as a yellow solid. LCMS method A: [M+H] ⁺ = 151.

Step 2: Methyl 4,4-difluoro-1-methylcyclohexyl oxalate
4,4-Difluoro-1-methylcyclohexan-1-ol (10.0 g, 66.6 mmol, 1.0 eq.) and DMAP (0.8 g, 6.7 mmol, 0.1 eq.) were dissolved in DCM (200 mL), then TEA (18.7 mL, 133.2 mmol, 2.0 eq) was added. Then, methyloxalochloridate (6.1 mL, 67.3 mmol, 1.0 eq.) was added dropwise. The reaction mixture was stirred at ambient temperature for 1 hour, 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 methyl 4,4-difluoro-1-methylcyclohexyl oxalate (11.2 g) as a yellow oil. obtained as. LCMS method A: [M+H] ⁺ =237.

Step 3: Add 2-((4,4-difluoro-1-methylcyclohexyl)oxy)-2-oxoacetate cesium methyl 4,4-difluoro-1-methylcyclohexyl oxalate (5.0 g, 21.2 mmol, 1.0 equiv.) Dissolved in THF (50 mL) and water (50 mL) and then added CsOH (3.2 g, 20.9 mmol, 1.0 eq.). Cesium 2-((4,4-difluoro-1-methylcyclohexyl)oxy)-2-oxoacetate (5.2 g) was obtained as white by stirring the reaction mixture for 1 h at ambient temperature and then concentrating under vacuum. Obtained as a solid. LCMS method A: [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 eq.) was dissolved in DMSO (30 mL) and then ( _NH4 ) _{2S 2O8} (2.3g, 9.9mmol, 0.7eq), Ir[dF( _CF3 )ppy] ₂ (dtbpy) _PF6 (1.6g, 1.4mmol, 0.1eq) and methyl 5 _- fluoropyridine-3-carboxylate (1.8g, 11.3mmol, 0.8eq) was added. The resulting solution was irradiated with royal blue (450 nm) LED light for 3 hours while stirring at 1000 rpm and 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 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3. -Methyl carboxylate (2.5g) was obtained as a yellow oil. LCMS method A: [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 eq.) was dissolved in MeOH (25 mL) and water (25 mL) and then NaOH (1.0g, 26.0mmol, 3.0eq) was added to the solution. 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 preparative HPLC with the following conditions: column, C18 silica gel; mobile phase, increasing from ACN/H ₂ O = 0% to ACN/H ₂ O = 100% within 30 min; detector, 254nm. This gave 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylic acid (2.1 g) as a yellow oil. LCMS method C: [M+H] ⁺ =274.

Step 6: 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carbonyl azide
6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylic acid (1.0 g, 3.7 mmol, 1.0 eq.) was dissolved in THF (20 mL), then TEA (1.0 mL, 7.3 mmol, 2.0 eq) and DPPA (1.5 g, 5.5 mmol, 1.5 eq) were added. The reaction mixture was stirred at ambient temperature overnight, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:50) to give 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3. -Carbonyl azide (900.0 mg) was obtained as a white oil. LCMS method E: [M+H] ⁺ =299.

Step 7: tert-butyl N-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]carbamate
6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carbonyl azide (1.0 g, 3.4 mmol, 1.0 eq.) was dissolved in t-BuOH (20 mL). The reaction mixture was heated to 80° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. This gave tert-butyl N-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]carbamate (850.0 mg) as a white solid. LCMS method A: [M+H] ⁺ = 345.

Step 8: 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-amine
tert-Butyl N-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]carbamate (900.0 mg, 2.6 mmol, 1.0 eq.) in HCl/1,4-dioxane (4N, 20mL). The resulting mixture was stirred at ambient temperature overnight. The solid was collected by filtration and dried to give 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-amine (350.0 mg) as a yellow oil. LCMS method E: [M+H] ⁺ =245.

The following intermediates were prepared using the same method as described for Intermediate 25B.

Scheme 7B: Synthesis of intermediate 27B (2-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-4-amine)

2,6-dichloropyridin-4-amine (1.0 g, 6.1 mmol, 1.0 equiv.) was dissolved in 4,4-difluoropiperidine (5.0 mL). The reaction mixture was heated to 150° 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 sodium sulfate, and concentrated under vacuum. The residue was purified by flash preparative HPLC with the following conditions: column, C18 silica gel; mobile phase, H ₂ O/MeCN = 90:10 increasing to H ₂ O/MeCN = 10:90 within 30 min; detection. instrument, 254nm. This gave 2-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-4-amine (260.0 mg) as a yellow solid. LCMS method E: [M+H] ⁺ =248.

Scheme 8B: Synthesis of intermediate 28B (5-fluoro-6-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)pyridin-3-amine)

Step 1: tert-butyl 3-fluoro-5-nitro-5,6-dihydro-2H-[2,3-bipyridine]-1-carboxylate
2-chloro-3-fluoro-5-nitropyridine (2.0 g, 11.3 mmol, 1.0 eq.) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- Tert-butyl 5,6-dihydro-2H-pyridine-1-carboxylate (5.3 g, 17.0 mmol, 1.5 eq.) was dissolved in 1,4-dioxane (30 mL) and water (3 mL) and then treated with Cs ₂ CO ₃ (11.1 g, 34.0 mmol, 3.0 eq.) and Xphos Pd G3 (959.0 mg, 1.1 mmol, 0.1 eq.) were added under nitrogen atmosphere. 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, 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 3-fluoro-5-nitro-5,6-dihydro-2H-[2,3- tert-butyl bipyridine]-1-carboxylate (412.1 mg) was obtained as a yellow solid. LCMS method C: [M+H] ⁺ =324.

Step 2: 3-fluoro-5-nitro-1,2,5,6-tetrahydro-2,3-bipyridine hydrochloride
Tert-butyl 3-fluoro-5-nitro-5,6-dihydro-2H-[2,3-bipyridine]-1-carboxylate (600.0, 1.9 mmol, 1.0 eq.) was dissolved in HCl/1,4-dioxane (4N , 15 mL). The reaction mixture was stirred at ambient temperature overnight and then concentrated under vacuum to give 3-fluoro-5-nitro-1,2,5,6-tetrahydro-2,3-bipyridine hydrochloride (315.2 mg). was obtained as a pale yellow solid. LCMS method A: [M+H] ⁺ =224.

Step 3: 3-fluoro-5-nitro-1-(2,2,2-trifluoroethyl)-5,6-dihydro-2H-2,3-bipyridine
3-Fluoro-5-nitro-1,2,5,6-tetrahydro-2,3-bipyridine hydrochloride (467.5 mg, 1.8 mmol, 1.0 eq.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate ( 499.1 mg, 2.2 mmol, 1.2 eq.) was dissolved in ACN (10 mL), then _K2CO3 (495.3 _mg , 3.6 mmol, 2.0 eq.) was added. The reaction mixture was stirred at ambient temperature for 3 hours 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 preparative HPLC with the following conditions: column, C18 silica gel; mobile phase, H ₂ O/MeCN = 90:10 increasing to H ₂ O/MeCN = 10:90 within 30 min; detection. instrument, 254nm. This gave 3-fluoro-5-nitro-1-(2,2,2-trifluoroethyl)-5,6-dihydro-2H-2,3-bipyridine (250.0 mg) as a yellow solid. . LCMS method A: [M+H] ⁺ =306.

Step 4: 5-fluoro-6-[1-(2,2,2-trifluoroethyl)piperidin-3-yl]pyridin-3-amine
3-Fluoro-5-nitro-1-(2,2,2-trifluoroethyl)-5,6-dihydro-2H-2,3-bipyridine (250.0 mg, 0.8 mmol, 1.0 eq.) in MeOH (6 mL) Pd/C (10%w%, 25.3mg) was then added under nitrogen. The mixture was sparged with nitrogen, placed under a hydrogen gas atmosphere (balloon), and then stirred at ambient temperature overnight. 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 (1:1) to give 5-fluoro-6-[1-(2,2,2-trifluoroethyl)piperidine. -3-yl]pyridin-3-amine (198.2 mg) was obtained as a yellow oil. LCMS method E: [M+H] ⁺ =278.

Scheme 9B: Synthesis of intermediate 29B (5-fluoro-6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-amine)

Step 1: tert-butyl 4-(3-fluoro-5-nitropyridin-2-yl)piperazine-1-carboxylate
2-Chloro-3-fluoro-5-nitropyridine (2.0 g, 11.3 mmol, 1.0 eq.) was dissolved in ACN (20 mL), then tert-butyl piperazine-1-carboxylate (2.0 g, 11.3 mmol, 1.5 (eq.) and _K2CO3 (6.3 _g , 45.3 mmol, 4.0 eq.) 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 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 4-(3-fluoro-5-nitropyridin-2-yl)piperazine-1-carvone. Tert-butyl acid (2.1 g) was obtained as a yellow solid. LCMS method A: [M+H] ⁺ =327.

Step 2: 1-(3-fluoro-5-nitropyridin-2-yl)piperazine
tert-Butyl 4-(3-fluoro-5-nitropyridin-2-yl)piperazine-1-carboxylate (2.1 g, 6.4 mmol, 1.0 eq.) dissolved in HCl/1,4-dioxane (4N, 40 mL) did. The reaction mixture was stirred at ambient temperature overnight and concentrated under vacuum. The residue was purified by flash preparative HPLC with the following conditions: column, C18 silica gel; mobile phase, H ₂ O/MeCN = 90:10 increasing to H ₂ O/MeCN = 10:90 within 30 min; detection. instrument, 254nm. This gave 1-(3-fluoro-5-nitropyridin-2-yl)piperazine (1.1 g) as a yellow oil. LCMS method A: [M+H] ⁺ =227.

Step 3: 1-(3-fluoro-5-nitropyridin-2-yl)-4-(2-methoxyethyl)piperazine
1-(3-fluoro-5-nitropyridin-2-yl)piperazine (1.0 g, 4.4 mmol, 1.0 eq.) and 2-bromoethyl methyl ether (0.9 g, 6.6 mmol, 1.5 eq.) in ACN (20 mL). Dissolved and then added _K2CO3 (1.2g, 8.8mmol, 2.0eq) _. 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 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 1-(3-fluoro-5-nitropyridin-2-yl)-4-(2 -methoxyethyl)piperazine (1.0g) was obtained as a yellow solid. LCMS method A: [M+H] ⁺ =285.

Step 4: 5-fluoro-6-[4-(2-methoxyethyl)piperazin-1-yl]pyridin-3-amine
1-(3-fluoro-5-nitropyridin-2-yl)-4-(2-methoxyethyl)piperazine (1.1 g, 3.9 mmol, 1.0 eq.) was dissolved in MeOH (20 mL) and then Pd/C (10% wt., 110.1 mg) was added under nitrogen. The mixture was sparged with nitrogen, placed under a hydrogen gas atmosphere (balloon), and then stirred at ambient temperature overnight. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash preparative HPLC with the following conditions: column, C18 silica gel; mobile phase, H ₂ O/MeCN = 90:10 increasing to H ₂ O/MeCN = 10:90 within 30 min; detection. instrument, 254nm. This gave 5-fluoro-6-[4-(2-methoxyethyl)piperazin-1-yl]pyridin-3-amine (805.2 mg) as a yellow solid. LCMS method D: [M+H] ⁺ =255.

Scheme 10B: Synthesis of intermediate 30B (6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-amine)

Step 1: Methyl 6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3-carboxylate
Methyl 5-fluoropyridine-3-carboxylate (6.0 g, 38.7 mmol, 1.0 eq.) was dissolved in DCE (60 mL) and water (60 mL), then AgNO ₃ (1.3 g, 7.7 mmol, 0.2 eq.), Selectfluor (27.4g, 77.4mmol, 2.0eq), TFA (4.4g, 38.7mmol, 1.0eq) and 3,3-difluorocyclobutane-1-carboxylic acid (10.5g, 77.4mmol, 2.0eq) were added. The reaction mixture was heated to 50° C. for 24 hours, then cooled to 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 (1:1) to give 6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3-carboxylic acid. Methyl (1.4g) was obtained as a white solid. LCMS method A: [M+H] ⁺ =246.

Step 2: 6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3-carboxylic acid
Methyl 6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3-carboxylate (2.0 g, 8.2 mmol, 1.0 eq.) was dissolved in MeOH (10 mL) and water (10 mL) and then dissolved in LiOH ( 390.7mg, 16.3mmol, 2.0eq) was added. The reaction mixture was heated to 80° C. for 30 minutes, then cooled to ambient temperature and concentrated under vacuum. 6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3 was obtained by diluting the residue with water, adjusting pH to 5 with aqueous HCl (2M), extracting with ethyl acetate, and concentrating in vacuo. -carboxylic acid (1.5g) was obtained as a white solid. LCMS method D: [M+H] ⁺ =232.

Step 3: 6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3-carbonyl azide
6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3-carboxylic acid (2.0g, 8.7mmol, 1.0eq) and TEA (2.4mL, 17.3mmol, 2.0eq) dissolved in THF (100mL) Then DPPA (3.6g, 13.0mmol, 1.5eq) was added. The reaction mixture was stirred at ambient temperature for 16 hours, 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 6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3-carbonyl azide. (1.5g) was obtained as a white solid. LCMS method A: [M+H] ⁺ =257.

Step 4: tert-butyl N-[6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-yl]carbamate
6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3-carbonyl azide (1.5 g, 5.9 mmol, 1.0 eq.) was dissolved in t-BuOH (50 mL). The resulting solution was heated to 80° C. for 16 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give N-[6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3 tert-butyl]carbamate (1.5 g) was obtained as a white solid. LCMS method G: [M+H] ⁺ =303.

Step 5: 6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-amine
Tert-butyl N-[6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-yl]carbamate (1.5 g, 5.0 mmol, 1.0 eq.) was dissolved in HCl/1,4-dioxane (4N, 40 mL). The reaction mixture was stirred at ambient temperature for 16 hours and concentrated under vacuum to give 6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-amine hydrogen chloride (1.0 g) as a white solid. Obtained. LCMS method C: [M+H] ⁺ =203.

Scheme 11B: Synthesis of intermediate 31B (5-fluoro-6-(6-azaspiro[2.5]octan-6-yl)nicotinic acid)

Step 1: Methyl 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate
Methyl 6-bromo-5-fluoropyridine-3-carboxylate (5.0 g, 21.4 mmol, 1.0 eq.) was dissolved in DMF (50 mL), then K ₂ CO ₃ (8.9 g, 64.1 mmol, 3.0 eq.) and 6-Azaspiro[2.5]octane (2.9g, 25.6mmol, 1.2eq) 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} Na SO and concentrated under vacuum to give 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoro Methyl pyridine-3-carboxylate (5.5g) was obtained as a pale yellow solid. LCMS method A: [M+H] ⁺ =265.

Step 2: 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylic acid
Methyl 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate (5.5 g, 20.8 mmol, 1.0 eq.) was dissolved in MeOH (50 mL) and water (50 mL), LiOH (12.0g, 83.2mmol, 4.0eq) was then added. The reaction mixture was stirred at ambient temperature overnight, then concentrated under vacuum. The residue was diluted with water and adjusted to pH 5 with concentrated HCl. The precipitated solid was collected by filtration and washed with water to give 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylic acid (5.0 g) as a pale yellow solid. I got it as a thing. LCMS method E: [M+H] ⁺ =251.

The following intermediates were prepared using the same method as described for Intermediate 31B.

Scheme 12B: Synthesis of intermediate 38B (5-chloro-6-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)nicotinic acid)

Step 1: Methyl 3-chloro-1'-(2,2,2-trifluoroethyl)-3',6'-dihydro-2'H-[2,4'-bipyridine]-5-carboxylate
Methyl 6-bromo-5-chloropyridine-3-carboxylate (1.0g, 4.0mmol, 1.0eq) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) )-1-(2,2,2-trifluoroethyl)-3,6-dihydro-2H-pyridine (2.3 g, 7.9 mmol, 2.0 eq.) in 1,4-dioxane (10 mL) and water (1 mL). Dissolved and then _Cs2CO3 ( _2.6g , 8.0mmol, 2.0eq) and Pd(dppf) _Cl2 (292.1mg, 0.4mmol, 0.1eq) were added under nitrogen atmosphere. 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 3-chloro-1'-(2,2,2-trifluoroethyl)-3'. Methyl ,6'-dihydro-2'H-[2,4'-bipyridine]-5-carboxylate (1.0 g) was obtained as a white solid. LCMS method A: [M+H] ⁺ =335.

Step 2: Methyl 5-chloro-6-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]pyridine-3-carboxylate methyl 3-chloro-1 (1.0 g, 3.0 mmol, 1.0 eq.) was dissolved in DCM (20 mL) and then _PtO2 (67.8 mg, 0.3 mmol, 0.1 eq.) was added. The reaction mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), and then stirred at ambient temperature for 16 hours. 5-chloro-6-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]pyridine-3-carboxylic acid by removing the solids by filtration and concentrating the filtrate under vacuum. Methyl (812.2 mg) was obtained as a white solid. LCMS method E: [M+H] ⁺ =337.

Step 3: 5-chloro-6-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]pyridine-3-carboxylic acid
Methyl 5-chloro-6-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]pyridine-3-carboxylate (800.0 mg, 2.4 mmol, 1.0 eq.) in MeOH (5 mL) and water (5 mL) and then added NaOH (190.0 mg, 4.8 mmol, 2.0 eq.). The reaction mixture was heated to 80° C. for 30 minutes, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water and adjusted to pH 5 with aqueous HCl (4M). 5- _chloro -6-[ _1- (2,2, 2-Trifluoroethyl)piperidin-4-yl]pyridine-3-carboxylic acid (585.5mg) was obtained as a white solid. LCMS method C: [M+H] ⁺ =323.

The following intermediates were prepared using the same method as described for Intermediate 38B.

Scheme 13B: Synthesis of intermediate 40B (1-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-1H-pyrazole-4-carboxylic acid)

Step 1: 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-iodopyridine
6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-amine (3.0 g, 13.0 mmol, 1.0 eq.) was dissolved in aqueous HCl (6 M, 50 mL) and cooled to 0 °C. , then a solution of NaNO ₂ (1.3 g, 19.5 mmol, 1.5 eq.) in water (2 mL) was added dropwise while maintaining the reaction mixture at 0 °C. After 30 minutes at 0°C, KI (4.3g, 26.0mmol, 2.0 eq.) was added in portions while maintaining the temperature at 0°C. After the addition was complete, the solution was stirred at 0° C. for an additional 2 hours. After quenching with 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 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5- Iodopyridine (2.0g) was obtained as a yellow solid. LCMS method A: [M+H] ⁺ =343.

Step 2: Ethyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-4-carboxylate
2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-iodopyridine (2.0 g, 5.8 mmol, 1.0 eq.) was dissolved in DMF (20 mL), then Cs ₂ CO ₃ (5.7 g, 17.5 mmol, 3.0 eq), ethyl 1H-pyrazole-4-carboxylate (1.0 g, 7.0 mmol, 1.2 eq), _N1 , _N2 -dimethylcyclohexane-1,2-diamine (0.5 mL, 2.9 mmol, 0.5 eq) and CuI (220.9 mg, 0.3 mmol, 0.2 eq) were added. The resulting solution was heated to 80° C. overnight, then cooled to ambient temperature and quenched by addition of water. The resulting solution was extracted with ethyl acetate, 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 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoro Ethyl pyridin-3-yl]pyrazole-4-carboxylate (1.0 g) was obtained as a yellow solid. LCMS method A: [M+H] ⁺ = 355.

Step 3: 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-4-carboxylic acid
Ethyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-4-carboxylate (1.0 g, 2.8 mmol, 1.0 eq.) was dissolved in MeOH (5 mL) and Dissolved in water (5 mL) and then added NaOH (225.8 mg, 5.6 mmol, 2.0 eq.). The reaction mixture was heated to 60° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water and adjusted to pH 6 with aqueous HCl (1M). The precipitated solid was collected by filtration, washed with water, and dried to give 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-4. -carboxylic acid (510.0 mg) was obtained as a white solid. LCMS method E: [M+H] ⁺ =327.

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

Scheme 14B: Intermediate 43B (1-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-1H-1,2,3-triazole-4-carboxylic acid) synthesis of

Step 1: 5-azido-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine
6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-amine (400.0 mg, 1.7 mmol, 1.0 eq.) was dissolved in ACN (10 mL) and cooled to 0 °C, then , t-BuNO ₂ (0.3 mL, 2.7 mmol, 1.6 eq.) was added dropwise while maintaining the solution at 0 °C. The reaction mixture was stirred at 0°C for 30 minutes. Next, TMSN ₃ (0.3 mL, 2.5 mmol, 1.5 equivalents) was added dropwise at 0°C. The resulting mixture was stirred for an additional 2 hours at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give 5-azido-2-(4,4-difluoropiperidin-1-yl)-3- Fluoropyridine (380.0 mg) was obtained as a yellow oil. LCMS method A: [M+H] ⁺ =258.

Step 2: Methyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylate
5-azido-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (350.0 mg, 1.4 mmol, 1.0 equiv.) in 1,4-dioxane (3.6 mL) and water (0.4 mL). Dissolve and then methyl propionate (228.8 mg, 2.7 mmol, 2.0 eq.), sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5 -dihydrofuran-3-olate (53.9 mg, 0.3 mmol, 0.2 eq.) and _CuSO4 (21.7 mg, 0.1 mmol, 0.1 eq.) were added. The reaction mixture was stirred at ambient temperature overnight and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoro Methyl pyridin-3-yl]-1,2,3-triazole-4-carboxylate (150.0 mg) was obtained as a yellow solid. LCMS method G: [M+H] ⁺ =341.

Step 3: 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylic acid
Methyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylate (300.0 mg, 0.9 mmol, 1.0 eq. ) was dissolved in MeOH (3 mL) and water (7 mL), then NaOH (70.3 mg, 1.8 mmol, 2.0 eq.) 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 and adjusted to pH 6 with 1M aqueous HCl. 1-[6-( _4,4 -difluoropiperidine- ₁ -yl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylic acid (200.1 mg) was obtained as a yellow solid. LCMS method E: [M+H] ⁺ =328.

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

Scheme 15B: Intermediate 51B (1-(4-((3,3-difluoroazetidin-1-yl)methyl)-3-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid) synthesis of

Step 1: 1-[(4-bromo-2-fluorophenyl)methyl]-3,3-difluoroazetidine
4-Bromo-1-(bromomethyl)-2- _{fluorobenzene} (1.0 g, 3.7 mmol, 1.0 eq.) was dissolved in ACN (20 mL), then _K2CO3 (1.6 g, 11.2 mmol, 3.0 eq.) and 3,3-difluoroazetidine (347.4 mg, 3.7 mmol, 1.0 eq.) was added. The reaction mixture was stirred at ambient temperature overnight, then concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous _Na SO and concentrated under vacuum to give 1-[(4-bromo- ₂ -fluorophenyl)methyl]. -3,3-difluoroazetidine (821.2 mg) was obtained as a yellow oil. LCMS method A: [M+H] ⁺ =280.

Step 2: 1-[(4-azido-2-fluorophenyl)methyl]-3,3-difluoroazetidine
1-[(4-bromo-2-fluorophenyl)methyl]-3,3-difluoroazetidine (800.0 mg, 2.9 mmol, 1.0 eq.) was dissolved in DMF (10 mL), then methyl[2-(methyl amino)ethyl]amine (0.6 mL, 5.7 mmol, 2.0 eq.), sodium ascorbate (56.9 mg, 0.3 mmol, 0.1 eq.), CuI (54.4 mg, 0.3 mmol, 0.1 eq.) and _NaN3 (371.4 mg, 5.7 mmol , 2.0 eq.) was added under nitrogen atmosphere. 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 Na ₂ SO ₄ 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-[(4-azido-2-fluorophenyl)methyl]-3,3-difluoro Azetidine (412.3 mg) was obtained as a yellow oil. LCMS method E: [M+H] ⁺ =243.

Step 3: Methyl 1-[4-[(3,3-difluoroazetidin-1-yl)methyl]-3-fluorophenyl]-1,2,3-triazole-4-carboxylate
1-[(4-azido-2-fluorophenyl)methyl]-3,3-difluoroazetidine (500.0 mg, 2.1 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (7 mL) and water (3 mL). , then methyl propionate (260.3 mg, 3.1 mmol, 1.5 eq.), sodium ascorbate (41.1 mg, 0.2 mmol, 0.1 eq.), and _CuSO4 (33.0 mg, 0.2 mmol, 0.1 eq.) were added. The reaction mixture was stirred at ambient temperature overnight and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over _anhydrous Na SO and concentrated under vacuum to give 1-[ ₄ -[(3,3-difluoroazetidine Methyl-1-yl)methyl]-3-fluorophenyl]-1,2,3-triazole-4-carboxylate (322.2 mg) was obtained as a yellow solid. LCMS method A: [M+H] ⁺ =327.

Step 4: 1-[4-[(3,3-difluoroazetidin-1-yl)methyl]-3-fluorophenyl]-1,2,3-triazole-4-carboxylic acid
Methyl 1-[4-[(3,3-difluoroazetidin-1-yl)methyl]-3-fluorophenyl]-1,2,3-triazole-4-carboxylate (500.0 mg, 1.5 mmol, 1.0 eq. ) was dissolved in MeOH (5 mL) and water (10 mL), then NaOH (122.6 mg, 3.1 mmol, 2.0 eq.) 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 and adjusted to pH 6 with 1M aqueous HCl. The resulting solution was extracted with ethyl acetate, washed with brine, and concentrated under vacuum to give 1-[4-[(3,3-difluoroazetidin-1-yl)methyl]-3 -fluorophenyl]-1,2,3-triazole-4-carboxylic acid (285.2 mg) was obtained as a yellow solid. LCMS method E: [M+H] ⁺ =313.

Scheme 16B: Intermediate 52B (1-(6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl)-1H-1,2,3-triazole-4-carboxylic acid) synthesis of

Step 1: Ethyl 1-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylate
6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-amine (300.0 mg, 1.2 mmol, 1.0 equiv.) was dissolved in EtOH (3 mL) and AcOH (3 mL), then 2 Ethyl -diazo-3-oxopropanoate (261.8 mg, 1.8 mmol, 1.5 eq.) was added. The reaction mixture was heated to 50° C. overnight, then cooled to ambient temperature and concentrated under vacuum. This gives ethyl 1-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylate (400.0 mg) a yellow color. Obtained as a solid. LCMS method A: [M+H] ⁺ =369.

Step 2: 1-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylic acid
Ethyl 1-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylate (400.0 mg, 1.1 mmol, 1.0 eq. ) was dissolved in MeOH (4 mL) and water (4 mL), then NaOH (86.9 mg, 2.2 mmol, 2.0 eq.) 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 preparative HPLC with the following conditions: column, C18 silica gel; mobile phase, increasing from ACN/H ₂ O = 0% to ACN/H ₂ O = 100% within 15 min; detector, 254nm. This produced 1-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylic acid (295.2 mg) as a yellow solid. Obtained as an object. LCMS method E: [M+H] ⁺ =341.

The following intermediates were prepared using the same method as described for intermediate 52B.

Scheme 17B: Intermediate 56B (1-(5-fluoro-6-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)pyridin-3-yl)-1H-1,2,3 Synthesis of -triazole-4-carboxylic acid)

Step 1: Ethyl 1-(6-bromo-5-fluoropyridin-3-yl)-1,2,3-triazole-4-carboxylate
6-Bromo-5-fluoropyridin-3-amine (1.0 g, 5.2 mmol, 1.0 eq.) was dissolved in EtOH (30 mL) and HOAc (20 mL), then ethyl 2-diazo-3-oxopropanoate (1.1 g, 7.7 mmol, 1.5 eq) was added. The reaction mixture was heated to 50° C. for 16 hours, then cooled to ambient temperature and concentrated under vacuum. Ethyl 1-(6-bromo-5-fluoropyridin-3-yl)-1,2,3-triazole-4-carboxylate was obtained by diluting the residue with water, collecting the solid by filtration, and drying. (1.2g) was obtained as a yellow solid. LCMS method A: [M+H] ⁺ = 315.

Step 2: 1-[6-[1-(tert-butoxycarbonyl)-2,5-dihydropyrrol-3-yl]-5-fluoropyridin-3-yl]-1,2,3-triazole-4- ethyl carboxylate
Ethyl 1-(6-bromo-5-fluoropyridin-3-yl)-1,2,3-triazole-4-carboxylate (1.0 g, 3.2 mmol, 1.0 eq.) and 3-(4,4,5, Tert-butyl 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (1.1 g, 3.8 mmol, 1.2 eq.) was dissolved in 1,4-dioxane (20 mL). ) and water (2 mL), then Pd(dppf)Cl ₂ (232.2 mg, 0.3 mmol, 0.1 eq.) and Cs ₂ CO ₃ (4.1 g, 12.7 mmol, 4.0 eq.) were added under nitrogen atmosphere. Ta. The reaction mixture was heated to 80° C. for 6 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 Na ₂ SO ₄ 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 1-[6-[1-(tert-butoxycarbonyl)-2,5-dihydropyrrole. Ethyl -3-yl]-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylate (612.2 mg) was obtained as an off-white solid. LCMS method E: [M+H] ⁺ =404.

Step 3: Ethyl 1-[6-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylate
Ethyl 1-[6-[1-(tert-butoxycarbonyl)-2,5-dihydropyrrol-3-yl]-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylate (900.0 mg, 2.2 mmol, 1.0 eq.) was dissolved in MeOH (15 mL), then Pd/C (10% wt., 90.0 mg) was added under nitrogen atmosphere. The mixture was sparged with nitrogen, placed under a hydrogen gas atmosphere (balloon), and then stirred at ambient temperature overnight. 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 (1:1) to give 1-[6-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]- Ethyl 5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylate (605.2 mg) was obtained as an off-white solid. LCMS method A: [M+H] ⁺ =406.

Step 4: Ethyl 1-[5-fluoro-6-(pyrrolidin-3-yl)pyridin-3-yl]-1,2,3-triazole-4-carboxylate
Ethyl 1-[6-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylate (500.0mg, 1.2mmol , 1.0 eq.) was dissolved in DCM (3 mL) and TFA (10 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched by the addition of water. The solution was adjusted to pH 7 with saturated aqueous Na ₂ CO ₃ . 1-[5-fluoro-6-(pyrrolidin-3-yl) was extracted by extracting the resulting solution with ethyl acetate, washing with brine, drying over _anhydrous MgSO and concentrating under vacuum Ethyl pyridin-3-yl]-1,2,3-triazole-4-carboxylate (351.2 mg) was obtained as an off-white solid. The crude product was used directly in the next step without further purification. LCMS method E: [M+H] ⁺ =306.

Step 5: 1-[5-fluoro-6-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]pyridin-3-yl]-1,2,3-triazole-4-carvone ethyl acid
Ethyl 1-[5-fluoro-6-(pyrrolidin-3-yl)pyridin-3-yl]-1,2,3-triazole-4-carboxylate (300.0 mg, 1.0 mmol, 1.0 eq.) and TEA (0.4 mL, 2.9 mmol, 3.0 eq.) was dissolved in ACN (10 mL), then 2,2,2-trifluoroethyl trifluoromethanesulfonate (273.7 mg, 1.2 mmol, 1.2 eq.) was added. The reaction mixture was stirred at ambient temperature for 30 minutes and then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ 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 1-[5-fluoro-6-[1-(2,2,2-trifluoro Ethyl)pyrrolidin-3-yl]pyridin-3-yl]-1,2,3-triazole-4-carboxylate (252.5mg) was obtained as an off-white solid. LCMS method A: [M+H] ⁺ = 388.

Step 6: 1-[5-fluoro-6-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]pyridin-3-yl]-1,2,3-triazole-4-carvone acid
Ethyl 1-[5-fluoro-6-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]pyridin-3-yl]-1,2,3-triazole-4-carboxylate ( 100.0 mg, 0.3 mmol, 1.0 eq.) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (62.0 mg, 1.5 mmol, 6.0 eq.) was added. The reaction mixture was stirred at ambient temperature for 2 hours, then concentrated under vacuum. The crude _1- [ ₅ -fluorol -6-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]pyridin-3-yl]-1,2,3-triazole-4-carboxylic acid (83.2 mg) in off-white Obtained as a solid. LCMS method E: [M+H] ⁺ =360.

Scheme 18B: Synthesis of intermediate 57B (5-(6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl)isoxazole-3-carboxylic acid)

Step 1: 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoro-N-methoxy-N-methylpyridine-3-carboxamide
6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylic acid (2.5 g, 9.1 mmol, 1.0 eq.) was dissolved in DMF (50 mL) and then N,O-dimethyl Hydroxylamine hydrochloride (1.3g, 13.7mmol, 1.5eq), HATU (5.2g, 13.7mmol, 1.5eq) and DIEA (6.4mL, 36.6mmol, 4.0eq) were added. The reaction mixture was stirred at ambient temperature for 1 hour, 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 (1:3) to give 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoro-N- Methoxy-N-methylpyridine-3-carboxamide (1.7g) was obtained as a yellow oil. LCMS method A: [M+H] ⁺ =317.

Step 2: 1-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]ethanone
6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoro-N-methoxy-N-methylpyridine-3-carboxamide (1.7 g, 5.4 mmol, 1.0 eq.) was dissolved in THF (15 mL). Cooled to 0°C, then MeMgBr (3M in THF, 3.2mL, 9.6mmol, 1.5eq) was added dropwise while maintaining the solution at 0°C. The reaction mixture was stirred at 0° C. for 1 h, then quenched by the addition of ice water. _1- [6-( _4,4 -difluoro-1- Methylcyclohexyl)-5-fluoropyridin-3-yl]ethanone (1.4g) was obtained as a yellow oil. LCMS method G: [M+H] ⁺ =272.

Step 3: Ethyl 4-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-2,4-dioxobutanoate
1-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]ethanone (1.4 g, 5.2 mmol, 1.0 eq.) was dissolved in EtOH (14 mL) and then dissolved in sodium Ethoxide (351.2 mg, 5.2 mmol, 1.0 eq.) was added. Ethyl oxalate (1.0 mL, 7.7 mmol, 1.5 eq.) was then added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours, then cooled to 0° C. and quenched by the addition of water. _{4- [} Ethyl 6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-2,4-dioxobutanoate (1.5 g) was obtained as a brown oil. LCMS method A: [M+H] ⁺ =372.

Step 4: Ethyl 5-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2-oxazole-3-carboxylate
Ethyl 4-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-2,4-dioxobutanoate (1.5 g, 4.0 mmol, 1.0 eq.) in EtOH (15 mL) Then hydroxylamine hydrochloride (0.4g, 6.0mmol, 1.5eq) was added. The reaction mixture was heated to 80° C. for 2 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 (1:5) to give 5-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoro Ethyl pyridin-3-yl]-1,2-oxazole-3-carboxylate (1.2 g) was obtained as a brown oil. LCMS method G: [M+H] ⁺ =369.

Step 5: 5-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2-oxazole-3-carboxylic acid
Ethyl 5-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2-oxazole-3-carboxylate (1.2 g, 3.3 mmol, 1.0 eq.) Dissolved in MeOH (10 mL) and water (10 mL), then added NaOH (260.6 mg, 6.5 mmol, 2.0 eq.). 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 preparative HPLC with the following conditions: column, C18 silica gel; mobile phase, increasing from ACN/H ₂ O = 0% to ACN/H ₂ O = 100% within 25 min; detector, 254nm. This produced 5-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2-oxazole-3-carboxylic acid (1.0 g) as a brown solid. Obtained. LCMS method A: [M+H] ⁺ =341.

The following intermediates were prepared using the same method as described for intermediate 57B.

Scheme 19B: Intermediate 66B (3-(5-chloro-6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-3-yl)isoxazole-5-carboxylic acid) synthesis of

Step 1: 5-chloro-N-methoxy-N-methyl-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridine-3-carboxamide
5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridine-3-carboxylic acid (1.8g, 5.6mmol, 1.0eq) and N,O-dimethylhydroxylamine The hydrochloride salt (813.6 mg, 8.3 mmol, 1.5 eq.) was dissolved in DMF (18 mL), then HATU (4.2 g, 11.1 mmol, 2.0 eq.) and DIEA (3.9 mL, 22.2 mmol, 4.0 eq.) were added. The reaction mixture was stirred at ambient temperature overnight and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 5-chloro-N-methoxy-N-methyl-6-[4-(2,2 ,2-trifluoroethyl)piperazin-1-yl]pyridine-3-carboxamide (1.8g) was obtained as a yellow solid. LCMS method A: [M+H] ⁺ =367.

Step 2: 5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridine-3-carbaldehyde
5-chloro-N-methoxy-N-methyl-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridine-3-carboxamide (1.5 g, 4.1 mmol, 1.0 eq.) It was dissolved in THF (17 mL) and cooled to 0°C. LiAlH ₄ (155.2 mg, 4.1 mmol, 1.0 eq.) was then added in portions while maintaining the solution at 0°C. The reaction mixture was stirred at 0° C. for 2 hours, then quenched by the addition of saturated aqueous NH ₄ Cl. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give 5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazine. -1-yl]pyridine-3-carbaldehyde (1.0 g) was obtained as a yellow solid. LCMS method E: [M+H] ⁺ =308.

Step 3: (E) -N-([5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]methylidene)hydroxylamine
5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridine-3-carbaldehyde (1.0 g, 3.3 mmol, 1.0 eq.) and hydroxylamine hydrochloride (271.0 mg , 3.9 mmol, 1.2 eq.) was added to a solution of EtOH (10 mL) and water (10 mL), followed by NaOH (195.0 mg, 4.9 mmol, 1.5 eq.). The reaction mixture was heated to 90° C. for 2 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 Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN/water, gradient from 0% to 100% in 30 min; detector, UV254 nm. This resulted in (E)-N-([5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]methylidene)hydroxylamine (800.0 mg ) was obtained as a brown solid. LCMS method A: [M+H] ⁺ =323.

Step 4: Methyl 3-[5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2-oxazole-5-carboxylate (E)-N-([5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]methylidene)hydroxylamine (1.0g, 3.1mmol , 1.0 eq.) and methyl propiolate (260.5 mg, 3.1 mmol, 1.0 eq.) were dissolved in CHCl ₃ (10 mL), then NaHCO ₃ (390.5 mg, 4.6 mmol, 1.5 eq.) and NCS (413.8 mg, 3.1 mmol , 1.0 eq) was added. The reaction mixture was stirred at ambient temperature overnight and then quenched by the addition of water. 3-[5 _- chloro-6-[ _4- (2 ,2,2-Trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2-oxazole-5-carboxylate (811.2 mg) was obtained as a yellow solid. LCMS method A: [M+H] ⁺ =405.

Step 5: 3-[5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2-oxazole-5-carboxylic acid
Methyl 3-[5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2-oxazole-5-carboxylate (500.0mg , 1.2 mmol, 1.0 eq.) was dissolved in MeOH (5.0 mL) and water (5.0 mL), then LiOH (118.3 mg, 4.9 mmol, 4.0 eq.) was added. The reaction mixture was stirred at ambient temperature for 2 hours, then concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN/water, gradient from 0% to 100% in 30 min; detector, UV 254 nm. This allows 3-[5-chloro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2-oxazole-5-carboxylic acid ( 295.4 mg) was obtained as an off-white solid. LCMS method B: [M+H] ⁺ =391.

The following intermediates were prepared using the same method as described for Intermediate 66B.

Scheme 20B: Synthesis of intermediate 70B (2-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)thiazole-5-carboxylic acid)

Step 1: 5-bromo-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine
2,5-dibromo-3-fluoropyridine (10.0 g, 39.2 mmol, 1.0 eq.) was dissolved in DMF (100 mL), then Cs ₂ CO ₃ (25.7 g, 78.5 mmol, 2.0 eq.) and 4,4- Difluoropiperidine (7.1g, 58.8mmol, 1.5eq) was added. The reaction mixture was heated to 80° C. for 48 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 Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash preparative HPLC with the following conditions: column, C18 silica gel; mobile phase, increasing from ACN/H ₂ O = 60% to ACN/H ₂ O = 100% within 20 min; detector, 254nm. This gave 5-bromo-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (2.0 g) as a yellow solid. LCMS method A: [M+H] ⁺ =295.

Step 2: 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
5-Bromo-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (2.0 g, 6.8 mmol, 1.0 eq.) was dissolved in DMSO (30 mL), then AcOK (1.3 g, 13.6 mmol, 2.0 eq.), bis(pinacolato)diborane (3.4 g, 13.5 mmol, 2.0 eq.) and Pd(dppf) _Cl2 (495.9 mg, 0.7 mmol, 0.1 eq.) were added under nitrogen atmosphere. 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 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 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.6g) was obtained as a yellow oil. LCMS method A: [M+H] ⁺ =343.

Step 3: Methyl 2-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-thiazole-5-carboxylate
2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (300.0 mg, 0.9 mmol, 1.0 eq.) and methyl 2-bromo-1,3-thiazole-5-carboxylate (233.6 mg, 1.1 mmol, 1.2 eq.) were dissolved in 1,4-dioxane (5 mL) and water (5 mL); _Cs2CO3 ( _857.0 mg, 2.6 _mmol , 3.0 eq.) and Pd( _dppf ) _Cl2CH2Cl2 (71.4 mg, 0.09 mmol, 0.1 eq.) were then added under nitrogen atmosphere. The reaction mixture was heated to 90° C. for 6 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 (1:3) to give 2-[6-(4,4-difluoropiperidin-1-yl)-5-fluoro Methyl pyridin-3-yl]-1,3-thiazole-5-carboxylate (200.0 mg) was obtained as an off-white solid. LCMS method A: [M+H] ⁺ =358.

Step 4: 2-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-thiazole-5-carboxylic acid
Methyl 2-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-thiazole-5-carboxylate (300.0 mg, 0.8 mmol, 1.0 eq.) Dissolved in MeOH (6 mL) and water (6 mL), then added NaOH (167.9 mg, 4.2 mmol, 5.0 eq.). The reaction mixture was heated to 60° C. for 3 hours, then cooled to ambient temperature and quenched by the addition of ice water. The resulting solution was adjusted to pH 4 with concentrated HCl, extracted with ethyl acetate, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum to obtain 2-[6-(4,4-difluoro). Piperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-thiazole-5-carboxylic acid (242.1 mg) was obtained as an off-white solid. LCMS method E: [M+H] ⁺ = 344.

The following intermediates were prepared using the same method as described for Intermediate 70B.

Scheme 21B: Intermediate 80B (5-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-1,2,4-oxadiazole-3-carboxylic acid) synthesis of

Step 1: 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carbonyl chloride
6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carboxylic acid (1.7 g, 6.5 mmol, 1.0 eq.) was dissolved in DCM (17 mL) and cooled to 0 °C and then To this, oxalyl chloride (0.8 mL, 9.8 mmol, 1.5 eq) and DMF (0.1 mL) were added dropwise while maintaining the solution at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and then concentrated under vacuum to give 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carbonyl chloride (1.5 g). Obtained as a white solid.

Step 2: [(E)-N-[(E)-6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carbonyloxy]carbamimidoyl]ethyl formate 6- (4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carbonyl (1.4 g, 5.0 mmol, 1.0 eq.) was dissolved in THF (14 mL) and cooled to 0 °C, then [( E) -N'-Hydroxycarbamimidoyl]ethyl formate (663.8 mg, 5.0 mmol, 1.0 eq.) was added. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried _{over anhydrous} Na SO and concentrated under vacuum to obtain [(E)-N-[(E)-6- Ethyl (4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carbonyloxy]carbamimidoyl]formate (1.0 g) was obtained as a white solid. LCMS method A: [M+H] ⁺ = 375.

Step 3: Ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-oxadiazole-3-carboxylate [(E) -N-[(E)-6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carbonyloxy]carbamimidoyl]ethyl formate (1.0 g, 2.7 mmol, 1.0 eq.) was dissolved in EtOH (10 mL) and acetic acid (6 mL). The reaction mixture was heated to 100° C. overnight, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water and then adjusted to pH ₈ with saturated aqueous _Na2CO3 . The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN/water, gradient from 20% to 100% in 30 min; detector, UV 254 nm. This produced ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-oxadiazole-3-carboxylate (800.0 mg) was obtained as a white solid. LCMS method A: [M+H] ⁺ =357.

Step 4: 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-oxadiazole-3-carboxylic acid
Ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-oxadiazole-3-carboxylate (600.0 mg, 1.7 mmol, 1.0 eq.) was dissolved in MeOH (6 mL) and water (6 mL), then LiOH (161.3 mg, 6.7 mmol, 4.0 eq.) was added. The reaction mixture was stirred at ambient temperature for 3 hours, then concentrated under vacuum. The resulting solution was adjusted to pH 5 with concentrated HCl. The crude product was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN/water, gradient from 0% to 100% in 30 min; detector, UV254nm. This produced 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-oxadiazole-3-carboxylic acid (505.1 mg). Obtained as a red solid. LCMS method B: [M+H] ⁺ =329.

Scheme 22B: Synthesis of intermediate 81B (3-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-1,2,4-thiadiazole-5-carboxylic acid)

Step 1: 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carboxamide
6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carboxylic acid (4.0 g, 15.4 mmol, 1.0 eq.) was dissolved in DMF (40 mL), then HATU (8.8 g, 23.1 mmol, 1.5 eq.), DIEA (8.0 mL, 46.1 mmol, 3.0 eq.) and _NH4Cl (1.23 g, 23.058 mmol, 1.5 eq.) were added. The reaction mixture was stirred at ambient temperature overnight and then quenched by the addition of water. The solid was collected by filtration and dried to give 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carboxamide (3.5 g) as an off-white solid. LCMS method A: [M+H] ⁺ =260.

Step 2: 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxathiazol-2-one
6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carboxamide (3.5 g, 13.5 mmol, 1.0 eq) was dissolved in toluene (50 mL) and then chloro(chlorosulfanyl)methanone (3.5g, 27.0mmol, 2.0eq) was added. The reaction mixture was heated to 100 °C overnight, then cooled to ambient temperature and concentrated under vacuum to give 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine. -3-yl]-1,3,4-oxathiazol-2-one (3.0 g) was obtained as a yellow solid. LCMS method C: [M+H] ⁺ =274.

Step 3: Ethyl 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-thiadiazole-5-carboxylate
5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxathiazol-2-one (3.0g, 9.5mmol, 1.0eq) was dissolved in dodecane (10 mL) and then ethyl carbonocyanidate (1.4 g, 14.2 mmol, 1.5 eq.) was added. The reaction mixture was heated to 130° 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 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoro Ethyl pyridin-3-yl]-1,2,4-thiadiazole-5-carboxylate (1.2 g) was obtained as a yellow solid. LCMS method A: [M+H] ⁺ =260.

Step 4: 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-thiadiazole-5-carboxylic acid
Ethyl 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-thiadiazole-5-carboxylate (1.2 g, 3.2 mmol, 1.0 eq. ) was dissolved in MeOH (10 mL) and water (10 mL), then NaOH (257.8 mg, 6.4 mmol, 2.0 eq.) was added. The reaction mixture was stirred at ambient temperature for 30 minutes, then concentrated under vacuum. The residue was diluted with water and adjusted to pH 7 with aqueous HCl (0.5M). 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-thiadiazole-5-carboxylic acid by collecting the solid by filtration. (321.2 mg) was obtained as a white solid. LCMS method B: [M+H] ⁺ = 345.

Scheme 23B: Synthesis of intermediate 82B (3-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)isothiazole-5-carboxylic acid)

Step 1: Methyl 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2-thiazole-5-carboxylate
5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxathiazol-2-one (1.0g, 3.2mmol, 1.0eq) was dissolved in o-dichlorobenzene (10 mL) and then methyl propionate (1.6 g, 19.0 mmol, 6.0 eq.) was added. The reaction mixture was heated to 135° C. overnight, 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 (1:8) to give 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoro Methyl pyridin-3-yl]-1,2-thiazole-5-carboxylate (350.0 mg) was obtained as a yellow solid. LCMS method A: [M+H] ⁺ =358.

Step 2: 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2-thiazole-5-carboxylic acid
Methyl 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2-thiazole-5-carboxylate (330.0 mg, 0.9 mmol, 1.0 eq.) Dissolved in MeOH (2 mL) and water (2 mL), then added NaOH (55.4 mg, 1.4 mmol, 1.5 eq.). The reaction mixture was stirred at ambient temperature overnight and concentrated under vacuum. The residue was diluted with water and adjusted to pH 7 with aqueous HCl (6M). The precipitated solid was collected by filtration and washed with water to give 3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2-thiazole. -5-carboxylic acid (250.0 mg) was obtained as a yellow solid. LCMS method G: [M+H] ⁺ =344.

Scheme 24B: Synthesis of intermediate 83B (4-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)oxazole-2-carboxylic acid)

Step 1: 6-(4,4-difluoropiperidin-1-yl)-5-fluoro-N-methoxy-N-methylpyridine-3-carboxamide
6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carboxylic acid (4.6 g, 17.7 mmol, 1.0 eq.) and N,O-dimethylhydroxylamine hydrochloride (2.6 g, 26.6 mmol , 1.5 eq.) was dissolved in DMF (50 mL), then HATU (10.1 g, 26.5 mmol, 1.5 eq.) and DIEA (12.3 mL, 70.7 mmol, 4.0 eq.) were added. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of water. 6-(4,4-difluoropiperidin-1 _- yl) was extracted by extracting the resulting solution with ethyl acetate, washing with brine, drying over _anhydrous Na SO and concentrating under vacuum. -5-Fluoro-N-methoxy-N-methylpyridine-3-carboxamide (4.2g) was obtained as a yellow oil. LCMS method A: [M+H] ⁺ =272.

Step 2: 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]ethanone
6-(4,4-difluoropiperidin-1-yl)-5-fluoro-N-methoxy-N-methylpyridine-3-carboxamide (1.6 g, 5.3 mmol, 1.0 eq.) was dissolved in THF (20 mL). Cooled to 0°C and then MeMgBr (3M in THF, 2.7mL, 8.1mmol, 1.5eq) was added dropwise under nitrogen atmosphere while maintaining the solution at 0°C. The reaction mixture was stirred at 0° C. for 2 hours, then quenched by the addition of saturated aqueous NH ₄ Cl. 1-[6-( _4,4 -difluoropiperidine- ₁ -yl)-5-fluoropyridin-3-yl]ethenone (900.0 mg) was obtained as a yellow solid. LCMS method A: [M+H] ⁺ =259.

Step 3: 2-bromo-1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]ethanone
1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]ethanone (3.0 g, 11.6 mmol, 1.0 eq.) was dissolved in ACN (15 mL) and then NBS (3.1 g, 17.4 mmol, 1.5 eq.) and TsOH (3.0 g, 17.4 mmol, 1.5 eq.) were added. The reaction mixture was heated to 100° C. overnight, then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with saturated aqueous _NaHCO3 , 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 (1:4) to give 2-bromo-1-[6-(4,4-difluoropiperidin-1-yl). -5-fluoropyridin-3-yl]ethanone (2.0 g) was obtained as a yellow solid. LCMS method A: [M+H] ⁺ =337.

Step 4: 2-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-2-oxoethyl acetate
2-bromo-1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]ethanone (2.0 g, 5.9 mmol, 1.0 eq.) and acetic acid (0.5 mL g, 8.9 mmol, 1.5 eq.) was dissolved in MeOH (6 mL) and water (14 mL) _, then _K2CO3 (0.8 g, 5.9 mmol, 1.0 eq.) was added. The reaction mixture was heated to 70° C. for 3 hours, then cooled to ambient temperature and diluted with ethyl acetate. _2- [6-( _4,4 -difluoropiperidin _- 1-yl )-5-fluoropyridin-3-yl]-2-oxoethyl (1.5 g) was obtained as a yellow solid. LCMS method E: [M+H] ⁺ =317.

Step 5: Ethyl acetate 2-[6-(4 ,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-2-oxoethyl (1.5g, 4.7mmol, 1.0eq) and ethyl carbamoylformate (1.7g, 14.3mmol, 3.0 (eq.) was dissolved in xylene (30 mL), then BF ₃ .Et ₂ O (6.3 mL, 23.7 mmol, 5.0 eq.) was added dropwise. The reaction mixture was heated to 130° C. for 48 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 4-[6-(4,4-difluoropiperidin-1-yl)-5-fluoro Ethyl pyridin-3-yl]-1,3-oxazole-2-carboxylate (510.0 mg) was obtained as a yellow solid. LCMS method C: [M+H] ⁺ =356.

Step 6: 4-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-oxazole-2-carboxylic acid
Ethyl 4-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-oxazole-2-carboxylate (500.0 mg, 1.4 mmol, 1.0 eq.) Dissolved in MeOH (5 mL) and water (5 mL), then added NaOH (112.6 mg, 2.8 mmol, 2.0 eq.). The reaction mixture was heated to 60° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water and adjusted to pH 6 with aqueous HCl (0.5M). The solid was collected by filtration, washed with water, and dried to give 4-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3- 215.2 mg of oxazole-2-carboxylic acid) was obtained as a yellow solid. LCMS method C: [M+H] ⁺ =328.

Scheme 25B: Synthesis of intermediate 84B (5-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylic acid)

Step 1: Ethyl 4-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-2,4-dioxobutanoate
1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]ethenone (600.0 mg, 2.3 mmol, 1.0 eq.) and EtONa (158.1 mg, 2.3 mmol, 1.0 eq.) was dissolved in EtOH (6 mL) and then ethyl oxalate (0.3 mL, 2.3 mmol, 1.0 eq.) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of water. _{4- [} Ethyl 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-2,4-dioxobutanoate (610.0 mg) was obtained as a yellow solid. LCMS method A: [M+H] ⁺ =359.

Step 2: Ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1H-pyrazole-3-carboxylate
_Ethyl 4-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-2,4-dioxobutanoate (900.0 mg, 2.5 mmol, 1.0 eq.) and _NH2NH2 - _H2O (0.2 mL, 2.5 mmol, 1.0 eq.) was dissolved in AcOH (10 mL). The reaction mixture was stirred at ambient temperature for 2 hours, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoro Ethyl pyridin-3-yl]-1H-pyrazole-3-carboxylate (450.0 mg) was obtained as a yellow solid. LCMS method A: [M+H] ⁺ = 355.

Step 3: 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1H-pyrazole-3-carboxylic acid
Ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1H-pyrazole-3-carboxylate (450.0 mg, 1.3 mmol, 1.0 eq.) was dissolved in MeOH ( 5 mL) and water (5 mL), then NaOH (101.6 mg, 2.5 mmol, 2.0 eq.) 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 (2M) and concentrated under vacuum. The residue was purified by back-flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN/water, gradient from 0% to 100% in 30 min; detector, UV254 nm. This gave 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1H-pyrazole-3-carboxylic acid (320.0 mg) as a white solid. Ta. LCMS method B: [M+H] ⁺ =327.

Scheme 26B: Synthesis of intermediate 85B (5-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxylic acid)

Step 1: Ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1-methylpyrazole-3-carboxylate
Ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1H-pyrazole-3-carboxylate (300.0 mg, 0.8 mmol, 1.0 eq.) was dissolved in THF ( 3 mL) and cooled to 0 °C, then NaH (60% wt., 50.8 mg, 1.3 mmol, 1.5 eq.) was added under nitrogen atmosphere while maintaining the solution at 0 °C. After stirring for 10 min at 9°C, MeI (0.1 mL, 1.6 mmol, 1.5 eq.) was added. The reaction mixture was stirred at ambient temperature overnight and then quenched by the addition of MeOH at 0°C. The resulting solution was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 5-[6-(4 ,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1-methylpyrazole-3-carboxylate (150.0 mg) was obtained as a white solid. LCMS method A: [M+H] ⁺ =369.

Step 2: 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1-methylpyrazole-3-carboxylic acid
Ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1-methylpyrazole-3-carboxylate (150.0 mg, 0.4 mmol, 1.0 eq.) in MeOH (2 mL) and water (2 mL), then NaOH (32.6 mg, 0.8 mmol, 2.0 eq.) 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 and adjusted to pH 6 with aqueous HCl (2M). The resulting solution was concentrated under vacuum and the residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN/water, 0% to 100% in 25 min. gradient to; detector, UV254nm. This gave 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1-methylpyrazole-3-carboxylic acid (105.2 mg) as a white solid. It was done. LCMS method C: [M+H] ⁺ =341.

Scheme 27B: Synthesis of intermediate 86B (1-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylic acid)

Step 1: Methyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-3-carboxylate
5-bromo-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (1.0 g, 3.4 mmol, 1.0 eq.) and methyl 1H-pyrazole-3-carboxylate (514.1 mg, 4.1 mmol, (1.2 eq.) was dissolved in DMF (15 mL), then (1S,2S) _-N1 , _N2 -dimethylcyclohexane-1,2-diamine (96.4 mg, 0.7 mmol, 0.2 eq.), CuI (129.1 mg, 0.7 _mmol , 0.2 eq) and _K2CO3 (1.4 g, 10.1 mmol, 3.0 eq) were 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 and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoro Methyl pyridin-3-yl]pyrazole-3-carboxylate (610.0 mg) was obtained as a yellow solid. LCMS method A: [M+H] ⁺ = 341.

Step 2: 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-3-carboxylic acid
Methyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-3-carboxylate (600.0 mg, 1.8 mmol, 1.0 eq.) was dissolved in MeOH (5 mL) and Dissolved in water (5 mL) and then added NaOH (141.0 mg, 3.5 mmol, 2.0 eq.). The reaction mixture was heated to 60° C. for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water and adjusted to pH 6 with aqueous HCl (1M). The precipitated solid was collected by filtration, washed with water, and dried to give 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]pyrazole-3. -carboxylic acid (421.5 mg) was obtained as a white solid. LCMS method E: [M+H] ⁺ =327.

The following intermediates were prepared using the same method as described for Intermediate 86B.

Scheme 28B: Intermediate 88B (5-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-1,3,4-oxadiazole-2-carboxylic acid) synthesis of

Step 1: 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carbohydrazide
Methyl 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3 _- carboxylate (2.0 g, 7.3 mmol, 1.0 eq.) was dissolved in EtOH (30 mL) then _NH2NH2 - Added _H2O (3.5 mL, 70.0 mmol, 10.0 eq.). The resulting solution was heated to 90° C. for 16 hours, then cooled to ambient temperature and concentrated under vacuum. 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carbohydrazide (1.3 g) was obtained as a white solid by diluting the residue with water and collecting the solid by filtration. Obtained. LCMS method A: [M+H] ⁺ =275.

Step 2: Ethyl 2-[[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]formohydrazide]-2-oxoacetate
6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-3-carbohydrazide (1.3 g, 4.7 mmol, 1.0 eq.) and TEA (2.0 mL, 14.2 mmol, 3.0 eq.) were dissolved in DCM (20 mL ) and then ethyl chloroglyoxylate (0.5 mL, 5.0 mmol, 1.0 eq.) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of water. The resulting solution was extracted with dichloromethane, 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 2-[[6-(4,4-difluoropiperidin-1-yl)-5- Ethyl fluoropyridin-3-yl]formohydrazide]-2-oxoacetate (1.1 g) was obtained as a white solid. LCMS method D: [M+H] ⁺ =375.

Step 3: Ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxadiazole-2-carboxylate
Ethyl 2-[[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]formohydrazide]-2-oxoacetate (1.0 g, 2.7 mmol, 1.0 eq.) and TEA ( 1.1 mL, 8.0 mmol, 3.0 eq.) was dissolved in DCM (20 mL), then TsCl (764.0 mg, 4.0 mmol, 1.5 eq.) was added. The reaction mixture was stirred at ambient temperature for 2 hours, 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 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoro Ethyl pyridin-3-yl]-1,3,4-oxadiazole-2-carboxylate (506.2 mg) was obtained as a white solid. LCMS method A: [M+H] ⁺ =357.

Step 4: 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxadiazole-2-carboxylic acid
Ethyl 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxadiazole-2-carboxylate (500.0 mg, 1.4 mmol, 1.0 eq.) was dissolved in MeOH (3 mL) and water (3 mL), then NaOH (112.3 mg, 2.8 mmol, 2.0 eq.) was added. The crude 5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoro Pyridin-3-yl]-1,3,4-oxadiazole-2-carboxylic acid (212.2 mg) was obtained as a white solid, which was used directly in the next step without further work-up. LCMS method E: [M+H] ⁺ =329.

Intermediate 89B (1-(6-bromo-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl)-1H-1,2,3-triazole-4 -carboxamide) synthesis steps 1 to 4:

Step 1: Ethyl 2-diazo-3-oxopropanoate
A mixture of DMF (32.0 g, 438.2 mmol, 33.7 mL, 0.50 eq.) and SOCl ₂ (52.1 g, 438.2 mmol, 31.8 mL, 0.5 eq.) was heated at 40° C. for 2 hours. The solid obtained by concentrating the reaction mixture under reduced pressure was then dissolved in CHCl ₃ (250 mL) and cooled to 0°C. Ethyl 2-diazoacetate (100 g, 876.4 mmol, 1 eq.) was added dropwise over 1 hour while maintaining the temperature at 0.degree. After the addition was complete, the mixture was stirred at 25° C. for 12 hours. The solvent was removed under reduced pressure and then MTBE (800.0 mL) was added to obtain a slurry. The yellow precipitate was collected by filtration, dissolved in 10% aqueous acetic acid, and then extracted with MTBE (3 x 300 mL). The combined organic extracts were washed with aqueous sodium bicarbonate (2M, 3 x 300 mL), hydrochloric acid (10%; 3 x 300 mL), water (3 x 300 mL) and brine (3 x 300 mL). Ethyl 2-diazo- ₃ -oxo-propanoate (15.0 g, 95.0 mmol, 11% yield, 90% purity) was obtained as a yellow oil by drying the organic layer over anhydrous MgSO and concentrating under reduced pressure. Obtained.

Step 2: Ethyl 1-(6-bromo-5-fluoropyridin-3-yl)-1H-1,2,3-triazole-4-carboxylate
6-bromo-5-fluoro-pyridin-3-amine (12.1 g, 63.4 mmol, 1.0 eq.) and ethyl 2-diazo-3-oxo-propanoate (15.0 g, 95.0 mmol, 90% purity, 1.5 eq.) Dissolved in EtOH (300 mL). AcOH (210.0 g, 3.5 mol, 200 mL, 55.2 eq.) was then added and the mixture was heated to 50 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. Ethyl 1-(6-bromo-5-fluoro-3-pyridyl)triazole-4-carboxylate (16.0 g, 50.8 mmol, yield 80%) as a yellow solid.

Step 3: 1-(6-bromo-5-fluoropyridin-3-yl)-1H-1,2,3-triazole-4-carboxylic acid
Ethyl 1-(6-bromo-5-fluoro-3-pyridyl)triazole-4-carboxylate (16 g, 50.8 mmol, 1 eq.) was dissolved in MeOH (300 mL). NaOH (2M, 50.78mL, 2 eq.) was then added. The mixture was stirred at 20°C for 4 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. H ₂ O (30 mL) was then added and the mixture was adjusted to pH 4 by dropwise addition of aqueous HCl (2M). The resulting solid was collected by filtration and washed with water to give 1-(6-bromo-5-fluoro-3-pyridyl)triazole-4-carboxylic acid (12 g, 41.8 mmol, yield 82%) was obtained as a white solid.

Step 4: (1-(6-bromo-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl)-1H-1,2,3-triazole-4 -Synthesis of carboxamide (intermediate 89B)

1-(6-bromo-5-fluoro-3-pyridyl)triazole-4-carboxylic acid (5.0g, 17.4mmol, 1.0eq) and 5,6-difluoro-1H-indol-3-amine (4.0g, 16.7 mmol, purity 70%, 9.6 eq.) was dissolved in DMF (300 mL). Pyridine (11.0 g, 139.3 mmol, 11.3 mL, 8.0 eq.) and EDCI (3.3 g, 17.4 mmol, 1.0 eq.) were then added. The mixture was stirred at 20° C. for 2 hours, then water (1 L) and DCM (1 L) were added to the reaction mixture. The resulting solid was collected by filtration and washed with water and DCM. Compound 1-(6-bromo-5-fluoro-3-pyridyl)-N-(5,6-difluoro-1H-indol-3-yl)triazole-4-carboxamide (6.0 g, 13.0 mmol, 75% yield ) was obtained as a white solid.

Example 1: N-(5,6-difluoro-1H-indol-3-yl)-1-((6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl)methyl)-1H -imidazole-4-carboxamide (compound 105)

1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]imidazole-4-carboxylic acid (200.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in DMF (5 mL). , followed by 5,6-difluoro-1H-indol-3-amine hydrogen chloride (120.5 mg, 0.6 mmol, 1.0 equiv.), HATU (336.2 mg, 0.9 mmol, 1.5 equiv.) and DIEA (0.3 mL, 1.8 mmol, 3.0 equivalent amount) was added. The reaction mixture was stirred at ambient temperature for 2 hours and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The crude product was purified by preparative HPLC with the following conditions: column, YMC-Actus Triart C18, 30*250, 5 μm; mobile phase, water (10 mM NH ₄ HCO ₃ + 0.1% NH ₃ H ₂ O) and ACN (38% phase B to 60% in 10 min); detector, UV254nm. This allows N-(5,6-difluoro-1H-indol-3-yl)-1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]imidazole-4 -Carboxamide (17.1 mg) was obtained as a white solid. LCMS method D: [M+H] ⁺ =490.

The analogs in the table below were prepared using the same method as described for Example 1.

Example 12: 1-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-N-(5-fluoro-1H-pyrrolo[2,3-b]pyridine -3-yl)-1H-imidazole-4-carboxamide

1-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-1H-imidazole-4-carboxylic acid (129.5 mg, 0.4 mmol, 1.0 eq.) was dissolved in THF (10 mL). ), then 5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine hydrogen chloride (74.7 mg, 0.4 mmol, 1.0 eq.), TEA (0.6 mL, 4.0 mmol, 10.0 eq.) and _T3P (189.5 mg, 0.6 mmol, 1.5 eq.) were added. The resulting solution was stirred at ambient temperature overnight and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by preparative HPLC (Prep-HPLC) with the following conditions: Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (0.05% FA), Mobile phase B: ACN; Flow rate: 50 mL/min; Gradient: 35% B to 65% B in 7 min; 254 nm. This allows 1-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-N-(5-fluoro-1H-pyrrolo[2,3-b]pyridine- 3-yl)-1H-imidazole-4-carboxamide (41.4 mg) was obtained as a white solid. LCMS method J: [M+H] ⁺ =460.

The analogs in the table below were prepared using the same method described for Example 12.

Example 22: N-(5,6-difluoro-1H-indol-3-yl)-1-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)- 1H-1,2,3-triazole-4-carboxamide) (Compound 102)

Step 1: N-(5,6-difluoro-1H-indol-3-yl)propiolamide
5,6-Difluoro-1H-indol-3-amine hydrogen chloride (730.0 mg, 3.6 mmol, 1.0 eq.) was dissolved in THF (30 mL) and cooled to 0 °C, then propiolic acid (499.9 mg, 7.1 mmol) , 2.0 eq.), TEA (1.5 mL, 10.7 mmol, 3.0 eq.) and _T3P (6.8 g, 10.7 mmol, 3.0 eq.) were added at 0<0>C. The reaction mixture was stirred at ambient temperature for 3 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on a silica gel column, eluting with ethyl acetate/petroleum ether (1:3) to give N-(5,6-difluoro-1H-indol-3-yl)prop-2 -inamide (350mg) was obtained as a pale yellow solid. LCMS method A: [M+H] ⁺ =221.

Step 2: 5-azido-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine
6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-amine (400.0 mg, 1.7 mmol, 1.0 eq.) was dissolved in ACN (10 mL) and cooled to 0 °C, then , t-BuNO ₂ (0.3 mL, 2.7 mmol, 1.6 eq.) was added dropwise while maintaining the mixture at 0 °C. After 30 minutes at 0°C, TMSN ₃ (0.3 mL, 2.5 mmol, 1.5 eq.) was added dropwise at 0°C. The reaction mixture was stirred for an additional 2 hours at ambient temperature before being quenched by the addition of water. The resulting mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give 5-azido-2-(4,4-difluoropiperidin-1-yl)-3- Fluoropyridine (380mg) was obtained as a yellow oil.

Step 3: N-(5,6-difluoro-1H-indol-3-yl)-1-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-1H -1,2,3-triazole-4-carboxamide
5-azido-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (150.0 mg, 0.6 mmol, 1.0 eq.) was dissolved in dioxane/water (5/0.5 mL) and then treated with N -(5,6-difluoro-1H-indol-3-yl)propiolamide (130.0mg, 0.6mmol, 1.0eq), sodium (R)-2-((S)-1,2-dihydroxyethyl)- 4-Hydroxy-5-oxo-2,5-dihydrofuran-3-olate (24.0 mg, 0.1 mmol, 0.2 eq.) and _CuSO4 (19.0 mg, 0.1 mmol, 0.2 eq.) were added. The reaction mixture was stirred at ambient temperature for 15 hours and then quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was further purified by preparative HPLC with the following conditions: XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (10 mM NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 50 mL/ min; gradient: 35% B to 80% B in 7 min; 254 nm. RT1: 6.95 minutes. This allows N-(5,6-difluoro-1H-indol-3-yl)-1-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-1H -1,2,3-triazole-4-carboxamide (135.5 mg) was obtained as an off-white solid. LCMS method H: [MH] ^- = 476.

Example 23: N-(5,6-difluoro-1H-indol-3-yl)-5-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)iso Oxazole-3-carboxamide (compound 208)

5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2-oxazole-3-carboxylic acid (250.0 mg, 0.8 mmol, 1.0 equiv.) in DMF (3 mL) and then 5,6-difluoro-1H-indol-3-amine hydrogen chloride (223.1 mg, 1.1 mmol, 1.5 eq.) and HATU (435.7 mg, 1.1 mmol, 1.5 eq.) were added. Then DIEA (0.5 mL, 2.9 mmol, 4.0 eq.) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by back-flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN/water, gradient from 0% to 100% in 20 min; detector, UV254 nm. This allows N-(5,6-difluoro-1H-indol-3-yl)-5-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1 ,2-oxazole-3-carboxamide (127.2 mg) was obtained as a pink solid. LCMS method J: [M+H] ⁺ =478.

The analogs in the table below were prepared using the same method described for Example 23.

Example 76: N-(5,6-difluoro-1H-indol-3-yl)-3-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)iso Oxazole-5-carboxamide (compound 210)

3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2-oxazole-5-carboxylic acid (200.0 mg, 0.6 mmol, 1.0 equiv.) in DMF (2 mL) and then 5,6-difluoro-1H-indol-3-amine hydrogen chloride (186.2 mg, 0.9 mmol, 1.5 eq.) and HATU (348.6 mg, 0.9 mmol, 1.5 eq.) were added. Then DIEA (0.4 mL, 2.4 mmol, 4.0 eq.) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by back-flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN/water, gradient from 0% to 100% in 20 min; detector, UV254 nm. This allows N-(5,6-difluoro-1H-indol-3-yl)-3-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1 ,2-oxazole-5-carboxamide (145.8 mg) was obtained as an off-white solid. LCMS method H: [M+H] ⁺ =478.

Example 77: N-(5,6-difluoro-1H-indol-3-yl)-4-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)oxazole -2-carboxamide (compound 193)

4-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,3-oxazole-2-carboxylic acid (200.0 mg, 0.6 mmol, 1.0 equiv.) in DMF (5 mL) and then _T3P (wt. 50% in ethyl acetate, 0.6 mL, 0.9 mmol, 1.5 eq.) and 5,6-difluoro-1H-indol-3-amine hydrogen chloride (187.6 mg , 0.9 mmol, 1.5 eq) was added. Then TEA (0.3 mL, 1.8 mmol, 3.0 eq.) was added. The reaction mixture was stirred at ambient temperature overnight and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by back-flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN/water, gradient from 0% to 100% in 30 min; detector, UV 254 nm. This allows N-(5,6-difluoro-1H-indol-3-yl)-4-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1 ,3-oxazole-2-carboxamide (25.9 mg) was obtained as an off-white solid. LCMS method F: [M+H] ⁺ =478.

The analogs in the table below were prepared using the same method described for Example 77.

Example 80: N-(5,6-difluoro-1H-indol-3-yl)-3-(5-fluoro-6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl) ) pyridin-3-yl) isoxazole-5-carboxamide (compound 160)

3-[5-fluoro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2-oxazole-5-carboxylic acid (300.0 mg, 0.8 mmol, 1.0 eq.) and 5,6-difluoro-1H-indol-3-amine hydrogen chloride (196.8 mg, 1.0 mmol, 1.2 eq.) were dissolved in DMF (10 mL), then NMM (486.4 mg, 4.8 mmol , 6.0 eq.) and PyBOP (417.1 mg, 0.8 mmol, 1.0 eq.) were added. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by preparative HPLC with the following conditions: column, XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₄ OH) and ACN. (from 50% phase B to 70% in 7 minutes); detector, UV254nm. This allows N-(5,6-difluoro-1H-indol-3-yl)-3-[5-fluoro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl] Pyridin-3-yl]-1,2-oxazole-5-carboxamide (63.3 mg) was obtained as a white solid. LCMS method H: [M+H] ⁺ =525.

The analogs in the table below were prepared using the same method described for Example 80.

Example 82: N-(5-chloro-1H-indol-3-yl)-3-(5-fluoro-6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridine -3-yl)isoxazole-5-carboxamide (compound 171)

3-[5-fluoro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2-oxazole-5-carboxylic acid (300.0 mg, 0.8 mmol, 1.0 eq.) and 5-chloro-1H-indol-3-amine (160.3 mg, 1.0 mmol, 1.2 eq.) were dissolved in DMF (10 mL), then NMM (121.6 mg, 1.2 mmol, 1.5 eq.) and PyBOP (625.7 mg, 1.2 mmol, 1.5 eq.) were added. The reaction mixture was stirred at ambient temperature for 3 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions: Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol/L NH ₄ HCO ₃ ), Mobile phase B: ACN; Flow rate : 60 mL/min; Gradient: 50% B to 75% B in 8 min; Wavelength: 220 nm. RT (min): 7.82. This results in N-(5-chloro-1H-indol-3-yl)-3-[5-fluoro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridine- 3-yl]-1,2-oxazole-5-carboxamide (65.3 mg) was obtained as a white solid. LCMS method H: [M+H] ⁺ =523.

Example 83: N-(5,6-difluoro-1H-indol-3-yl)-5-(5-fluoro-6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl) ) pyridin-3-yl) isoxazole-3-carboxamide (compound 204)

5-[5-fluoro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl]-1,2-oxazole-3-carboxylic acid (300.0 mg, 0.8 mmol, 1.0 eq.) and DCC (248.1 mg, 1.2 mmol, 1.5 eq.) were dissolved in DCM (30 mL), followed by DMAP (146.9 mg, 1.2 mmol, 1.5 eq.) and 5,6-difluoro-1H-indole. -3-Amine hydrogen chloride (196.8 mg, 1.0 mmol, 1.2 eq.) was added. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by preparative HPLC with the following conditions: column, XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₄ OH) and ACN. (from 50% phase B to 75% in 7 minutes); detector, UV254nm. This allows N-(5,6-difluoro-1H-indol-3-yl)-5-[5-fluoro-6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl] Pyridin-3-yl]-1,2-oxazole-3-carboxamide (138.2 mg) was obtained as a yellow solid. LCMS method H: [M+H] ⁺ =525.

The analogs in the table below were prepared using the same method described for Example 83.

Example 85: N-(5,6-difluoro-1H-indol-3-yl)-1-(5-fluoro-6-(1-methylcyclohexyl)pyridin-3-yl)-1H-1,2, 3-triazole-4-carboxamide (compound 148)

Step 1: N-(5,6-difluoro-1H-indol-3-yl)propiolamide
5,6-Difluoro-1H-indol-3-amine hydrogen chloride (730.0 mg, 3.6 mmol, 1.0 eq.) was dissolved in THF (30 mL) and cooled to 0 °C, then propiolic acid (499.9 mg, 7.1 mmol) , 2.0 eq.), TEA (1.5 mL, 10.7 mmol, 3.0 eq.) and _T3P (wt. 50% in ethyl acetate, 0.7 mL, 10.7 mmol, 3.0 eq.) were added at 0<0>C. The reaction mixture was stirred at ambient temperature for 3 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on a silica gel column, eluting with ethyl acetate/petroleum ether (1:3) to give N-(5,6-difluoro-1H-indol-3-yl)prop-2 -inamide (350mg) was obtained as a pale yellow solid. LCMS method A: [M+H] ⁺ =221.

Step 2: 5-azido-3-fluoro-2-(1-methylcyclohexyl)pyridine
5-Fluoro-6-(1-methylcyclohexyl)pyridin-3-amine (300.0 mg, 1.4 mmol, 1.0 eq.) was dissolved in ACN (6 mL) and cooled to 0 °C, then the mixture was brought to 0 °C. While maintaining, t- _BuNO2 (0.5 mL, 4.3 mmol, 3.0 eq.) was added dropwise. After 30 minutes at 0°C, TMSN ₃ (0.5 mL, 4.3 mmol, 3.0 eq.) was added dropwise at 0°C. The reaction mixture was stirred for an additional 2 hours at 0°C and then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give 5-azido-3-fluoro-2-(1-methylcyclohexyl)pyridine (260.0 mg). was obtained as a yellow oil.

Step 3: N-(5,6-difluoro-1H-indol-3-yl)-1-[5-fluoro-6-(1-methylcyclohexyl)pyridin-3-yl]-1,2,3-triazole -4-carboxamide
5-azido-3-fluoro-2-(1-methylcyclohexyl)pyridine (250.0 mg, 1.1 mmol, 1.0 eq.) was dissolved in dioxane/water (5/0.5 mL) and then N-(5,6- difluoro-1H-indol-3-yl) propiolamide (235.0 mg, 1.1 mmol, 1.0 eq.), sodium ascorbate (21.2 mg, 0.1 mmol, 0.1 eq.) and _CuSO4 (17.0 mg, 0.1 mmol, 0.1 eq.) added. The reaction mixture was stirred at ambient temperature for 15 hours and then quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was further purified by preparative HPLC with the following conditions: XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (10 mM NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 50 mL/ min; gradient: 35% B to 80% B in 7 min; 254 nm. RT1: 6.95 minutes. This allows N-(5,6-difluoro-1H-indol-3-yl)-1-[5-fluoro-6-(1-methylcyclohexyl)pyridin-3-yl]-1,2,3-triazole -4-Carboxamide (121.8 mg) was obtained as an off-white solid. LCMS method K: [M+H] ⁺ =455.

The analogs in the table below were prepared using the same method described for Example 85.

Example 98: N-(5,6-difluoro-1H-indol-3-yl)-1-(6-((4,4-difluoropiperidin-1-yl)methyl)-5-fluoropyridine-3- yl)-1H-1,2,3-triazole-4-carboxamide (compound 206)

Step 1: 5-bromo-3-fluoropyridine-2-carbaldehyde
2,5-dibromo-3-fluoropyridine (2.0 g, 7.8 mmol, 1.0 eq) was dissolved in THF (40 mL) and cooled to -78°C. Next, n-BuLi (2M in THF, 8.0 mL, 16.0 mmol, 1.0 eq.) was added dropwise while maintaining the solution at -78 °C. After 10 minutes, a solution of DMF (0.6 mL, 7.8 mmol, 1.0 eq.) in THF (2 mL) was added dropwise at -78° C. and the reaction mixture was allowed to warm to ambient temperature and stirred for an additional 2 hours. The reaction was quenched by the addition of saturated aqueous NH ₄ Cl, extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give 5-bromo-3-fluoropyridine-2-carbaldehyde (1.3 g) as a yellow oil. obtained as. LCMS method C: [M+H] ⁺ =204.

Step 2: (5-bromo-3-fluoropyridin-2-yl)methanol
5-Bromo-3-fluoropyridine-2-carbaldehyde (1.3g, 6.4mmol, 1.0eq) was dissolved in THF (20mL) and cooled to 0°C. _NaBH4 (0.5g, 12.7mmol, 2.0eq) was then added in portions while maintaining the reaction mixture at 0<0>C. The reaction mixture was stirred at ambient temperature overnight, then quenched by the addition of saturated aqueous NH ₄ Cl. (5-Bromo-3-fluoropyridin-2-yl)methanol (1.1 g) was dissolved in yellow by extracting the resulting solution with ethyl acetate, drying over anhydrous sodium sulfate, and concentrating under vacuum. Obtained as an oil. LCMS method C: [M+H] ⁺ =206.

Step 3: Dissolve 5-bromo-2-(bromomethyl)-3-fluoropyridine (5-bromo-3-fluoropyridin-2-yl)methanol (1.0 g, 4.9 mmol, 1.0 eq.) in DCM (10 mL). The mixture was cooled to 0°C and then phosphorus tribromide (1.6g, 5.8mmol, 1.2eq) was added while maintaining the solution at 0°C. The reaction mixture was stirred at 0° C. for 2 hours, then diluted with ethyl acetate. Crude 5-bromo-2-(bromomethyl)-3-fluoropyridine (1.0 g) was obtained by washing the resulting solution with saturated aqueous _NaHCO3 , drying over anhydrous sodium sulfate, and concentrating under vacuum. was obtained as a yellow oil. LCMS method C: [M+H] ⁺ =206.

Step 4: 5-bromo-2-[(4,4-difluoropiperidin-1-yl)methyl]-3-fluoropyridine
5-bromo-2-(bromomethyl)-3-fluoropyridine (1.0 g, 3.7 mmol, 1.0 eq.) was dissolved in ACN (10 mL), then 4,4-difluoropiperidine (540.5 mg, 4.5 mmol, 1.2 eq. ) and _{K2CO3 (} 1.5g, 11.1mmol, 3.0eq) were added. The reaction mixture was heated to 60° C. for 4 hours, then cooled to ambient temperature and quenched by the addition of water. The crude 5 _- bromo- ₂ -[(4,4-difluoro Piperidin-1-yl)methyl]-3-fluoropyridine (800.0 mg) was obtained as a white solid. LCMS method C: [M+H] ⁺ =309.

Step 5: 5-azido-2-[(4,4-difluoropiperidin-1-yl)methyl]-3-fluoropyridine
5-bromo-2-[(4,4-difluoropiperidin-1-yl)methyl]-3-fluoropyridine (800.0 mg, 2.6 mmol, 1.0 eq.) was dissolved in EtOH (7 mL) and water (3 mL); Next, (1S,2S)-1,2-diethylcyclohexane (363.0 mg, 2.6 mmol, 1.0 eq.), CuI (492.9 mg, 2.6 mmol, 1.0 eq.) and sodium azide (336.5 mg, 5.2 mmol, 2.0 eq.) were added. , added under nitrogen atmosphere. The reaction mixture was heated to 80° C. for 2 hours, then cooled to ambient temperature and diluted with ethyl acetate. After removing the solids by filtration, the filtrate was 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 5-azido-2-[(4,4-difluoropiperidin-1-yl)methyl] -3-fluoropyridine (400.0 mg) was obtained as a brown solid. LCMS method C: [M+H] ⁺ =272.

Step 6: N-(5,6-difluoro-1H-indol-3-yl)-1-[6-[(4,4-difluoropiperidin-1-yl)methyl]-5-fluoropyridin-3-yl ]-1,2,3-triazole-4-carboxamide
5-azido-2-[(4,4-difluoropiperidin-1-yl)methyl]-3-fluoropyridine (200.0 mg, 0.7 mmol, 1.0 eq.) was dissolved in dioxane (10 mL) and water (1 mL), Then N-(5,6-difluoro-1H-indol-3-yl)prop-2-ynamide (194.8mg, 0.9mmol, 1.2eq), _CuSO4 (11.8mg, 0.1mmol, 0.1eq) and ascorbic acid Sodium (14.7 mg, 0.1 mmol, 0.1 eq.) was added under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature overnight 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 preparative HPLC with the following conditions: column, XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₄ OH) and ACN. (from 40% phase B to 58% in 7 minutes); detector, UV254nm. This allows N-(5,6-difluoro-1H-indol-3-yl)-1-[6-[(4,4-difluoropiperidin-1-yl)methyl]-5-fluoropyridin-3-yl ]-1,2,3-triazole-4-carboxamide (25.0 mg) was obtained as a yellow solid. LCMS method F: [M+H] ⁺ =492.

Example 99/100: (R or S)-N-(5,6-difluoro-1H-indol-3-yl)-1-(6-(4,4-difluoropiperidin-1-yl-3,3 ,5,5-d4)-5-fluoropyridin-3-yl)-1H-1,2,3-triazole-4-carboxamide; Compound 162 (first peak, absolute stereochemistry undetermined) and Compound 163 (second peak) peak, absolute stereochemistry undetermined)

Racemic form (N-(5,6-difluoro-1H-indol-3-yl)-1-[5-fluoro-6-[3-(trifluoromethyl)pyrrolidin-1-yl]pyridin-3-yl] -1,2,3-triazole-4-carboxamide (compound 200) (60.0 mg) was separated by preparative chiral HPLC (Prep-Chiral-HPLC) under the following conditions: Column: CHIRALPAK IE, 2*25 cm; 5 μm; Mobile phase A: Hex (0.5% 2M _NH3 -MeOH) -- HPLC, Mobile phase B: EtOH -- HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 15.5 min; Wavelength :220/254nm. RT1 (min): 11.16; RT2 (min): 13.16. This results in compound 162 (first peak, 27.9 mg) as a white solid and compound 163 (second peak, 25.3 mg) as a white solid. Obtained as a solid.

Compound 162: (R or S)-N-(5,6-difluoro-1H-indol-3-yl)-1-[5-fluoro-6-[3-(trifluoromethyl)pyrrolidin-1-yl] pyridin-3-yl]-1,2,3-triazole-4-carboxamide; LCMS Method H: [M+H] ⁺ =496.

Compound 163: (R or S)-N-(5,6-difluoro-1H-indol-3-yl)-1-[5-fluoro-6-[3-(trifluoromethyl)pyrrolidin-1-yl] pyridin-3-yl]-1,2,3-triazole-4-carboxamide; LCMS Method H: [M+H] ⁺ =496.

Example 101: 1-(6-cyclohexyl-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl)-1H-1,2,3-triazole-4 -Carboxamide (compound 170)

Step 1: 1-(6-(cyclohex-1-en-1-yl)-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl)-1H- 1,2,3-triazole-4-carboxamide
1-(6-bromo-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl)-1H-1,2,3-triazole-4-carboxamide (130.7 mg, 0.3 mmol, 1.0 eq.) and 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (124.8 mg, 0.6 mmol, 2.0 eq. ) was dissolved in dioxane (3 mL). XPhos Pd G3 (12.7 mg, 0.015 mmol, 0.05 eq.) and K ₃ PO ₄ aqueous solution (450 μl, 2M, 3.0 eq.) were then added under nitrogen atmosphere. The reaction mixture was heated at 80°C for 16 hours. 1-(6-(cyclohex-1-en-1-yl)-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indole-3) obtained by concentrating the reaction mixture -yl)-1H-1,2,3-triazole-4-carboxamide was used in the next step without further purification.

Step 2: 1-(6-cyclohexyl-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl)-1H-1,2,3-triazole-4- carboxamide

1-(6-(cyclohex-1-en-1-yl)-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl)-1H-1,2 ,3-triazole-4-carboxamide (87.6, 0.2 mmol, 1.0 eq.) was dissolved in DCM (2 mL). Pd(AcO) ₂ (2.2 mg, 0.01 mmol, 0.05 eq.), AcOH (50 μl) and TES (200 μl) were then added under nitrogen atmosphere. The mixture was stirred at 30°C for 16 hours. The mixture was concentrated under reduced pressure to remove dioxane. _{1- ( 6} -cyclohexyl -5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl)-1H-1,2,3-triazole-4-carboxamide was obtained. MS-ESI, 441.2 [M+H ⁺ ].

The analogs in the table below were prepared using the same method described for Example 101.

Example 109: N-(5,6-difluoro-1H-indol-3-yl)-1-(5-fluoro-6-(5-azaspiro[2.4]heptan-5-yl)pyridin-3-yl) -1H-1,2,3-triazole-4-carboxamide (compound 188)

1-(6-bromo-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl)-1H-1,2,3-triazole-4-carboxamide (130.8 mg, 0.3 mmol, 1.0 eq.) and 5-azaspiro[2.4]heptane (58.3 mg, 0.6 mmol, 2.0 eq.) were dissolved in t-AmOH (3 mL). Then K ₃ PO ₄ (189.9 mg, 0.9 mmol, 3.0 eq.) and RuPhos Pd G3 (12.5 mg, 0.15 mmol, 0.05 eq.) were added under nitrogen atmosphere. The reaction mixture was heated at 100°C for 16 hours. The mixture was concentrated under reduced pressure to remove t-AmOH. _N- (5,6 _{- difluoro-} 1H-indol-3-yl)-1-(5-fluoro-6-(5-azaspiro[2.4]heptan-5-yl)pyridin-3-yl)-1H-1,2,3-triazole-4- Carboxamide was obtained. MS-ESI, 454.2 [M+H ⁺ ].

The analogs in the table below were prepared using the same method described for Example 109.

biological assay
THP1-Dual™ cells (KO-IFNAR2) were used to measure STING pathway activation by compounds described herein.

THP1-Dual™ KO-IFNAR2 cells (obtained from invivogen) were maintained in RPMI, 10% FCS, 5ml P/S, 2mM L-glut, 10mM Hepes, and 1mM sodium pyruvate. Compounds were spotted by Echo into empty 384-well tissue culture plates (Greiner 781182) at final concentrations of 0.0017-100 μM. Cells were plated in TC plates at 40 μL per well, 2×10E6 cells/mL. 2'3'cGAMP (MW718.38, obtained from Invivogen) was prepared in Optimem medium for activation by STING ligand.

The following solutions were prepared for each 1 x 384 plate.
○ Solution A: 2mL Optimem containing one of the following irritants:
・60μL of 10mM 2'3'cGAMP → 150μM stock solution ○Solution B: 2mL of Optimem containing 60μL of Lipofectamine 2000 → Incubate at RT for 5 minutes

2 mL of solution A and 2 ml of solution B were mixed and incubated at room temperature (RT) for 20 minutes. 20 μL of transfection solution (A+B) was added on top of the plated cells to give a final 2',3'cGAMP concentration of 15 μM. The plates were then immediately centrifuged at 340g for 1 min, after which they were incubated for 24 hours at 37°C, 5% _CO2 , >98% humidity. Next, luciferase reporter activity was 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 a white 384 plate in flat bottom square wells. One bag of QUANTI-Luc™ Plus was dissolved in 25 mL of water. 100 μL of QLC stabilizer was added per 25 mL of QUANTI-Luc™ Plus solution. Next, 50 μL of QUANTI-Luc™ Plus/QLC solution was added per well. Luminescence was measured with a plate reader (eg Spectramax I3X (Molecular Devices GF3637001)).

Next, luciferase reporter activity was measured. _EC50 values were calculated by using standard methods known in the art.

Table BA shows the activity of the compounds in the 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 = “+”.

化合物であって、
式中、
Z、Y¹、Y²、およびY³は、CR¹、C（＝O）、N、およびNR²からなる群より独立して選択され、
X¹は、O、S、N、NR²、およびCR¹からなる群より選択され、
X²は、O、S、N、NR⁴、およびCR⁵からなる群より選択され、
各

は独立して単結合もしくは二重結合であり、但し、X¹およびX²を含む5員環はヘテロアリールであり、Z、Y¹、Y²、およびY³を含む6員環はアリールもしくはヘテロアリールであり、
各R¹は、H;R^c;R^g;および-（L¹）_b1-R^gからなる群より独立して選択され、
各R²は、H;R^d;R^g;および-（L²）_b2-R^gからなる群より独立して選択され、
R⁴は、HおよびR^dからなる群より選択され、
R⁵は、H;R^c;およびR^hからなる群より選択され、
R⁶は、H;R^d;およびR^hからなる群より選択され、
環Bは、環原子5個のヘテロアリーレンであって、環原子のうちの1～4個が、N、NH、N（R^d）、O、およびSからなる群よりそれぞれ独立して選択されるヘテロ原子であり、環Bのヘテロアリーレンが、オキソおよびR^cからなる群より独立して選択される1～2個の置換基で置換されていてもよく、但し、環Bが環炭素原子を介してC（＝O）NR⁶基に結合している、ヘテロアリーレンであり、
各L^Aは、1～2個のR^a1で置換されていてもよいC_1～3アルキレン;-O-;-NH-;-NR^d;-S（O）_0～2;およびC（O）からなる群より独立して選択され、
a1は、0、1、もしくは2であり、
環Cは、
・オキソ、R^c、およびR^hからなる群より独立して選択される1～4個の置換基でそれぞれ置換されていてもよい、C_3～12シクロアルキレンもしくはC_3～12シクロアルケニレン;
・環原子3～12個のヘテロシクリレンもしくはヘテロシクロアルケニレンであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロシクリレンもしくはヘテロシクロアルケニレンが、オキソ、R^c、およびR^hからなる群より独立して選択される1～4個の置換基で置換されていてもよい、ヘテロシクリレンもしくはヘテロシクロアルケニレン;
・環原子5～12個のヘテロアリーレンであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロアリーレンが、R^cおよびR^hからなる群より独立して選択される1～4個の置換基で置換されていてもよい、ヘテロアリーレン;ならびに
・R^cおよびR^hからなる群より独立して選択される1～4個の置換基で置換されていてもよい、C_6～10アリーレン
からなる群より選択され、
R⁷は、R^gおよび-（L⁷）_b7-R^gからなる群より選択され、
R^aおよびR^a1の各出現は、-OH;-ハロ;-NR^eR^f;C_1～4アルコキシ;C_1～4ハロアルコキシ;-C（＝O）O（C_1～4アルキル）;-C（＝O）（C_1～4アルキル）;-C（＝O）OH;-CONR'R'';-S（O）_1～2NR'R'';-S（O）_1～2（C_1～4アルキル）;およびシアノからなる群より独立して選択され、
R^cの各出現は、ハロ;シアノ;1～6個の独立して選択されるR^aで置換されていてもよいC_1～10アルキル;C_2～6アルケニル;C_2～6アルキニル;C_1～4アルコキシ;C_1～4ハロアルコキシ;-S（O）_1～2（C_1～4アルキル）;-S（O）（＝NH）（C_1～4アルキル）;-NR^eR^f;-OH;-S（O）_1～2NR'R'';-C_1～4チオアルコキシ;-NO₂;-C（＝O）（C_1～10アルキル）;-C（＝O）O（C_1～4アルキル）;-C（＝O）OH;-C（＝O）NR'R'';および-SF₅からなる群より独立して選択され、
R^dの各出現は、1～3個の独立して選択されるR^aで置換されていてもよいC_1～6アルキル;-C（O）（C_1～4アルキル）;-C（O）O（C_1～4アルキル）;-CONR'R'';-S（O）_1～2NR'R'';-S（O）_1～2（C_1～4アルキル）;-OH;およびC_1～4アルコキシからなる群より独立して選択され、
R^eおよびR^fの各出現は、H;NR'R''、-OH、およびRⁱからなる群よりそれぞれ独立して選択される1～3個の置換基で置換されていてもよいC_1～6アルキル;-C（O）（C_1～4アルキル）;-C（O）O（C_1～4アルキル）;-CONR'R'';-S（O）_1～2NR'R'';-S（O）_1～2（C_1～4アルキル）;-OH;ならびにC_1～4アルコキシからなる群より独立して選択され、
R^gの各出現は、
・それぞれ、オキソ、R^c、R^h、および-（L^g）_bg-R^hからなる群より独立して選択される1～4個の置換基で置換されていてもよい、C_3～12シクロアルキルもしくはC_3～12シクロアルケニル;
・環原子3～12個のヘテロシクリルもしくはヘテロシクロアルケニルであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロシクリルもしくはヘテロシクロアルケニルが、オキソ、R^c、R^h、および-（L^g）_bg-R^hからなる群より独立して選択される1～4個の置換基で置換されていてもよい、ヘテロシクリルもしくはヘテロシクロアルケニル;
・環原子5～12個のヘテロアリールであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロアリールが、R^c、R^h、および-（L^g）_bg-R^hからなる群より独立して選択される1～4個の置換基で置換されていてもよい、ヘテロアリール;ならびに
・R^c、R^h、および-（L^g）_bg-R^hからなる群より独立して選択される1～4個の置換基で置換されていてもよい、C_6～10アリール
からなる群より独立して選択され、
R^hの各出現は、
・それぞれ1～4個のRⁱで置換されていてもよい、C_3～12シクロアルキルもしくはC_3～12シクロアルケニル;
・環原子3～12個のヘテロシクリルもしくはヘテロシクロアルケニルであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロシクリルもしくはヘテロシクロアルケニルが1～4個のRⁱで置換されていてもよい、ヘテロシクリルもしくはヘテロシクロアルケニル;
・環原子5～12個のヘテロアリールであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロアリールが1～4個のRⁱで置換されていてもよい、ヘテロアリール;ならびに
・1～4個のRⁱで置換されていてもよいC_6～10アリール
からなる群より独立して選択され、
Rⁱの各出現は、C_1～6アルキル;C_1～4ハロアルキル;C_1～4アルコキシ;C_1～4ハロアルコキシ;およびハロからなる群より独立して選択され、
L¹、L²、L⁷、およびL^gの各出現は、-O-、-NH-、-NR^d、-S（O）_0～2、C（O）、および、1～3個のR^aで置換されていてもよいC_1～3アルキレンからなる群より選択され、
b1、b2、b7、およびbgは、それぞれ独立して1、2、もしくは3であり、かつ
R'およびR''の各出現は、H;-OH;およびC_1～4アルキルからなる群より独立して選択される、
化合物、またはその薬学的に許容される塩もしくはその互変異性体。
2. Z、Y¹、Y²、およびY³のそれぞれが独立してNまたはCR¹である、項目1の化合物。
3. 式（Ia）:

の化合物またはその薬学的に許容される塩であり、式中、R^1a、R^1b、R^1c、およびR^1dはそれぞれ、独立して選択されるR¹である、項目1または項目2の化合物。
4. Z、Y¹、Y²、およびY³のうちの1～2つ（例えば1つ）がNであり、Z、Y¹、Y²、およびY³のうちの残りのそれぞれが、独立して選択されるCR¹である、項目1または項目2の化合物。
5. 以下の式:

の化合物またはその薬学的に許容される塩からなる群より選択され、式中、R^1a、R^1b、R^1c、およびR^1dはそれぞれ、独立して選択されるR¹である、項目1～項目2または項目4のいずれかの化合物。
6. X¹がNR²である、項目1～項目5のいずれかの化合物。
7. X¹がNHである、項目1～項目6のいずれかの化合物。
8. X²がCR⁵である、項目1～項目7のいずれかの化合物。
9. X²がCHである、項目1～項目8のいずれかの化合物。
10. X¹がNR²であり、X²がCR⁵である、項目1～項目5のいずれかの化合物。
11. X¹がNHであり、X²がCHである、項目1～項目5または項目10のいずれかの化合物。
12. 式（Ia-1）:

の化合物またはその薬学的に許容される塩であり、式中、R^1a、R^1b、R^1c、およびR^1dがそれぞれ、独立して選択されるR¹である、項目1の化合物。
13. 以下の式:

の化合物またはその薬学的に許容される塩からなる群より選択され、式中、R^1a、R^1b、R^1c、およびR^1dがそれぞれ、独立して選択されるR¹である、項目1の化合物。
14. R²がHである、項目12または項目13の化合物。
15. R⁵がHである、項目12～項目14のいずれかの化合物。
16. 各R¹がHである、項目1～項目15のいずれかの化合物。
17. 1～2個のR¹が、R^c1およびR^g1からなる群より独立して選択され、残りの各R¹がHであり、R^c1が、独立して選択されるR^cであり、R^g1が、独立して選択されるR^gである、項目1～項目15のいずれかの化合物。
18. R¹の2個の出現が、R^c1およびR^g1からなる群より独立して選択され、残りの各R¹がHである、項目17の化合物。
19. R¹の2個の出現が、独立して選択されるR^c1であり、残りの各R¹がHである、項目17または項目18の化合物。
20. R¹の1個の出現が、R^c1およびR^g1からなる群より選択され、残りの各R¹がHである、項目17の化合物。
21. R¹の1個の出現がR^c1であり、残りの各R¹がHである、項目17または項目20の化合物。
22. R¹の1個の出現がR^g1であり、残りの各R¹がHである、項目17または項目20の化合物。
23. 各R^c1が、独立して選択されるハロ、例えば-F、-Cl、または-Brである、項目17～項目22のいずれかの化合物。
24. 各R^c1が独立して-Fまたは-Cl、例えば-Fである、項目23の化合物。
25. 各R^g1が、
環原子5～10個のヘテロアリールであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびSからなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロアリールが、R^c、R^h、および-（L^g）_bg-R^hからなる群より独立して選択される1～4個の置換基で置換されていてもよい、ヘテロアリール;ならびに
R^c、R^h、および-（L^g）_bg-R^hからなる群より独立して選択される1～4個の置換基で置換されていてもよい、C_6～10アリール
からなる群より独立して選択される、項目17～項目24のいずれかの化合物。
26. 各R^g1が、
環原子5～6個のヘテロアリールであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびSからなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロアリールが1～4個のR^cで置換されていてもよい、ヘテロアリール;ならびに
1～4個のR^cで置換されていてもよいC₆アリール
からなる群より独立して選択される、項目25の化合物。
27. 各R^g1が、独立して、環原子5個のヘテロアリールであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびSからなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロアリールが1～4個のR^cで置換されていてもよい、ヘテロアリールである、項目25または項目26の化合物。
28. 各R^g1が、1～2個のR^cで置換されていてもよいピラゾリル、例えば、1～6個の独立して選択されるR^aで置換されていてもよい（例えば無置換の）1～2個の独立して選択されるC_1～6（例えばC_1～3）アルキルで置換されていてもよいピラゾリルである、項目27の化合物。
29. R^1aがHである、項目3、項目5、または項目12～項目13のいずれかの化合物。
30. R^1bがHである、項目3、項目5、項目12～項目13、または項目29のいずれかの化合物。
31. R^1bがハロ、例えば-Fまたは-Cl（例えば-F）である、項目3、項目5、項目12～項目13、または項目29のいずれかの化合物。
32. R^1bが、環原子5個のヘテロアリールであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびSからなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロアリールが1～2個のR^cで置換されていてもよい、ヘテロアリールである、項目3、項目5、項目12～項目13、または項目29のいずれかの化合物。
33. R^1bが、1～2個のR^cで置換されていてもよいピラゾリルであり、例えば、各R^cが、1～6個の独立して選択されるR^aで置換されていてもよい（例えば無置換の）独立して選択されるC_1～6（例えばC_1～3）アルキルである、項目32の化合物。
34. R^1cがHである、項目3、項目5、項目12～項目13、または項目29～項目33のいずれかの化合物。
35. R^1cがハロ、例えば-Fまたは-Cl（例えば-F）である、項目3、項目5、項目12～項目13、または項目29～項目33のいずれかの化合物。
36. R^1dがHである、項目3、項目5、項目12～項目13、または項目29～項目35のいずれかの化合物。
37. R^1dがハロ、例えば-Fまたは-Cl（例えば-F）である、項目3、項目5、項目12～項目13、または項目29～項目35のいずれかの化合物。
38. R^1aおよびR^1dがHであり、R^1bおよびR^1cが、独立して選択されるハロ、例えば-Fまたは-Cl、例えば-Fである、項目3、項目5、または項目12～項目13のいずれかの化合物。
39. R^1aおよびR^1dがHであり、R^1bおよびR^1cのうちの一方がHであり、R^1bおよびR^1cのうちの他方が、ハロ、例えば-Fまたは-Cl、例えば-Fである、項目3、項目5、または項目12～項目13のいずれかの化合物。
40. R^1aおよびR^1dがHであり、R^1cが、ハロまたはH、例えば-F、-Cl、またはHであり、R^1bが、環原子5個のヘテロアリールであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびSからなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロアリールが1～4個のR^cで置換されていてもよい、ヘテロアリールである、項目3、項目5または項目12～項目13のいずれかの化合物。
41. R⁶がHである、項目1～項目40のいずれかの化合物。
42. 環Bが、環原子5個のヘテロアリーレンであって、環原子のうちの1～3個が、N、NH、O、およびSからなる群よりそれぞれ独立して選択されるヘテロ原子であり、環Bのヘテロアリーレンが1～2個のR^cBで置換されていてもよく、各R^cBが、独立して選択されるR^cである、ヘテロアリーレンである、項目1～項目41のいずれかの化合物。
43. 環Bが、環原子5個のヘテロアリーレンであって、環原子のうちの2～3個が、N、NH、N（R^d）、O、およびS（例えばNおよびNH）からなる群よりそれぞれ独立して選択されるヘテロ原子であり、環Bのヘテロアリーレンが1～2個のR^cBで置換されていてもよく、各R^cBが、独立して選択されるR^cである、ヘテロアリーレンである、項目1～項目42のいずれかの化合物。
44. 環Bが、1個のR^cBで置換されていてもよいイミダゾリレン、ピラゾリレン、またはトリアゾリレン（例えば1,2,3-トリアゾリレン）からなる群より選択される、項目43の化合物。
45. 環Bが、1個のR^cBで置換されていてもよい

であり、ここで、aaが（L^A）_a1への接続点である、項目44の化合物。
46. 環Bが、1個のR^cBで置換されていてもよい

であり、ここで、aaが（L^A）_a1への接続点である、項目44の化合物。
47. 環Bが、1個のR^cBで置換されていてもよい

であり、ここで、aaが（L^A）_a1への接続点である、項目44の化合物。
48. 環Bが、それぞれ1個のR^cBで置換されていてもよい

であり、ここで、aaが（L^A）_a1への接続点である、項目44の化合物。
49. 各R^cBが、独立して、ハロであるか、または1～3個の独立して選択されるR^a（例えば1～3個の独立して選択されるハロ）で置換されていてもよいC_1～3アルキルである、項目42～項目48または項目163～項目169のいずれかの化合物。
50. a1が0である、項目1～項目49または項目163～項目169のいずれかの化合物。
51. a1が1である、項目1～項目49または項目163～項目169のいずれかの化合物。
52. L^Aが、1～2個のR^a1で置換されていてもよいC_1～3アルキレンである、項目1～項目49、項目51、または項目163～項目169のいずれかの化合物。
53. L^AがCH₂またはCH（Me）、例えばCH₂である、項目52の化合物。
54. 環Cが、
・環原子5～10個のヘテロアリーレンであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロアリーレンが、R^cCおよびR^hCからなる群より独立して選択される1～4個の置換基で置換されていてもよい、ヘテロアリーレン;ならびに
・R^cCおよびR^hCからなる群より独立して選択される1～4個の置換基で置換されていてもよく、ここで、各R^cCが、独立して選択されるR^cであり、各R^hCが、独立して選択されるR^hである、C_6～10アリーレン
からなる群より選択される、項目1～項目53または項目163～項目169のいずれかの化合物。
55. 環Cが、
・環原子5～6（例えば6）個のヘテロアリーレンであって、1～3個（例えば1～2個）の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロアリーレンが、R^cCからなる群より独立して選択される1～4個の置換基で置換されていてもよい、ヘテロアリーレン;ならびに
・R^cCからなる群より独立して選択される1～4個の置換基で置換されていてもよい、C₆アリーレン
からなる群より選択される、項目54または項目163～項目169のいずれかの化合物。
56. 環Cが、
・R^cCからなる群より独立して選択される1～3個（例えば1個）の置換基で置換されていてもよいピリジレン;および
・R^cCからなる群より独立して選択される1～4個（例えば1～2個）の置換基で置換されていてもよい、C₆アリーレン
からなる群より選択される、項目54、項目55、または項目163～項目169のいずれかの化合物。
57. 環Cが、以下の式:

の基であり、式中、Q¹、Q²、Q³、およびQ⁴のそれぞれ1つは、N、CH、およびCR^cCからなる群より独立して選択され、bbはR⁷への接続点である、項目54～項目56または項目163～項目169のいずれかの化合物。
58. Q²がCHである、項目57または項目163～項目169のいずれかの化合物。
59. Q³がCHである、項目57、項目58、または項目163～項目169のいずれかの化合物。
60. Q⁴がNである、項目57～項目59または項目163～項目169のいずれかの化合物。
61. Q¹がCHである、項目57～項目60または項目163～項目169のいずれかの化合物。
62. Q¹がCR^cCである、項目57～項目60または項目163～項目169のいずれかの化合物。
63. 環Cが

、例えば

である、項目57または項目163～項目169のいずれかの化合物。
64. 各R^cCが、-ハロ、および、1～6個の独立して選択されるR^a（例えば1～6個の独立して選択されるハロ、例えば-F）で置換されていてもよいC_1～6（例えばC_1～3）アルキルからなる群より独立して選択される、項目54～項目63または項目163～項目169のいずれかの化合物。
65. 各R^cCが独立してハロ、例えば-Clまたは-F、例えば-Fである、項目54～項目64または項目163～項目169のいずれかの化合物。
66. R⁷がR^gである、項目1～項目65または項目170～項目173のいずれかの化合物。
67. R⁷が、
・オキソ、R^c7、R^h7、および-（L^g）_bg-R^h7からなる群より独立して選択される1～4個の置換基で置換されていてもよい、C_3～12シクロアルキル;ならびに
・環原子4～12個のヘテロシクリルであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロシクリルが、オキソ、R^c7、R^h7、および-（L^g）_bg-R^h7からなる群より独立して選択される1～4個の置換基で置換されていてもよく、ここで、各R^c7が、独立して選択されるR^cであり、R^h7が、独立して選択されるR^hである、ヘテロシクリル
からなる群より選択される、項目1～項目66または項目170～項目173のいずれかの化合物。
68. R⁷が、
・オキソ、R^c7、およびR^h7からなる群より独立して選択される1～4個の置換基で置換されていてもよい、C_4～8シクロアルキル;ならびに
・環原子4～8個のヘテロシクリルであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロシクリルが、オキソ、R^c7、およびR^h7からなる群より独立して選択される1～4個の置換基で置換されていてもよい、ヘテロシクリル
からなる群より選択される、項目67または項目170～項目173のいずれかの化合物。
69. R⁷が、
・R^c7からなる群より独立して選択される1～4個の置換基で置換されていてもよい、C₆シクロアルキル;ならびに
・環原子6個のヘテロシクリルであって、1～2個（例えば1個）の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロシクリルが、R^c7からなる群より独立して選択される1～4個の置換基で置換されていてもよい、ヘテロシクリル
からなる群より選択される、項目68または項目170～項目173のいずれかの化合物。
70. R⁷が、以下の式:

の基であり、式中、X⁷は、CH、CR^c7、またはN、例えばCHまたはNである、項目69または項目170～項目173のいずれかの化合物。
71. 2個のR^c7基が存在する、項目69、項目70、または項目170～項目173のいずれかの化合物。
72. R⁷が、以下の式:

の基であり、式中、X⁷はNまたはCHであり、各R^c7は独立して選択されるR^cである、項目1～項目71または項目170～項目173のいずれかの化合物。
73. 各R^c7が、
独立して選択される、ハロ、または、1～6個のR^a（例えば1～6個の独立して選択されるハロ）で置換されていてもよいC_1～3アルキル
である、項目67～項目72または項目170～項目173のいずれかの化合物。
74. 各R^c7が、独立して、ハロ、例えば-Fである、項目67～項目73または項目170～項目173のいずれかの化合物。
75. R⁷が

であり、ここで、X⁷がNまたはCHである、項目1～項目74または項目170～項目173のいずれかの化合物。
76. 式（I-a1-1）:

の化合物またはその薬学的に許容される塩であり、
式中、
R^1a、R^1b、R^1c、およびR^1dのそれぞれ1つは、独立して選択されるR¹であり、
B⁴はCまたはNであり、
B¹、B²、およびB³は、それぞれ独立して、CH、CR^cB、NH、N（R^d）、N、O、またはSであり、
Q¹、Q²、Q³、およびQ⁴は、N、CH、およびCR^cCからなる群よりそれぞれ独立して選択され、
R^cBおよびR^cCの各出現は、独立して選択されるR^cであり、かつ
各

は独立して単結合または二重結合であり、但し、B¹～B⁴を含む環はヘテロアリールである、
項目1の化合物。
77. R^1aおよびR^1dがHであり、R^1bおよびR^1cが、独立して、Hまたはハロ、例えばハロ（例えば-Fまたは-Cl、例えば-F）である、項目76の化合物。
78. R^1a、R^1b、R^1c、およびR^1dのそれぞれ1つがHである、項目76の化合物。
79. R^1aおよびR^1dがHであり、R^1cがハロまたはH、例えば-F、-Cl、またはHであり、R^1bが、環原子5個のヘテロアリールであって、1～3個の環原子が、N、N（H）、N（R^d）、O、およびSからなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロアリールが、R^cからなる群より独立して選択される1～4個の置換基で置換されていてもよい、ヘテロアリールである、項目76の化合物。
80. R²がHである、項目76～項目79のいずれかの化合物。
81. R⁵がHである、項目76～項目80のいずれかの化合物。
82. R⁶がHである、項目76～項目81のいずれかの化合物。
83. R²がHであり、R⁵がHであり、R⁶がHである、項目76～項目82のいずれかの化合物。
84. B⁴がNであり、B¹がNであり、B³がCHであり、B²がCHである、項目76～項目83のいずれかの化合物。
85. B⁴がNであり、B¹がNであり、B³がCHであり、B²がNである、項目76～項目83のいずれかの化合物。
86. B⁴がNであり、B¹がNであり、B³がCHであり、B²がCR^cBである、項目76～項目83のいずれかの化合物。
87. B⁴がNであり、B¹がCHであり、B³がCHであり、B²がNである、項目76～項目83のいずれかの化合物。
88. B⁴がNであり、B¹がCHであり、B³がNであり、B²がCHである、項目76～項目83のいずれかの化合物。
89. a1が0である、項目76～項目88のいずれかの化合物。
90. a1が1である、項目76～項目88のいずれかの化合物。
91. L^AがCH₂またはCH（Me）である、項目76～項目88または項目90のいずれかの化合物。
92. Q¹およびQ³がCHである、項目76～項目91のいずれかの化合物。
93. Q⁴がNであり、Q²がCHまたはCR^cC、例えばCR^cCである、項目76～項目92のいずれかの化合物。
94. Q¹～Q⁴を含む環が

であり、ここで、bbがR⁷への接続点である、項目76～項目93のいずれかの化合物。
95. R^cCがハロ、例えば-Fまたは-Cl、例えば-Fである、項目76～項目94のいずれかの化合物。
96. R⁷が、
・R^c7からなる群より独立して選択される1～4個の置換基で置換されていてもよい、C₆シクロアルキル;ならびに
・環原子6個のヘテロシクリルであって、1～2個（例えば1個）の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロシクリルが、R^c7からなる群より独立して選択される1～4個の置換基で置換されていてもよく、ここで、各R^c7が、独立して選択されるR^cである、ヘテロシクリル
からなる群より選択される、項目76～項目95のいずれかの化合物。
97. R⁷が、以下の式:

の基であり、式中、X⁷は、CH、CR⁷、またはN、例えばCHまたはNである、項目96の化合物。
98. 2個のR^c7基が存在する、項目96または項目97の化合物。
99. R⁷が、以下の式:

の基であり、式中、X⁷はNまたはCHであり、各R^c7は独立して選択されるR^cである、項目76～項目98のいずれかの化合物。
100. 各R^c7が、
独立して選択される、ハロ、または、1～6個のR^a（例えば1～6個の独立して選択されるハロ）で置換されていてもよいC_1～3アルキル
である、項目96～項目99のいずれかの化合物。
101. 各R^c7が、独立して、ハロ、例えば-Fである、項目96～項目100のいずれかの化合物。
102. R⁷が、X⁷がNまたはCHである

、例えば

である、項目76～項目101のいずれかの化合物。
103. 表C1に示す化合物またはそれらの薬学的に許容される塩からなる群より選択される、項目1の化合物。
104. 項目1～項目103のいずれかの化合物と1つまたは複数の薬学的に許容される賦形剤とを含む、薬学的組成物。
105. STING活性を阻害するための方法であって、STINGを項目1～項目103のいずれかに定義される化合物もしくはその薬学的に許容される塩または項目104に定義される薬学的組成物と接触させる工程を含む、方法。
106. 阻害することが、STINGをアンタゴナイズすることを含む、項目105の方法。
107. インビトロで実行される、項目105～項目106のいずれかの方法。
108. STINGを含む1つまたは複数の細胞を含む試料を化合物と接触させる工程を含む、項目107の方法。
109. 1つまたは複数の細胞が1つまたは複数のがん細胞である、項目107または項目108の方法。
110. 試料が1つまたは複数のがん細胞をさらに含み、がんが、黒色腫、子宮頸がん、乳がん、卵巣がん、前立腺がん、精巣がん、尿路上皮がん、膀胱がん、非小細胞肺がん、小細胞肺がん、肉腫、結腸直腸腺がん、消化管間質腫瘍、胃食道がん、結腸直腸がん、膵がん、腎がん、肝細胞がん、悪性中皮腫、白血病、リンパ腫、脊髄形成異常症候群、多発性骨髄腫、移行上皮がん、神経芽細胞腫、形質細胞新生物、ウィルムス腫瘍、または原発性肝細胞がんからなる群より選択される、項目108または項目109の方法。
111. インビボで実行される、項目105または項目106の方法。
112. STINGシグナル伝達の増大（例えば亢進）が疾患の病態および/または症状および/または進行の一因となる疾患を有する対象に、化合物を投与する工程を含む、項目111の方法。
113. 対象がヒトである、項目112の方法。
114. 疾患ががんである、項目113の方法。
115. がんが、黒色腫、子宮頸がん、乳がん、卵巣がん、前立腺がん、精巣がん、尿路上皮がん、膀胱がん、非小細胞肺がん、小細胞肺がん、肉腫、結腸直腸腺がん、消化管間質腫瘍、胃食道がん、結腸直腸がん、膵がん、腎がん、肝細胞がん、悪性中皮腫、白血病、リンパ腫、脊髄形成異常症候群、多発性骨髄腫、移行上皮がん、神経芽細胞腫、形質細胞新生物、ウィルムス腫瘍、または原発性肝細胞がんからなる群より選択される、項目114の方法。
116. がんが難治性のがんである、項目114または項目115の方法。
117. 化合物が、1つまたは複数の追加のがん治療と組み合わせて投与される、項目112の方法。
118. 1つまたは複数の追加のがん治療が、外科手術、放射線治療、化学治療、毒素治療、免疫治療、寒冷治療、もしくは遺伝子治療、またはそれらの組み合わせを含む、項目117の方法。
119. 化学治療が、1つまたは複数の追加の化学治療剤を投与することを含む、項目118の方法。
120. 1つまたは複数の追加の化学治療剤が、アルキル化剤（例えばシスプラチン、カルボプラチン、メクロレタミン、シクロホスファミド、クロラムブシル、イホスファミドおよび/またはオキサリプラチン）;代謝拮抗物質（例えばアザチオプリンおよび/またはメルカプトプリン）;テルペノイド（例えばビンカアルカロイドおよび/またはタキサン;例えばビンクリスチン、ビンブラスチン、ビノレルビンおよび/またはビンデシン、タキソール、パクリタキセルおよび/またはドセタキセル）;トポイソメラーゼ（例えばI型トポイソメラーゼおよび/または2型トポイソメラーゼ;例えばカンプトテシン、例えばイリノテカンおよび/またはトポテカン;アムサクリン、エトポシド、リン酸エトポシドおよび/またはテニポシド）;細胞傷害性抗生物質（例えばアクチノマイシン、アントラサイクリン、ドキソルビシン、ダウノルビシン、バルルビシン、イダルビシン、エピルビシン、ブレオマイシン、プリカマイシンおよび/またはマイトマイシン）;ホルモン（例えば黄体形成ホルモン放出ホルモンアゴニスト;例えばロイプロリジン、ゴセレリン、トリプトレリン、ヒストレリン、ビカルタミド、フルタミドおよび/またはニルタミド）;抗体（例えばアブシキシマブ、アダリムマブ、アレムツズマブ、アトリズマブ、バシリキシマブ、ベリムマブ、ベバシズマブ、ブレツキシマブベドチン、カナキヌマブ、セツキシマブ、セルトリズマブペゴル（Ceertolizumab pegol）、ダクリズマブ、デノスマブ、エクリズマブ、エファリズマブ、ゲムツズマブ、ゴリムマブ、ゴリムマブ、イブリツモマブチウキセタン、インフリキシマブ、イピリムマブ、ムロモナブ-CD3、ナタリズマブ、オファツムマブ、オマリズマブ、パリビズマブ、パニツムマブ、ラニビズマブ、リツキシマブ、トシリズマブ、トシツモマブおよび/またはトラスツズマブ）;抗血管新生剤;サイトカイン;血栓剤;増殖阻害性物質;駆虫剤;ならびに、免疫チェックポイント受容体を標的とする免疫チェックポイント阻害物質から選択され、免疫チェックポイント阻害物質が、CTLA-4、PD-1、PD-L1、PD-1-PD-L1、PD-1-PD-L2、インターロイキン-2（IL-2）、インドールアミン2,3-ジオキシゲナーゼ（IDO）、IL-10、トランスフォーミング増殖因子-β（TGFβ）、T細胞免疫グロブリンおよびムチン3（TIM3またはHAVCR2）、ガレクチン9-TIM3、ホスファチジルセリン-TIM3、リンパ球活性化遺伝子3タンパク質（LAG3）、MHCクラスII-LAG3、4-1BB-4-1BBリガンド、OX40-OX40リガンド、GITR、GITRリガンド-GITR、CD27、CD70-CD27、TNFRSF25、TNFRSF25-TL1A、CD40L、CD40-CD40リガンド、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リガンド、B7-H3、B7-H4、VISTA、TMIGD2、HHLA2-TMIGD2、BTNL2を含むブチロフィリン類、シグレックファミリー、TIGITおよびPVRファミリーメンバー、KIR、ILTおよびLIR、NKG2DおよびNKG2A、MICAおよびMICB、CD244、CD28、CD86-CD28、CD86-CTLA、CD80-CD28、CD39、CD73アデノシン-CD39-CD73、CXCR4-CXCL12、ホスファチジルセリン、TIM3、ホスファチジルセリン-TIM3、SIRPA-CD47、VEGF、ニューロピリン、CD160、CD30、ならびにCD155（例えばCTLA-4またはPD1またはPD-L1）からなる群より選択される、項目119の方法。
121. 化合物が腫瘍内に投与される、項目112～項目120のいずれかの方法。
122. がんを処置する方法であって、そのような処置を必要とする対象に、有効量の項目1～項目103のいずれかに定義される化合物または項目104に定義される薬学的組成物を投与する工程を含む、方法。
123. がんが、黒色腫、子宮頸がん、乳がん、卵巣がん、前立腺がん、精巣がん、尿路上皮がん、膀胱がん、非小細胞肺がん、小細胞肺がん、肉腫、結腸直腸腺がん、消化管間質腫瘍、胃食道がん、結腸直腸がん、膵がん、腎がん、肝細胞がん、悪性中皮腫、白血病、リンパ腫、脊髄形成異常症候群、多発性骨髄腫、移行上皮がん、神経芽細胞腫、形質細胞新生物、ウィルムス腫瘍、または原発性肝細胞がんからなる群より選択される、項目122の方法。
124. がんが難治性のがんである、項目122または項目123の方法。
125. 化合物が、1つまたは複数の追加のがん治療と組み合わせて投与される、項目122の方法。
126. 1つまたは複数の追加のがん治療が、外科手術、放射線治療、化学治療、毒素治療、免疫治療、寒冷治療、もしくは遺伝子治療、またはそれらの組み合わせを含む、項目125の方法。
127. 化学治療が、1つまたは複数の追加の化学治療剤を投与することを含む、項目126の方法。
128. 1つまたは複数の追加の化学治療剤が、アルキル化剤（例えばシスプラチン、カルボプラチン、メクロレタミン、シクロホスファミド、クロラムブシル、イホスファミドおよび/またはオキサリプラチン）;代謝拮抗物質（例えばアザチオプリンおよび/またはメルカプトプリン）;テルペノイド（例えばビンカアルカロイドおよび/またはタキサン;例えばビンクリスチン、ビンブラスチン、ビノレルビンおよび/またはビンデシン、タキソール、パクリタキセルおよび/またはドセタキセル）;トポイソメラーゼ（例えばI型トポイソメラーゼおよび/または2型トポイソメラーゼ;例えばカンプトテシン、例えばイリノテカンおよび/またはトポテカン;アムサクリン、エトポシド、リン酸エトポシドおよび/またはテニポシド）;細胞傷害性抗生物質（例えばアクチノマイシン、アントラサイクリン、ドキソルビシン、ダウノルビシン、バルルビシン、イダルビシン、エピルビシン、ブレオマイシン、プリカマイシンおよび/またはマイトマイシン）;ホルモン（例えば黄体形成ホルモン放出ホルモンアゴニスト;例えばロイプロリジン、ゴセレリン、トリプトレリン、ヒストレリン、ビカルタミド、フルタミドおよび/またはニルタミド）;抗体（例えばアブシキシマブ、アダリムマブ、アレムツズマブ、アトリズマブ、バシリキシマブ、ベリムマブ、ベバシズマブ、ブレツキシマブベドチン、カナキヌマブ、セツキシマブ、セルトリズマブペゴル、ダクリズマブ、デノスマブ、エクリズマブ、エファリズマブ、ゲムツズマブ、ゴリムマブ、ゴリムマブ、イブリツモマブチウキセタン、インフリキシマブ、イピリムマブ、ムロモナブ-CD3、ナタリズマブ、オファツムマブ、オマリズマブ、パリビズマブ、パニツムマブ、ラニビズマブ、リツキシマブ、トシリズマブ、トシツモマブおよび/またはトラスツズマブ）;抗血管新生剤;サイトカイン;血栓剤;増殖阻害性物質;駆虫剤;ならびに、免疫チェックポイント受容体を標的とする免疫チェックポイント阻害物質から選択され、免疫チェックポイント阻害物質が、CTLA-4、PD-1、PD-L1、PD-1-PD-L1、PD-1-PD-L2、インターロイキン-2（IL-2）、インドールアミン2,3-ジオキシゲナーゼ（IDO）、IL-10、トランスフォーミング増殖因子-β（TGFβ）、T細胞免疫グロブリンおよびムチン3（TIM3またはHAVCR2）、ガレクチン9-TIM3、ホスファチジルセリン-TIM3、リンパ球活性化遺伝子3タンパク質（LAG3）、MHCクラスII-LAG3、4-1BB-4-1BBリガンド、OX40-OX40リガンド、GITR、GITRリガンド-GITR、CD27、CD70-CD27、TNFRSF25、TNFRSF25-TL1A、CD40L、CD40-CD40リガンド、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リガンド、B7-H3、B7-H4、VISTA、TMIGD2、HHLA2-TMIGD2、BTNL2を含むブチロフィリン類、シグレックファミリー、TIGITおよびPVRファミリーメンバー、KIR、ILTおよびLIR、NKG2DおよびNKG2A、MICAおよびMICB、CD244、CD28、CD86-CD28、CD86-CTLA、CD80-CD28、CD39、CD73アデノシン-CD39-CD73、CXCR4-CXCL12、ホスファチジルセリン、TIM3、ホスファチジルセリン-TIM3、SIRPA-CD47、VEGF、ニューロピリン、CD160、CD30、ならびにCD155（例えばCTLA-4またはPD1またはPD-L1）からなる群より選択される、項目126の方法。
129. 化合物が腫瘍内に投与される、項目122～項目128のいずれかの方法。
130. その必要がある対象における免疫応答を誘導する方法であって、有効量の、項目1～項目103のいずれかに定義される化合物または項目104に定義される薬学的組成物を対象に投与する工程を含む、方法。
131. 対象ががんを有する、項目130の方法。
132. 対象が、1つまたは複数のがん治療を受けたことがあり、かつ/または受けており、かつ/または受けることになっている、項目131の方法。
133. がんが、黒色腫、子宮頸がん、乳がん、卵巣がん、前立腺がん、精巣がん、尿路上皮がん、膀胱がん、非小細胞肺がん、小細胞肺がん、肉腫、結腸直腸腺がん、消化管間質腫瘍、胃食道がん、結腸直腸がん、膵がん、腎がん、肝細胞がん、悪性中皮腫、白血病、リンパ腫、脊髄形成異常症候群、多発性骨髄腫、移行上皮がん、神経芽細胞腫、形質細胞新生物、ウィルムス腫瘍、または原発性肝細胞がんからなる群より選択される、項目131の方法。
134. がんが難治性のがんである、項目131～項目133のいずれかの方法。
135. 免疫応答が先天性免疫応答である、項目130の方法。
136. 少なくとも1つまたは複数のがん治療が、外科手術、放射線治療、化学治療、毒素治療、免疫治療、寒冷治療、もしくは遺伝子治療、またはそれらの組み合わせを含む、項目135の方法。
137. 化学治療が、1つまたは複数の追加の化学治療剤を投与することを含む、項目136の方法。
138. 1つまたは複数の追加の化学治療剤が、アルキル化剤（例えばシスプラチン、カルボプラチン、メクロレタミン、シクロホスファミド、クロラムブシル、イホスファミドおよび/またはオキサリプラチン）;代謝拮抗物質（例えばアザチオプリンおよび/またはメルカプトプリン）;テルペノイド（例えばビンカアルカロイドおよび/またはタキサン;例えばビンクリスチン、ビンブラスチン、ビノレルビンおよび/またはビンデシン、タキソール、パクリタキセルおよび/またはドセタキセル）;トポイソメラーゼ（例えばI型トポイソメラーゼおよび/または2型トポイソメラーゼ;例えばカンプトテシン、例えばイリノテカンおよび/またはトポテカン;アムサクリン、エトポシド、リン酸エトポシドおよび/またはテニポシド）;細胞傷害性抗生物質（例えばアクチノマイシン、アントラサイクリン、ドキソルビシン、ダウノルビシン、バルルビシン、イダルビシン、エピルビシン、ブレオマイシン、プリカマイシンおよび/またはマイトマイシン）;ホルモン（例えば黄体形成ホルモン放出ホルモンアゴニスト;例えばロイプロリジン、ゴセレリン、トリプトレリン、ヒストレリン、ビカルタミド、フルタミドおよび/またはニルタミド）;抗体（例えばアブシキシマブ、アダリムマブ、アレムツズマブ、アトリズマブ、バシリキシマブ、ベリムマブ、ベバシズマブ、ブレツキシマブベドチン、カナキヌマブ、セツキシマブ、セルトリズマブペゴル、ダクリズマブ、デノスマブ、エクリズマブ、エファリズマブ、ゲムツズマブ、ゴリムマブ、ゴリムマブ、イブリツモマブチウキセタン、インフリキシマブ、イピリムマブ、ムロモナブ-CD3、ナタリズマブ、オファツムマブ、オマリズマブ、パリビズマブ、パニツムマブ、ラニビズマブ、リツキシマブ、トシリズマブ、トシツモマブおよび/またはトラスツズマブ）;抗血管新生剤;サイトカイン;血栓剤;増殖阻害性物質;駆虫剤;ならびに、免疫チェックポイント受容体を標的とする免疫チェックポイント阻害物質から選択され、免疫チェックポイント阻害物質が、CTLA-4、PD-1、PD-L1、PD-1-PD-L1、PD-1-PD-L2、インターロイキン-2（IL-2）、インドールアミン2,3-ジオキシゲナーゼ（IDO）、IL-10、トランスフォーミング増殖因子-β（TGFβ）、T細胞免疫グロブリンおよびムチン3（TIM3またはHAVCR2）、ガレクチン9-TIM3、ホスファチジルセリン-TIM3、リンパ球活性化遺伝子3タンパク質（LAG3）、MHCクラスII-LAG3、4-1BB-4-1BBリガンド、OX40-OX40リガンド、GITR、GITRリガンド-GITR、CD27、CD70-CD27、TNFRSF25、TNFRSF25-TL1A、CD40L、CD40-CD40リガンド、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リガンド、B7-H3、B7-H4、VISTA、TMIGD2、HHLA2-TMIGD2、BTNL2を含むブチロフィリン類、シグレックファミリー、TIGITおよびPVRファミリーメンバー、KIR、ILTおよびLIR、NKG2DおよびNKG2A、MICAおよびMICB、CD244、CD28、CD86-CD28、CD86-CTLA、CD80-CD28、CD39、CD73アデノシン-CD39-CD73、CXCR4-CXCL12、ホスファチジルセリン、TIM3、ホスファチジルセリン-TIM3、SIRPA-CD47、VEGF、ニューロピリン、CD160、CD30、ならびにCD155（例えばCTLA-4またはPD1またはPD-L1）からなる群より選択される、項目137の方法。
139. STINGシグナル伝達の増大（例えば亢進）が疾患の病態および/または症状および/または進行の一因となる疾患の処置方法であって、そのような処置を必要とする対象に、有効量の項目1～項目103のいずれかに定義される化合物または項目104に定義される薬学的組成物を投与する工程を含む、方法。
140. STINGシグナル伝達の増大（例えば亢進）が疾患の病態および/または症状および/または進行の一因となる疾患を有する対象に、有効量の項目1～項目103のいずれかに定義される化合物または項目104に定義される薬学的組成物を投与する工程を含む、処置の方法。
141. 項目1～項目103のいずれかに定義される化合物または項目104に定義される薬学的組成物を対象に投与する工程を含み、STINGシグナル伝達の増大（例えば亢進）が疾患の病態および/または症状および/または進行の一因となる疾患を処置するのに有効な量で化合物または組成物を投与し、それによって、疾患を処置する、処置の方法。
142. 疾患ががんである、項目139～項目141のいずれかの方法。
143. がんが、黒色腫、子宮頸がん、乳がん、卵巣がん、前立腺がん、精巣がん、尿路上皮がん、膀胱がん、非小細胞肺がん、小細胞肺がん、肉腫、結腸直腸腺がん、消化管間質腫瘍、胃食道がん、結腸直腸がん、膵がん、腎がん、肝細胞がん、悪性中皮腫、白血病、リンパ腫、脊髄形成異常症候群、多発性骨髄腫、移行上皮がん、神経芽細胞腫、形質細胞新生物、ウィルムス腫瘍、または原発性肝細胞がんからなる群より選択される、項目142の方法。
144. がんが難治性のがんである、項目142または項目143の方法。
145. 化合物が、1つまたは複数の追加のがん治療と組み合わせて投与される、項目142～項目144のいずれかの方法。
146. 1つまたは複数の追加のがん治療が、外科手術、放射線治療、化学治療、毒素治療、免疫治療、寒冷治療、もしくは遺伝子治療、またはそれらの組み合わせを含む、項目145の方法。
147. 化学治療が、1つまたは複数の追加の化学治療剤を投与することを含む、項目146の方法。
148. 1つまたは複数の追加の化学治療剤が、アルキル化剤（例えばシスプラチン、カルボプラチン、メクロレタミン、シクロホスファミド、クロラムブシル、イホスファミドおよび/またはオキサリプラチン）;代謝拮抗物質（例えばアザチオプリンおよび/またはメルカプトプリン）;テルペノイド（例えばビンカアルカロイドおよび/またはタキサン;例えばビンクリスチン、ビンブラスチン、ビノレルビンおよび/またはビンデシン、タキソール、パクリタキセルおよび/またはドセタキセル）;トポイソメラーゼ（例えばI型トポイソメラーゼおよび/または2型トポイソメラーゼ;例えばカンプトテシン、例えばイリノテカンおよび/またはトポテカン;アムサクリン、エトポシド、リン酸エトポシドおよび/またはテニポシド）;細胞傷害性抗生物質（例えばアクチノマイシン、アントラサイクリン、ドキソルビシン、ダウノルビシン、バルルビシン、イダルビシン、エピルビシン、ブレオマイシン、プリカマイシンおよび/またはマイトマイシン）;ホルモン（例えば黄体形成ホルモン放出ホルモンアゴニスト;例えばロイプロリジン、ゴセレリン、トリプトレリン、ヒストレリン、ビカルタミド、フルタミドおよび/またはニルタミド）;抗体（例えばアブシキシマブ、アダリムマブ、アレムツズマブ、アトリズマブ、バシリキシマブ、ベリムマブ、ベバシズマブ、ブレツキシマブベドチン、カナキヌマブ、セツキシマブ、セルトリズマブペゴル、ダクリズマブ、デノスマブ、エクリズマブ、エファリズマブ、ゲムツズマブ、ゴリムマブ、ゴリムマブ、イブリツモマブチウキセタン、インフリキシマブ、イピリムマブ、ムロモナブ-CD3、ナタリズマブ、オファツムマブ、オマリズマブ、パリビズマブ、パニツムマブ、ラニビズマブ、リツキシマブ、トシリズマブ、トシツモマブおよび/またはトラスツズマブ）;抗血管新生剤;サイトカイン;血栓剤;増殖阻害性物質;駆虫剤;ならびに、免疫チェックポイント受容体を標的とする免疫チェックポイント阻害物質から選択され、免疫チェックポイント阻害物質が、CTLA-4、PD-1、PD-L1、PD-1-PD-L1、PD-1-PD-L2、インターロイキン-2（IL-2）、インドールアミン2,3-ジオキシゲナーゼ（IDO）、IL-10、トランスフォーミング増殖因子-β（TGFβ）、T細胞免疫グロブリンおよびムチン3（TIM3またはHAVCR2）、ガレクチン9-TIM3、ホスファチジルセリン-TIM3、リンパ球活性化遺伝子3タンパク質（LAG3）、MHCクラスII-LAG3、4-1BB-4-1BBリガンド、OX40-OX40リガンド、GITR、GITRリガンド-GITR、CD27、CD70-CD27、TNFRSF25、TNFRSF25-TL1A、CD40L、CD40-CD40リガンド、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リガンド、B7-H3、B7-H4、VISTA、TMIGD2、HHLA2-TMIGD2、BTNL2を含むブチロフィリン類、シグレックファミリー、TIGITおよびPVRファミリーメンバー、KIR、ILTおよびLIR、NKG2DおよびNKG2A、MICAおよびMICB、CD244、CD28、CD86-CD28、CD86-CTLA、CD80-CD28、CD39、CD73アデノシン-CD39-CD73、CXCR4-CXCL12、ホスファチジルセリン、TIM3、ホスファチジルセリン-TIM3、SIRPA-CD47、VEGF、ニューロピリン、CD160、CD30、ならびにCD155（例えばCTLA-4またはPD1またはPD-L1）からなる群より選択される、項目147の方法。
149. 化合物が腫瘍内に投与される、項目139～項目148のいずれかの方法。
150. STINGに関連する疾患、障害、または状態の処置方法であって、そのような処置を必要とする対象に、有効量の項目1～項目103のいずれかに定義される化合物または項目104に定義される薬学的組成物を投与する工程を含む、方法。
151. 疾患、障害、または状態が、I型インターフェロン症、アイカルディ・グティエール症候群（AGS）、ループスの遺伝的形態、炎症関連障害、および関節リウマチから選択される、項目150の方法。
152. 疾患、障害、または状態がI型インターフェロン症（例えば乳児発症性STING関連血管炎（SAVI））である、項目151の方法。
153. I型インターフェロン症が乳児発症性STING関連血管炎（SAVI））である、項目152の方法。
154. 疾患、障害、または状態がアイカルディ・グティエール症候群（AGS）である、項目151の方法。
155. 疾患、障害、または状態がループスの遺伝的形態である、項目151の方法。
156. 疾患、障害、または状態が炎症関連障害である、項目151の方法。
157. 炎症関連障害が全身性エリテマトーデスである、項目156の方法。
158. 項目1～項目103のいずれかに定義される化合物またはその薬学的に許容される塩もしくは互変異性体と、1つまたは複数の治療活性作用物質とを含む、組合せ。
159. 医薬として使用するための、項目1～項目103のいずれかに定義される化合物またはその薬学的に許容される塩もしくは互変異性体、または、項目104に定義される薬学的組成物。
160. STING阻害によってモジュレートされる疾患、状態、または障害の処置において使用するための、項目1～項目103のいずれかに定義される化合物またはその薬学的に許容される塩もしくは互変異性体、または、項目104に定義される薬学的組成物。
161. 項目105～項目157のいずれかにおいて言及される疾患の処置において使用するための、項目1～項目103のいずれかに定義される化合物またはその薬学的に許容される塩もしくは互変異性体、または、項目104に定義される薬学的組成物。
162. 項目105～項目157のいずれかにおいて言及される疾患を処置するための医薬の製造における、項目1～項目103のいずれかに定義される化合物またはその薬学的に許容される塩もしくは互変異性体、または、項目104に定義される薬学的組成物の使用。
163. 環Bが、
1個のR^cBで置換されていてもよい、イソオキサゾリレン、オキサジアゾリレン、オキサゾリレン、チアゾリレン、イソチアゾリレン、またはチアジアゾリレン
からなる群より選択される、項目43の化合物。
164. 環Bが、それぞれ1個のR^cBで置換されていてもよい

であり、ここで、aaが（L^A）_a1への接続点である、項目163の化合物。
165. 環Bが、それぞれ1個のR^cBで置換されていてもよい

であり、ここで、aaが（L^A）_a1への接続点である、項目43または項目163の化合物。
166. 環Bが、それぞれ1個のR^cBで置換されていてもよい

であり、ここで、aaが（L^A）_a1への接続点である、項目43または項目163の化合物。
167. 環Bが、それぞれ1個のR^cBで置換されていてもよい

であり、ここで、aaが（L^A）_a1への接続点である、項目43または項目163の化合物。
168. 環Bが、それぞれ1個のR^cBで置換されていてもよい

であり、ここで、aaが（L^A）_a1への接続点である、項目43または項目163の化合物。
169. 環Bが、それぞれ1個のR^cBで置換されていてもよい

であり、ここで、aaが（L^A）_a1への接続点である、項目43または項目163の化合物。
170. R⁷が、
・R^c7からなる群より独立して選択される1～4個の置換基で置換されていてもよい、C_4～5シクロアルキル;ならびに
・環原子5～6個のヘテロシクリルであって、1～2個（例えば1個）の環原子が、N、N（H）、N（R^d）、O、およびS（O）_0～2からなる群よりそれぞれ独立して選択されるヘテロ原子であり、ヘテロシクリルが、R^c7からなる群より独立して選択される1～4個の置換基で置換されていてもよい、ヘテロシクリル
からなる群より選択される、項目68の化合物。
171. R⁷が、以下の式:

の基であり、式中、X⁷は、CH、CR^c7、またはN、例えばCHまたはNである、項目68の化合物。
172. R⁷が、以下の式:

の基であり、式中、R^dは、1～3個の独立して選択されるR^aで置換されていてもよいC_1～6アルキルからなる群より独立して選択され、m7は0または1である、項目68の化合物。
173. R⁷が、
それぞれ1～2個のR^c7で置換されていてもよい、テトラヒドロピラニル、モルホリニル、5-アザスピロ［2.5］オクタニル、または2-アザビシクロ［2.2.1］ヘプタニル
からなる群より選択され、例えば、R⁷が、

であることができる、項目68の化合物。 Numbered Sections The compounds, compositions, methods, and other subject matter described herein are further described in the numbered sections below.
1. Formula I:

A compound,
During the ceremony,
Z, Y ¹ , Y ² , and Y ³ are independently selected from the group consisting of CR ¹ , C(=O), N, and NR ² ;
X ¹ is selected from the group consisting of O, S, N, NR ² and CR ¹ ;
^X2 is selected from the group consisting of O, S, N, ^NR4 , and ^CR5 ;
each

are independently a single bond or a double bond, provided that the 5-membered ring containing X ¹ and X ² is heteroaryl, and the 6-membered ring containing Z, Y ¹ , Y ² , and Y ³ is aryl or is a heteroaryl,
each R ¹ is independently selected from the group consisting of H;R ^c ;R ^g ; and -(L ¹ ) _b1 -R ^g ;
each R ² is independently selected from the group consisting of H;R ^d ;R ^g ; and -(L ² ) _b2 -R ^g ;
R ⁴ is selected from the group consisting of H and R ^d ;
R ⁵ is selected from the group consisting of H; R ^c ; and R ^h ;
R ⁶ is selected from the group consisting of H; R ^d ; and R ^h ;
Ring B is a 5 ring atom heteroarylene in which 1 to 4 of the ring atoms are each independently selected from the group consisting of N, NH, N(R ^d ), O, and S. and the heteroarylene of ring B is optionally substituted with 1 to 2 substituents independently selected from the group consisting of oxo and R ^c , provided that ring B is a ring carbon atom is a heteroarylene bonded to the C(=O)NR ⁶ group through
^and _C ^{( O} _{_} ) are independently selected from the group consisting of
a1 is 0, 1, or 2,
Ring C is
- C _{3-12 cycloalkylene or C 3-12 cycloalkenylene} , each optionally substituted with 1 to 4 substituents independently selected from the group consisting of oxo, R ^c , and R ^h ;
・Heterocyclylene or heterocycloalkenylene with 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R ^d ), O, and S(O) _{0 to 2} heteroatoms each independently selected from the group consisting of 1 to 4 substituted heterocyclylene or heterocycloalkenylene independently selected from the group consisting of oxo, R ^c , and R ^h heterocyclylene or heterocycloalkenylene, optionally substituted with groups;
・Heteroarylene with 5 to 12 ring atoms, in which 1 to 3 ring atoms are from the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2} a heteroarylene, each independently selected heteroatom, wherein the heteroarylene is optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c and R ^h ; and - selected from the group consisting of C _6-10 arylene, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c and R ^h ,
R ⁷ is selected from the group consisting of R ^g and -(L ⁷ ) _b7 -R ^g ;
Each occurrence of R ^a and R ^a1 is -OH;-halo;-NR ^e R ^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) _1~2 NR'R'';-S(O) _{1~ 2} (C _1-4 alkyl); and cyano;
Each occurrence of R ^c represents halo; cyano; C _1-10 alkyl optionally substituted with 1 to 6 independently selected R ^a ; C _2-6 alkenyl; C _2-6 alkynyl; _1-4 alkoxy;C _1-4 haloalkoxy;-S(O) _1-2 (C _1-4 alkyl);-S(O)(=NH)(C _1-4 alkyl);-NR ^e R ^f ;-OH;-S(O) _1~2 NR'R'';-C _{1~4thioalkoxy} ;-NO ₂ ;-C(=O) (C _1~10 alkyl);-C(=O) independently selected from the group consisting of O(C _1-4 alkyl); -C(=O)OH; -C(=O)NR'R''; and -SF ₅ ;
Each occurrence of R ^d is C _1-6 alkyl, optionally substituted with 1 to 3 independently selected R ^a ;-C(O)(C _1-4 alkyl);-C(O )O(C _1-4 alkyl);-CONR'R'';-S(O) _1-2 NR'R'';-S(O) _1-2 (C _1-4 alkyl);-OH; and C _1-4 alkoxy;
Each ^occurrence of R ^e and R ^f is a C _1-6 alkyl;-C(O)(C _1-4 alkyl);-C(O)O(C _1-4 alkyl);-CONR'R'';-S(O) _1-2 NR'R '';-S(O) _1-2 (C _1-4 alkyl);-OH; and C _1-4 alkoxy;
Each occurrence of R ^g is
・C _3-12 , each optionally substituted with 1 to 4 substituents independently selected from the group consisting of oxo, R ^c , R ^h , and -(L ^g ) _bg -R ^h cycloalkyl or C _3-12 cycloalkenyl;
- Heterocyclyl or heterocycloalkenyl with 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R ^d ), O, and S(O) from _{0 to 2} and the heterocyclyl or heterocycloalkenyl is independently selected from the group consisting of oxo, R ^c , R ^h , and -(L ^g ) _bg -R ^h heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents;
- Heteroaryl of 5 to 12 ring atoms, in which 1 to 3 ring atoms are from the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2} each independently selected heteroatom, wherein the heteroaryl is one to four substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h optionally substituted heteroaryl; and 1 to 4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h ; independently selected from the group consisting of C _6-10 aryls,
Each occurrence of R ^h is
・C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each optionally substituted with 1 to 4 R ⁱ ;
- Heterocyclyl or heterocycloalkenyl with 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R ^d ), O, and S(O) from _{0 to 2} heteroatom(s) independently selected from the group consisting of heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1 to 4 R ⁱ ;
- Heteroaryl of 5 to 12 ring atoms, in which 1 to 3 ring atoms are from the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2} Heteroaryl, each independently selected heteroatom, where the heteroaryl is optionally substituted with 1 to 4 R ⁱ ; and C optionally substituted with 1 to 4 R ⁱ independently selected from a group consisting of _{6 to 10} aryles,
each occurrence of R ⁱ is independently selected from the group consisting of C _1-6 alkyl; C _1-4 haloalkyl; C _1-4 alkoxy; C _1-4 haloalkoxy; and halo;
Each occurrence of L ¹ , L ² , L ⁷ , and L ^g represents -O-, -NH-, -NR ^d , -S(O) _0-2 , C(O), and 1-3 selected from the group consisting of C _1-3 alkylene optionally substituted with R ^a ,
b1, b2, b7, and bg are each independently 1, 2, or 3, and
each occurrence of R' and R'' is independently selected from the group consisting of H;-OH; and C _1-4 alkyl;
A compound, or a pharmaceutically acceptable salt thereof or a tautomer thereof.
2. The compound of item 1, wherein each of Z, Y ¹ , Y ² , and Y ³ is independently N or CR ¹ .
3. Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein R ^1a , R ^1b , R ^1c , and R ^1d are each independently selected R ¹ . .
4. One or two (for example, one) of Z, Y ¹ , Y ² , and Y ³ are N, and each of the remaining Z, Y ¹ , Y ² , and Y ³ is independent The compound of item 1 or item 2 which is CR ¹ selected as
5. The following formula:

or a pharmaceutically acceptable salt thereof, wherein R ^1a , R ^1b , R ^1c , and R ^1d are each independently selected R ¹ . A compound of either item 2 or item 4.
6. A compound according to any of items 1 to 5, wherein X ¹ is NR ² .
7. A compound according to any of items 1 to 6, wherein X ¹ is NH.
8. A compound according to any of items 1 to 7, wherein X ² is CR ⁵ .
9. A compound according to any of items 1 to 8, wherein X ² is CH.
10. The compound of any of items 1 to 5, wherein X ¹ is NR ² and X ² is CR ⁵ .
11. The compound of any of items 1 to 5 or 10, wherein X ¹ is NH and X ² is CH.
12. Formula (Ia-1):

or a pharmaceutically acceptable salt thereof, wherein R ^1a , R ^1b , R ^1c , and R ^1d are each independently selected R ¹ .
13. The following formula:

or a pharmaceutically acceptable salt thereof, wherein R ^1a , R ^1b , R ^1c , and R ^1d are each independently selected R ¹ . Compound.
14. The compound of item 12 or item 13, wherein R ² is H.
15. The compound according to any of items 12 to 14, wherein R ⁵ is H.
16. A compound according to any of items 1 to 15, wherein each R ¹ is H.
17. 1 to 2 R ¹ are independently selected from the group consisting of R ^c1 and R ^g1 , each remaining R ¹ is H, and R ^c1 is an independently selected R ^c , R ^g1 is independently selected R ^g .
18. The compound of item 17, wherein two occurrences of R ¹ are independently selected from the group consisting of R ^c1 and R ^g1 and each remaining R ¹ is H.
19. The compound of item 17 or item 18, wherein two occurrences of R ¹ are independently selected R ^c1 and each remaining R ¹ is H.
20. The compound of item 17, wherein one occurrence of R ¹ is selected from the group consisting of R ^c1 and R ^g1 and each remaining R ¹ is H.
21. A compound of item 17 or item 20, wherein one occurrence of R ¹ is R ^c1 and each remaining R ¹ is H.
22. A compound of item 17 or item 20, wherein one occurrence of R ¹ is R ^g1 and each remaining R ¹ is H.
23. A compound according to any of items 17 to 22, wherein each R ^c1 is independently selected halo, such as -F, -Cl, or -Br.
24. A compound according to item 23, wherein each R ^c1 is independently -F or -Cl, such as -F.
25. Each R ^g1 is
Heteroaryl of 5 to 10 ring atoms, with 1 to 3 ring atoms each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S is a heteroatom, and the heteroaryl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h ; heteroaryl; and
From the group consisting of C _6-10 aryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h The compound of any of items 17 to 24, independently selected.
26. Each R ^g1 is
Heteroaryl of 5 to 6 ring atoms, with 1 to 3 ring atoms each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S heteroaryl, which is a heteroatom, and the heteroaryl is optionally substituted with 1 to 4 R ^c ; and
A compound of item 25 independently selected from the group consisting of C ₆ aryl optionally substituted with 1 to 4 R ^c .
27. Each R ^g1 is independently a 5 ring atom heteroaryl, with 1 to 3 ring atoms consisting of N, N(H), N(R ^d ), O, and S. A compound of item 25 or item 26, wherein each heteroatom is independently selected from the group and is a heteroaryl, wherein the heteroaryl is optionally substituted with 1 to 4 R ^c .
28. Each R ^g1 may be optionally substituted with 1 to 2 R ^c pyrazolyl, e.g. optionally substituted with 1 to 6 independently selected R ^a (e.g. unsubstituted ) A compound of item 27 which is pyrazolyl optionally substituted with 1 to 2 independently selected C _1-6 (eg C _1-3 )alkyl.
29. The compound of item 3, item 5, or any of items 12 to 13, wherein R ^1a is H.
30. The compound of any of item 3, item 5, item 12-13, or item 29, wherein R ^1b is H.
31. The compound of any of item 3, item 5, item 12-13, or item 29, wherein R ^1b is halo, such as -F or -Cl (eg -F).
32. R ^1b is a 5 ring atom heteroaryl in which 1 to 3 ring atoms are each independently from the group consisting of N, N(H), N(R ^d ), O, and S. any of item 3, item 5, item ¹² to item 13, or item 29, which is a heteroatom selected from compound.
33. R ^1b is pyrazolyl optionally substituted with 1 to 2 R ^c , for example each R ^c may be substituted with 1 to 6 independently selected R ^a A compound of item 32 which is a good (eg, unsubstituted) independently selected C _1-6 (eg, C _1-3 ) alkyl.
34. The compound of any of Item 3, Item 5, Item 12 to Item 13, or Item 29 to Item 33, wherein R ^1c is H.
35. The compound of any of item 3, item 5, item 12 to item 13, or item 29 to item 33, wherein R ^1c is halo, such as -F or -Cl (eg -F).
36. The compound of any of Item 3, Item 5, Item 12 to Item 13, or Item 29 to Item 35, wherein R ^1d is H.
37. The compound of any of item 3, item 5, item 12 to item 13, or item 29 to item 35, wherein R ^1d is halo, such as -F or -Cl (eg -F).
38. Item 3, item 5, or item 12-, 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. Any compound of item 13.
39. R ^1a and R ^1d are H, one of R ^1b and R ^1c is H, and the other of R ^1b and R ^1c is halo, such as -F or -Cl, such as -F. A compound listed in Item 3, Item 5, or Items 12 to 13.
40. 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, with 1 to 3 ring atoms are each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and the heteroaryl has 1 to 4 R ^c A compound according to any of Items 3, 5, or 12 to 13, which is an optionally substituted heteroaryl.
41. A compound according to any of items 1 to 40, wherein R ⁶ is H.
42. Ring B is a heteroarylene of 5 ring atoms, in which 1 to 3 of the ring atoms are heteroatoms each independently selected from the group consisting of N, NH, O, and S. of items 1 to 41, wherein the heteroarylene of ring B is optionally substituted with 1 to 2 R ^cB , each R ^cB being an independently selected R ^c any compound.
43. Ring B is a 5 ring atom heteroarylene in which 2 to 3 of the ring atoms consist of N, NH, N(R ^d ), O, and S (e.g., N and NH) a heteroatom, each independently selected from the group, wherein the heteroarylene of ring B is optionally substituted with 1 to 2 R ^cB , each R ^cB being an independently selected R ^c , a heteroarylene, according to any one of Items 1 to 42.
44. A compound according to item 43, wherein ring B is selected from the group consisting of imidazolylene, pyrazolylene, or triazorylene (eg 1,2,3-triazolylene) optionally substituted with one R ^cB .
45. Ring B may be substituted with one R ^cB

and where aa is the point of attachment to (L ^A ) _a1 .
46. Ring B may be substituted with one R ^cB

and where aa is the point of attachment to (L ^A ) _a1 .
47. Ring B may be substituted with one R ^cB

and where aa is the point of attachment to (L ^A ) _a1 .
48. Ring B may each be substituted with one R ^cB

and where aa is the point of attachment to (L ^A ) _a1 .
49. Each R ^cB is independently a halo or is substituted with 1 to 3 independently selected R ^a (e.g., 1 to 3 independently selected halos) The compound of any of Items 42 to 48 or Items 163 to 169, which may be C _1-3 alkyl.
50. The compound of any of Items 1 to 49 or Items 163 to 169, wherein a1 is 0.
51. The compound of any of Items 1 to 49 or Items 163 to 169, wherein a1 is 1.
52. The compound of any of Items 1 to 49, Item 51, or Items 163 to 169, wherein L ^A is C _1-3 alkylene optionally substituted with 1 to 2 R ^a1 .
53. A compound according to item 52, wherein L ^A is _CH2 or CH(Me), such as _CH2 .
54. Ring C is
・Heteroarylene with 5 to 10 ring atoms, in which 1 to 3 ring atoms are from the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2} a heteroarylene, each independently selected heteroatom, wherein the heteroarylene is optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^cC and R ^hC ; and - optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^cC and R ^hC , where each R ^cC is independently selected R ^c ; The compound of any of items 1 to 53 or items 163 to 169, wherein each R ^hC is an independently selected R ^h selected from the group consisting of C _6-10 arylene.
55. Ring C is
- Heteroarylene of 5 to 6 (e.g. 6) ring atoms, in which 1 to 3 (e.g. 1 to 2) ring atoms are N, N(H), N(R ^d ), O, and S(O) is a heteroatom each independently selected from the group consisting of _{0 to 2} , and the heteroarylene is substituted with 1 to 4 substituents independently selected from the group consisting of R ^cC . and C ₆ arylene, optionally substituted with 1 to 4 substituents independently selected from the group consisting of; and - R ^cC ; A compound of any of Items 163 to 169.
56. Ring C is
・Pyridylene optionally substituted with 1 to 3 (for example, 1) substituents independently selected from the group consisting of R ^cC ; and ・1 to 1 independently selected from the group consisting of R ^cC A compound according to any one of Item 54, Item 55, or Item 163 to Item 169, selected from the group consisting of C ₆ arylene, optionally substituted with 4 (eg, 1 to 2) substituents.
57. Ring C has the following formula:

, where each one of Q ¹ , Q ² , Q ³ , and Q ⁴ is independently selected from the group consisting of N, CH, and CR ^cC , and bb is the connection to R ⁷ The compound of any of Items 54 to 56 or Items 163 to 169, which is a point.
58. The compound of item 57 or any of items 163 to 169, wherein Q ² is CH.
59. The compound of item 57, item 58, or any of items 163 to 169, wherein Q ³ is CH.
60. The compound of any of Items 57 to 59 or Items 163 to 169, wherein Q ⁴ is N.
61. The compound of any of Items 57 to 60 or Items 163 to 169, wherein Q ¹ is CH.
62. The compound of any of Items 57 to 60 or Items 163 to 169, wherein Q ¹ is CR ^cC .
63. Ring C is

,for example

The compound of Item 57 or any of Items 163 to 169, which is
64. Even if each R ^cC is substituted with -halo and 1 to 6 independently selected R ^a (e.g. 1 to 6 independently selected halo, e.g. -F) The compound of any of items 54 to 63 or items 163 to 169, independently selected from the group consisting of C _1-6 (eg, C _1-3 )alkyl.
65. A compound according to any of items 54 to 64 or items 163 to 169, wherein each R ^cC is independently halo, such as -Cl or -F, such as -F.
66. The compound of any of Items 1 to 65 or Items 170 to 173, wherein R ⁷ is R ^g .
67. R ⁷ is
・C 3-12 cycloalkyl optionally substituted with 1 to 4 substituents independently selected from _the group consisting of oxo, R ^c7 , R ^h7 , and -(L ^g ) _bg -R ^h7 ; and - Heterocyclyl of 4 to 12 ring atoms, in which 1 to 3 ring atoms are the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2} from 1 to 4 substituents, each independently selected from the group consisting of oxo, R ^c7 , R ^h7 , and -(L ^g ) _bg -R ^h7 optionally substituted with a group selected from the group consisting of heterocyclyl, where each R ^c7 is an independently selected R ^c and R ^h7 is an independently selected R ^h . Compounds of any of Items 1 to 66 or Items 170 to 173.
68. R ⁷ is
- C 4-8 cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of oxo, R ^c7 , and R ^h7 ; and - 4 _to 8 ring atoms heterocyclyl, in which 1 to 3 ring atoms are each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2;} and the heterocyclyl is selected from the group consisting of heterocyclyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of oxo, R ^c7 , and R ^h7 or any compound of Items 170 to 173.
69. R ⁷ is
・C ₆ cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c7 ; and ・Heterocyclyl with 6 ring atoms, with 1 to 2 ( For example, one ring atom) is a heteroatom each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2} , and heterocyclyl is , R ^c7 , optionally substituted with 1 to 4 substituents independently selected from the group consisting of: .
70. R ⁷ is the following formula:

wherein X ⁷ is CH, CR ^c7 , or N, such as CH or N.
71. The compound of item 69, item 70, or any of items 170 to 173, wherein two R ^c7 groups are present.
72. R ⁷ is the following formula:

wherein X ⁷ is N or CH and each R ^c7 is an independently selected R ^c .
73. Each R ^c7 is
Item 67 which is halo or C _1-3 alkyl optionally substituted with independently selected halo or 1 to 6 R ^a (e.g. 1 to 6 independently selected halo) ～Item 72 or any compound of Item 170～Item 173.
74. A compound of any of items 67 to 73 or items 170 to 173, wherein each R ^c7 is independently halo, such as -F.
75. R ⁷

and wherein X ⁷ is N or CH.
76. Formula (I-a1-1):

or a pharmaceutically acceptable salt thereof,
During the ceremony,
each one of R ^1a , R ^1b , R ^1c , and R ^1d is independently selected R ¹ ;
B ⁴ is C or N,
B ¹ , B ² , and B ³ are each independently CH, CR ^cB , NH, N(R ^d ), N, O, or S;
Q ¹ , Q ² , Q ³ , and Q ⁴ are each independently selected from the group consisting of N, CH, and CR ^cC ;
Each occurrence of R ^cB and R ^cC is an independently selected R ^c , and each

are independently a single bond or a double bond, provided that the ring containing B ¹ to B ⁴ is a heteroaryl,
Compound of item 1.
77. A compound according to item 76, wherein R ^1a and R ^1d are H and R ^1b and R ^1c are independently H or halo, eg halo (eg -F or -Cl, eg -F).
78. The compound of item 76, wherein each one of R ^1a , R ^1b , R ^1c , and R ^1d is H.
79. 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, with 1 to 3 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and the heteroaryl is independently selected from the group consisting of R ^c A compound of item 76 which is a heteroaryl optionally substituted with 1 to 4 substituents selected from
80. The compound of any of items 76 to 79, wherein R ² is H.
81. The compound of any of items 76 to 80, wherein R ⁵ is H.
82. The compound of any of items 76 to 81, wherein R ⁶ is H.
83. The compound of any of items 76 to 82, wherein R ² is H, R ⁵ is H, and R ⁶ is H.
84. The compound of any of items 76 to 83, wherein B ⁴ is N, B ¹ is N, B ³ is CH, and B ² is CH.
85. The compound of any of items 76 to 83, wherein B ⁴ is N, B ¹ is N, B ³ is CH, and B ² is N.
86. The compound of any of items 76 to 83, wherein B ⁴ is N, B ¹ is N, B ³ is CH, and B ² is CR ^cB .
87. The compound of any of items 76 to 83, wherein B ⁴ is N, B ¹ is CH, B ³ is CH, and B ² is N.
88. The compound of any of items 76 to 83, wherein B ⁴ is N, B ¹ is CH, B ³ is N, and B ² is CH.
89. A compound according to any of items 76 to 88, wherein a1 is 0.
90. The compound of any of items 76 to 88, wherein a1 is 1.
91. A compound according to any of items 76 to 88 or 90, wherein L ^A is CH ₂ or CH(Me).
92. The compound of any of items 76 to 91, wherein Q ¹ and Q ³ are CH.
93. A compound according to any of items 76 to 92, wherein Q ⁴ is N and Q ² is CH or CR ^cC , such as CR ^cC .
94. The ring containing Q ¹ to Q ⁴ is

and wherein bb is the point of attachment to R ⁷ .
95. A compound according to any of items 76 to 94, wherein R ^cC is halo, such as -F or -Cl, such as -F.
96. R ⁷ is
・C ₆ cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c7 ; and ・Heterocyclyl with 6 ring atoms, with 1 to 2 ( For example, one ring atom) is a heteroatom each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2} , and heterocyclyl is , R ^c7 , wherein each R ^c7 is an independently selected R ^c , consisting of heterocyclyl; The compound of any one of items 76 to 95 selected from the group.
97. R ⁷ is the following formula:

A compound of item 96, wherein X ⁷ is CH, CR ⁷ or N, such as CH or N.
98. A compound of item 96 or item 97 in which two R ^c7 groups are present.
99. R ⁷ is the following formula:

wherein X ⁷ is N or CH and each R ^c7 is an independently selected R ^c .
100. Each R ^c7 is
Item 96 which is halo or C _1-3 alkyl optionally substituted with independently selected halo or 1 to 6 R ^a (e.g. 1 to 6 independently selected halo) - Any compound of item 99.
101. A compound according to any of items 96 to 100, wherein each R ^c7 is independently halo, such as -F.
102. R ⁷ and X ⁷ are N or CH

,for example

The compound according to any one of items 76 to 101, which is
103. A compound of item 1 selected from the group consisting of the compounds shown in Table C1 or their pharmaceutically acceptable salts.
104. A pharmaceutical composition comprising a compound of any of items 1 to 103 and one or more pharmaceutically acceptable excipients.
105. A method for inhibiting STING activity, the method comprising inhibiting STING with a compound defined in any of items 1 to 103 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition defined in item 104. A method comprising the step of contacting.
106. The method of item 105, wherein inhibiting comprises antagonizing STING.
107. Any method of items 105 to 106 performed in vitro.
108. The method of item 107, comprising contacting a sample containing one or more cells containing STING with a compound.
109. The method of item 107 or item 108, wherein the one or more cells are one or more cancer cells.
110. The sample further contains one or more cancer cells, and the cancer is melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, or bladder cancer. Non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, medium malignant selected from the group consisting of dermoma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms tumor, or primary hepatocellular carcinoma; Method of item 108 or item 109.
111. The method of item 105 or item 106, performed in vivo.
112. The method of item 111, comprising administering the compound to a subject having a disease in which increased (e.g., enhanced) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease.
113. The method of item 112, where the subject is a human.
114. The method of item 113, where the disease is cancer.
115. Cancer is melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colon Rectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multifocal The method of item 114 selected from the group consisting of myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms tumor, or primary hepatocellular carcinoma.
116. The method of item 114 or item 115, where the cancer is intractable cancer.
117. The method of item 112, wherein the compound is administered in combination with one or more additional cancer treatments.
118. The method of item 117, wherein the one or more additional cancer treatments include surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy, or a combination thereof.
119. The method of item 118, wherein the chemotherapy comprises administering one or more additional chemotherapeutic agents.
120. The one or more additional chemotherapeutic agents may include alkylating agents (e.g. cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); antimetabolites (e.g. azathioprine and/or mercapto); terpenoids (e.g. vinca alkaloids and/or taxanes; e.g. vincristine, vinblastine, vinorelbine and/or vindesine, taxol, paclitaxel and/or docetaxel); topoisomerases (e.g. type I topoisomerase and/or type 2 topoisomerase; e.g. camptothecin, e.g. irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); cytotoxic antibiotics (e.g. actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin) ); hormones (e.g. luteinizing hormone-releasing hormone agonists; e.g. leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); antibodies (e.g. abciximab, adalimumab, alemtuzumab, atolizumab, basiliximab, belimumab, bevacizumab, bretuximab); Vedotin, canakinumab, cetuximab, certolizumab pegol, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab , palivizumab, panitumumab, ranibizumab, rituximab, tocilizumab, tositumomab and/or trastuzumab); antiangiogenic agents; cytokines; thrombotic agents; antiproliferative substances; anthelmintic agents; and immune checkpoints targeting immune checkpoint receptors The immune checkpoint inhibitor is selected from the following: 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, KIR, ILT and LIR, 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 (eg, CTLA-4 or PD1 or PD-L1).
121. The method of any of items 112 to 120, wherein the compound is administered intratumorally.
122. 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 of items 1 to 103 or a pharmaceutical composition as defined in item 104. A method comprising the step of administering.
123. Cancer is melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colon Rectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multifocal The method of item 122 selected from the group consisting of myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms tumor, or primary hepatocellular carcinoma.
124. The method of item 122 or item 123, where the cancer is intractable cancer.
125. The method of item 122, wherein the compound is administered in combination with one or more additional cancer treatments.
126. The method of item 125, wherein the one or more additional cancer treatments include surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy, or a combination thereof.
127. The method of item 126, wherein the chemotherapy comprises administering one or more additional chemotherapeutic agents.
128. The one or more additional chemotherapeutic agents may include alkylating agents (e.g. cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); antimetabolites (e.g. azathioprine and/or mercapto); terpenoids (e.g. vinca alkaloids and/or taxanes; e.g. vincristine, vinblastine, vinorelbine and/or vindesine, taxol, paclitaxel and/or docetaxel); topoisomerases (e.g. type I topoisomerase and/or type 2 topoisomerase; e.g. camptothecin, e.g. irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); cytotoxic antibiotics (e.g. actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin) ); hormones (e.g. luteinizing hormone-releasing hormone agonists; e.g. leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); antibodies (e.g. abciximab, adalimumab, alemtuzumab, atolizumab, basiliximab, belimumab, bevacizumab, bretuximab); Vedotin, canakinumab, cetuximab, certolizumab pegol, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumumab , ranibizumab, rituximab, tocilizumab, tositumomab and/or trastuzumab); antiangiogenic agents; cytokines; thrombotic agents; antiproliferative agents; anthelmintics; and immune checkpoint inhibitors that target immune checkpoint receptors. The immune checkpoint inhibitors include CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), and 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 ligands, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, butyrophilins including BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, 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, The method of item 126, wherein the method is selected from the group consisting of CD160, CD30, and CD155 (eg, CTLA-4 or PD1 or PD-L1).
129. The method of any of items 122 to 128, wherein the compound is administered intratumorally.
130. A method of inducing an immune response in a subject in need thereof, comprising administering to the subject an effective amount of a compound as defined in any of Items 1 to 103 or a pharmaceutical composition as defined in Item 104. A method comprising the step of:
131. The method of item 130, where the subject has cancer.
132. The method of item 131, wherein the subject has received and/or is receiving and/or will receive one or more cancer treatments.
133. Cancer is melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colon cancer. Rectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multifocal The method of item 131 selected from the group consisting of myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms tumor, or primary hepatocellular carcinoma.
134. Any method from item 131 to item 133 where the cancer is intractable.
135. The method of item 130, wherein the immune response is an innate immune response.
136. The method of item 135, wherein the at least one or more cancer treatments include surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy, or a combination thereof.
137. The method of item 136, wherein the chemotherapy comprises administering one or more additional chemotherapeutic agents.
138. The one or more additional chemotherapeutic agents may include alkylating agents (e.g. cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); antimetabolites (e.g. azathioprine and/or mercapto); terpenoids (e.g. vinca alkaloids and/or taxanes; e.g. vincristine, vinblastine, vinorelbine and/or vindesine, taxol, paclitaxel and/or docetaxel); topoisomerases (e.g. type I topoisomerase and/or type 2 topoisomerase; e.g. camptothecin, e.g. irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); cytotoxic antibiotics (e.g. actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin) ); hormones (e.g. luteinizing hormone-releasing hormone agonists; e.g. leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); antibodies (e.g. abciximab, adalimumab, alemtuzumab, atolizumab, basiliximab, belimumab, bevacizumab, bretuximab); Vedotin, canakinumab, cetuximab, certolizumab pegol, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumumab , ranibizumab, rituximab, tocilizumab, tositumomab and/or trastuzumab); antiangiogenic agents; cytokines; thrombotic agents; antiproliferative agents; anthelmintics; and immune checkpoint inhibitors that target immune checkpoint receptors. The immune checkpoint inhibitors include CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), and 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 ligands, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, butyrophilins including BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, 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, The method of item 137, wherein the method is selected from the group consisting of CD160, CD30, and CD155 (eg, CTLA-4 or PD1 or PD-L1).
139. A method of treating a disease in which increased (e.g., enhanced) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease, the method comprising: administering to a subject in need of such treatment an effective amount of A method comprising administering a compound as defined in any of items 1 to 103 or a pharmaceutical composition as defined in item 104.
140. An effective amount of a compound as defined in any of items 1 to 103 in a subject having a disease in which increased (e.g., enhanced) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease. or a method of treatment comprising administering a pharmaceutical composition as defined in item 104.
141. The step of administering to a subject a compound defined in any of items 1 to 103 or a pharmaceutical composition defined in item 104, wherein the increase (e.g., enhancement) of STING signaling is associated with the pathology of a disease and/or the pharmaceutical composition defined in item 104. or a method of treatment, wherein the compound or composition is administered in an amount effective to treat the symptoms and/or the disease contributing to the progression, thereby treating the disease.
142. The disease is cancer, any method from item 139 to item 141.
143. Cancer is melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colon Rectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multifocal The method of item 142 selected from the group consisting of myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms tumor, or primary hepatocellular carcinoma.
144. The method of item 142 or item 143, where the cancer is intractable cancer.
145. The method of any of items 142-144, wherein the compound is administered in combination with one or more additional cancer treatments.
146. The method of item 145, wherein the one or more additional cancer treatments include surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy, or a combination thereof.
147. The method of item 146, wherein the chemotherapy comprises administering one or more additional chemotherapeutic agents.
148. The one or more additional chemotherapeutic agents may include alkylating agents (e.g. cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); antimetabolites (e.g. azathioprine and/or mercapto); terpenoids (e.g. vinca alkaloids and/or taxanes; e.g. vincristine, vinblastine, vinorelbine and/or vindesine, taxol, paclitaxel and/or docetaxel); topoisomerases (e.g. type I topoisomerase and/or type 2 topoisomerase; e.g. camptothecin, e.g. irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); cytotoxic antibiotics (e.g. actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin) ); hormones (e.g. luteinizing hormone-releasing hormone agonists; e.g. leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); antibodies (e.g. abciximab, adalimumab, alemtuzumab, atolizumab, basiliximab, belimumab, bevacizumab, bretuximab); Vedotin, canakinumab, cetuximab, certolizumab pegol, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumumab , ranibizumab, rituximab, tocilizumab, tositumomab and/or trastuzumab); antiangiogenic agents; cytokines; thrombotic agents; antiproliferative agents; anthelmintics; and immune checkpoint inhibitors that target immune checkpoint receptors. The immune checkpoint inhibitors include CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), and 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 ligands, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, butyrophilins including BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, 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, The method of item 147, wherein the method is selected from the group consisting of CD160, CD30, and CD155 (eg, CTLA-4 or PD1 or PD-L1).
149. The method of any of items 139 to 148, wherein the compound is administered intratumorally.
150. A method of treating a disease, disorder, or condition associated with STING, comprising administering to a subject in need of such treatment an effective amount of a compound defined in any of items 1 to 103 or item 104. A method comprising administering a defined pharmaceutical composition.
151. The method of item 150, wherein the disease, disorder, or condition is selected from type I interferonosis, Aicardi-Gouthière syndrome (AGS), a genetic form of lupus, an inflammation-related disorder, and rheumatoid arthritis.
152. The method of item 151, wherein the disease, disorder, or condition is type I interferonosis (e.g., infantile-onset STING-associated vasculitis (SAVI)).
153. The method of item 152, wherein the type I interferonosis is infantile-onset STING-associated vasculitis (SAVI).
154. The method of item 151, where the disease, disorder, or condition is Aicardi-Gouthière syndrome (AGS).
155. The method of item 151, wherein the disease, disorder, or condition is a genetic form of lupus.
156. The method of item 151, wherein the disease, disorder, or condition is an inflammation-related disorder.
157. The method of item 156, wherein the inflammation-related disorder is systemic lupus erythematosus.
158. A combination comprising a compound as defined in any of items 1 to 103, or a pharmaceutically acceptable salt or tautomer thereof, and one or more therapeutically active agents.
159. A compound as defined in any of items 1 to 103, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition as defined in item 104, for use as a medicament.
160. A compound as defined in any of items 1 to 103, or a pharmaceutically acceptable salt or tautomer thereof, for use in the treatment of a disease, condition, or disorder modulated by STING inhibition. , or a pharmaceutical composition as defined in item 104.
161. A compound as defined in any of items 1 to 103 or a pharmaceutically acceptable salt or tautomer thereof for use in the treatment of a disease mentioned in any of items 105 to 157. , or a pharmaceutical composition as defined in item 104.
162. A compound defined in any of items 1 to 103, or a pharmaceutically acceptable salt or tautomer thereof, in the manufacture of a medicament for treating a disease referred to in any of items 105 to 157. or use of a pharmaceutical composition as defined in item 104.
163. Ring B is
A compound of item 43 selected from the group consisting of isoxazolylene, oxadiazolylene, oxazolylene, thiazolylene, isothiazolylene, or thiadiazolylene, optionally substituted with one R ^cB .
164. Ring B may be each substituted with one R ^cB

and where aa is the point of attachment to (L ^A ) _a1 .
165. Ring B may be each substituted with one R ^cB

and the compound of item 43 or item 163, where aa is the point of attachment to (L ^A ) _a1 .
166. Ring B may be each substituted with one R ^cB

and the compound of item 43 or item 163, where aa is the point of attachment to (L ^A ) _a1 .
167. Ring B may each be substituted with one R ^cB

and the compound of item 43 or item 163, where aa is the point of attachment to (L ^A ) _a1 .
168. Ring B may each be substituted with one R ^cB

and the compound of item 43 or item 163, where aa is the point of attachment to (L ^A ) _a1 .
169. Ring B may be each substituted with one R ^cB

and the compound of item 43 or item 163, where aa is the point of attachment to (L ^A ) _a1 .
170. R ⁷ is
・C _{4-5 cycloalkyl, optionally substituted with 1 to 4} substituents independently selected from the group consisting of R ^c7 ; and ・Heterocyclyl of 5 to 6 ring atoms, wherein 1 ~2 (e.g. 1) 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 the heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c7 .
171. R ⁷ is the following formula:

A compound of item 68, wherein X ⁷ is CH, CR ^c7 , or N, such as CH or N.
172. R ⁷ is the following formula:

in which R ^d is independently selected from the group consisting of C _1-6 alkyl optionally substituted with 1 to 3 independently selected R ^a , and m7 is 0 or 1, the compound of item 68.
173. R ⁷ is
selected from the group consisting of tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octanyl, or 2-azabicyclo[2.2.1]heptanyl, each optionally substituted with 1 to 2 R ^c7 , for example, R ⁷ is

The compound of item 68, which can be

Claims (17)

Formula I:

A compound,
During the ceremony,
Z, Y ¹ , Y ² , and Y ³ are independently selected from the group consisting of CR ¹ , C(=O), N, and NR ² ;
X ¹ is selected from the group consisting of O, S, N, NR ² and CR ¹ ;
^X2 is selected from the group consisting of O, S, N, ^NR4 , and ^CR5 ;
each

are independently a single bond or a double bond, provided that the 5-membered ring containing X ¹ and X ² is heteroaryl, and the 6-membered ring containing Z, Y ¹ , Y ² , and Y ³ is aryl or is a heteroaryl,
each R ¹ is independently selected from the group consisting of H;R ^c ;R ^g ; and -(L ¹ ) _b1 -R ^g ;
each R ² is independently selected from the group consisting of H;R ^d ;R ^g ; and -(L ² ) _b2 -R ^g ;
R ⁴ is selected from the group consisting of H and R ^d ;
R ⁵ is selected from the group consisting of H; R ^c ; and R ^h ;
R ⁶ is selected from the group consisting of H; R ^d ; and R ^h ;
Ring B is a 5 ring atom heteroarylene, wherein 1 to 4 of the ring atoms are each independently selected from the group consisting of N, NH, N(R ^d ), O, and S. and the heteroarylene of ring B is optionally substituted with 1 to 2 substituents independently selected from the group consisting of oxo and R ^c , provided that ring B is a ring carbon said heteroarylene bonded to the C(=O)NR ⁶ group via an atom;
^and _C ^{( O} _{_} ) are independently selected from the group consisting of
a1 is 0, 1, or 2,
Ring C is
- C _{3-12 cycloalkylene or C 3-12 cycloalkenylene} , each optionally substituted with 1 to 4 substituents independently selected from the group consisting of oxo, R ^c , and R ^h ;
・Heterocyclylene or heterocycloalkenylene with 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R ^d ), O, and S(O) _{0 to 2} , wherein said heterocyclylene or heterocycloalkenylene has 1 to 4 heteroatoms independently selected from the group consisting of oxo, R ^c and R ^h the above-mentioned heterocyclylene or heterocycloalkenylene, which may be substituted with a substituent;
・Heteroarylene with 5 to 12 ring atoms, in which 1 to 3 ring atoms are from the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2} the heteroarylene, each of which is an independently selected heteroatom, and the heteroarylene is optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c and R ^h ; ; and - selected from the group consisting of C _6-10 arylene, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c and R ^h ,
R ⁷ is selected from the group consisting of R ^g and -(L ⁷ ) _b7 -R ^g ;
Each occurrence of R ^a and R ^a1 is -OH;-halo;-NR ^e R ^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) _1~2 NR'R'';-S(O) _{1~ 2} (C _1-4 alkyl); and cyano;
Each occurrence of R ^c represents halo; cyano; C _1-10 alkyl optionally substituted with 1 to 6 independently selected R ^a ; C _2-6 alkenyl; C _2-6 alkynyl; _1-4 alkoxy;C _1-4 haloalkoxy;-S(O) _1-2 (C _1-4 alkyl);-S(O)(=NH)(C _1-4 alkyl);-NR ^e R ^f ;-OH;-S(O) _1~2 NR'R'';-C _{1~4thioalkoxy} ;-NO ₂ ;-C(=O) (C _1~10 alkyl);-C(=O) independently selected from the group consisting of O(C _1-4 alkyl); -C(=O)OH; -C(=O)NR'R''; and -SF ₅ ;
Each occurrence of R ^d is C _1-6 alkyl, optionally substituted with 1 to 3 independently selected R ^a ;-C(O)(C _1-4 alkyl);-C(O )O(C _1-4 alkyl);-CONR'R'';-S(O) _1-2 NR'R'';-S(O) _1-2 (C _1-4 alkyl);-OH; and C _1-4 alkoxy;
Each ^occurrence of R ^e and R ^f is a C _1-6 alkyl;-C(O)(C _1-4 alkyl);-C(O)O(C _1-4 alkyl);-CONR'R'';-S(O) _1-2 NR'R '';-S(O) _1-2 (C _1-4 alkyl);-OH; and C _1-4 alkoxy;
Each occurrence of R ^g is
・C _3-12 , each optionally substituted with 1 to 4 substituents independently selected from the group consisting of oxo, R ^c , R ^h , and -(L ^g ) _bg -R ^h cycloalkyl or C _3-12 cycloalkenyl;
- Heterocyclyl or heterocycloalkenyl with 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R ^d ), O, and S(O) from _{0 to 2} wherein the heterocyclyl or heterocycloalkenyl is independently selected from the group consisting of oxo, R ^c , ^Rh , and -(L ^g ) _bg -R ^h the above-mentioned heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents;
- Heteroaryl of 5 to 12 ring atoms, in which 1 to 3 ring atoms are from the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2} each independently selected heteroatom, and said heteroaryl has 1 to 4 substituents independently selected from the group consisting of R ^c , R ^h , and -(L ^g ) _bg -R ^h and 1 to 4 substituents independently selected from the group consisting of -R ^c , R ^h , and -(L ^g ) _bg -R ^h ; independently selected from the group consisting of C _6-10 aryls, which may be
Each occurrence of R ^h is
・C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each optionally substituted with 1 to 4 R ⁱ ;
- Heterocyclyl or heterocycloalkenyl with 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R ^d ), O, and S(O) from _{0 to 2} each heteroatom independently selected from the group consisting of: said heterocyclyl or heterocycloalkenyl, wherein said heterocyclyl or heterocycloalkenyl is optionally substituted with 1 to 4 R ⁱ ;
- Heteroaryl of 5 to 12 ring atoms, in which 1 to 3 ring atoms are from the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2} each independently selected heteroatom, wherein said heteroaryl is optionally substituted with 1 to 4 R ⁱ ; and - optionally substituted with 1 to 4 R ⁱ independently selected from the group consisting of good C _6-10 aryls,
each occurrence of R ⁱ is independently selected from the group consisting of C _1-6 alkyl; C _1-4 haloalkyl; C _1-4 alkoxy; C _1-4 haloalkoxy; and halo;
Each occurrence of L ¹ , L ² , L ⁷ , and L ^g represents -O-, -NH-, -NR ^d , -S(O) _0-2 , C(O), and 1-3 selected from the group consisting of C _1-3 alkylene optionally substituted with R ^a ,
b1, b2, b7, and bg are each independently 1, 2, or 3, and
each occurrence of R' and R'' is independently selected from the group consisting of H;-OH; and C _1-4 alkyl;
The above compound, or a pharmaceutically acceptable salt thereof or a tautomer thereof. Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein R ^1a , R ^1b , R ^1c , and R ^1d are each independently selected R ¹ . one of Z, ^Y1 , ^Y2 , and ^Y3 is N, and each of the remaining of Z, ^Y1 , ^Y2 , and ^Y3 is independently selected ^CR1 ; A compound according to claim 1. 4. A compound according to any one of claims 1 to 3, wherein X ¹ is NR ² and X ² is CR ⁵ , optionally X ¹ is NH and X ² is CH. 5. A compound according to any one of claims 1 to 4, wherein 1 to 2 R ¹ are independently selected from the group consisting of R ^c and R ^g and each remaining R ¹ is H. Each R ^c is independently selected halo, e.g. -F, -Cl, or -Br, e.g. each R ^c is independently -F or -Cl, e.g. -F, each R ^g is independently a 5 ring atom heteroaryl, wherein 1 to 3 ring atoms are each from the group consisting of N, N(H), N(R ^d ), O, and S. 6. A compound according to any one of claims 1 to 5, wherein said heteroaryl is an independently selected heteroatom, said heteroaryl being optionally substituted with 1 to 4 R ^c . R ^1a and R ^1d are H, R ^1b and R ^1c are independently selected halo, such as -F or -Cl, such as -F, or
R ^1a and R ^1d are H, one of R ^1b and R ^1c is H, and the other of R ^1b and R ^1c is halo, e.g. -F or -Cl, e.g. -F ,or
R ^1a and R ^1d are H, R ^1c is halo or H, such as -F, -Cl, or H, and R ^1b is a heteroaryl of 5 ring atoms, the ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S, and the heteroaryl is substituted with 1 to 4 R ^c The above heteroaryl may be
A compound according to claim 2, or a compound according to any one of claims 4 to 6 when dependent on claim 2. Ring B is a heteroarylene of 5 ring atoms, wherein 2 to 3 of the ring atoms are from the group consisting of N, NH, N(R ^d ), O, and S, such as N and NH. each of which is an independently selected heteroatom, and the heteroarylene of ring B is optionally substituted with 1 to 2 R ^c ,
For example, ring B is
selected from the group consisting of imidazolylene, pyrazolylene or triazolelene, such as 1,2,3-triazolylene, each optionally substituted with one R ^c ;
For example, each heteroarylene in ring B may be substituted with one R ^c

, where aa is the connection point to (L ^A ) _a1 ,
A compound according to any one of claims 1 to 7. a1 is 0 or a1 is 1 and optionally L ^A is C _1-3 alkylene optionally substituted with 1 to 2 R ^a1 , for example L ^A is CH ₂ or CH(Me). Ring C is
・Heteroarylene with 5 to 10 ring atoms, in which 1 to 3 ring atoms are from the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2} The heteroarylene is each independently selected heteroatom, and the heteroarylene is optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c and R ^h , and -C _6-10 arylene, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c and R ^h ;
For example, ring C is
- a heteroarylene of 5 to 6 ring atoms, for example 6, in which 1 to 3 ring atoms, for example 1 to 2 ring atoms are N, N(H), N(R ^d ), O, and S (O) is a heteroatom each independently selected from the group consisting of _{0 to 2} , and the heteroarylene is substituted with 1 to 4 substituents independently selected from the group consisting of R ^c and C ₆ arylene ^, which may be substituted with 1 to 4 substituents independently selected from the group consisting of;
For example, ring C is
・Pyridylene optionally substituted with 1 to 3, for example, 1 substituent, independently selected from the group consisting of R ^c ; and ・1 to 4 independently selected from the group consisting of R ^c selected from the group consisting of C ₆ arylene optionally substituted with, for example, 1 to 2 substituents;
For example, if ring C has the following formula:

, where each one of Q ¹ , Q ² , Q ³ , and Q ⁴ is independently selected from the group consisting of N, CH, and CR ^c , and bb is the connection to R ⁷ is a point,
A compound according to any one of claims 1 to 9. R ⁷ is
・C 3-12 cycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting _of oxo, R ^c7 , R ^h , and -(L ^g ) _bg -R ^h ; and - Heterocyclyl of 4 to 12 ring atoms, in which 1 to 3 ring atoms are the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2} 1 to 4 heteroatoms independently selected from the group consisting of oxo, R ^c7 , R ^h , and -(L ^g ) _bg -R ^h optionally substituted with substituents selected from the group consisting of said heterocyclyl, wherein each R ^c7 is an independently selected R ^c ;
For example, R ⁷ is
- C 4-8 cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of oxo, R ^c7 , and ^Rh ; and - 4 _to 8 ring atoms heterocyclyl, in which 1 to 3 ring atoms are each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2;} and the heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of oxo, R ^c7 , and R ^h ,
For example, R ⁷ is
・C ₆ cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c7 ; and ・Heterocyclyl of 6 ring atoms, with 1 to 2 ring atoms; For example, one ring atom is a heteroatom each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(O) _{0 to 2} , and the heterocyclyl is , R ^c7 , optionally substituted with 1 to 4 substituents independently selected from the group consisting of:
For example, R ⁷ is the following formula:

in which X ⁷ is CH, CR ^c7 , or N, such as CH or N;
For example, R ⁷ is the following formula:

in which X ⁷ is N or CH, each R ^c7 is an independently selected R ^c , and optionally,
Each R ^c7 is independently selected halo or C _1-3 alkyl optionally substituted with 1 to 6 R ^a , such as halo, or 1 to 6 independently selected is C _1-3 alkyl optionally substituted with selected halo,
A compound according to any one of claims 1 to 10. Formula (I-a1-1):

or a pharmaceutically acceptable salt thereof,
During the ceremony,
each one of R ^1a , R ^1b , R ^1c , and R ^1d is independently selected R ¹ ;
B ⁴ is C or N;
B ¹ , B ² , and B ³ are each independently CH, CR ^cB , NH, N(R ^d ), N, O, or S;
Q ¹ , Q ² , Q ³ , and Q ⁴ are each independently selected from the group consisting of N, CH, and CR ^cC ;
Each occurrence of R ^cB and R ^cC is an independently selected R ^c , and each

are independently a single bond or a double bond, provided that the ring containing B ¹ to B ⁴ is a heteroaryl,
A compound according to claim 1. 2. The compound according to claim 1, selected from the group consisting of the compounds shown in Table C1 or their pharmaceutically acceptable salts. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and one or more pharmaceutically acceptable excipients. 15. A method for inhibiting STING activity, comprising contacting STING with a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 14. The method described above, comprising the steps of: 15. A method of inducing an immune response in a subject in need thereof, comprising administering to said subject an effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof according to claim 14. said method, comprising administering a pharmaceutical composition of the invention. Diseases, disorders or conditions associated with STING, such as those in which increased STING signaling, such as enhanced STING signaling, contributes to the pathology and/or symptoms and/or progression of a disease, such as cancer; or a method of treating a condition in which a subject in need of such treatment receives an effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or according to claim 14. said method, comprising administering a pharmaceutical composition of the invention.