TW202216685A - Compounds and compositions for treating conditions associated with sting activity - Google Patents

Abstract

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

Description

Compounds and compositions for treating conditions associated with STING activity

The present invention describes chemical entities (eg, compounds or pharmaceutically acceptable salts and/or hydrates and/or co-crystals and/or drug combinations of such compounds) that inhibit (eg, antagonize) Stimulating Factor of Interferon Gene (STING). Such chemical entities can be used, for example, to treat a condition, disease or disorder in an individual (eg, a human) in which increased (eg, excessive) STING activation (eg, STING signaling) contributes to the condition, disease or disorder (eg, cancer) ) pathology and/or symptoms and/or progression. The present invention also describes compositions containing them and methods of using and making them.

STING is also known as transmembrane protein 173 (TMEM173) and MPYS/MITA/ERIS, which are proteins encoded by the TMEM173 gene in humans. STING has also 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 and surrounding cells from local infection in an autocrine and paracrine manner.

The STING pathway is critical for mediating cytoplasmic DNA recognition. In this context, STING, a transmembrane protein localized to the endoplasmic reticulum (ER), is used as a binding agent for 2', 3' cyclic GMP-AMP (hereafter cGAMP, which is generated by cGAS after dsDNA binding) Second messenger receptors. In addition, STING can also be used as a major pattern recognition receptor for bacterial cyclic dinucleotides (CDNs) and small molecule agonists. Endogenous or prokaryotic CDNs are recognized via the carboxy-terminal domain of STING, which faces the cytosol and creates a V-shaped binding pocket formed by STING homodimers. Ligand-induced activation of STING triggers its relocalization of the Golgi (Golgi), a process essential for promoting STING interaction with TBK1. This protein complex in turn signals through the transcription factor IRF-3 to induce type I interferons (IFNs) and other co-regulatory antiviral factors. In addition, STING has also been shown to trigger NF-κB and MAP kinase activation. After initiation of signal transduction, STING is rapidly degraded, a step believed to be important for terminating the inflammatory response.

STING hyperactivation is associated with a subgroup of monogenic autoinflammatory conditions (so-called Type I interferonopathy). Examples of such diseases include the clinical syndrome known as STING-associated vasculopathy of infancy (SAVI), which is caused by a gain-of-function mutation in TMEM173, the gene name for STING. In addition, STING is associated with the pathogenesis of Aicardi-Goutières Syndrome (AGS) and inherited forms of lupus. Unlike SAVI, dysregulation of nucleic acid metabolism is responsible for persistent innate immune activation in AGS. In addition to these genetic disorders, emerging evidence suggests that STING has a more prevalent pathogenic role in various inflammation-related disorders such as systemic lupus erythematosus, rheumatoid arthritis, and cancer. Therefore, small molecule-based pharmacological interventions of the STING signaling pathway can still significantly treat many diseases.

The present invention describes chemical entities (eg, compounds or pharmaceutically acceptable salts and/or hydrates and/or co-crystals and/or drug combinations of such compounds) that inhibit (eg, antagonize) Stimulating Factor of Interferon Gene (STING). Such chemical entities can be used, for example, to treat a condition, disease or disorder in an individual (eg, a human) in which increased (eg, excessive) STING activation (eg, STING signaling) contributes to the condition, disease or disorder (eg, cancer) ) pathology and/or symptoms and/or progression. The present invention also describes compositions containing them and methods of using and making them.

STING "antagonists" include compounds that directly bind or modify STING at the protein level so as to reduce STING activity, eg, by inhibiting, blocking, or attenuating agonist-mediated responses, altering distribution, or otherwise. STING antagonists comprise chemical entities that interfere with or inhibit STING signaling.

( I) 其中 Z 、 Y ¹ 、 Y ² 、 Y ³ 、 X ¹ 、 X ² 、 R ⁶ 、環 B 、 L ^A 、 a1 、環 C及 R ⁷ 可如本文之任何位置處所定義。 In one aspect, a compound of formula ( I ) or a pharmaceutically acceptable salt thereof is described:

( I ) wherein Z , ^Y1 , ^Y2 , ^Y3 , ^X1 , ^X2 , ^R6 , Ring B , ^LA , a1 , Ring C and ^R7 may be as defined anywhere herein.

In one aspect, a pharmaceutical composition is described that comprises a chemical entity described herein (eg, a compound described herein in a general or specific manner, or a pharmaceutically acceptable salt thereof, or a composition comprising the same) and one or more pharmaceuticals acceptable excipients.

In one aspect, methods of inhibiting (eg, antagonizing) STING activity are described, comprising combining STING with a chemical entity described herein (eg, a compound described herein in a general or specific manner, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof). composition) contact. Methods include in vitro methods such as contacting a sample comprising one or more cells comprising STING, such as innate immune cells such as mast cells, macrophages, dendritic cells (DCs) and natural killer cells, with chemical entities . The methods may also include in vivo methods; eg, administering a chemical entity to an individual (eg, a human) suffering from a disease in which increased (eg, excessive) STING signaling contributes to the pathology and/or symptoms and/or of the disease progress.

In one aspect, described are methods of treating a condition, disease, or disorder that is ameliorated by antagonizing STING, such as treating a condition, disease, or disorder in an individual (eg, a human) in which increased (eg, excessive) STING activation ( For example, STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (eg, cancer). These methods comprise administering to an individual in need of such treatment an effective amount of a chemical entity described herein (eg, a compound described herein in a general or specific manner, or a pharmaceutically acceptable salt thereof, or a composition containing the same).

In another aspect, a method of treating cancer is described comprising administering to an individual in need of such treatment an effective amount of a chemical entity described herein (eg, a compound described herein generally or specifically, or a pharmaceutically acceptable form thereof). salts or compositions containing them).

In another aspect, methods of treating other STING-related conditions are described, such as, for example, type I interferonopathy (eg, STING-associated vasculopathy of infancy (SAVI)), Icardi-Gu Tires Syndrome (AGS), inherited forms of lupus, and inflammation-related disorders such as systemic lupus erythematosus and rheumatoid arthritis. These methods comprise administering to an individual in need of such treatment an effective amount of a chemical entity described herein (eg, a compound described herein in a general or specific manner, or a pharmaceutically acceptable salt thereof, or a composition containing the same).

In another aspect, described is a method of inhibiting STING-dependent type I interferon production in an individual in need thereof, comprising administering to the individual an effective amount of a chemical entity described herein (eg, described herein in a general or specific manner). compound or a pharmaceutically acceptable salt thereof or a composition containing it).

In another aspect, methods of treating a disease in which increased (eg, excessive) STING activation (eg, STING signaling) contributes to the pathology and/or symptoms and/or progression of the disease are described. These methods comprise administering to an individual in need of such treatment an effective amount of a chemical entity described herein (eg, a compound described herein in a general or specific manner, or a pharmaceutically acceptable salt thereof, or a composition containing the same).

In another aspect, methods of treatment are described comprising administering to an individual an effective amount of a chemical entity described herein (eg, a compound described herein in a general or specific manner, or a pharmaceutically acceptable salt thereof, or a combination comprising the same) wherein the individual has (or is prone to have) a disease in which increased (eg, excessive) STING activation (eg, STING signaling) contributes to the pathology and/or symptoms and/or progression of the disease.

In another aspect, a method of treatment comprises administering to a subject a chemical entity described herein (eg, a compound described herein in a general or specific manner, or a pharmaceutically acceptable salt thereof, or a composition comprising the same), wherein the effective The chemical entity is administered in an amount to treat a disease in which increased (eg, excessive) STING activation (eg, STING signaling) contributes to the pathology and/or symptoms and/or progression of the disease, thereby treating the disease.

Embodiments may include one or more of the following features.

The chemical entities can be administered in combination with one or more other therapeutic agents and/or regimens. For example, the method may further comprise administering one or more (eg, two, three, four, five, six, or more) additional agents.

The chemical entity may be administered in combination with one or more other therapeutic agents and/or regimens useful for the treatment of other STING-related conditions such as, for example, type I interferon lesions (eg, infant-onset STING-related vasculopathy). (SAVI)), Icardi-Gutierrez Syndrome (AGS), inherited forms of lupus and inflammation-related disorders such as systemic lupus erythematosus and rheumatoid arthritis.

The chemical entity can be combined with one or more other cancer therapies (eg, surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cold therapy, or gene therapy; eg, comprising administering one or more (eg, two, three, four) one, five, six or more) other chemotherapeutic agents) are administered in combination. Non-limiting examples of other chemotherapeutic agents are selected from alkylating agents (eg, cisplatin, carboplatin, mechlorethamine, cyclophosphamide, nitrogen mustards) Chlorambucil, ifosfamide and/or oxaliplatin); antimetabolites (eg, azathioprine and/or mercaptopurine); terpenoids (eg Vinca alkaloids and/or taxanes; eg Vincristine, Vinblastine, Vinorelbine and/or Vindesine, Taxol) , Pacllitaxel 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 ( For example, actinomycin, anthracycline, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin, and/or mitomycin); hormones (eg, luteinizing hormone-releasing hormone agonists; eg, leuprolidine, goserelin (goserelin), triptorelin (triptorelin), histrelin (histrelin), bicalutamide (bicalutamide), flutamide (flutamide) and/or nilutamide (nilutamide); Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Belimumab Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab b), Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Generic Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumumab ( Panitumuab), Ranibizumab, Rituximab, Tocilizumab, Tositumomab, and/or Trastuzumab); Antibodies Angiogenic agents; interferons; thrombotic agents; growth inhibitors; anthelmintics; and immune checkpoint inhibitors targeting immune checkpoint receptors selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1 - PD-L1, PD-1 - PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, Transforming Growth Factor-β (TGFβ), T Cell Immunoglobulin and Mucin 3 (TIM3 or HAVCR2), Galectin 9 - TIM3, Phosphatidylserine - TIM3, Lymphocyte Activation Gene 3 Protein (LAG3), MHC class II - LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand - GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM - BTLA, HVEM - CD160, HVEM - LIGHT, HVEM-BTLA-CD160, CD80, CD80 - PDL-1, PDL2 - CD80, CD244, CD48 - CD244, CD244, ICOS, ICOS- ICOS ligands, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilin (including BTNL2), Siglec family, TIGIT and PVR family members, KIR, ILT and LI R, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86 - CD28, CD86 - CTLA, CD80 - CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine Serine - TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30 and CD155 (eg CTLA-4 or PD1 or PD-L1).

An individual may have cancer; for example, the individual has and/or is undergoing and/or will undergo one or more cancer therapies.

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

The chemical entity can be administered intratumorally.

The methods may further comprise identifying the individual.

Other embodiments include those set forth in the description and/or claims.

Other Definitions A number of other terms are defined below to assist in understanding the disclosure set forth herein. In general, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are well known and commonly employed in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. The entire contents of each of the patents, applications, published applications, and other publications mentioned throughout the specification and accompanying appendices are incorporated herein by reference.

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

The term "acceptable" as used herein with respect to a formulation, composition or ingredient means no lasting deleterious effect on the general health of the individual being treated.

"API" means Active Pharmaceutical Ingredient.

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

The term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material . In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for contact with human and animal tissues or organs without undue toxicity, irritation , allergic reactions, immunogenicity, or other problems or complications, and are commensurate with a reasonable benefit/risk ratio. See, eg , Remington: The Science and Practice of Pharmacy , 21st Ed .; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients , 6th Ed .; Rowe et al., eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009 Edited by Ash and Ash; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation , 2nd Edition ; Edited by Gibson; 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 that does not abrogate the biological activity and properties of the compound. In certain instances, by reacting a compound described herein with an acid (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like) to obtain a pharmaceutically acceptable salt. In some cases, pharmaceutically acceptable salts are obtained by reacting a compound having an acidic group as described herein with a base to form salts such as: ammonium salts; alkali metal salts such as sodium or potassium salts; Alkaline earth metal salts, such as calcium or magnesium salts; salts of organic bases such as dicyclohexylamine, N -methyl-D-glucamine, tris(hydroxymethyl)methylamine; and salts with organic bases such as arginine, lysine Acids and the like with amino acids; or obtained by other methods previously identified. The pharmacologically acceptable salt is not particularly limited as long as it can be used in pharmaceuticals. Examples of salts of the compounds described herein with bases include the following salts: those formed with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; those formed with organic bases such as methylamine, ethylamine, and ethanolamine its salts; its salts with basic amino acids such as lysine and ornithine; and ammonium salts. Salts can be acid addition salts, specific examples being those formed using mineral acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric and phosphoric acids; organic acids such as formic, acetic, Propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid and ethanesulfonic acid; acidic amino acids such as aspartic acid and gluten amino acid.

The term "pharmaceutical composition" refers to the compounds described herein together with other chemical components (collectively referred to herein as "excipients" such as carriers, stabilizers, diluents, dispersing agents, suspending agents and/or thickening agents agent) mixture. Pharmaceutical compositions facilitate the administration of compounds to an organism. Various techniques for administering compounds exist in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

The term "individual" refers to animals including, but not limited to, primates (eg, humans), monkeys, cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "individual" and "patient" are used interchangeably herein in reference to, eg, a mammalian subject (eg, a human).

In the context of treating a disease or disorder, the terms "treat, treating and treatment" are intended to include alleviation or elimination of a disorder, disease or condition or one or more symptoms associated with a disorder, disease or condition; The progression, spread or worsening of a disorder or condition or one or more of its symptoms. "Treatment of cancer" means one or more of the following effects: (1) inhibiting tumor growth to some extent, including (i) slowing and (ii) completely preventing growth; (2) reducing the number of tumor cells; ( 3) maintaining tumor size; (4) reducing tumor size; (5) inhibiting (including (i) reducing, (ii) slowing or (iii) completely preventing) tumor cell infiltration into peripheral organs; (6) inhibiting (including (i) reduce, (ii) slow or (iii) completely prevent) metastasis; (7) enhance anti-tumor immune response, which can lead to (i) maintenance of tumor size, (ii) reduction of tumor size, (iii) tumor slowdown Growing, (iv) reducing, slowing or preventing invasion and/or (8) reducing to some extent the severity or number of symptoms associated with one or more conditions.

The term "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "alkyl" refers to a saturated acyclic hydrocarbon group which may be straight or branched with the indicated number of carbon atoms. For example, C _1-10 indicates that there may be 1 to 10 (inclusive) carbon atoms in the group. Alkyl groups can be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, n-hexyl. The term "saturated" as used in this context means that only single bonds exist between the constituent carbon atoms and other available valences are occupied by hydrogen and/or other substituents as defined herein.

The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by an independently selected halo group.

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

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

The term "alkenyl" refers to an acyclic hydrocarbon chain that may be straight or branched with one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, _C2-6 indicates that there may be 2 to 6 (inclusive) carbon atoms in the group. Alkenyl groups can be unsubstituted or substituted with one or more substituents.

The term "alkynyl" refers to an acyclic hydrocarbon chain that may be straight or branched with one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, _C2-6 indicates that there may be 2 to 6 (inclusive) carbon atoms in the group. Alkynyl groups can be unsubstituted or substituted with one or more substituents.

The term "aryl" refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group in which at least one ring in the system is aromatic (eg, 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon carbotricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

The term "cycloalkyl" as used herein refers to those having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3 - a cyclic saturated hydrocarbon group of 6 ring carbons, wherein the cycloalkyl group is optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups may contain multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl include: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, Bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0 ]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spiro rings (eg, spiro bicyclic rings in which the two rings are joined by only one atom). Non-limiting examples of spirocyclic cycloalkyl groups include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4] Nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane and the like. The term "saturated" as used in this context means that only single bonds exist between the constituent carbon atoms.

The term "cycloalkenyl" as used herein means having 3 to 20 ring carbons, preferably 3 to 16 ring carbons and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons Partially unsaturated cyclic hydrocarbon groups of ring carbons in which the cycloalkenyl groups are optionally substituted. Examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. For partially unsaturated cyclic hydrocarbon groups, the cycloalkenyl group may have any degree of unsaturation provided that one or more double bonds are present in the ring, none of the rings in the ring system are aromatic, and the cycloalkenyl group Overall not fully saturated. Cycloalkenyl groups may contain multiple fused and/or bridged and/or spiro rings.

The term "heteroaryl" as used herein means a single group having 5 to 20 ring atoms or 5, 6, 9, 10 or 14 ring atoms and having 6, 10 or 14 pi electrons in common in a ring array -, bi-, tri- or polycyclic groups; wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heterocyclic compounds independently selected from the group consisting of N, O, and S Atom (but not necessarily a ring containing a heteroatom, eg, tetrahydroisoquinolyl, eg, tetrahydroquinolyl). Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thienyl, pyridyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiooxadiazolyl, pyrazolyl, isoxazolyl, thiazolyl oxadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzoyl Triazolyl, Ethanol, Indazolyl, Indolyl, Isoquinolinyl, Isothiazolyl, Naphthyridinyl, Purinyl, Thienopyridyl, Pyrido[2,3- d ]pyrimidinyl, Pyrrole Lo[2,3- b ]pyridyl, quinazolinyl, quinolyl, thieno[2,3- c ]pyridyl, pyrazolo[3,4- b ]pyridyl, pyrazolo[3 ,4- c ]pyridyl, pyrazolo[4,3- c ]pyridine, pyrazolo[4,3- b ]pyridyl, tetrazolyl, oxane, 2,3-dihydrobenzo[ b ][1,4]dioxene, benzo[ d ][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dioxane Hydrobenzo[ b ][1,4]thiane, isoindoline and others. In some embodiments, the heteroaryl group is selected from the group consisting of thienyl, pyridyl, furyl, pyrazolyl, imidazolyl, isoindolyl, pyranyl, pyrazinyl, and pyrimidinyl.

The term "heterocyclyl" refers to rings having 3-16 ring atoms (eg, 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring systems) and 1-3 heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic) or 1-9 heteroatoms (if tricyclic or polycyclic) mono-, bi-, tri- or polycyclic saturated ring systems, such heteroatoms Atoms are selected from O, N, or S (eg, carbon atoms and 1-3, 1-6, or 1-9 N, O, or S heteroatoms (if monocyclic, bicyclic, or tricyclic, respectively)), wherein the 0, 1, 2 or 3 atoms may be substituted by substituents. Examples of heterocyclyl groups include hexahydropyrazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl groups may contain multiple fused and bridged rings. Non-limiting examples of fused/bridged heterocyclyl groups include: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1] Pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole , 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0] Octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1. 0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[ 3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[3.1.1]heptane Bicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like. Heterocyclyl also includes spirocycles (eg, spirobicycles in which the two rings are joined via only one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[ 3.5] Nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane alkane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[ 4.4] Nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[ 5.5]Undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane and the like. The term "saturated" as used in this context means that only single bonds exist between the constituent ring atoms and other available valencies are occupied by hydrogen and/or other substituents as defined herein.

The term "heterocycloalkenyl" as used herein means having 3-16 ring atoms (eg, 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring systems) and 1-3 heterocyclic ring systems Atom (if monocyclic), 1-6 heteroatoms (if bicyclic) or 1-9 heteroatoms (if tricyclic or polycyclic) partially unsaturated cyclic ring system, such heteroatoms are selected From O, N or S (eg carbon atoms and 1-3, 1-6 or 1-9 N, O or S heteroatoms (if monocyclic, bicyclic or tricyclic, respectively)), wherein O, 1, 2 or 3 atoms may be substituted by substituents. Examples of heterocycloalkenyl groups include, but are not limited to, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothienyl. For partially unsaturated cyclic groups, the heterocycloalkenyl group may have any degree of unsaturation provided that one or more double bonds are present in the ring, none of the rings in the ring system are aromatic, and that the heterocycle Cycloalkenyl groups as a whole are not fully saturated. Heterocycloalkenyl groups may contain multiple fused and/or bridged and/or spiro rings.

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

As used herein, when a ring is described as being "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (in addition to those attributable to the ring itself; such as among the atoms that make up the ring). one or more double or triple bonds), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

))；(ii)單一環原子(螺稠合環系統) (例如

、或

)；或(iii)環原子鄰接陣列(所有橋長度皆＞ 0之橋接環系統) (例如

、

或

)。 For the avoidance of doubt and unless otherwise specified, for rings and cyclic groups (eg, aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like), it is to be understood that such rings and cyclic groups encompass those having fused rings, including those wherein the point of fusion is at In the following positions: (i) adjacent ring atoms (e.g. [xx0] ring system, where 0 represents a zero-atom bridge (e.g.

)); (ii) a single ring atom (spiro-fused ring system) (e.g.

,or

); or (iii) a contiguous array of ring atoms (a bridged ring system with all bridge lengths > 0) (e.g.

,

or

).

In addition, the atoms constituting the compounds of the embodiments of the present invention are intended to encompass all isotopic forms of such atoms. Isotopes as used herein include atoms that have the same atomic number but different mass numbers. By general example and without limitation, hydrogen isotopes include tritium and deuterium, and carbon isotopes ^{include13C and14C} .

之化合物涵蓋含有部分：

之互變異構體形式。類似地，闡述為視情況經羥基取代之吡啶基或嘧啶基部分涵蓋吡啶酮或嘧啶酮互變異構體形式。 In addition, compounds disclosed herein in a general or specific manner are intended to encompass all tautomeric forms. So, for example, with the section:

The compounds covered contain parts:

the tautomeric form. Similarly, pyridinone or pyrimidinone tautomeric forms are encompassed by pyridinone or pyrimidinone tautomeric forms set forth as optionally substituted with hydroxy.

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 scope of the claims.

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of US Provisional Application No. 63/052,117, filed July 15, 2020, the entire contents of which are incorporated herein by reference.

The present invention describes chemical entities (eg, compounds or pharmaceutically acceptable salts and/or hydrates and/or co-crystals and/or drug combinations of such compounds) that inhibit (eg, antagonize) Stimulating Factor of Interferon Gene (STING). Such chemical entities can be used, for example, to treat a condition, disease or disorder in an individual (eg, a human) in which increased (eg, excessive) STING activation (eg, STING signaling) contributes to the condition, disease or disorder (eg, cancer) ) pathology and/or symptoms and/or progression. The present invention also describes compositions containing them and methods of using and making them.

式 I或其醫藥上可接受之鹽或其互變異構體，其中： Z 、 Y ¹ 、 Y ² 及 Y ³ 獨立地選自由以下組成之群：C R ¹ 、C(=O)、N及N R ² ； X ¹ 係選自由以下組成之群：O、S、N、N R ² 及C R ¹ ； X ² 係選自由以下組成之群：O、S、N、N R ⁴ 及C R ⁵ ； 每一

獨立地係單鍵或雙鍵，條件係包括 X ¹ 及 X ² 之5員環係雜芳基，且包括 Z 、 Y ¹ 、 Y ² 及 Y ³ 之6員環係芳基或雜芳基； 每一 R ¹ 獨立地選自由以下組成之群：H； R ^c ； R ^g ；及 -(L ¹) _b1-R ^g ； 每一 R ² 獨立地選自由以下組成之群：H； R ^d ； R ^g ；及 -(L ²) _b2-R ^g ； R ⁴ 係選自由以下組成之群：H及 R ^d ； R ⁵ 係選自由以下組成之群：H； R ^c ；及 R ^h ； R ⁶ 係選自由以下組成之群：H； R ^d ；及 R ^h ； 環 B係具有5個環原子之伸雜芳基，其中1-4個環原子係各自獨立地選自由N、NH、N( R ^d )、O及S組成之群之雜原子；其中 環 B之伸雜芳基視情況經1-2個獨立地選自由側氧基及 R ^c 組成之群之取代基取代，條件係 環 B經由環碳原子連接至C(=O)N R ⁶ 基團； 每一 L ^A 獨立地選自由以下組成之群：視情況經1-2個 R ^a1 取代之C _1-3伸烷基；-O-；-NH-；-N R ^d ；-S(O) _0-2；及C(O)； a1為0、1或2； 環 C係選自由以下組成之群： •  C _3-12伸環烷基或C _3-12伸環烯基，其各自視情況經1-4個獨立地選自由以下組成之群之取代基取代：側氧基、 R ^c 及 R ^h ； •  具有3-12個環原子之伸雜環基或伸雜環烯基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中伸雜環基或伸雜環烯基視情況經1-4個獨立地選自由以下組成之群之取代基取代：側氧基、 R ^c 及 R ^h ； •  具有5-12個環原子之伸雜芳基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中伸雜芳基視情況經1-4個獨立地選自由以下組成之群之取代基取代： R ^c 及 R ^h ；及 •  C _6-10伸芳基，其視情況經1-4個獨立地選自由以下組成之群之取代基取代： R ^c 及 R ^h ； R ⁷ 係選自由以下組成之群： R ^g 及 -(L ⁷) _b7-R ^g ； R ^a 及 R ^a1 在每次出現時獨立地選自由以下組成之群：-OH；-鹵基；-N R ^eR ^f ；C _1-4烷氧基；C _1-4鹵代烷氧基；-C(=O)O(C _1-4烷基)；-C(=O)(C _1-4烷基)；-C(=O)OH；-CON R’R’’；-S(O) _1-2N R’R’’；-S(O) _1-2(C _1-4烷基)；及氰基； R ^c 在每次出現時獨立地選自由以下組成之群：鹵基；氰基；視情況經1-6個獨立選擇之 R ^a 取代之C _1-10烷基；C _2-6烯基；C _2-6炔基；C _1-4烷氧基；C _1-4鹵代烷氧基；-S(O) _1-2(C _1-4烷基)；-S(O)(=NH)(C _1-4烷基)；-N R ^eR ^f ；-OH；-S(O) _1-2N R’R’’；-C _1-4硫基烷氧基；-NO ₂；-C(=O)(C _1-10烷基)；-C(=O)O(C _1-4烷基)；-C(=O)OH；-C(=O)N R’R’’；及-SF ₅； R ^d 在每次出現時獨立地選自由以下組成之群：視情況經1-3個獨立選擇之 R ^a 取代之C _1-6烷基；-C(O)(C _1-4烷基)；-C(O)O(C _1-4烷基)；-CON R’R’’；-S(O) _1-2N R’R’’；-S(O) _1-2(C _1-4烷基)；-OH；及C _1-4烷氧基； R ^e 及 R ^f 在每次出現時獨立地選自由以下組成之群：H；C _1-6烷基，其視情況經1-3個各自獨立地選自由N R’R’’、-OH及 R ⁱ 組成之群之取代基取代；-C(O)(C _1-4烷基)；-C(O)O(C _1-4烷基)；-CON R’R’’；-S(O) _1-2N R’R’’；-S(O) _1-2(C _1-4烷基)；-OH；及C _1-4烷氧基； R ^g 在每次出現時獨立地選自由以下組成之群： •  C _3-12環烷基或C _3-12環烯基，其中之每一者視情況經1-4個獨立地選自由以下組成之群之取代基取代：側氧基、 R ^c 、 R ^h 及-( L ^g) _bg-R ^h ； •  具有3-12個環原子之雜環基或雜環烯基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中雜環基或雜環烯基視情況經1-4個獨立地選自由以下組成之群之取代基取代：側氧基、 R ^c 、 R ^h 及-( L ^g) _bg-R ^h ； •  具有5-12個環原子之雜芳基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中雜芳基視情況經1-4個獨立地選自由以下組成之群之取代基取代： R ^c 、 R ^h 及-( L ^g) _bg-R ^h ；及 •  C _6-10芳基，其視情況經1-4個獨立地選自由以下組成之群之取代基取代： R ^c 、 R ^h 及-( L ^g) _bg-R ^h ； R ^h 在每次出現時獨立地選自由以下組成之群： •  C _3-12環烷基或C _3-12環烯基，其中之每一者視情況經1-4個 R ⁱ 取代； •  具有3-12個環原子之雜環基或雜環烯基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中雜環基或雜環烯基視情況經1-4個 R ⁱ 取代； •  具有5-12個環原子之雜芳基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中雜芳基視情況經1-4個 R ⁱ 取代；及 •  C _6-10芳基，其視情況經1-4個 R ⁱ 取代； R ⁱ 在每次出現時獨立地選自由以下組成之群：C _1-6烷基；C _1-4鹵代烷基；C _1-4烷氧基；C _1-4鹵代烷氧基；及鹵基； L ¹ 、 L ² 、 L ⁷ 及 L ^g 在每次出現時係選自由以下組成之群：-O-、-NH-、-N R ^d 、-S(O) _0-2、C(O)及視情況經1-3個 R ^a 取代之C _1-3伸烷基； b1、 b2、 b7及 bg各自獨立地為1、2或3；且 R’及 R’’在每次出現時獨立地選自由以下組成之群：H；-OH；及C _1-4烷基。 Compounds of Formula I In one aspect, provided herein are compounds of Formula I :

Formula I or a pharmaceutically acceptable salt or tautomer thereof, wherein: Z , Y ¹ , Y ² and Y ³ are independently selected from the group consisting of C R ¹ , C(=O), N and NR ² ; X ¹ is selected from the group consisting of: O, S, N, NR ² and CR ¹ ; X ² is selected from the group consisting of: O, S, N, NR ⁴ and CR ⁵ ; each

is independently a single bond or a double bond, provided that a 5-membered ring system heteroaryl group including ^X1 and ^X2 , and a 6-membered ring system aryl or heteroaryl group including Z , ^Y1 , ^Y2 , and ^Y3 ; Each R ¹ is independently selected from the group consisting of: H; R ^c ; R ^g ; and -(L ¹ ) _{b 1} -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 heteroaryl group having 5 ring atoms, wherein 1-4 ring atoms are each independently selected from N, NH, N( A heteroatom of the group consisting of R ^d ), O and S; wherein the heteroaryl group of ring B is optionally substituted with 1-2 substituents independently selected from the group consisting of pendant oxy and R ^c , provided that the ring B is attached to the C(=O)N R ⁶ group through a ring carbon atom; each L ^A is independently selected from the group consisting of: C _1-3 alkylene optionally substituted with 1-2 R ^a1 ; -O-; -NH-; -N R ^d ; -S(O) _0-2 ; and C(O); a1 is 0, 1, or 2; ring C is selected from the group consisting of: • C _{3- 12} cycloalkylene or _C3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of pendant oxy, ^Rc and ^Rh ; • having 3 -12 ring-atoms heterocyclylene or heterocycloalkenyl, wherein 1-3 ring atoms are each independently selected from N, N(H), N( R ^d ), O and S(O) ₀ - a heteroatom of the group consisting of ₂ , and wherein the heterocyclylene or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: pendant oxy, R ^c and R ^h ; • Heteroaryl having 5-12 ring atoms, wherein 1-3 ring atoms are each independently selected from N, N(H), N( ^Rd ), O and S(O) _0-2 A heteroatom of the group consisting of, and wherein heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of: R ^c and R ^h ; and • C _6-10 aryl, which Optionally substituted with 1-4 substituents independently selected from the group consisting of: ^Rc and ^Rh ; ^R7 is selected from the group consisting of: ^Rg and -( ^L7 ) _b7 - ^Rg ; R ^a and R ^a1 are at each occurrence independently selected from the group consisting of: -OH; -halo; -N R ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; (=O)O(C _1-4 alkyl); -C(=O)(C _1-4 alkyl); -C( -CON R'R'' ; -S(O) _1-2 N R'R'' ; -S(O) _1-2 (C _1-4 alkyl); and cyano; R ^c is independently selected at each occurrence from the group consisting of: halo; cyano; C _1-10 alkyl optionally substituted with 1-6 independently selected ^Ra ; C _2-6 alkenyl; C _2-6 alkynyl; C _1-4 alkoxy; C _1-4 haloalkoxy; -S(O) _1-2 (C _1-4 alkyl); -S(O)(=NH)(C -N R ^e R ^f ; -OH; -S(O) _1-2 N R'R'' ; -C _1-4 thioalkoxy; -NO _{2 ;} -C( -C(=O)O( _C1-4 alkyl); _-C (=O)OH; -C(=O)N R'R'' ; and _-SF5 ; ^Rd at each occurrence is independently selected from the group consisting of: _C1-6 alkyl optionally substituted with 1-3 independently selected ^Ras ; -C(O)( _{C1- 4} alkyl);-C(O)O(C _1-4 alkyl);-CON R'R'' ;-S(O) _1-2N R'R'' ;-S(O) _{1- 2} (C _1-4 alkyl); -OH; and C _1-4 alkoxy; R ^e and R ^f at each occurrence are independently selected from the group consisting of: H; C _1-6 alkyl, It is optionally substituted with 1-3 substituents each independently selected from the group consisting of NR'R'' , -OH and ^Ri ; -C(O)(C _1-4 alkyl); -C( O)O(C _1-4 alkyl);-CON R'R'' ;-S(O) _1-2N R'R'' ;-S(O) _1-2 (C _1-4 alkyl ); -OH; and C _1-4 alkoxy; R ^g at each occurrence is independently selected from the group consisting of: • C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each of which One is optionally substituted with 1-4 substituents independently selected from the group consisting of pendant oxy, ^Rc , ^Rh , and -( ^Lg ) _bg - ^Rh ; • having 3-12 ring atoms The heterocyclyl or heterocycloalkenyl, wherein 1-3 ring atoms are independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 . atom, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: pendant oxy, ^Rc , ^Rh , and -( ^Lg ) _bg -R ^h ; • Heteroaryl groups having 5-12 ring atoms, wherein 1-3 ring atoms are each independently selected from N, N(H), N( ^Rd ), O, and S(O) _0-2 A heteroatom of the group consisting of, and wherein the heteroaryl group is optionally substituted with 1-4 substituents independently selected from the group consisting of: R ^c , R ^h and -( L ^g ) _bg -R ^h ; and • C _6-10 aryl, optionally substituted with 1-4 substituents independently selected from the group consisting of: R ^c , R ^h and -( ^Lg ) _bg - ^Rh ; ^Rh at each occurrence is independently selected from the group consisting of: • _{C3-12cycloalkyl} or _{C3-12cycloalkenyl} , each of which Optionally substituted with 1-4 R ⁱ ; • Heterocyclyl or heterocycloalkenyl having 3-12 ring atoms, wherein 1-3 ring atoms are each independently selected from N, N(H), N ( R ^d ), O, and S(O) _0-2 as a heteroatom of the group, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 R ⁱ ; • having 5-12 ring atoms The heteroaryl group, wherein 1-3 ring atoms are each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 heteroatoms of the group, and wherein the heteroatom Aryl, optionally substituted with 1-4 ^Ri ; and • _C6-10 aryl, optionally substituted with 1-4 ^Ri ; ^Ri at each occurrence 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; L ¹ , L ² , L ⁷ and L ^g at each occurrence is selected from the group consisting of -O-, -NH-, -N R ^d , -S(O) _0-2 , C(O) and optionally C _1-3 substituted with 1-3 R ^a alkylene; b1 , b2 , b7 , and bg are each independently 1, 2, or 3; and R' and R'' are at each occurrence independently selected from the group consisting of: H; -OH; and _{C1 -4} alkyl.

Variables 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 C R ¹ .

In some embodiments, each of Z , ^Y1 , ^Y2 , and ^Y3 is an independently selected ^CR1 .

式( Ia) 或其醫藥上可接受之鹽，其中： R ^1a 、 R ^1b 、 R ^1c 及 R ^1d 各自係獨立選擇之 R ¹ 。 In certain embodiments, the compound is a compound of formula ( Ia ):

Formula ( Ia ) or a pharmaceutically acceptable salt thereof, wherein: R ^1a , R ^1b , R ^1c and R ^1d are each independently selected R ¹ .

In some embodiments, 1-2 (eg, 1) of Z , ^Y1 , ^Y2 , and ^Y3 are N; and each remaining of Z , ^{Y1 ,} Y2, and ^Y3 is independently selected C R ¹ .

或其醫藥上可接受之鹽，其中： R ^1a 、 R ^1b 、 R ^1c 及 R ^1d 各自係獨立選擇之 R ¹ 。 In some of these embodiments, the compound is selected from the group consisting of compounds of the following formulae:

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

或其醫藥上可接受之鹽，其中： R ^1a 、 R ^1b 及 R ^1c 各自係獨立選擇之 R ¹ 。 In certain embodiments, the compound is a compound of formula ( Ib) :

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

或其醫藥上可接受之鹽，其中： R ^1a 、 R ^1b 及 R ^1d 各自係獨立選擇之 R ¹ 。 In certain embodiments, the compound is a compound of formula ( Ic) :

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

或其醫藥上可接受之鹽，其中： R ^1a 、 R ^1c 及 R ^1d 各自係獨立選擇之 R ¹ 。 In certain embodiments, the compound is a compound of formula ( Id) :

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

或其醫藥上可接受之鹽，其中： R ^1b 、 R ^1c 及 R ^1d 各自係獨立選擇之 R ¹ 。 In certain embodiments, the compound is a compound of formula ( Ie) :

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

In some embodiments, X ¹ is NR ² . In certain of these embodiments, ^X1 is NH.

In some embodiments, X ² is CR ⁵ . In certain of these embodiments, ^X2 is CH.

In some embodiments, X ¹ is NR ² ; and X ² is CR ⁵ . In certain embodiments, ^X1 is ^NR2 ; and ^X2 is CH. In certain embodiments, X ¹ is NH; and X ² is CR ² . ^In certain embodiments, X1 is NH; and X2 is ^CH .

式 (Ia-1)或其醫藥上可接受之鹽，其中： R ^1a 、 R ^1b 、 R ^1c 及 R ^1d 各自係獨立選擇之 R ¹ 。在式( Ia-1)之某些實施例中， R ² 係H。在式( Ia-1)之某些實施例中， R ⁵ 係H。在式( Ia-1)之某些實施例中， R ² 係H；且 R ⁵ 係H。 In some embodiments, the compound is a compound of formula ( Ia-1 ):

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 . In certain embodiments of formula ( Ia-1) , R ² is H. In certain embodiments of formula ( Ia-1) , R ⁵ is H. In certain embodiments of formula ( Ia-1) , R ² is H; and R ⁵ is H.

或其醫藥上可接受之鹽，其中： R ^1a 、 R ^1b 、 R ^1c 及 R ^1d 各自係獨立選擇之 R ¹ 。 In some embodiments, the compound is selected from the group consisting of compounds of the following formulae:

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

或其醫藥上可接受之鹽，其中： R ^1a 、 R ^1b 及 R ^1c 各自係獨立選擇之 R ¹ 。在式( Ib-1)之某些實施例中， R ² 係H。在式( Ib-1)之某些實施例中， R ⁵ 係H。在式( Ib-1)之某些實施例中， R ² 係H；且 R ⁵ 係H。 In certain embodiments, the compound is a compound of formula ( Ib-1) :

or a pharmaceutically acceptable salt thereof, wherein: R ^1a , R ^1b and R ^1c are each independently selected R ¹ . In certain embodiments of formula ( Ib-1) , R ² is H. In certain embodiments of formula ( Ib-1) , R ⁵ is H. In certain embodiments of formula ( Ib-1) , R ² is H; and R ⁵ is H.

或其醫藥上可接受之鹽，其中： R ^1a 、 R ^1b 及 R ^1d 各自係獨立選擇之 R ¹ 。在式( Ic-1)之某些實施例中， R ² 係H。在式( Ic-1)之某些實施例中， R ⁵ 係H。在式( Ic-1)之某些實施例中， R ² 係H；且 R ⁵ 係H。 In certain embodiments, the compound is a compound of formula ( Ic-1) :

or a pharmaceutically acceptable salt thereof, wherein: R ^1a , R ^1b and R ^1d are each independently selected R ¹ . In certain embodiments of formula ( Ic-1) , R ² is H. In certain embodiments of formula ( Ic-1) , R ⁵ is H. In certain embodiments of formula ( Ic-1) , R ² is H; and R ⁵ is H.

或其醫藥上可接受之鹽，其中： R ^1a 、 R ^1c 及 R ^1d 各自係獨立選擇之 R ¹ 。在式( Id-1)之某些實施例中， R ² 係H。在式( Id-1)之某些實施例中， R ⁵ 係H。在式( Id-1)之某些實施例中， R ² 係H；且 R ⁵ 係H。 In certain embodiments, the compound is a compound of formula ( Id-1) :

or a pharmaceutically acceptable salt thereof, wherein: R ^1a , R ^1c and R ^1d are each independently selected R ¹ . In certain embodiments of formula ( Id-1) , R ² is H. In certain embodiments of formula ( Id-1) , ^R5 is H. In certain embodiments of formula ( Id-1) , R ² is H; and R ⁵ is H.

或其醫藥上可接受之鹽，其中： R ^1b 、 R ^1c 及 R ^1d 各自係獨立選擇之 R ¹ 。在式( Ie-1)之某些實施例中， R ² 係H。在式( Ie-1)之某些實施例中， R ⁵ 係H。在式( Ie-1)之某些實施例中， R ² 係H；且 R ⁵ 係H。 In certain embodiments, the compound is a compound of formula ( Ie-1) :

or a pharmaceutically acceptable salt thereof, wherein: R ^1b , R ^1c and R ^1d are each independently selected R ¹ . In certain embodiments of formula ( Ie-1) , R ² is H. In certain embodiments of formula ( Ie-1) , R ⁵ is H. In certain embodiments of formula ( Ie-1) , R ² is H; and R ⁵ is H.

Variable 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, 1-2 R ¹ are each independently selected from the group consisting of R ^c1 and R ^g1 ; and each remaining R ¹ is H, wherein R ^c1 is an independently selected R ^c ; and R ^g1 is Independently selected R ^g .

In certain of these embodiments, R ¹ is independently selected from the group consisting of R ^c1 and R ^g1 on both occurrences; and each remaining R ¹ is H.

For example, each of ^R1 is an independently selected ^Rc1 on both occurrences; and each remaining ^R1 is H. In some of these embodiments, each R ^c1 is an independently selected halo group (eg, -F or -Cl).

In certain embodiments (where 1-2 R ¹ are independently selected from the group consisting of R ^c1 and R ^g1 and each remaining R ¹ is H, wherein R ^c1 is an independently selected R ^c ; and R ^g1 is independently selected R ^g ), R ¹ is selected from the group consisting of R ^c1 and R ^g1 in one occurrence; and each remaining R ¹ is H. In some of these embodiments, ^R1 is ^Rc1 in one occurrence; and each remaining ^R1 is H. In some of these embodiments, R ^c1 is halo (eg, -F or -Cl, eg, -F).

In certain embodiments (where 1-2 R ¹ are independently selected from the group consisting of R ^c1 and R ^g1 and each remaining R ¹ is H, wherein R ^c1 is an independently selected R ^c ; and R ^g1 is independently selected R ^g ), R ¹ is R ^g1 in one occurrence; and each remaining R ¹ is H.

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

In certain embodiments (where 1-2 R ¹ are independently selected from the group consisting of R ^c1 and R ^g1 ; and each remaining R ¹ is H, wherein R ^c1 is an independently selected R ^c ; and R ^g1 are independently selected R ^g ), and each R ^g1 is independently selected from the group consisting of: a heteroaryl group having 5-10 ring atoms, wherein 1-3 ring atoms are each independently selected from N, N ( A heteroatom of the group consisting of H), N( R ^d ), O, and S, and wherein the heteroaryl group is optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c , R ^h and -( ^Lg ) _bg - ^Rh ; and _C6-10 aryl, optionally substituted with 1-4 substituents independently selected from the group consisting of: ^Rc , ^Rh , and -( ^Lg ) _bg -R ^h .

In some of these embodiments, each R ^g1 is independently selected from the group consisting of: a heteroaryl group having 5-6 ring atoms, wherein 1-3 ring atoms are each independently selected from N , N(H), N( ^Rd ), O, and S heteroatoms of the group consisting of, and wherein heteroaryl is optionally substituted with 1-4 ^Rc ; and _C6 aryl, optionally substituted with 1- 4 R ^c substitutions.

In certain of the foregoing embodiments, each R ^g1 is independently a heteroaryl group having 5 ring atoms, wherein 1-3 ring atoms are each independently selected from N, N(H), N( R ^d ), a heteroatom of the group consisting of O and S, and wherein heteroaryl is optionally substituted with 1-4 ^Rc . As a non-limiting example of one of the foregoing embodiments, each R ^g1 can be pyrazolyl, optionally substituted by 1-2 R ^c (eg, 1-2 independently selected C _1-6 (eg, C _1-3 ) ) alkyl) optionally substituted with 1-6 independently selected R ^a (eg, unsubstituted).

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

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

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

In some embodiments, the compound is a compound of formula ( Ia) , (Ia-1) , (Ib) , (Ib-1) , (Ic) , (Ic-1) , (Ie) or (Ie-1) and R ^1b is a heteroaryl group having 5 ring atoms, wherein 1-3 ring atoms are each independently selected from the group consisting of N, N(H), N( ^Rd ), O and S. Heteroatoms , and wherein the heteroaryl group is optionally substituted with 1-2 R ^c . Each R ^1b optionally substituted with 1-2 R ^c pyrazolyl, for example, each R ^c is independently selected optionally substituted with 1-6 independently selected R ^a (eg, without substituted) C _1-6 (eg C _1-3 ) alkyl.

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

In some embodiments, the compound is a compound of formula ( Ia) , (Ia-1) , (Ib) , (Ib-1) , (Id) , (Id-1) , (Ie), or (Ie-1) ; R ^1c is halo, eg -F or -Cl (eg -F).

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

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

In some embodiments, the compound is of formula ( Ia) , (Ia-1) , (Ib) , (Ib-1) , (Ic) , (Ic-1) , (Id) , (Id-1) , ( Compounds of Ie) or (Ie-1) ; R ^1a and R ^1d , when present, are H; and R ^1b and R ^1c , when present, are independently selected halo groups (eg -F or -Cl, eg -F).

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

In some embodiments, the compound is of formula ( Ia) , (Ia-1) , (Ib) , (Ib-1) , (Ic) , (Ic-1) , (Id) , (Id-1) , ( Compounds of Ie) or (Ie-1) ; R ^1a and R ^1d , when present, are H; R ^1c , when present, is halo or H (eg -F, -Cl) or H; and R ^1b , when present, is A heteroaryl group having 5 ring atoms, wherein 1-3 ring atoms are each independently selected from the group consisting of N, N(H), N( R ^d ), O and S. Base is optionally substituted with 1-4 R ^c .

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

Variable Ring B In some embodiments, Ring B is a heteroaryl group having 5 ring atoms, wherein 1-3 ring atoms are each independently selected from the group consisting of N, NH, O, and S heteroatoms, wherein the heteroaryl of Ring B is optionally substituted with 1-2 ^RcBs ; and each ^RcB is an independently selected ^Rc .

In some embodiments, Ring B is a heteroaryl group having 5 ring atoms, wherein 2-3 ring atoms are each independently selected from the group consisting of N, NH, N( ^Rd ), O, and S heteroatom, wherein the heteroaryl of Ring B is optionally substituted with 1-2 R ^cB ; and each R ^cB is an independently selected R ^c .

In some embodiments, Ring B is a heteroaryl group having 5 ring atoms, wherein 2-3 ring atoms are each independently selected from the group consisting of N and NH heteroatoms, wherein Ring B is a heteroaryl group Base is optionally substituted with 1-2 R ^cBs ; and each R ^cB is an independently selected R ^c . As a non-limiting example of the foregoing embodiments, Ring B is selected from the group consisting of triazolyl, triazolyl, or triazolyl (eg, 1,2,3-triazolyl), as the case may be, by a triazolyl R ^cB substituted.

In certain embodiments, Ring B is elimidazolyl optionally substituted with one R ^cB .

，其中 aa 係與 (L ^A) _a1 之連結點 。 In certain embodiments, Ring B is optionally substituted with one R ^cB

, where aa is the junction with (L ^A ) _a1 .

，其中 aa 係與 (L ^A) _a1 之連結點 。 In certain embodiments, Ring B is optionally substituted with one R ^cB

, where aa is the junction with (L ^A ) _a1 .

In certain embodiments, Ring B is triazolyl (eg, 1,2,3-triazolyl) optionally substituted with one R ^cB .

，其中 aa 係與 (L ^A) _a1 之連結點 。 In certain embodiments, Ring B is optionally substituted with one R ^cB

, where aa is the junction with (L ^A ) _a1 .

In certain embodiments, Ring B is pyrazolyl optionally substituted with one R ^cB .

或

，其中 aa 係與 (L ^A) _a1 之連結點 。 In certain embodiments, Ring B is each optionally substituted with one R ^cB

or

, where aa is the junction with (L ^A ) _a1 .

或

，其中 aa 係與 (L ^A) _a1 之連結點 。 In certain embodiments, Ring B is each optionally substituted with one R ^cB

or

, where aa is the junction with (L ^A ) _a1 .

In certain embodiments, each R ^cB is independently halo or optionally C _1-3 alkyl, optionally with 1-3 independently selected R ^a (eg, 1-3 independently selected R a ) halogen) substituted.

In some embodiments, Ring B is selected from the group consisting of: ex-isoxazolyl, ex-oxadiazolyl, ex-oxazolyl, ex-thiazolyl, ex-isothiazolyl, or ex-thiadiazolyl, depending on The case is replaced by an R ^cB .

或

，其中之每一者視情況經一個 R ^cB 取代，其中 aa 係與 (L ^A) _a1 之連結點 。 In certain embodiments, Ring B is

or

, each of which is optionally substituted with an R ^cB , where aa is the point of attachment to (L ^A ) _a1 .

或

，其中之每一者視情況經一個 R ^cB 取代，其中 aa 係與 (L ^A) _a1 之連結點 。 In certain embodiments, Ring B is

or

, each of which is optionally substituted with an R ^cB , where aa is the point of attachment to (L ^A ) _a1 .

或

，其中之每一者視情況經一個 R ^cB 取代，其中 aa 係與 (L ^A) _a1 之連結點 。 In certain embodiments, Ring B is

or

, each of which is optionally substituted with an R ^cB , where aa is the point of attachment to (L ^A ) _a1 .

或

，其中 aa 係與 (L ^A) _a1 之連結點 。 In certain embodiments, Ring B is optionally substituted with one R ^cB

or

, where aa is the junction with (L ^A ) _a1 .

或

，其中之每一者視情況經一個 R ^cB 取代，其中 aa 係與 (L ^A) _a1 之連結點 。 In certain embodiments, Ring B is

or

, each of which is optionally substituted with an R ^cB , where aa is the point of attachment to (L ^A ) _a1 .

或

，其中之每一者視情況經一個 R ^cB 取代，其中 aa 係與 (L ^A) _a1 之連結點 。 In certain embodiments, Ring B is

or

, each of which is optionally substituted with an R ^cB , where aa is the point of attachment to (L ^A ) _a1 .

In certain embodiments, each R ^cB is independently halo or optionally C _1-3 alkyl, optionally with 1-3 independently selected R ^a (eg, 1-3 independently selected R a ) halogen) substituted.

Variables a1 and ^LA In some embodiments, a1 is zero. In some other embodiments, a1 is 1.

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

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

Variable Ring C In some embodiments, Ring C is selected from the group consisting of: • Heteroaryl having 5-10 ring atoms, wherein 1-3 ring atoms are each independently selected from N, N( A heteroatom of the group consisting of H), N( R ^d ), O and S(O) _0-2 , and wherein heteroaryl is optionally selected from the group consisting of R ^cC and R ^hC through 1-4 and • C _6-10 aryl, optionally substituted with 1-4 substituents independently selected from the group consisting of: R ^cC and R ^hC ; wherein each R ^cC is independently selected and each R ^{hC is} an independently selected R ^h .

In certain of these embodiments, Ring C is selected from the group consisting of: • Heteroaryl having 5-6 (eg 6) ring atoms, of which 1-3 (eg 1-2) The ring atoms are each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 heteroatoms, and wherein the heteroaryl group is optionally 1-4 Substituted with substituents independently selected from the group consisting of ^RcC ; and • _C6aryl , optionally substituted with 1-4 substituents independently selected from the group consisting of ^RcC .

In certain embodiments (where Ring C is selected from the group consisting of: a heteroaryl group having 5-10 ring atoms, wherein 1-3 ring atoms are each independently selected from N, N(H) ), N( R ^d ), O, and S(O) _0-2 of the group consisting of heteroatoms, and wherein the heteroaryl group is optionally selected from the group consisting of R ^cC and R ^hC through 1-4 Substituent substitution; and C _6-10 aryl, optionally substituted with 1-4 substituents independently selected from the group consisting of R ^cC and R ^hC , wherein each R ^cC is an independently selected R ^c ; and each R ^hC is an independently selected R ^h ), Ring C is selected from the group consisting of: • pyridyl, optionally 1-3 (eg, 1) independently selected from the group consisting of R ^cC Substituent substitution; and • _C6 aryl, optionally substituted with 1-4 (eg, 1-2) substituents independently selected from the group consisting of ^RcC .

，其中 Q ¹ 、Q ² 、Q ³ 及 Q ⁴ 中之每一者獨立地選自由N、CH及C R ^cC 組成之群；且 bb 係與 R ⁷ 之連結點，其中每一 R ^cC 係獨立選擇之 R ^c 。 In certain embodiments, Ring C is a group of the formula:

, where each 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 junction with R ⁷ , where each R ^cC is independently Choose R ^c .

In certain embodiments, each of Q ¹ , Q ² , Q ³ , and Q ⁴ is independently CH or ^{CR cC} . In certain other embodiments, ^one of 1-2 (eg, 1) of ^Q1 , ^Q2 , ^Q3 , and ^Q4 is N; and each of the remainder of Q1 , ^Q2 , ^Q3 , and ^Q4 independently CH or C R ^cC .

In certain embodiments, ^Q2 is CH. In certain embodiments, ^Q3 is CH. In certain embodiments, ^Q4 is N. In certain embodiments, ^Q1 is CH. In certain other embodiments, ^Q1 is ^CRcC .

或

，例如

。 In certain embodiments, Ring C is

or

,E.g

.

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

In certain embodiments, each ^RcC is independently halo, eg, -Cl or -F, eg, -F.

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

In some embodiments, R ⁷ is selected from the group consisting of: • C _3-12 cycloalkyl, optionally substituted with 1-4 substituents independently selected from the group consisting of pendant oxy, R ^c7 , R ^h7 and -( L ^g ) _bg -R ^h7 ; and • a heterocyclyl group having 4-12 ring atoms, wherein 1-3 ring atoms are each independently selected from N, N(H), A heteroatom of the group consisting of N( R ^d ), O and S(O) _0-2 , and wherein the heterocyclyl group is optionally independently selected from pendant oxy, R ^c7 , R ^h7 and -( ^Lg ) Substituent substitution of the group consisting of _bg - ^Rh7 , wherein each ^Rc7 is an independently selected ^Rc ; and ^Rh7 is an independently selected ^Rh .

In certain of these embodiments, R ⁷ is selected from the group consisting of: • C _4-8 (eg C ₄ , C ₅ or C ₆ ) cycloalkyl, optionally via 1-4 independently substituted with substituents selected from the group consisting of: pendant oxy, R ^c7 and R ^h7 ; and • heterocyclyl having 4-8 (eg 4, 5 or 6) ring atoms, of which 1-3 rings Atoms are each independently selected from the group consisting of N, N(H), N( R ^d ), O, and S(O) _0-2 heteroatoms, and wherein the heterocyclyl group is optionally replaced by 1-4 independently Substituted with a substituent selected from the group consisting of pendant oxy, R ^c7 and R ^h7 .

In certain of the foregoing embodiments, ^R7 is selected from the group consisting of: • _C6cycloalkyl , optionally substituted with 1-4 substituents independently selected from the group consisting of ^Rc7 ; and • Heterocyclyl having 6 ring atoms, wherein 1-2 (eg one) ring atoms are each independently selected from N, N(H), N( ^Rd ), O and S(O) _0-2 A heteroatom of the group consisting of, and wherein the heterocyclyl group is optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c7 .

，其中 X ⁷ 係CH、C R ^c7 或N (例如CH或N)。在某些實施例中(在 R ⁷ 係

時)，存在兩個 R ^c7 基團。 In some of these embodiments, ^R is a group of the formula:

, wherein X ⁷ is CH, ^{CR c7} or N (eg CH or N). In certain embodiments (in the ^R7 series

), there are two R ^c7 groups.

，其中 X ⁷ 係N或CH；且每一 R ^c7 係獨立選擇之 R ^c 。在某些實施例中， R ⁷ 係

，其中 X ⁷ 係N或CH；例如

或

。 In certain embodiments, R ⁷ is a group 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

, where X ⁷ is N or CH; for example

or

.

In certain of the foregoing embodiments, ^R7 is selected from the group consisting of: • C4cycloalkyl, optionally substituted with _1-4 substituents independently selected from the group consisting of ^Rc7 ; and • Heterocyclyl having 4 ring atoms, wherein 1-2 (eg one) ring atoms are each independently selected from N, N(H), N( ^Rd ), O and S(O) _0-2 A heteroatom of the group consisting of, and wherein the heterocyclyl group is optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c7 .

，其中 X ⁷ 係CH、C R ^c7 或N (例如CH或N)。在某些實施例中(在 R ⁷ 係

時)，存在兩個 R ^c7 基團。 In some of these embodiments, ^R is a group of the formula:

, wherein X ⁷ is CH, ^{CR c7} or N (eg CH or N). In certain embodiments (in the ^R7 series

), there are two R ^c7 groups.

，其中 X ⁷ 係N或CH；且每一 R ^c7 係獨立選擇之 R ^c 。在某些實施例中， R ⁷ 係

，其中 X ⁷ 係N或CH；例如

或

。 In certain embodiments, R ⁷ is a group 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

, where X ⁷ is N or CH; for example

or

.

或

。 In certain embodiments, ^R7 is selected from the group consisting of tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octyl, or 2-azabicyclo[2.2.1]heptyl alkanes, each of which is optionally substituted with 1-2 R ^c7 . For example, ^R7 can be:

or

.

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

In some embodiments, R ⁷ is selected from the group consisting of: • C _4-5 cycloalkyl, optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c7 ; and • having Heterocyclyl of 5-6 ring atoms, wherein 1-2 (eg, one) ring atoms are each independently selected from N, N(H), N( ^Rd ), O, and S(O) _0-2 A heteroatom of the group consisting of, and wherein the heterocyclyl group is optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c7 .

或

，其中 X ⁷ 係CH、C R ^c7 或N (例如CH或N)。 In certain embodiments, R ⁷ is a group of the formula:

or

, wherein X ⁷ is CH, ^{CR c7} or N (eg CH or N).

或

，其中 R ^d 獨立地選自由以下組成之群：視情況經1-3個獨立選擇之 R ^a 取代之C _1-6烷基。 In certain embodiments, R ⁷ is a group of the formula:

or

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

或

。 In certain embodiments, ^R7 is selected from the group consisting of tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octyl, or 2-azabicyclo[2.2.1]heptyl alkanes, each of which is optionally substituted with 1-2 R ^c7 . For example, ^R7 can be:

or

.

式 (I-a1-1)或其醫藥上可接受之鹽，其中： R ^1a 、 R ^1b 、 R ^1c 及 R ^1d 中之每一者係獨立選擇之 R ¹ ； B ⁴ 係C或N； B ¹ 、 B ² 及 B ³ 各自獨立地係CH、C R ^cB 、NH、N( R ^d )、N、O或S； Q ¹ 、 Q ² 、 Q ³ 及 Q ⁴ 各自獨立地選自由以下組成之群：N、CH及C R ^cC ； R ^cB 及 R ^cC 在每次出現時係獨立選擇之 R ^c ；且 每一

獨立地係單鍵或雙鍵，條件係包含 B ¹-B ⁴ 之環為雜芳基。 Non-Limiting Combinations In some embodiments, the compound is a compound of formula ( I-a1-1) :

Formula (I-a1-1) or a pharmaceutically acceptable salt thereof, wherein: each of R ^1a , R ^1b , R ^1c and R ^1d is an 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 Groups: N, CH, and C R ^cC ; R ^cB and R ^cC are independently selected R ^c at each occurrence; and each

is independently a single bond or a double bond, provided that the ring comprising B ¹ -B ⁴ is a heteroaryl group.

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 (eg, -F or -Cl, eg, -F).

In some embodiments of formula ( I-a1-1) , each 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 (eg, -F, -Cl or H); and R ^1b has 5 ring atoms The heteroaryl group, wherein 1-3 ring atoms are each independently selected from the group consisting of N, N(H), N( R ^d ), O and S. - substituted with 4 substituents independently selected from the group consisting of ^Rc .

In some embodiments of formula ( I-a1-1) , R ² is H. In some embodiments of formula ( I-a1-1) , R ⁵ is H. In some embodiments of formula ( I-a1-1) , R ² is H; and R ⁵ is H.

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

In some embodiments of formula ( I-a1-1) , R ² is H; R ⁵ is H; and R ⁶ is H.

In some embodiments of formula ( I-a1-1) , ^B4 is N; ^B1 is N; ^B3 is CH or ^CRcB ; and ^B2 is CH or ^CRcB . In certain embodiments, ^B4 is N; ^B1 is N; ^B3 is CH; and ^B2 is CH. In certain embodiments, ^B4 is N; ^B1 is N; ^B3 is CH; and ^B2 is ^CRcB .

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, ^B4 is N; ^B1 is N; ^B3 is CH; and ^B2 is N.

In some embodiments of formula ( I-a1-1) , ^B4 is N; ^B1 is CH or ^CRcB ; ^B3 is CH or ^CRcB ; and ^B2 is N. In certain embodiments, ^B4 is N; ^B1 is CH; ^B3 is CH; and ^B2 is N.

In some embodiments of formula ( I-a1-1) , ^B4 is N; ^B1 is CH or ^CRcB ; ^B3 is N; and ^B2 is CH or ^CRcB . In certain embodiments, ^B4 is N; ^B1 is CH; ^B3 is N; and ^B2 is CH.

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) , ^LA is _CH2 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) , Q ⁴ is N; and Q ² is CH or ^{CR cC} (eg, ^{CR cC} ).

，其中 bb 係與 R ⁷ 之連結點。 In some embodiments of formula ( I-a1-1) , the ring system comprising Q ¹ -Q ⁴ :

, where bb is the junction with R ⁷ .

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 selected from the group consisting of: • C ₆ cycloalkyl, optionally 1-4 independently selected from the group consisting of R ^c7 Substituent substitution; and • Heterocyclyl having 6 ring atoms, wherein 1-2 (eg, one) ring atoms are each independently selected from N, N(H), N( ^Rd ), O, and S( O) a heteroatom of the group consisting of _0-2 , and wherein the heterocyclyl group is optionally substituted with 1-4 substituents independently selected from the group consisting of ^Rc7 , wherein each ^Rc7 is an independently selected ^Rc .

，其中 X ⁷ 係CH、C R ⁷ 或N(例如CH或N)。在該等實施例中之某些中，存在兩個 R ^c7 基團。 In some embodiments of formula ( I-a1-1) , R ⁷ is a group of the following formula:

, wherein X ⁷ is CH, C R ⁷ or N (eg CH or N). In some of these embodiments, two R ^c7 groups are present.

，其中 X ⁷ 係N或CH；且每一 R ^c7 係獨立選擇之 R ^c 。在該等實施例中之某些中， R ⁷ 係

，其中 X ⁷ 係N或CH，例如

或

。 In some embodiments of formula ( I-a1-1) , R ⁷ is a group of 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

, where X ⁷ is N or CH, for example

or

.

In some embodiments of formula ( I-a1-1) , R ⁷ is selected from the group consisting of: • C ₄ cycloalkyl, optionally 1-4 independently selected from the group consisting of R ^c7 Substituent substitution; and • Heterocyclyl having 4 ring atoms, wherein 1-2 (eg, one) ring atoms are each independently selected from N, N(H), N( ^Rd ), O, and S( O) a heteroatom of the group consisting of _0-2 , and wherein the heterocyclyl group is optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c7 .

，其中 X ⁷ 係CH、C R ^c7 或N (例如CH或N)。在某些實施例中(在 R ⁷ 係

時)，存在兩個 R ^c7 基團。 In some embodiments of formula ( I-a1-1) , R ⁷ is a group of the following formula:

, wherein X ⁷ is CH, ^{CR c7} or N (eg CH or N). In certain embodiments (in the ^R7 series

), there are two R ^c7 groups.

，其中 X ⁷ 係N或CH；且每一 R ^c7 係獨立選擇之 R ^c 。在某些實施例中， R ⁷ 係

，其中 X ⁷ 係N或CH；例如

或

。 In some embodiments of formula ( I-a1-1) , R ⁷ is a group of 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

, where X ⁷ is N or CH; for example

or

.

或

。 In some embodiments of formula ( I-a1-1) , R ⁷ is selected from the group consisting of tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octyl, or 2- Azabicyclo[2.2.1]heptane, each of which is optionally substituted with 1-2 ^Rc7 . For example, ^R7 can be:

or

.

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

獨立地係單鍵或雙鍵，條件係包含 B ¹-B ⁴ 之環為雜芳基； R ⁷ 係

，其中 X ⁷ 係N或CH， 其中 R ^c 在每次出現時獨立地選自由以下組成之群：鹵基；C _1-10烷基，其視情況經1-6個獨立選擇之 R ^a 取代； 其中 R ^a 在每次出現時獨立地選自由以下組成之群：-OH；-鹵基；C _1-4烷氧基；C _1-4鹵代烷氧基。 In some embodiments, the compound is a compound of formula ( I-a1-1) , wherein: R ^1a and R ^1d are H; R ^1b , R ^1c are each independently selected from: H; and R ^c , R ² , R ⁵ , R ⁶ are each independently H; B ¹ is selected from CH and N; B ² and B ⁴ are each independently N; B ³ is CH; Q ¹ is N; Q ² and Q ³ are each independently CH; Q ⁴ is C R ^c ; and each

It is independently a single bond or a double bond, and the condition is that the ring containing B ¹ -B ⁴ is a heteroaryl group; R ⁷ is a

, wherein X ⁷ is N or CH, wherein R ^c at each occurrence is independently selected from the group consisting of: halo; C _1-10 alkyl, optionally substituted with 1-6 independently selected R ^a ; wherein ^Ra is at each occurrence independently selected from the group consisting of: -OH; -halo; C _1-4 alkoxy; C _1-4 haloalkoxy.

式 (I-f1-1)或其醫藥上可接受之鹽，其中： Z係N或C R ^1a ； Y ¹ 係N或C R ^1b ； Y ² 係N或C R ^1c ； Y ³ 係N或C R ^1d ，條件係 Z 、 Y ¹ 、 Y ² 及 Y ³ 中之1-2 (例如1)者係N； R ^1a 、 R ^1b 、 R ^1c 及 R ^1d 中之每一者係獨立選擇之 R ¹ ； B ⁴ 係C或N； B ¹ 、 B ² 及 B ³ 各自獨立地係CH、C R ^cB 、NH、N( R ^d )、N、O或S； Q ¹ 、 Q ² 、 Q ³ 及 Q ⁴ 各自獨立地選自由以下組成之群：N、CH及C R ^cC ； R ^cB 及 R ^cC 在每次出現時係獨立選擇之 R ^c ；且 每一

獨立地係單鍵或雙鍵，條件係包含 B ¹-B ⁴ 之環為雜芳基。 In some embodiments, the compound is a compound of formula ( I-f1-1) :

Formula (I-f1-1) or a pharmaceutically acceptable salt thereof, wherein: Z is N or C R ^1a ; Y ¹ is N or C R ^1b ; Y ² is N or C R ^1c ; Y ³ is N or C R ^1d , provided that 1-2 of Z , Y ¹ , Y ² and Y ³ (eg 1) are N; each of R ^1a , R ^1b , R ^1c and R ^1d is an independently selected R ¹ ; ^B4 is C or N; ^B1 , ^B2 and ^B3 are each independently CH, ^CRcB , NH, N( ^Rd ), N, O or S; ^Q1 , ^Q2 , ^Q3 and Q ⁴ is each independently selected from the group consisting of: N, CH, and C R ^cC ; R ^cB and R ^cC are at each occurrence an independently selected R ^c ; and each

is independently a single bond or a double bond, provided that the ring comprising ^{B1 -} B4 is a heteroaryl group.

In some embodiments of formula ( I-f1-1) , one of Z , ^Y1 , ^Y2 , and ^Y3 is N.

式 (I-b1-1)或其醫藥上可接受之鹽。 In some embodiments of formula ( I-f1-1) , the compound is a compound of formula ( I-b1-1) :

Formula (I-b1-1) or a pharmaceutically acceptable salt thereof.

式 (I-c1-1)或其醫藥上可接受之鹽。 In some embodiments of formula (I- f1-1 ), the compound is a compound of formula ( I-c1-1) :

Formula (I-c1-1) or a pharmaceutically acceptable salt thereof.

式 (I-d1-1)或其醫藥上可接受之鹽。 In some embodiments of formula (I- f1-1 ), the compound is a compound of formula ( I-d1-1) :

Formula (I-d1-1) or a pharmaceutically acceptable salt thereof.

式 (I-e1-1)或其醫藥上可接受之鹽。 In some embodiments of formula (I- f1-1 ), the compound is a compound of formula ( I-d1-1) :

Formula (I-e1-1) or a pharmaceutically acceptable salt thereof.

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

In some embodiments of formula (I-f1-1) (eg, formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)), R ^1a and R ^1d , when present, are H; and R ^1b and R ^1c , when present, are independently selected halo groups (eg, -F or -Cl, eg, -F).

In some embodiments of formula (I-f1-1) (eg, formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)), Each of R ^1a , R ^1b , R ^1c and R ^1d is H when present.

In some embodiments of formula (I-f1-1) (eg, formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)), R ^1a and R ^1d , when present, are H; R ^1c , when present, is halo or H (eg, -F, -Cl, or H); and R ^1b , when present, is a heteroaryl group having 5 ring atoms, wherein 1-3 ring atoms are each independently selected from the group consisting of N, N(H), N(R ^d ), O and S heteroatoms, and wherein heteroaryl is optionally selected independently by 1-4 Substituent substitution of the group consisting of free R ^c .

In some embodiments of formula (I-f1-1) (eg, formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)), R ^1d , when present, is an independently selected halo group (eg -F or -Cl). In certain of these embodiments, each of ^R1a , ^R1b , and ^R1c is H when present.

In some embodiments of formula (I-f1-1) (eg, 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), R ² is H; and R ⁵ is H.

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

In some embodiments of formula (I-f1-1) (eg, 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) (eg, formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)), B4 is N; B1 is N; ^B3 is CH or ^CRcB ; and ^{B2 is CH} or ^CRcB . ^In certain embodiments, B4 is N ^; B1 is N; ^B3 is CH; and B2 is ^CH . ^In certain embodiments, B4 is N; B1 is N; ^B3 is ^CH ; and ^{B2 is CRcB .}

In some embodiments of formula (I-f1-1) (eg, 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, B4 is N ^; B1 is N; ^B3 is ^CH ; and B2 is N.

In some embodiments of formula (I-f1-1) (eg, 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 ; and B ² is N. ^In certain embodiments, B4 is N ^; B1 is CH; ^B3 is ^CH ; and B2 is N.

In some embodiments of formula (I-f1-1) (eg, 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; and B ² is CH or CR ^cB . ^In certain embodiments, B4 is N ^; B1 is CH; ^B3 is N; and B2 is ^CH .

In some embodiments of formula (I-f1-1) (eg, 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 ), LA is _CH2 or CH(Me).

In some embodiments of formula (I-f1-1) (eg, formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)), ^Q1 and ^Q3 are CH or CR ^cC (eg CH). In some embodiments of formula (I-f1-1), ^Q4 is N; and ^Q2 is CH or ^CRcC (eg, ^CRcC ).

，其中 bb係與R ⁷之連結點。 In some embodiments of formula (I-f1-1) (eg, formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)), Ring system including Q ¹ -Q ⁴ :

, where bb is the junction with R ⁷ .

In some embodiments of formula (I-f1-1) (eg, 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) (eg, formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)), The R ⁷ series is selected from the group consisting of:

_C6cycloalkyl , optionally substituted with 1-4 substituents independently selected from the group consisting of ^Rc7 ; and

Heterocyclyl having 6 ring atoms, wherein 1-2 (eg, one) ring atoms are each independently selected from N, N(H), N(R ^d ), O, and S(O) _0-2 A heteroatom of the group of and wherein the heterocyclyl group is optionally substituted with 1-4 substituents independently selected from the group consisting of ^Rc7 , wherein each ^Rc7 is an independently selected ^Rc .

，其中X ⁷係CH、CR ⁷或N (例如CH或N)。在該等實施例中之某些中，存在兩個R ^c7基團。 In some embodiments of formula (I-f1-1) (eg, formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)), R ⁷ is a group of the formula:

, wherein X ⁷ is CH, CR ⁷ or N (eg CH or N). In some of these embodiments, two R ^c7 groups are present.

，其中X ⁷係N或CH；且每一R ^c7係獨立選擇之R ^c。在該等實施例中之某些中，R ⁷係

，其中X ⁷係N或CH，例如

或

。 In some embodiments of formula (I-f1-1) (eg, formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)), R ⁷ is a group of the 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

, where X ⁷ is N or CH, for example

or

.

In some embodiments of formula (I-f1-1) (eg, formula (I-b1-1), (I-c1-1), (I-d1-1), or (I-e1-1)), R ⁷ is selected from the group consisting of: • C ₄ cycloalkyl, optionally substituted with 1-4 substituents independently selected from the group consisting of ^R c 7 ; and • Heterocyclyl having 4 ring atoms , wherein 1-2 (eg, one) ring atoms are each independently selected from the group consisting of N, N(H), N( R ^d ), O, and S(O) _0-2 heteroatoms of the group, and wherein the heteroatoms The cyclyl group is optionally substituted with 1-4 substituents independently selected from the group consisting of ^Rc7 .

，其中 X ⁷ 係CH、C R ^c7 或N (例如CH或N)。在某些實施例中(在 R ⁷ 係

時)，存在兩個 R ^c7 基團。 In some embodiments of formula ( I-f1-1) (eg, formula ( I-b1-1) , (I-c1-1) , (I-d1-1), or (I-e1-1)) , R ⁷ is a group of the formula:

, wherein X ⁷ is CH, ^{CR c7} or N (eg CH or N). In certain embodiments (in the ^R7 series

), there are two R ^c7 groups.

，其中 X ⁷ 係N或CH；且每一 R ^c7 係獨立選擇之 R ^c 。在某些實施例中， R ⁷ 係

，其中 X ⁷ 係N或CH；例如

或

。 In some embodiments of formula ( I-f1-1) (eg, formula ( I-b1-1) , (I-c1-1) , (I-d1-1), or (I-e1-1)) , R ⁷ is a group of the formula:

, wherein X ⁷ is N or CH; and each R ^c7 is an independently selected R ^c . In certain embodiments, ^R7 is

, where X ⁷ is N or CH; for example

or

.

或

。 In some embodiments of formula ( I-f1-1) (eg, formula ( I-b1-1) , (I-c1-1) , (I-d1-1), or (I-e1-1)) , ^R7 is selected from the group consisting of tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octyl, or 2-azabicyclo[2.2.1]heptane, each of which Optionally substituted with 1-2 R ^c7 . For example, ^R7 can be:

or

.

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

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

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Non-Limiting Exemplary Compounds In some embodiments, the compound is selected from the group consisting of a compound described in Table C1 or a pharmaceutically acceptable salt thereof. Table C1 Numbering structure Numbering structure 101

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Pharmaceutical Compositions and Administration Overview In some embodiments, chemical entities, such as compounds that inhibit (eg, antagonize) STING, or pharmaceutically acceptable salts and/or hydrates and/or co-crystals thereof, are administered in the form of pharmaceutical compositions. and/or pharmaceutical combination), the pharmaceutical composition comprising a chemical entity and one or more pharmaceutically acceptable excipients and optionally one or more other therapeutic agents as described herein.

In some embodiments, the chemical entities can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (eg, d-alpha-tocopherol polyethylene glycol 1000). succinate), surfactants used in pharmaceutical dosage forms (such as Tween, poloxamer, or other similar polymeric delivery matrices), serum proteins (such as human serum albumin), buffer substances (such as phosphates), tris, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g. protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate), polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene blocks polymer and lanolin. Cyclodextrins (such as α-, β- and γ-cyclodextrins) or chemically modified derivatives (such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins) or other Solubilized derivatives can also be used to enhance the delivery of the compounds described herein. Dosage forms or compositions can be prepared that contain in the range of 0.005% to 100% of the chemical entities as set forth herein, with the remainder consisting of non-toxic excipients. The contemplated compositions may contain 0.001%-100% of the chemical entities provided herein, in one embodiment 0.1-95%, in another 75-85%, in another 20- 80%. The actual preparation of such dosage forms is known or apparent to those skilled in the art; see, for example, 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 an individual in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, dermal, intracervical, intrasinus, intratracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intrabursal, Intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular intra-, intra-ovarian, intra-peritoneal, intra-prostatic, intra-pulmonary, intra-sinus, intra-spinal, intra-synovial, intra-testicular, intra-thecal, intra-tubular, intra-tumor, intra-uterine, intra-vascular, intravenous, nasal, trans Nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, transureteral, transurethral, and trans vaginal. In certain embodiments, the preferred route of administration is parenteral (eg, intratumoral).

Compositions can be formulated for parenteral administration, eg, formulated for injection via intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. Typically, these compositions can be prepared as injectables (either as liquid solutions or suspensions); solid forms suitable for preparation of solutions or suspensions when a liquid is added prior to injection can also be prepared; and emulsifiable preparations can also be prepared. The preparation of such formulations is known to those skilled in the art in light of the present invention.

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

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

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

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 in the form of gels, creams, enemas or rectal suppositories include, but are not limited to, any one or more of the following: cocoa butter glycerin Esters, synthetic polymers (such as polyvinylpyrrolidone), PEG (such as PEG ointment), glycerin, glycerin gelatin, hydrogenated vegetable oils, poloxamers, polyethylene glycols of different molecular weights, and polyethylene glycol petrolatum (Vaseline) ), anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, p-hydroxyl in phenoxyethanol Parabens, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomer, carbopol, methyloxybenzoic acid Esters, Macrogol Cetearyl Ether, Cocoyl Caprylate, Isopropyl Alcohol, Propylene Glycol, Liquid Paraffin, Xanthan Gum, Carboxyl-Metabisulfite, Sodium Edetate, Sodium Benzoate, Potassium Metabisulfite, Grapefruit Seed Extract, Methylsulfonylmethane (MSM), Lactic Acid, Glycine, Vitamins (eg Vitamins A and E) and Potassium Acetate.

In certain embodiments, suppositories can be prepared by admixing the chemical entities described herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or a suppository wax, which excipients Or the carrier is solid at ambient temperature but liquid at body temperature and will therefore melt in the rectum and release the active compound. 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 topical delivery to the digestive or gastrointestinal tract by means of oral administration (eg, solid or liquid dosage forms).

Solid dosage forms for oral administration include capsules, lozenges, pills, powders and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients (eg sodium citrate or dicalcium phosphate) and/or the following: a) fillers or extenders such as starch , lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as Glycerin, d) disintegrants such as 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) wetting agents such as cetearyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, stearin Magnesium acid, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, lozenges and pills, the dosage form may also include buffering agents. Similar types of solid compositions can also be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

In one embodiment, the composition will take the form of a unit dosage form (eg, a pill or lozenge) and thus the composition may contain the chemical entities provided herein together with a diluent (eg, lactose, sucrose, dicalcium phosphate, or the like), Lubricants (eg magnesium stearate or the like) and binders (eg starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like). In another solid dosage form, powders, marumes, solutions or suspensions (eg, in propylene carbonate, vegetable oils, PEG, poloxamer 124, or triglycerides) are encapsulated in capsules (gelatin or fiber) plain capsules). Also contemplated are unit dosage forms in which one or more of the chemical entities or other active agents provided herein are physically separated; eg, granulated capsules (or lozenges in capsules) of each drug; bilayer lozenges; bicompartmental gels cap etc. Enteric coated or delayed release oral dosage forms are also contemplated.

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

In certain embodiments, the excipients are sterile and generally free of undesired materials. These compositions can be sterilized by conventional, well-known sterilization techniques. Sterility is not required for various oral dosage form excipients such as lozenges and capsules. USP/NF standards are usually sufficient.

In certain embodiments, the solid oral dosage form may further comprise one or more chemical entities that chemically and/or structurally facilitate the delivery of the composition to the stomach or lower gastrointestinal tract (eg, ascending colon and/or transverse colon and/or components of the distal colon and/or small intestine). Exemplary formulation techniques are described, for example, in Filipski, KJ et al., Current Topics in Medicinal Chemistry, 2013 , 13, 776-802 , which is incorporated herein by reference in its entirety.

Examples include upper gastrointestinal targeting technologies such as Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

Other examples include lower gastrointestinal targeting technologies. To target various regions in the intestinal tract, several enteric/pH reactive coatings and excipients are available. These materials are typically polymers designed to dissolve or corrode at specific pH ranges selected based on the region of the gastrointestinal tract where drug release is desired. These materials are also used to protect acid labile drugs from gastric juices or to limit exposure in situations where the active ingredient can irritate the upper gastrointestinal tract (eg hydroxypropyl methylcellulose phthalate series, Coateric (polyacetate phthalate) Vinyl diformate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymer) and Marcoat). Other technologies include dosage forms responsive to local flora in the gastrointestinal tract, pressure-controlled colonic delivery capsules, and Pulsincap.

Ophthalmic compositions may include, but are not limited to, any one or more of the following: viscous elements (eg, carboxymethyl cellulose, glycerol, polyvinylpyrrolidone, polyethylene glycol); stabilizers (eg Pluronic (triblock copolymer), cyclodextrin); preservatives (eg Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol and zinc chloride); Alcon Laboratories , Inc.), Purite (stabilized oxychlorine complex; Allergan, Inc.)).

Topical compositions may include ointments and creams. Ointments are semisolid preparations usually based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are usually viscous liquid or semi-solid emulsions, and are usually oil-in-water or water-in-oil. Cream bases are generally washable with water and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase (sometimes also referred to as the "internal" phase) typically includes petrolatum and fatty alcohols (eg, cetyl or stearyl alcohol); the aqueous phase typically, but not necessarily, exceeds the oil phase in volume, and typically contains a humectant. Emulsifiers in cream formulations are usually nonionic, anionic, cationic or amphoteric surfactants. With respect to other carriers or vehicles, the ointment base should be inert, stable, non-irritating and non-sensitive.

In any of the foregoing embodiments, the pharmaceutical compositions described herein can comprise one or more of the following: lipids, inter-bilayer cross-linked multilamellar vesicles, poly(D,L-lactic acid-based) co-glycolic acid) [PLGA] or polyanhydride-based biodegradable nanoparticles or microparticles and lipid bilayers supported by nanoporous particles.

dose

However, the dosage may vary depending upon the needs of the patient, the severity of the condition being treated, and the particular compound employed. Appropriate dosages for a particular situation can be determined by those skilled in the art of medicine. The total daily dose may be divided and administered in portions throughout the day or by providing continuous delivery.

In some embodiments, at about 0.001 mg/Kg to about 500 mg/Kg (eg, about 0.01 mg/Kg to about 100 mg/Kg, about 0.01 mg/Kg to about 10 mg/Kg, about 0.01 mg/Kg to Doses of about 1 mg/Kg, about 0.01 mg/Kg to about 0.1 mg/Kg, about 0.1 mg/Kg to about 100 mg/Kg, about 0.1 mg/Kg to about 10 mg/Kg) are administered as described herein compound.

The regimen may be daily (eg, in a single dose or in two or more divided doses) or non-daily (eg, every other day, every two days, every three days, once a week, twice a week, every The aforementioned doses are administered biweekly, monthly).

In some embodiments, the compounds described herein are administered for a period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In another embodiment, the period of cessation of dosing 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 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months , 8 months, 9 months, 10 months, 11 months, 12 months or more. In one embodiment, the compound is administered to the subject over a period of treatment followed by a period of time. In another embodiment, the therapeutic compound is administered during a first period and followed by a second period, wherein administration is stopped during the second period, followed by a third period of administration of the therapeutic compound, and then After the third period, the system stops investing in the fourth period. In one aspect of this embodiment, administration of the therapeutic compound for a period of time and then withholding administration for a period of time is repeated for a determined or indeterminate period of time. In another embodiment, the administration period 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 another embodiment, the period of cessation of dosing 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 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months , 8 months, 9 months, 10 months, 11 months, 12 months or more.

Methods of Treatment In some embodiments, methods of treating an individual having a condition, disease, or disorder in which increased (eg, excessive) STING activity (eg, STING signaling) contributes to the condition, disease, or disorder (eg, pathology and/or symptoms and/or progression of immune disorders, cancer).

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, lung cancer (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung cancer) squamous cell carcinoma), squamous cell carcinoma (e.g. epithelial squamous cell carcinoma), cervical cancer, ovarian cancer, prostate cancer, prostate neoplasm, liver cancer, bladder cancer, peritoneal cancer, hepatocellular carcinoma, gastric or stomach cancer ) (including gastrointestinal cancer, gastrointestinal stromal tumor), pancreatic cancer, head and neck cancer, glioblastoma, retinoblastoma, astrocytoma, theca cell tumor, androcytoma, hepatoma, blood malignancies (including non-Hodgkins lymphoma (NHL), multiple myeloma, myelodysplastic disorders, myeloproliferative disorders, chronic myeloid leukemia, and acute hematologic malignancies), intrauterine Membrane or uterine cancer, endometriosis, endometrial stromal sarcoma, fibrosarcoma, choriocarcinoma, salivary gland cancer, vulvar cancer, thyroid cancer, esophageal cancer, liver cancer, anal cancer, penile cancer, nasopharyngeal cancer, throat cancer carcinoma, Kaposi's sarcoma, mast cell sarcoma, ovarian sarcoma, uterine sarcoma, melanoma, malignant mesothelioma, skin cancer, schwannoma, oligodendroglioma, neuroblastoma, Neuroectodermal Tumors, Rhabdomyosarcoma, Osteosarcoma, Leiomyosarcoma, Ewing Sarcoma, Peripheral Primitive Neuroectodermal Tumor, Urinary Tract Cancer, Thyroid Cancer, Wilms' Tumor, Abnormal vascular proliferation, edema (eg, associated with brain tumors) and Meigs' syndrome associated with neoplasmosis. In some instances, the cancer is melanoma.

In some embodiments, the condition, disease, or disorder is a neurological disorder, including those involving the central nervous system (brain, brainstem, and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (a portion of which is located in the central and peripheral nerves) system) disease. Non-limiting examples of cancer include acquired epilepsy aphasia; acute and chronic encephalomyelitis; adrenoleukodystrophy; age-related macular degeneration; corpus callosum hypoplasia; agnosia; Aicardi syndrome; Alexander disease ( Alexander disease; Alpers' disease; Cruciate limb paralysis; Alzheimer's disease; Vascular dementia; Amyotrophic lateral sclerosis; Anencephaly; Angelman syndrome ; angiomatosis; hypotrophy; aphasia; apraxia; arachnoid cyst; arachnoiditis; Anronl-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet's disease; Bell's palsy ( Bell's palsy); benign essential blepharospasm; benign focal muscular atrophy; benign intracranial hypertension; Binswanger's disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; Brain abscess; brain injury; brain tumor (including glioblastoma multiforme); spinal cord tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome; causal nerve pain; central pain syndrome; central pontine myelinolysis; head disorders; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie -Tooth disease); chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy; chronic pain; chronic regional pain syndrome; Ko-le II Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial paralysis; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorder; library Cushing's syndrome; cytomegaloid inclusion disease; cytomegalovirus infection; chorea-foot syndrome; Dandy-Walker syndrome; Dawson disease ); De Morsier's syndrome; Dejerine-Klumke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; autonomic dysfunction; dysgraphia; Dyslexia; dystonia; early childhood epileptic encephalopathy; empty sella syndrome; encephalitis; brain herniation; cerebral trigeminal angiomatosis; epilepsy; Erb's palsy; essential tremor; Fabry disease (Fabry's disease); Fahr's syndrome; Fainting; Familial spastic paralysis; Febrile seizures; Fisher syndrome; Friedreich's ataxia; Frontotemporal bone Dementia and other "tau lesions"; Gaucher's disease; Gerstmann's syndrome; giant cell arteritis; giant cell inclusion body disease; spheroid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1-related myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; hereditary disease Polyneuritis-like ataxia; ear shingles; herpes zoster; Hirayama syndrome; HIV-related dementia and neuropathy (and neurological manifestations of AIDS); holoprosencephaly; Huntington's disease disease) and other polyglutamic acid repeat diseases; hydrops anencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; pigment disorders; infantile phytanic acid storage disease; infantile refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sell syndrome Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Weeland Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome drome); Landau-Kleffner syndrome; Lateral medullary (Wallenberg) syndrome; Learning disability; Leigh's disease; Leigh's-Gasto Lennox-Gustaut syndrome; Lesch-Nyhan syndrome; Leukodystrophy; Lewy body dementia; lissencephaly; atresia syndrome; Lou Gehrig's disease ( Lou Gehrig's disease (i.e., motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; Lyme disease - neurological sequelae; Machado-Joseph disease; cerebral hypertrophy; giant brain ; Melkersson-Rosenthal syndrome; Menieres disease; Meningitis; Menkes disease; Metachromatic leukodystrophy; Microcephaly; Migraine ; Miller Fisher syndrome; mini-stroke; mitochondrial myopathy; Mobius syndrome; unilimb muscular atrophy; motor neuron disease; cerebral abnormal vascular network disease; mucopolysaccharide Cumulative disease; multi-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with positional hypotension; muscular dystrophy; myasthenia gravis; demyelinating chronic sclerosis; Infantile myoclonic encephalopathy; myoclonus; myopathy; myotonia; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal wax lipofuscinosis; abnormal migration of brain neurons; Niemann-Pick disease; O'Sullivan-McLeod syndrome; occipital neuralgia; recessive spinal nerve Ductal insufficiency syndrome; Ohtahara syndrome; olivopontocerebellar atrophy; strabismus opsoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson's disease; congenital paramyotonia; paraneoplastic disease; paroxysmal; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralysis; peripheral neuropathy; painful Neuropathy and neuropathic pain; persistent vegetative state; generalized development retardation; optical sneeze reflex; phytanic acid storage disease; Pick's disease; nerve pinching; pituitary tumor; polymyositis; penetrating brain malformation; late polio syndrome; postherpetic neuralgia; infection Posterior encephalomyelitis; orthostatic hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion disease; progressive unilateral atrophy; progressive multifocal leukoencephalopathy; progressive Sclerosing gray matter atrophy; progressive supranuclear palsy; pseudotumor; Ramsay-Hunt syndrome (types I and II); Rasmussen's encephalitis; reflex sympathetic nerves Malnutrition syndrome; Refsum disease; repetitive motion disorder; repetitive compression injury; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Rey's syndrome (Reye's syndrome); Chorea (Saint Vitus dance); Sandhoff disease (Sandhoff disease); Schilder's disease (Schilder's disease); ; Shy-Drager syndrome; Sjögren's syndrome; Sleep apnea; Soto's syndrome; Spasticity; Spina bifida; Spinal cord injury; Spinal cord tumor; Spinal cord Muscular atrophy; Stiff-Person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subcortical arteriosclerotic encephalopathy; Sydenham dance Sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; spinal cord involvement syndrome; Thomsen disease; thoracic outlet syndrome; trigeminal Tic Douloureux; Todd's paralysis; Tourette's Syndrome; Transient Ischemic Attack; Disseminated Spongiform Encephalopathy; Transverse Myelitis; Traumatic Brain Injury; Tremor; Trigeminal Neuralgia ; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis, including temporal arteritis; Von Hippel-Lindau disease; Wallenberg's syndrome syndrome); Wednich-Hoffmann Werdnig-Hoffman disease; West syndrome; cervical spine poke; Williams syndrome; Wildon's disease; amyotrophic lateral sclerosis and Zellweger Syndrome (Zellweger syndrome).

In some embodiments, the condition, disease or disorder is a STING-related condition, eg, type I interferonopathy (eg, STING-associated vasculopathy of infancy (SAVI)), Icardi-Gutierrez Syndrome (AGS) ), inherited forms of lupus, and inflammation-related disorders (eg, systemic lupus erythematosus and rheumatoid arthritis). In certain embodiments, the condition, disease or disorder is an autoimmune disease (eg, a cytoplasmic DNA-triggered autoinflammatory disease). Non-limiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (IBD) (including Crohn's disease (CD) and ulcerative colitis (UC)), It is a chronic inflammatory condition with polygenic susceptibility. 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, by Colitis induced by treatment using receptive cell therapy, colitis associated with one or more alloimmune diseases (eg, graft-versus-host disease, such as acute graft-versus-host disease and chronic graft-versus-host disease), radiation enteritis, Collagen colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In certain of these embodiments, the condition is an alloimmune disease (eg, graft-versus-host disease, eg, acute graft-versus-host disease and chronic graft-versus-host disease), celiac disease, irritable bowel syndrome, a 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 can treat diseases, including diseases caused by foreign pathogens. Exemplary foreign pathogen infections that can be treated and/or prevented by the methods of the present invention include bacterial (eg, gram-positive or gram-negative bacteria) infections, fungal infections, parasitic infections, and Viral infection. In one embodiment of the present invention, the infection is a bacterial infection (eg, E. coli , Klebsiella pneumoniae , Pseudomonas aeruginosa , Salmonella spp ). . ), Staphylococcus aureus , Streptococcus spp. , or vancomycin-resistant Enterococcus infections) or sepsis. In another embodiment, the infection is a fungal infection (eg, mold, yeast, or higher fungal infection). In yet another embodiment, the infection is a parasitic infection (eg, unicellular or multicellular parasites including Giardia duodenalis , Cryptosporidium parvum , Cyclospora cayetanensis , and Toxoplasma worm ( Toxoplasma gondiz ) infection). In yet another embodiment, the infection is a viral infection (eg, associated with AIDS, avian influenza, chickenpox, cold sores, common cold, gastroenteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS and Lower or upper respiratory tract infection (eg, respiratory syncytial virus-associated virus infection).

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 (including, eg, myocardial infarction).

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

In some embodiments, the condition, disease, or disorder is mucositis (also known as stomatitis), which can result from chemotherapy or radiation therapy (alone or in combination) and damage caused by exposure to radiation outside of the radiation therapy context happen.

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

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

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

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

In some embodiments, the methods described herein can further comprise administering one or more other therapies (eg, one or more other therapeutic agents and/or one or more treatment regimens) in combination with administering the compounds described herein.

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

One or more other cancer therapies may include, but are not limited to, surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cold therapy, cancer vaccines (eg, HPV vaccine, Hepatitis B vaccine, Oncophage, Provenge), and gene therapy, and its combination. Immunotherapy includes, but is not limited to, receptive cell therapy, derived stem cells and/or dendritic cells, blood transfusion, lavage, and/or other treatments (including but not limited to tumor freezing).

In some embodiments, the one or more other cancer therapies are chemotherapy, which may include the administration of one or more other chemotherapeutic agents.

In certain embodiments, other chemotherapeutic agents are immunomodulatory moieties, such as immune checkpoint inhibitors. In certain of these embodiments, the immune checkpoint inhibitor targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1 , PD-1 - PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-beta (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-BTLA-CD160, CD80, CD80 - PDL-1, PDL2 - CD80, CD244, CD48 - CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4 , VISTA, TMIGD2, HHLA2-TMIGD2, buttophilin (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). See, for example, Postow, M. J. Clin. Oncol . 2015 , 33 , 1.

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

In certain embodiments, the other chemotherapeutic agents are alkylating agents. Alkylating agents are so named because of their ability to alkylate a number of nucleophilic functional groups under conditions present in cells, including but not limited to, cancer cells. In another embodiment, the alkylating agent includes, but is not limited to, cisplatin, carboplatin, diclofenac, cyclophosphamide, chlorambucil, ifosfamide, and/or oxalidomide Thaliplatin. In one example, the alkylating agent may act by forming covalent bonds with amine groups, carboxyl groups, sulfhydryl groups, and phosphate groups in biologically important molecules to impair cellular function, or it may act by modifying cellular DNA come to make a difference. In another embodiment, the alkylating agent is a synthetic, semi-synthetic or derivative.

In certain embodiments, the other chemotherapeutic agents are antimetabolites. Antimetabolites disguise themselves as purines or pyrimidines (the building blocks of DNA) and generally prevent these substances from being incorporated into DNA during the "S" phase (of the cell cycle), thereby terminating normal development and division. Antimetabolites can also affect RNA synthesis. In one embodiment, the antimetabolites include, but are not limited to, azathioprine and/or mercaptopurine. In another embodiment, the antimetabolite is a synthetic, semi-synthetic or derivative.

In certain embodiments, the other chemotherapeutic agents are plant alkaloids and/or terpenoids. These alkaloids are derived from plants and typically block cell division by preventing microtubule function. In one embodiment, the plant alkaloids and/or terpenoids are vinca alkaloids, podophyllotoxin and/or taxanes. Vinca alkaloids typically bind to specific sites on tubulin, thereby inhibiting the assembly of tubulin into microtubules (usually during the M phase of the cell cycle). In one embodiment, the vinca alkaloid is derived from, but not limited to, Madagascar periwinkle, Catharanthus roseus (previously known as Vinca rosea). In one embodiment, the vinca alkaloids include, but are not limited to, vincristine, vinblastine, vinorelbine, and/or vindesine. In one embodiment, the taxane includes, but is not limited to, paclitaxel, Paclitaxel, and/or docetaxel. In another embodiment, the plant alkaloid or terpenoid is a synthetic, semi-synthetic or derivative. In another embodiment, the podophyllotoxin is, but is not limited to, etoposide and/or teniposide. In one embodiment, the taxane is, but is not limited to, docetaxel and/or ortataxel. In one embodiment, the cancer therapeutic agent is a topoisomerase. Topoisomerases are essential enzymes for maintaining the topological structure of DNA. Inhibition of type I or type II topoisomerases can interfere with the transcription and replication of DNA by disturbing the proper DNA supercoiling. In another embodiment, the topoisomerase is, but is not limited to, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In one embodiment, the type I topoisomerase inhibitor is, but is not limited to, camptothecin. In another embodiment, the camptothecin is (but 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 another embodiment, the epipodophyllotoxin is, but is not limited to, amsacridine, etoposide, etoposide phosphate, and/or teniposide. In another embodiment, the topoisomerase-based synthetic, semi-synthetic, or derivative includes those found in nature, such as, but not limited to, epipodophyllotoxin (occurring naturally in American Mayapple ) (substance in the root of Podophyllum peltatum).

In certain embodiments, the other chemotherapeutic agent is a stilbene. In another embodiment, the stilbene includes, but is not limited to, Resveratrol, Piceatannol, Pinosylvin, Pterostilbene, Viniferin ), Ampelopsin A, Ampelopsin E, Diptoindonesin C, Diptoindonesin F, ε-Veptin, Flexuosol A, Gnetin H, Hemsleyanol D, Hopeaphenol, trans-Diplonsin B, Astringin, Piceid and Diplonsin A . In another embodiment, the stilbene-based synthetic, semi-synthetic or derivative.

In certain embodiments, the other chemotherapeutic agents are cytotoxic antibiotics. In one embodiment, the cytotoxic antibiotic is, but is not limited to, actinomycin, anthracenedione, anthracycline, thalidomide, dichloroacetic acid, nicotinic acid, 2-deoxyglucose, and/or Chlofazimine. In one embodiment, the actinomycin is, but 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 another embodiment, the anthracyclines are (but are not limited to) bleomycin, doxorubicin (Adriamycin), daunorubicin (daunomycin), rubicin, idarubicin, mitomycin, prukamycin and/or valrubicin. In another embodiment, the cytotoxic antibiotic is a synthetic, semi-synthetic or derivative.

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

In certain embodiments, the other chemotherapeutic agent is selected from the group consisting of abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene , Bicalutamide, BMS 184476, 2,3,4,5,6-Pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, Bleomycin, N,N -Dimethyl-L-Valamido-L-Valamido-N-methyl-L-Valamido-L-prolino-1-Lproline-tert-butylglycol Amine, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′-deoxy-8′-norvinblastine , docetaxol, docetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, arabinoside Cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin ), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyurea taxane, ifosfamide, liarozole, lonidamine (lonidamine), lomustine (CCNU), MDV3100, diclofenac (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxane, nilutamide, ornax onapristone, paclitaxel, prednimustine, procarbazine, RPR109881, stramustine phosphate, tamoxifen, tasonermin , Paclitaxel, tretinoin, vinblastine, vincristine, vindesine sulfate and vinflunine.

In certain embodiments, the other chemotherapeutic agents are platinum, cisplatin, carboplatin, oxaliplatin, diclofenac, cyclophosphamide, chlorambucil, azathioprine, mercaptopurine, Vincristine, Vinblastine, Vinorelbine, Vindesine, Etoposide and Teniposide, Paclitaxel, Docetaxel, Irinotecan, Topotecan, Amacridine, Etoposide, Phosphate Etoposide, teniposide, 5-fluorouracil, leucovorin, methotrexate, gemcitabine, taxane, leucovorin, mitomycin C, tega Fluoro-uracil (Tegafur-uracil), idarubicin, fludarabine (fludarabine), mitoxantrone, ifosfamide and doxorubicin. Other agents include mTOR (mammalian target of rapamycin) inhibitors including, but not limited to, rapamycin, everolimus, temsirolimus, and desevere Deforolimus.

In still other embodiments, the other chemotherapeutic agents may be selected from those described in US Pat. No. 7,927,613, which is incorporated herein by reference in its entirety.

In some embodiments, other therapeutic agents and/or regimens may be used to treat persons with other STING-related conditions such as, for example, Type I interferonopathy (eg, infant-onset STING-related vasculopathy (SAVI). )), Icardi-Gutierrez Syndrome (AGS), inherited forms of lupus and inflammation-related disorders such as systemic lupus erythematosus and rheumatoid arthritis, and the like.

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

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of lupus include steroids, topical immunomodulators such as tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel) ®)), thalidomide (Thalomid®), nonsteroidal anti-inflammatory drugs (NSAIDs; such as ibuprofen and naproxen), antimalarial drugs (such as hydroxychloroquine (Plaquenil)), corticosteroids (such as prisone) ) and immunomodulators (eg, ibrutinib, iberdomide, voclosporin, cenerimod, azathioprine (Imuran®), cyclophosphamide (Cytoxan) ®, Neosar®, Endoxan®) and cyclosporine (Neoral, Sandimmune®, Gengraf®) and mycophenolate mofetil), baricitinb, iguratimod, filgo filogotinib, GS-9876, rapamycin, and PF-06650833) and biological agents such as belimumab (Benlysta®), anifrolumab, prezalumab ), MEDI0700, obinutuzumab, vebalizumab, lulizumab, atacicept, PF-06823859 and lupizor, rituximab Xiximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirolizumab, edratide, IFN-α-kinoid, OMS721, RC18, RSLV-132, theralizumab, XmAb5871 and ustekinumab (Stelara®). For example, non-limiting therapeutic agents for systemic lupus erythematosus include non-steroidal anti-inflammatory drugs (NSAIDs; such as ibuprofen and naproxen), antimalarial drugs (such as hydroxychloroquine (Plaquenil)), corticosteroids ( e.g. Prisone) and immunomodulators (e.g. Iberdamine, cyclosporine, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®) and cyclosporine (Neoral, Sandimmune®, Gengraf®) and mycophenolate mofetil, baricitinib, filgotinib and PF-06650833) and biological agents such as belimumab (Benlysta®), anilumab, Preilumab, MEDI0700, Vebalizumab, Lulizumab, Acecept, PF-06823859, Rupizol, Rituximab, BT063, BI655064, BIIB059, Aldesmid (Proleukin®), dapilizumab, edreotide, IFN-α-kinoid, RC18, RSLV-132, tiralizumab, XmAb5871 and ustekinumab (Stelara®)). As another example, non-limiting examples of therapeutic agents for cutaneous lupus include steroids, immunomodulators such as tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel®), GS-9876 , filgotinib, and thalidomide (Thalomid®). Agents and regimens for the treatment of drug-induced and/or neonatal lupus may also be administered.

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of STING-associated vasculopathy (SAVI) in infancy include JAK inhibitors (eg, tofacitinib, ruxolitinib, filgotinib) filgotinib and baricitinib).

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of Icardi-Gutierrez Syndrome (AGS) include physical therapy, treatment for respiratory complications, anticonvulsant therapy for seizures, tube feeding , Nucleoside reverse transcriptase inhibitors (e.g. emtricitabine (e.g. Emtriva®), tenofovir (e.g. Viread®), emtricitabine/tenofovir (e.g. Truvada®) , zidovudine, lamivudine and abacavir) and JAK inhibitors such as tofacitinib, ruxolitinib, filgotinib and barrex tinib).

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of IBD include 6-mercaptopurine, AbGn-168H, ABX464, ABT-494, adalimumab, AJM300, alicaforsen, AMG139, anrukinzumab, apremilast, ATR-107 (PF0530900), autologous CD34-selective peripheral blood stem cell transplantation, azathioprine, bertilimumab, BI 655066, BMS -936557, pegylated certolizumab (Cimzia®), cobitolimod, corticosteroids (e.g., Preisone, Methylprednisolone, Preisone), CP- 690,550, CT-P13, cyclosporine, DIMS0150, E6007, E6011, etrasimod, etrolizumab, fecal microbial transplantation, filgotinib, fingolimod , firategrast (SB-683699) (previously T-0047), GED0301, GLPG0634, GLPG0974, guselkumab, golimumab, GSK1399686, HMPL-004 (andrographis Andrographis paniculata ) extract), IMU-838, infliximab, interleukin 2 (IL-2), Janus kinase (JAK) inhibitor, laquinimod, masaiti Masitinib (AB1010), Matrix Metalloproteinase 9 (MMP 9) Inhibitors (e.g. GS-5745), MEDI2070, Mesalamine, Methotrexate, Mirikizumab (LY3074828), Natalizumab, NNC 0142-0000-0002, NNC0114-0006, ozanimod, peficitinib (JNJ-54781532), PF-00547659, PF-04236921, PF-06687234, QAX576, RHB-104, rifaximin, risankizumab, RPC1063, SB012, SHP647, sulfasalazine, TD-1473, thalidomide, tildrakizumab ) (MK 3222), TJ301, TN F-Kinoid®, tofacitinib, tralokinumab, TRK-170, upadacitinib, ustekinumab, UTTR1147A, V565, vatelizumab, VB-201, vedolizumab and vidofludimus.

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

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

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of Crohn's disease (CD) include adalimumab, autologous CD34-selective peripheral blood stem cell transplantation, 6-mercaptopurine, azathioprine, poly- Glycolated certolizumab (Cimzia®), corticosteroids (eg, prisone), irolizumab, E6011, fecal microbial transplantation, filgotinib, guselkumab, infliximab , IL-2, JAK inhibitors, Matrix Metalloproteinase 9 (MMP 9) inhibitors (eg GS-5745), MEDI2070, Mesalamine, Methotrexate, Natalizumab, Ozamod, RHB- 104. Rifaximin, resalizumab, SHP647, sulfasalazine, thalidomide, upatinib, V565, and vedolizumab.

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of UC include AbGn-168H, ABT-494, ABX464, Apremilast, PF-00547659, PF-06687234, 6-mercaptopurine, adalimumab , azathioprine, burtilimumab, brazikumab (MEDI2070), cobitolimod, pegylated certolizumab (Cimzia®), CP-690,550, corticosteroids (e.g. Functional budesonide (multimax budesonide, methylpresunone), cyclosporine, E6007, etriximod, erolizumab, fecal microbial transplantation, filgotinib, guselkumab, Golimumab, IL-2, IMU-838, Infliximab, Matrix Metalloproteinase 9 (MMP9) Inhibitors (eg GS-5745), Mesalamine, Mesalamine, Migilizumab (LY3074828 ), RPC1063, resalizumab (BI 6555066), SHP647, sulfasalazine, TD-1473, TJ301, tarelizumab (MK 3222), tofacitinib, tofacitinib, ustekin Monoclonal antibody, UTTR1147A and vedolizumab.

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of autoimmune colitis include corticosteroids (eg, budesonide, prednisone, prednisolone, becloxal dipropionate) Beclometasone dipropionate), diphenoxylate/atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, eg, US Patent Application Publication No. 2012/0202848 number) and vedolizumab.

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of iatrogenic autoimmune colitis include corticosteroids (eg, budesonide, prisone, prisulone, beclomethasone dipropionate), Diphenoxylate/atropine, infliximab, loperamide, TIP60 inhibitors (see, eg, US Patent Application Publication No. 2012/0202848), and vedolizumab.

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of colitis induced by one or more chemotherapeutic agents include corticosteroids (eg, budesonide, prisone, prisulone, becloxalin metasone), diphenoxylate/atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, eg, US Patent Application Publication No. 2012/0202848), and vedolizumab.

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of colitis induced by treatment using receptive cell therapy include corticosteroids (eg, budesonide, prisone, prisulon, dipropionic acid) beclomethasone), diphenoxylate/atropine, infliximab, loperamide, TIP60 inhibitors (see, eg, US Patent Application Publication No. 2012/0202848), and vedolizumab.

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of colitis associated with one or more alloimmune diseases include corticosteroids (eg, budesonide, prisone, prisulon, becloxaloate). metasone), sulfasalazine, and eicopentaenoic acid.

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

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of collagenous colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (eg, budesonide, prisone, prisunin, beclomethasone dipropionate), loperamide, mesalamine, methotrexate, probiotics and Sulfasalazine.

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of lymphocytic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, cholestyramine, colestipol, corticosteroids (eg, budesonide). Ned, Prysone, Prysulon, Beclomethasone Dipropionate), Loperamide, Mesalamine, Methotrexate, and Sulfasalazine.

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of microscopic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, Boswellia serrata extract, cholestyramine, colestipol , corticosteroids (eg, budesonide, prisone, prisulon, beclomethasone dipropionate), fecal microbial transplantation, loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine Pyridine.

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of alloimmune diseases include intrauterine platelet transfusions, intravenous immune globulin, maternal steroids, abatacept, alemtuzumab, alpha 1-antitrypsin, AMG592, antithymocyte globulin, barcitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g. methylprednisone (methylprednisone), cyclosporine, daclizumab, defibrotide, denileukin diftitox, glasdegib, ibrutinib ( ibrutinib), IL-2, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neihulizumab ), pentostatin, pevonedistat, photobiomodulation, light therapy, ruxolitinib, sirolimus, sonidegib, tacrolimus, Zizumab and vismodegib.

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

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of graft-versus-host disease include abatacept, alemtuzumab, alpha 1-antitrypsin, AMG592, antithymocyte globulin, baricitinib , basiliximab, bortezomib, berentozumab, cannabidiol, corticosteroids (e.g., methylpreisone, prisone), cyclosporine, daclizumab, defibrotide, Denileukin, Gladji, Ibrutinib, IL-2, Imatinib, Infliximab, Itatinib, LBH589, Maraviroc, Mycophenolate Mofetil, Natalizumab Antibiotics, Nehulimumab, Pentostatin, Pevendisda, Photobiomodulation, Light Therapy, Ruxolitinib, Sirolimus, Sonnydag, Tacrolimus, Tocilizumab and Vimodji.

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of acute graft-versus-host disease include alemtuzumab, alpha-1 antitrypsin, antithymocyte globulin, basiliximab, berento Monoclonal antibodies, corticosteroids (eg, methylpreisone, prisone), cyclosporine, daclizumab, defibrotide, denileukin, ibrutinib, infliximab, itatinib Nitrates, LBH589, mycophenolate mofetil, natalizumab, neulizumab, pentostatin, light therapy, ruxolitinib, sirolimus, tacrolimus, and tocilizumab.

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of chronic graft-versus-host disease include abatataxel, alemtuzumab, AMG592, antithymocyte globulin, basiliximab, bortezomib , corticosteroids (e.g. methylpreisone, prisone), cyclosporine, daclizumab, denialukin, Gladgi, ibrutinib, IL-2, imatinib, infliximab Monoclonal antibodies, mycophenolate mofetil, pentostatin, photobiomodulation, phototherapy, ruxolitinib, sirolimus, sonidegi, tacrolimus, tocilizumab, and vemoda lucky.

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

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of psoriasis include topical corticosteroids, topical crisaborole/AN2728, topical SNA-120, topical SAN021, topical tapinarof, Topical tocafinib, topical IDP-118, topical M518101, topical calcipotriene and betamethasone dipropriate (eg MC2-01 cream and Taclonex®), topical P -3073, topical LEO 90100 (Enstilar®), topical betamethasone dipropionate (Sernivo®), halobetasol propionate (Ultravate®), vitamin D analogs such as calcipotriene (Dovonex ®) and calcitriol (Vectical®), anthralin (e.g. Dritho-scalp® and Dritho-crème®), topical retinoids (e.g. tazarotene) (e.g. Tazorac® and Avage®), calcineurin inhibitors (e.g. Tacrolimus (Prograf®) and pimecrolimus (Elidel®)), salicylic acid, coal tar, wetting agents, phototherapy (e.g. exposure in sunlight, UVB phototherapy, narrow-band UVB phototherapy, Goeckerman therapy, psoralen + UVA (PUVA) therapy and excimer laser), retinoids (such as Avi Acitretin (Soriatane®)), Methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), Apo805K1, Baricitinib, FP187, KD025, prurisol, VTP -43742, XP23829, ZPL-389, CF101 (piclidenoson), LAS41008, VPD-737 (serlopitant), upatinib (ABT-494), apremilast ( aprmilast), tofacitibin, cyclosporine (Neoral®, Sandimmune®, Gengraf®), biologics (e.g., etanercept (Enbrel®), etanercept-szzs (Elrezi®), infliximab liximab (Remicade®), adalimumab (Humira®), adalimumab-adbm (Cyltezo®), ustec Monoclonal antibody (Stelara®), Golimumab (Simponi®), Apremilast (Otezla®), secukinumab (Cosentyx®), pegylated certolizumab, secukinumab, Tirelizumab-asmn, infliximab-dyyb, abatacept, ixekizumab (Taltz®), ABP 710, BCD-057, BI695501, bimekizumab ) (UCB4940), CHS-1420, GP2017, Gusekumab (CNTO 1959), HD203, M923, MSB11022, Migilizumab (LY3074828), PF-06410293, PF-06438179, Resalizumab (BI655066 ), SB2, SB4, SB5, siliq (brodalumab), namilumab (MT203), tirelizumab (MK-3222) and ixekizumab (Taltz) ®)), thioguanine and hydroxyurea (eg Droxia® and Hydrea®).

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of cutaneous T-cell lymphoma include phototherapy (eg, exposure to sunlight, UVB phototherapy, narrow band UVB phototherapy, Geckman therapy, psoralen + ultraviolet Phototherapy (PUVA) and excimer laser), external light therapy, radiation therapy (e.g. spot radiation and whole body skin electron beam therapy), stem cell transplantation, corticosteroids, imiquimod, bexarotene gel , topical bis-chloroethyl-nitrourea, diclofenac gel, vorinostat (Zolinza®), romidepsin (Istodax®), pralatrexate ( pralatrexate) (Folotyn®), biologics (eg, alemtuzumab (Campath®), brentuximab vedotin (SGN-35), mogamulizumab, and IPH4102) .

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of uveitis include corticosteroids (eg, intravitreal triamcinolone acetonide injectable suspension), antibiotics, antiviral agents (eg, acyclovir (acyclovir), dexamethasone (dexamethasone), immunomodulators (such as tacrolimus, leflunomide, cyclophosphamide (Cytoxan®, Neosar®, Endoxan®) and cyclosporine ( Neoral®, Sandimmune®, Gengraf®), chlorambucil, azathioprine, methotrexate, and mycophenolate mofetil), biological agents such as infliximab (Remicade®), adalimumab anti (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®), abatataxel, sallimumab (Kevzara®) and clotuzumab (Zenapax®), cytotoxic drugs, surgical implants (eg, fluocinolone inserts), and vitrectomy.

Non-limiting examples of other therapeutic agents and/or regimens for the treatment of mucositis include AG013, SGX942 (dusquetide), amifostine (Ethyol®), cold therapy, cepacol lozenges tablets, capsaicin lozenges, mucoadhesives (e.g. MuGard®), oral diphenhydramine (e.g. Benadry® elixir), oral adhesives (e.g. polyvinylpyrrolidone-clear Sodium phosphate gel (Gelclair®), oral lubricants (e.g. Oral Balance®), caphosol, chamomilla recutita mouthwash, edible grape plant exosomes, antibacterial mouthwash agents (such as chlorhexidine gluconate (such as Peridex® or Periogard®), topical pain relievers (such as lidocaine, benzocaine, dyclonine hydrochloride ( dyclonine hydrochloride), xylocaine (e.g. 2% viscous xylocaine) and Ulcerease® (0.6% phenol), corticosteroids (e.g. prisone), analgesics (e.g. ibuprofen, naphthalene) Proxen, acetaminophen and opioids), GC4419, palifermin (keratinocyte growth factor; Kepivance®), ATL-104, clonidine lauriad, IZN-6N4 , SGX942, rebamipide, nepidermin, soluble beta-1,3/1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN - 6N4, quercetin, granules including vaccinium myrtillus extract, macleaya cordata alkaloids and echinacea angustifolia extract (eg SAMITAL® ) and gastrointestinal admixtures (acid reducing agents such as aluminum hydroxide and magnesium hydroxide such as Maalox, antifungals such as nystatin, and analgesics such as hurricane solution). For example, Non-limiting example treatments for oral mucositis include AG013, amifostine (Ethyol®), cold therapy, Spirax lozenges, mucoadhesives (e.g. MuGard®), oral diphenhydramine (e.g. Benadry) ® Elixirs) , Oral Adhesives (e.g. Polyvinylpyrrolidone-Sodium Hyaluronate Gel (Gelclair®)), Oral Lubricants (e.g. Oral Balance®), Compass, German Chamomile Mouthwash, Edible Grape Plant Cells Exosomes, antibacterial mouthwashes (eg, chlorhexidine gluconate (eg, Peridex® or Periogard®), topical pain relievers (eg, lidocaine, benzocaine, dyclonine hydrochloride, xylocaine) Caffeine (e.g. viscous xylocaine 2% and Ulcerease® (0.6% phenol)), corticosteroids (e.g. prisone), pain relievers (e.g. ibuprofen, naproxen, acetaminophen and opioids), GC4419 , Palivamine (keratinocyte growth factor; Kepivance®), ATL-104, Konidin-Lauriad, IZN-6N4, SGX942, rebamipide, nepidamine, soluble beta-1,3/ 1,6 dextran, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin and gastrointestinal mixtures (acid reducing agents (such as aluminum hydroxide and magnesium hydroxide, such as Maalox), antifungal agents such as nystatin, and pain relievers such as hurricane solution). As another example, a non-limiting example of a therapeutic agent for esophageal mucositis includes xylocaine (eg, 2% gel viscous xylocaine). As another example, therapeutics for intestinal mucositis, therapeutics for improving intestinal mucositis, and therapeutics for signs and symptoms of intestinal mucositis include gastrointestinal admixtures (acid reducing agents such as aluminum hydroxide and Magnesium hydroxide such as Maalox), antifungal agents such as nystatin, and pain relievers such as hurricane solution).

In certain embodiments, before contacting or administering the chemical entity (eg, about one hour before, or about 6 hours before, or about 12 hours before, or about 24 hours before, or about 48 hours before, or about 1 week before, or about 1 months) to administer a second therapeutic agent or regimen to the individual.

In other embodiments, the second therapeutic agent or regimen is administered to the individual at about the same time as the contacting or administration of the chemical entity. For example, the second therapeutic agent or regimen and the chemical entity are provided to the individual simultaneously in the same dosage form. As another example, the second therapeutic agent or regimen and the chemical entity are provided simultaneously to the individual in separate dosage forms.

In still other embodiments, after contacting or administering the chemical entity (eg, about one hour later or about 6 hours later or about 12 hours later or about 24 hours later or about 48 hours later or about 1 week later or about 1 week later months) a second therapeutic agent or regimen is administered to the individual.

Patient Selection In some embodiments, the methods described herein further comprise the step of identifying an individual (eg, a patient) in need of treatment (eg, by biopsy, endoscopy, or other conventional methods known in the art). In certain embodiments, STING proteins can be used as biomarkers for certain types of cancer, such as colon and prostate cancer. In other embodiments, identifying an individual may comprise analyzing a patient's tumor microenvironment for the absence of T cells and/or the presence of exhausted T cells, eg, a patient with one or more cold tumors. Such patients may include those resistant to treatment with checkpoint inhibitors. In certain embodiments, such patients can be treated with the chemical entities herein to, for example, recruit T cells to the tumor, and in some cases, further treat with one or more checkpoint inhibitors (eg, in T cells) cells become exhausted).

In some embodiments, the chemical entities, methods, and compositions described herein can be administered to certain populations of therapy-resistant patients (eg, patients resistant to checkpoint inhibitors; eg, having one or more cold tumors (eg, deficient in T cells or T-cell-depleted tumors).

Compound Preparation As will be appreciated by those skilled in the art, methods for synthesizing the various compounds herein are well known to those skilled in the art. Synthetic chemical transformations and protecting group methods (protection and deprotection) that can be used to synthesize the compounds described herein are known in the art and include, for example, those described in: R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2nd edition, 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. The starting materials used to prepare the compounds of the present invention are known materials, prepared by known methods, or commercially available. Those skilled in the art will also recognize that the conditions and reagents described herein are interchangeable with substitute equivalents recognized in the art. For example, in many reactions, triethylamine can react with other bases (eg, non-nucleophilic bases such as diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6- di-tert-butylpyridine or tetrabutylphosphazene) interchange.

Those skilled in the art will recognize various analytical methods that can be used to characterize the compounds described herein, including, for example, ^1H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy. The foregoing list is a subset of the 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 reaction schemes are included. Variations of these examples within the scope of the claims are within the purview of those skilled in the art, and are deemed to be within the scope of the invention as set forth and claimed herein. The reader should appreciate that those skilled in the art provided with the present disclosure will be able to make and use the present invention without the need for exhaustive examples.

The following abbreviations have the meaning indicated: Ac = Acetyl ACN = Acetonitrile Boc ₂ O = Di-tert-butylpyrocarbonate Bu = Butyl DCM = Dichloromethane DIEA = N,N -Diisopropylethylamine DMF = N,N -Dimethylformamide DMSO = Dimethylidene DPPA = Diphenyl azidophosphate Dppf = Bis(diphenylphosphino)ferrocene HATU = 2-(7 hexafluorophosphate -Azabenzotriazol-1-yl) -N , N , N' , N' -tetramethyluronium HPLC=High Performance Liquid Chromatography LC-MS=Liquid Chromatography-Mass Spectrometry Me=Methyl NMR = NMR RT = retention time TEA = triethylamine THF = tetrahydrofuran TMS = tetramethylsilane T ₃ P = 2,4,6-tripropyl-2,4,6-trioxy-1,3, 5,2,4,6-Trioxatriphosphine 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-pyridyl- κN]phenyl-κC]-, (OC-6-33)-, hexafluorophosphate (1-) (1:1) NBS = N -bromosuccinimide NCS = N-chlorosuccinimide NMM = N-methylmorpholine PyBOP = Benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate Selectfluor = 1-chloromethyl-4-fluoro-1,4-diazonium bicyclo[2.2 .2] Octane bis(tetrafluoroborate) TFA = trifluoroacetic acid Ts = p-toluenesulfonyl t -AmOH = tertiary amyl alcohol TES = triethylsilane AcOH = acetic acid SOCl ₂ = arsenic chloride CHCl ₃ = chloroform MTBE = 2-methoxy-2-methylpropane MgSO ₄ = anhydrous magnesium sulfate EtOH = ethanol NaOH = sodium hydroxide HCl = hydrochloric acid EDCI = 1-(3-dimethylaminopropyl)-3 -Ethyl Py = pyridine RuPhos Pd G3 = methanesulfonate (2-dicyclohexylphosphino-2,6-di-isopropoxy-1,1-biphenyl)(2-amino-1,1 - Biphenyl-2-yl)palladium(II) XPhos Pd G3 =methanesulfonate (2-dicyclohexylphosphino-2,4,6-tri-isopropyl-1,1-biphenyl) (2 -amino-1,1-biphenyl-2-yl)palladium(II) _{K3PO4 =} potassium phosphate EtOAc=ethyl acetate _Na2SO4 =sodium _sulfate FA=formic acid Me OH = Methanol SpeedVac = Savant SC250EXP SpeedVac Concentrator

Example Materials and Methods LC-MS was recorded using one of the following methods. LCMS Method A : Kinetex EVO C18 100A, 30*3mm, 0.5 µL injection, 1.2 mL/min flow rate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase _A (MPA): Water/5mM _NH4HCO3 and Mobile Phase B (MPB): Acetonitrile. Elution: 10% - 95% MPB in 2.00 min, hold at 95% MPB for 0.30 min, 95% - 10% MPB in 0.10 min. LCMS Method B : Xselect CSH C18, 50*3mm, 1.0 µL injection, 1.2 mL/min flow rate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A (MPA): water/0.1% FA and mobile phase B (MPB): acetonitrile/0.1% FA. Elution: 5% - 100% MPB in 2.00 min, hold at 100% MPB for 0.70 min, 100% - 5% MPB in 0.05 min, then equilibrate to 5% MPB and hold for 0.15 min. LCMS Method C : XBridge Shield RP18, 50*4.6mm, 0.5 µL injection, 1.2 mL/min flow rate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.04% NH3.H2O and Mobile Phase B (MPB): Acetonitrile. Elution: 10% - 95% MPB in 2.00 min, hold at 95% MPB for 0.79 min, 95% - 10% MPB in 0.06 min, then equilibrate to 10% MPB and hold for 0.15 min. LCMS Method D : Shim-pack XR-ODS, 50*3mm, 0.3 µL injection, 1.2 mL/min flow rate, 30-2000 amu scan range, 254 nm UV detection. Mobile phase A (MPA): water/0.05 TFA and mobile phase B (MPB): acetonitrile/0.05% TFA. Elution: 5% - 100% MPB in 1.10 min, hold at 100% MPB for 0.60 min, 100% - 5% MPB in 0.05 min, then equilibrate to 5% MPB and hold for 0.25 min. LCMS Method E : XBridge BEH C18, 50*3mm, 4.0 µL injection, 1.2 mL/min flow rate, 30-2000 amu scan range, 254 nm UV detection. Mobile phase A (MPA): water/ ₅ mM _NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 5% - 95% MPB in 2.00 min, hold at 95% MPB for 0.70 min, 95% - 5% MPB in 0.05 min, then equilibrate to 5% MPB and hold for 0.25 min. LCMS Method F : Kinetex 2.6µm EVO C18 100A, 50*3mm, 0.6 µL injection, 1.2 mL/min flow rate, 30-2000 amu scan range, 254 nm UV detection. Mobile phase A (MPA): water/ ₅ mM _NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 10% - 95% MPB in 1.20 min, hold at 95% MPB for 0.50 min, 95% - 10% MPB in 0.05 min, then equilibrate to 10% MPB and hold for 0.10 min. LCMS Method G : kinetex 2.6µm EVO, 50*3mm, 0.5 µL injection, 1.2 mL/min flow rate, 30-2000 amu scan range, 254 nm UV detection. Mobile phase A (MPA): water/ ₅ mM _NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 10% - 95% MPB in 2.00 min, hold at 95% MPB for 0.70 min, 95% - 10% MPB in 0.05 min, then equilibrate to 10% MPB and hold for 0.25 min. LCMS Method H : Titank C18, 50*3mm, 0.5 µL injection, 1.5 mL/min flow rate, 30-2000 amu scan range, 254 nm UV detection. Mobile phase A (MPA): water/ ₅ mM _NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 10% - 95% MPB in 1.80 min, hold at 95% MPB for 0.80 min, 95% - 10% MPB in 0.15 min, then equilibrate to 10% MPB and hold for 0.25 min. LCMS Method I : XBridge BEH C18, 50*3mm, 4.0 µL injection, 1.2 mL/min flow rate, 30-2000 amu scan range, 254 nm UV detection. Mobile phase A (MPA): water/ ₅ mM _NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 5% - 95% MPB in 2.00 min, hold at 95% MPB for 0.70 min, 95% - 5% MPB in 0.05 min, then equilibrate to 5% MPB and hold for 0.25 min. LCMS Method J : HALOC18, 30*3mm, 0.5 µL injection, 1.5 mL/min flow rate, 30-2000 amu scan range, 254 nm UV detection. Mobile phase A (MPA): water/0.05% TFA and mobile phase B (MPB): acetonitrile/0.05% TFA. Elution: 5% - 100% MPB in 1.20 min, hold at 100% MPB for 0.60 min, 100% - 5% MPB in 0.02 min, then equilibrate to 5% MPB and hold for 0.18 min. LCMS Method K : Ascentis Express C18, 50*3mm, 0.5 µL injection, 1.5 mL/min flow rate, 30-2000 amu scan range, 254 nm UV detection. Mobile phase A (MPA): water/0.05% TFA and mobile phase B (MPB): acetonitrile/0.05% TFA. Elution: 5% - 100% MPB in 2.00 min, hold at 100% MPB for 0.70 min, 100% - 5% MPB in 0.05 min, then equilibrate to 5% MPB and hold for 0.25 min.

NMR were recorded on 300.03 Mz BRUKER NMR (DUL-CH, ULTRASHIELD ^™ 300, AVANCE II, 300 B-ACS ^™ 120) or BRUKER NMR 400.13 Mz (BBFO, ULTRASHIELD ^™ 400, AVANCE III 400, B-ACS ^™ 120).

PREPARATION EXAMPLES Schemes for the preparation of key intermediates : The following schemes illustrate the preparation of key intermediates.

步驟 1 ： 2-(4,4- 二氟六氫吡啶 -1- 基 )-3- 甲基 -5- 硝基吡啶將2-氯-3-甲基-5-硝基吡啶(5.0 g, 28.9 mmol, 1.0當量)溶於ACN (100 mL)中，然後添加4,4-二氟六氫吡啶(4.2 g, 34.7 mmol, 1.2當量)及Cs ₂CO ₃(18.8 g, 57.9 mmol, 2.0當量)。將所得混合物加熱至80℃並保持16小時，且然後冷卻至室溫。在過濾並使用MeOH洗滌固體之後，在真空下濃縮濾液以得到褐色固體形式之2-(4,4-二氟六氫吡啶-1-基)-3-甲基-5-硝基吡啶(6 g)。LCMS方法B：[M+H] ⁺= 258。 步驟 2 ： 6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 甲基吡啶 -3- 胺將2-(4,4-二氟六氫吡啶-1-基)-3-甲基-5-硝基吡啶(6.0 g, 23.3 mmol, 1.0當量)溶於MeOH (50 mL)中，然後添加Pd/C (1.0 g, 10% wt.)。使用氮吹掃混合物，置於氫氣氣氛(氣囊)下，然後在環境溫度下攪拌過夜。藉由過濾去除固體且在真空下濃縮濾液以得到褐色油狀物形式之6-(4,4-二氟六氫吡啶-1-基)-5-甲基吡啶-3-胺(4.8 g)。LCMS方法B：[M+H] ⁺= 228。 步驟 3-4 ： 1-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 甲基吡啶 -3- 基 ] 咪唑 -4- 甲酸乙酯將6-(4,4-二氟六氫吡啶-1-基)-5-甲基吡啶-3-胺(2.0 g, 8.8 mmol, 1.0當量)溶於EtOH (20 mL)及AcOH (1 mL)中，然後添加2-硝基乙酸乙酯(1.1 g, 8.8 mmol, 1.0當量)。將反應混合物加熱至80℃並保持30 min，然後冷卻至環境溫度。然後添加三乙氧基甲烷(6.5 g, 44.0 mmol, 5.0當量)且將所得溶液在80℃下加熱2小時。在冷卻至環境溫度之後，添加AcOH (10 mL)及三乙氧基甲烷(10 mL)，隨後逐份添加Fe (0.3 g, 5.4 mmol, 1.0當量)。將反應混合物加熱至80℃並保持3小時，然後冷卻至環境溫度並在真空下濃縮。使用水稀釋殘餘物，使用乙酸乙酯萃取，藉由無水硫酸鈉乾燥並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:3)洗脫)來純化殘餘物以得到灰白色固體形式之1-[6-(4,4-二氟六氫吡啶-1-基)-5-甲基吡啶-3-基]咪唑-4-甲酸乙酯(600 mg)。方法A：[M+H] ⁺= 351。 步驟 5 ： 1-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 甲基吡啶 -3- 基 ] 咪唑 -4- 甲酸將1-[6-(4,4-二氟六氫吡啶-1-基)-5-甲基吡啶-3-基]咪唑-4-甲酸乙酯(500.0 mg, 1.4 mmol, 1.0當量)溶於MeOH/H ₂O (5:1, 12 mL)中，然後添加NaOH (85.6 mg, 2.1 mmol, 1.5當量)。將所得溶液加熱至50℃並保持2小時，然後冷卻至環境溫度並在真空下濃縮。使用水稀釋殘餘物，然後使用HCl水溶液(6 M)將溶液調節至pH 2。藉由過濾收集固體並乾燥以得到灰白色固體形式之1-[6-(4,4-二氟六氫吡啶-1-基)-5-甲基吡啶-3-基]咪唑-4-甲酸(300 mg)。方法A：[M+H] ⁺= 323。 使用與針對中間體1所闡述相同之方法來製備下列中間體。 中間體 起始材料 A 起始材料 B 結構 LCMS 數據 中間體 2

CH(OEt) ₃

方法A：MS-ESI: 324 [M-H] ^- 中間體 3

CH(OEt) ₃

方法B：MS-ESI: 340 [M+H] ⁺ 中間體 4

CH ₃CH(OEt) ₃

方法A：MS-ESI: 325 [M-H] ^- Scheme 1 : Synthesis of Intermediate 1 (1-(6-(4,4 -difluorohexahydropyridin- 1 -yl )-5 -methylpyridin- 3 -yl )-1H- imidazole- 4 - carboxylic acid )

Step 1 : 2-(4,4 -Difluorohexahydropyridin- 1 -yl )-3 -methyl -5- nitropyridine was mixed with 2-chloro-3-methyl-5-nitropyridine (5.0 g, 28.9 mmol, 1.0 equiv) was dissolved in ACN (100 mL), then 4,4-difluorohexahydropyridine (4.2 g, 34.7 mmol, 1.2 equiv) and _{Cs2CO3 (} 18.8 g, 57.9 mmol, 2.0 equiv) were added ). The resulting mixture was heated to 80°C for 16 hours, and then cooled to room temperature. After filtering and washing the solid with MeOH, the filtrate was concentrated in vacuo to give 2-(4,4-difluorohexahydropyridin-1-yl)-3-methyl-5-nitropyridine(6) as a brown solid g). LCMS Method B: [M+H] ⁺ =258. Step 2 : 6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5 -methylpyridin- 3 -amine 2-(4,4-difluorohexahydropyridin-1-yl)-3 -Methyl-5-nitropyridine (6.0 g, 23.3 mmol, 1.0 equiv) was dissolved in MeOH (50 mL), then Pd/C (1.0 g, 10% wt.) was added. The mixture was purged with nitrogen, placed under a hydrogen atmosphere (balloon), and stirred at ambient temperature overnight. The solids were removed by filtration and the filtrate was concentrated in vacuo to give 6-(4,4-difluorohexahydropyridin-1-yl)-5-methylpyridin-3-amine as a brown oil (4.8 g) . LCMS Method B: [M+H] ⁺ =228. Step 3-4 : 1-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5 -methylpyridin- 3 -yl ] imidazole- 4 -carboxylic acid ethyl ester -Difluorohexahydropyridin-1-yl)-5-methylpyridin-3-amine (2.0 g, 8.8 mmol, 1.0 equiv) was dissolved in EtOH (20 mL) and AcOH (1 mL), then 2- Ethyl nitroacetate (1.1 g, 8.8 mmol, 1.0 equiv). The reaction mixture was heated to 80 °C for 30 min and then cooled to ambient temperature. Triethoxymethane (6.5 g, 44.0 mmol, 5.0 equiv) 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 equiv) in portions. The reaction mixture was heated to 80°C for 3 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. 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-difluorohexahydrogen as an off-white solid) Pyridin-1-yl)-5-methylpyridin-3-yl]imidazole-4-carboxylic acid ethyl ester (600 mg). Method A: [M+H] ⁺ = 351. Step 5 : 1-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5 -methylpyridin- 3 -yl ] imidazole- 4 - carboxylic acid was added to 1-[6-(4,4- Difluorohexahydropyridin-1-yl)-5-methylpyridin-3-yl]imidazole-4-carboxylic acid ethyl ester (500.0 mg, 1.4 mmol, 1.0 equiv) was dissolved in MeOH/ _H2O (5:1, 12 mL), then NaOH (85.6 mg, 2.1 mmol, 1.5 equiv) was added. The resulting solution was heated to 50°C for 2 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and the solution was adjusted to pH 2 with aqueous HCl (6 M). The solid was collected by filtration and dried to give 1-[6-(4,4-difluorohexahydropyridin-1-yl)-5-methylpyridin-3-yl]imidazole-4-carboxylic acid as an off-white solid ( 300 mg). Method A: [M+H] ⁺ = 323. The following intermediates were prepared using the same procedures as described for Intermediate 1 . Intermediate starting material A starting material B structure LCMS data Intermediate 2

CH(OEt) ₃

Method A: MS-ESI: 324 [MH] ^- Intermediate 3

CH(OEt) ₃

Method B: MS-ESI: 340 [M+H] ⁺ Intermediate 4

CH ₃ CH(OEt) ₃

Method A: MS-ESI: 325 [MH] ^-

步驟 1 ： 1-[[6-(4,4- 二氟環己基 )-5- 氟吡啶 -3- 基 ] 甲基 ] 吡唑 -4- 甲酸乙酯將5-(溴甲基)-2-(4,4-二氟環己基)-3-氟吡啶(500.0 mg, 1.6 mmol, 1.0當量)溶於ACN (20 mL)中，然後添加K ₂CO ₃(704.9 mg, 5.1 mmol, 3.0當量)及1 H-吡唑-4-甲酸乙酯(238.2 mg, 1.7 mmol, 1.0當量)。將反應混合物在環境溫度下攪拌16小時。藉由過濾去除固體且在真空下濃縮濾液。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)純化殘餘物以得到白色固體形式之1-[[6-(4,4-二氟環己基)-5-氟吡啶-3-基]甲基]吡唑-4-甲酸乙酯(300 mg)。LCMS方法B：[M+H] ⁺= 368。 步驟 2 ： 1-[[6-(4,4- 二氟環己基 )-5- 氟吡啶 -3- 基 ] 甲基 ] 吡唑 -4- 甲酸將1-[[6-(4,4-二氟環己基)-5-氟吡啶-3-基]甲基]吡唑-4-甲酸乙酯(300.0 mg, 0.8 mmol, 1.0當量)溶於MeOH (2 mL)及水(2 mL)中，然後添加NaOH (65.3 mg, 1.6 mmol, 2.0當量)。將反應混合物加熱至80℃並保持1小時，然後冷卻至環境溫度並在真空下濃縮。使用水稀釋殘餘物，然後使用HCl水溶液(6 M)將溶液調節至pH 5。藉由過濾收集固體並乾燥以得到白色固體形式之1-[[6-(4,4-二氟環己基)-5-氟吡啶-3-基]甲基]吡唑-4-甲酸(250 mg)。LCMS方法B：[M+H] ⁺= 340。 Scheme 2 : Synthesis of Intermediate 6 (1-((6-(4,4 -difluorocyclohexyl )-5- fluoropyridin - 3 -yl ) methyl )-1H- pyrazole- 4 - carboxylic acid )

Step 1 : 1-[[6-(4,4 -Difluorocyclohexyl )-5- fluoropyridin - 3 -yl ] methyl ] pyrazole- 4 -carboxylic acid ethyl ester -(4,4-Difluorocyclohexyl)-3-fluoropyridine (500.0 mg, 1.6 mmol, 1.0 equiv) was dissolved in ACN ( ₂₀ mL), then K2CO3 ( _704.9 mg, 5.1 mmol, 3.0 equiv) was added ) and 1 H -pyrazole-4-carboxylic acid ethyl ester (238.2 mg, 1.7 mmol, 1.0 equiv). 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 as a white solid )-5-fluoropyridin-3-yl]methyl]pyrazole-4-carboxylic acid ethyl ester (300 mg). LCMS Method B: [M+H] ⁺ =368. Step 2 : 1-[[6-(4,4 -Difluorocyclohexyl )-5- fluoropyridin - 3 -yl ] methyl ] pyrazole- 4 - carboxylic acid was added to 1-[[6-(4,4- Difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]pyrazole-4-carboxylic acid ethyl ester (300.0 mg, 0.8 mmol, 1.0 equiv) was dissolved in MeOH (2 mL) and water (2 mL) , then NaOH (65.3 mg, 1.6 mmol, 2.0 equiv) was added. The reaction mixture was heated to 80°C for 1 hour, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and the solution was adjusted to pH 5 with aqueous HCl (6 M). The solid was collected by filtration and dried to give 1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]pyrazole-4-carboxylic acid as a white solid (250 mg). LCMS Method B: [M+H] ⁺ =340.

步驟 1 ： 1-[[6-(4,4- 二氟環己基 )-5- 氟吡啶 -3- 基 ] 甲基 ] 咪唑 -4- 甲酸乙酯及 3-[[6-(4,4- 二氟環己基 )-5- 氟吡啶 -3- 基 ] 甲基 ] 咪唑 -4- 甲酸乙酯將5-(溴甲基)-2-(4,4-二氟環己基)-3-氟吡啶(800.0 mg, 2.6 mmol, 1.0當量)溶於ACN (15 mL)中，然後添加K ₂CO ₃(1.1 g, 7.8 mmol, 3.0當量)及1H-咪唑-4-甲酸乙酯(363.8 mg, 2.6 mmol, 1.0當量)。將反應混合物加熱至80℃並保持2小時 在過濾並使用MeOH洗滌之後，在真空下濃縮濾液。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:10至1:1)洗脫)來純化殘餘物以得到淺黃色固體形式之1-[[6-(4,4-二氟環己基)-5-氟吡啶-3-基]甲基]咪唑-4-甲酸乙酯(化合物8A, 350 mg)及白色固體形式之3-[[6-(4,4-二氟環己基)-5-氟吡啶-3-基]甲基]咪唑-4-甲酸乙酯(化合物8B, 370 mg)。化合物8A之LCMS，方法B：[M+H] ⁺= 368。化合物8A之 ¹H NMR (400 MHz, DMSO- d ₆): δ 8.45 (d, 1H), 8.05 (d, 1H), 7.95 (d, 1H), 7.73-7.69 (m, 1H), 5.30 (s, 2H), 4.21 (q, 2H), 3.20-3.16 (m, 1H), 2.15-1.83 (m, 8H), 1.25 (t, 3H)；化合物8B之LCMS，方法B：[M+H] ⁺= 368。化合物8B之 ¹H NMR (400 MHz, DMSO- d ₆): δ 8.27 (d, 1H), 8.21 (s, 1H), 7.71 (s, 1H), 7.50-7.45 (m, 1H), 5.57 (s, 2H), 4.23 (q, 2H), 3.19-3.14 (m, 1H), 2.15-1.80 (m, 8H), 1.22 (t, 3H)。 步驟 2 ： 1-((6-(4,4- 二氟環己基 )-5- 氟吡啶 -3- 基 ) 甲基 )-1 H- 咪唑 -4- 甲酸將1-[[6-(4,4-二氟環己基)-5-氟吡啶-3-基]甲基]咪唑-4-甲酸乙酯(200.0 mg, 0.5 mmol, 1.0當量)溶於MeOH (4 mL)及水(4 mL)中，然後添加NaOH (65.3 mg, 1.6 mmol, 3.0當量)。將反應混合物在80℃下攪拌2小時，然後在真空下濃縮。使用水稀釋殘餘物並使用HCl水溶液(6 M)調節至pH 5。藉由過濾收集所得固體並藉由急速製備型HPLC使用下列條件進行純化：管柱，C18；移動相，在30 min內自0增至100%之ACN/H ₂O；檢測器，254 nm。此會產生白色固體形式之1-[[6-(4,4-二氟環己基)-5-氟吡啶-3-基]甲基]咪唑-4-甲酸(160 mg)。LCMS方法B：[M+H] ⁺= 340。 步驟 3 ： 1-((6-(4,4- 二氟環己基 )-5- 氟吡啶 -3- 基 ) 甲基 )-1 H- 咪唑 -5- 甲酸使用與針對步驟2所闡述相同之方法來提供白色固體形式之1-((6-(4,4-二氟環己基)-5-氟吡啶-3-基)甲基)-1 H-咪唑-5-甲酸(160 mg)。LCMS方法B：[M+H] ⁺= 340。 使用與針對 中間體 7 及 8所闡述相同之方法來製備下列中間體。 中間體 起始材料 A 起始材料 B 結構 LCMS 數據 中間體 9

方法 B ： MS- ESI: 340 [M+H] ⁺ Scheme 3 : Intermediates 7 and 8 (1-((6-(4,4 -difluorocyclohexyl )-5- fluoropyridin - 3 -yl ) methyl )-1H- imidazole- 4 - carboxylic acid and 1- Synthesis of ((6-(4,4 -Difluorocyclohexyl )-5- fluoropyridin - 3 -yl ) methyl )-1H- imidazole -5- carboxylic acid )

Step 1 : 1-[[6-(4,4 -Difluorocyclohexyl )-5- fluoropyridin - 3 -yl ] methyl ] imidazole- 4 -carboxylic acid ethyl ester and 3-[[6-(4,4 -Difluorocyclohexyl )-5- fluoropyridin - 3 -yl ] methyl ] imidazole- 4 -carboxylic acid ethyl ester 5-(bromomethyl)-2-(4,4-difluorocyclohexyl)-3- Fluoropyridine (800.0 mg, 2.6 mmol, 1.0 equiv) was dissolved in ACN ( ₁₅ mL), then K2CO3 (1.1 _g , 7.8 mmol, 3.0 equiv) and ethyl 1H-imidazole-4-carboxylate (363.8 mg) were added , 2.6 mmol, 1.0 equiv). The reaction mixture was heated to 80°C for 2 hours. After filtering 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 to 1:1) to give 1-[[6-(4,1-[[6-(4, 4-Difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]imidazole-4-carboxylic acid ethyl ester (Compound 8A, 350 mg) and 3-[[6-(4,4- Difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]imidazole-4-carboxylic acid ethyl ester (compound 8B, 370 mg). LCMS of Compound 8A, Method B: [M+H] ⁺ = 368. ¹ H NMR (400 MHz, DMSO- d ₆ ) of compound 8A: δ 8.45 (d, 1H), 8.05 (d, 1H), 7.95 (d, 1H), 7.73-7.69 (m, 1H), 5.30 (s , 2H), 4.21 (q, 2H), 3.20-3.16 (m, 1H), 2.15-1.83 (m, 8H), 1.25 (t, 3H); LCMS of compound 8B, method B: [M+H] ⁺ = 368. ¹ H NMR (400 MHz, DMSO- d ₆ ) of compound 8B: δ 8.27 (d, 1H), 8.21 (s, 1H), 7.71 (s, 1H), 7.50-7.45 (m, 1H), 5.57 (s , 2H), 4.23 (q, 2H), 3.19-3.14 (m, 1H), 2.15-1.80 (m, 8H), 1.22 (t, 3H). Step 2 : 1-((6-(4,4 -Difluorocyclohexyl )-5- fluoropyridin - 3 -yl ) methyl )-1H - imidazole- 4 - carboxylic acid was added to 1-[[6-(4 ,4-difluorocyclohexyl)-5-fluoropyridin-3-yl]methyl]imidazole-4-carboxylic acid ethyl ester (200.0 mg, 0.5 mmol, 1.0 equiv) was dissolved in MeOH (4 mL) and water (4 mL) ), then NaOH (65.3 mg, 1.6 mmol, 3.0 equiv) was added. The reaction mixture was stirred at 80°C for 2 hours and then concentrated in vacuo. The residue was diluted with water and adjusted to pH 5 with aqueous HCl (6 M). The resulting solid was collected by filtration and purified by flash prep HPLC using the following conditions: column, C18; mobile phase, ACN/ _H2O increasing from 0 to 100% in 30 min; detector, 254 nm. 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 The same as described for step 2 was used method to provide 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 procedures as described for intermediates 7 and 8 . Intermediate starting material A starting material B structure LCMS data Intermediate 9

Method B : MS-ESI: 340 [M+H] ⁺

步驟 1 ： 2-(4,4- 二氟環己基 )-3- 氟 -5- 碘吡啶將6-(4,4-二氟環己基)-5-氟吡啶-3-胺(400.0 mg, 1.7 mmol, 1.0當量)溶於HCl水溶液(6 M, 10 mL)中並冷卻至0℃，然後逐滴添加NaNO ₂(179.8 mg, 2.6 mmol, 1.5當量)於水(0.5 mL)中之溶液，且將反應混合物維持於0℃下。在0℃下經30 min之後，逐份添加KI (576.8 mg, 3.5 mmol, 2.0當量)，且將溫度維持於0℃下。在完成添加之後，將溶液在0℃下再攪拌2小時。在使用水驟冷之後，使用乙酸乙酯萃取所得溶液並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)純化殘餘物以得到淺黃色固體形式之2-(4,4-二氟環己基)-3-氟-5-碘吡啶(120 mg)。LCMS方法A：[M+H] ⁺= 342。 步驟 2 ： 1-(6-(4,4- 二氟環己基 )-5- 氟吡啶 -3- 基 )-1 H- 吡唑 -4- 甲酸乙酯將2-(4,4-二氟環己基)-3-氟-5-碘吡啶(500.0 mg, 1.5 mmol, 1.0當量)溶於DMF (5 mL)中，然後添加Cs ₂CO ₃(1.4 g, 4.4 mmol, 3.0當量)、1 H-吡唑-4-甲酸乙酯(246.5 mg, 1.8 mmol, 1.2當量)、 N ₁ , N ₂ -二甲基環己烷-1,2-二胺(0.1 mL, 0.7 mmol, 0.5當量)及CuI (57.3 mg, 0.3 mmol, 0.2當量)。將所得溶液加熱至80℃並保持8小時，然後冷卻至環境溫度並藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到淺黃色固體形式之1-[6-(4,4-二氟環己基)-5-氟吡啶-3-基]吡唑-4-甲酸乙酯(120 mg)。LCMS方法A：[M+H] ⁺= 354。 步驟 3 ： 1-(6-(4,4- 二氟環己基 )-5- 氟吡啶 -3- 基 )-1 H- 吡唑 -4- 甲酸將1-[6-(4,4-二氟環己基)-5-氟吡啶-3-基]吡唑-4-甲酸乙酯(110.0 mg, 0.3 mmol, 1.0當量)溶於MeOH (5 mL)中，然後添加NaOH水溶液(2 mL, 2M)。將反應混合物在環境溫度下攪拌2小時，然後使用5 mL水稀釋。使用HCl水溶液(2M)將溶液調節至pH 5並在真空下濃縮。藉由急速製備型HPLC使用下列條件來純化粗產物：管柱，矽膠；移動相，在25 min內自0增至70%之ACN/水。此會產生淺黃色固體形式之1-[6-(4,4-二氟環己基)-5-氟吡啶-3-基]吡唑-4-甲酸(70 mg)。LCMS方法A：[M+H] ⁺= 326。 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 equiv) 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 equiv) in water (0.5 mL) was added dropwise, And the reaction mixture was maintained at 0°C. After 30 min at 0 °C, KI (576.8 mg, 3.5 mmol, 2.0 equiv) was added in portions and the temperature was maintained 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 as a pale yellow solid -Fluoro-5-iodopyridine (120 mg). LCMS Method A: [M+H] ⁺ =342. Step 2 : 1-(6-(4,4 -Difluorocyclohexyl )-5- fluoropyridin - 3 -yl )-1H - pyrazole- 4 -carboxylic acid ethyl ester to 2-(4,4-difluoro Cyclohexyl)-3-fluoro-5-iodopyridine (500.0 mg, 1.5 mmol, 1.0 equiv) was dissolved in DMF ( ₅ mL), then _Cs2CO3 (1.4 g, 4.4 mmol, 3.0 equiv), 1H were added - pyrazole-4-carboxylic acid ethyl ester (246.5 mg, 1.8 mmol, 1.2 equiv), N ₁ , N ₂ -dimethylcyclohexane-1,2-diamine (0.1 mL, 0.7 mmol, 0.5 equiv) and CuI (57.3 mg, 0.3 mmol, 0.2 equiv). 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 in vacuo. 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-difluorocyclic ring as a pale yellow solid) Hexyl)-5-fluoropyridin-3-yl]pyrazole-4-carboxylic acid ethyl ester (120 mg). LCMS Method A: [M+H] ⁺ =354. Step 3 : 1-(6-(4,4 -Difluorocyclohexyl )-5- fluoropyridin - 3 -yl )-1H - pyrazole- 4 - carboxylic acid Fluorocyclohexyl)-5-fluoropyridin-3-yl]pyrazole-4-carboxylic acid ethyl ester (110.0 mg, 0.3 mmol, 1.0 equiv) was dissolved in MeOH (5 mL), then aqueous NaOH (2 mL, 2M) was added ). The reaction mixture was stirred at ambient temperature for 2 hours and then diluted with 5 mL of water. The solution was adjusted to pH 5 using aqueous HCl (2M) and concentrated in vacuo. The crude product was purified by flash prep HPLC using the following conditions: column, silica gel; mobile phase, 0 to 70% ACN/water in 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.

步驟 1 ： 5,6- 二氟 -3- 硝基 -1 H- 吲哚將5,6-二氟-1 H-吲哚(25.0 g, 163.3 mmol, 1.0當量)溶於ACN (300 mL)中並冷卻至0℃，然後添加AgNO ₃(33.3 g, 195.9 mmol, 1.2當量)。將所得混合物攪拌15 min，然後逐批添加苯甲醯氯(27.5 g, 195.9 mmol, 1.2當量)，且將反應混合物維持於0℃下。在0℃下再過3小時之後，藉由添加冰水來將反應混合物驟冷。使用飽和NaHCO ₃水溶液將反應混合物調節至pH 8，然後使用DCM萃取並在真空下濃縮有機層。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(2:1)洗脫)來純化殘餘物以得到褐色固體形式之5,6-二氟-3-硝基-1 H-吲哚(24 g)。LCMS方法A：[M+H] ⁺= 199。 步驟 2 ： N -(5,6- 二氟 -1 H- 吲哚 -3- 基 ) 胺基甲酸第三丁基酯將5,6-二氟-3-硝基-1 H-吲哚(24.0 g, 121.1 mmol, 1.0當量)溶於MeOH (300 mL)中，然後在氮下添加Pd/C (2.4 g, wt 10%)及(Boc) ₂O (39.7 g, 181.7 mmol, 1.5當量)。使用氮吹掃混合物，置於氫氣氣氛(氣囊)下，然後在環境溫度下攪拌過夜。藉由過濾去除固體且在真空下濃縮濾液。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:4)洗脫)來純化殘餘物以得到黃色固體形式之 N-(5,6-二氟-1 H-吲哚-3-基)胺基甲酸第三丁基酯(22 g)。LCMS方法C：[M+H] ⁺= 269。 步驟 3 ： 5,6- 二氟 -1 H- 吲哚 -3- 胺鹽酸鹽將 N-(5,6-二氟-1 H-吲哚-3-基)胺基甲酸第三丁基酯(17.0 g, 63.4 mmol, 1.0當量)溶於HCl/1,4-二噁烷(4N, 200 mL)中。將所得混合物在環境溫度下攪拌30 min且然後在真空下濃縮以得到黃色固體形式之5,6-二氟-1H-吲哚-3-胺鹽酸鹽(12 g)。LCMS方法C：[M+H] ⁺= 169。 使用與針對中間體11所闡述相同之方法來製備下表中之中間體。 中間體 起始材料 結構 LCMS 數據 中間體 12

方法E：MS-ESI: 209 [M+H] ⁺ 中間體 13

方法E：MS-ESI: 209 [M+H]+ Scheme 5 : Synthesis of Intermediate 11 (5,6 -difluoro -1H- indol- 3 - amine hydrochloride )

Step 1 : 5,6 -Difluoro - 3 -nitro - 1H - indole 5,6-Difluoro- 1H -indole (25.0 g, 163.3 mmol, 1.0 equiv) was dissolved in ACN (300 mL) and cooled to 0 °C, then AgNO3 ₍ 33.3 g, 195.9 mmol, 1.2 equiv) was added. The resulting mixture was stirred for 15 min, then benzyl chloride (27.5 g, 195.9 mmol, 1.2 equiv) was added in portions and the reaction mixture was maintained at 0 °C. After a further 3 hours at 0°C, the reaction mixture was quenched by adding ice water. The reaction mixture was adjusted to pH 8 using saturated aqueous NaHCO ₃ , 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 as a brown solid - Indole (24 g). LCMS Method A: [M+H] ⁺ =199. Step 2 : 5,6 - Difluoro - 3 - nitro - 1H - indole ( 24.0 g, 121.1 mmol, 1.0 equiv) was dissolved in MeOH (300 mL), then Pd/C (2.4 g, wt 10%) and (Boc)2O (39.7 _g , 181.7 mmol, 1.5 equiv) were added under nitrogen . The mixture was purged with nitrogen, placed under a hydrogen atmosphere (balloon), and 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 -indone as a yellow solid) tert-butyl dol-3-yl)carbamate (22 g). 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 The ester (17.0 g, 63.4 mmol, 1.0 equiv) was dissolved in HCl/1,4-dioxane (4N, 200 mL). The resulting mixture was stirred at ambient temperature for 30 min and then concentrated in vacuo to give 5,6-difluoro-lH-indol-3-amine hydrochloride (12 g) as a yellow solid. LCMS method C: [M+H] ⁺ =169. The intermediates in the table below were prepared using the same procedures as described for intermediate 11. Intermediate starting material structure LCMS data Intermediate 12

Method E: MS-ESI: 209 [M+H] ⁺ Intermediate 13

Method E: MS-ESI: 209 [M+H]+

步驟 1 ： 5- 氟 -1 H- 吡咯并 [2,3- b] 吡啶 -3- 羰基疊氮化物將5-氟-1 H-吡咯并[2,3-b]吡啶-3-甲酸(1.0 g, 5.6 mmol, 1.0當量)及DPPA (3.0 g, 11.1 mmol, 2.0當量)溶於THF (10.0 mL)中，然後添加TEA (1.6 mL, 11.1 mmol, 2.0當量)。將所得混合物在環境溫度下攪拌過夜並在真空下濃縮。使用水稀釋殘餘物，使用乙酸乙酯萃取，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以得到白色固體形式之5-氟-1 H-吡咯并[2,3- b]吡啶-3-羰基疊氮化物(900 mg)。LCMS方法E：[M+H] ⁺= 206。 步驟 2 ： N -[5- 氟 -1 H- 吡咯并 [2,3-b] 吡啶 -3- 基 ] 胺基甲酸第三丁基酯添加於t-BuOH (8.0 mL)中之5-氟-1 H-吡咯并[2,3- b]吡啶-3-羰基疊氮化物(300.0 mg, 1.5 mmol, 1.0當量)。將所得混合物在100℃下攪拌過夜且然後在真空下濃縮。藉由急速管柱層析在矽膠管柱上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到黃色固體形式之 N-[5-氟-1 H-吡咯并[2,3-b]吡啶-3-基]胺基甲酸第三丁基酯(350 mg)。LCMS方法E：[M+H] ⁺= 251。 步驟 3 ： 5- 氟 -1 H- 吡咯并 [2,3- b] 吡啶 -3- 胺鹽酸鹽將 N-[5-氟-1 H-吡咯并[2,3- b]吡啶-3-基]胺基甲酸第三丁基酯(300.0 mg)溶於HCl/1,4-二噁烷(4M, 10.0 mL)中。將所得溶液在環境溫度下攪拌4小時且然後在真空下濃縮以得到黃色固體形式之粗製5-氟-1 H-吡咯并[2,3- b]吡啶-3-胺鹽酸鹽(350 mg)。LCMS方法E：[M+H] ⁺= 151。 Scheme 6 : Synthesis of Intermediate 14 (5- fluoro -1H- pyrrolo [2,3-b] pyridin - 3 - amine hydrochloride )

Step 1 : 5- Fluoro - 1H - pyrrolo [2,3- b ] pyridine - 3 -carbonylazide 5-fluoro- 1H -pyrrolo[2,3-b]pyridine-3-carboxylic acid ( 1.0 g, 5.6 mmol, 1.0 equiv) and DPPA (3.0 g, 11.1 mmol, 2.0 equiv) were dissolved in THF (10.0 mL), then TEA (1.6 mL, 11.1 mmol, 2.0 equiv) was added. The resulting mixture was stirred at ambient temperature overnight and concentrated in vacuo. The residue was diluted with water, extracted with ethyl acetate, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 5-fluoro- 1H -pyrrolo[2,3- b ]pyridine-3 as a white solid - Carbonyl azide (900 mg). LCMS Method E: [M+H] ⁺ =206. Step 2 : N- [5- Fluoro - 1H - pyrrolo [2,3-b] pyridin - 3 -yl ] carbamic acid tert-butyl ester 5-fluoro in t-BuOH (8.0 mL) -1H -pyrrolo[2,3- b ]pyridine-3-carbonylazide (300.0 mg, 1.5 mmol, 1.0 equiv). The resulting mixture was stirred at 100°C overnight and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:1) to give N- [5-fluoro- 1H -pyrrolo as a yellow solid [2,3-b]pyridin-3-yl]carbamate tert-butyl ester (350 mg). LCMS Method E: [M+H] ⁺ =251. Step 3 : 5- Fluoro - 1H - pyrrolo [2,3- b ] pyridin - 3 -amine hydrochloride N- [5-fluoro- 1H -pyrrolo[2,3- b ]pyridine-3 -yl] tert-butyl 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 in vacuo to give crude 5-fluoro- 1H -pyrrolo[2,3- b ]pyridin-3-amine hydrochloride as a yellow solid (350 mg ). LCMS Method E: [M+H] ⁺ =151.

步驟 1 ： 5- 溴 -1 H- 吲哚 -3- 羰基疊氮化物將5-溴-1 H-吲哚-3-甲酸(1.0 g, 4.2 mmol, 1.0當量)溶於THF (10.0 mL)中，然後添加DPPA (2.3 g, 8.3 mmol, 2.0當量)及TEA (1.8 mL, 12.5 mmol, 3.0當量)。將所得溶液在環境溫度下攪拌過夜且然後在真空下濃縮。使用MeOH稀釋殘餘物且藉由過濾收集所分離固體以得到白色固體形式之5-溴-1 H-吲哚-3-羰基疊氮化物(900 mg)。LCMS方法E：[M+H] ⁺= 265。 步驟 2 ： N -(5- 溴 -1 H- 吲哚 -3- 基 ) 胺基甲酸第三丁基酯將5-溴-1 H-吲哚-3-羰基疊氮化物(900.0 mg, 3.4 mmol, 1.0當量)溶於 t-BuOH (6 mL)中。將所得溶液在80℃下加熱過夜，然後在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到黃色固體形式之 N-(5-溴-1 H-吲哚-3-基)胺基甲酸第三丁基酯(910 mg)。LCMS方法E：[M+H] ⁺= 311。 步驟 3 ： N -[5-(1- 異丙基吡唑 -4- 基 )-1H- 吲哚 -3- 基 ] 胺基甲酸第三丁基酯將 N-(5-溴-1 H-吲哚-3-基)胺基甲酸第三丁基酯(500.0 mg, 1.6 mmol, 1.0當量)溶於1,4-二噁烷(6 mL)及水(0.6 mL)中，然後在氮氣氛下添加1-異丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)吡唑(417.3 mg, 1.8 mmol, 1.1當量)、Xphos Pd G3 (136.0 mg, 0.2 mmol, 0.1當量)及Cs ₂CO ₃(1.0 g, 3.2 mmol, 2.0當量)。將溶液在100℃下加熱過夜，然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液並在真空下濃縮有機層。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到白色固體形式之 N-[5-(1-異丙基吡唑-4-基)-1 H-吲哚-3-基]胺基甲酸第三丁基酯(400 mg)。LCMS方法E：[M+H] ⁺= 341。 步驟 4 ： 5-(1- 異丙基吡唑 -4- 基 )-1 H- 吲哚 -3- 胺鹽酸鹽將 N-[5-(1-異丙基吡唑-4-基)-1 H-吲哚-3-基]胺基甲酸第三丁基酯(400.0 mg, 1.2 mmol, 1.0當量)溶於HCl/1,4-二噁烷(4M, 8.0 mL)中。將所得溶液在環境溫度下攪拌4小時且然後在真空下濃縮以得到灰色固體形式之粗製5-(1-異丙基吡唑-4-基)-1 H-吲哚-3-胺鹽酸鹽(400 mg)。LCMS方法E：[M+H] ⁺= 241。 使用與針對中間體15所闡述相同之方法來製備下列中間體。 中間體 起始材料 A 起始材料 B 結構 LCMS 數據 中間體 16

方法E：MS-ESI: 231 [M+H] ⁺ 中間體 17

方法E：MS-ESI: 259 [M+H] ⁺ Scheme 7 : Synthesis of Intermediate 15 (5-(1- isopropyl- 1H- pyrazol- 4 -yl )-1H- indol- 3 - amine hydrochloride )

Step 1 : 5- Bromo - 1H - indole- 3 - carbonyl azide 5-Bromo- 1H -indole-3-carboxylic acid (1.0 g, 4.2 mmol, 1.0 equiv) was dissolved in THF (10.0 mL) Then DPPA (2.3 g, 8.3 mmol, 2.0 equiv) and TEA (1.8 mL, 12.5 mmol, 3.0 equiv) were added. The resulting solution was stirred at ambient temperature overnight and then concentrated in vacuo. The residue was diluted with MeOH and the isolated solid was collected by filtration to give 5-bromo- lH -indole-3-carbonylazide (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-carbonylazide (900.0 mg, 3.4 mmol, 1.0 equiv) was dissolved in t -BuOH (6 mL). The resulting solution was heated at 80°C overnight, then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:1) to give N- (5-bromo- 1H -indole-3 as a yellow solid) -yl) tert-butyl carbamate (910 mg). LCMS Method E: [M+H] ⁺ =311. Step 3 : N- [5-(1- Isopropylpyrazol- 4 -yl )-1H- indol- 3 -yl ] carbamic acid tert-butyl ester to N- (5-bromo-1H- tert-butyl 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), then under nitrogen atmosphere 1-Isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-2-yl)pyrazole (417.3 mg, 1.8 mmol, 1.1 equiv) was added under , Xphos Pd G3 (136.0 mg, 0.2 mmol, 0.1 equiv) and _{Cs2CO3 (} 1.0 g, 3.2 mmol, 2.0 equiv). The solution was heated at 100°C overnight and then quenched by addition of water. The resulting solution was extracted with ethyl acetate and the organic layer was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:1) to give N- [5-(1-isopropylpyrazole- 4-yl)-1 H -indol-3-yl]carbamic acid tert-butyl ester (400 mg). LCMS Method E: [M+H] ⁺ =341. Step 4 : 5-(1- Isopropylpyrazol- 4 -yl ) -1H - indol- 3 - amine hydrochloride N- [5-(1-isopropylpyrazol-4-yl) -1H- Indol -3-yl]carbamate tert-butyl ester (400.0 mg, 1.2 mmol, 1.0 equiv) was dissolved in HCl/1,4-dioxane (4M, 8.0 mL). The resulting solution was stirred at ambient temperature for 4 hours and then concentrated in vacuo to give crude 5-(1-isopropylpyrazol-4-yl)-1 H -indol-3-amine hydrochloride as a grey solid Salt (400 mg). LCMS Method E: [M+H] ⁺ =241. The following intermediates were prepared using the same procedures as described for intermediate 15. Intermediate starting material A starting material B structure LCMS data Intermediate 16

Method E: MS-ESI: 231 [M+H] ⁺ Intermediate 17

Method E: MS-ESI: 259 [M+H] ⁺

步驟 1 ： 6-(4,4- 二氟環己 -1- 烯 -1- 基 )-5- 氟吡啶 -3- 胺將6-溴-5-氟吡啶-3-胺(500.0 mg, 2.6 mmol, 1.00當量)溶於1,4-二噁烷(10 mL)及水(1 mL)中，然後在氮氣氛下添加K ₂CO ₃(1.1 g, 7.9 mmol, 3.0當量)、2-(4,4-二氟環己-1-烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼㖦(766.8 mg, 3.1 mmol, 1.2當量)及Pd(dppf)Cl ₂(383.1 mg, 0.5 mmol, 0.2當量)。將反應混合物加熱至90℃並保持2小時，然後冷卻至環境溫度並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:2)洗脫)來純化殘餘物以得到灰白色固體形式之6-(4,4-二氟環己-1-烯-1-基)-5-氟吡啶-3-胺(420 mg)。LCMS方法C：[M+H] ⁺= 229。 步驟 2 ： 6-(4,4- 二氟環己基 )-5- 氟吡啶 -3- 胺將6-(4,4-二氟環己-1-烯-1-基)-5-氟吡啶-3-胺(400.0 mg, 1.8 mmol, 1.0當量)溶於MeOH (20 mL)中，然後添加Pd/C (93.3 mg, 0.9 mmol, 0.5當量)。使用氮吹掃混合物，置於氫氣氣氛(氣囊)下，然後在環境溫度下攪拌2小時。藉由過濾去除固體且在真空下濃縮濾液以得到灰白色固體形式之6-(4,4-二氟環己基)-5-氟吡啶-3-胺(300 mg)。LCMS方法C：[M+H] ⁺= 231。 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 equiv) was dissolved in 1,4-dioxane (10 mL) and water (1 mL), then K ₂ CO ₃ (1.1 g, 7.9 mmol, 3.0 equiv), 2-( 4,4-Difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron (766.8 mg, 3.1 mmol, 1.2 equiv) and Pd(dppf)Cl2 ( _383.1 mg, 0.5 mmol, 0.2 equiv). The reaction mixture was heated to 90°C for 2 hours, then cooled to ambient temperature and concentrated in vacuo. 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- as an off-white solid) En-1-yl)-5-fluoropyridin-3-amine (420 mg). LCMS method C: [M+H] ⁺ =229. Step 2 : 6-(4,4 -Difluorocyclohexyl )-5- fluoropyridin - 3 -amine -3-amine (400.0 mg, 1.8 mmol, 1.0 equiv) was dissolved in MeOH (20 mL) and Pd/C (93.3 mg, 0.9 mmol, 0.5 equiv) was added. The mixture was purged with nitrogen, placed under a hydrogen atmosphere (balloon), and stirred at ambient temperature for 2 hours. The solids were removed by filtration and the filtrate was concentrated in vacuo to give 6-(4,4-difluorocyclohexyl)-5-fluoropyridin-3-amine (300 mg) as an off-white solid. LCMS Method C: [M+H] ⁺ =231.

步驟 1 ： 2-(4,4- 二氟六氫吡啶 -1- 基 )-3- 氟 -5- 硝基吡啶將2-氯-3-氟-5-硝基吡啶(10.0 g, 56.6 mmol, 1.0當量)溶於DMF (150 mL)中，然後添加Cs ₂CO ₃(37.3 g, 114.5 mmol, 2.0當量)及4,4-二氟六氫吡啶(9.8 g, 81.0 mmol, 1.4當量)。將反應混合物加熱至90℃並保持15小時，然後冷卻至環境溫度並藉由添加水來驟冷。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:3)洗脫)來純化殘餘物以得到黃色固體形式之2-(4,4-二氟六氫吡啶-1-基)-3-氟-5-硝基吡啶(13.3 g) 。LCMS方法D：[M+H] ⁺= 262。 步驟 2 ： 6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 胺將2-(4,4-二氟六氫吡啶-1-基)-3-氟-5-硝基吡啶(13.2 g, 50.5 mmol, 1.0當量)溶於MeOH (100 mL)中，然後添加Pd/C (2.0 g, 18.8 mmol, 0.4當量)。使用氮吹掃混合物，置於氫氣氣氛(氣囊)下，然後在環境溫度下攪拌15小時。藉由過濾去除固體且在真空下濃縮濾液。藉由急速管柱層析在矽膠上(使用二氯甲烷/甲醇(97:3)洗脫)來純化殘餘物以得到黃色固體形式之6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-胺(11.4 g)。LCMS方法D：[M+H] ⁺= 232。 Scheme 9 : Synthesis of Intermediate 19 (6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -amine )

Step 1 : 2-(4,4 -Difluorohexahydropyridin- 1 -yl )-3 - fluoro -5- nitropyridine 2-chloro-3-fluoro-5-nitropyridine (10.0 g, 56.6 mmol , 1.0 equiv) was dissolved in DMF (150 mL), then _{Cs2CO3 (} 37.3 g, 114.5 mmol, 2.0 equiv) and 4,4-difluorohexahydropyridine (9.8 g, 81.0 mmol, 1.4 equiv) were added. The reaction mixture was heated to 90°C for 15 hours, then cooled to ambient temperature and quenched by 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-difluorohexahydropyridine-1 as a yellow solid) -yl)-3-fluoro-5-nitropyridine (13.3 g) . LCMS Method D: [M+H] ⁺ =262. Step 2 : 6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -amine Fluoro-5-nitropyridine (13.2 g, 50.5 mmol, 1.0 equiv) was dissolved in MeOH (100 mL) and Pd/C (2.0 g, 18.8 mmol, 0.4 equiv) was added. The mixture was purged with nitrogen, placed under a hydrogen atmosphere (balloon), and 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-difluorohexahydropyridine-1- as a yellow solid) yl)-5-fluoropyridin-3-amine (11.4 g). LCMS Method D: [M+H] ⁺ =232.

步驟 1 ： 6-(4,4- 二氟環己 -1- 烯 -1- 基 )-5- 氟吡啶 -3- 甲酸甲酯將6-溴-5-氟吡啶-3-甲酸甲酯(2.0 g, 8.5 mmol, 1.0當量)溶於1,4-二噁烷(2 mL)及水(2 mL)中，然後在氮氣氛下添加Cs ₂CO ₃(5.6 g, 17.1 mmol, 2.0當量)、2-(4,4-二氟環己-1-烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼㖦(2.1 g, 8.5 mmol, 1.0當量)及Pd(dppf)Cl ₂CH ₂Cl ₂(1.4 g, 1.7 mmol, 0.2當量)。將反應混合物在90℃下加熱過夜，然後冷卻至環境溫度並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:10)洗脫)來純化殘餘物以得到黃色固體形式之6-(4,4-二氟環己-1-烯-1-基)-5-氟吡啶-3-甲酸甲酯(2.2 g)。LCMS方法A：[M+H] ⁺= 272。 步驟 2 ： 6-(4,4- 二氟環己基 )-5- 氟吡啶 -3- 甲酸甲酯將6-(4,4-二氟環己-1-烯-1-基)-5-氟吡啶-3-甲酸甲酯(2.0 g, 7.4 mmol, 1.0當量)溶於DCM (80 mL)中，然後添加PtO ₂(837.2 mg, 3.7 mmol, 0.5當量)。使用氮吹掃混合物，置於氫氣氣氛(氣囊)下，然後在環境溫度下攪拌過夜。藉由過濾去除固體且在真空下濃縮濾液以得到灰白色油狀物形式之6-(4,4-二氟環己基)-5-氟吡啶-3-甲酸甲酯(2 g)。LCMS方法I：[M+H] ⁺= 274。 步驟 3 ： [6-(4,4- 二氟環己基 )-5- 氟吡啶 -3- 基 ] 甲醇將6-(4,4-二氟環己基)-5-氟吡啶-3-甲酸甲酯(2.0 g, 7.3 mmol, 1.0當量)溶於THF (20 mL)中並冷卻至0℃，然後逐份添加LiAlH ₄(0.6 g, 14.6 mmol, 2.0當量)。將所得溶液在0℃下攪拌30 min且然後藉由添加Na ₂SO ₄•10H ₂O來驟冷。在藉由過濾去除固體之後，在真空下濃縮濾液。藉由急速管柱層析在矽膠上(使用二氯甲烷/甲醇(10:1)洗脫)來純化殘餘物以得到白色固體形式之[6-(4,4-二氟環己基)-5-氟吡啶-3-基]甲醇(1.1 g)。LCMS方法B：[M+H] ⁺= 246。 步驟 4 ： 5-( 溴甲基 )-2-(4,4- 二氟環己基 )-3- 氟吡啶將[6-(4,4-二氟環己基)-5-氟吡啶-3-基]甲醇(1.0 g, 4.1 mmol, 1.0當量)溶於DCM (10 mL)中並冷卻至0℃，然後添加PBr ₃(0.4 mL, 4.1 mmol, 1.0當量)，且將混合物維持於0℃下。將反應混合物在0℃下攪拌1小時且然後藉由添加飽和NaHCO ₃水溶液來驟冷。使用乙酸乙酯萃取所得溶液並在真空下濃縮以得到白色固體形式之5-(溴甲基)-2-(4,4-二氟環己基)-3-氟吡啶(800 mg)。LCMS方法A：[M+H] ⁺=308。 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 equiv) was dissolved in 1,4-dioxane (2 mL) and water ( ₂ mL), then _Cs2CO3 (5.6 g, 17.1 mmol, 2.0 equiv) was added under nitrogen atmosphere , 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron (2.1 g, 8.5 mmol) , 1.0 equiv) and Pd(dppf)Cl ₂ CH ₂ Cl ₂ (1.4 g, 1.7 mmol, 0.2 equiv). The reaction mixture was heated at 90°C overnight, then cooled to ambient temperature and concentrated in vacuo. 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- as a yellow solid) Alken-1-yl)-5-fluoropyridine-3-carboxylic acid methyl ester (2.2 g). LCMS Method A: [M+H] ⁺ =272. Step 2 : 6-(4,4 -Difluorocyclohexyl )-5- fluoropyridine - 3 - carboxylic acid methyl ester Methyl fluoropyridine-3-carboxylate (2.0 g, 7.4 mmol, 1.0 equiv) was dissolved in DCM (80 mL), then _PtO2 (837.2 mg, 3.7 mmol, 0.5 equiv) was added. The mixture was purged with nitrogen, placed under a hydrogen atmosphere (balloon), and stirred at ambient temperature overnight. The solids were removed by filtration and the filtrate was concentrated in vacuo to give methyl 6-(4,4-difluorocyclohexyl)-5-fluoropyridine-3-carboxylate (2 g) as an off-white oil. LCMS Method I: [M+H] ⁺ =274. Step 3 : [6-(4,4 -Difluorocyclohexyl )-5- fluoropyridin - 3 -yl ] methanol The ester (2.0 g, 7.3 mmol, 1.0 equiv) was dissolved in THF (20 mL) and cooled to 0 °C, then LiAlH4 ₍ 0.6 g, 14.6 mmol, 2.0 equiv) was added portionwise. The resulting solution was stirred at ₀ °C for 30 min and then quenched by adding _Na2SO4 • _10H2O . After removal of 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 as a white solid -Fluoropyridin-3-yl]methanol (1.1 g). LCMS Method B: [M+H] ⁺ =246. Step 4 : 5-( Bromomethyl )-2-(4,4 -difluorocyclohexyl )-3 - fluoropyridine [6-(4,4-difluorocyclohexyl)-5-fluoropyridine-3- base] methanol (1.0 g, 4.1 mmol, 1.0 equiv) was dissolved in DCM (10 mL) and cooled to 0 °C, then _PBr3 (0.4 mL, 4.1 mmol, 1.0 equiv) was added and the mixture was maintained at 0 °C . The reaction mixture was stirred at 0 °C for 1 hour and then quenched by addition of saturated aqueous NaHCO ₃ . The resulting solution was extracted with ethyl acetate and concentrated in vacuo to give 5-(bromomethyl)-2-(4,4-difluorocyclohexyl)-3-fluoropyridine (800 mg) as a white solid. LCMS Method A: [M+H] ⁺ =308.

步驟 1 ： 5,6- 二氟 -3- 硝基 -1 H- 吲哚將5,6-二氟-1 H-吲哚(25.0 g, 163.3 mmol, 1.0當量)溶於ACN (300 mL)中並冷卻至0℃，然後添加AgNO ₃(33.3 g, 195.9 mmol, 1.2當量)。將所得混合物攪拌15 min，然後逐批添加苯甲醯氯(27.5 g, 195.9 mmol, 1.2當量)，且將反應混合物維持於0℃下。在0℃下再過3小時之後，藉由添加冰水來將反應混合物驟冷。使用飽和NaHCO ₃水溶液將反應混合物調節至pH 8，然後使用DCM萃取並在真空下濃縮有機層。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(2:1)洗脫)來純化殘餘物以得到褐色固體形式之5,6-二氟-3-硝基-1 H-吲哚(24 g)。LCMS方法A：[M+H] ⁺= 199。 步驟 2 ： N -(5,6- 二氟 -1 H- 吲哚 -3- 基 ) 胺基甲酸第三丁基酯將5,6-二氟-3-硝基-1 H-吲哚(24.0 g, 121.1 mmol, 1.0當量)溶於MeOH (300 mL)中，然後在氮下添加Pd/C (2.4 g, wt 10%)及(Boc) ₂O (39.7 g, 181.7 mmol, 1.5當量)。使用氮吹掃混合物，置於氫氣氣氛(氣囊)下，然後在環境溫度下攪拌過夜。藉由過濾去除固體且在真空下濃縮濾液。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:4)洗脫)來純化殘餘物以得到黃色固體形式之 N-(5,6-二氟-1 H-吲哚-3-基)胺基甲酸第三丁基酯(22.0 g)。LCMS方法C：[M+H] ⁺= 269。 步驟 3 ： 5,6- 二氟 -1 H- 吲哚 -3- 胺鹽酸鹽將 N-(5,6-二氟-1 H-吲哚-3-基)胺基甲酸第三丁基酯(17.0 g, 63.4 mmol, 1.0當量)溶於HCl/1,4-二噁烷(4N, 200 mL)中。將所得混合物在環境溫度下攪拌30 min且然後在真空下濃縮以得到黃色固體形式之5,6-二氟-1H-吲哚-3-胺鹽酸鹽(12.0 g)。LCMS方法C：[M+H] ⁺= 169。 使用與針對中間體1B所闡述相同之方法來製備下列中間體。 中間體 起始材料 結構 LCMS 數據 中間體 2B

方法E： MS-ESI: 185 [M+H] ⁺ 中間體 3B

方法E： MS-ESI: 203 [M+H] ⁺ 中間體 4B

方法E： MS-ESI: 181 [M+H] ⁺ 中間體 5B

方法E： MS-ESI: 185 [M+H] ⁺ Scheme 1B : Synthesis of Intermediate 1B (5,6 -difluoro -1H- indol- 3 - amine hydrochloride )

Step 1 : 5,6 -Difluoro - 3 -nitro - 1H - indole 5,6-Difluoro- 1H -indole (25.0 g, 163.3 mmol, 1.0 equiv) was dissolved in ACN (300 mL) and cooled to 0 °C, then AgNO3 ₍ 33.3 g, 195.9 mmol, 1.2 equiv) was added. The resulting mixture was stirred for 15 min, then benzyl chloride (27.5 g, 195.9 mmol, 1.2 equiv) was added in portions and the reaction mixture was maintained at 0 °C. After a further 3 hours at 0°C, the reaction mixture was quenched by addition of ice water. The reaction mixture was adjusted to pH 8 with saturated aqueous NaHCO ₃ , 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 as a brown solid - Indole (24 g). LCMS Method A: [M+H] ⁺ =199. Step 2 : 5,6 - Difluoro - 3 - nitro - 1H - indole ( 24.0 g, 121.1 mmol, 1.0 equiv) was dissolved in MeOH (300 mL), then Pd/C (2.4 g, wt 10%) and (Boc)2O (39.7 _g , 181.7 mmol, 1.5 equiv) were added under nitrogen . The mixture was purged with nitrogen, placed under a hydrogen atmosphere (balloon), and 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 -indone as a yellow solid) tert-butyl dol-3-yl)carbamate (22.0 g). 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 The ester (17.0 g, 63.4 mmol, 1.0 equiv) was dissolved in HCl/1,4-dioxane (4N, 200 mL). The resulting mixture was stirred at ambient temperature for 30 min and then concentrated in vacuo to give 5,6-difluoro-lH-indol-3-amine hydrochloride (12.0 g) as a yellow solid. LCMS method C: [M+H] ⁺ =169. The following intermediates were prepared using the same procedures as described for Intermediate IB. Intermediate starting material structure LCMS data Intermediate 2B

Method E: MS-ESI: 185 [M+H] ⁺ Intermediate 3B

Method E: MS-ESI: 203 [M+H] ⁺ Intermediate 4B

Method E: MS-ESI: 181 [M+H] ⁺ Intermediate 5B

Method E: MS-ESI: 185 [M+H] ⁺

步驟 1 ： 6-(4,4- 二氟環己 -1- 烯 -1- 基 )-5- 氟吡啶 -3- 胺將6-溴-5-氟吡啶-3-胺(500.0 mg, 2.6 mmol, 1.00當量)溶於1,4-二噁烷(10 mL)及水(1 mL)中，然後在氮氣氛下添加K ₂CO ₃(1.1 g, 7.9 mmol, 3.0當量)、2-(4,4-二氟環己-1-烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼㖦(766.8 mg, 3.1 mmol, 1.2當量)及Pd(dppf)Cl ₂(383.1 mg, 0.5 mmol, 0.2當量)。將反應混合物加熱至90℃並保持2小時，然後冷卻至環境溫度並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:2)洗脫)來純化殘餘物以得到灰白色固體形式之6-(4,4-二氟環己-1-烯-1-基)-5-氟吡啶-3-胺(420 mg)。LCMS方法C：[M+H] ⁺= 229。 步驟 2 ： 6-(4,4- 二氟環己基 )-5- 氟吡啶 -3- 胺將6-(4,4-二氟環己-1-烯-1-基)-5-氟吡啶-3-胺(400.0 mg, 1.8 mmol, 1.0當量)溶於MeOH (20 mL)中，然後添加Pd/C (10% wt., 93.3 mg)。使用氮吹掃混合物，置於氫氣氣氛(氣囊)下，然後在環境溫度下攪拌2小時。藉由過濾去除固體且在真空下濃縮濾液以得到灰白色固體形式之6-(4,4-二氟環己基)-5-氟吡啶-3-胺(300 mg)。LCMS方法C：[M+H] ⁺= 231。 使用與針對中間體6B所闡述相同之方法來製備下列中間體。 中間體 起始 材料 A 起始 材料 B 結構 LCMS 數據 中間體 7B

方法E： MS-ESI: 278 [M+H] ⁺ 中間體 8B

方法E： MS-ESI: 230 [M+H] ⁺ 中間體 9B

方法E： MS-ESI: 277 [M+H] ⁺ 中間體 10B

方法E： MS-ESI: 260 [M+H] ⁺ 中間體 11B

方法E： MS-ESI: 227 [M+H] ⁺ 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 equiv) was dissolved in 1,4-dioxane (10 mL) and water (1 mL), then K ₂ CO ₃ (1.1 g, 7.9 mmol, 3.0 equiv), 2-( 4,4-Difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron (766.8 mg, 3.1 mmol, 1.2 equiv) and Pd(dppf)Cl2 ( _383.1 mg, 0.5 mmol, 0.2 equiv). The reaction mixture was heated to 90°C for 2 hours, then cooled to ambient temperature and concentrated in vacuo. 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- as an off-white solid) En-1-yl)-5-fluoropyridin-3-amine (420 mg). LCMS method C: [M+H] ⁺ =229. Step 2 : 6-(4,4 -Difluorocyclohexyl )-5- fluoropyridin - 3 -amine -3-amine (400.0 mg, 1.8 mmol, 1.0 equiv) was dissolved in MeOH (20 mL) and Pd/C (10% wt., 93.3 mg) was added. The mixture was purged with nitrogen, placed under a hydrogen atmosphere (balloon), and stirred at ambient temperature for 2 hours. The solids were removed by filtration and the filtrate was concentrated in vacuo 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 procedures as described for Intermediate 6B. Intermediate starting material A starting material B structure LCMS data Intermediate 7B

Method E: MS-ESI: 278 [M+H] ⁺ Intermediate 8B

Method E: MS-ESI: 230 [M+H] ⁺ Intermediate 9B

Method E: MS-ESI: 277 [M+H] ⁺ Intermediate 10B

Method E: MS-ESI: 260 [M+H] ⁺ Intermediate 11B

Method E: MS-ESI: 227 [M+H] ⁺

步驟 1 ： 2-(4,4- 二氟六氫吡啶 -1- 基 )-3- 氟 -5- 硝基吡啶將2-氯-3-氟-5-硝基吡啶(10.0 g, 56.6 mmol, 1.0當量)溶於DMF (150 mL)中，然後添加Cs ₂CO ₃(37.3 g, 114.5 mmol, 2.0當量)及4,4-二氟六氫吡啶(9.8 g, 81.0 mmol, 1.4當量)。將反應混合物加熱至90℃並保持15小時，然後冷卻至環境溫度並藉由添加水來驟冷。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:3)洗脫)來純化殘餘物以得到黃色固體形式之2-(4,4-二氟六氫吡啶-1-基)-3-氟-5-硝基吡啶(13.3 g) 。LCMS方法D：[M+H] ⁺= 262。 步驟 2 ： 6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 胺將2-(4,4-二氟六氫吡啶-1-基)-3-氟-5-硝基吡啶(13.2 g, 50.5 mmol, 1.0當量)溶於MeOH (100 mL)中，然後添加Pd/C (10% wt., 2.0 g)。使用氮吹掃混合物，置於氫氣氣氛(氣囊)下，然後在環境溫度下攪拌15小時。藉由過濾去除固體且在真空下濃縮濾液。藉由急速管柱層析在矽膠上(使用二氯甲烷/甲醇(97:3)洗脫)來純化殘餘物以得到黃色固體形式之6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-胺(11.4 g)。LCMS方法D：[M+H] ⁺= 232。 使用與針對中間體12B所闡述相同之方法來製備下列中間體。 中間體 起始材料 A 起始材料 B 結構 LCMS 數據 中間體 13B

方法E： MS-ESI: 222 [M+H] ⁺ 中間體 14B

方法E： MS-ESI: 218 [M+H] ⁺ 中間體 15B

方法E： MS-ESI: 228 [M+H] ⁺ 中間體 16B

方法E： MS-ESI: 279 [M+H] ⁺ 中間體 17B

方法E： MS-ESI: 251 [M+H] ⁺ 中間體 18B

方法E： MS-ESI: 250 [M+H] ⁺ 中間體 19B

方法E： MS-ESI: 275 [M+H] ⁺ 中間體 20B

方法E： MS-ESI: 236 [M+H] ⁺ Scheme 3B : Synthesis of Intermediate 12B (6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -amine )

Step 1 : 2-(4,4 -Difluorohexahydropyridin- 1 -yl )-3 - fluoro -5- nitropyridine 2-chloro-3-fluoro-5-nitropyridine (10.0 g, 56.6 mmol , 1.0 equiv) was dissolved in DMF (150 mL), then _{Cs2CO3 (} 37.3 g, 114.5 mmol, 2.0 equiv) and 4,4-difluorohexahydropyridine (9.8 g, 81.0 mmol, 1.4 equiv) were added. The reaction mixture was heated to 90°C for 15 hours, then cooled to ambient temperature and quenched by 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-difluorohexahydropyridine-1 as a yellow solid) -yl)-3-fluoro-5-nitropyridine (13.3 g) . LCMS Method D: [M+H] ⁺ =262. Step 2 : 6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -amine Fluoro-5-nitropyridine (13.2 g, 50.5 mmol, 1.0 equiv) was dissolved in MeOH (100 mL) and Pd/C (10% wt., 2.0 g) was added. The mixture was purged with nitrogen, placed under a hydrogen atmosphere (balloon), and 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-difluorohexahydropyridine-1- as a yellow solid) yl)-5-fluoropyridin-3-amine (11.4 g). LCMS Method D: [M+H] ⁺ =232. The following intermediates were prepared using the same procedures as described for Intermediate 12B. Intermediate starting material A starting material B structure LCMS data Intermediate 13B

Method E: MS-ESI: 222 [M+H] ⁺ Intermediate 14B

Method E: MS-ESI: 218 [M+H] ⁺ Intermediate 15B

Method E: MS-ESI: 228 [M+H] ⁺ Intermediate 16B

Method E: MS-ESI: 279 [M+H] ⁺ Intermediate 17B

Method E: MS-ESI: 251 [M+H] ⁺ Intermediate 18B

Method E: MS-ESI: 250 [M+H] ⁺ Intermediate 19B

Method E: MS-ESI: 275 [M+H] ⁺ Intermediate 20B

Method E: MS-ESI: 236 [M+H] ⁺

步驟 1 ： 3- 氯 -2-(4,4- 二氟六氫吡啶 -1- 基 )-5- 硝基吡啶將2-溴-3-氯-5-硝基吡啶(10.0 g, 42.1 mmol, 1.0當量)及4,4-二氟六氫吡啶(5.6 g, 46.3 mmol, 1.1當量)溶於DMF (100 mL)中，然後添加Cs ₂CO ₃(27.4 g, 84.2 mmol, 2.0當量)。將反應混合物加熱至90℃過夜，然後冷卻至環境溫度並藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以得到褐色固體形式之3-氯-2-(4,4-二氟六氫吡啶-1-基)-5-硝基吡啶(9.5 g)。LCMS方法A：[M+H] ⁺= 278。 步驟 2 ： 5- 氯 -6-(4,4- 二氟六氫吡啶 -1- 基 ) 吡啶 -3- 胺將3-氯-2-(4,4-二氟六氫吡啶-1-基)-5-硝基吡啶(9.0 g, 32.4 mmol, 1.0當量)溶於EtOH (90 mL)中，然後逐份添加SnCl ₂(30.7 g, 162.1 mmol, 5.0當量)。將反應混合物加熱至60℃過夜，然後冷卻至環境溫度並藉由添加水來驟冷。使用固體NaOH將溶液調節至pH 12，使用乙酸乙酯萃取，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以得到黑色固體形式之5-氯-6-(4,4-二氟六氫吡啶-1-基)吡啶-3-胺(7.1 g)。LCMS方法E：[M+H] ⁺= 248。 使用與針對中間體21B所闡述相同之方法來製備下列中間體。 中間體 起始材料 結構 LCMS 數據 中間體 22B

方法E： MS-ESI: 295 [M+H] ⁺ Scheme 4B : Synthesis of Intermediate 21B (5- chloro -6-(4,4 -difluorohexahydropyridin- 1 -yl ) pyridin - 3 - amine )

Step 1 : 3- Chloro -2-(4,4 -difluorohexahydropyridin- 1 -yl )-5- nitropyridine 2-Bromo-3-chloro-5-nitropyridine (10.0 g, 42.1 mmol , 1.0 equiv) and 4,4-difluorohexahydropyridine (5.6 g, 46.3 mmol, 1.1 equiv) were dissolved in DMF (100 mL), then _{Cs2CO3 (} 27.4 g, 84.2 mmol, 2.0 equiv) was added. The reaction mixture was heated to 90°C overnight, then cooled to ambient temperature and quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 3-chloro-2-(4,4-difluorohexahydropyridine-1- as a brown solid yl)-5-nitropyridine (9.5 g). LCMS Method A: [M+H] ⁺ =278. Step 2 : 5- Chloro -6-(4,4 -difluorohexahydropyridin- 1 -yl ) pyridin - 3 - amine 3-chloro-2-(4,4-difluorohexahydropyridin-1-yl )-5-nitropyridine (9.0 g, 32.4 mmol, 1.0 equiv) was dissolved in EtOH (90 mL), then SnCl2 (30.7 _g , 162.1 mmol, 5.0 equiv) was added portionwise. The reaction mixture was heated to 60°C overnight, then cooled to ambient temperature and quenched by addition of water. The solution was adjusted to pH 12 with solid NaOH, extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 5-chloro-6-(4,4- as a black solid Difluorohexahydropyridin-1-yl)pyridin-3-amine (7.1 g). LCMS Method E: [M+H] ⁺ =248. The following intermediates were prepared using the same procedures as described for Intermediate 21B. Intermediate starting material structure LCMS data Intermediate 22B

Method E: MS-ESI: 295 [M+H] ⁺

步驟 1 ： 1-(4- 硝基吡啶 -2- 基 )-4-(2,2,2- 三氟乙基 ) 六氫吡嗪將2-氯-4-硝基吡啶(2.0 g, 12.6 mmol, 1.0當量)及1-(2,2,2-三氟乙基)六氫吡嗪(2.5 g, 15.1 mmol, 1.2當量)溶於1,4-二噁烷(20 mL)中，然後在氮氣氛下添加Cs ₂CO ₃(12.3 g, 37.8 mmol, 3.0當量)及XPhos Pd G3 (1.1 g, 1.3 mmol, 0.1當量)。將反應混合物加熱至80℃並保持12小時，然後冷卻至環境溫度並藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到黃色固體形式之1-(4-硝基吡啶-2-基)-4-(2,2,2-三氟乙基)六氫吡嗪(1.2 g)。LCMS方法A：[M+H] ⁺= 291。 步驟 2 ： 2-(4-(2,2,2- 三氟乙基 ) 六氫吡嗪 -1- 基 ) 吡啶 -4- 胺將1-(4-硝基吡啶-2-基)-4-(2,2,2-三氟乙基)六氫吡嗪(1.0 g, 3.4 mmol, 1.0當量)溶於MeOH (15 mL)中，然後在氮氣氛下添加Pd/C (10% wt., 36.7 mg)。使用氮吹掃混合物，置於氫氣氣氛(氣囊)下，然後在環境溫度下攪拌過夜。藉由過濾去除固體且在真空下濃縮濾液以得到褐色固體形式之粗製2-(4-(2,2,2-三氟乙基)六氫吡嗪-1-基)吡啶-4-胺(560.0 mg)，其未經進一步純化即直接用於下一步驟中。LCMS方法E：[M+H] ⁺= 261。 使用與針對中間體23B所闡述相同之方法來製備下列中間體。 中間體 起始 材料 A 起始 材料 B 結構 LCMS 數據 中間體 24B

方法E： MS-ESI: 214 [M+H] ⁺ Scheme 5B : Synthesis of Intermediate 23B (2-(4-(2,2,2- trifluoroethyl ) hexahydropyrazin- 1 -yl ) pyridin - 4 - amine )

Step 1 : 1-(4 -Nitropyridin -2- yl )-4-(2,2,2- trifluoroethyl ) hexahydropyrazine was mixed with 2-chloro-4-nitropyridine (2.0 g, 12.6 mmol, 1.0 equiv) and 1-(2,2,2-trifluoroethyl)hexahydropyrazine (2.5 g, 15.1 mmol, 1.2 equiv) were dissolved in 1,4-dioxane (20 mL), then _{Cs2CO3 (} 12.3 g, 37.8 mmol, 3.0 equiv) and XPhos Pd G3 (1.1 g, 1.3 mmol, 0.1 equiv) were added under nitrogen atmosphere. The reaction mixture was heated to 80°C for 12 hours, then cooled to ambient temperature and quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried _over anhydrous _Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:1) to give 1-(4-nitropyridin-2-yl)- as a yellow solid 4-(2,2,2-Trifluoroethyl)hexahydropyrazine (1.2 g). LCMS Method A: [M+H] ⁺ =291. Step 2 : 2-(4-(2,2,2- Trifluoroethyl ) hexahydropyrazin- 1 -yl ) pyridin - 4 - amine 1-(4-nitropyridin-2-yl)-4 -(2,2,2-Trifluoroethyl)hexahydropyrazine (1.0 g, 3.4 mmol, 1.0 equiv) was dissolved in MeOH (15 mL), then Pd/C (10% wt. , 36.7 mg). The mixture was purged with nitrogen, placed under a hydrogen atmosphere (balloon), and stirred at ambient temperature overnight. The solids were removed by filtration and the filtrate was concentrated in vacuo to give crude 2-(4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl)pyridin-4-amine as a brown solid ( 560.0 mg), which was used directly in the next step without further purification. LCMS Method E: [M+H] ⁺ =261. The following intermediates were prepared using the same procedures as described for Intermediate 23B. Intermediate starting material A starting material B structure LCMS data Intermediate 24B

Method E: MS-ESI: 214 [M+H] ⁺

步驟 1 ： 4,4- 二氟 -1- 甲基環己烷 -1- 醇將4,4-二氟環己烷-1-酮(10.0 g, 74.6 mmol, 1.0當量)溶於Et ₂O (100.0 mL)中並冷卻至0℃，然後逐滴添加MeMgBr (3 M於THF中，80.0 mL, 240 mmol, 3.0當量)，且將溶液維持於0℃下。將反應混合物在0℃下攪拌2小時且然後藉由添加冰水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以得到黃色固體形式之4,4-二氟-1-甲基環己烷-1-醇(9.5 g)。LCMS方法A：[M+H] ⁺= 151。 步驟 2 ：草酸 4,4- 二氟 -1- 甲基環己基酯甲基酯將4,4-二氟-1-甲基環己烷-1-醇(10.0 g, 66.6 mmol, 1.0當量)及DMAP (0.8 g, 6.7 mmol, 0.1當量)溶於DCM (200 mL)中，然後添加TEA (18.7 mL, 133.2 mmol, 2.0當量)。隨後逐滴添加氯草酸甲酯(6.1 mL, 67.3 mmol, 1.0當量)。將反應混合物在環境溫度下攪拌1小時且然後在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:20)洗脫)來純化殘餘物以得到黃色油狀物形式之草酸4,4-二氟-1-甲基環己基酯甲基酯(11.2 g)。LCMS方法A：[M+H] ⁺= 237。 步驟 3 ： 2-((4,4- 二氟 -1- 甲基環己基 ) 氧基 )-2- 側氧基乙酸銫將草酸4,4-二氟-1-甲基環己基酯甲基酯(5.0 g, 21.2 mmol, 1.0當量)溶於THF (50 mL)及水(50 mL)中，然後添加CsOH (3.2 g, 20.9 mmol, 1.0當量)。將反應混合物在環境溫度下攪拌1小時且然後在真空下濃縮以得到白色固體形式之2-((4,4-二氟-1-甲基環己基)氧基)-2-側氧基乙酸銫(5.2 g)。LCMS方法A：[M+H] ⁺= 272。 步驟 4 ： 6-(4,4- 二氟 -1- 甲基環己基 )-5- 氟吡啶 -3- 甲酸甲酯將2-((4,4-二氟-1-甲基環己基)氧基)-2-側氧基乙酸銫(5.0 g, 14.1 mmol, 1.0當量)溶於DMSO (30 mL)中，然後添加(NH ₄) ₂S ₂O ₈(2.3 g, 9.9 mmol, 0.7當量)、Ir[dF(CF ₃)ppy] ₂(dtbpy)PF ₆(1.6 g, 1.4 mmol, 0.1當量)及5-氟吡啶-3-甲酸甲酯(1.8 g, 11.3 mmol, 0.8當量)。在1000 rpm攪拌下使用Royal Blue (450 nm) LED光將所得溶液照耀3小時，且然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:10)洗脫)來純化殘餘物以得到黃色油狀物形式之6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-甲酸甲酯(2.5 g)。LCMS方法A：[M+H] ⁺= 272。 步驟 5 ： 6-(4,4- 二氟 -1- 甲基環己基 )-5- 氟吡啶 -3- 甲酸將6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-甲酸甲酯(2.5 g, 8.7 mmol, 1.0當量)溶於MeOH (25 mL)及水(25 mL)中，然後添加NaOH (1.0 g, 26.0 mmol, 3.0當量)。將反應混合物加熱至80℃並保持1小時，然後冷卻至環境溫度並在真空下濃縮。藉由急速製備型HPLC使用下列條件來純化殘餘物：管柱，C18矽膠；移動相，在30 min內自ACN/H ₂O=0%增至ACN/H ₂O=100%；檢測器，254 nm。此會產生黃色油狀物形式之6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-甲酸(2.1 g)。LCMS方法C：[M+H] ⁺= 274 步驟 6 ： 6-(4,4- 二氟 -1- 甲基環己基 )-5- 氟吡啶 -3- 羰基疊氮化物將6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-甲酸(1.0 g, 3.7 mmol, 1.0當量)溶於THF (20 mL)中，然後添加TEA (1.0 mL, 7.3 mmol, 2.0當量)及DPPA (1.5 g, 5.5 mmol, 1.5當量)。將反應混合物在環境溫度下攪拌過夜且然後在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:50)洗脫)來純化殘餘物以得到白色油狀物形式之6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-羰基疊氮化物(900.0 mg)。LCMS方法E：[M+H] ⁺= 299。 步驟 7 ： N -[6-(4,4- 二氟 -1- 甲基環己基 )-5- 氟吡啶 -3- 基 ] 胺基甲酸第三丁基酯將6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-羰基疊氮化物(1.0 g, 3.4 mmol, 1.0當量)溶於t-BuOH (20 mL)中。將反應混合物加熱至80℃並保持2小時，然後冷卻至環境溫度並在真空下濃縮。此會產生白色固體形式之 N-[6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-基]胺基甲酸第三丁基酯(850.0 mg)。LCMS方法A：[M+H] ⁺= 345。 步驟 8 ： 6-(4,4- 二氟 -1- 甲基環己基 )-5- 氟吡啶 -3- 胺將 N-[6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-基]胺基甲酸第三丁基酯(900.0 mg, 2.6 mmol, 1.0當量)溶於HCl/1,4-二噁烷(4N, 20 mL)中。將所得混合物在環境溫度下攪拌過夜。藉由過濾收集固體並乾燥以得到黃色油狀物形式之6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-胺(350.0 mg)。LCMS方法E：[M+H] ⁺= 245。 使用與針對中間體25B所闡述相同之方法來製備下列中間體。 中間體 起始材料 結構 LCMS 數據 中間體 26B

方法E：MS-ESI:209 [M+H] ⁺ Scheme 6B : Synthesis of Intermediate 25B (6-(4,4 -difluoro - 1 -methylcyclohexyl )-5- fluoropyridin - 3 -amine )

Step 1 : 4,4 -Difluoro - 1 -methylcyclohexane- 1 - ol 4,4-Difluorocyclohexane-1-one (10.0 g, 74.6 mmol, 1.0 equiv) was dissolved in _Et2O (100.0 mL) and cooled to 0 °C, then MeMgBr (3 M in THF, 80.0 mL, 240 mmol, 3.0 equiv) was added dropwise and the solution was maintained at 0 °C. The reaction mixture was stirred at 0°C for 2 hours and then quenched by addition of ice water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 4,4-difluoro-1-methylcyclohexane-1-ol as a yellow solid ( 9.5 g). LCMS Method A: [M+H] ⁺ =151. Step 2 : 4,4 -Difluoro - 1 -methylcyclohexyl oxalate methyl ester 4,4-Difluoro-1-methylcyclohexane-1-ol (10.0 g, 66.6 mmol, 1.0 equiv) and DMAP (0.8 g, 6.7 mmol, 0.1 equiv) were dissolved in DCM (200 mL), then TEA (18.7 mL, 133.2 mmol, 2.0 equiv) was added. Methyl chlorooxalate (6.1 mL, 67.3 mmol, 1.0 equiv) was then added dropwise. The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:20) to give 4,4-difluoro-1-methyl oxalate as a yellow oil Cyclohexyl ester methyl ester (11.2 g). LCMS Method A: [M+H] ⁺ =237. Step 3 : Cesium 2-((4,4 -Difluoro - 1 -methylcyclohexyl ) oxy )-2- oxoacetate 4,4-difluoro-1-methylcyclohexyl oxalate methyl The ester (5.0 g, 21.2 mmol, 1.0 equiv) was dissolved in THF (50 mL) and water (50 mL), then CsOH (3.2 g, 20.9 mmol, 1.0 equiv) was added. The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated in vacuo to give 2-((4,4-difluoro-1-methylcyclohexyl)oxy)-2-pendoxoacetic acid as a white solid Cesium (5.2 g). LCMS Method A: [M+H] ⁺ =272. Step 4 : 6-(4,4 -Difluoro - 1 -methylcyclohexyl )-5- fluoropyridine - 3 - carboxylic acid methyl ester was mixed with 2-((4,4-difluoro-1-methylcyclohexyl) Cesium oxy)-2-oxoacetate (5.0 g, 14.1 mmol, 1.0 equiv) was dissolved in DMSO (30 mL), then (NH ₄ ) ₂ S ₂ O ₈ (2.3 g, 9.9 mmol, 0.7 equiv) was added ), Ir[dF( _CF3 )ppy] ₂ (dtbpy) _PF6 (1.6 g, 1.4 mmol, 0.1 equiv) and methyl 5-fluoropyridine-3-carboxylate (1.8 g, 11.3 mmol, 0.8 equiv). The resulting solution was irradiated with Royal Blue (450 nm) LED light for 3 hours with stirring at 1000 rpm and then quenched by adding water. The resulting solution was extracted with ethyl acetate and concentrated in vacuo. 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- as a yellow oil) Methylcyclohexyl)-5-fluoropyridine-3-carboxylic acid methyl ester (2.5 g). LCMS Method A: [M+H] ⁺ =272. Step 5 : 6-(4,4 -Difluoro - 1 -methylcyclohexyl )-5- fluoropyridine - 3 - carboxylic acid 6-(4,4-difluoro-1-methylcyclohexyl)-5- Methyl fluoropyridine-3-carboxylate (2.5 g, 8.7 mmol, 1.0 equiv) was dissolved in MeOH (25 mL) and water (25 mL), then NaOH (1.0 g, 26.0 mmol, 3.0 equiv) was added. The reaction mixture was heated to 80°C for 1 hour, then cooled to ambient temperature and concentrated in vacuo. The residue was purified by flash prep HPLC using the following conditions: column, C18 silica; mobile phase, ACN/ _H2O =0% to ACN/ _H2O =100% in 30 min; detector, 254 nm. 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 -carbonylazide 6-(4, 4-Difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylic acid (1.0 g, 3.7 mmol, 1.0 equiv) was dissolved in THF (20 mL), then TEA (1.0 mL, 7.3 mmol, 2.0 equiv) and DPPA (1.5 g, 5.5 mmol, 1.5 equiv). The reaction mixture was stirred at ambient temperature overnight and then concentrated in vacuo. 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- as a white oil) Methylcyclohexyl)-5-fluoropyridine-3-carbonylazide (900.0 mg). LCMS Method E: [M+H] ⁺ =299. Step 7 : N- [6-(4,4 -Difluoro - 1 -methylcyclohexyl )-5- fluoropyridin - 3 -yl ] carbamic acid tert-butyl ester Fluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carbonylazide (1.0 g, 3.4 mmol, 1.0 equiv) 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 in vacuo. This gave tert-butyl N- [6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]carbamate as a white solid (850.0 mg). LCMS Method A: [M+H] ⁺ =345. Step 8 : 6-(4,4 -Difluoro - 1 -methylcyclohexyl )-5- fluoropyridin - 3 -amine N- [6-(4,4-difluoro-1-methylcyclohexyl) - tert-butyl 5-fluoropyridin-3-yl]carbamate (900.0 mg, 2.6 mmol, 1.0 equiv) was dissolved in HCl/1,4-dioxane (4N, 20 mL). 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 procedures as described for Intermediate 25B. Intermediate starting material structure LCMS data Intermediate 26B

Method E: MS-ESI: 209 [M+H] ⁺

將2,6-二氯吡啶-4-胺(1.0 g, 6.1 mmol, 1.0當量)溶於4,4-二氟六氫吡啶(5.0 mL)中。將反應混合物加熱至150℃過夜，然後冷卻至環境溫度並藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水硫酸鈉乾燥並在真空下濃縮。藉由急速製備型HPLC使用下列條件來純化殘餘物：管柱，C18矽膠；移動相，在30 min內自H2O/MeCN=90:10增至H2O/MeCN=10:90；檢測器，254 nm。此會產生黃色固體形式之2-氯-6-(4,4-二氟六氫吡啶-1-基)吡啶-4-胺(260.0 mg)。LCMS方法E：[M+H] ⁺= 248。 Scheme 7B : Synthesis of Intermediate 27B (2- chloro -6-(4,4 -difluorohexahydropyridin- 1 -yl ) pyridin - 4 - amine )

2,6-Dichloropyridin-4-amine (1.0 g, 6.1 mmol, 1.0 equiv) was dissolved in 4,4-difluorohexahydropyridine (5.0 mL). The reaction mixture was heated to 150°C overnight, then cooled to ambient temperature and quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash prep HPLC using the following conditions: column, C18 silica; mobile phase, from H2O/MeCN=90:10 to H2O/MeCN=10:90 in 30 min; detector, 254 nm . This gave 2-chloro-6-(4,4-difluorohexahydropyridin-1-yl)pyridin-4-amine (260.0 mg) as a yellow solid. LCMS Method E: [M+H] ⁺ =248.

步驟 1 ： 3- 氟 -5- 硝基 -5,6- 二氫 -2 H-[2,3- 聯吡啶 ]-1- 甲酸第三丁基酯將2-氯-3-氟-5-硝基吡啶(2.0 g, 11.3 mmol, 1.0當量)及3-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-5,6-二氫-2 H-吡啶-1-甲酸第三丁基酯(5.3 g, 17.0 mmol, 1.5當量)溶於1,4-二噁烷(30 mL)及水(3 mL)中，然後在氮氣氛下添加Cs ₂CO ₃(11.1 g, 34.0 mmol, 3.0當量)及Xphos Pd G3 (959.0 mg, 1.1 mmol, 0.1當量)。將反應混合物加熱至60℃過夜，然後冷卻至環境溫度並藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，藉由無水硫酸鈉乾燥並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:5)洗脫)來純化殘餘物以得到黃色固體形式之3-氟-5-硝基-5,6-二氫-2 H-[2,3-聯吡啶]-1-甲酸第三丁基酯(412.1 mg)。LCMS方法C：[M+H] ⁺= 324。 步驟 2 ： 3- 氟 -5- 硝基 -1,2,5,6- 四氫 -2,3- 聯吡啶鹽酸鹽將3-氟-5-硝基-5,6-二氫-2 H-[2,3-聯吡啶]-1-甲酸第三丁基酯(600.0, 1.9 mmol, 1.0當量)溶於HCl/1,4-二噁烷(4N, 15 mL)中。將反應混合物在環境溫度下攪拌過夜，然後在真空下濃縮以得到淺黃色固體形式之3-氟-5-硝基-1,2,5,6-四氫-2,3-聯吡啶鹽酸鹽(315.2 mg)。LCMS方法A：[M+H] ⁺= 224。 步驟 3 ： 3- 氟 -5- 硝基 -1-(2,2,2- 三氟乙基 )-5,6- 二氫 -2 H-2,3- 聯吡啶將3-氟-5-硝基-1,2,5,6-四氫-2,3-聯吡啶鹽酸鹽(467.5 mg, 1.8 mmol, 1.0當量)及三氟甲烷磺酸2,2,2-三氟乙基酯(499.1 mg, 2.2 mmol, 1.2當量)溶於ACN (10 mL)中，然後添加K ₂CO ₃(495.3 mg, 3.6 mmol, 2.0當量)。將反應混合物在環境溫度下攪拌3小時且然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，藉由無水硫酸鈉乾燥並在真空下濃縮。藉由急速製備型HPLC使用下列條件來純化殘餘物：管柱，C18矽膠；移動相，在30 min內自H ₂O/MeCN=90:10增至H ₂O/MeCN=10:90；檢測器，254nm。此會產生黃色固體形式之3-氟-5-硝基-1-(2,2,2-三氟乙基)-5,6-二氫-2 H-2,3-聯吡啶(250.0 mg)。LCMS方法A：[M+H] ⁺= 306。 步驟 4 ： 5- 氟 -6-[1-(2,2,2- 三氟乙基 ) 六氫吡啶 -3- 基 ] 吡啶 -3- 胺將3-氟-5-硝基-1-(2,2,2-三氟乙基)-5,6-二氫-2 H-2,3-聯吡啶(250.0 mg, 0.8 mmol, 1.0當量)溶於MeOH (6 mL)中，然後在氮下添加Pd/C (10% w%, 25.3 mg)。使用氮吹掃混合物，置於氫氣氣氛(氣囊)下，然後在環境溫度下攪拌過夜。藉由過濾去除固體且在真空下濃縮濾液。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到黃色油狀物形式之5-氟-6-[1-(2,2,2-三氟乙基)六氫吡啶-3-基]吡啶-3-胺(198.2 mg)。LCMS方法E：[M+H] ⁺= 278。 Scheme 8B : Synthesis of Intermediate 28B (5- fluoro -6-(1-(2,2,2- trifluoroethyl ) hexahydropyridin- 3 -yl ) pyridin - 3 - amine )

Step 1 : 3- Fluoro -5- nitro -5,6 -dihydro -2H-[ 2,3 -bipyridine ]-1 -carboxylic acid tert-butyl ester Nitropyridine (2.0 g, 11.3 mmol, 1.0 equiv) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-2-yl)-5,6-di Hydro- 2H -pyridine-1-carboxylic acid tert-butyl ester (5.3 g, 17.0 mmol, 1.5 equiv) was dissolved in 1,4-dioxane (30 mL) and water (3 mL), then under nitrogen atmosphere _{Cs2CO3 (} 11.1 g, 34.0 mmol, 3.0 equiv) and Xphos Pd G3 (959.0 mg, 1.1 mmol, 0.1 equiv) were added under. The reaction mixture was heated to 60°C overnight, then cooled to ambient temperature and quenched by addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:5) to give 3-fluoro-5-nitro-5,6-di as a yellow solid Hydrogen-2H-[2,3-bipyridine]-1-carboxylic acid tert-butyl ester (412.1 mg). LCMS Method C: [M+H] ⁺ =324. Step 2 : 3- Fluoro -5- nitro -1,2,5,6 -tetrahydro -2,3 -bipyridine hydrochloride 3-fluoro-5-nitro-5,6-dihydro-2 H- [2,3-bipyridine]-1-carboxylic acid tert-butyl ester (600.0, 1.9 mmol, 1.0 equiv) was dissolved in HCl/1,4-dioxane (4N, 15 mL). The reaction mixture was stirred at ambient temperature overnight, then concentrated in vacuo to give 3-fluoro-5-nitro-1,2,5,6-tetrahydro-2,3-bipyridine hydrochloride as a pale yellow solid Salt (315.2 mg). LCMS Method A: [M+H] ⁺ =224. Step 3 : 3- Fluoro -5- nitro- 1-(2,2,2- trifluoroethyl )-5,6 -dihydro - 2H -2,3 -bipyridine Nitro-1,2,5,6-tetrahydro-2,3-bipyridine hydrochloride (467.5 mg, 1.8 mmol, 1.0 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (499.1 mg, 2.2 mmol, 1.2 equiv) was dissolved in ACN ( ₁₀ mL), then K2CO3 ( _495.3 mg, 3.6 mmol, 2.0 equiv) was added. The reaction mixture was stirred at ambient temperature for 3 hours and then quenched by addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash prep HPLC using the following conditions: column, C18 silica; mobile phase, from _H2O /MeCN=90:10 to _H2O /MeCN=10:90 in 30 min; detection device, 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 ) hexahydropyridin- 3 -yl ] pyridin - 3 - amine 2,2,2-Trifluoroethyl)-5,6-dihydro- 2H -2,3-bipyridine (250.0 mg, 0.8 mmol, 1.0 equiv) was dissolved in MeOH (6 mL) and then under nitrogen Pd/C (10% w%, 25.3 mg) was added. The mixture was purged with nitrogen, placed under a hydrogen atmosphere (balloon), and 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, 5-fluoro-6-[1-(2, 2,2-Trifluoroethyl)hexahydropyridin-3-yl]pyridin-3-amine (198.2 mg). LCMS Method E: [M+H] ⁺ =278.

步驟 1 ： 4-(3- 氟 -5- 硝基吡啶 -2- 基 ) 六氫吡嗪 -1- 甲酸第三丁基酯將2-氯-3-氟-5-硝基吡啶(2.0 g, 11.3 mmol, 1.0當量)溶於ACN (20 mL)中，然後添加六氫吡嗪-1-甲酸第三丁基酯(2.0 g, 11.3 mmol, 1.5當量)及K ₂CO ₃(6.3 g, 45.3 mmol, 4.0當量)。將反應混合物加熱至80℃過夜，然後冷卻至環境溫度並藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，藉由無水硫酸鈉乾燥並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到黃色固體形式之4-(3-氟-5-硝基吡啶-2-基)六氫吡嗪-1-甲酸第三丁基酯(2.1 g)。LCMS方法A：[M+H] ⁺= 327。 步驟 2 ： 1-(3- 氟 -5- 硝基吡啶 -2- 基 ) 六氫吡嗪將4-(3-氟-5-硝基吡啶-2-基)六氫吡嗪-1-甲酸第三丁基酯(2.1 g, 6.4 mmol, 1.0當量)溶於HCl/1,4-二噁烷(4N, 40 mL)中。將反應混合物在環境溫度下攪拌過夜並在真空下濃縮。藉由急速製備型HPLC使用下列條件來純化殘餘物：管柱，C18矽膠；移動相，在30 min內自H ₂O/MeCN=90:10增至H ₂O/MeCN=10:90；檢測器，254nm。此會產生黃色油狀物形式之1-(3-氟-5-硝基吡啶-2-基)六氫吡嗪(1.1 g)。LCMS方法A：[M+H] ⁺= 227。 步驟 3 ： 1-(3- 氟 -5- 硝基吡啶 -2- 基 )-4-(2- 甲氧基乙基 ) 六氫吡嗪將1-(3-氟-5-硝基吡啶-2-基)六氫吡嗪(1.0 g, 4.4 mmol, 1.0當量)及2-溴乙基甲基醚(0.9 g, 6.6 mmol, 1.5當量)溶於ACN (20 mL)中，然後添加K ₂CO ₃(1.2 g, 8.8 mmol, 2.0當量)。將反應混合物加熱至80℃過夜，然後冷卻至環境溫度並藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，藉由無水硫酸鈉乾燥並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到黃色固體形式之1-(3-氟-5-硝基吡啶-2-基)-4-(2-甲氧基乙基)六氫吡嗪(1.0 g)。LCMS方法A：[M+H] ⁺= 285。 步驟 4 ： 5- 氟 -6-[4-(2- 甲氧基乙基 ) 六氫吡嗪 -1- 基 ] 吡啶 -3- 胺將1-(3-氟-5-硝基吡啶-2-基)-4-(2-甲氧基乙基)六氫吡嗪(1.1 g, 3.9 mmol, 1.0當量)溶於MeOH (20 mL)中，然後在氮下添加Pd/C (10% wt., 110.1 mg)。使用氮吹掃混合物，置於氫氣氣氛(氣囊)下，然後在環境溫度下攪拌過夜。藉由過濾去除固體且在真空下濃縮濾液。藉由急速製備型HPLC使用下列條件來純化殘餘物：管柱，C18矽膠；移動相，在30 min內自H ₂O/MeCN=90:10增至H ₂O/MeCN=10:90；檢測器，254nm。此會產生黃色固體形式之5-氟-6-[4-(2-甲氧基乙基)六氫吡嗪-1-基]吡啶-3-胺(805.2 mg)。LCMS方法D：[M+H] ⁺= 255。 Scheme 9B : Synthesis of Intermediate 29B (5- fluoro -6-(4-(2 -methoxyethyl ) hexahydropyrazin- 1 -yl ) pyridin - 3 - amine )

Step 1 : 2 - Chloro - 3 - fluoro - 5 - nitropyridine (2.0 g , 11.3 mmol, 1.0 equiv) was dissolved in ACN (20 mL), followed by the addition of tert-butyl hexahydropyrazine-1-carboxylate (2.0 g, 11.3 mmol, 1.5 equiv) and K ₂ CO ₃ (6.3 g, 45.3 mmol, 4.0 equiv). The reaction mixture 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, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:1) to give 4-(3-fluoro-5-nitropyridine-2 as a yellow solid) -yl) tert-butyl hexahydropyrazine-1-carboxylate (2.1 g). LCMS Method A: [M+H] ⁺ =327. Step 2 : 1-(3- Fluoro -5- nitropyridin -2- yl ) hexahydropyrazine 4-(3-fluoro-5-nitropyridin-2-yl)hexahydropyrazine-1-carboxylic acid The tert-butyl ester (2.1 g, 6.4 mmol, 1.0 equiv) was dissolved in HCl/1,4-dioxane (4N, 40 mL). The reaction mixture was stirred at ambient temperature overnight and concentrated in vacuo. The residue was purified by flash prep HPLC using the following conditions: column, C18 silica; mobile phase, from _H2O /MeCN=90:10 to _H2O /MeCN=10:90 in 30 min; detection device, 254nm. This gave 1-(3-fluoro-5-nitropyridin-2-yl)hexahydropyrazine (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 ) hexahydropyrazine was converted to 1-(3-fluoro-5-nitropyridine- 2-yl)hexahydropyrazine (1.0 g, 4.4 mmol, 1.0 equiv) and 2-bromoethyl methyl ether (0.9 g, 6.6 mmol, 1.5 equiv) were dissolved in ACN ( ₂₀ mL), then K was added _CO3 (1.2 g, 8.8 mmol, 2.0 equiv). The reaction mixture 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, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:1) to give 1-(3-fluoro-5-nitropyridine-2 as a yellow solid) -yl)-4-(2-methoxyethyl)hexahydropyrazine (1.0 g). LCMS Method A: [M+H] ⁺ =285. Step 4 : 5- Fluoro -6-[4-(2 -methoxyethyl ) hexahydropyrazin- 1 -yl ] pyridin - 3 - amine -yl)-4-(2-methoxyethyl)hexahydropyrazine (1.1 g, 3.9 mmol, 1.0 equiv) was dissolved in MeOH (20 mL), then Pd/C (10% wt) was added under nitrogen ., 110.1 mg). The mixture was purged with nitrogen, placed under a hydrogen atmosphere (balloon), and stirred at ambient temperature overnight. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash prep HPLC using the following conditions: column, C18 silica; mobile phase, from _H2O /MeCN=90:10 to _H2O /MeCN=10:90 in 30 min; detection device, 254nm. This gave 5-fluoro-6-[4-(2-methoxyethyl)hexahydropyrazin-1-yl]pyridin-3-amine (805.2 mg) as a yellow solid. LCMS Method D: [M+H] ⁺ =255.

步驟 1 ： 6-(3,3- 二氟環丁基 )-5- 氟吡啶 -3- 甲酸甲酯將5-氟吡啶-3-甲酸甲酯(6.0 g, 38.7 mmol, 1.0當量)溶於DCE (60 mL)及水(60 mL)中，然後添加AgNO ₃(1.3 g, 7.7 mmol, 0.2當量)、Selectfluor (27.4 g, 77.4 mmol, 2.0當量)、TFA (4.4 g, 38.7 mmol, 1.0當量)及3,3-二氟環丁烷-1-甲酸(10.5 g, 77.4 mmol, 2.0當量)。將反應混合物加熱至50℃並保持24小時，然後冷卻至環境溫度。藉由過濾去除固體且在真空下濃縮濾液。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到白色固體形式之 6-(3,3-二氟環丁基)-5-氟吡啶-3-甲酸甲酯(1.4 g)。LCMS方法A：[M+H] ⁺= 246。 步驟 2 ： 6-(3,3- 二氟環丁基 )-5- 氟吡啶 -3- 甲酸將6-(3,3-二氟環丁基)-5-氟吡啶-3-甲酸甲酯(2.0 g, 8.2 mmol, 1.0當量)溶於MeOH (10 mL)及水(10 mL)中，然後添加LiOH (390.7 mg, 16.3 mmol, 2.0當量)。將反應混合物加熱至80℃並保持30 min，然後冷卻至環境溫度並在真空下濃縮。使用水稀釋殘餘物，使用HCl水溶液(2 M)調節至pH 5，使用乙酸乙酯萃取並在真空下濃縮以得到白色固體形式之6-(3,3-二氟環丁基)-5-氟吡啶-3-甲酸(1.5 g)。LCMS方法D：[M+H] ⁺= 232。 步驟 3 ： 6-(3,3- 二氟環丁基 )-5- 氟吡啶 -3- 羰基疊氮化物將6-(3,3-二氟環丁基)-5-氟吡啶-3-甲酸(2.0 g, 8.7 mmol, 1.0當量)及TEA (2.4 mL, 17.3 mmol, 2.0當量)溶於THF (100 mL)中，然後添加DPPA (3.6 g, 13.0 mmol, 1.5當量)。將反應混合物在環境溫度下攪拌16小時，然後在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到白色固體形式之6-(3,3-二氟環丁基)-5-氟吡啶-3-羰基疊氮化物(1.5 g)。LCMS方法A：[M+H] ⁺= 257。 步驟 4 ： N -[6-(3,3- 二氟環丁基 )-5- 氟吡啶 -3- 基 ] 胺基甲酸第三丁基酯將6-(3,3-二氟環丁基)-5-氟吡啶-3-羰基疊氮化物(1.5 g, 5.9 mmol, 1.0當量)溶於 t-BuOH (50 mL)中。將所得溶液加熱至80℃並保持16小時，然後冷卻至環境溫度並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到白色固體形式之 N-[6-(3,3-二氟環丁基)-5-氟吡啶-3-基]胺基甲酸第三丁基酯(1.5 g)。LCMS方法G：[M+H] ⁺= 303。 步驟 5 ： 6-(3,3- 二氟環丁基 )-5- 氟吡啶 -3- 胺將 N-[6-(3,3-二氟環丁基)-5-氟吡啶-3-基]胺基甲酸第三丁基酯(1.5 g, 5.0 mmol, 1.0當量)溶於HCl/1,4-二噁烷(4N, 40 mL)中。將反應混合物在環境溫度下攪拌16小時並在真空下濃縮以得到白色固體形式之6-(3,3-二氟環丁基)-5-氟吡啶-3-胺鹽酸鹽(1.0 g)。LCMS方法C：[M+H] ⁺= 203。 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 equiv) was dissolved in DCE (60 mL) and water (60 mL) _were then added AgNO3 (1.3 g, 7.7 mmol, 0.2 equiv), Selectfluor (27.4 g, 77.4 mmol, 2.0 equiv), TFA (4.4 g, 38.7 mmol, 1.0 equiv) ) and 3,3-difluorocyclobutane-1-carboxylic acid (10.5 g, 77.4 mmol, 2.0 equiv). The reaction mixture was heated to 50°C for 24 hours and 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)- as a white solid- Methyl 5-fluoropyridine-3-carboxylate (1.4 g). 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 equiv) was dissolved in MeOH (10 mL) and water (10 mL), then LiOH (390.7 mg, 16.3 mmol, 2.0 equiv) was added. The reaction mixture was heated to 80 °C for 30 min, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, adjusted to pH 5 with aqueous HCl (2 M), extracted with ethyl acetate and concentrated in vacuo to give 6-(3,3-difluorocyclobutyl)-5- as a white solid Fluoropyridine-3-carboxylic acid (1.5 g). LCMS Method D: [M+H] ⁺ =232. Step 3 : 6-(3,3 -Difluorocyclobutyl )-5- fluoropyridine - 3 -carbonylazide 6-(3,3-difluorocyclobutyl)-5-fluoropyridine-3- Formic acid (2.0 g, 8.7 mmol, 1.0 equiv) and TEA (2.4 mL, 17.3 mmol, 2.0 equiv) were dissolved in THF (100 mL), then DPPA (3.6 g, 13.0 mmol, 1.5 equiv) was added. The reaction mixture was stirred at ambient temperature for 16 hours and then concentrated in vacuo. 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)- as a white solid- 5-Fluoropyridine-3-carbonylazide (1.5 g). LCMS Method A: [M+H] ⁺ =257. Step 4 : N- [6-(3,3 -difluorocyclobutyl )-5- fluoropyridin - 3 -yl ] carbamate tert-butyl ester to 6-(3,3-difluorocyclobutyl) )-5-fluoropyridine-3-carbonylazide (1.5 g, 5.9 mmol, 1.0 equiv) 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-difluorocyclobutane) as a white solid yl)-5-fluoropyridin-3-yl]carbamic acid tert-butyl ester (1.5 g). LCMS Method G: [M+H] ⁺ =303. Step 5 : 6-(3,3 -Difluorocyclobutyl )-5- fluoropyridin - 3 -amine N- [6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3- tert-butyl]carbamate (1.5 g, 5.0 mmol, 1.0 equiv) was dissolved in HCl/1,4-dioxane (4N, 40 mL). The reaction mixture was stirred at ambient temperature for 16 hours and concentrated in vacuo to give 6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-amine hydrochloride (1.0 g) as a white solid . LCMS method C: [M+H] ⁺ =203.

步驟 1 ： 6-[6- 氮雜螺 [2.5] 辛烷 -6- 基 ]-5- 氟吡啶 -3- 甲酸 甲酯將6-溴-5-氟吡啶-3-甲酸甲酯(5.0 g, 21.4 mmol, 1.0當量)溶於DMF (50 mL)中，然後添加K ₂CO ₃(8.9 g, 64.1 mmol, 3.0當量)及6-氮雜螺[2.5]辛烷(2.9 g, 25.6 mmol, 1.2當量)。將反應混合物加熱至80℃過夜，然後冷卻至環境溫度並藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以得到淺黃色固體形式之6-[6-氮雜螺[2.5]辛烷-6-基]-5-氟吡啶-3-甲酸甲酯(5.5 g)。LCMS方法A：[M+H] ⁺= 265。 步驟 2 ： 6-[6- 氮雜螺 [2.5] 辛烷 -6- 基 ]-5- 氟吡啶 -3- 甲酸將6-[6-氮雜螺[2.5]辛烷-6-基]-5-氟吡啶-3-甲酸甲酯(5.5 g, 20.8 mmol, 1.0當量)溶於MeOH (50 mL)及水(50 mL)中，然後添加LiOH (12.0 g, 83.2 mmol, 4.0當量)。將反應混合物在環境溫度下攪拌過夜且然後在真空下濃縮。使用水稀釋殘餘物並使用濃HCl調節至pH 5。藉由過濾收集所沈澱固體並使用水洗滌以提供淺黃色固體形式之6-[6-氮雜螺[2.5]辛烷-6-基]-5-氟吡啶-3-甲酸(5.0 g)。LCMS方法E：[M+H] ⁺= 251。 使用與針對中間體31B所闡述相同之方法來製備下列中間體。 中間體 起始 材料 A 起始 材料 B 結構 LCMS 數據 中間體 32B

方法E： MS-ESI: 261 [M+H] ⁺ 中間體 33B

方法E： MS-ESI: 261 [M+H] ⁺ 中間體 34B

方法E： MS-ESI: 281 [M+H] ⁺ 中間體 35B

方法E： MS-ESI: 265 [M+H] ⁺ 中間體 36B

方法E： MS-ESI: 308 [M+H] ⁺ 中間體 37B

方法E： MS-ESI: 324 [M+H] ⁺ 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 equiv) was dissolved in DMF (50 mL), followed by the addition of K ₂ CO ₃ (8.9 g, 64.1 mmol, 3.0 equiv) and 6-azaspiro[2.5]octane (2.9 g, 25.6 mmol, 1.2 equivalents). The reaction mixture 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, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoro as a pale yellow solid Methyl pyridine-3-carboxylate (5.5 g). LCMS Method A: [M+H] ⁺ =265. Step 2 : 6-[6 -Azaspiro [2.5] octan -6- yl ]-5- fluoropyridine - 3 - carboxylic acid 6-[6-azaspiro[2.5]octan-6-yl]- Methyl 5-fluoropyridine-3-carboxylate (5.5 g, 20.8 mmol, 1.0 equiv) was dissolved in MeOH (50 mL) and water (50 mL), then LiOH (12.0 g, 83.2 mmol, 4.0 equiv) was added. The reaction mixture was stirred at ambient temperature overnight and then concentrated in vacuo. 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 provide 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylic acid (5.0 g) as a pale yellow solid. LCMS Method E: [M+H] ⁺ =251. The following intermediates were prepared using the same procedures as described for Intermediate 31B. Intermediate starting material A starting material B structure LCMS data Intermediate 32B

Method E: MS-ESI: 261 [M+H] ⁺ Intermediate 33B

Method E: MS-ESI: 261 [M+H] ⁺ Intermediate 34B

Method E: MS-ESI: 281 [M+H] ⁺ Intermediate 35B

Method E: MS-ESI: 265 [M+H] ⁺ Intermediate 36B

Method E: MS-ESI: 308 [M+H] ⁺ Intermediate 37B

Method E: MS-ESI: 324 [M+H] ⁺

步驟 1 ： 3- 氯 -1'-(2,2,2- 三氟乙基 )-3',6'- 二氫 -2'H-[2,4'- 聯吡啶 ]-5- 甲酸甲酯將6-溴-5-氯吡啶-3-甲酸甲酯(1.0 g, 4.0 mmol, 1.0當量)及4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-1-(2,2,2-三氟乙基)-3,6-二氫-2 H-吡啶(2.3 g, 7.9 mmol, 2.0當量)溶於1,4-二噁烷(10 mL)及水(1 mL)中，然後在氮氣氛下添加Cs ₂CO ₃(2.6 g, 8.0 mmol, 2.0當量)及Pd(dppf)Cl ₂(292.1 mg, 0.4 mmol, 0.1當量)。將所得溶液加熱至90℃並保持16小時，然後冷卻至環境溫度並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到白色固體形式之3-氯-1'-(2,2,2-三氟乙基)-3',6'-二氫-2'H-[2,4'-聯吡啶]-5-甲酸甲酯(1.0 g)。LCMS方法A：[M+H] ⁺= 335。 步驟 2 ： 5- 氯 -6-[1-(2,2,2- 三氟乙基 ) 六氫吡啶 -4- 基 ] 吡啶 -3- 甲酸甲酯將甲基3-氯-1 (1.0 g, 3.0 mmol, 1.0當量)溶於DCM (20 mL)中，然後添加PtO ₂(67.8 mg, 0.3 mmol, 0.1當量)。使用氮吹掃混合物，置於氫氣氣氛(氣囊)下，然後在環境溫度下攪拌16小時。藉由過濾去除固體且在真空下濃縮濾液以得到白色固體形式之5-氯-6-[1-(2,2,2-三氟乙基)六氫吡啶-4-基]吡啶-3-甲酸甲酯(812.2 mg)。LCMS方法E：[M+H] ⁺= 337。 步驟 3 ： 5- 氯 -6-[1-(2,2,2- 三氟乙基 ) 六氫吡啶 -4- 基 ] 吡啶 -3- 甲酸將5-氯-6-[1-(2,2,2-三氟乙基)六氫吡啶-4-基]吡啶-3-甲酸甲酯(800.0 mg, 2.4 mmol, 1.0當量)溶於MeOH (5 mL)及水(5 mL)中，然後添加NaOH (190.0 mg, 4.8 mmol, 2.0當量)。將反應混合物加熱至80℃並保持30 min，然後冷卻至環境溫度並在真空下濃縮。使用水稀釋殘餘物，使用HCl水溶液(4 M)調節至pH 5。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以得到白色固體形式之5-氯-6-[1-(2,2,2-三氟乙基)六氫吡啶-4-基]吡啶-3-甲酸(585.5 mg)。LCMS方法C：[M+H] ⁺= 323。 使用與針對中間體38B所闡述相同之方法來製備下列中間體。 中間體 起始材料 A 起始材料 B 結構 LCMS 數據 中間體 39B

方法E： MS-ESI: 260 [M+H] ⁺ Scheme 12B : Synthesis of Intermediate 38B (5- chloro -6-(1-(2,2,2- trifluoroethyl ) hexahydropyridin- 4 -yl ) nicotinic acid )

Step 1 : 3- Chloro- 1'-(2,2,2- trifluoroethyl )-3',6' -dihydro- 2'H-[2,4' -bipyridine ]-5- carboxylic acid methyl Ester of 6-bromo-5-chloropyridine-3-carboxylic acid methyl ester (1.0 g, 4.0 mmol, 1.0 equiv) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxo Boron-2-yl)-1-(2,2,2-trifluoroethyl)-3,6-dihydro- 2H -pyridine (2.3 g, 7.9 mmol, 2.0 equiv) was dissolved in 1,4- Dioxane (10 mL) and water ( ₁ mL), then _Cs2CO3 (2.6 g, 8.0 mmol, 2.0 equiv) and Pd(dppf)Cl2 (292.1 _mg , 0.4 mmol, 0.1 equiv) were added under nitrogen atmosphere equivalent). 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- as a white solid) Trifluoroethyl)-3',6'-dihydro-2'H-[2,4'-bipyridine]-5-carboxylic acid methyl ester (1.0 g). LCMS Method A: [M+H] ⁺ =335. Step 2 : Methyl 5- chloro -6-[1-(2,2,2- trifluoroethyl ) hexahydropyridin- 4 -yl ] pyridine - 3 - carboxylate methyl 3-chloro-1 (1.0 g , 3.0 mmol, 1.0 equiv) was dissolved in DCM (20 mL), then PtO ₂ (67.8 mg, 0.3 mmol, 0.1 equiv) was added. The mixture was purged with nitrogen, placed under a hydrogen atmosphere (balloon), and stirred at ambient temperature for 16 hours. The solids were removed by filtration and the filtrate was concentrated under vacuum to give 5-chloro-6-[1-(2,2,2-trifluoroethyl)hexahydropyridin-4-yl]pyridine-3- as a white solid Methyl formate (812.2 mg). LCMS Method E: [M+H] ⁺ =337. Step 3 : 5- Chloro -6-[1-(2,2,2- trifluoroethyl ) hexahydropyridin- 4 -yl ] pyridine - 3 - carboxylic acid was converted to 5-chloro-6-[1-(2, 2,2-Trifluoroethyl)hexahydropyridin-4-yl]pyridine-3-carboxylic acid methyl ester (800.0 mg, 2.4 mmol, 1.0 equiv) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (190.0 mg, 4.8 mmol, 2.0 equiv) was added. The reaction mixture was heated to 80 °C for 30 min, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water and adjusted to pH 5 with aqueous HCl (4 M). The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 5-chloro-6-[1-(2,2,2-trifluoroethyl as a white solid yl)hexahydropyridin-4-yl]pyridine-3-carboxylic acid (585.5 mg). LCMS method C: [M+H] ⁺ =323. The following intermediates were prepared using the same procedures as described for Intermediate 38B. Intermediate starting material A starting material B structure LCMS data Intermediate 39B

Method E: MS-ESI: 260 [M+H] ⁺

步驟 1 ： 2-(4,4- 二氟六氫吡啶 -1- 基 )-3- 氟 -5- 碘吡啶將6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-胺(3.0 g, 13.0 mmol, 1.0當量)溶於HCl水溶液(6 M, 50 mL)中並冷卻至0℃，然後逐滴添加NaNO ₂(1.3 g, 19.5 mmol, 1.5當量)於水(2 mL)中之溶液，且將反應混合物維持於0℃下。在0℃下保持30 min之後，逐份添加KI (4.3 g, 26.0 mmol, 2.0當量)，且將溫度維持於0℃下。在完成添加之後，將溶液在0℃下再攪拌2小時。在使用水驟冷之後，使用乙酸乙酯萃取所得溶液並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到黃色固體形式之2-(4,4-二氟六氫吡啶-1-基)-3-氟-5-碘吡啶(2.0 g)。LCMS方法A：[M+H] ⁺= 343。 步驟 2 ： 1-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ] 吡唑 -4- 甲酸乙酯將2-(4,4-二氟六氫吡啶-1-基)-3-氟-5-碘吡啶(2.0 g, 5.8 mmol, 1.0當量)溶於DMF (20 mL)中，然後添加Cs ₂CO ₃(5.7 g, 17.5 mmol, 3.0當量)、1 H-吡唑-4-甲酸乙酯(1.0 g, 7.0 mmol, 1.2當量)、 N ₁ , N ₂ -二甲基環己烷-1,2-二胺(0.5 mL, 2.9 mmol, 0.5當量)及CuI (220.9 mg, 0.3 mmol, 0.2當量)。將所得溶液加熱至80℃過夜，然後冷卻至環境溫度並藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌並在真空下濃縮。　 藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到黃色固體形式之1-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]吡唑-4-甲酸乙酯(1.0 g)。LCMS方法A：[M+H] ⁺= 355。 步驟 3 ： 1-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ] 吡唑 -4- 甲酸將1-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]吡唑-4-甲酸乙酯(1.0 g, 2.8 mmol, 1.0當量)溶於MeOH (5 mL)及水(5 mL)中，然後添加NaOH (225.8 mg, 5.6 mmol, 2.0當量)。將反應混合物加熱至60℃並保持2小時，然後冷卻至環境溫度並在真空下濃縮。使用水稀釋殘餘物，使用HCl水溶液(1 M)調節至pH 6。藉由過濾收集所沈澱固體，使用水洗滌並乾燥以得到白色固體形式之1-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]吡唑-4-甲酸(510.0 mg)。LCMS方法E：[M+H] ⁺= 327。 使用與針對中間體40B所闡述相同之方法來製備下列中間體。 中間體 起始材料 結構 LCMS 數據 中間體 41B

中間體 30B

方法E： MS-ESI: 298 [M+H] ⁺ 中間體 42B

中間體 11B

方法E： MS-ESI: 322 [M+H] ⁺ Scheme 13B : Synthesis of Intermediate 40B (1-(6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl )-1H- pyrazole- 4 - carboxylic acid )

Step 1 : 2-(4,4 -Difluorohexahydropyridin- 1 -yl )-3 - fluoro -5- iodopyridine 6-(4,4-difluorohexahydropyridin-1-yl)-5- Fluoropyridin-3-amine (3.0 g, 13.0 mmol, 1.0 equiv) was dissolved in aqueous HCl (6 M, 50 mL) and cooled to 0 °C, then NaNO2 (1.3 _g , 19.5 mmol, 1.5 equiv) was added dropwise solution in water (2 mL) and the reaction mixture was maintained at 0 °C. After 30 min at 0 °C, KI (4.3 g, 26.0 mmol, 2.0 equiv) was added in portions and the temperature was maintained 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-difluorohexahydropyridine-1 as a yellow solid) -yl)-3-fluoro-5-iodopyridine (2.0 g). LCMS Method A: [M+H] ⁺ =343. Step 2 : 1-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ] pyrazole- 4 -carboxylic acid ethyl ester Fluorohexahydropyridin-1-yl)-3-fluoro-5-iodopyridine (2.0 g, 5.8 mmol, 1.0 equiv) was dissolved in DMF (20 mL), then _{Cs2CO3 (} 5.7 g, 17.5 mmol, 3.0 equiv), 1H -pyrazole-4-carboxylic acid ethyl ester (1.0 g, 7.0 mmol, 1.2 equiv), _N1 , _N2 -dimethylcyclohexane-1,2-diamine (0.5 mL, 2.9 mmol, 0.5 equiv) and CuI (220.9 mg, 0.3 mmol, 0.2 equiv). 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 in vacuo. 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-difluorohexahydrogen as a yellow solid) Pyridin-1-yl)-5-fluoropyridin-3-yl]pyrazole-4-carboxylic acid ethyl ester (1.0 g). LCMS Method A: [M+H] ⁺ =355. Step 3 : 1-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ] pyrazole- 4 - carboxylic acid was converted to 1-[6-(4,4- Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]pyrazole-4-carboxylic acid ethyl ester (1.0 g, 2.8 mmol, 1.0 equiv) was dissolved in MeOH (5 mL) and water (5 mL) ), then NaOH (225.8 mg, 5.6 mmol, 2.0 equiv) was added. The reaction mixture was heated to 60°C for 2 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and adjusted to pH 6 with aqueous HCl (1 M). The precipitated solid was collected by filtration, washed with water and dried to give 1-[6-(4,4-difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]pyridine as a white solid oxazole-4-carboxylic acid (510.0 mg). LCMS Method E: [M+H] ⁺ =327. The following intermediates were prepared using the same procedures as described for Intermediate 40B. Intermediate starting material structure LCMS data Intermediate 41B

Intermediate 30B

Method E: MS-ESI: 298 [M+H] ⁺ Intermediate 42B

Intermediate 11B

Method E: MS-ESI: 322 [M+H] ⁺

步驟 1 ： 5- 疊氮基 -2-(4,4- 二氟六氫吡啶 -1- 基 )-3- 氟吡啶將6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-胺(400.0 mg, 1.7 mmol, 1.0當量)溶於ACN (10 mL)中並冷卻至0℃，然後逐滴添加t-BuNO ₂(0.3 mL, 2.7 mmol, 1.6當量)，且將溶液維持於0℃下。將反應混合物在0℃下攪拌30 min。隨後在0℃下逐滴添加TMSN ₃(0.3 mL, 2.5 mmol, 1.5當量)。將所得混合物在環境溫度下再攪拌2小時且然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:2)洗脫)來純化殘餘物以得到黃色油狀物形式之5-疊氮基-2-(4,4-二氟六氫吡啶-1-基)-3-氟吡啶(380.0 mg)。LCMS方法A：[M+H] ⁺=258。 步驟 2 ： 1-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1,2,3- 三唑 -4- 甲酸 甲酯將5-疊氮基-2-(4,4-二氟六氫吡啶-1-基)-3-氟吡啶(350.0 mg, 1.4 mmol, 1.0當量)溶於1,4-二噁烷(3.6 mL)及水(0.4 mL)中，然後添加丙炔酸甲酯(228.8 mg, 2.7 mmol, 2.0當量)、(R)-2-((S)-1,2-二羥基乙基)-4-羥基-5-側氧基-2,5-二氫呋喃-3-醇鈉(53.9 mg, 0.3 mmol, 0.2當量)及CuSO ₄(21.7 mg, 0.1 mmol, 0.1當量)。將反應混合物在環境溫度下攪拌過夜且然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:2)洗脫)來純化殘餘物以得到黃色固體形式之 1-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,2,3-三唑-4-甲酸甲酯(150.0 mg)。LCMS方法G：[M+H] ⁺= 341。 步驟 3 ： 1-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1,2,3- 三唑 -4- 甲酸將1-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,2,3-三唑-4-甲酸甲酯(300.0 mg, 0.9 mmol, 1.0當量)溶於MeOH (3 mL)及水(7 mL)中，然後添加NaOH (70.3 mg, 1.8 mmol, 2.0當量)。將反應混合物加熱至80℃並保持2小時，且然後冷卻至環境溫度並在真空下濃縮。使用水稀釋殘餘物，使用1M HCl水溶液調節至pH 6。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以提供黃色固體形式之1-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,2,3-三唑-4-甲酸(200.1 mg)。LCMS方法E：[M+H] ⁺= 328。 使用與針對中間體43B所闡述相同之方法來製備下列中間體。 中間體 起始材料 B 結構 LCMS 數據 中間體 44B

中間體 13B

方法E：MS-ESI: 318 [M+H] ⁺ 中間體 45B

中間體 14B

方法E：MS-ESI: 314 [M+H] ⁺ 中間體 46B

中間體 15B

方法E：MS-ESI: 324 [M+H] ⁺ 中間體 47B

中間體 21B

方法E：MS-ESI: 344 [M+H] ⁺ 中間體 48B

中間體 7B

方法E：MS-ESI: 374 [M+H] ⁺ 中間體 49B

中間體 16B

方法E：MS-ESI: 375 [M+H] ⁺ 中間體 50B

中間體 6B

方法E：MS-ESI: 327 [M+H] ⁺ Scheme 14B : Intermediate 43B (1-(6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl )-1H-1,2,3 - triazole- 4- formic acid ) synthesis

Step 1 : 5- azido- 2-(4,4 -difluorohexahydropyridin- 1 -yl )-3 - fluoropyridine 6-(4,4-difluorohexahydropyridin-1-yl)- 5-Fluoropyridin-3-amine (400.0 mg, 1.7 mmol, 1.0 equiv) was dissolved in ACN (10 mL) and cooled to 0°C, then t-BuNO ₂ (0.3 mL, 2.7 mmol, 1.6 equiv) was added dropwise , and the solution was maintained at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. _TMSN3 (0.3 mL, 2.5 mmol, 1.5 equiv) was then added dropwise at 0 °C. The resulting mixture was stirred for an additional 2 hours at ambient temperature and then quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried _over anhydrous _Na2SO4 and concentrated in vacuo. 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 as a yellow oil) -Difluorohexahydropyridin-1-yl)-3-fluoropyridine (380.0 mg). LCMS Method A: [M+H] ⁺ =258. Step 2 : 1-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1,2,3- triazole - 4 - carboxylic acid methyl ester -Azido-2-(4,4-difluorohexahydropyridin-1-yl)-3-fluoropyridine (350.0 mg, 1.4 mmol, 1.0 equiv) was dissolved in 1,4-dioxane (3.6 mL) and water (0.4 mL), followed by the addition of methyl propiolate (228.8 mg, 2.7 mmol, 2.0 equiv), (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy -5-Sodium oxy-2,5-dihydrofuran-3-olate (53.9 mg, 0.3 mmol, 0.2 equiv) and CuSO4 ₍ 21.7 mg, 0.1 mmol, 0.1 equiv). The reaction mixture was stirred at ambient temperature overnight and then quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried _over anhydrous _Na2SO4 and concentrated in vacuo. 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-difluorohexahydrogen as a yellow solid) Pyridin-1-yl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylic acid methyl ester (150.0 mg). LCMS Method G: [M+H] ⁺ =341. Step 3 : 1-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1,2,3- triazole - 4 - carboxylic acid 6-(4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylic acid methyl ester (300.0 mg, 0.9 mmol, 1.0 equiv) was dissolved in MeOH (3 mL) and water (7 mL), then NaOH (70.3 mg, 1.8 mmol, 2.0 equiv) was added. The reaction mixture was heated to 80°C for 2 hours, and 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, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to afford 1-[6-(4,4-difluorohexahydropyridin-1-yl as a yellow solid )-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylic acid (200.1 mg). LCMS Method E: [M+H] ⁺ =328. The following intermediates were prepared using the same procedures as described for Intermediate 43B. Intermediate starting material B structure LCMS data Intermediate 44B

Intermediate 13B

Method E: MS-ESI: 318 [M+H] ⁺ Intermediate 45B

Intermediate 14B

Method E: MS-ESI: 314 [M+H] ⁺ Intermediate 46B

Intermediate 15B

Method E: MS-ESI: 324 [M+H] ⁺ Intermediate 47B

Intermediate 21B

Method E: MS-ESI: 344 [M+H] ⁺ Intermediate 48B

Intermediate 7B

Method E: MS-ESI: 374 [M+H] ⁺ Intermediate 49B

Intermediate 16B

Method E: MS-ESI: 375 [M+H] ⁺ Intermediate 50B

Intermediate 6B

Method E: MS-ESI: 327 [M+H] ⁺

步驟 1 ： 1-[(4- 溴 -2- 氟苯基 ) 甲基 ]-3,3- 二氟氮雜環丁烷將4-溴-1-(溴甲基)-2-氟苯(1.0 g, 3.7 mmol, 1.0當量)溶於ACN (20 mL)中，然後添加K ₂CO ₃(1.6 g, 11.2 mmol, 3.0當量)及3,3-二氟氮雜環丁烷(347.4 mg, 3.7 mmol, 1.0當量)。將反應混合物在環境溫度下攪拌過夜，且然後在真空下濃縮。使用水稀釋殘餘物，使用乙酸乙酯萃取，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以提供黃色油狀物形式之1-[(4-溴-2-氟苯基)甲基]-3,3-二氟氮雜環丁烷(821.2 mg)。LCMS方法A：[M+H] ⁺= 280。 步驟 2 ： 1-[(4- 疊氮基 -2- 氟苯基 ) 甲基 ]-3,3- 二氟氮雜環丁烷將1-[(4-溴-2-氟苯基)甲基]-3,3-二氟氮雜環丁烷(800.0 mg, 2.9 mmol, 1.0當量)溶於DMF (10 mL)中，然後在氮氣氛下添加甲基[2-(甲基胺基)乙基]胺(0.6 mL, 5.7 mmol, 2.0當量)、抗壞血酸鈉(56.9 mg, 0.3 mmol, 0.1當量)、CuI (54.4 mg, 0.3 mmol, 0.1當量)及NaN ₃(371.4 mg, 5.7 mmol, 2.0當量)。將反應混合物加熱至80℃過夜，且然後冷卻至環境溫度並使用乙酸乙酯稀釋。使用鹽水洗滌所得溶液，藉由無水Na ₂SO ₄乾燥並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:4)洗脫)來純化殘餘物以得到黃色油狀物形式之1-[(4-疊氮基-2-氟苯基)甲基]-3,3-二氟氮雜環丁烷(412.3 mg)。LCMS方法E：[M+H] ⁺= 243。 步驟 3 ： 1-[4-[(3,3- 二氟氮雜環丁 -1- 基 ) 甲基 ]-3- 氟苯基 ]-1,2,3- 三唑 -4- 甲酸甲酯將1-[(4-疊氮基-2-氟苯基)甲基]-3,3-二氟氮雜環丁烷(500.0 mg, 2.1 mmol, 1.0當量)溶於1,4-二噁烷(7 mL)及水(3 mL)中，然後添加丙炔酸甲酯(260.3 mg, 3.1 mmol, 1.5當量)、抗壞血酸鈉(41.1 mg, 0.2 mmol, 0.1當量)及CuSO ₄(33.0 mg, 0.2 mmol, 0.1當量)。將反應混合物在環境溫度下攪拌過夜，然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以得到黃色固體形式之1-[4-[(3,3-二氟氮雜環丁-1-基)甲基]-3-氟苯基]-1,2,3-三唑-4-甲酸甲酯(322.2 mg)。LCMS方法A：[M+H] ⁺= 327。 步驟 4 ： 1-[4-[(3,3- 二氟氮雜環丁 -1- 基 ) 甲基 ]-3- 氟苯基 ]-1,2,3- 三唑 -4- 甲酸將1-[4-[(3,3-二氟氮雜環丁-1-基)甲基]-3-氟苯基]-1,2,3-三唑-4-甲酸甲酯(500.0 mg, 1.5 mmol, 1.0當量)溶於MeOH (5 mL)及水(10 mL)中，然後添加NaOH (122.6 mg, 3.1 mmol, 2.0當量)。將反應混合物加熱至80℃並保持2小時，然後冷卻至環境溫度並在真空下濃縮。使用水稀釋殘餘物，使用1M HCl水溶液調節至pH 6。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌並在真空下濃縮以提供黃色固體形式之1-[4-[(3,3-二氟氮雜環丁-1-基)甲基]-3-氟苯基]-1,2,3-三唑-4-甲酸(285.2 mg)。LCMS方法E：[M+H] ⁺= 313。 Scheme 15B : Intermediate 51B (1-(4-((3,3 -difluoroazetidin- 1 -yl ) methyl )-3 - fluorophenyl )-1H-1,2,3- tris oxazole- 4 - carboxylic acid ) synthesis

Step 1 : 1-[(4- Bromo -2- fluorophenyl ) methyl ]-3,3 - difluoroazetidine 1.0 g, 3.7 mmol, 1.0 equiv) was dissolved in ACN (20 mL), then K ₂ CO ₃ (1.6 g, 11.2 mmol, 3.0 equiv) and 3,3-difluoroazetidine (347.4 mg, 3.7 mmol, 1.0 equiv). The reaction mixture was stirred at ambient temperature overnight, and then concentrated in vacuo. The residue was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to afford 1-[(4-bromo-2-fluorophenyl as a yellow oil ) methyl]-3,3-difluoroazetidine (821.2 mg). LCMS Method A: [M+H] ⁺ =280. Step 2 : 1-[(4- Azido- 2- fluorophenyl ) methyl ]-3,3 -difluoroazetidine Methyl]-3,3-difluoroazetidine (800.0 mg, 2.9 mmol, 1.0 equiv) was dissolved in DMF (10 mL), then methyl[2-(methylamino) was added under nitrogen atmosphere Ethyl]amine (0.6 mL, 5.7 mmol, 2.0 equiv), sodium ascorbate (56.9 mg, 0.3 mmol, 0.1 equiv), CuI (54.4 mg, 0.3 mmol, 0.1 equiv) and NaN3 ₍ 371.4 mg, 5.7 mmol, 2.0 equivalent). The reaction mixture was heated to 80°C overnight, and then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with brine, dried _over anhydrous _Na2SO4 and concentrated in vacuo. 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- as a yellow oil) Fluorophenyl)methyl]-3,3-difluoroazetidine (412.3 mg). LCMS Method E: [M+H] ⁺ =243. Step 3 : 1-[4-[(3,3 -Difluoroazetidin- 1 -yl ) methyl ]-3 -fluorophenyl ]-1,2,3- triazole - 4 - carboxylic acid methyl ester 1-[(4-Azido-2-fluorophenyl)methyl]-3,3-difluoroazetidine (500.0 mg, 2.1 mmol, 1.0 equiv) was dissolved in 1,4-dioxane alkane (7 mL) and water (3 mL), followed by the addition of methyl propiolate (260.3 mg, 3.1 mmol, 1.5 equiv), sodium ascorbate (41.1 mg, 0.2 mmol, 0.1 equiv) and CuSO ₄ (33.0 mg, 0.2 mmol, 0.1 equiv). The reaction mixture was stirred at ambient temperature overnight and then quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 1-[4-[(3,3-difluoroazetidine-1 as a yellow solid -yl)methyl]-3-fluorophenyl]-1,2,3-triazole-4-carboxylic acid methyl ester (322.2 mg). 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 -[4-[(3,3-Difluoroazetidin-1-yl)methyl]-3-fluorophenyl]-1,2,3-triazole-4-carboxylic acid methyl ester (500.0 mg, 1.5 mmol, 1.0 equiv) was dissolved in MeOH (5 mL) and water (10 mL), then NaOH (122.6 mg, 3.1 mmol, 2.0 equiv) was added. The reaction mixture was heated to 80°C for 2 hours, then cooled to ambient temperature and concentrated in vacuo. 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 in vacuo to provide 1-[4-[(3,3-difluoroazetidin-1-yl)methyl]-3- as a yellow solid Fluorophenyl]-1,2,3-triazole-4-carboxylic acid (285.2 mg). LCMS Method E: [M+H] ⁺ =313.

步驟 1 ： 1-[6-(4,4- 二氟 -1- 甲基環己基 )-5- 氟吡啶 -3- 基 ]-1,2,3- 三唑 -4- 甲酸乙酯將6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-胺(300.0 mg, 1.2 mmol, 1.0當量)溶於EtOH (3 mL)及AcOH (3 mL)中，然後添加2-重氮-3-側氧基丙酸乙酯(261.8 mg, 1.8 mmol, 1.5當量)。將反應混合物加熱至50℃過夜，然後冷卻至環境溫度並在真空下濃縮。此會產生黃色固體形式之1-[6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-基]-1,2,3-三唑-4-甲酸乙酯(400.0 mg)。LCMS方法A：[M+H] ⁺= 369。 步驟 2 ： 1-[6-(4,4- 二氟 -1- 甲基環己基 )-5- 氟吡啶 -3- 基 ]-1,2,3- 三唑 -4- 甲酸將1-[6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-基]-1,2,3-三唑-4-甲酸乙酯(400.0 mg, 1.1 mmol, 1.0當量)溶於MeOH (4 mL)及水(4 mL)中，然後添加NaOH (86.9 mg, 2.2 mmol, 2.0當量)。將反應混合物加熱至80℃並保持2小時，然後冷卻至環境溫度並在真空下濃縮。藉由急速製備型HPLC使用下列條件來純化殘餘物：管柱，C18矽膠；移動相，在15 min內自ACN/H ₂O=0%增至ACN/H ₂O=100%；檢測器，254 nm。此會產生黃色固體形式之1-[6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-基]-1,2,3-三唑-4-甲酸(295.2 mg)。LCMS方法E：[M+H] ⁺= 341。 使用與針對中間體52B所闡述相同之方法來製備下列中間體。 中間體 起始材料 結構 LCMS 數據 中間體 53B

中間體 8B

方法E： MS-ESI: 326 [M+H] ⁺ 中間體 54B

中間體 9B

方法E： MS-ESI: 373 [M+H] ⁺ 中間體 55B

中間體 27B

方法E： MS-ESI: 344 [M+H] ⁺ Scheme 16B : Intermediate 52B (1-(6-(4,4 -difluoro - 1 -methylcyclohexyl )-5- fluoropyridin - 3 -yl )-1H-1,2,3 - triazole- 4- formic acid ) synthesis

Step 1 : 1-[6-(4,4 -Difluoro - 1 -methylcyclohexyl )-5- fluoropyridin - 3 -yl ]-1,2,3- triazole - 4 -carboxylic acid ethyl ester -(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 ethyl 2-diazo-3-pendoxopropanoate (261.8 mg, 1.8 mmol, 1.5 equiv) was added. The reaction mixture was heated to 50°C overnight, then cooled to ambient temperature and concentrated in vacuo. This yields 1-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylic acid as a yellow solid Ethyl ester (400.0 mg). 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 6-(4,4-Difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylic acid ethyl ester (400.0 mg, 1.1 mmol, 1.0 equiv) was dissolved in MeOH (4 mL) and water (4 mL), then NaOH (86.9 mg, 2.2 mmol, 2.0 equiv) was added. The reaction mixture was heated to 80°C for 2 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was purified by flash prep HPLC using the following conditions: column, C18 silica; mobile phase, ACN/ _H2O =0% to ACN/ _H2O =100% in 15 min; detector, 254 nm. This yields 1-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylic acid as a yellow solid (295.2 mg). LCMS Method E: [M+H] ⁺ =341. The following intermediates were prepared using the same procedures as described for Intermediate 52B. Intermediate starting material structure LCMS data Intermediate 53B

Intermediate 8B

Method E: MS-ESI: 326 [M+H] ⁺ Intermediate 54B

Intermediate 9B

Method E: MS-ESI: 373 [M+H] ⁺ Intermediate 55B

Intermediate 27B

Method E: MS-ESI: 344 [M+H] ⁺

步驟 1 ： 1-(6- 溴 -5- 氟吡啶 -3- 基 )-1,2,3- 三唑 -4- 甲酸乙酯將6-溴-5-氟吡啶-3-胺(1.0 g, 5.2 mmol, 1.0當量)溶於EtOH (30 mL)及HOAc (20 mL)中，然後添加2-重氮-3-側氧基丙酸乙酯(1.1 g, 7.7 mmol, 1.5當量)。將反應混合物加熱至50℃並保持16小時，且然後冷卻至環境溫度並在真空下濃縮。使用水稀釋殘餘物且藉由過濾收集固體並乾燥以得到黃色固體形式之1-(6-溴-5-氟吡啶-3-基)-1,2,3-三唑-4-甲酸乙酯(1.2 g)。LCMS方法A：[M+H] ⁺= 315。 步驟 2 ： 1-[6-[1-( 第三丁氧基羰基 )-2,5- 二氫吡咯 -3- 基 ]-5- 氟吡啶 -3- 基 ]-1,2,3- 三唑 -4- 甲酸 乙酯將1-(6-溴-5-氟吡啶-3-基)-1,2,3-三唑-4-甲酸乙酯(1.0 g, 3.2 mmol, 1.0當量)及3-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-2,5-二氫吡咯-1-甲酸第三丁基酯(1.1 g, 3.8 mmol, 1.2當量)溶於1,4-二噁烷(20 mL)及水(2 mL)中，然後在氮氣氛下添加Pd(dppf)Cl ₂(232.2 mg, 0.3 mmol, 0.1當量)及Cs ₂CO ₃(4.1 g, 12.7 mmol, 4.0當量)。將反應混合物加熱至80℃並保持6小時，然後冷卻至環境溫度並藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到灰白色固體形式之1-[6-[1-(第三丁氧基羰基)-2,5-二氫吡咯-3-基]-5-氟吡啶-3-基]-1,2,3-三唑-4-甲酸乙酯(612.2 mg)。LCMS方法E：[M+H] ⁺= 404。 步驟 3 ： 1-[6-[1-( 第三丁氧基羰基 ) 吡咯啶 -3- 基 ]-5- 氟吡啶 -3- 基 ]-1,2,3- 三唑 -4- 甲酸 乙酯將1-[6-[1-(第三丁氧基羰基)-2,5-二氫吡咯-3-基]-5-氟吡啶-3-基]-1,2,3-三唑-4-甲酸乙酯(900.0 mg, 2.2 mmol, 1.0當量)溶於MeOH (15 mL)中，然後在氮氣氛下添加Pd/C (10% wt., 90.0 mg)。使用氮吹掃混合物，置於氫氣氣氛(氣囊)下，然後在環境溫度下攪拌過夜。藉由過濾去除固體且在真空下濃縮濾液。　藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到灰白色固體形式之1-[6-[1-(第三丁氧基羰基)吡咯啶-3-基]-5-氟吡啶-3-基]-1,2,3-三唑-4-甲酸乙酯(605.2 mg)。LCMS方法A：[M+H] ⁺= 406。 步驟 4 ： 1-[5- 氟 -6-( 吡咯啶 -3- 基 ) 吡啶 -3- 基 ]-1,2,3- 三唑 -4- 甲酸 乙酯將1-[6-[1-(第三丁氧基羰基)吡咯啶-3-基]-5-氟吡啶-3-基]-1,2,3-三唑-4-甲酸乙酯(500.0 mg, 1.2 mmol, 1.0當量)溶於DCM (3 mL)及TFA (10 mL)中。將反應混合物在環境溫度下攪拌1小時且然後藉由添加水來驟冷。使用飽和Na ₂CO ₃水溶液將溶液調節至pH 7。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水MgSO ₄乾燥並在真空下濃縮以得到灰白色固體形式之1-[5-氟-6-(吡咯啶-3-基)吡啶-3-基]-1,2,3-三唑-4-甲酸乙酯(351.2 mg)。粗產物未經進一步純化即直接用於下一步驟中。LCMS方法E：[M+H] ⁺= 306。 步驟 5 ： 1-[5- 氟 -6-[1-(2,2,2- 三氟乙基 ) 吡咯啶 -3- 基 ] 吡啶 -3- 基 ]-1,2,3- 三唑 -4- 甲酸 乙酯將1-[5-氟-6-(吡咯啶-3-基)吡啶-3-基]-1,2,3-三唑-4-甲酸乙酯(300.0 mg, 1.0 mmol, 1.0當量)及TEA (0.4 mL, 2.9 mmol, 3.0當量)溶於ACN (10 mL)中，然後添加三氟甲烷磺酸2,2,2-三氟乙基酯(273.7 mg, 1.2 mmol, 1.2當量)。將反應混合物在環境溫度下攪拌30 min且然後藉由添加水來驟冷。使用乙酸乙酯萃取所得混合物，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到灰白色固體形式之1-[5-氟-6-[1-(2,2,2-三氟乙基)吡咯啶-3-基]吡啶-3-基]-1,2,3-三唑-4-甲酸乙酯(252.5 mg)。LCMS方法A：[M+H] ⁺= 388。 步驟 6 ： 1-[5- 氟 -6-[1-(2,2,2- 三氟乙基 ) 吡咯啶 -3- 基 ] 吡啶 -3- 基 ]-1,2,3- 三唑 -4- 甲酸將1-[5-氟-6-[1-(2,2,2-三氟乙基)吡咯啶-3-基]吡啶-3-基]-1,2,3-三唑-4-甲酸乙酯(100.0 mg, 0.3 mmol, 1.0當量)溶於MeOH (5 mL)及水(5 mL)中，然後添加NaOH (62.0 mg, 1.5 mmol, 6.0當量)。將反應混合物在環境溫度下攪拌2小時且然後在真空下濃縮。使用水稀釋殘餘物，使用濃HCl調節至pH 5，使用乙酸乙酯萃取，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以得到灰白色固體形式之粗製1-[5-氟-6-[1-(2,2,2-三氟乙基)吡咯啶-3-基]吡啶-3-基]-1,2,3-三唑-4-甲酸(83.2 mg)。LCMS方法E：[M+H] ⁺= 360。 Scheme 17B : Intermediate 56B (1-(5- fluoro -6-(1-(2,2,2- trifluoroethyl ) pyrrolidin- 3 -yl ) pyridin - 3 -yl )-1H-1, Synthesis of 2,3 - triazole - 4 - carboxylic acid )

Step 1 : 1-(6- Bromo -5- fluoropyridin - 3 -yl )-1,2,3- triazole - 4 -carboxylic acid ethyl ester was mixed with 6-bromo-5-fluoropyridin-3-amine (1.0 g , 5.2 mmol, 1.0 equiv) was dissolved in EtOH (30 mL) and HOAc (20 mL), then ethyl 2-diazo-3-oxypropionate (1.1 g, 7.7 mmol, 1.5 equiv) was added. The reaction mixture was heated to 50°C for 16 hours, and then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water and the solid was collected by filtration and dried to give ethyl 1-(6-bromo-5-fluoropyridin-3-yl)-1,2,3-triazole-4-carboxylate as a yellow solid (1.2 g). LCMS Method A: [M+H] ⁺ =315. Step 2 : 1-[6-[1-( Third-butoxycarbonyl )-2,5 -dihydropyrrol- 3 -yl ]-5- fluoropyridin - 3 -yl ]-1,2,3- tri Ethyl azole- 4 - carboxylate ethyl 1-(6-bromo-5-fluoropyridin-3-yl)-1,2,3-triazole-4-carboxylate (1.0 g, 3.2 mmol, 1.0 equiv) and 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaboro-2-yl)-2,5-dihydropyrrole-1-carboxylic acid tert-butyl ester (1.1 g , 3.8 mmol, 1.2 equiv) was dissolved in 1,4-dioxane (20 mL) and water ( ₂ mL), then Pd(dppf)Cl (232.2 mg, 0.3 mmol, 0.1 equiv) was added under nitrogen atmosphere and _{Cs2CO3 (} 4.1 g, 12.7 mmol, 4.0 equiv). The reaction mixture was heated to 80°C for 6 hours, then cooled to ambient temperature and quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried _over anhydrous _Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:1) to give 1-[6-[1-(tert-butoxyl) as an off-white solid carbonyl)-2,5-dihydropyrrol-3-yl]-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylic acid ethyl ester (612.2 mg). LCMS Method E: [M+H] ⁺ =404. Step 3 : 1-[6-[1-( Third-butoxycarbonyl ) pyrrolidin- 3 -yl ]-5- fluoropyridin - 3 -yl ]-1,2,3- triazole - 4 - carboxylic acid ethyl The ester will be 1-[6-[1-(tert-butoxycarbonyl)-2,5-dihydropyrrol-3-yl]-5-fluoropyridin-3-yl]-1,2,3-triazole Ethyl-4-carboxylate (900.0 mg, 2.2 mmol, 1.0 equiv) was dissolved in MeOH (15 mL) and Pd/C (10% wt., 90.0 mg) was added under nitrogen atmosphere. The mixture was purged with nitrogen, placed under a hydrogen atmosphere (balloon), and 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-butoxyl) as an off-white solid Carbonyl)pyrrolidin-3-yl]-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylic acid ethyl ester (605.2 mg). LCMS Method A: [M+H] ⁺ =406. Step 4 : 1-[5- Fluoro -6-( pyrrolidin- 3 -yl ) pyridin - 3 -yl ]-1,2,3- triazole - 4 - carboxylic acid ethyl ester (Third-butoxycarbonyl)pyrrolidin-3-yl]-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylic acid ethyl ester (500.0 mg, 1.2 mmol, 1.0 equiv) Dissolve in DCM (3 mL) and TFA (10 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched by addition of water. The solution was adjusted to pH ₇ using saturated aqueous _Na2CO3 . The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous _MgSO4 and concentrated in vacuo to give 1-[5-fluoro-6-(pyrrolidin-3-yl)pyridine-3- as an off-white solid [methyl]-1,2,3-triazole-4-carboxylic acid ethyl ester (351.2 mg). 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- Ethyl 4 - carboxylate 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 equiv) and TEA (0.4 mL, 2.9 mmol, 3.0 equiv) were dissolved in ACN (10 mL), then 2,2,2-trifluoroethyl trifluoromethanesulfonate (273.7 mg, 1.2 mmol, 1.2 equivalents). The reaction mixture was stirred at ambient temperature for 30 min and then quenched by addition of water. The resulting mixture was extracted with ethyl acetate, washed with brine, dried _over anhydrous _Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:1) to give 1-[5-fluoro-6-[1-(2 as an off-white solid ,2,2-Trifluoroethyl)pyrrolidin-3-yl]pyridin-3-yl]-1,2,3-triazole-4-carboxylic acid ethyl ester (252.5 mg). 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- carboxylic acid converts 1-[5-fluoro-6-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]pyridin-3-yl]-1,2,3-triazole Ethyl-4-carboxylate (100.0 mg, 0.3 mmol, 1.0 equiv) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (62.0 mg, 1.5 mmol, 6.0 equiv) was added. The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo. The residue was diluted with water, adjusted to pH 5 with concentrated HCl, extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give crude 1-[5-fluoro as an off-white solid -6-[1-(2,2,2-Trifluoroethyl)pyrrolidin-3-yl]pyridin-3-yl]-1,2,3-triazole-4-carboxylic acid (83.2 mg). LCMS Method E: [M+H] ⁺ =360.

步驟 1 ： 6-(4,4- 二氟 -1- 甲基環己基 )-5- 氟 - N- 甲氧基 - N- 甲基吡啶 -3- 甲醯胺將6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-甲酸(2.5 g, 9.1 mmol, 1.0當量)溶於DMF (50 mL)中，然後添加 N,O-二甲基羥基胺鹽酸鹽(1.3 g, 13.7 mmol, 1.5當量)、HATU (5.2 g, 13.7 mmol, 1.5當量)及DIEA (6.4 mL, 36.6 mmol, 4.0當量)。將反應混合物在環境溫度下攪拌1小時，然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:3)洗脫)來純化殘餘物以得到黃色油狀物形式之6-(4,4-二氟-1-甲基環己基)-5-氟- N-甲氧基- N-甲基吡啶-3-甲醯胺(1.7 g)。LCMS方法A：[M+H] ⁺= 317。 步驟 2 ： 1-[6-(4,4- 二氟 -1- 甲基環己基 )-5- 氟吡啶 -3- 基 ] 乙酮將6-(4,4-二氟-1-甲基環己基)-5-氟- N-甲氧基- N-甲基吡啶-3-甲醯胺(1.7 g, 5.4 mmol, 1.0當量)溶於THF (15 mL)中並冷卻至0℃，然後逐滴添加MeMgBr (3M in THF, 3.2 mL, 9.6 mmol, 1.5當量)，其將溶液維持於0℃下。將反應混合物在0℃下攪拌1小時且然後藉由添加冰水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以得到黃色油狀物形式之1-[6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-基]乙酮(1.4 g)。LCMS方法G：[M+H] ⁺= 272。 步驟 3 ： 4-[6-(4,4- 二氟 -1- 甲基環己基 )-5- 氟吡啶 -3- 基 ]-2,4- 二側氧基丁酸乙酯將1-[6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-基]乙酮(1.4 g, 5.2 mmol, 1.0當量)溶於EtOH (14 mL)中，然後添加乙醇鈉(351.2 mg, 5.2 mmol, 1.0當量)。隨後逐滴添加草酸乙酯(1.0 mL, 7.7 mmol, 1.5當量)。將反應混合物在環境溫度下攪拌2小時，且然後冷卻至0℃並藉由添加水來驟冷。使用HCl水溶液(4 M)將所得溶液調節至pH 5，使用乙酸乙酯萃取，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以得到褐色油狀物形式之4-[6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-基]-2,4-二側氧基丁酸乙酯(1.5 g)。LCMS方法A：[M+H] ⁺= 372。 步驟 4 ： 5-[6-(4,4- 二氟 -1- 甲基環己基 )-5- 氟吡啶 -3- 基 ]-1,2- 噁唑 -3- 甲酸乙酯將4-[6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-基]-2,4-二側氧基丁酸乙酯(1.5 g, 4.0 mmol, 1.0當量)溶於EtOH (15 mL)中，然後添加羥基胺鹽酸鹽(0.4 g, 6.0 mmol, 1.5當量)。將反應混合物加熱至80℃並保持2小時，然後冷卻至環境溫度並藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:5)洗脫)來純化殘餘物以得到褐色油狀物形式之5-[6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-基]-1,2-噁唑-3-甲酸乙酯(1.2 g)。LCMS方法G：[M+H] ⁺= 369。 步驟 5 ： 5-[6-(4,4- 二氟 -1- 甲基環己基 )-5- 氟吡啶 -3- 基 ]-1,2- 噁唑 -3- 甲酸將5-[6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-基]-1,2-噁唑-3-甲酸乙酯(1.2 g, 3.3 mmol, 1.0當量)溶於MeOH (10 mL)及水(10 mL)中，然後添加NaOH (260.6 mg, 6.5 mmol, 2.0當量)。將反應混合物加熱至80℃並保持2小時，然後冷卻至環境溫度並在真空下濃縮。藉由急速製備型HPLC使用下列條件來純化殘餘物：管柱，C18矽膠；移動相，在25 min內自ACN/H ₂O=0%增至ACN/H ₂O=100%；檢測器，254 nm。此會產生褐色固體形式之5-[6-(4,4-二氟-1-甲基環己基)-5-氟吡啶-3-基]-1,2-噁唑-3-甲酸(1.0 g)。LCMS方法A：[M+H] ⁺= 341。 使用與針對中間體57B所闡述相同之方法來製備下列中間體。 中間體 起始材料 結構 LCMS 數據 中間體 58B

中間體 32B

方法E： MS-ESI: 328 [M+H] ⁺ 中間體 59B

中間體 33B

方法E： MS-ESI: 328 [M+H] ⁺ 中間體 60B

中間體 34B

方法E： MS-ESI: 348 [M+H] ⁺ 中間體 61B

中間體 35B

方法E： MS-ESI: 332 [M+H] ⁺ 中間體 62B

中間體 31B

方法E：MS-ESI: 318 [M+H] ⁺ 中間體 63B

中間體 38B

方法E：MS-ESI: 390 [M+H] ⁺ 中間體 64B

中間體 36B

方法E：MS-ESI: 375 [M+H] ⁺ 中間體 65B

中間體 39B

方法E：MS-ESI: 327 [M+H] ⁺ 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 Difluoro-1-methylcyclohexyl)-5-fluoropyridine-3-carboxylic acid (2.5 g, 9.1 mmol, 1.0 equiv) was dissolved in DMF (50 mL) and N,O -dimethylhydroxylamine salt was added acid (1.3 g, 13.7 mmol, 1.5 equiv), HATU (5.2 g, 13.7 mmol, 1.5 equiv) and DIEA (6.4 mL, 36.6 mmol, 4.0 equiv). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched by addition of water. The resulting solution was extracted with ethyl acetate and concentrated in vacuo. 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- as a yellow oil) Methylcyclohexyl)-5-fluoro- N -methoxy- N -methylpyridine-3-carboxamide (1.7 g). LCMS Method A: [M+H] ⁺ =317. Step 2 : 1-[6-(4,4 -Difluoro - 1 -methylcyclohexyl )-5- fluoropyridin - 3 -yl ] ethanone Cyclohexyl)-5-fluoro- N -methoxy- N -methylpyridine-3-carboxamide (1.7 g, 5.4 mmol, 1.0 equiv) was dissolved in THF (15 mL) and cooled to 0 °C, then MeMgBr (3M in THF, 3.2 mL, 9.6 mmol, 1.5 equiv) was added dropwise maintaining the solution at 0 °C. The reaction mixture was stirred at 0°C for 1 hour and then quenched by addition of ice water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 1-[6-(4,4-difluoro-1-methyl as a yellow oil Cyclohexyl)-5-fluoropyridin-3-yl]ethanone (1.4 g). LCMS Method G: [M+H] ⁺ =272. Step 3 : 4-[6-(4,4 -Difluoro - 1 -methylcyclohexyl )-5- fluoropyridin - 3 -yl ]-2,4 -dioxybutyric acid ethyl ester 6-(4,4-Difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]ethanone (1.4 g, 5.2 mmol, 1.0 equiv) was dissolved in EtOH (14 mL), then added Sodium ethoxide (351.2 mg, 5.2 mmol, 1.0 equiv). Ethyl oxalate (1.0 mL, 7.7 mmol, 1.5 equiv) was then added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours, and then cooled to 0°C and quenched by addition of water. The resulting solution was adjusted to pH 5 with aqueous HCl (4 M), extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 4-[6 as a brown oil -(4,4-Difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-2,4-di-oxybutyric acid ethyl ester (1.5 g). LCMS Method A: [M+H] ⁺ =372. Step 4 : 5-[6-(4,4 -Difluoro - 1 -methylcyclohexyl )-5- fluoropyridin - 3 -yl ]-1,2- oxazole- 3 -carboxylic acid ethyl ester 6-(4,4-Difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-2,4-di-oxybutyric acid ethyl ester (1.5 g, 4.0 mmol, 1.0 equiv) Dissolve in EtOH (15 mL), then add hydroxylamine hydrochloride (0.4 g, 6.0 mmol, 1.5 equiv). The reaction mixture was heated to 80°C for 2 hours, then cooled to ambient temperature and quenched by addition of water. The resulting solution was extracted with ethyl acetate and concentrated in vacuo. 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 as a brown oil) -1-Methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2-oxazole-3-carboxylic acid ethyl ester (1.2 g). 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 was added to 5-[6- (4,4-Difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2-oxazole-3-carboxylic acid ethyl ester (1.2 g, 3.3 mmol, 1.0 equiv) was dissolved in MeOH (10 mL) and water (10 mL), then NaOH (260.6 mg, 6.5 mmol, 2.0 equiv) was added. The reaction mixture was heated to 80°C for 2 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was purified by flash prep HPLC using the following conditions: column, C18 silica; mobile phase, ACN/ _H2O =0% to ACN/ _H2O =100% in 25 min; detector, 254 nm. This yielded 5-[6-(4,4-difluoro-1-methylcyclohexyl)-5-fluoropyridin-3-yl]-1,2-oxazole-3-carboxylic acid (1.0 g). LCMS Method A: [M+H] ⁺ =341. The following intermediates were prepared using the same procedures as described for intermediate 57B. Intermediate starting material structure LCMS data Intermediate 58B

Intermediate 32B

Method E: MS-ESI: 328 [M+H] ⁺ Intermediate 59B

Intermediate 33B

Method E: MS-ESI: 328 [M+H] ⁺ Intermediate 60B

Intermediate 34B

Method E: MS-ESI: 348 [M+H] ⁺ Intermediate 61B

Intermediate 35B

Method E: MS-ESI: 332 [M+H] ⁺ Intermediate 62B

Intermediate 31B

Method E: MS-ESI: 318 [M+H] ⁺ Intermediate 63B

Intermediate 38B

Method E: MS-ESI: 390 [M+H] ⁺ Intermediate 64B

Intermediate 36B

Method E: MS-ESI: 375 [M+H] ⁺ Intermediate 65B

Intermediate 39B

Method E: MS-ESI: 327 [M+H] ⁺

步驟 1 ： 5- 氯 - N- 甲氧基 - N- 甲基 -6-[4-(2,2,2- 三氟乙基 ) 六氫吡嗪 -1- 基 ] 吡啶 -3- 甲醯胺將5-氯-6-[4-(2,2,2-三氟乙基)六氫吡嗪-1-基]吡啶-3-甲酸(1.8 g, 5.6 mmol, 1.0當量)及 N,O-二甲基羥基胺鹽酸鹽(813.6 mg, 8.3 mmol, 1.5當量)溶於DMF (18 mL)中，然後添加HATU (4.2 g, 11.1 mmol, 2.0當量)及DIEA (3.9 mL, 22.2 mmol, 4.0當量)。將反應混合物在環境溫度下攪拌過夜且然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到黃色固體形式之5-氯- N-甲氧基- N-甲基-6-[4-(2,2,2-三氟乙基)六氫吡嗪-1-基]吡啶-3-甲醯胺(1.8 g)。LCMS方法A：[M+H] ⁺= 367。 步驟 2 ： 5- 氯 -6-[4-(2,2,2- 三氟乙基 ) 六氫吡嗪 -1- 基 ] 吡啶 -3- 甲醛將5-氯- N-甲氧基- N-甲基-6-[4-(2,2,2-三氟乙基)六氫吡嗪-1-基]吡啶-3-甲醯胺(1.5 g, 4.1 mmol, 1.0當量)溶於THF (17 mL)中並冷卻至0℃。然後逐份添加LiAlH ₄(155.2 mg, 4.1 mmol, 1.0當量)，且將溶液維持於0℃下。將反應混合物在0℃下攪拌2小時，且然後藉由添加飽和NH ₄Cl水溶液來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:2)洗脫)來純化殘餘物以得到黃色固體形式之5-氯-6-[4-(2,2,2-三氟乙基)六氫吡嗪-1-基]吡啶-3-甲醛(1.0 g)。LCMS方法E：[M+H] ⁺= 308。 步驟 3 ： ( E)- N-([5- 氯 -6-[4-(2,2,2- 三氟乙基 ) 六氫吡嗪 -1- 基 ] 吡啶 -3- 基 ] 亞甲基 ) 羥基胺將5-氯-6-[4-(2,2,2-三氟乙基)六氫吡嗪-1-基]吡啶-3-甲醛(1.0 g, 3.3 mmol, 1.0當量)及羥基胺鹽酸鹽(271.0 mg, 3.9 mmol, 1.2當量)添加至EtOH (10 mL)及水(10 mL)之溶液中，然後添加NaOH (195.0 mg, 4.9 mmol, 1.5當量)。將反應混合物加熱至90℃並保持2小時，然後冷卻至環境溫度並藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮。藉由反相急速層析使用下列條件來純化殘餘物：管柱，C18矽膠；移動相，ACN/水，在30 min內0%至100%之梯度；檢測器，UV 254 nm。此會產生褐色固體形式之(E)- N-([5-氯-6-[4-(2,2,2-三氟乙基)六氫吡嗪-1-基]吡啶-3-基]亞甲基)羥基胺(800.0 mg)。LCMS方法A：[M+H] ⁺= 323。 步驟 4 ： 3-[5- 氯 -6-[4-(2,2,2- 三氟乙基 ) 六氫吡嗪 -1- 基 ] 吡啶 -3- 基 ]-1,2- 噁唑 -5- 甲酸甲酯將( E)- N-([5-氯-6-[4-(2,2,2-三氟乙基)六氫吡嗪-1-基]吡啶-3-基]亞甲基)羥基胺(1.0 g, 3.1 mmol, 1.0當量)及丙炔酸甲酯(260.5 mg, 3.1 mmol, 1.0當量)溶於CHCl ₃(10 mL)中，然後添加NaHCO ₃(390.5 mg, 4.6 mmol, 1.5當量)及NCS (413.8 mg, 3.1 mmol, 1.0當量)。將反應混合物在環境溫度下攪拌過夜，且然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以得到黃色固體形式之3-[5-氯-6-[4-(2,2,2-三氟乙基)六氫吡嗪-1-基]吡啶-3-基]-1,2-噁唑-5-甲酸甲酯(811.2 mg)。LCMS方法A：[M+H] ⁺= 405。 步驟 5 ： 3-[5- 氯 -6-[4-(2,2,2- 三氟乙基 ) 六氫吡嗪 -1- 基 ] 吡啶 -3- 基 ]-1,2- 噁唑 -5- 甲酸將3-[5-氯-6-[4-(2,2,2-三氟乙基)六氫吡嗪-1-基]吡啶-3-基]-1,2-噁唑-5-甲酸甲酯(500.0 mg, 1.2 mmol, 1.0當量)溶於MeOH (5.0 mL)及水(5.0 mL)中，然後添加LiOH (118.3 mg, 4.9 mmol, 4.0當量)。將反應混合物在環境溫度下攪拌2小時且然後在真空下濃縮。藉由反相急速層析使用下列條件來純化殘餘物：管柱，C18矽膠；移動相，ACN/水，在30 min內0%至100%之梯度；檢測器，UV 254 nm。此會產生灰白色固體形式之3-[5-氯-6-[4-(2,2,2-三氟乙基)六氫吡嗪-1-基]吡啶-3-基]-1,2-噁唑-5-甲酸(295.4 mg)。LCMS方法B：[M+H] ⁺= 391。 使用與針對中間體66B所闡述相同之方法來製備下列中間體。 中間體 起始材料 結構 LCMS 數據 中間體 67B

中間體 36B

方法E： MS-ESI: 375 [M+H] ⁺ 中間體 68B

中間體 31B

方法E： MS-ESI: 318 [M+H] ⁺ 中間體 69B

中間體 32B

方法E： MS-ESI: 328 [M+H] ⁺ Scheme 19B : Intermediate 66B (3-(5- chloro -6-(4-(2,2,2- trifluoroethyl ) hexahydropyrazin- 1 -yl ) pyridin - 3 -yl ) isoxazole -5- carboxylic acid ) synthesis

Step 1 : 5- Chloro - N - methoxy- N - methyl -6-[4-(2,2,2- trifluoroethyl ) hexahydropyrazin- 1 -yl ] pyridine - 3 -carboxylate Amine 5-chloro-6-[4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl]pyridine-3-carboxylic acid (1.8 g, 5.6 mmol, 1.0 equiv) and N, O -dimethylhydroxylamine hydrochloride (813.6 mg, 8.3 mmol, 1.5 equiv) was dissolved in DMF (18 mL), then HATU (4.2 g, 11.1 mmol, 2.0 equiv) and DIEA (3.9 mL, 22.2 mmol) were added , 4.0 equiv). The reaction mixture was stirred at ambient temperature overnight and then quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried _over anhydrous _Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:1) to give 5-chloro- N -methoxy- N -methyl as a yellow solid -6-[4-(2,2,2-Trifluoroethyl)hexahydropyrazin-1-yl]pyridine-3-carboxamide (1.8 g). LCMS Method A: [M+H] ⁺ =367. Step 2 : 5- Chloro - 6-[4-(2,2,2- trifluoroethyl ) hexahydropyrazin- 1 -yl ] pyridine - 3 - carbaldehyde -Methyl-6-[4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl]pyridine-3-carboxamide (1.5 g, 4.1 mmol, 1.0 equiv) in THF (17 mL) and cooled to 0 °C. LiAlH ₄ (155.2 mg, 4.1 mmol, 1.0 equiv) was then added in portions and the solution was maintained at 0 °C. The reaction mixture was stirred at 0°C for 2 hours and then quenched by addition of saturated aqueous _NH4Cl . The resulting solution was extracted with ethyl acetate, washed with brine, dried _over anhydrous _Na2SO4 and concentrated in vacuo. 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)hexahydropyrazin-1-yl]pyridine-3-carbaldehyde (1.0 g). LCMS Method E: [M+H] ⁺ =308. Step 3 : ( E ) -N -([5- Chloro -6-[4-(2,2,2- trifluoroethyl ) hexahydropyrazin- 1 -yl ] pyridin - 3 -yl ] methylene ) hydroxylamine was mixed with 5-chloro-6-[4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl]pyridine-3-carbaldehyde (1.0 g, 3.3 mmol, 1.0 equiv) and Hydroxylamine hydrochloride (271.0 mg, 3.9 mmol, 1.2 equiv) was added to a solution of EtOH (10 mL) and water (10 mL) followed by NaOH (195.0 mg, 4.9 mmol, 1.5 equiv). The reaction mixture was heated to 90°C for 2 hours, then cooled to ambient temperature and quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried _over anhydrous _Na2SO4 and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase, ACN/water, gradient 0% to 100% in 30 min; detector, UV 254 nm. This yields (E) -N -([5-chloro-6-[4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl]pyridin-3-yl as a brown solid ]methylene)hydroxylamine (800.0 mg). LCMS Method A: [M+H] ⁺ =323. Step 4 : 3-[5- Chloro -6-[4-(2,2,2- trifluoroethyl ) hexahydropyrazin- 1 -yl ] pyridin - 3 -yl ]-1,2 - oxazole- Methyl 5- carboxylate ( E ) -N -([5-chloro-6-[4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl]pyridin-3-yl] Methylene)hydroxylamine (1.0 g, 3.1 mmol, 1.0 equiv) and methyl propiolate (260.5 mg, 3.1 mmol, 1.0 equiv) were dissolved in _CHCl3 (10 mL), then _NaHCO3 (390.5 mg, 4.6 mmol, 1.5 equiv) and NCS (413.8 mg, 3.1 mmol, 1.0 equiv). The reaction mixture was stirred at ambient temperature overnight and then quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 3-[5-chloro-6-[4-(2,2,2- as a yellow solid Trifluoroethyl)hexahydropyrazin-1-yl]pyridin-3-yl]-1,2-oxazole-5-carboxylic acid methyl ester (811.2 mg). LCMS Method A: [M+H] ⁺ =405. Step 5 : 3-[5- Chloro -6-[4-(2,2,2- trifluoroethyl ) hexahydropyrazin- 1 -yl ] pyridin - 3 -yl ]-1,2 - oxazole- 5- carboxylic acid 3-[5-chloro-6-[4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl]pyridin-3-yl]-1,2-oxazole Methyl-5-carboxylate (500.0 mg, 1.2 mmol, 1.0 equiv) was dissolved in MeOH (5.0 mL) and water (5.0 mL), then LiOH (118.3 mg, 4.9 mmol, 4.0 equiv) was added. The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase, ACN/water, gradient 0% to 100% in 30 min; detector, UV 254 nm. This yields 3-[5-chloro-6-[4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl]pyridin-3-yl]-1,2 as an off-white solid -oxazole-5-carboxylic acid (295.4 mg). LCMS Method B: [M+H] ⁺ =391. The following intermediates were prepared using the same procedures as described for Intermediate 66B. Intermediate starting material structure LCMS data Intermediate 67B

Intermediate 36B

Method E: MS-ESI: 375 [M+H] ⁺ Intermediate 68B

Intermediate 31B

Method E: MS-ESI: 318 [M+H] ⁺ Intermediate 69B

Intermediate 32B

Method E: MS-ESI: 328 [M+H] ⁺

步驟 1 ： 5- 溴 -2-(4,4- 二氟六氫吡啶 -1- 基 )-3- 氟吡啶將2,5-二溴-3-氟吡啶(10.0 g, 39.2 mmol, 1.0當量)溶於DMF (100 mL)中，然後添加Cs ₂CO ₃(25.7 g, 78.5 mmol, 2.0當量)及4,4-二氟六氫吡啶(7.1 g, 58.8 mmol, 1.5當量)。將反應混合物加熱至80℃並保持48小時，然後冷卻至環境溫度並藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮。藉由急速製備型HPLC使用下列條件來純化殘餘物：管柱，C18矽膠；移動相，在20 min內自ACN/H ₂O=60%增至ACN/H ₂O=100%；檢測器，254 nm。此會產生黃色固體形式之5-溴-2-(4,4-二氟六氫吡啶-1-基)-3-氟吡啶(2.0 g)。LCMS方法A：[M+H] ⁺= 295。 步驟 2 ： 2-(4,4- 二氟六氫吡啶 -1- 基 )-3- 氟 -5-(4,4,5,5- 四甲基 -1,3,2- 二氧硼㖦 -2- 基 ) 吡啶將5-溴-2-(4,4-二氟六氫吡啶-1-基)-3-氟吡啶(2.0 g, 6.8 mmol, 1.0當量)溶於DMSO (30 mL)中，然後在氮氣氛下添加AcOK (1.3 g, 13.6 mmol, 2.0當量)、雙(頻哪醇)二硼(3.4 g, 13.5 mmol, 2.0當量)及Pd(dppf)Cl ₂(495.9 mg, 0.7mmol, 0.1當量)。將反應混合物加熱至90℃過夜，然後冷卻至環境溫度並藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:10)洗脫)來純化殘餘物以得到黃色油狀物形式之2-(4,4-二氟六氫吡啶-1-基)-3-氟-5-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)吡啶(1.6 g)。LCMS方法A：[M+H] ⁺= 343。 步驟 3 ： 2-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1,3- 噻唑 -5- 甲酸甲酯將2-(4,4-二氟六氫吡啶-1-基)-3-氟-5-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)吡啶(300.0 mg, 0.9 mmol, 1.0當量)及 2-溴-1,3-噻唑-5-甲酸甲酯(233.6 mg, 1.1 mmol, 1.2當量)溶於1,4-二噁烷(5 mL)及水(5 mL)中，然後在氮氣氛下添加Cs ₂CO ₃(857.0 mg, 2.6 mmol, 3.0當量)及Pd(dppf)Cl ₂CH ₂Cl ₂(71.4 mg, 0.09 mmol, 0.1當量)。將反應混合物加熱至90℃並保持6小時，然後冷卻至環境溫度並藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:3)洗脫)來純化殘餘物以得到灰白色固體形式之 2-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,3-噻唑-5-甲酸甲酯(200.0 mg)。LCMS方法A：[M+H] ⁺= 358。 步驟 4 ： 2-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1,3- 噻唑 -5- 甲酸將2-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,3-噻唑-5-甲酸甲酯(300.0 mg, 0.8 mmol, 1.0當量)溶於MeOH (6 mL)及水(6 mL)中，然後添加NaOH (167.9 mg, 4.2 mmol, 5.0當量)。將反應混合物加熱至60℃並保持3小時，然後冷卻至環境溫度並藉由添加冰水來驟冷。使用濃HCl將所得溶液調節至pH 4，使用乙酸乙酯萃取，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以得到灰白色固體形式之2-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,3-噻唑-5-甲酸(242.1 mg)。LCMS方法E：[M+H] ⁺= 344。 使用與針對中間體70B所闡述相同之方法來製備下列中間體。 中間體 起始材料 A 起始材料 B 結構 LCMS 數據 中間體 71B

方法E： MS-ESI: 328 [M+H] ⁺ 中間體 72B

方法E： MS-ESI: 344 [M+H] ⁺ 中間體 73B

方法E： MS-ESI: 345 [M+H] ⁺ 中間體 74B

方法E： MS-ESI: 327 [M+H] ⁺ 中間體 75B

方法E： MS-ESI: 344 [M+H] ⁺ 中間體 76B

方法E： MS-ESI: 344 [M+H] ⁺ 中間體 77B

方法E： MS-ESI: 328 [M+H] ⁺ 中間體 78B

方法E： MS-ESI: 344 [M+H] ⁺ 中間體 79B

方法B： MS-ESI: 391 [M+H] ⁺ Scheme 20B : Synthesis of Intermediate 70B (2-(6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ) thiazole- 5- carboxylic acid )

Step 1 : 5- Bromo -2-(4,4 -difluorohexahydropyridin- 1 -yl )-3 - fluoropyridine 2,5-dibromo-3-fluoropyridine (10.0 g, 39.2 mmol, 1.0 equiv. ) was dissolved in DMF (100 mL), then _{Cs2CO3 (} 25.7 g, 78.5 mmol, 2.0 equiv) and 4,4-difluorohexahydropyridine (7.1 g, 58.8 mmol, 1.5 equiv) were added. The reaction mixture was heated to 80°C for 48 hours, then cooled to ambient temperature and quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried _over anhydrous _Na2SO4 and concentrated in vacuo. The residue was purified by flash prep HPLC using the following conditions: column, C18 silica; mobile phase, ACN/ _H2O =60% to ACN/ _H2O =100% in 20 min; detector, 254 nm. This gave 5-bromo-2-(4,4-difluorohexahydropyridin-1-yl)-3-fluoropyridine (2.0 g) as a yellow solid. LCMS Method A: [M+H] ⁺ =295. Step 2 : 2-(4,4 -Difluorohexahydropyridin- 1 -yl )-3 - fluoro -5-(4,4,5,5 -tetramethyl -1,3,2- dioxoboron) -2- yl ) pyridine 5-Bromo-2-(4,4-difluorohexahydropyridin-1-yl)-3-fluoropyridine (2.0 g, 6.8 mmol, 1.0 equiv) was dissolved in DMSO (30 mL) , then AcOK (1.3 g, 13.6 mmol, 2.0 equiv), bis(pinacol)diboron (3.4 g, 13.5 mmol, 2.0 equiv) and Pd(dppf)Cl (495.9 _mg , 0.7 equiv) were added under nitrogen atmosphere mmol, 0.1 equiv). The reaction mixture was heated to 90°C overnight, then cooled to ambient temperature and quenched by addition of water. The resulting solution was extracted with ethyl acetate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:10) to give 2-(4,4-difluorohexahydropyridine as a yellow oil) -1-yl)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-2-yl)pyridine (1.6 g). LCMS Method A: [M+H] ⁺ =343. Step 3 : 2-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1,3 -thiazole- 5- carboxylic acid methyl ester ,4-Difluorohexahydropyridin-1-yl)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboroyl)pyridine ( 300.0 mg, 0.9 mmol, 1.0 equiv) and methyl 2-bromo-1,3-thiazole-5-carboxylate (233.6 mg, 1.1 mmol, 1.2 equiv) were dissolved in 1,4-dioxane (5 mL) and water (5 mL), then _Cs2CO3 ( _{857.0 mg} , 2.6 mmol, 3.0 equiv) and Pd(dppf) _Cl2CH2Cl2 (71.4 _mg , 0.09 mmol, 0.1 equiv) were added under nitrogen atmosphere. The reaction mixture was heated to 90°C for 6 hours, then cooled to ambient temperature and quenched by addition of water. The resulting solution was extracted with ethyl acetate and concentrated in vacuo. 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-difluorohexahydrogen as an off-white solid) Pyridin-1-yl)-5-fluoropyridin-3-yl]-1,3-thiazole-5-carboxylic acid methyl ester (200.0 mg). LCMS Method A: [M+H] ⁺ =358. Step 4 : 2-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1,3 -thiazole- 5- carboxylic acid 4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1,3-thiazole-5-carboxylic acid methyl ester (300.0 mg, 0.8 mmol, 1.0 equiv) was dissolved in MeOH ( 6 mL) and water (6 mL), then NaOH (167.9 mg, 4.2 mmol, 5.0 equiv) was added. The reaction mixture was heated to 60°C for 3 hours, then cooled to ambient temperature and quenched by addition of ice water. The resulting solution was adjusted to pH 4 using concentrated HCl, extracted with ethyl acetate, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 2-[6-(4,4-difluorohexahydrogen as an off-white solid Pyridin-1-yl)-5-fluoropyridin-3-yl]-1,3-thiazole-5-carboxylic acid (242.1 mg). LCMS Method E: [M+H] ⁺ =344. The following intermediates were prepared using the same procedures as described for Intermediate 70B. Intermediate starting material A starting material B structure LCMS data Intermediate 71B

Method E: MS-ESI: 328 [M+H] ⁺ Intermediate 72B

Method E: MS-ESI: 344 [M+H] ⁺ Intermediate 73B

Method E: MS-ESI: 345 [M+H] ⁺ Intermediate 74B

Method E: MS-ESI: 327 [M+H] ⁺ Intermediate 75B

Method E: MS-ESI: 344 [M+H] ⁺ Intermediate 76B

Method E: MS-ESI: 344 [M+H] ⁺ Intermediate 77B

Method E: MS-ESI: 328 [M+H] ⁺ Intermediate 78B

Method E: MS-ESI: 344 [M+H] ⁺ Intermediate 79B

Method B: MS-ESI: 391 [M+H] ⁺

步驟 1 ： 6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 羰基氯將6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-甲酸(1.7 g, 6.5 mmol, 1.0當量)溶於DCM (17 mL)中並冷卻至0℃，然後逐滴添加草醯氯(0.8 mL, 9.8 mmol, 1.5當量)及DMF (0.1 mL)，且將溶液維持於0℃下。將反應混合物在0℃下攪拌2小時，且然後在真空下濃縮以得到白色固體形式之6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-羰基氯(1.5 g)。 步驟 2 ： [( E)- N-[( E)-6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 羰基氧基 ] 甲脒基 ] 甲酸 乙酯將6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-羰基氯(1.4 g, 5.0 mmol, 1.0當量)溶於THF (14 mL)中並冷卻至0℃，然後添加[( E)- N'-羥基甲脒基]甲酸乙酯(663.8 mg, 5.0 mmol, 1.0當量)。將反應混合物在環境溫度下攪拌2小時，且然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以得到白色固體形式之[( E)- N-[( E)-6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-羰基氧基]甲脒基]甲酸乙酯(1.0 g)。LCMS方法A：[M+H] ⁺= 375。 步驟 3 ： 5-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1,2,4- 氧雜二唑 -3- 甲酸 乙酯將[( E)- N-[( E)-6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-羰基氧基]甲脒基]甲酸乙酯(1.0 g, 2.7 mmol, 1.0當量)溶於EtOH (10 mL)及乙酸(6 mL)中。將反應混合物加熱至100℃過夜，然後冷卻至環境溫度並在真空下濃縮。使用水稀釋殘餘物，然後使用飽和Na ₂CO ₃水溶液調節至pH 8。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮。藉由反相急速層析使用下列條件來純化殘餘物：管柱，C18矽膠；移動相，ACN/水，在30 min內20%至100%之梯度；檢測器，UV 254 nm。此會產生白色固體形式之 5-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,2,4-氧雜二唑-3-甲酸乙酯(800.0 mg)。LCMS方法A：[M+H] ⁺= 357。 步驟 4 ： 5-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1,2,4- 氧雜二唑 -3- 甲酸將5-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,2,4-氧雜二唑-3-甲酸乙酯(600.0 mg, 1.7 mmol, 1.0當量)溶於MeOH (6 mL)及水(6 mL)中，然後添加LiOH (161.3 mg, 6.7 mmol, 4.0當量)。將反應混合物在環境溫度下攪拌3小時且然後在真空下濃縮。使用濃HCl將所得溶液調節至pH 5。藉由反相急速層析使用下列條件來純化粗產物：管柱，C18矽膠；移動相，ACN/水，在30 min內0%至100%之梯度；檢測器，UV 254 nm。此會產生紅色固體形式之5-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,2,4-氧雜二唑-3-甲酸(505.1 mg)。LCMS方法B：[M+H] ⁺= 329。 Scheme 21B : Intermediate 80B (5-(6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl )-1,2,4 - oxadiazole- 3- formic acid ) synthesis

Step 1 : 6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridine - 3 -carbonyl chloride -Fluoropyridine-3-carboxylic acid (1.7 g, 6.5 mmol, 1.0 equiv) was dissolved in DCM (17 mL) and cooled to 0°C, then oxalic chloride (0.8 mL, 9.8 mmol, 1.5 equiv) and DMF were added dropwise (0.1 mL), and the solution was maintained at 0 °C. The reaction mixture was stirred at 0°C for 2 hours and then concentrated in vacuo to give 6-(4,4-difluorohexahydropyridin-1-yl)-5-fluoropyridine-3-carbonyl chloride as a white solid (1.5 g). Step 2 : Ethyl [( E ) -N -[( E )-6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridine - 3 -carbonyloxy ] carboxamidino ] carboxylate 6-(4,4 - Difluorohexahydropyridin-1-yl)-5-fluoropyridine-3-carbonyl chloride (1.4 g, 5.0 mmol, 1.0 equiv) was dissolved in THF (14 mL) and cooled to 0 °C, then ethyl [( E )-N' - hydroxycarboxamidino]carboxylate (663.8 mg, 5.0 mmol, 1.0 equiv) was added. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give [( E ) -N -[( E )-6-(4,4- as a white solid Difluorohexahydropyridin-1-yl)-5-fluoropyridine-3-carbonyloxy]formamidino]carboxylic acid ethyl ester (1.0 g). LCMS Method A: [M+H] ⁺ =375. Step 3 : 5-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1,2,4 -oxadiazole- 3 - carboxylic acid ethyl ester Ethyl [( E ) -N -[( E )-6-(4,4-difluorohexahydropyridin-1-yl)-5-fluoropyridine-3-carbonyloxy]formamidino]carboxylate ( 1.0 g, 2.7 mmol, 1.0 equiv) 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 in vacuo. The residue was diluted with water, then adjusted to pH ₈ with saturated aqueous _Na2CO3 . The resulting solution was extracted with ethyl acetate, washed with brine, dried _over anhydrous _Na2SO4 and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase, ACN/water, gradient 20% to 100% in 30 min; detector, UV 254 nm. This yields 5-[6-(4,4-difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-oxadiazole-3 as a white solid - Ethyl formate (800.0 mg). LCMS Method A: [M+H] ⁺ =357. Step 4 : 5-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1,2,4 -oxadiazole- 3 - carboxylic acid -[6-(4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-oxadiazole-3-carboxylic acid ethyl ester (600.0 mg, 1.7 mmol, 1.0 equiv) was dissolved in MeOH (6 mL) and water (6 mL), then LiOH (161.3 mg, 6.7 mmol, 4.0 equiv) was added. The reaction mixture was stirred at ambient temperature for 3 hours and then concentrated in vacuo. The resulting solution was adjusted to pH 5 using concentrated HCl. The crude product was purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase, ACN/water, gradient 0% to 100% in 30 min; detector, UV 254 nm. This yields 5-[6-(4,4-difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-oxadiazole-3 as a red solid - Formic acid (505.1 mg). LCMS Method B: [M+H] ⁺ =329.

步驟 1 ： 6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 甲醯胺將6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-甲酸(4.0 g, 15.4 mmol, 1.0當量)溶於DMF (40 mL)中，然後添加HATU (8.8 g, 23.1 mmol, 1.5當量)、DIEA (8.0 mL, 46.1 mmol, 3.0當量)及NH ₄Cl (1.23 g, 23.058 mmol, 1.5當量)。將反應混合物在環境溫度下攪拌過夜，然後藉由添加水來驟冷。藉由過濾收集固體並乾燥以得到灰白色固體形式之6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-甲醯胺(3.5 g)。LCMS方法A：[M+H] ⁺= 260。 步驟 2 ： 5-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1,3,4- 氧雜噻唑 -2- 酮將6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-甲醯胺(3.5 g, 13.5 mmol, 1.0當量)溶於甲苯(50 mL)中，然後添加氯(氯硫烷基)甲酮(3.5 g, 27.0 mmol, 2.0當量)。將反應混合物加熱至100℃過夜，然後冷卻至環境溫度並在真空下濃縮以得到黃色固體形式之5-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,3,4-氧雜噻唑-2-酮(3.0 g)。LCMS方法C：[M+H] ⁺= 274。 步驟 3 ： 3-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1,2,4- 噻二唑 -5- 甲酸乙酯將5-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,3,4-氧雜噻唑-2-酮(3.0 g, 9.5 mmol, 1.0當量)溶於十二烷(10 mL)中，然後添加氰甲酸乙酯(1.4 g, 14.2 mmol, 1.5當量)。將反應混合物加熱至130℃並保持16小時，然後冷卻至環境溫度並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到黃色固體形式之3-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,2,4-噻二唑-5-甲酸乙酯(1.2 g)。LCMS方法A：[M+H] ⁺= 260。 步驟 4 ： 3-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1,2,4- 噻二唑 -5- 甲酸將3-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,2,4-噻二唑-5-甲酸乙酯(1.2 g, 3.2 mmol, 1.0當量)溶於MeOH (10 mL)及水(10 mL)中，然後添加NaOH (257.8 mg, 6.4 mmol, 2.0當量)。將反應混合物在環境溫度下攪拌30 min且然後在真空下濃縮。使用水稀釋殘餘物，使用HCl水溶液(0.5 M)調節至pH 7。藉由過濾收集固體以得到白色固體形式之3-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,2,4-噻二唑-5-甲酸(321.2 mg)。LCMS方法B：[M+H] ⁺= 345。 Scheme 22B : Intermediate 81B (3-(6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl )-1,2,4- thiadiazole- 5 -formic acid ) synthesis

Step 1 : 6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -carboxamide 5-Fluoropyridine-3-carboxylic acid (4.0 g, 15.4 mmol, 1.0 equiv) was dissolved in DMF (40 mL) followed by HATU (8.8 g, 23.1 mmol, 1.5 equiv), DIEA (8.0 mL, 46.1 mmol, 3.0 equiv) and _NH4Cl (1.23 g, 23.058 mmol, 1.5 equiv). The reaction mixture was stirred at ambient temperature overnight, then quenched by addition of water. The solid was collected by filtration and dried to give 6-(4,4-difluorohexahydropyridin-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 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1,3,4 -oxothiazol- 2- one (4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridine-3-carboxamide (3.5 g, 13.5 mmol, 1.0 equiv) was dissolved in toluene (50 mL) and chlorine (chloro) was added sulfanyl)methanone (3.5 g, 27.0 mmol, 2.0 equiv). The reaction mixture was heated to 100 °C overnight, then cooled to ambient temperature and concentrated in vacuo to give 5-[6-(4,4-difluorohexahydropyridin-1-yl)-5-fluoropyridine as a yellow solid -3-yl]-1,3,4-oxathiazol-2-one (3.0 g). LCMS method C: [M+H] ⁺ =274. Step 3 : Ethyl 3-[6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1,2,4- thiadiazole- 5 -carboxylate 5-[6-(4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxothiazol-2-one (3.0 g, 9.5 mmol , 1.0 equiv) was dissolved in dodecane (10 mL), then ethyl cyanoformate (1.4 g, 14.2 mmol, 1.5 equiv) 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-difluorohexahydrogen as a yellow solid) Pyridin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-thiadiazole-5-carboxylic acid ethyl ester (1.2 g). LCMS Method A: [M+H] ⁺ =260. Step 4 : 3-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1,2,4- thiadiazole- 5- carboxylic acid [6-(4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-thiadiazole-5-carboxylic acid ethyl ester (1.2 g, 3.2 mmol , 1.0 equiv) was dissolved in MeOH (10 mL) and water (10 mL), then NaOH (257.8 mg, 6.4 mmol, 2.0 equiv) was added. The reaction mixture was stirred at ambient temperature for 30 min and then concentrated under vacuum. The residue was diluted with water and adjusted to pH 7 with aqueous HCl (0.5 M). The solid was collected by filtration to give 3-[6-(4,4-difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1,2,4-thiadiene as a white solid oxazole-5-carboxylic acid (321.2 mg). LCMS Method B: [M+H] ⁺ =345.

步驟 1 ： 3-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1,2- 噻唑 -5- 甲酸 甲酯將5-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,3,4-氧雜噻唑-2-酮(1.0 g, 3.2 mmol, 1.0當量)溶於鄰二氯苯(10 mL)中，然後添加丙炔酸甲酯(1.6 g, 19.0 mmol, 6.0當量)。將反應混合物加熱至135℃過夜，然後冷卻至環境溫度並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:8)洗脫)來純化殘餘物以得到黃色固體形式之3-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,2-噻唑-5-甲酸甲酯(350.0 mg)。LCMS方法A：[M+H] ⁺= 358。 步驟 2 ： 3-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1,2- 噻唑 -5- 甲酸將3-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,2-噻唑-5-甲酸甲酯(330.0 mg, 0.9 mmol, 1.0當量)溶於MeOH (2 mL)及水(2 mL)中，然後添加NaOH (55.4 mg, 1.4 mmol, 1.5當量)。將反應混合物在環境溫度下攪拌過夜並在真空下濃縮。使用水稀釋殘餘物，使用HCl水溶液(6 M)調節至pH 7。藉由過濾收集所沈澱固體並使用水洗滌以得到黃色固體形式之3-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,2-噻唑-5-甲酸(250.0 mg)。LCMS方法G：[M+H] ⁺= 344。 Scheme 23B : Synthesis of Intermediate 82B (3-(6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ) isothiazole- 5- carboxylic acid )

Step 1 : 3-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1,2- thiazole- 5- carboxylic acid methyl ester -(4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxathiazol-2-one (1.0 g, 3.2 mmol, 1.0 equiv) Dissolve in o-dichlorobenzene (10 mL), then add methyl propiolate (1.6 g, 19.0 mmol, 6.0 equiv). The reaction mixture was heated to 135°C overnight, then cooled to ambient temperature and concentrated in vacuo. 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-difluorohexahydrogen as a yellow solid) Pyridin-1-yl)-5-fluoropyridin-3-yl]-1,2-thiazole-5-carboxylic acid methyl ester (350.0 mg). LCMS Method A: [M+H] ⁺ =358. Step 2 : 3-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1,2- thiazole- 5- carboxylic acid was converted to 3-[6-( 4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1,2-thiazole-5-carboxylic acid methyl ester (330.0 mg, 0.9 mmol, 1.0 equiv) was dissolved in MeOH ( 2 mL) and water (2 mL), then NaOH (55.4 mg, 1.4 mmol, 1.5 equiv) was added. The reaction mixture was stirred at ambient temperature overnight and concentrated in vacuo. The residue was diluted with water and adjusted to pH 7 with aqueous HCl (6 M). The precipitated solid was collected by filtration and washed with water to give 3-[6-(4,4-difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1 as a yellow solid, 2-thiazole-5-carboxylic acid (250.0 mg). LCMS Method G: [M+H] ⁺ =344.

步驟 1 ： 6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟 - N- 甲氧基 - N- 甲基吡啶 -3- 甲醯胺將6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-甲酸(4.6 g, 17.7 mmol, 1.0當量)及 N,O-二甲基羥基胺鹽酸鹽(2.6 g, 26.6 mmol, 1.5當量)溶於DMF (50 mL)中，然後添加HATU (10.1 g, 26.5 mmol, 1.5當量)及DIEA (12.3 mL, 70.7 mmol, 4.0當量)。將反應混合物在環境溫度下攪拌2小時，然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以得到黃色油狀物形式之6-(4,4-二氟六氫吡啶-1-基)-5-氟- N-甲氧基- N-甲基吡啶-3-甲醯胺(4.2 g)。LCMS方法A：[M+H] ⁺= 272。 步驟 2 ： 1-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ] 乙酮將6-(4,4-二氟六氫吡啶-1-基)-5-氟- N-甲氧基- N-甲基吡啶-3-甲醯胺(1.6 g, 5.3 mmol, 1.0當量)溶於THF (20 mL)中並冷卻至0℃，然後在氮氣氛下逐滴添加MeMgBr (3M於THF中，2.7 mL, 8.1 mmol, 1.5當量)，且將溶液維持於0℃下。將反應混合物在0℃下攪拌2小時，然後藉由添加飽和NH ₄Cl水溶液來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以得到黃色固體形式之1-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]乙烯酮(900.0 mg)。LCMS方法A：[M+H] ⁺= 259。 步驟 3 ： 2- 溴 -1-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ] 乙酮將1-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]乙酮(3.0 g, 11.6 mmol, 1.0當量)溶於ACN (15 mL)中，然後添加NBS (3.1 g, 17.4 mmol, 1.5當量)及TsOH (3.0 g, 17.4 mmol, 1.5當量)。將反應混合物加熱至100℃過夜，然後冷卻至環境溫度並使用乙酸乙酯稀釋。使用飽和NaHCO ₃水溶液洗滌所得溶液，藉由無水Na ₂SO ₄乾燥並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:4)洗脫)來純化殘餘物以得到黃色固體形式之2-溴-1-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]乙酮(2.0 g)。LCMS方法A：[M+H] ⁺= 337。 步驟 4 ：乙酸 2-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-2- 側氧基乙基酯將2-溴-1-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]乙酮(2.0 g, 5.9 mmol, 1.0當量)及乙酸(0.5 mL g, 8.9 mmol, 1.5當量)溶於MeOH (6 mL)及水(14 mL)中，然後添加K ₂CO ₃(0.8 g, 5.9 mmol, 1.0當量)。將反應混合物加熱至70℃並保持3小時，然後冷卻至環境溫度並使用乙酸乙酯稀釋。使用飽和NaHCO ₃溶液洗滌所得溶液，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以得到黃色固體形式之乙酸2-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-2-側氧基乙基酯(1.5 g)。LCMS方法E：[M+H] ⁺= 317。 步驟 5 ： 4-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1,3- 噁唑 -2- 甲酸乙酯將乙酸2-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-2-側氧基乙基酯(1.5 g, 4.7 mmol, 1.0當量)及胺甲醯基甲酸乙酯(1.7 g, 14.3 mmol, 3.0當量)溶於二甲苯(30 mL)中，然後逐滴添加BF ₃•Et ₂O (6.3 mL, 23.7 mmol, 5.0當量)。將反應混合物加熱至130℃並保持48小時，然後冷卻至環境溫度並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到黃色固體形式之4-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,3-噁唑-2-甲酸乙酯(510.0 mg)。LCMS方法C：[M+H] ⁺= 356。 步驟 6 ： 4-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1,3- 噁唑 -2- 甲酸將4-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,3-噁唑-2-甲酸乙酯(500.0 mg, 1.4 mmol, 1.0當量)溶於MeOH (5 mL)及水(5 mL)中，然後添加NaOH (112.6 mg, 2.8 mmol, 2.0當量)。將反應混合物加熱至60℃並保持2小時，然後冷卻至環境溫度並在真空下濃縮。使用水稀釋殘餘物，使用HCl水溶液(0.5 M)調節至pH 6。藉由過濾收集固體，使用水洗滌並乾燥以得到黃色固體形式之4-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,3-噁唑-2-甲酸(215.2 mg)。LCMS方法C：[M+H] ⁺= 328。 Scheme 24B : Synthesis of Intermediate 83B (4-(6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ) oxazole -2- carboxylic acid )

Step 1 : 6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoro - N - methoxy- N -methylpyridine- 3 -carboxamide Difluorohexahydropyridin-1-yl)-5-fluoropyridine-3-carboxylic acid (4.6 g, 17.7 mmol, 1.0 equiv) and N,O -dimethylhydroxylamine hydrochloride (2.6 g, 26.6 mmol, 1.5 equiv) was dissolved in DMF (50 mL), then HATU (10.1 g, 26.5 mmol, 1.5 equiv) and DIEA (12.3 mL, 70.7 mmol, 4.0 equiv) were added. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 6-(4,4-difluorohexahydropyridin-1-yl) as a yellow oil -5-Fluoro- N -methoxy- N -methylpyridine-3-carboxamide (4.2 g). LCMS Method A: [M+H] ⁺ =272. Step 2 : 1-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ] ethanone -yl)-5-fluoro- N -methoxy- N -methylpyridine-3-carboxamide (1.6 g, 5.3 mmol, 1.0 equiv) was dissolved in THF (20 mL) and cooled to 0 °C, then MeMgBr (3M in THF, 2.7 mL, 8.1 mmol, 1.5 equiv) was added dropwise under nitrogen atmosphere and the solution was maintained at 0 °C. The reaction mixture was stirred at 0°C for 2 hours, then quenched by addition of saturated aqueous _NH4Cl . The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 1-[6-(4,4-difluorohexahydropyridin-1-yl as a yellow solid )-5-fluoropyridin-3-yl]ketene (900.0 mg). LCMS Method A: [M+H] ⁺ =259. Step 3 : 2- Bromo - 1-[6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ] ethanone Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]ethanone (3.0 g, 11.6 mmol, 1.0 equiv) was dissolved in ACN (15 mL) and NBS (3.1 g, 17.4 mmol) was added , 1.5 equiv) and TsOH (3.0 g, 17.4 mmol, 1.5 equiv). 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 NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. 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- as a yellow solid) Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]ethanone (2.0 g). LCMS Method A: [M+H] ⁺ =337. Step 4 : Acetate 2-[6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-2- side oxyethyl ester to 2-bromo-1- [6-(4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]ethanone (2.0 g, 5.9 mmol, 1.0 equiv) and acetic acid (0.5 mL g, 8.9 mmol, 1.5 equiv) was dissolved in MeOH (6 mL) and water ( ₁₄ mL), then K2CO3 (0.8 _g , 5.9 mmol, 1.0 equiv) was added. The reaction mixture was heated to 70°C for 3 hours, then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with saturated NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum to give acetic acid 2-[6-(4,4-difluorohexahydropyridin-1-yl)- acetic acid as a yellow solid 5-Fluoropyridin-3-yl]-2-side oxyethyl ester (1.5 g). LCMS Method E: [M+H] ⁺ =317. Step 5 : 4-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1,3 -oxazole -2 -carboxylic acid ethyl ester [6-(4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-2-side oxyethyl ester (1.5 g, 4.7 mmol, 1.0 equiv) and carboxamide Ethyl carboxylate (1.7 g, 14.3 mmol, 3.0 equiv) was dissolved in xylene (30 mL), then _BF3 • _Et2O (6.3 mL, 23.7 mmol, 5.0 equiv) 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-difluorohexahydrogen as a yellow solid) Pyridin-1-yl)-5-fluoropyridin-3-yl]-1,3-oxazole-2-carboxylic acid ethyl ester (510.0 mg). LCMS Method C: [M+H] ⁺ =356. Step 6 : 4-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1,3 -oxazole -2- carboxylic acid (4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1,3-oxazole-2-carboxylic acid ethyl ester (500.0 mg, 1.4 mmol, 1.0 equiv) was dissolved in MeOH (5 mL) and water (5 mL), then NaOH (112.6 mg, 2.8 mmol, 2.0 equiv) was added. The reaction mixture was heated to 60°C for 2 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and adjusted to pH 6 with aqueous HCl (0.5 M). The solid was collected by filtration, washed with water and dried to give 4-[6-(4,4-difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1 as a yellow solid, 3-oxazole-2-carboxylic acid (215.2 mg). LCMS Method C: [M+H] ⁺ =328.

步驟 1 ： 4-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-2,4- 二側氧基丁酸 乙酯將1-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]乙烯酮(600.0 mg, 2.3 mmol, 1.0當量)及EtONa (158.1 mg, 2.3 mmol, 1.0當量)溶於EtOH (6 mL)中，然後逐滴添加草酸乙酯(0.3 mL, 2.3 mmol, 1.0當量)。將反應混合物在環境溫度下攪拌2小時，然後藉由添加水來驟冷。使用HCl水溶液(4 M)將所得溶液調節至pH 6，使用乙酸乙酯萃取，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以得到黃色固體形式之4-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-2,4-二側氧基丁酸乙酯(610.0 mg)。LCMS方法A：[M+H] ⁺= 359。 步驟 2 ： 5-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1 H- 吡唑 -3- 甲酸 乙酯將4-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-2,4-二側氧基丁酸乙酯(900.0 mg, 2.5 mmol, 1.0當量)及NH ₂NH ₂•H ₂O (0.2 mL, 2.5 mmol, 1.0當量)溶於AcOH (10 mL)中。將反應混合物在環境溫度下攪拌2小時，且然後在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:5)洗脫)來純化殘餘物以得到黃色固體形式之 5-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1 H-吡唑-3-甲酸乙酯(450.0 mg)。LCMS方法A：[M+H] ⁺= 355。 步驟 3 ： 5-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1 H- 吡唑 -3- 甲酸將5-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1 H-吡唑-3-甲酸乙酯(450.0 mg, 1.3 mmol, 1.0當量)溶於MeOH (5 mL)及水(5 mL)中，然後添加NaOH (101.6 mg, 2.5 mmol, 2.0當量)。將反應混合物加熱至80℃並保持2小時，然後冷卻至環境溫度並在真空下濃縮。使用水稀釋殘餘物，使用HCl水溶液(2 M)調節至pH 6並在真空下濃縮。藉由反相急速層析使用下列條件來純化殘餘物：管柱，C18矽膠；移動相，ACN/水，在30 min內0%至100%之梯度；檢測器，UV 254 nm。此會產生白色固體形式之5-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1 H-吡唑-3-甲酸(320.0 mg)。LCMS方法B：[M+H] ⁺= 327。 Scheme 25B : Synthesis of Intermediate 84B (5-(6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl )-1H- pyrazole- 3 - carboxylic acid )

Step 1 : 4-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-2,4 -dioxybutyric acid ethyl ester 6-(4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]ketene (600.0 mg, 2.3 mmol, 1.0 equiv) and EtONa (158.1 mg, 2.3 mmol, 1.0 equiv) ) was dissolved in EtOH (6 mL), then ethyl oxalate (0.3 mL, 2.3 mmol, 1.0 equiv) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by addition of water. The resulting solution was adjusted to pH 6 with aqueous HCl (4 M), extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 4-[6-( as a yellow solid 4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-2,4-di-oxybutyric acid ethyl ester (610.0 mg). LCMS Method A: [M+H] ⁺ =359. Step 2 : 5-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1H - pyrazole- 3 - carboxylic acid ethyl ester -(4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-2,4-di-oxybutyric acid ethyl ester (900.0 mg, 2.5 mmol, 1.0 equiv) and _NH2NH2 • _H2O (0.2 mL, _2.5 mmol, 1.0 equiv) was dissolved in AcOH (10 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo. 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-difluorohexahydrogen as a yellow solid) Pyridin-1-yl)-5-fluoropyridin-3-yl]-1H-pyrazole-3-carboxylic acid ethyl ester (450.0 mg). LCMS Method A: [M+H] ⁺ =355. Step 3 : 5-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1H - pyrazole- 3 - carboxylic acid 4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1H-pyrazole-3-carboxylic acid ethyl ester (450.0 mg, 1.3 mmol, 1.0 equiv) was dissolved in MeOH ( 5 mL) and water (5 mL), then NaOH (101.6 mg, 2.5 mmol, 2.0 equiv) was added. The reaction mixture was heated to 80°C for 2 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water, adjusted to pH 6 with aqueous HCl (2 M) and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase, ACN/water, gradient 0% to 100% in 30 min; detector, UV 254 nm. This gave 5-[6-(4,4-difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1H-pyrazole-3-carboxylic acid (320.0 mg) as a white solid ). LCMS Method B: [M+H] ⁺ =327.

步驟 1 ： 5-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1- 甲基吡唑 -3- 甲酸 乙酯將5-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1 H-吡唑-3-甲酸乙酯(300.0 mg, 0.8 mmol, 1.0當量)溶於THF (3 mL)中並冷卻至0℃，然後在氮氣氛下添加NaH (60% wt., 50.8 mg, 1.3 mmol, 1.5當量)，且將溶液維持於0℃下。在9℃下攪拌10 min之後，添加MeI (0.1 mL, 1.6 mmol, 1.5當量)。將反應混合物在環境溫度下攪拌過夜，且然後在0℃下藉由添加MeOH來驟冷。在真空下濃縮所得溶液且藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:5)洗脫)來純化殘餘物以得到白色固體形式之 5-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1-甲基吡唑-3-甲酸乙酯(150.0 mg)。LCMS方法A：[M+H] ⁺= 369。 步驟 2 ： 5-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1- 甲基吡唑 -3- 甲酸將5-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1-甲基吡唑-3-甲酸乙酯(150.0 mg, 0.4 mmol, 1.0當量)溶於MeOH (2 mL)及水(2 mL)中，然後添加NaOH (32.6 mg, 0.8 mmol, 2.0當量)。將反應混合物加熱至80℃並保持2小時，然後冷卻至環境溫度並在真空下濃縮。使用水稀釋殘餘物，使用HCl水溶液(2 M)調節至pH 6。在真空下濃縮所得溶液，且藉由反相急速層析使用下列條件來純化殘餘物：管柱，C18矽膠；移動相，ACN/水，在25 min內0%至100%之梯度；檢測器，UV 254 nm。此會產生白色固體形式之5-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1-甲基吡唑-3-甲酸(105.2 mg)。LCMS方法C：[M+H] ⁺= 341。 Scheme 26B : Intermediate 85B (5-(6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl )-1 -methyl -1H- pyrazole- 3 -formic acid ) synthesis

Step 1 : 5-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1 -methylpyrazole- 3 - carboxylic acid ethyl ester 6-(4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1H-pyrazole-3-carboxylic acid ethyl ester (300.0 mg, 0.8 mmol, 1.0 equiv) was dissolved in In THF (3 mL) and cooled to 0 °C, then NaH (60% wt., 50.8 mg, 1.3 mmol, 1.5 equiv) was added under nitrogen atmosphere and the solution was maintained at 0 °C. After stirring for 10 min at 9 °C, MeI (0.1 mL, 1.6 mmol, 1.5 equiv) was added. The reaction mixture was stirred at ambient temperature overnight, and then quenched by 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 as a white solid , 4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1-methylpyrazole-3-carboxylic acid ethyl ester (150.0 mg). LCMS Method A: [M+H] ⁺ =369. Step 2 : 5-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1 -methylpyrazole- 3 - carboxylic acid was added to 5-[6- (4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1-methylpyrazole-3-carboxylic acid ethyl ester (150.0 mg, 0.4 mmol, 1.0 equiv) was dissolved in MeOH (2 mL) and water (2 mL), then NaOH (32.6 mg, 0.8 mmol, 2.0 equiv) was added. The reaction mixture was heated to 80°C for 2 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and adjusted to pH 6 with aqueous HCl (2 M). The resulting solution was concentrated under vacuum and the residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN/water, gradient 0% to 100% in 25 min; detector , UV 254 nm. This yielded 5-[6-(4,4-difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1-methylpyrazole-3-carboxylic acid (105.2 mg). LCMS method C: [M+H] ⁺ =341.

步驟 1 ： 1-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ] 吡唑 -3- 甲酸甲酯將5-溴-2-(4,4-二氟六氫吡啶-1-基)-3-氟吡啶(1.0 g, 3.4 mmol, 1.0當量)及1 H-吡唑-3-甲酸甲酯(514.1 mg, 4.1 mmol, 1.2當量)溶於DMF (15 mL)中，然後添加( 1S,2S)- N ₁, N ₂-二甲基環己烷-1,2-二胺(96.4 mg, 0.7 mmol, 0.2當量)、CuI (129.1 mg, 0.7 mmol, 0.2當量)及K ₂CO ₃(1.4 g, 10.1 mmol, 3.0當量)。將反應混合物加熱至80℃過夜，然後冷卻至環境溫度並使用乙酸乙酯稀釋。使用鹽水洗滌所得溶液，然後在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到黃色固體形式之 1-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]吡唑-3-甲酸甲酯(610.0 mg)。LCMS方法A：[M+H] ⁺= 341。 步驟 2 ： 1-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ] 吡唑 -3- 甲酸將1-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]吡唑-3-甲酸甲酯(600.0 mg, 1.8 mmol, 1.0當量)溶於MeOH (5 mL)及水(5 mL)中，然後添加NaOH (141.0 mg, 3.5 mmol, 2.0當量)。將反應混合物加熱至60℃並保持2小時，然後冷卻至環境溫度並在真空下濃縮。使用水稀釋殘餘物並使用HCl水溶液(1 M)調節至pH 6。藉由過濾收集所沈澱固體，使用水洗滌並乾燥以得到白色固體形式之1-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]吡唑-3-甲酸(421.5 mg)。LCMS方法E：[M+H] ⁺= 327。 使用與針對中間體86B所闡述相同之方法來製備下列中間體。 中間體 起始材料 結構 LCMS 數據 中間體 87B

方法E： MS-ESI: 374 [M+H] ⁺ Scheme 27B : Synthesis of Intermediate 86B (1-(6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl )-1H- pyrazole- 3 - carboxylic acid )

Step 1 : 1-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ] pyrazole- 3 - carboxylic acid methyl ester ,4-difluorohexahydropyridin-1-yl)-3-fluoropyridine (1.0 g, 3.4 mmol, 1.0 equiv) and 1H -pyrazole-3-carboxylic acid methyl ester (514.1 mg, 4.1 mmol, 1.2 equiv) Dissolve in DMF (15 mL), then add ( 1S,2S ) -N1,N2 - _{dimethylcyclohexane -} 1,2-diamine (96.4 mg, 0.7 mmol, 0.2 equiv), CuI (129.1 mg, 0.7 mmol, 0.2 equiv) and K2CO3 ₍ 1.4 _g , 10.1 mmol, 3.0 equiv). The reaction mixture was heated to 80°C overnight, then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with brine and concentrated in vacuo. 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-difluorohexahydrogen as a yellow solid) Pyridin-1-yl)-5-fluoropyridin-3-yl]pyrazole-3-carboxylic acid methyl ester (610.0 mg). LCMS Method A: [M+H] ⁺ =341. Step 2 : 1-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ] pyrazole- 3 - carboxylic acid was added to 1-[6-(4,4- Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]pyrazole-3-carboxylic acid methyl ester (600.0 mg, 1.8 mmol, 1.0 equiv) was dissolved in MeOH (5 mL) and water (5 mL) ), then NaOH (141.0 mg, 3.5 mmol, 2.0 equiv) was added. The reaction mixture was heated to 60°C for 2 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and adjusted to pH 6 with aqueous HCl (1 M). The precipitated solid was collected by filtration, washed with water and dried to give 1-[6-(4,4-difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]pyridine as a white solid oxazole-3-carboxylic acid (421.5 mg). LCMS Method E: [M+H] ⁺ =327. The following intermediates were prepared using the same procedures as described for Intermediate 86B. Intermediate starting material structure LCMS data Intermediate 87B

Method E: MS-ESI: 374 [M+H] ⁺

步驟 1 ： 6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 甲醯肼將6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-甲酸甲酯(2.0 g, 7.3 mmol, 1.0當量)溶於EtOH (30 mL)中，然後添加NH ₂NH ₂•H ₂O (3.5 mL, 70.0 mmol, 10.0當量)。將所得溶液加熱至90℃並保持16小時，然後冷卻至環境溫度並在真空下濃縮。使用水稀釋殘餘物，且藉由過濾收集固體以得到白色固體形式之6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-甲醯肼(1.3 g)。LCMS方法A：[M+H] ⁺= 275。 步驟 2 ： 2-[[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ] 甲醯肼基 ]-2- 側氧基乙酸乙酯將6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-甲醯肼(1.3 g, 4.7 mmol, 1.0當量)及TEA (2.0 mL, 14.2 mmol, 3.0當量)溶於DCM (20 mL)中，然後逐滴添加氯乙醛酸乙酯(0.5 mL, 5.0 mmol, 1.0當量)。將反應混合物在環境溫度下攪拌2小時，然後藉由添加水來驟冷。使用二氯甲烷萃取所得溶液，藉由無水硫酸鈉乾燥並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到白色固體形式之2-[[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]甲醯肼基]-2-側氧基乙酸乙酯(1.1 g)。LCMS方法D：[M+H] ⁺= 375。 步驟 3 ： 5-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1,3,4- 氧雜二唑 -2- 甲酸乙酯將2-[[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]甲醯肼基]-2-側氧基乙酸乙酯(1.0 g, 2.7 mmol, 1.0當量)及TEA (1.1 mL, 8.0 mmol, 3.0當量)溶於DCM (20 mL)，然後添加TsCl (764.0 mg, 4.0 mmol, 1.5當量)。將反應混合物在環境溫度下攪拌2小時且然後在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:2)洗脫)來純化殘餘物以得到白色固體形式之5-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,3,4-氧雜二唑-2-甲酸乙酯(506.2 mg)。LCMS方法A：[M+H] ⁺= 357。 步驟 4 ： 5-[6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 ]-1,3,4- 氧雜二唑 -2- 甲酸將5-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,3,4-氧雜二唑-2-甲酸乙酯(500.0 mg, 1.4 mmol, 1.0當量)溶於MeOH (3 mL)及水(3 mL)中，然後添加NaOH (112.3 mg, 2.8 mmol, 2.0當量)。將反應混合物加熱至80℃並保持30 min，然後冷卻至環境溫度並在真空下濃縮以得到白色固體形式之粗製5-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,3,4-氧雜二唑-2-甲酸(212.2 mg)，其未經進一步後處理即直接用於下一步驟中。LCMS方法E：[M+H] ⁺= 329。 Scheme 28B : Intermediate 88B (5-(6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl )-1,3,4 - oxadiazole- 2- formic acid ) synthesis

Step 1 : 6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridine - 3 -carbazide Methyl 5-fluoropyridine-3-carboxylate (2.0 g, 7.3 mmol, 1.0 equiv) was dissolved in EtOH (30 mL), then _{NH2NH2 • H2O} (3.5 mL, 70.0 mmol, 10.0 equiv) was added. The resulting solution was heated to 90°C for 16 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was diluted with water, and the solid was collected by filtration to give 6-(4,4-difluorohexahydropyridin-1-yl)-5-fluoropyridine-3-carbazide (1.3 g) as a white solid . LCMS Method A: [M+H] ⁺ =275. Step 2 : ethyl 2-[[6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ] carbazide ]-2 - pendoxoacetate -(4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridine-3-carbazide (1.3 g, 4.7 mmol, 1.0 equiv) and TEA (2.0 mL, 14.2 mmol, 3.0 equiv) were dissolved In DCM (20 mL), then ethyl chloroglyoxylate (0.5 mL, 5.0 mmol, 1.0 equiv) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by addition of water. The resulting solution was extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:1) to give 2-[[6-(4,4-difluorohexanol as a white solid Hydropyridin-1-yl)-5-fluoropyridin-3-yl]carbazide ethyl]-2-oxoacetate (1.1 g). LCMS Method D: [M+H] ⁺ =375. Step 3 : 5-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1,3,4 -oxadiazole- 2 -carboxylic acid ethyl ester Ethyl 2-[[6-(4,4-difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]carbazide]-2-oxoacetate (1.0 g, 2.7 mmol, 1.0 equiv) and TEA (1.1 mL, 8.0 mmol, 3.0 equiv) were dissolved in DCM (20 mL), then TsCl (764.0 mg, 4.0 mmol, 1.5 equiv) was added. The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo. 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-difluorohexahydrogen as a white solid) Pyridin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxadiazole-2-carboxylic acid ethyl ester (506.2 mg). LCMS Method A: [M+H] ⁺ =357. Step 4 : 5-[6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ]-1,3,4 -oxadiazole -2- carboxylic acid -[6-(4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1,3,4-oxadiazole-2-carboxylic acid ethyl ester (500.0 mg, 1.4 mmol, 1.0 equiv) was dissolved in MeOH (3 mL) and water (3 mL), then NaOH (112.3 mg, 2.8 mmol, 2.0 equiv) was added. The reaction mixture was heated to 80 °C for 30 min, then cooled to ambient temperature and concentrated in vacuo to give crude 5-[6-(4,4-difluorohexahydropyridin-1-yl)- as a white solid 5-Fluoropyridin-3-yl]-1,3,4-oxadiazole-2-carboxylic acid (212.2 mg) was used directly in the next step without further workup. LCMS Method E: [M+H] ⁺ =329.

步驟 1 ： 2- 重氮 -3- 側氧基丙酸乙酯將DMF (32.0 g, 438.2 mmol, 33.7 mL, 0.50當量)及SOCl ₂(52.1 g, 438.2 mmol, 31.8 mL, 0.5當量)之混合物在40℃下加熱2小時。在減壓下濃縮反應混合物以得到固體，然後將該固體溶於CHCl ₃(250 mL)中並冷卻至0℃。經1小時逐滴添加2-重氮乙酸乙酯(100 g, 876.4 mmol, 1當量)，且將溫度維持於0℃下。在完成添加之後，將混合物在25℃下攪拌12小時。在減壓下去除溶劑且然後添加MTBE (800.0 mL)以得到漿液。藉由過濾收集黃色沈澱物，溶於10%乙酸水溶液中，然後使用MTBE (3 × 300 mL)萃取。使用碳酸氫鈉水溶液(2 M；3 × 300 mL)、鹽酸(10%；3 × 300 mL)、水(3 × 300 mL)及鹽水(3 × 300 mL)洗滌合併之有機萃取物。藉由無水MgSO ₄乾燥有機層並在減壓下濃縮以得到黃色油狀物形式之2-重氮-3-側氧基-丙酸乙酯(15.0 g, 95.0 mmol, 11%產率，90%純度)。

步驟 2 ： 1-(6- 溴 -5- 氟吡啶 -3- 基 )-1H-1,2,3- 三唑 -4- 甲酸乙酯將6-溴-5-氟-吡啶-3-胺(12.1 g, 63.4 mmol, 1.0當量)及2-重氮-3-側氧基-丙酸乙酯(15.0 g, 95.0 mmol, 90%純度，1.5當量)溶於EtOH (300 mL)中。然後添加AcOH (210.0 g, 3.5 mol, 200 mL, 55.2當量)且將混合物在50℃下加熱16小時。在減壓下濃縮反應混合物以去除溶劑。使用冷水稀釋殘餘物且經由過濾收集所得固體以得到黃色固體形式之1-(6-溴-5-氟-3-吡啶基)三唑-4-甲酸乙酯(16.0 g, 50.8 mmol, 80%產率)。

步驟 3 ： 1-(6- 溴 -5- 氟吡啶 -3- 基 )-1H-1,2,3- 三唑 -4- 甲酸將1-(6-溴-5-氟-3-吡啶基)三唑-4-甲酸乙酯(16 g, 50.8 mmol, 1當量)溶於MeOH (300 mL)中。然後添加NaOH (2 M, 50.78 mL, 2當量)。將混合物在20℃下攪拌4小時。在減壓下濃縮反應混合物以去除MeOH。然後添加H ₂O (30 mL)且藉由逐滴添加HCl水溶液(2 M)來將混合物調節至pH 4。藉由過濾收集所得固體並使用水洗滌以得到白色固體形式之1-(6-溴-5-氟-3-吡啶基)三唑-4-甲酸(12 g, 41.8 mmol, 82%產率)。 步驟 4 ： (1-(6- 溴 -5- 氟吡啶 -3- 基 )- N-(5,6- 二氟 -1H- 吲哚 -3- 基 )-1H-1,2,3- 三唑 -4- 甲醯胺 ( 中間體 89B) 之合成

將1-(6-溴-5-氟-3-吡啶基)三唑-4-甲酸(5.0 g, 17.4 mmol, 1.0當量)及5,6-二氟-1H-吲哚-3-胺(4.0 g, 16.7 mmol, 70%純度，9.6當量)溶於DMF (300 mL)中。然後添加吡啶(11.0 g, 139.3 mmol, 11.3 mL, 8.0當量)及EDCI (3.3 g, 17.4 mmol, 1.0當量)。將混合物在20℃下攪拌2小時，然後將水(1 L)及DCM (1 L)添加至反應混合物中。藉由過濾收集所得固體並使用水及DCM洗滌。獲得白色固體形式之化合物1-(6-溴-5-氟-3-吡啶基)- N-(5,6-二氟-1H-吲哚-3-基)三唑-4-甲醯胺(6.0 g, 13.0 mmol, 75%產率)。 Intermediate 89B (1-(6- Bromo -5- fluoropyridin - 3 -yl )-N-(5,6 -difluoro -1H- indol- 3 -yl )-1H-1,2,3- tri Synthesis step 1- step 4 of oxazole- 4 -carboxamide ) :

Step 1 : Ethyl 2- diazo - 3 -oxypropionate A mixture of DMF (32.0 g, 438.2 mmol, 33.7 mL, 0.50 equiv) and _SOCl2 (52.1 g, 438.2 mmol, 31.8 mL, 0.5 equiv) Heat at 40°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a solid, which was then dissolved in _CHCl3 (250 mL) and cooled to 0 °C. Ethyl 2-diazoacetate (100 g, 876.4 mmol, 1 equiv) was added dropwise over 1 hour, maintaining the temperature at 0 °C. 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 extracted with MTBE (3 x 300 mL). The combined organic extracts were washed with aqueous sodium bicarbonate (2 M; 3 x 300 mL), hydrochloric acid (10%; 3 x 300 mL), water (3 x 300 mL) and brine (3 x 300 mL). The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure to give 2-diazo-3-pendoxo-propionic acid ethyl ester as a yellow oil (15.0 g, 95.0 mmol, 11% yield, 90 %purity).

Step 2 : 1-(6- Bromo -5- fluoro-pyridin - 3 -yl )-1H-1,2,3- triazole - 4 -carboxylic acid ethyl ester (12.1 g, 63.4 mmol, 1.0 equiv) and 2-diazo-3-pendoxo-propionic acid ethyl ester (15.0 g, 95.0 mmol, 90% purity, 1.5 equiv) were dissolved in EtOH (300 mL). AcOH (210.0 g, 3.5 mol, 200 mL, 55.2 equiv) was then added and the mixture was heated at 50 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with cold water and the resulting solid was collected via filtration to give ethyl 1-(6-bromo-5-fluoro-3-pyridyl)triazole-4-carboxylate (16.0 g, 50.8 mmol, 80%) as a yellow solid Yield).

Step 3 : 1-(6- Bromo -5- fluoropyridin - 3 -yl )-1H-1,2,3- triazole - 4 - carboxylic acid ) triazole-4-carboxylic acid ethyl ester (16 g, 50.8 mmol, 1 equiv) was dissolved in MeOH (300 mL). Then NaOH (2 M, 50.78 mL, 2 equiv) was added. The mixture was stirred at 20°C for 4 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. _H2O (30 mL) was then added and the mixture was adjusted to pH 4 by dropwise addition of aqueous HCl (2 M). 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, 82% yield) 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- tris Synthesis of oxazole- 4 -carboxamide ( intermediate 89B)

1-(6-Bromo-5-fluoro-3-pyridyl)triazole-4-carboxylic acid (5.0 g, 17.4 mmol, 1.0 equiv) and 5,6-difluoro-1H-indol-3-amine ( 4.0 g, 16.7 mmol, 70% purity, 9.6 equiv) was dissolved in DMF (300 mL). Pyridine (11.0 g, 139.3 mmol, 11.3 mL, 8.0 equiv) and EDCI (3.3 g, 17.4 mmol, 1.0 equiv) 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-pyridinyl)-N-(5,6-difluoro-1H-indol-3-yl)triazole-4-carboxamide was obtained as a white solid (6.0 g, 13.0 mmol, 75% yield).

將1-[[6-(4,4-二氟環己基)-5-氟吡啶-3-基]甲基]咪唑-4-甲酸(200.0 mg, 0.6 mmol, 1.0當量)溶於DMF (5 mL)中，然後添加5,6-二氟-1H-吲哚-3-胺鹽酸鹽(120.5 mg, 0.6 mmol, 1.0當量)、HATU (336.2 mg, 0.9 mmol, 1.5當量)及DIEA (0.3 mL, 1.8 mmol, 3.0當量)。將反應混合物在環境溫度下攪拌2小時並藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液並在真空下濃縮。藉由製備型HPLC使用下列條件來純化粗產物：管柱，YMC-Actus Triart C18, 30*250, 5µm；移動相，水(10 mM NH ₄HCO ₃+ 0.1% NH ₃.H ₂O)及ACN (在10 min內相B自38%至最高60%)；檢測器，uv 254 nm。此會產生白色固體形式之 N-(5,6-二氟-1 H-吲哚-3-基)-1-[[6-(4,4-二氟環己基)-5-氟吡啶-3-基]甲基]咪唑-4-甲醯胺(17.1 mg)。LCMS方法D：[M+H] ⁺= 490.1H NMR (300 MHz, DMSO- d ₆): δ 11.02 (s, 1H), 9.74 (s, 1H), 8.46 (s, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.79-7.70 (m, 3H), 7.37-7.31 (m, 1H), 5.32 (s, 2H), 3.19-3.15 (m, 1H), 2.09-1.83 (m, 8H)。 使用與針對 實例 1所闡述相同之方法來製備下表中之類似物。 實例編號 化合物 編號 所用起始材料 結構 LCMS 數據 2 112 中間體13 /中間體3

方法G：MS-ESI: 459 [M+H] ⁺。    3 109 中間體11 /中間體9

方法D：MS-ESI: 490 [M+H] ⁺。 4 116 中間體17 /中間體7

方法D：MS-ESI: 580 [M+H] ⁺。 5 108 中間體15 /中間體7

方法D：MS-ESI: 562 [M+H] ⁺。 6 107 中間體13 /中間體7

方法D：MS-ESI: 472 [M+H] ⁺。 7 103 中間體11 /中間體2

方法D：MS-ESI: 476 [M+H] ⁺。 8 119 中間體11 /中間體6

方法D：MS-ESI: 490 [M+H] ⁺。 10 104 中間體11 /中間體8

方法D：MS-ESI: 490 [M+H] ⁺。 11 125 中間體16 /中間體3

方法J：MS-ESI: 539 [M+H] ⁺。    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), then 5,6-difluoro-1H-indol-3-amine hydrochloride (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 equiv). The reaction mixture was stirred at ambient temperature for 2 hours and quenched by addition of water. The resulting solution was extracted with ethyl acetate and concentrated in vacuo. The crude product was purified by preparative HPLC using the following conditions: column, YMC-Actus Triart C18, 30*250, ₅ µm; mobile phase, water ( ₁₀ mM _{NH4HCO3 +} 0.1% NH3.H2O) and ACN (Phase B from 38% to up to 60% in 10 min); detector, uv 254 nm. This yields N- (5,6-difluoro- 1H -indol-3-yl)-1-[[6-(4,4-difluorocyclohexyl)-5-fluoropyridine- 3-yl]methyl]imidazol-4-carboxamide (17.1 mg). LCMS Method D: [M+H] ⁺ = 490.1H NMR (300 MHz, DMSO- d ₆ ): δ 11.02 (s, 1H), 9.74 (s, 1H), 8.46 (s, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.79-7.70 (m, 3H), 7.37-7.31 (m, 1H), 5.32 (s, 2H), 3.19-3.15 (m, 1H), 2.09-1.83 (m, 8H). The analogs in the table below were prepared using the same method as described for Example 1 . instance number Compound number Starting materials used structure LCMS data 2 112 Intermediate 13 / Intermediate 3

Method G: MS-ESI: 459 [M+H] ⁺ . 3 109 Intermediate 11 / Intermediate 9

Method D: MS-ESI: 490 [M+H] ⁺ . 4 116 Intermediate 17 / Intermediate 7

Method D: MS-ESI: 580 [M+H] ⁺ . 5 108 Intermediate 15 / Intermediate 7

Method D: MS-ESI: 562 [M+H] ⁺ . 6 107 Intermediate 13 / Intermediate 7

Method D: MS-ESI: 472 [M+H] ⁺ . 7 103 Intermediate 11 / Intermediate 2

Method D: MS-ESI: 476 [M+H] ⁺ . 8 119 Intermediate 11 / Intermediate 6

Method D: MS-ESI: 490 [M+H] ⁺ . 10 104 Intermediate 11 / Intermediate 8

Method D: MS-ESI: 490 [M+H] ⁺ . 11 125 Intermediate 16 / Intermediate 3

Method J: MS-ESI: 539 [M+H] ⁺ .

將1-(6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基)-1 H-咪唑-4-甲酸(129.5 mg, 0.4 mmol, 1.0當量)溶於THF (10 mL)中，然後添加5-氟-1 H-吡咯并[2,3- b]吡啶-3-胺鹽酸鹽(74.7 mg, 0.4 mmol, 1.0當量)、TEA (0.6 mL, 4.0 mmol, 10.0當量)及T ₃P (189.5 mg, 0.6 mmol, 1.5當量)。將所得溶液在環境溫度下攪拌過夜且然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液並在真空下濃縮。藉由製備型HPLC使用下列條件來純化殘餘物：管柱：XBridge Prep OBD C18管柱，30×150mm 5µm；移動相A：水(0.05% FA)，移動相B：ACN；流速：50 mL/min；梯度：在7 min內35% B至65% B；254 nm。此會產生白色固體形式之1-(6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基)- N-(5-氟-1 H-吡咯并[2,3-b]吡啶-3-基)-1 H-咪唑-4-甲醯胺(41.4 mg)。LCMS方法J：[M+H] ⁺= 460.1H NMR (400 MHz, DMSO- d ₆ ): δ 11.63 (s, 1H), 10.14 (s, 1H), 8.56 (d, 1H), 8.45-8.41 (m, 2H), 8.22-8.18 (m, 3H), 7.92 (s, 1H), 3.62 (t, 4H), 2.16-2.06 (m, 4H)。 使用與針對 實例 12所闡述相同之方法來製備下表中之類似物。 實例編號 化合物編號 起始材料 結構 LCMS 數據 13 114 1 H-吲哚-3-胺/中間體4

方法F：MS-ESI: 454 [M+H] ⁺。 14 110 中間體15 /中間體2

方法F：MS-ESI: 548 [M+H] ⁺。 15 111 1 H-吲哚-3-胺/中間體10

方法F：MS-ESI: 440 [M+H] ⁺。 16 122 中間體11 /中間體3

方法F：MS-ESI: 477 [M+H] ⁺。 17 110 中間體11 /中間體1

方法D：MS-ESI: 473 [M+H] ⁺。 18 106 1 H-吲哚-3-胺/中間體2

方法K：MS-ESI: 440 [M+H] ⁺。 19 123 中間體12 /中間體3

方法G：MS-ESI: 460 [M+H] ⁺。 20 115 中間體15 /中間體3

方法J：MS-ESI: 549 [M+H] ⁺。 21 121 1 H-吲哚-3-胺/中間體3

方法F：MS-ESI: 441 [M+H] ⁺。    Example 12 : 1-(6-(4,4 -Difluorohexahydropyridin- 1 -yl )-5- fluoropyridin - 3 -yl ) -N- (5- fluoro - 1H - pyrrolo [2,3 -b] pyridin - 3 -yl ) -1H - imidazol- 4 -carboxamide

1-(6-(4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl)-1H-imidazole-4-carboxylic acid (129.5 mg, 0.4 mmol, 1.0 equiv) Dissolve in THF (10 mL), then add 5-fluoro- 1H -pyrrolo[2,3- b ]pyridin-3-amine hydrochloride (74.7 mg, 0.4 mmol, 1.0 equiv), TEA (0.6 mL) , 4.0 mmol, 10.0 equiv) and T ₃ P (189.5 mg, 0.6 mmol, 1.5 equiv). The resulting solution was stirred at ambient temperature overnight and then quenched by addition of water. The resulting solution was extracted with ethyl acetate and concentrated in vacuo. The residue was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30 x 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 yields 1-(6-(4,4-difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl) -N- (5-fluoro- 1H -pyrrolo as a white solid [2,3-b]pyridin-3-yl) -1H -imidazol-4-carboxamide (41.4 mg). LCMS Method J: [M+H] ⁺ = 460.1H NMR (400 MHz, DMSO- d ₆ ): δ 11.63 (s, 1H), 10.14 (s, 1H), 8.56 (d, 1H), 8.45-8.41 ( m, 2H), 8.22-8.18 (m, 3H), 7.92 (s, 1H), 3.62 (t, 4H), 2.16-2.06 (m, 4H). The analogs in the table below were prepared using the same method as described for Example 12 . instance number Compound number starting material structure LCMS data 13 114 1 H -Indol-3-amine/Intermediate 4

Method F: MS-ESI: 454 [M+H] ⁺ . 14 110 Intermediate 15 / Intermediate 2

Method F: MS-ESI: 548 [M+H] ⁺ . 15 111 1H -Indol-3-amine/Intermediate 10

Method F: MS-ESI: 440 [M+H] ⁺ . 16 122 Intermediate 11 / Intermediate 3

Method F: MS-ESI: 477 [M+H] ⁺ . 17 110 Intermediate 11 / Intermediate 1

Method D: MS-ESI: 473 [M+H] ⁺ . 18 106 1 H -Indol-3-amine/Intermediate 2

Method K: MS-ESI: 440 [M+H] ⁺ . 19 123 Intermediate 12 / Intermediate 3

Method G: MS-ESI: 460 [M+H] ⁺ . 20 115 Intermediate 15 / Intermediate 3

Method J: MS-ESI: 549 [M+H] ⁺ . twenty one 121 1 H -Indol-3-amine/Intermediate 3

Method F: MS-ESI: 441 [M+H] ⁺ .

步驟 1 ： N -(5,6- 二氟 -1 H- 吲哚 -3- 基 ) 丙炔醯胺將5,6-二氟-1H-吲哚-3-胺鹽酸鹽(730.0 mg, 3.6 mmol, 1.0當量)溶於THF (30 mL)中並冷卻至0℃，然後在0℃下添加丙炔酸(499.9 mg, 7.1 mmol, 2.0當量)、TEA (1.5 mL, 10.7 mmol, 3.0當量)及T ₃P (6.8 g, 10.7 mmol, 3.0當量)。將反應混合物在環境溫度下攪拌3小時且然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水硫酸鈉乾燥並在真空下濃縮。藉由急速管柱層析在矽膠管柱上(使用乙酸乙酯/石油醚(1:3)洗脫)來純化殘餘物以得到淺黃色固體形式之 N-(5,6-二氟-1 H-吲哚-3-基)丙-2-炔醯胺(350 mg)。LCMS方法A：[M+H] ⁺= 221。 步驟 2 ： 5- 疊氮基 -2-(4,4- 二氟六氫吡啶 -1- 基 )-3- 氟吡啶將6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-胺(400.0 mg, 1.7 mmol, 1.0當量)溶於ACN (10 mL)中並冷卻至0℃，然後逐滴添加 t-BuNO ₂(0.3 mL, 2.7 mmol, 1.6當量)，且將混合物維持於0℃下。在0℃下保持30 min之後，在0℃下逐滴添加TMSN ₃(0.3 mL, 2.5 mmol, 1.5當量)。將反應混合物在環境溫度下再攪拌2小時，然後藉由添加水來驟冷。使用乙酸乙酯萃取所得混合物，藉由無水硫酸鈉乾燥並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:2)洗脫)來純化殘餘物以得到黃色油狀物形式之5-疊氮基-2-(4,4-二氟六氫吡啶-1-基)-3-氟吡啶(380 mg)。 步驟 3 ： N -(5,6- 二氟 -1 H- 吲哚 -3- 基 )-1-(6-(4,4- 二氟六氫吡啶 -1- 基 )-5- 氟吡啶 -3- 基 )-1 H-1,2,3- 三唑 -4- 甲醯胺將5-疊氮基-2-(4,4-二氟六氫吡啶-1-基)-3-氟吡啶(150.0 mg, 0.6 mmol, 1.0當量)溶於二噁烷/水(5/0.5 mL)中，然後添加 N-(5,6-二氟-1 H-吲哚-3-基)丙炔醯胺(130.0 mg, 0.6 mmol, 1.0當量)、(R)-2-((S)-1,2-二羥基乙基)-4-羥基-5-側氧基-2,5-二氫呋喃-3-醇鈉(24.0 mg, 0.1 mmol, 0.2當量)及CuSO ₄(19.0 mg, 0.1 mmol, 0.2當量)。將反應混合物在環境溫度下攪拌15小時且然後藉由添加水來驟冷。使用乙酸乙酯萃取反應混合物，藉由無水硫酸鈉乾燥並在真空下濃縮。藉由製備型HPLC使用下列條件進一步純化殘餘物：XBridge Prep OBD C18管柱，30×150mm 5µm；移動相A：水(10 mM NH ₄HCO ₃)，移動相B：ACN；流速：50 mL/min；梯度：在7 min內35% B至80% B；254 nm；RT1:6.95 min。此會產生灰白色固體形式之 N-(5,6-二氟-1 H-吲哚-3-基)-1-(6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基)-1 H-1,2,3-三唑-4-甲醯胺(135.5 mg)。LCMS方法H：[M-H] ^-= 476。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.14 (s, 1H), 10.58 (s, 1H), 9.35 (s, 1H), 8.68 (s, 1H), 8.32-8.28 (m, 1H), 7.92-7.87 (m, 1H), 7.84 (s, 1H), 7.42-7.37 (m, 1H), 3.70-3.67 (m, 4H), 2.17-2.07 (m, 4H)。 Example 22 : N- (5,6 -Difluoro - 1H - indol- 3 -yl )-1-(6-(4,4 -difluorohexahydropyridin- 1 -yl )-5 - fluoropyridine- 3- yl )-1H- 1,2,3 - triazole - 4 -carboxamide ) ( Compound 102)

Step 1 : N- (5,6 -Difluoro - 1H - indol- 3 -yl ) propynamide 5,6-difluoro-1H-indol-3-amine hydrochloride (730.0 mg, 3.6 mmol, 1.0 equiv) was dissolved in THF (30 mL) and cooled to 0 °C, then propyolic acid (499.9 mg, 7.1 mmol, 2.0 equiv), TEA (1.5 mL, 10.7 mmol, 3.0 equiv) were added at 0 °C ) and T ₃ P (6.8 g, 10.7 mmol, 3.0 equiv). The reaction mixture was stirred at ambient temperature for 3 hours and then quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:3) to give N- (5,6-difluoro-1 as a pale yellow solid) H -indol-3-yl)prop-2-ynamide (350 mg). LCMS Method A: [M+H] ⁺ =221. Step 2 : 5- azido- 2-(4,4 -difluorohexahydropyridin- 1 -yl )-3 - fluoropyridine 6-(4,4-difluorohexahydropyridin-1-yl)- 5-Fluoropyridin-3-amine (400.0 mg, 1.7 mmol, 1.0 equiv) was dissolved in ACN (10 mL) and cooled to 0 °C, then t - _BuNO2 (0.3 mL, 2.7 mmol, 1.6 equiv) was added dropwise , and the mixture was maintained at 0 °C. After 30 min at 0 °C, TMSN ₃ (0.3 mL, 2.5 mmol, 1.5 equiv) was added dropwise at 0 °C. The reaction mixture was stirred for an additional 2 hours at ambient temperature, then quenched by addition of water. The resulting mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:2) to give 5-azido-2-(4,4 as a yellow oil) -Difluorohexahydropyridin-1-yl)-3-fluoropyridine (380 mg). Step 3 : N- (5,6 -Difluoro - 1H - indol- 3 -yl )-1-(6-(4,4 -difluorohexahydropyridin- 1 -yl )-5 - fluoropyridine- 3- yl )-1H- 1,2,3 - triazole - 4 -carboxamide 5-azido-2-(4,4-difluorohexahydropyridin-1-yl)-3-fluoro Pyridine (150.0 mg, 0.6 mmol, 1.0 equiv) was dissolved in dioxane/water (5/0.5 mL), then N- (5,6-difluoro- 1H -indol-3-yl)propyne was added Amide (130.0 mg, 0.6 mmol, 1.0 equiv), (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxy-2,5-dihydro Sodium furan-3-ol (24.0 mg, 0.1 mmol, 0.2 equiv) and CuSO4 ₍ 19.0 mg, 0.1 mmol, 0.2 equiv). The reaction mixture was stirred at ambient temperature for 15 hours and then quenched by addition of water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was further purified by preparative HPLC using the following conditions: XBridge Prep OBD C18 column, 30 x 150 mm 5 µm; mobile phase A: water (10 mM _{NH4HCO3 )} , mobile phase B: ACN; flow rate: 50 mL/ min; gradient: 35% B to 80% B in 7 min; 254 nm; RT1: 6.95 min. This yielded N- (5,6-difluoro- 1H -indol-3-yl)-1-(6-(4,4-difluorohexahydropyridin-1-yl)-5 as an off-white solid -Fluoropyridin -3-yl)-1H-1,2,3-triazole-4-carboxamide (135.5 mg). LCMS Method H: [MH] ^- = 476. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.14 (s, 1H), 10.58 (s, 1H), 9.35 (s, 1H), 8.68 (s, 1H), 8.32-8.28 (m, 1H), 7.92-7.87 (m, 1H), 7.84 (s, 1H), 7.42-7.37 (m, 1H), 3.70-3.67 (m, 4H), 2.17-2.07 (m, 4H).

將5-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,2-噁唑-3-甲酸(250.0 mg, 0.8 mmol, 1.0當量)溶於DMF (3 mL)中，然後添加5,6-二氟-1 H-吲哚-3-胺鹽酸鹽(223.1 mg, 1.1 mmol, 1.5當量)及HATU (435.7 mg, 1.1 mmol, 1.5當量)。隨後逐滴添加DIEA (0.5 mL, 2.9 mmol, 4.0當量)。將反應混合物在環境溫度下攪拌2小時且然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮。藉由反相急速層析使用下列條件來純化殘餘物：管柱，C18矽膠；移動相，ACN/水，在20 min內0%至100%之梯度；檢測器，UV 254 nm。此會產生粉紅色固體形式之 N-(5,6-二氟-1 H-吲哚-3-基)-5-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,2-噁唑-3-甲醯胺(127.2 mg)。LCMS方法J：[M+H] ⁺= 478。 ¹H NMR (400 MHz, CD ³OD- d ₄ ): δ 8.54 (s, 1H), 7.90-7.81 (m, 1H), 7.78 (s, 1H), 7.63-7.58 (m, 1H), 7.27-7.23 (m, 1H), 7.16 (s, 1H), 3.83-3.80 (m, 4H), 2.16-2.06 (m, 4H)。 使用與針對 實例 23所闡述相同之方法來製備下表中之類似物。 實例編號 化合物編號 所用起始材料 結構 LCMS 數據 23 141 中間體1B /中間體52B

方法K： MS-ESI: 491 [M+H] ⁺。    24 137 中間體1B /中間體57B

方法K： MS-ESI: 491 [M+H] ⁺。    25 139 中間體3B /中間體58B

方法H： MS-ESI: 512 [M+H] ⁺。    26 140 中間體1B /中間體65B

方法H： MS-ESI: 477 [M+H] ⁺。    27 142 中間體1B /中間體80B

方法H： MS-ESI: 479 [M+H] ⁺。    28 143 中間體1B /中間體53B

方法F： MS-ESI: 476 [M+H] ⁺。    29 147 中間體1B /中間體54B

方法I： MS-ESI: 523 [M+H] ⁺。    30 146 中間體1B /中間體70N\B

方法I： MS-ESI: 494 [M+H] ⁺。    31 145 中間體1B /中間體71B

方法H： MS-ESI: 478 [M+H] ⁺。    32 149 中間體1B /中間體56B

方法H： MS-ESI: 510 [M+H] ⁺。    33 150 中間體1B /中間體85B

方法H： MS-ESI: 491 [M+H] ⁺。    34 151 中間體1B /中間體59B

方法H： MS-ESI: 478 [M+H] ⁺。    35 152 中間體1B /中間體60B

方法F： MS-ESI: 498 [M+H] ⁺。    36 161 中間體1B /中間體61B

方法H： MS-ESI: 482 [M+H] ⁺。    37 175 中間體1B /中間體68B

方法H： MS-ESI: 468 [M+H] ⁺。    38 176 中間體1B /中間體62B

方法H： MS-ESI: 468 [M+H] ⁺。    39 178 中間體5B /中間體43B

方法H： MS-ESI: 494 [M+H] ⁺。    40 179 中間體1B /中間體55B

方法H： MS-ESI: 494 [M+H] ⁺。    41 181 中間體1B /中間體63B

方法H： MS-ESI: 540 [M+H] ⁺。    42 190 中間體1B /中間體72B

方法H： MS-ESI: 494 [M+H] ⁺。    43 192 中間體1B /中間體81B

方法F： MS-ESI: 495 [M+H] ⁺。    44 196 中間體1B /中間體79B

方法H： MS-ESI: 541 [M+H] ⁺。    45 202 1 H-吲哚-3-胺/中間體58B

方法F： MS-ESI: 442 [M+H] ⁺。    46 205 中間體1B /中間體73B

方法I： MS-ESI: 495 [M+H] ⁺。    47 219 中間體1B /中間體75B

方法K： MS-ESI: 494 [M+H] ⁺。    48 213 中間體1B /中間體76B

方法K： MS-ESI: 494 [M+H] ⁺。    49 218 中間體1B /中間體77B

方法K： MS-ESI: 478 [M+H] ⁺。    50 216 中間體1B /中間體44B

方法H： MS-ESI: 468 [M+H] ⁺。    51 220 中間體1B /中間體86B

方法H： MS-ESI: 477 [M+H] ⁺。    52 221 中間體1B /中間體84B

方法H： MS-ESI: 477 [M+H] ⁺。    53 222 中間體1B /中間體45B

方法H： MS-ESI: 464 [M+H] ⁺。    54 223 5-氯-1 H-吲哚-3-胺/中間體46B

方法H： MS-ESI: 472 [M+H] ⁺。    55 224 中間體1B /中間體78B

方法K： MS-ESI: 494 [M+H] ⁺。    56 232 中間體1B /中間體40B

方法J： MS-ESI: 477 [M+H] ⁺。    57 225 5-氯-1 H-吲哚-3-胺/中間體40B

方法H： MS-ESI: 475 [M+H] ⁺。    58 226 5-氯-1 H-吲哚-3-胺/中間體41B

方法H： MS-ESI: 446 [M+H] ⁺。    59 227 5-氯-1 H-吲哚-3-胺/中間體42B

方法H： MS-ESI: 470 [M+H] ⁺。    60 228 5-氯-1 H-吲哚-3-胺/中間體47B

方法H： MS-ESI: 492 [M+H] ⁺。    61 229 中間體1B /中間體46B

方法H： MS-ESI: 474 [M+H] ⁺。    62 230 中間體1B /中間體48B

方法H： MS-ESI: 524 [M+H] ⁺。    63 231 5-氯-1 H-吲哚-3-胺/中間體87B

方法H： MS-ESI: 522 [M+H] ⁺。    64 233 中間體1B /中間體49B

方法H： MS-ESI: 525 [M+H] ⁺。    65 236 1 H-吲哚-3-胺/中間體49B

方法H： MS-ESI: 489 [M+H] ⁺。    66 236 5-氯-1 H-吲哚-3-胺/中間體49B

方法H： MS-ESI: 523 [M+H] ⁺。    67 237 1 H-吲哚-3-胺/中間體50B

方法I： MS-ESI: 441 [M+H] ⁺。    68 238 5-氯-1 H-吲哚-3-胺/中間體43B

方法J： MS-ESI: 476 [M+H] ⁺。    69 239 1 H-吲哚-3-胺/中間體43B

方法F： MS-ESI: 442 [M+H] ⁺。    70 240 中間體1B /中間體51B

方法J： MS-ESI: 463 [M+H] ⁺。    71 155 中間體1B /中間體66B

方法H： MS-ESI: 541 [M+H] ⁺。    72 214 中間體1B /中間體74B

方法H： MS-ESI: 477 [M+H] ⁺。    73 138 中間體2B /中間體58B

方法F： MS-ESI: 494 [M+H] ⁺。    74 199 中間體1B /中間體88B

方法I： MS-ESI: 479 [M+H] ⁺。    Example 23 : N- (5,6 -Difluoro -1H- indol- 3 -yl )-5-(6-(4,4 -difluorohexahydropyridin- 1 -yl )-5- fluoropyridine -3 -yl ) isoxazole- 3 - carboxamide ( compound 208)

5-[6-(4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1,2-oxazole-3-carboxylic acid (250.0 mg, 0.8 mmol, 1.0 equiv) was dissolved in DMF (3 mL), then 5,6-difluoro- 1H -indol-3-amine hydrochloride (223.1 mg, 1.1 mmol, 1.5 equiv) and HATU (435.7 mg, 1.1 mmol) were added , 1.5 equiv). DIEA (0.5 mL, 2.9 mmol, 4.0 equiv) was then added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried _over anhydrous _Na2SO4 and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase, ACN/water, gradient 0% to 100% in 20 min; detector, UV 254 nm. This yields N- (5,6-difluoro- 1H -indol-3-yl)-5-[6-(4,4-difluorohexahydropyridin-1-yl)- as a pink solid 5-Fluoropyridin-3-yl]-1,2-oxazole-3-carboxamide (127.2 mg). LCMS Method J: [M+H] ⁺ =478. ¹ H NMR (400 MHz, CD ³ OD- d ₄ ): δ 8.54 (s, 1H), 7.90-7.81 (m, 1H), 7.78 (s, 1H), 7.63-7.58 (m, 1H), 7.27- 7.23 (m, 1H), 7.16 (s, 1H), 3.83-3.80 (m, 4H), 2.16-2.06 (m, 4H). The analogs in the table below were prepared using the same method as described for Example 23 . instance number Compound number Starting materials used structure LCMS data twenty three 141 Intermediate 1B / Intermediate 52B

Method K: MS-ESI: 491 [M+H] ⁺ . twenty four 137 Intermediate 1B / Intermediate 57B

Method K: MS-ESI: 491 [M+H] ⁺ . 25 139 Intermediate 3B / Intermediate 58B

Method H: MS-ESI: 512 [M+H] ⁺ . 26 140 Intermediate 1B / Intermediate 65B

Method H: MS-ESI: 477 [M+H] ⁺ . 27 142 Intermediate 1B / Intermediate 80B

Method H: MS-ESI: 479 [M+H] ⁺ . 28 143 Intermediate 1B / Intermediate 53B

Method F: MS-ESI: 476 [M+H] ⁺ . 29 147 Intermediate 1B / Intermediate 54B

Method I: MS-ESI: 523 [M+H] ⁺ . 30 146 Intermediate 1B / Intermediate 70N\B

Method I: MS-ESI: 494 [M+H] ⁺ . 31 145 Intermediate 1B / Intermediate 71B

Method H: MS-ESI: 478 [M+H] ⁺ . 32 149 Intermediate 1B / Intermediate 56B

Method H: MS-ESI: 510 [M+H] ⁺ . 33 150 Intermediate 1B / Intermediate 85B

Method H: MS-ESI: 491 [M+H] ⁺ . 34 151 Intermediate 1B / Intermediate 59B

Method H: MS-ESI: 478 [M+H] ⁺ . 35 152 Intermediate 1B / Intermediate 60B

Method F: MS-ESI: 498 [M+H] ⁺ . 36 161 Intermediate 1B / Intermediate 61B

Method H: MS-ESI: 482 [M+H] ⁺ . 37 175 Intermediate 1B / Intermediate 68B

Method H: MS-ESI: 468 [M+H] ⁺ . 38 176 Intermediate 1B / Intermediate 62B

Method H: MS-ESI: 468 [M+H] ⁺ . 39 178 Intermediate 5B / Intermediate 43B

Method H: MS-ESI: 494 [M+H] ⁺ . 40 179 Intermediate 1B / Intermediate 55B

Method H: MS-ESI: 494 [M+H] ⁺ . 41 181 Intermediate 1B / Intermediate 63B

Method H: MS-ESI: 540 [M+H] ⁺ . 42 190 Intermediate 1B / Intermediate 72B

Method H: MS-ESI: 494 [M+H] ⁺ . 43 192 Intermediate 1B / Intermediate 81B

Method F: MS-ESI: 495 [M+H] ⁺ . 44 196 Intermediate 1B / Intermediate 79B

Method H: MS-ESI: 541 [M+H] ⁺ . 45 202 1 H -Indol-3-amine/Intermediate 58B

Method F: MS-ESI: 442 [M+H] ⁺ . 46 205 Intermediate 1B / Intermediate 73B

Method I: MS-ESI: 495 [M+H] ⁺ . 47 219 Intermediate 1B / Intermediate 75B

Method K: MS-ESI: 494 [M+H] ⁺ . 48 213 Intermediate 1B / Intermediate 76B

Method K: MS-ESI: 494 [M+H] ⁺ . 49 218 Intermediate 1B / Intermediate 77B

Method K: MS-ESI: 478 [M+H] ⁺ . 50 216 Intermediate 1B / Intermediate 44B

Method H: MS-ESI: 468 [M+H] ⁺ . 51 220 Intermediate 1B / Intermediate 86B

Method H: MS-ESI: 477 [M+H] ⁺ . 52 221 Intermediate 1B / Intermediate 84B

Method H: MS-ESI: 477 [M+H] ⁺ . 53 222 Intermediate 1B / Intermediate 45B

Method H: MS-ESI: 464 [M+H] ⁺ . 54 223 5-Chloro- 1H -indol-3-amine/Intermediate 46B

Method H: MS-ESI: 472 [M+H] ⁺ . 55 224 Intermediate 1B / Intermediate 78B

Method K: MS-ESI: 494 [M+H] ⁺ . 56 232 Intermediate 1B / Intermediate 40B

Method J: MS-ESI: 477 [M+H] ⁺ . 57 225 5-Chloro- 1H -indol-3-amine/Intermediate 40B

Method H: MS-ESI: 475 [M+H] ⁺ . 58 226 5-Chloro- 1H -indol-3-amine/Intermediate 41B

Method H: MS-ESI: 446 [M+H] ⁺ . 59 227 5-Chloro- 1H -indol-3-amine/Intermediate 42B

Method H: MS-ESI: 470 [M+H] ⁺ . 60 228 5-Chloro- 1H -indol-3-amine/Intermediate 47B

Method H: MS-ESI: 492 [M+H] ⁺ . 61 229 Intermediate 1B / Intermediate 46B

Method H: MS-ESI: 474 [M+H] ⁺ . 62 230 Intermediate 1B / Intermediate 48B

Method H: MS-ESI: 524 [M+H] ⁺ . 63 231 5-Chloro- 1H -indol-3-amine/Intermediate 87B

Method H: MS-ESI: 522 [M+H] ⁺ . 64 233 Intermediate 1B / Intermediate 49B

Method H: MS-ESI: 525 [M+H] ⁺ . 65 236 1 H -Indol-3-amine/Intermediate 49B

Method H: MS-ESI: 489 [M+H] ⁺ . 66 236 5-Chloro- 1H -indol-3-amine/Intermediate 49B

Method H: MS-ESI: 523 [M+H] ⁺ . 67 237 1 H -Indol-3-amine/Intermediate 50B

Method I: MS-ESI: 441 [M+H] ⁺ . 68 238 5-Chloro- 1H -indol-3-amine/Intermediate 43B

Method J: MS-ESI: 476 [M+H] ⁺ . 69 239 1 H -Indol-3-amine/Intermediate 43B

Method F: MS-ESI: 442 [M+H] ⁺ . 70 240 Intermediate 1B / Intermediate 51B

Method J: MS-ESI: 463 [M+H] ⁺ . 71 155 Intermediate 1B / Intermediate 66B

Method H: MS-ESI: 541 [M+H] ⁺ . 72 214 Intermediate 1B / Intermediate 74B

Method H: MS-ESI: 477 [M+H] ⁺ . 73 138 Intermediate 2B / Intermediate 58B

Method F: MS-ESI: 494 [M+H] ⁺ . 74 199 Intermediate 1B / Intermediate 88B

Method I: MS-ESI: 479 [M+H] ⁺ .

將3-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,2-噁唑-5-甲酸(200.0 mg, 0.6 mmol, 1.0當量)溶於DMF (2 mL)中，然後添加5,6-二氟-1 H-吲哚-3-胺鹽酸鹽(186.2 mg, 0.9 mmol, 1.5當量)及HATU (348.6 mg, 0.9 mmol, 1.5當量)。隨後逐滴添加DIEA (0.4 mL, 2.4 mmol, 4.0當量)。將反應混合物在環境溫度下攪拌2小時且然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮。藉由反相急速層析使用下列條件來純化殘餘物：管柱，C18矽膠；移動相，ACN/水，在20 min內0%至100%之梯度；檢測器，UV 254 nm。此會產生灰白色固體形式之 N-(5,6-二氟-1 H-吲哚-3-基)-3-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,2-噁唑-5-甲醯胺(145.8 mg)。LCMS方法H：[M+H] ⁺= 478。 ¹H NMR (400 MHz, DMSO- d ₆ ): δ 11.24 (s, 1H), 10.88 (s, 1H), 8.63 (s, 1H), 8.10-8.06 (m, 1H), 7.95-7.89 (m, 2H), 7.81 (s, 1H), 7.44-7.39 (m, 1H), 3.73-3.70 (m, 4H), 2.16-2.06 (m, 4H)。 Example 75 : N- (5,6 -Difluoro - 1H - indol- 3 -yl )-3-(6-(4,4 -difluorohexahydropyridin- 1 -yl )-5 - fluoropyridine- 3- yl ) isoxazole- 5- carboxamide ( Compound 210)

3-[6-(4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1,2-oxazole-5-carboxylic acid (200.0 mg, 0.6 mmol, 1.0 equiv) was dissolved in DMF (2 mL), then 5,6-difluoro- 1H -indol-3-amine hydrochloride (186.2 mg, 0.9 mmol, 1.5 equiv) and HATU (348.6 mg, 0.9 mmol) were added , 1.5 equiv). DIEA (0.4 mL, 2.4 mmol, 4.0 equiv) was then added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried _over anhydrous _Na2SO4 and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase, ACN/water, gradient 0% to 100% in 20 min; detector, UV 254 nm. This yields N- (5,6-difluoro- 1H -indol-3-yl)-3-[6-(4,4-difluorohexahydropyridin-1-yl)-5 as an off-white solid -Fluoropyridin-3-yl]-1,2-oxazole-5-carboxamide (145.8 mg). LCMS Method H: [M+H] ⁺ =478. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 11.24 (s, 1H), 10.88 (s, 1H), 8.63 (s, 1H), 8.10-8.06 (m, 1H), 7.95-7.89 (m, 2H), 7.81 (s, 1H), 7.44-7.39 (m, 1H), 3.73-3.70 (m, 4H), 2.16-2.06 (m, 4H).

將4-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,3-噁唑-2-甲酸(200.0 mg, 0.6 mmol, 1.0當量)溶於DMF (5 mL)中，然後添加T ₃P (50 wt.%於乙酸乙酯中，0.6 mL, 0.9 mmol, 1.5當量)及5,6-二氟-1 H-吲哚-3-胺鹽酸鹽(187.6 mg, 0.9 mmol, 1.5當量)。隨後添加TEA (0.3 mL, 1.8 mmol, 3.0當量)。將反應混合物在環境溫度下攪拌過夜且然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水硫酸鈉乾燥並在真空下濃縮。藉由反相急速層析使用下列條件來純化殘餘物：管柱，C18矽膠；移動相，ACN/水，在30 min內0%至100%之梯度；檢測器，UV 254 nm。此會產生灰白色固體形式之 N-(5,6-二氟-1 H-吲哚-3-基)-4-[6-(4,4-二氟六氫吡啶-1-基)-5-氟吡啶-3-基]-1,3-噁唑-2-甲醯胺(25.9 mg)。LCMS方法F：[M+H] ⁺= 478。 ¹H NMR (400 MHz, DMSO- d ₆ ): δ 11.17 (s, 1H), 10.82 (s, 1H), 8.66 (s, 1H), 8.17-8.13 (m, 1H), 7.93-7.86 (m, 2H), 7.45 (s, 1H), 7.43-7.38 (m, 1H), 3.76-3.73 (m, 4H), 2.16-2.06 (m, 4H)。 使用與針對 實例 76所闡述相同之方法來製備下表中之類似物。 實例編號 化合物編號 所用起始材料 結構 LCMS 數據 77 191 中間體1B /中間體82B

方法F： MS-ESI: 494 [M+H] ⁺。    78 203 5-氯-1 H-茚-3 胺/中間體64B

方法H： MS-ESI: 523 [M+H] ⁺。    Example 76 : N- (5,6 -Difluoro - 1H - indol- 3 -yl )-4-(6-(4,4 -difluorohexahydropyridin- 1 -yl )-5 - fluoropyridine- 3- yl ) oxazole -2- carboxamide ( compound 193)

4-[6-(4,4-Difluorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-1,3-oxazole-2-carboxylic acid (200.0 mg, 0.6 mmol, 1.0 equiv) was dissolved in DMF ( ₅ mL), then T3P (50 wt.% in ethyl acetate, 0.6 mL, 0.9 mmol, 1.5 equiv) and 5,6-difluoro- lH -indole- 3-amine hydrochloride (187.6 mg, 0.9 mmol, 1.5 equiv). TEA (0.3 mL, 1.8 mmol, 3.0 equiv) was then added. The reaction mixture was stirred at ambient temperature overnight and then quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase, ACN/water, gradient 0% to 100% in 30 min; detector, UV 254 nm. This yields N- (5,6-difluoro- 1H -indol-3-yl)-4-[6-(4,4-difluorohexahydropyridin-1-yl)-5 as an off-white solid -Fluoropyridin-3-yl]-1,3-oxazole-2-carboxamide (25.9 mg). LCMS Method F: [M+H] ⁺ =478. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 11.17 (s, 1H), 10.82 (s, 1H), 8.66 (s, 1H), 8.17-8.13 (m, 1H), 7.93-7.86 (m, 2H), 7.45 (s, 1H), 7.43-7.38 (m, 1H), 3.76-3.73 (m, 4H), 2.16-2.06 (m, 4H). The analogs in the table below were prepared using the same method as described for Example 76 . instance number Compound number Starting materials used structure LCMS data 77 191 Intermediate 1B / Intermediate 82B

Method F: MS-ESI: 494 [M+H] ⁺ . 78 203 5-Chloro- 1H -indene-3amine/Intermediate 64B

Method H: MS-ESI: 523 [M+H] ⁺ .

將3-[5-氟-6-[4-(2,2,2-三氟乙基)六氫吡嗪-1-基]吡啶-3-基]-1,2-噁唑-5-甲酸(300.0 mg, 0.8 mmol, 1.0當量)及5,6-二氟-1 H-吲哚-3-胺鹽酸鹽(196.8 mg, 1.0 mmol, 1.2當量)溶於DMF (10 mL)中，然後添加NMM (486.4 mg, 4.8 mmol, 6.0當量)及PyBOP (417.1 mg, 0.8 mmol, 1.0當量)。將反應混合物在環境溫度下攪拌2小時，且然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮。藉由製備型HPLC使用下列條件來純化殘餘物：管柱，XBridge Prep OBD C18管柱，30*150 mm, 5 µm；移動相，水(10 mmol/L NH ₄HCO ₃+0.1% NH ₄OH)及ACN (在7 min內相B自50%至最高70%)；檢測器，UV 254 nm。此會產生白色固體形式之 N-(5,6-二氟-1 H-吲哚-3-基)-3-[5-氟-6-[4-(2,2,2-三氟乙基)六氫吡嗪-1-基]吡啶-3-基]-1,2-噁唑-5-甲醯胺(63.3 mg)。LCMS方法H：[M+H] ⁺= 525。 ¹H NMR (400 MHz, DMSO- d ₆ ): δ 11.25 (s, 1H), 10.89 (s, 1H), 8.61 (d, J= 1.6 Hz, 1H), 8.06-8.02 (m, 1H), 7.95-7.89 (m, 2H), 7.80 (s, 1H), 7.44-7.39 (m, 1H), 3.60-3.58 (m, 4H), 3.30-3.25 (m, 2H), 2.79-2.76 (m, 4H)。 使用與針對 實例 79所闡述相同之方法來製備下表中之類似物。 實例編號 化合物編號 所用起始材料 結構 LCMS 數據 80 159 中間體4B /中間體67B

方法H： MS-ESI: 537 [M+H] ⁺。 Example 79 : N- (5,6 -Difluoro - 1H - indol- 3 -yl )-3-(5- fluoro -6-(4-(2,2,2- trifluoroethyl ) hexahydro ) Pyrazin - 1 -yl ) pyridin - 3 -yl ) isoxazole- 5- carboxamide ( Compound 160)

3-[5-Fluoro-6-[4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl]pyridin-3-yl]-1,2-oxazole-5- Formic acid (300.0 mg, 0.8 mmol, 1.0 equiv) and 5,6-difluoro- 1H -indol-3-amine hydrochloride (196.8 mg, 1.0 mmol, 1.2 equiv) were dissolved in DMF (10 mL), Then NMM (486.4 mg, 4.8 mmol, 6.0 equiv) and PyBOP (417.1 mg, 0.8 mmol, 1.0 equiv) were added. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried _over anhydrous _Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC using the following conditions: column, XBridge Prep OBD C18 column, 30*150 mm, 5 µm; mobile phase, water ( ₁₀ mmol/L _NH4HCO3 + 0.1% _NH4OH ) and ACN (phase B from 50% to up to 70% in 7 min); detector, UV 254 nm. This yields N- (5,6-difluoro- 1H -indol-3-yl)-3-[5-fluoro-6-[4-(2,2,2-trifluoroethyl) as a white solid (63.3 mg). LCMS Method H: [M+H] ⁺ =525. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 11.25 (s, 1H), 10.89 (s, 1H), 8.61 (d, J = 1.6 Hz, 1H), 8.06-8.02 (m, 1H), 7.95 -7.89 (m, 2H), 7.80 (s, 1H), 7.44-7.39 (m, 1H), 3.60-3.58 (m, 4H), 3.30-3.25 (m, 2H), 2.79-2.76 (m, 4H) . The analogs in the table below were prepared using the same method as described for Example 79 . instance number Compound number Starting materials used structure LCMS data 80 159 Intermediate 4B / Intermediate 67B

Method H: MS-ESI: 537 [M+H] ⁺ .

將3-[5-氟-6-[4-(2,2,2-三氟乙基)六氫吡嗪-1-基]吡啶-3-基]-1,2-噁唑-5-甲酸(300.0 mg, 0.8 mmol, 1.0當量)及5-氯-1 H-吲哚-3-胺(160.3 mg, 1.0 mmol, 1.2當量)溶於DMF (10 mL)中，然後添加NMM (121.6 mg, 1.2 mmol, 1.5當量)及PyBOP (625.7 mg, 1.2 mmol, 1.5當量)。將反應混合物在環境溫度下攪拌3小時且然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮。藉由製備型HPLC使用下列條件來純化殘餘物：管柱：XBridge Prep OBD C18管柱，30*150 mm, 5μm；移動相A：水(10 mmol/L NH ₄HCO ₃)，移動相B：ACN；流速：60 mL/min；梯度：在8 min內50% B至75% B；波長：220 nm；RT (min): 7.82。此會產生白色固體形式之 N-(5-氯-1 H-吲哚-3-基)-3-[5-氟-6-[4-(2,2,2-三氟乙基)六氫吡嗪-1-基]吡啶-3-基]-1,2-噁唑-5-甲醯胺(65.3 mg)。LCMS方法H：[M+H] ⁺= 523。 ¹H NMR (400 MHz, DMSO- d ₆ ): δ 11.28 (s, 1H), 10.88 (s, 1H), 8.61 (d, J= 1.2 Hz, 1H), 8.06 (d, J= 2.0 Hz, 1H), 8.02 (d, J= 2.0 Hz, 1H), 7.90 (d, J= 2.4 Hz, 1H), 7.81 (s, 1H), 7.42 (d, J= 8.8 Hz, 1H), 7.16-7.13 (m, 1H), 3.61-3.58 (m, 4H), 3.30-3.22 (m, 2H), 2.79-2.76 (m, 4H)。 Example 81 : N- (5- Chloro - 1H - indol- 3 -yl )-3-(5- fluoro -6-(4-(2,2,2 - trifluoroethyl ) hexahydropyrazine- 1- yl ) pyridin - 3 -yl ) isoxazole- 5- carboxamide ( Compound 171)

3-[5-Fluoro-6-[4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl]pyridin-3-yl]-1,2-oxazole-5- Formic acid (300.0 mg, 0.8 mmol, 1.0 equiv) and 5-chloro- 1H -indol-3-amine (160.3 mg, 1.0 mmol, 1.2 equiv) were dissolved in DMF (10 mL) and NMM (121.6 mg) was added , 1.2 mmol, 1.5 equiv) and PyBOP (625.7 mg, 1.2 mmol, 1.5 equiv). The reaction mixture was stirred at ambient temperature for 3 hours and then quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried _over anhydrous _Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L _{NH4HCO3 )} , 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 yields N- (5-chloro- 1H -indol-3-yl)-3-[5-fluoro-6-[4-(2,2,2-trifluoroethyl)hexanol as a white solid Hydropyrazin-1-yl]pyridin-3-yl]-1,2-oxazole-5-carboxamide (65.3 mg). LCMS Method H: [M+H] ⁺ =523. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 11.28 (s, 1H), 10.88 (s, 1H), 8.61 (d, J = 1.2 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H) ), 8.02 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.81 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.16-7.13 (m , 1H), 3.61-3.58 (m, 4H), 3.30-3.22 (m, 2H), 2.79-2.76 (m, 4H).

將5-[5-氟-6-[4-(2,2,2-三氟乙基)六氫吡嗪-1-基]吡啶-3-基]-1,2-噁唑-3-甲酸(300.0 mg, 0.8 mmol, 1.0當量)及DCC (248.1 mg, 1.2 mmol, 1.5當量)溶於DCM (30 mL)中，然後添加DMAP (146.9 mg, 1.2 mmol, 1.5當量)及5,6-二氟-1 H-吲哚-3-胺鹽酸鹽(196.8 mg, 1.0 mmol, 1.2當量)。將反應混合物在環境溫度下攪拌2小時且然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮。藉由製備型HPLC使用下列條件來純化殘餘物：管柱，XBridge Prep OBD C18管柱，30*150 mm, 5 µm；移動相，水(10 mmol/L NH ₄HCO ₃+0.1% NH ₄OH)及ACN (在7 min內相B自50%至最高75%)；檢測器，UV 254 nm。此會產生黃色固體形式之 N-(5,6-二氟-1 H-吲哚-3-基)-5-[5-氟-6-[4-(2,2,2-三氟乙基)六氫吡嗪-1-基]吡啶-3-基]-1,2-噁唑-3-甲醯胺(138.2 mg)。LCMS方法H：[M+H] ⁺= 525。 ¹H NMR (400 MHz, DMSO- d ₆ ): δ 11.20 (s, 1H), 10.81 (s, 1H), 8.61 (d, J= 1.6 Hz, 1H), 8.12-8.08 (m, 1H), 7.93-7.88 (m, 2H), 7.42 (s, 1H), 7.41-7.38 (m, 1H), 3.63-3.60 (m, 4H), 3.30-3.22 (m, 2H), 2.78-2.74 (m, 4H)。 使用與針對 實例 82所闡述相同之方法來製備下表中之類似物。 實例編號 化合物編號 所用起始材料 結構 LCMS 數據 83 234 5-氯-1 H-吲哚-3-胺/中間體58B

方法F：MS-ESI: 476 [M+H] ⁺。 Example 82 : N- (5,6 -Difluoro - 1H - indol- 3 -yl )-5-(5- fluoro -6-(4-(2,2,2- trifluoroethyl ) hexahydro ) Pyrazin - 1 -yl ) pyridin - 3 -yl ) isoxazole- 3 -carboxamide ( Compound 204)

5-[5-Fluoro-6-[4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl]pyridin-3-yl]-1,2-oxazole-3- Formic acid (300.0 mg, 0.8 mmol, 1.0 equiv) and DCC (248.1 mg, 1.2 mmol, 1.5 equiv) were dissolved in DCM (30 mL), then DMAP (146.9 mg, 1.2 mmol, 1.5 equiv) and 5,6- Difluoro-1 H -indol-3-amine hydrochloride (196.8 mg, 1.0 mmol, 1.2 equiv). The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried _over anhydrous _Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC using the following conditions: column, XBridge Prep OBD C18 column, 30*150 mm, 5 µm; mobile phase, water ( ₁₀ mmol/L _NH4HCO3 + 0.1% _NH4OH ) and ACN (phase B from 50% to up to 75% in 7 min); detector, UV 254 nm. This yields N- (5,6-difluoro- 1H -indol-3-yl)-5-[5-fluoro-6-[4-(2,2,2-trifluoroethyl) as a yellow solid yl)hexahydropyrazin-1-yl]pyridin-3-yl]-1,2-oxazole-3-carboxamide (138.2 mg). LCMS Method H: [M+H] ⁺ =525. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 11.20 (s, 1H), 10.81 (s, 1H), 8.61 (d, J = 1.6 Hz, 1H), 8.12-8.08 (m, 1H), 7.93 -7.88 (m, 2H), 7.42 (s, 1H), 7.41-7.38 (m, 1H), 3.63-3.60 (m, 4H), 3.30-3.22 (m, 2H), 2.78-2.74 (m, 4H) . The analogs in the table below were prepared using the same method as described for Example 82 . instance number Compound number Starting materials used structure LCMS data 83 234 5-Chloro- 1H -indol-3-amine/Intermediate 58B

Method F: MS-ESI: 476 [M+H] ⁺ .

步驟 1 ： N -(5,6- 二氟 -1 H- 吲哚 -3- 基 ) 丙炔醯胺將5,6-二氟-1H-吲哚-3-胺鹽酸鹽(730.0 mg, 3.6 mmol, 1.0當量)溶於THF (30 mL)中並冷卻至0℃，然後在0℃下添加丙炔酸(499.9 mg, 7.1 mmol, 2.0當量)、TEA (1.5 mL, 10.7 mmol, 3.0當量)及T ₃P (50 wt.%於乙酸乙酯中，0.7 mL, 10.7 mmol, 3.0當量)。將反應混合物在環境溫度下攪拌3小時且然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水硫酸鈉乾燥並在真空下濃縮。藉由急速管柱層析在矽膠管柱上(使用乙酸乙酯/石油醚(1:3)洗脫)來純化殘餘物以得到淺黃色固體形式之 N-(5,6-二氟-1 H-吲哚-3-基)丙-2-炔醯胺(350 mg)。LCMS方法A：[M+H] ⁺= 221。 步驟 2 ： 5- 疊氮基 -3- 氟 -2-(1- 甲基環己基 ) 吡啶將5-氟-6-(1-甲基環己基)吡啶-3-胺(300.0 mg, 1.4 mmol, 1.0當量)溶於ACN (6 mL)中並冷卻至0℃，然後逐滴添加 t-BuNO ₂(0.5 mL, 4.3 mmol, 3.0當量)，且將混合物維持於0℃下。在0℃下保持30 min之後，在0℃下逐滴添加TMSN ₃(0.5 mL, 4.3 mmol, 3.0當量)。將反應混合物在0℃下再攪拌2小時，然後藉由添加水來驟冷。使用乙酸乙酯萃取所得混合物，藉由無水硫酸鈉乾燥並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:10)洗脫)來純化殘餘物以得到黃色油狀物形式之5-疊氮基-3-氟-2-(1-甲基環己基)吡啶(260.0 mg)。 步驟 3 ： N -(5,6- 二氟 -1 H- 吲哚 -3- 基 )-1-[5- 氟 -6-(1- 甲基環己基 ) 吡啶 -3- 基 ]-1,2,3- 三唑 -4- 甲醯胺將5-疊氮基-3-氟-2-(1-甲基環己基)吡啶(250.0 mg, 1.1 mmol, 1.0當量)溶於二噁烷/水(5/0.5 mL)中，然後添加 N-(5,6-二氟-1 H-吲哚-3-基)丙炔醯胺(235.0 mg, 1.1 mmol, 1.0當量)、抗壞血酸鈉(21.2 mg, 0.1 mmol, 0.1當量)及CuSO ₄(17.0 mg, 0.1 mmol, 0.1當量)。將反應混合物在環境溫度下攪拌15小時且然後藉由添加水來驟冷。使用乙酸乙酯萃取反應混合物，藉由無水硫酸鈉乾燥並在真空下濃縮。藉由製備型HPLC使用下列條件來進一步純化殘餘物：XBridge Prep OBD C18管柱，30×150mm 5µm；移動相A：水(10 mM NH ₄HCO ₃)，移動相B：ACN；流速：50 mL/min；梯度：在7 min內35% B至80% B；254 nm；RT1:6.95 min。此會產生灰白色固體形式之 N-(5,6-二氟-1 H-吲哚-3-基)-1-[5-氟-6-(1-甲基環己基)吡啶-3-基]-1,2,3-三唑-4-甲醯胺(121.8 mg)。LCMS方法K： [M+H] ⁺= 455。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.16 (s, 1H), 10.63 (s, 1H), 9.50 (s, 1H), 9.09 (s, 1H), 8.42-8.38 (m, 1H), 7.93-7.85 (m, 1H), 7.85 (s, 1H), 7.42-7.38 (m, 1H), 2.34-2,32 (m, 2H), 1.59-1.54 (m, 4H), 1.44-1.39 (m, 4H), 1.31 (s, 3H)。 使用與針對 實例 84所闡述相同之方法來製備下表中之類似物。 實例編號 化合物編號 所用起始材料 結構 LCMS 數據 85 177 中間體1B /中間體10B

方法H：MS-ESI: 506 [M+H] ⁺。 86 180 中間體1B /中間體23B

方法H：MS-ESI: 507 [M+H] ⁺。 87 197 中間體1B /中間體17B

方法H：MS-ESI: 497 [M+H] ⁺。 88 198 中間體1B /中間體22B

方法H：MS-ESI: 541 [M+H] ⁺。 89 200 中間體1B /中間體18B

方法H：MS-ESI: 496 [M+H] ⁺。 90 201 5-氯-1H-吲哚-3-胺/ 中間體19B

方法H：MS-ESI: 519 [M+H] ⁺。 91 207 中間體1B /中間體28B

方法H：MS-ESI: 524 [M+H] ⁺。 92 209 中間體1B /中間體20B

方法H：MS-ESI: 482 [M+H] ⁺。 93 211 中間體1B /中間體24B

方法H：MS-ESI: 460 [M+H] ⁺。 94 212 中間體1B /中間體21B

方法H：MS-ESI: 494 [M+H] ⁺。 95 215 中間體1B /中間體6B

方法K： MS-ESI: 477 [M+H] ⁺。 96 217 中間體1B /中間體29B

方法H：MS-ESI: 501 [M+H] ⁺。 Example 84 : 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 ) propynamide 5,6-difluoro-1H-indol-3-amine hydrochloride (730.0 mg, 3.6 mmol, 1.0 equiv) was dissolved in THF (30 mL) and cooled to 0 °C, then propyolic acid (499.9 mg, 7.1 mmol, 2.0 equiv), TEA (1.5 mL, 10.7 mmol, 3.0 equiv) were added at 0 °C ) and _T3P (50 wt.% in ethyl acetate, 0.7 mL, 10.7 mmol, 3.0 equiv). The reaction mixture was stirred at ambient temperature for 3 hours and then quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:3) to give N- (5,6-difluoro-1 as a pale yellow solid) H -indol-3-yl)prop-2-ynamide (350 mg). 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 equiv) was dissolved in ACN (6 mL) and cooled to 0 °C, then t -BuNO ₂ (0.5 mL, 4.3 mmol, 3.0 equiv) was added dropwise and the mixture was maintained at 0 °C. After 30 min at 0 °C, TMSN ₃ (0.5 mL, 4.3 mmol, 3.0 equiv) was added dropwise at 0 °C. The reaction mixture was stirred at 0°C for an additional 2 hours and then quenched by addition of water. The resulting mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:10) to give 5-azido-3-fluoro-2- as a yellow oil (1-Methylcyclohexyl)pyridine (260.0 mg). 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 equiv) was dissolved in dioxane/ water (5/0.5 mL), then N- (5,6-difluoro- 1H -indol-3-yl)propynamide (235.0 mg, 1.1 mmol, 1.0 equiv), sodium ascorbate (21.2 mg, 0.1 mmol, 0.1 equiv) and CuSO4 ₍ 17.0 mg, 0.1 mmol, 0.1 equiv). The reaction mixture was stirred at ambient temperature for 15 hours and then quenched by addition of water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was further purified by preparative HPLC using the following conditions: XBridge Prep OBD C18 column, 30 x 150 mm 5 µm; mobile phase A: water (10 mM _{NH4HCO3 )} , mobile phase B: ACN; flow rate: 50 mL /min; Gradient: 35% B to 80% B in 7 min; 254 nm; RT1: 6.95 min. This yielded N- (5,6-difluoro- 1H -indol-3-yl)-1-[5-fluoro-6-(1-methylcyclohexyl)pyridin-3-yl as an off-white solid ]-1,2,3-triazole-4-carboxamide (121.8 mg). LCMS Method K: [M+H] ⁺ =455. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.16 (s, 1H), 10.63 (s, 1H), 9.50 (s, 1H), 9.09 (s, 1H), 8.42-8.38 (m, 1H), 7.93-7.85 (m, 1H), 7.85 (s, 1H), 7.42-7.38 (m, 1H), 2.34-2,32 (m, 2H), 1.59-1.54 (m, 4H), 1.44-1.39 (m , 4H), 1.31 (s, 3H). The analogs in the table below were prepared using the same method as described for Example 84 . instance number Compound number Starting materials used structure LCMS data 85 177 Intermediate 1B / Intermediate 10B

Method H: MS-ESI: 506 [M+H] ⁺ . 86 180 Intermediate 1B / Intermediate 23B

Method H: MS-ESI: 507 [M+H] ⁺ . 87 197 Intermediate 1B / Intermediate 17B

Method H: MS-ESI: 497 [M+H] ⁺ . 88 198 Intermediate 1B / Intermediate 22B

Method H: MS-ESI: 541 [M+H] ⁺ . 89 200 Intermediate 1B / Intermediate 18B

Method H: MS-ESI: 496 [M+H] ⁺ . 90 201 5-Chloro-1H-indol-3-amine/ Intermediate 19B

Method H: MS-ESI: 519 [M+H] ⁺ . 91 207 Intermediate 1B / Intermediate 28B

Method H: MS-ESI: 524 [M+H] ⁺ . 92 209 Intermediate 1B / Intermediate 20B

Method H: MS-ESI: 482 [M+H] ⁺ . 93 211 Intermediate 1B / Intermediate 24B

Method H: MS-ESI: 460 [M+H] ⁺ . 94 212 Intermediate 1B / Intermediate 21B

Method H: MS-ESI: 494 [M+H] ⁺ . 95 215 Intermediate 1B / Intermediate 6B

Method K: MS-ESI: 477 [M+H] ⁺ . 96 217 Intermediate 1B / Intermediate 29B

Method H: MS-ESI: 501 [M+H] ⁺ .

步驟 1 ： 5- 溴 -3- 氟吡啶 -2- 甲醛將2,5-二溴-3-氟吡啶(2.0 g, 7.8 mmol, 1.0當量)溶於THF (40 mL)中並冷卻至-78℃。然後逐滴添加n-BuLi (2 M於THF中，8.0 mL, 16.0 mmol, 1.0當量)，且將溶液維持於-78℃下。在10 min之後，在-78℃下逐滴添加DMF (0.6 mL, 7.8 mmol, 1.0當量)於THF (2 mL)中之溶液且將反應混合物升溫至環境溫度，並再攪拌2小時。藉由添加飽和NH ₄Cl水溶液來終止反應，使用乙酸乙酯萃取，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:4)洗脫)來純化殘餘物以得到黃色油狀物形式之5-溴-3-氟吡啶-2-甲醛(1.3 g)。LCMS方法C：[M+H] ⁺= 204。 步驟 2 ： (5- 溴 -3- 氟吡啶 -2- 基 ) 甲醇將5-溴-3-氟吡啶-2-甲醛(1.3 g, 6.4 mmol, 1.0當量)溶於THF (20 mL)中並冷卻至0℃。然後逐份添加NaBH ₄(0.5 g, 12.7 mmol, 2.0當量)，且將反應混合物維持於0℃下。將反應混合物在環境溫度下攪拌過夜，且然後藉由添加飽和NH ₄Cl水溶液來驟冷。使用乙酸乙酯萃取所得溶液，藉由無水硫酸鈉乾燥並在真空下濃縮以提供黃色油狀物形式之(5-溴-3-氟吡啶-2-基)甲醇(1.1 g)。LCMS方法C：[M+H] ⁺= 206。 步驟 3 ： 5- 溴 -2-( 溴甲基 )-3- 氟吡啶將(5-溴-3-氟吡啶-2-基)甲醇(1.0 g, 4.9 mmol, 1.0當量)溶於DCM (10 mL)中並冷卻至0℃，然後添加三溴化磷(1.6 g, 5.8 mmol, 1.2當量)，且將溶液維持於0℃下。將反應混合物在0℃下攪拌2小時且然後使用乙酸乙酯稀釋。使用飽和NaHCO ₃水溶液洗滌所得溶液，藉由無水硫酸鈉乾燥並在真空下濃縮以提供黃色油狀物形式之粗製5-溴-2-(溴甲基)-3-氟吡啶(1.0 g)。LCMS方法C：[M+H] ⁺= 206。 步驟 4 ： 5- 溴 -2-[(4,4- 二氟六氫吡啶 -1- 基 ) 甲基 ]-3- 氟吡啶將5-溴-2-(溴甲基)-3-氟吡啶(1.0 g, 3.7 mmol, 1.0當量)溶於ACN (10 mL)中，然後添加4,4-二氟六氫吡啶(540.5 mg, 4.5 mmol, 1.2當量)及K ₂CO ₃(1.5 g, 11.1 mmol, 3.0當量)。將反應混合物加熱至60℃並保持4小時，然後冷卻至環境溫度並藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，使用鹽水洗滌，藉由無水Na ₂SO ₄乾燥並在真空下濃縮以提供白色固體形式之粗製5-溴-2-[(4,4-二氟六氫吡啶-1-基)甲基]-3-氟吡啶(800.0 mg)。LCMS方法C：[M+H] ⁺= 309。 步驟 5 ： 5- 疊氮基 -2-[(4,4- 二氟六氫吡啶 -1- 基 ) 甲基 ]-3- 氟吡啶將5-溴-2-[(4,4-二氟六氫吡啶-1-基)甲基]-3-氟吡啶(800.0 mg, 2.6 mmol, 1.0當量)溶於EtOH (7 mL)及水(3 mL)中，然後在氮氣氛下添加( 1S,2S)-1,2-二乙基環己烷(363.0 mg, 2.6 mmol, 1.0當量)、CuI (492.9 mg, 2.6 mmol, 1.0當量)及疊氮化鈉(336.5 mg, 5.2 mmol, 2.0當量)。將反應混合物加熱至80℃並保持2小時，然後冷卻至環境溫度並使用乙酸乙酯稀釋。在藉由過濾去除固體之後，藉由無水硫酸鈉乾燥濾液並在真空下濃縮。藉由急速管柱層析在矽膠上(使用乙酸乙酯/石油醚(1:1)洗脫)來純化殘餘物以得到褐色固體形式之5-疊氮基-2-[(4,4-二氟六氫吡啶-1-基)甲基]-3-氟吡啶(400.0 mg)。LCMS方法C：[M+H] ⁺= 272。 步驟 6 ： N -(5,6- 二氟 -1 H- 吲哚 -3- 基 )-1-[6-[(4,4- 二氟六氫吡啶 -1- 基 ) 甲基 ]-5- 氟吡啶 -3- 基 ]-1,2,3- 三唑 -4- 甲醯胺將5-疊氮基-2-[(4,4-二氟六氫吡啶-1-基)甲基]-3-氟吡啶(200.0 mg, 0.7 mmol, 1.0當量)溶於二噁烷(10 mL)及水(1 mL)中，然後在氮氣氛下添加 N-(5,6-二氟-1 H-吲哚-3-基)丙-2-炔醯胺(194.8 mg, 0.9 mmol, 1.2當量)、CuSO ₄(11.8 mg, 0.1 mmol, 0.1當量)及抗壞血酸鈉(14.7 mg, 0.1 mmol, 0.1當量)。將反應混合物在環境溫度下攪拌過夜且然後藉由添加水來驟冷。使用乙酸乙酯萃取所得溶液，藉由無水硫酸鈉乾燥並在真空下濃縮。藉由製備型HPLC使用下列條件來純化殘餘物：管柱，XBridge Prep OBD C18管柱，30*150 mm, 5 µm；移動相，水(10 mmol/L NH ₄HCO ₃+0.1% NH ₄OH)及ACN (在7 min內相B自40%至最高58%)；檢測器，UV 254 nm。此會產生黃色固體形式之 N-(5,6-二氟-1 H-吲哚-3-基)-1-[6-[(4,4-二氟六氫吡啶-1-基)甲基]-5-氟吡啶-3-基]-1,2,3-三唑-4-甲醯胺(25.0 mg)。LCMS方法F：[M+H] ⁺= 492。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.16 (s, 1H), 10.65 (s, 1H), 9.54 (s, 1H), 9.12 (d, J= 1.6 Hz, 1H), 8.51-8.48 (m, 1H), 7.93-7.88 (m, 1H), 7.85 (d, J= 2.4 Hz, 1H), 7.42-7.38 (m, 1H), 3.84 (s, 2H), 2.64-2.62 (m, 4H), 2.00-1.93 (m, 4H)。 Example 97 : N- (5,6 -Difluoro - 1H - indol- 3 -yl )-1-(6-((4,4 -difluorohexahydropyridin- 1 -yl ) methyl )-5 -Fluoropyridin - 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 equiv) was dissolved in THF (40 mL) and cooled to -78 °C. Then n-BuLi (2 M in THF, 8.0 mL, 16.0 mmol, 1.0 equiv) was added dropwise and the solution was maintained at -78°C. After 10 min, a solution of DMF (0.6 mL, 7.8 mmol, 1.0 equiv) in THF (2 mL) was added dropwise at -78 °C and the reaction mixture was warmed to ambient temperature and stirred for an additional 2 h. The reaction was quenched by addition of saturated aqueous _NH4Cl , extracted with ethyl acetate, washed with brine, dried _over anhydrous _Na2SO4 and concentrated in vacuo. 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 as a yellow oil (1.3 g). LCMS Method C: [M+H] ⁺ =204. Step 2 : (5- Bromo - 3 - fluoropyridin -2- yl ) methanol 5-Bromo-3-fluoropyridine-2-carbaldehyde (1.3 g, 6.4 mmol, 1.0 equiv) was dissolved in THF (20 mL) and the Cool to 0°C. NaBH4 ₍ 0.5 g, 12.7 mmol, 2.0 equiv) was then added portionwise and the reaction mixture was maintained at 0 °C. The reaction mixture was stirred at ambient temperature overnight, and then quenched by addition of saturated aqueous _NH4Cl . The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo to provide (5-bromo-3-fluoropyridin-2-yl)methanol (1.1 g) as a yellow oil. LCMS method C: [M+H] ⁺ =206. Step 3 : 5- Bromo -2-( bromomethyl )-3 - fluoropyridine (5-bromo-3-fluoropyridin-2-yl)methanol (1.0 g, 4.9 mmol, 1.0 equiv) was dissolved in DCM (10 mL) and cooled to 0 °C, then phosphorus tribromide (1.6 g, 5.8 mmol, 1.2 equiv) was added and the solution was maintained at 0 °C. The reaction mixture was stirred at 0°C for 2 hours and then diluted with ethyl acetate. The resulting solution was washed with saturated aqueous _NaHCO3 , dried over anhydrous sodium sulfate and concentrated in vacuo to afford crude 5-bromo-2-(bromomethyl)-3-fluoropyridine (1.0 g) as a yellow oil. LCMS method C: [M+H] ⁺ =206. Step 4 : 5- Bromo -2-[(4,4 -difluorohexahydropyridin- 1 -yl ) methyl ]-3 - fluoropyridine (1.0 g, 3.7 mmol, 1.0 equiv) was dissolved in ACN (10 mL), then 4,4-difluorohexahydropyridine (540.5 mg, 4.5 mmol, _1.2 equiv) and K2CO3 (1.5 g, 11.1 equiv) _were added mmol, 3.0 equiv). The reaction mixture was heated to 60°C for 4 hours, then cooled to ambient temperature and quenched by addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to afford crude 5-bromo-2-[(4,4-difluorohexahydropyridine- 1-yl)methyl]-3-fluoropyridine (800.0 mg). LCMS Method C: [M+H] ⁺ =309. Step 5 : 5- Azido- 2-[(4,4 -difluorohexahydropyridin- 1 -yl ) methyl ]-3 - fluoropyridine was mixed with 5-bromo-2-[(4,4-difluoro Hexahydropyridin-1-yl)methyl]-3-fluoropyridine (800.0 mg, 2.6 mmol, 1.0 equiv) was dissolved in EtOH (7 mL) and water (3 mL), then added ( 1S, 2S )-1,2-diethylcyclohexane (363.0 mg, 2.6 mmol, 1.0 equiv), CuI (492.9 mg, 2.6 mmol, 1.0 equiv) and sodium azide (336.5 mg, 5.2 mmol, 2.0 equiv) . The reaction mixture was heated to 80°C for 2 hours, then cooled to ambient temperature and diluted with ethyl acetate. After removal of 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-) as a brown solid Difluorohexahydropyridin-1-yl)methyl]-3-fluoropyridine (400.0 mg). LCMS method C: [M+H] ⁺ =272. Step 6 : N- (5,6 -Difluoro - 1H - indol- 3 -yl )-1-[6-[(4,4 -difluorohexahydropyridin- 1 -yl ) methyl ]-5 -Fluoropyridin - 3 -yl ] -1,2,3- triazole - 4 -carboxamide 5-azido-2-[(4,4-difluorohexahydropyridin-1-yl)methyl ]-3-Fluoropyridine (200.0 mg, 0.7 mmol, 1.0 equiv) was dissolved in dioxane (10 mL) and water (1 mL), then N- (5,6-difluoro-1 was added under nitrogen atmosphere H -indol-3-yl)prop-2-ynamide (194.8 mg, 0.9 mmol, 1.2 equiv), CuSO ₄ (11.8 mg, 0.1 mmol, 0.1 equiv) and sodium ascorbate (14.7 mg, 0.1 mmol, 0.1 equiv) equivalent). The reaction mixture was stirred at ambient temperature overnight and then quenched by addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC using the following conditions: column, XBridge Prep OBD C18 column, 30*150 mm, 5 µm; mobile phase, water ( ₁₀ mmol/L _NH4HCO3 + 0.1% _NH4OH ) and ACN (phase B from 40% to up to 58% in 7 min); detector, UV 254 nm. This yields N- (5,6-difluoro- 1H -indol-3-yl)-1-[6-[(4,4-difluorohexahydropyridin-1-yl)methan as a yellow solid yl]-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxamide (25.0 mg). LCMS Method F: [M+H] ⁺ =492. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.16 (s, 1H), 10.65 (s, 1H), 9.54 (s, 1H), 9.12 (d, J = 1.6 Hz, 1H), 8.51-8.48 ( m, 1H), 7.93-7.88 (m, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.42-7.38 (m, 1H), 3.84 (s, 2H), 2.64-2.62 (m, 4H) , 2.00-1.93 (m, 4H).

前峰，絕對立體化學未證實

第二峰，絕對立體化學未證實

藉由製備型對掌性HPLC使用下列條件來分離外消旋( N-(5,6-二氟-1 H-吲哚-3-基)-1-[5-氟-6-[3-(三氟甲基)吡咯啶-1-基]吡啶-3-基]-1,2,3-三唑-4-甲醯胺( 化合物 200) (60.0 mg)：管柱：CHIRALPAK IE, 2*25 cm, 5 μm；移動相A：Hex (0.5% 2M NH ₃-MeOH)--HPLC，移動相B：EtOH--HPLC；流速：20 mL/min；梯度：在15.5 min內50% B至50% B；波長：220/254 nm；RT1(min): 11.16；RT2(min): 13.16。此會得到白色固體形式之化合物 162(前峰，27.9 mg)及白色固體形式之化合物 163(第二峰，25.3 mg)。 化合物 162：LCMS方法H：[M+H] ⁺= 496。 ¹H NMR (400 MHz, DMSO- d ₆ ): δ 11.14 (s, 1H), 10.56 (s, 1H), 9.30 (s, 1H), 8.58 (d, J= 1.6 Hz, 1H), 8.21-8.17 (m, 1H), 7.92-7.87 (m, 1H), 7.84 (d, J= 2.4 Hz, 1H), 7.42-7.37 (m, 1H), 3.96-3.91 (m, 1H), 3.84-3.80 (m, 1H), 3.75-3.71 (m, 2H), 3.41-3.38 (m, 1H), 2.29-2.26 (m, 1H), 2.14-2.09 (m, 1H)。 化合物 163：LCMS方法H：[M+H] ⁺= 496。 ¹H NMR (400 MHz, DMSO- d ₆ ): δ 11.14 (s, 1H), 10.55 (s, 1H), 9.30 (s, 1H), 8.58 (d, J= 1.6 Hz, 1H), 8.21-8.17 (m, 1H), 7.92-7.87 (m, 1H), 7.84 (d, J= 2.4 Hz, 1H), 7.42-7.37 (m, 1H), 3.96-3.91 (m, 1H), 3.84-3.80 (m, 1H), 3.75-3.71 (m, 2H), 3.41-3.38 (m, 1H), 2.29-2.26 (m, 1H), 2.14-2.09 (m, 1H)。 Example 98/99 : N- (5,6 -Difluoro - 1H - indol- 3 -yl )-1-(6-(4,4 -difluorohexahydropyridin- 1 -yl- 3,3, 5,5-d4)-5- fluoropyridin - 3 -yl )-1H- 1,2,3 - triazole - 4 -carboxamide ( Compound 162 ) (pre-peak, absolute stereochemistry not confirmed) and ( Compound 163 ) (second peak, absolute stereochemistry not confirmed).

Front peak, absolute stereochemistry not confirmed

Second peak, absolute stereochemistry not confirmed

Racemic ( 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): 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 in 15.5 min to 50% B; wavelength: 220/254 nm; RT1 (min): 11.16; RT2 (min): 13.16. This gave compound 162 as a white solid (pre-peak, 27.9 mg) and compound 163 as a white solid ( Second peak, 25.3 mg). Compound 162 : LCMS method H: [M+H] ⁺ = 496. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 11.14 (s, 1H), 10.56 (s, 1H ), 9.30 (s, 1H), 8.58 (d, J = 1.6 Hz, 1H), 8.21-8.17 (m, 1H), 7.92-7.87 (m, 1H), 7.84 (d, J = 2.4 Hz, 1H) , 7.42-7.37 (m, 1H), 3.96-3.91 (m, 1H), 3.84-3.80 (m, 1H), 3.75-3.71 (m, 2H), 3.41-3.38 (m, 1H), 2.29-2.26 ( m, 1H), 2.14-2.09 (m, 1H). Compound 163 : LCMS method H: [M+H] ⁺ = 496. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 11.14 (s, 1H) , 10.55 (s, 1H), 9.30 (s, 1H), 8.58 (d, J = 1.6 Hz, 1H), 8.21-8.17 (m, 1H), 7.92-7.87 (m, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.42-7.37 (m, 1H), 3.96-3.91 (m, 1H), 3.84-3.80 (m, 1H), 3.75-3.71 (m, 2H), 3.41-3.38 (m, 1H) ), 2.29-2.26 (m, 1H), 2.14-2.09 (m, 1H).

步驟 1 ： 1-(6-( 環己 -1- 烯 -1- 基 )-5- 氟吡啶 -3- 基 )- N-(5,6- 二氟 -1H- 吲哚 -3- 基 )-1H-1,2,3- 三唑 -4- 甲醯胺將1-(6-溴-5-氟吡啶-3-基)- N-(5,6-二氟-1H-吲哚-3-基)-1H-1,2,3-三唑-4-甲醯胺(130.7 mg, 0.3 mmol, 1.0當量)及2-(環己-1-烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼㖦(124.8 mg, 0.6 mmol, 2.0當量)溶於二噁烷(3 mL)中。然後在氮氣氛下添加XPhos Pd G3 (12.7 mg, 0.015 mmol, 0.05當量)及K ₃PO ₄水溶液(450 µl, 2M, 3.0當量)。將反應混合物在80℃下加熱16小時。濃縮反應混合物以得到1-(6-(環己-1-烯-1-基)-5-氟吡啶-3-基)- N-(5,6-二氟-1H-吲哚-3-基)-1H-1,2,3-三唑-4-甲醯胺，其未經進一步純化即用於下一步驟中。 步驟 2 ： 1-(6- 環己基 -5- 氟吡啶 -3- 基 )- N-(5,6- 二氟 -1H- 吲哚 -3- 基 )-1H-1,2,3- 三唑 -4- 甲醯胺

將1-(6-(環己-1-烯-1-基)-5-氟吡啶-3-基)- N-(5,6-二氟-1H-吲哚-3-基)-1H-1,2,3-三唑-4-甲醯胺(87.6, 0.2 mmol, 1.0當量)溶於DCM (2 mL)中。然後在氮氣氛下添加Pd(AcO) ₂(2.2 mg, 0.01 mmol, 0.05當量)、AcOH (50 µl )及TES (200 µl)。將混合物在30℃下攪拌16小時。在減壓下濃縮混合物以去除二噁烷。然後添加H ₂O (5 mL)並使用EtOAc萃取，藉由無水Na ₂SO ₄乾燥有機層，過濾，在減壓下濃縮並藉由HPLC純化以得到1-(6-環己基-5-氟吡啶-3-基)- N-(5,6-二氟-1H-吲哚-3-基)-1H-1,2,3-三唑-4-甲醯胺。MS-ESI, 441.2 [M+H ⁺]。 ¹H NMR (400 MHz, DMSO- d ₆) δ ppm 11.15 (br s, 1 H), 10.62 (s, 1 H), 9.47 (s, 1 H), 9.06 (d, J=1.8 Hz, 1 H), 8.39 (dd, J=10.5, 2.0 Hz, 1 H), 7.97-7.78 (m, 2 H), 7.39 (dd, J=11.3, 7.0 Hz, 1 H), 3.10-3.05 (br t, 1 H), 1.89-1.56 (m, 7 H ), 1.45-1.22 (m, 3 H)。 使用與針對 實例 100所闡述相同之方法來製備下表中之類似物。 實例編號 化合物編號 結構 IUPAC 名稱 LC-MS, MS-ESI, [M+H ⁺. 101 169

1-[6-(1-乙醯基六氫吡啶-4-基)-5-氟吡啶-3-基]-N-(5,6-二氟-1H-吲哚-3-基)-1H-1,2,3-三唑-4-甲醯胺 484.2 102 158

N-(5,6-二氟-1H-吲哚-3-基)-1-[5-氟-6-(噁烷-2-基)吡啶-3-基]-1H-1,2,3-三唑-4-甲醯胺 443.1 103 157

N-(5,6-二氟-1H-吲哚-3-基)-1-[5-氟-6-(噁烷-4-基)吡啶-3-基]-1H-1,2,3-三唑-4-甲醯胺 443.2 104 168

N-(5,6-二氟-1H-吲哚-3-基)-1-{5-氟-6-[4-(三氟甲基)環己基]吡啶-3-基}-1H-1,2,3-三唑-4-甲醯胺 509.2 105 167

N-(5,6-二氟-1H-吲哚-3-基)-1-[5-氟-6-(氧雜環戊烷-3-基)吡啶-3-基]-1H-1,2,3-三唑-4-甲醯胺 429.2 106 166

N-(5,6-二氟-1H-吲哚-3-基)-1-[6-(2,6-二甲基噁烷-4-基)-5-氟吡啶-3-基]-1H-1,2,3-三唑-4-甲醯胺 471.2 107 165

N-(5,6-二氟-1H-吲哚-3-基)-1-[5-氟-6-(4-氟環己基)吡啶-3-基]-1H-1,2,3-三唑-4-甲醯胺 459.2 Example 100 : 1-(6 -Cyclohexyl- 5- fluoropyridin - 3 - yl )-N- ( 5,6 -difluoro -1H- indol- 3 -yl )-1H-1,2,3- tris oxazol- 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 3-yl)-1H-1,2,3-triazole-4-carboxamide (130.7 mg, 0.3 mmol, 1.0 equiv) and 2-(cyclohex-1-en-1-yl)-4,4 ,5,5-Tetramethyl-1,3,2-dioxoboron (124.8 mg, 0.6 mmol, 2.0 equiv) was dissolved in dioxane (3 mL). Then XPhos Pd G3 (12.7 mg, 0.015 mmol, 0.05 equiv) and aqueous _K3PO4 (450 μl, 2M, 3.0 equiv) _were added under nitrogen atmosphere. The reaction mixture was heated at 80°C for 16 hours. The reaction mixture was concentrated to give 1-(6-(cyclohex-1-en-1-yl)-5-fluoropyridin - 3-yl)-N-(5,6-difluoro-1H-indole-3- base)-1H-1,2,3-triazole-4-carboxamide, which 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- tris oxazol- 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 equiv) was dissolved in DCM (2 mL). Then Pd(AcO) ₂ (2.2 mg, 0.01 mmol, 0.05 equiv), AcOH (50 µl) and TES (200 µl) were added under nitrogen atmosphere. The mixture was stirred at 30°C for 16 hours. The mixture was concentrated under reduced pressure to remove dioxane. H ₂ O (5 mL) was then added and extracted with EtOAc, the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure and purified by HPLC to give 1-(6-cyclohexyl-5-fluoro Pyridin-3-yl)-N-(5,6-difluoro - 1H-indol-3-yl)-1H-1,2,3-triazole-4-carboxamide. MS-ESI, 441.2 [M+H ⁺ ]. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 11.15 (br s, 1 H), 10.62 (s, 1 H), 9.47 (s, 1 H), 9.06 (d, J =1.8 Hz, 1 H ), 8.39 (dd, J =10.5, 2.0 Hz, 1 H), 7.97-7.78 (m, 2 H), 7.39 (dd, J =11.3, 7.0 Hz, 1 H), 3.10-3.05 (br t, 1 H), 1.89-1.56 (m, 7H), 1.45-1.22 (m, 3H). The analogs in the table below were prepared using the same method as described for Example 100 . instance number Compound number structure IUPAC name LC-MS, MS-ESI, [M+H ⁺ . 101 169

1-[6-(1-Acetylhexahydropyridin-4-yl)-5-fluoropyridin-3-yl]-N-(5,6-difluoro-1H-indol-3-yl)- 1H-1,2,3-triazole-4-carboxamide 484.2 102 158

N-(5,6-Difluoro-1H-indol-3-yl)-1-[5-fluoro-6-(oxan-2-yl)pyridin-3-yl]-1H-1,2, 3-triazole-4-carboxamide 443.1 103 157

N-(5,6-Difluoro-1H-indol-3-yl)-1-[5-fluoro-6-(oxan-4-yl)pyridin-3-yl]-1H-1,2, 3-triazole-4-carboxamide 443.2 104 168

N-(5,6-Difluoro-1H-indol-3-yl)-1-{5-fluoro-6-[4-(trifluoromethyl)cyclohexyl]pyridin-3-yl}-1H- 1,2,3-Triazole-4-carboxamide 509.2 105 167

N-(5,6-Difluoro-1H-indol-3-yl)-1-[5-fluoro-6-(oxolan-3-yl)pyridin-3-yl]-1H-1 ,2,3-triazole-4-carboxamide 429.2 106 166

N-(5,6-Difluoro-1H-indol-3-yl)-1-[6-(2,6-dimethyloxan-4-yl)-5-fluoropyridin-3-yl] -1H-1,2,3-triazole-4-carboxamide 471.2 107 165

N-(5,6-Difluoro-1H-indol-3-yl)-1-[5-fluoro-6-(4-fluorocyclohexyl)pyridin-3-yl]-1H-1,2,3 -Triazole-4-carboxamide 459.2

將1-(6-溴-5-氟吡啶-3-基)- N-(5,6-二氟-1H-吲哚-3-基)-1H-1,2,3-三唑-4-甲醯胺(130.8 mg, 0.3 mmol, 1.0當量)及5-氮雜螺[2.4]庚烷(58.3 mg, 0.6 mmol, 2.0當量)溶於 t-AmOH (3 mL)中。然後在氮氣氛下添加K ₃PO ₄(189.9 mg, 0.9 mmol, 3.0當量)及RuPhos Pd G3 (12.5 mg, 0.15 mmol, 0.05當量)。將反應混合物在100℃下加熱16小時。在減壓下濃縮混合物以去除 t-AmOH。然後添加H ₂O (5 mL)並使用EtOAc萃取，藉由無水Na ₂SO ₄乾燥，過濾，在減壓下濃縮並藉由HPLC純化以得到 N-(5,6-二氟-1H-吲哚-3-基)-1-(5-氟-6-(5-氮雜螺[2.4]庚烷-5-基)吡啶-3-基)-1 H-1,2,3-三唑-4-甲醯胺。MS-ESI, 454.2 [M+H ⁺]。 ¹H NMR (400 MHz, DMSO- d ₆) δ ppm 11.14 (s, 1 H), 10.55 (s, 1 H), 9.26 (s, 1 H), 8.60-8.46 (m, 1 H), 8.11 (dd, J=13.55, 2.26 Hz, 1 H), 7.96-7.75 (m, 2 H), 7.50-7.30 (m, 1 H), 3.82-3.79 (td, J=6.78, 2.51 Hz, 2 H), 3.56 (d, J=2.76 Hz, 2 H), 1.89 (t, J=6.90 Hz, 2 H), 0.70-0.55 (m, 4 H)。 使用與針對 實例 108所闡述相同之方法來製備下表中之類似物。 實例編號 化合物 編號 結構 IUPAC 名稱 LC-MS, MS-ESI, -- [M+H ⁺]. 109 195

N-(5,6-二氟-1H-吲哚-3-基)-1-[5-氟-6-(3-甲氧基六氫吡啶-1-基)吡啶-3-基]-1H-1,2,3-三唑-4-甲醯胺 472.1 110 174

N-(5,6-二氟-1H-吲哚-3-基)-1-{5-氟-6-[2-(甲氧基甲基)吡咯啶-1-基]吡啶-3-基}-1H-1,2,3-三唑-4-甲醯胺 472.2 111 187

1-(6-{3-氮雜雙環[3.1.0]己烷-3-基}-5-氟吡啶-3-基)-N-(5,6-二氟-1H-吲哚-3-基)-1H-1,2,3-三唑-4-甲醯胺 440.2 112 189

1-(6-{2-氮雜雙環[2.1.1]己烷-2-基}-5-氟吡啶-3-基)-N-(5,6-二氟-1H-吲哚-3-基)-1H-1,2,3-三唑-4-甲醯胺 440.2 113 173

N-(5,6-二氟-1H-吲哚-3-基)-1-(5-氟-6-{3-氧雜-6-氮雜雙環[3.1.1]庚烷-6-基}吡啶-3-基)-1H-1,2,3-三唑-4-甲醯胺 456.1 114 182

1-(6-{2-氮雜螺[3.3]庚烷-2-基}-5-氟吡啶-3-基)-N-(5,6-二氟-1H-吲哚-3-基)-1H-1,2,3-三唑-4-甲醯胺 454.2 115 184

N-(5,6-二氟-1H-吲哚-3-基)-1-(5-氟-6-{2-氧雜-6-氮雜螺[3.3]庚烷-6-基}吡啶-3-基)-1H-1,2,3-三唑-4-甲醯胺 456.2 116 172

N-(5,6-二氟-1H-吲哚-3-基)-1-{5-氟-6-[(2S)-2-甲基吡咯啶-1-基]吡啶-3-基}-1H-1,2,3-三唑-4-甲醯胺 442.2 117 185

N-(5,6-二氟-1H-吲哚-3-基)-1-{5-氟-6-[(1R,4R)-2-氧雜-5-氮雜雙環[2.2.1]庚烷-5-基]吡啶-3-基}-1H-1,2,3-三唑-4-甲醯胺 456.1 118 186

N-(5,6-二氟-1H-吲哚-3-基)-1-(5-氟-6-{6-氧雜-3-氮雜雙環[3.1.1]庚烷-3-基}吡啶-3-基)-1H-1,2,3-三唑-4-甲醯胺 456.1 119 154

N-(5,6-二氟-1H-吲哚-3-基)-1-(6-((2S,6S)-2,6-二甲基嗎啉基)-5-氟吡啶-3-基)-1H-1,2,3-三唑-4-甲醯胺 472.1 120 194

1-(6-((2-環丙基乙基)(甲基)胺基)-5-氟吡啶-3-基)-N-(5,6-二氟-1H-吲哚-3-基)-1H-1,2,3-三唑-4-甲醯胺 455.1 121 156

N-(5,6-二氟-1H-吲哚-3-基)-1-[5-氟-6-(3-氟六氫吡啶-1-基)吡啶-3-基]-1H-1,2,3-三唑-4-甲醯胺 460.2 122 164

1-[6-(4-氯六氫吡啶-1-基)-5-氟吡啶-3-基]-N-(5,6-二氟-1H-吲哚-3-基)-1H-1,2,3-三唑-4-甲醯胺 476.2 123 183

N-(5,6-二氟-1H-吲哚-3-基)-1-{5-氟-6-[(3S)-3-氟吡咯啶-1-基]吡啶-3-基}-1H-1,2,3-三唑-4-甲醯胺 446.2 124 153

1-{6-[環丁基(甲基)胺基]-5-氟吡啶-3-基}-N-(5,6-二氟-1H-吲哚-3-基)-1H-1,2,3-三唑-4-甲醯胺 442.1 125 144

1-(6-{5-氮雜螺[2.3]己烷-5-基}-5-氟吡啶-3-基)-N-(5,6-二氟-1H-吲哚-3-基)-1H-1,2,3-三唑-4-甲醯胺 440.2 Example 108 : N- (5,6 -Difluoro -1H- indol- 3 -yl )-1-(5- fluoro -6-(5 -azaspiro [2.4] heptan- 5 - yl ) pyridine- 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 -Formamide (130.8 mg, 0.3 mmol, 1.0 equiv) and 5-azaspiro[2.4]heptane (58.3 mg, 0.6 mmol, 2.0 equiv) were dissolved in t -AmOH (3 mL). _K3PO4 (189.9 mg, 0.9 mmol, 3.0 equiv) and _RuPhos Pd G3 (12.5 mg, 0.15 mmol, 0.05 equiv) were then 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. _H2O (5 mL) was then added and extracted with EtOAc, dried _over anhydrous _Na2SO4 , filtered, concentrated under reduced pressure and purified by HPLC to give N- (5,6-difluoro-lH-indone dol-3-yl)-1-(5-fluoro-6-(5-azaspiro[2.4]heptan-5-yl)pyridin-3-yl)-1H- 1,2,3 -triazole -4-Carboxamide. MS-ESI, 454.2 [M+H ⁺ ]. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 11.14 (s, 1 H), 10.55 (s, 1 H), 9.26 (s, 1 H), 8.60-8.46 (m, 1 H), 8.11 ( dd, J =13.55, 2.26 Hz, 1 H), 7.96-7.75 (m, 2 H), 7.50-7.30 (m, 1 H), 3.82-3.79 (td, J =6.78, 2.51 Hz, 2 H), 3.56 (d, J =2.76 Hz, 2 H), 1.89 (t, J =6.90 Hz, 2 H), 0.70-0.55 (m, 4 H). The analogs in the table below were prepared using the same method as described for Example 108 . instance number Compound number structure IUPAC name LC-MS, MS-ESI, -- [M+H ⁺ ]. 109 195

N-(5,6-Difluoro-1H-indol-3-yl)-1-[5-fluoro-6-(3-methoxyhexahydropyridin-1-yl)pyridin-3-yl]- 1H-1,2,3-triazole-4-carboxamide 472.1 110 174

N-(5,6-Difluoro-1H-indol-3-yl)-1-{5-fluoro-6-[2-(methoxymethyl)pyrrolidin-1-yl]pyridine-3- yl}-1H-1,2,3-triazole-4-carboxamide 472.2 111 187

1-(6-{3-Azabicyclo[3.1.0]hexane-3-yl}-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indole-3 -yl)-1H-1,2,3-triazole-4-carboxamide 440.2 112 189

1-(6-{2-Azabicyclo[2.1.1]hexane-2-yl}-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indole-3 -yl)-1H-1,2,3-triazole-4-carboxamide 440.2 113 173

N-(5,6-Difluoro-1H-indol-3-yl)-1-(5-fluoro-6-{3-oxa-6-azabicyclo[3.1.1]heptane-6- yl}pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamide 456.1 114 182

1-(6-{2-Azaspiro[3.3]heptan-2-yl}-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl )-1H-1,2,3-triazole-4-carboxamide 454.2 115 184

N-(5,6-Difluoro-1H-indol-3-yl)-1-(5-fluoro-6-{2-oxa-6-azaspiro[3.3]heptan-6-yl} Pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamide 456.2 116 172

N-(5,6-Difluoro-1H-indol-3-yl)-1-{5-fluoro-6-[(2S)-2-methylpyrrolidin-1-yl]pyridin-3-yl }-1H-1,2,3-triazole-4-carboxamide 442.2 117 185

N-(5,6-Difluoro-1H-indol-3-yl)-1-{5-fluoro-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1 ]Heptan-5-yl]pyridin-3-yl}-1H-1,2,3-triazole-4-carboxamide 456.1 118 186

N-(5,6-Difluoro-1H-indol-3-yl)-1-(5-fluoro-6-{6-oxa-3-azabicyclo[3.1.1]heptane-3- yl}pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamide 456.1 119 154

N-(5,6-Difluoro-1H-indol-3-yl)-1-(6-((2S,6S)-2,6-dimethylmorpholinyl)-5-fluoropyridine-3 -yl)-1H-1,2,3-triazole-4-carboxamide 472.1 120 194

1-(6-((2-Cyclopropylethyl)(methyl)amino)-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indole-3- base)-1H-1,2,3-triazole-4-carboxamide 455.1 121 156

N-(5,6-Difluoro-1H-indol-3-yl)-1-[5-fluoro-6-(3-fluorohexahydropyridin-1-yl)pyridin-3-yl]-1H- 1,2,3-Triazole-4-carboxamide 460.2 122 164

1-[6-(4-Chlorohexahydropyridin-1-yl)-5-fluoropyridin-3-yl]-N-(5,6-difluoro-1H-indol-3-yl)-1H- 1,2,3-Triazole-4-carboxamide 476.2 123 183

N-(5,6-Difluoro-1H-indol-3-yl)-1-{5-fluoro-6-[(3S)-3-fluoropyrrolidin-1-yl]pyridin-3-yl} -1H-1,2,3-triazole-4-carboxamide 446.2 124 153

1-{6-[Cyclobutyl(methyl)amino]-5-fluoropyridin-3-yl}-N-(5,6-difluoro-1H-indol-3-yl)-1H-1 ,2,3-triazole-4-carboxamide 442.1 125 144

1-(6-{5-Azaspiro[2.3]hexane-5-yl}-5-fluoropyridin-3-yl)-N-(5,6-difluoro-1H-indol-3-yl )-1H-1,2,3-triazole-4-carboxamide 440.2

Bioassays The STING pathway activation of the compounds described herein was measured using THP1-Dual™ cells (KO-IFNAR2).

THP1-Dual™ KO-IFNAR2 cells (obtained from invivogen) were maintained in RPMI (10% FCS, 5 ml P/S, 2 mM L-glut, 10 mM Hepes and 1 mM sodium pyruvate). Compounds were spotted in empty 384-well tissue culture plates (Greiner 781182) by Echo to final concentrations of 0.0017 - 100 µM. Cells were plated into TC plates at 40 μL/well, 2×10E6 cells/mL. For activation with STING ligand, 2'3' cGAMP (MW 718.38, obtained from Invivogen) was prepared in Optimem medium.

Prepare the following solutions for each 1x384 plate: o Solution A: 2 mL Optimem with one of the following stimuli: ▪ 60 µL 10 mM 2'3' cGAMP → 150 µM stock o Solution B: 2 mL Optimem Mix 2 mL of solution A and 2 ml of solution B with 60 μL of Lipofectamine 2000 → incubate for 5 min at room temperature and incubate at room temperature (RT) for 20 min. 20 µL of transfection solution (A+B) was added on top of the plated cells at a final 2'3' cGAMP concentration of 15 µM. Plates were then immediately centrifuged at 340 g for 1 min, followed by incubation at 37°C, 5% _CO2 , >98% humidity for 24h. The luciferase reporter gene activity was then measured. _EC50 values are calculated by using standard methods known in the industry.

Luciferase reporter gene assay : Transfer 10 µL of assay supernatant to a white 384-plate with flat bottom and square wells. Dissolve one sachet of QUANTI-Luc™ Plus in 25 mL of water. Add 100 µL of QLC stabilizer to every 25 mL of QUANTI-Luc™ Plus solution. Then add 50 µL of QUANTI-Luc™ Plus/QLC solution to each well. Luminescence is measured on a plate reader such as Spectramax 13X (Molecular Devices GF3637001).

The luciferase reporter gene activity was then measured. _EC50 values are calculated by using standard methods known in the industry.

Table BA shows compound activity in the STING reporter assay: <0.008 µM = "++++++"; ≥0.008 µM and <0.04 µM = "+++++"; ≥0.04 µM and <0.2 µM = "++++"; ≥0.2 µM and <1 µM = "+++"; ≥1 µM and <5 µM = "++"; ≥5 µM and <100 µM = "+". Table BA compound hSTING EC ₅₀ compound hSTING EC ₅₀ 101 +++ 114 ++ 102 +++ 115 +++ 104 +++ 116 ++ 105 +++ 119 ++++ 106 +++ 120 +++ 107 +++ 121 +++ 108 ++ 122 +++ 109 +++ 123 ++ 110 +++ 124 ++ 111 +++ 125 +++ 112 +++ 142 ++++ 191 +++ 143 ++++ 192 +++ 144 +++ 193 +++ 145 +++ 194 +++ 146 +++ 195 +++ 147 +++ 196 +++ 148 +++ 197 +++ 149 +++ 198 +++ 150 +++ 199 +++ 151 +++ 200 +++ 152 +++ 201 +++ 153 +++ 202 ++ 154 +++ 203 +++ 155 ++++ 204 ++++ 156 +++ 205 +++ 157 ++ 206 +++ 158 +++ 207 ++ 159 +++ 208 ++++ 160 ++++ 209 +++ 161 +++ 210 +++ 162 +++ 211 +++ 163 +++ 212 ++++ 164 +++ 213 +++ 165 +++ 214 +++ 166 +++ 215 ++++ 167 ++ 216 +++ 168 +++ 217 ++ 169 ++ 218 +++ 170 +++ 219 +++ 171 +++ 220 +++ 172 +++ 221 +++ 173 ++ 222 +++ 174 +++ 223 +++ 175 ++++ 224 +++ 176 ++++ 225 +++ 177 +++ 226 +++ 178 +++ 227 +++ 179 +++ 228 +++ 180 +++ 229 +++ 181 +++ 230 ++++ 182 +++ 231 +++ 183 +++ 232 +++ 184 ++ 233 +++ 185 +++ 234 ++++ 186 ++ 235 ++++ 187 +++ 236 ++++ 188 ++++ 237 +++ 189 +++ 238 +++ 190 +++ 239 +++ 240 +++

式 I或其醫藥上可接受之鹽或其互變異構體，其中： Z 、 Y ¹ 、 Y ² 及 Y ³ 獨立地選自由以下組成之群：C R ¹ 、C(=O)、N及N R ² ； X ¹ 係選自由以下組成之群：O、S、N、N R ² 及C R ¹ ； X ² 係選自由以下組成之群：O、S、N、N R ⁴ 及C R ⁵ ； 每一

獨立地係單鍵或雙鍵，條件係包括 X ¹ 及 X ² 之5員環係雜芳基，且包括 Z 、 Y ¹ 、 Y ² 及 Y ³ 之6員環係芳基或雜芳基； 每一 R ¹ 獨立地選自由以下組成之群：H； R ^c ； R ^g ；及 -(L ¹) _b1-R ^g ； 每一 R ² 獨立地選自由以下組成之群：H； R ^d ； R ^g ；及 -(L ²) _b2-R ^g ； R ⁴ 係選自由以下組成之群：H及 R ^d ； R ⁵ 係選自由以下組成之群：H； R ^c ；及 R ^h ； R ⁶ 係選自由以下組成之群：H； R ^d ；及 R ^h ； 環 B係具有5個環原子之伸雜芳基，其中1-4個環原子係各自獨立地選自由N、NH、N( R ^d )、O及S組成之群之雜原子；其中 環 B之伸雜芳基視情況經1-2個獨立地選自由側氧基及 R ^c 組成之群之取代基取代，條件係 環 B經由環碳原子連接至C(=O)N R ⁶ 基團； 每一 L ^A 獨立地選自由以下組成之群：視情況經1-2個 R ^a1 取代之C _1-3伸烷基；-O-；-NH-；-N R ^d ；-S(O) _0-2；及C(O)； a1為0、1或2； 環 C係選自由以下組成之群： •    C _3-12伸環烷基或C _3-12伸環烯基，其各自視情況經1-4個獨立地選自由以下組成之群之取代基取代：側氧基、 R ^c 及 R ^h ； •    具有3-12個環原子之伸雜環基或伸雜環烯基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中伸雜環基或伸雜環烯基視情況經1-4個獨立地選自由以下組成之群之取代基取代：側氧基、 R ^c 及 R ^h ； •    具有5-12個環原子之伸雜芳基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中伸雜芳基視情況經1-4個獨立地選自由以下組成之群之取代基取代： R ^c 及 R ^h ；及 •    C _6-10伸芳基，其視情況經1-4個獨立地選自由以下組成之群之取代基取代： R ^c 及 R ^h ； R ⁷ 係選自由以下組成之群： R ^g 及 -(L ⁷) _b7-R ^g ； R ^a 及 R ^a1 在每次出現時獨立地選自由以下組成之群：-OH；-鹵基；-N R ^eR ^f ；C _1-4烷氧基；C _1-4鹵代烷氧基；-C(=O)O(C _1-4烷基)；-C(=O)(C _1-4烷基)；-C(=O)OH；-CON R’R’’；-S(O) _1-2N R’R’’；-S(O) _1-2(C _1-4烷基)；及氰基； R ^c 在每次出現時獨立地選自由以下組成之群：鹵基；氰基；視情況經1-6個獨立選擇之 R ^a 取代之C _1-10烷基；C _2-6烯基；C _2-6炔基；C _1-4烷氧基；C _1-4鹵代烷氧基；-S(O) _1-2(C _1-4烷基)；-S(O)(=NH)(C _1-4烷基)；-N R ^eR ^f ；-OH；-S(O) _1-2N R’R’’；-C _1-4硫基烷氧基；-NO ₂；-C(=O)(C _1-10烷基)；-C(=O)O(C _1-4烷基)；-C(=O)OH；-C(=O)N R’R’’；及-SF ₅； R ^d 在每次出現時獨立地選自由以下組成之群：視情況經1-3個獨立選擇之 R ^a 取代之C _1-6烷基；-C(O)(C _1-4烷基)；-C(O)O(C _1-4烷基)；-CON R’R’’；-S(O) _1-2N R’R’’；-S(O) _1-2(C _1-4烷基)；-OH；及C _1-4烷氧基； R ^e 及 R ^f 在每次出現時獨立地選自由以下組成之群：H；C _1-6烷基，其視情況經1-3個各自獨立地選自由N R’R’’、-OH及 R ⁱ 組成之群之取代基取代；-C(O)(C _1-4烷基)；-C(O)O(C _1-4烷基)；-CON R’R’’；-S(O) _1-2N R’R’’；-S(O) _1-2(C _1-4烷基)；-OH；及C _1-4烷氧基； R ^g 在每次出現時獨立地選自由以下組成之群： •    C _3-12環烷基或C _3-12環烯基，其中之每一者視情況經1-4個獨立地選自由以下組成之群之取代基取代：側氧基、 R ^c 、 R ^h 及-( L ^g) _bg-R ^h ； •    具有3-12個環原子之雜環基或雜環烯基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中雜環基或雜環烯基視情況經1-4個獨立地選自由以下組成之群之取代基取代：側氧基、 R ^c 、 R ^h 及-( L ^g) _bg-R ^h ； •    具有5-12個環原子之雜芳基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中雜芳基視情況經1-4個獨立地選自由以下組成之群之取代基取代： R ^c 、 R ^h 及-( L ^g) _bg-R ^h ；及 •    C _6-10芳基，其視情況經1-4個獨立地選自由以下組成之群之取代基取代： R ^c 、 R ^h 及-( L ^g) _bg-R ^h ； R ^h 在每次出現時獨立地選自由以下組成之群： •    C _3-12環烷基或C _3-12環烯基，其中之每一者視情況經1-4個 R ⁱ 取代； •    具有3-12個環原子之雜環基或雜環烯基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中雜環基或雜環烯基視情況經1-4個 R ⁱ 取代； ·    具有5-12個環原子之雜芳基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中雜芳基視情況經1-4個 R ⁱ 取代；及 •    C _6-10芳基，其視情況經1-4個 R ⁱ 取代； R ⁱ 在每次出現時獨立地選自由以下組成之群：C _1-6烷基；C _1-4鹵代烷基；C _1-4烷氧基；C _1-4鹵代烷氧基；及鹵基； L ¹ 、 L ² 、 L ⁷ 及 L ^g 在每次出現時係選自由以下組成之群：-O-、-NH-、-N R ^d 、-S(O) _0-2、C(O)及視情況經1-3個 R ^a 取代之C _1-3伸烷基； b1、 b2、 b7及 bg各自獨立地為1、2或3；且 R’及 R’’在每次出現時獨立地選自由以下組成之群：H；-OH；及C _1-4烷基。 2.如條款1之化合物，其中 Z、 Y ¹ 、 Y ² 及 Y ³ 中之每一者獨立地係N或C R ¹ 。 3.如條款1或2之化合物，其中該化合物係式 ( Ia)化合物：

式( Ia) 或其醫藥上可接受之鹽，其中： R ^1a 、 R ^1b 、 R ^1c 及 R ^1d 各自係獨立選擇之 R ¹ 。 4.如條款1或2之化合物，其中 Z、 Y ¹ 、 Y ² 及 Y ³ 中之1-2 (例如1)者係N；且 Z、 Y ¹ 、 Y ² 及 Y ³ 中之每一剩餘者係獨立選擇之C R ¹ 。 5.如條款1至2或4中任一項之化合物，其中該化合物係選自由下列各式之化合物組成之群：

或其醫藥上可接受之鹽，其中： R ^1a 、 R ^1b 、 R ^1c 及 R ^1d 各自係獨立選擇之 R ¹ 。 6.如條款1至5中任一項之化合物，其中 X ¹ 係N R ² 。 7.如條款1至6中任一項之化合物，其中 X ¹ 係NH。 8.如條款1至7中任一項之化合物，其中 X ² 係C R ⁵ 。 9.如條款1至8中任一項之化合物，其中 X ² 係CH。 10.如條款1至5中任一項之化合物，其中 X ¹ 係N R ² ；且 X ² 係C R ⁵ 。 11.如條款1至5或10中任一項之化合物，其中 X ¹ 係NH；且 X ² 係CH。 12.如條款1之化合物，其中該化合物係式 ( Ia-1)化合物：

式 (Ia-1)或其醫藥上可接受之鹽，其中： R ^1a 、 R ^1b 、 R ^1c 及 R ^1d 各自係獨立選擇之 R ¹ 。 13.如條款1之化合物，其中該化合物係選自由下列各式之化合物組成之群：

或其醫藥上可接受之鹽，其中： R ^1a 、 R ^1b 、 R ^1c 及 R ^1d 各自係獨立選擇之 R ¹ 。 14.如條款12或13之化合物，其中 R ² 係H。 15.如條款12至14中任一項之化合物，其中 R ⁵ 係H。 16.如條款1至15中任一項之化合物，其中每一 R ¹ 係H。 17.如條款1至15中任一項之化合物，其中1-2個 R ¹ 獨立地選自由 R ^c1 及 R ^g1 組成之群；且每一剩餘 R ¹ 係H，其中 R ^c1 係獨立選擇之 R ^c ；且 R ^g1 係獨立選擇之 R ^g 。 18.如條款17之化合物，其中 R ¹ 在兩次出現時獨立地選自由 R ^c1 及 R ^g1 組成之群；且每一剩餘 R ¹ 係H。 19.如條款17或18之化合物，其中 R ¹ 在兩次出現時係獨立選擇之 R ^c1 ；且每一剩餘 R ¹ 係H。 20.如條款17之化合物，其中 R ¹ 在一次出現時係選自由 R ^c1 及 R ^g1 組成之群；且每一剩餘 R ¹ 係H。 21.如條款17或20之化合物，其中在一次出現時係 R ¹ is R ^c1 ；且每一剩餘 R ¹ 係H。 22.如條款17或20之化合物，其中 R ¹ 在一次出現時係 R ^g1 ；且每一剩餘 R ¹ 係H。 23.如條款17至22中任一項之化合物，其中每一 R ^c1 係獨立選擇之鹵基，例如-F、-Cl或-Br。 24.如條款23之化合物，其中每一 R ^c1 獨立地係-F或-Cl，例如-F。 25.如條款17至24中任一項之化合物，其中每一 R ^g1 獨立地選自由以下組成之群： 具有5-10個環原子之雜芳基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S組成之群之雜原子，且其中雜芳基視情況經1-4個獨立地選自由以下組成之群之取代基取代： R ^c 、 R ^h 及-( L ^g) _bg-R ^h ；及 C _6-10芳基，其視情況經1-4個獨立地選自由以下組成之群之取代基取代： R ^c 、 R ^h 及-( L ^g) _bg-R ^h 。 26.如條款25之化合物，其中每一 R ^g1 獨立地選自由以下組成之群： 具有5-6個環原子之雜芳基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S組成之群之雜原子，且其中雜芳基視情況經1-4個 R ^C 取代；及 C ₆芳基，其視情況經1-4個 R ^C 取代。 27.如條款25或26之化合物，其中每一 R ^g1 獨立地係具有5個環原子之雜芳基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S組成之群之雜原子，且其中該雜芳基視情況經1-4個 R ^c 取代 。 28.如條款27之化合物，其中每一 R ^g1 係視情況經1-2個 R ^c 取代之吡唑基，該取代基係例如1-2個獨立選擇之視情況經1-6個獨立選擇之 R ^a 取代(例如未經取代)之C _1-6(例如C _1-3)烷基。 29.如條款3、5或12至13中任一項之化合物，其中 R ^1a 係H。 30.如條款3、5、12至13或29中任一項之化合物，其中 R ^1b 係H。 31.如條款3、5、12至13或29中任一項之化合物，其中 R ^1b 係鹵基，例如-F或-Cl (例如-F)。 32.如條款3、5、12至13或29中任一項之化合物，其中 R ^1b 係具有5個環原子之雜芳基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S組成之群之雜原子，且其中該雜芳基視情況經1-2個 R ^c 取代。 33.如條款32之化合物，其中 R ^1b 係視情況經1-2個 R ^c 取代之吡唑基，舉例而言，每一 R ^c 係獨立選擇之視情況經1-6個獨立選擇之 R ^a 取代(例如未經取代)之C _1-6(例如C _1-3)烷基。 34.如條款3、5、12至13或29至33中任一項之化合物，其中 R ^1c 係H。 35.如條款3、5、12至13或29至33中任一項之化合物，其中 R ^1c 係鹵基，例如-F或-Cl (例如-F)。 36.如條款3、5、12至13或29至35中任一項之化合物，其中 R ^1d 係H。 37.如條款3、5、12至13或29至35中任一項之化合物，其中 R ^1d 係鹵基，例如-F或-Cl (例如-F)。 38.如條款3、5或12至13中任一項之化合物，其中 R ^1a 及 R ^1d 係H；且 R ^1b 及 R ^1c 係獨立選擇之鹵基，例如-F或-Cl，例如-F。 39.如條款3、5或12至13中任一項之化合物，其中 R ^1a 及 R ^1d 係H； R ^1b 及 R ^1c 中之一者係H；且 R ^1b 及 R ^1c 中之另一者係鹵基，例如-F或-Cl，例如-F。 40.如條款3、5或12至13中任一項之化合物，其中 R ^1a 及 R ^1d 係H； R ^1c 係鹵基或H，例如-F、-Cl或H；且 R ^1b 係具有5個環原子之雜芳基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S組成之群之雜原子，且其中該雜芳基視情況經1-4個 R ^c 取代。 41.如條款1至40中任一項之化合物，其中 R ⁶ 係H。 42.如條款1至41中任一項之化合物，其中 環 B係具有5個環原子之伸雜芳基，其中1-3個環原子係各自獨立地選自由N、NH、O及S組成之群之雜原子，其中 環 B之伸雜芳基視情況經1-2個 R ^cB 取代；且每一 R ^cB 係獨立選擇之 R ^c 。 43.如條款1至42中任一項之化合物，其中 環 B係具有5個環原子之伸雜芳基，其中2-3個環原子係各自獨立地選自由N、NH、N( R ^d )、O及S (例如N及NH)組成之群之雜原子，其中 環 B之伸雜芳基視情況經1-2個 R ^cB 取代；且每一 R ^cB 係獨立選擇之 R ^c 。 44.如條款43之化合物，其中 環 B係選自由以下組成之群：伸咪唑基、伸吡唑基或伸三唑基(例如1,2,3-伸三唑基)，其視情況經一個 R ^cB 取代。 45.如條款44之化合物，其中 環 B係視情況經一個 R ^cB 取代之

，其中 aa 係與 (L ^A) _a1 之連結點 。 46.如條款44之化合物，其中 環 B係視情況經一個 R ^cB 取代之

，其中 aa 係與 (L ^A) _a1 之連結點 。 47.如條款44之化合物，其中 環 B係視情況經一個 R ^cB 取代之

，其中 aa 係與 (L ^A) _a1 之連結點 。 48.如條款44之化合物，其中 環 B係

或

，其中之每一者視情況經一個 R ^cB 取代，其中 aa 係與 (L ^A) _a1 之連結點 。 49.如條款42至48或163至169中任一項之化合物，其中每一 R ^cB 獨立地係鹵基或視情況C _1-3烷基，該烷基視情況經1-3個獨立選擇之 R ^a (例如1-3個獨立選擇之鹵基)取代。 50.如條款1至49或163至169中任一項之化合物，其中 a1為0。 51.如條款1至49或163至169中任一項之化合物，其中 a1為1。 52.如條款1至49、51或163至169中任一項之化合物，其中 L ^A 係視情況經1-2個 R ^a1 取代之C _1-3伸烷基。 53.如條款52之化合物，其中 L ^A 係CH ₂或CH(Me)，例如CH ₂。 54.如條款1至53或163至169中任一項之化合物，其中 環 C係選自由以下組成之群： •  具有5-10個環原子之伸雜芳基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中伸雜芳基視情況經1-4個獨立地選自由 R ^cC 及 R ^hC 組成之群之取代基取代；且 •  C _6-10伸芳基，其視情況經1-4個獨立地選自由 R ^cC 及 R ^hC 組成之群之取代基取代，其中每一 R ^cC 係獨立選擇之 R ^c ；且每一 R ^hC 係獨立選擇之 R ^h 。 55.如條款54或163至169中任一項之化合物，其中 環 C係選自由以下組成之群： •  具有5-6 (例如6)個環原子之伸雜芳基，其中1-3 (例如1-2)個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中伸雜芳基視情況經1-4個獨立地選自由 R ^cC 組成之群之取代基取代；及 •  C ₆伸芳基，其視情況經1-4個獨立地選自由 R ^cC 組成之群之取代基取代。 56.如條款54、55或163至169中任一項之化合物，其中 環 C係選自由以下組成之群： •  伸吡啶基，其視情況經1-3 (例如1)個獨立地選自由 R ^cC 組成之群之取代基取代；及 •  C ₆伸芳基，其視情況經1-4 (例如1-2)個獨立地選自由 R ^cC 組成之群之取代基取代。 57.如條款54至56或163至169中任一項之化合物，其中 環 C係下式之基團：

，其中 Q ¹ 、 Q ² 、 Q ³ 及 Q ⁴ 中之每一者獨立地選自由N、CH及C R ^cC 組成之群；且 bb 係與 R ⁷ 之連結點。 58.如條款57或163至169中任一項之化合物，其中 Q ² 係CH。 59.如條款57、58或163至169中任一項之化合物，其中 Q ³ 係CH。 60.如條款57至59或163至169中任一項之化合物，其中 Q ⁴ 係N。 61.如條款57至60或163至169中任一項之化合物，其中 Q ¹ 係CH。 62.如條款57至60或163至169中任一項之化合物，其中 Q ¹ 係C R ^cC 。 63.如條款57或163至169中任一項之化合物，其中環 C係

或

，例如

。 64.如條款54至63或163至169中任一項之化合物，其中每一 R ^cC 獨立地選自由以下組成之群：-鹵基及C _1-6(例如C _1-3)烷基，該烷基視情況經1-6個獨立選擇之 R ^a (例如1-6個獨立選擇之鹵基，例如-F)取代。 65.如條款54至64或163至169中任一項之化合物，其中每一 R ^cC 獨立地係鹵基，例如-Cl或-F，例如-F。 66.如條款1至65或170至173中任一項之化合物，其中 R ⁷ 係 R ^g 。 67.如條款1至66或170至173中任一項之化合物，其中 R ⁷ 係選自由以下組成之群： •  C _3-12環烷基，其視情況經1-4個獨立地選自由以下組成之群之取代基取代：側氧基、 R ^c7 、 R ^h7 及-( L ^g) _bg-R ^h7 ；及 •  具有4-12個環原子之雜環基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中雜環基視情況經1-4個獨立地選自由側氧基、 R ^c7 、 R ^h7 及-( L ^g) _bg-R ^h7 組成之群之取代基取代，其中每一 R ^c7 係獨立選擇之 R ^c ；且 R ^h7 係獨立選擇之 R ^h 。 68.如條款67或170至173中任一項之化合物，其中 R ⁷ 係選自由以下組成之群： •  C _4-8環烷基，其視情況經1-4個獨立地選自由側氧基、 R ^c7 及 R ^h7 組成之群之取代基取代；及 •  具有4-8個環原子之雜環基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中雜環基視情況經1-4個獨立地選自由以下組成之群之取代基取代：側氧基、 R ^c7 及 R ^h7 。 69.如條款68或170至173中任一項之化合物，其中 R ⁷ 係選自由以下組成之群： •  C ₆環烷基，其視情況經1-4個獨立地選自由 R ^c7 組成之群之取代基取代；及 •  具有6個環原子之雜環基，其中1-2個(例如一個)環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中雜環基視情況經1-4個獨立地選自由 R ^c7 組成之群之取代基取代。 70.如條款69或170至173中任一項之化合物，其中 R ⁷ 係下式之基團：

，其中 X ⁷ 係CH、C R ^c7 或N，例如CH或N。 71.如條款69、70或170至173中任一項之化合物，其中存在兩個 R ^c7 基團。 72.如條款1至71或170至173中任一項之化合物，其中 R ⁷ 係下式之基團：

，其中 X ⁷ 係N或CH；且每一 R ^c7 係獨立選擇之 R ^c 。 73.如條款67至72或170至173中任一項之化合物，其中每一 R ^c7 係獨立選擇之鹵基或視情況經1-6個 R ^a (例如1-6個獨立選擇之鹵基)取代之C _1-3烷基。 74.如條款67至73或170至173中任一項之化合物，其中每一 R ^c7 獨立地係鹵基，例如-F。 75.如條款1至74或170至173中任一項之化合物，其中 R ⁷ 係

，其中 X ⁷ 係N或CH。 76.如條款1之化合物，其中該化合物係式 (I-a1-1)化合物：

式 (I-a1-1)或其醫藥上可接受之鹽，其中： R ^1a 、 R ^1b 、 R ^1c 及 R ^1d 中之每一者係獨立選擇之 R ¹ ； B ⁴ 係C或N； B ¹ 、 B ² 及 B ³ 各自獨立地係CH、C R ^cB 、NH、N( R ^d )、N、O或S； Q ¹ 、 Q ² 、 Q ³ 及 Q ⁴ 各自獨立地選自由以下組成之群：N、CH及C R ^cC ； R ^cB 及 R ^cC 在每次出現時係獨立選擇之 R ^c ；且 每一

獨立地係單鍵或雙鍵，條件係包含 B ¹-B ⁴ 之環為雜芳基。 77.如條款76之化合物，其中 R ^1a 及 R ^1d 係H；且 R ^1b 及 R ^1c 獨立地係H或鹵基，例如鹵基(例如-F或-Cl，例如-F)。 78.如條款76之化合物，其中 R ^1a 、 R ^1b 、 R ^1c 及 R ^1d 中之每一者係H。 79.如條款76之化合物，其中 R ^1a 及 R ^1d 係H； R ^1c 係鹵基或H，例如-F、-Cl或H；且 R ^1b 係具有5個環原子之雜芳基，其中1-3個環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S組成之群之雜原子，且其中該雜芳基視情況經1-4個獨立地選自由 R ^c 組成之群之取代基取代。 80.如條款76至79中任一項之化合物，其中 R ² 係H。 81.如條款76至80中任一項之化合物，其中 R ⁵ 係H。 82.如條款76至81中任一項之化合物，其中 R ⁶ 係H。 83.如條款76至82中任一項之化合物，其中 R ² 係H； R ⁵ 係H；且 R ⁶ 係H。 84.如條款76至83中任一項之化合物，其中 B ⁴ 係N； B ¹ 係N； B ³ 係CH；且 B ² 係CH。 85.如條款76至83中任一項之化合物，其中 B ⁴ 係N； B ¹ 係N； B ³ 係CH；且 B ² 係N。 86.如條款76至83中任一項之化合物，其中 B ⁴ 係N； B ¹ 係N； B ³ 係CH；且 B ² 係C R ^cB 。 87.如條款76至83中任一項之化合物，其中 B ⁴ 係N； B ¹ 係CH； B ³ 係CH；且 B ² 係N。 88.如條款76至83中任一項之化合物，其中 B ⁴ 係N； B ¹ 係CH； B ³ 係N；且 B ² 係CH。 89.如條款76至88中任一項之化合物，其中 a1為0。 90.如條款76至88中任一項之化合物，其中 a1為1。 91.如條款76至88或90中任一項之化合物，其中 L ^A 係CH ₂或CH(Me)。 92.如條款76至91中任一項之化合物，其中 Q ¹ 及 Q ³ 係CH。 93.如條款76至92中任一項之化合物，其中 Q ⁴ 係N；且 Q ² 係CH或C R ^cC ，例如C R ^cC 。 94.如條款76至93中任一項之化合物，其中包含 Q ¹-Q ⁴ 之環係：

，其中 bb 係與 R ⁷ 之連結點。 95.如條款76至94中任一項之化合物，其中 R ^cC 係鹵基，例如-F或-Cl，例如-F。 96.如條款76至95中任一項之化合物，其中 R ⁷ 係選自由以下組成之群： •  C ₆環烷基，其視情況經1-4個獨立地選自由 R ^c7 組成之群之取代基取代；及 •  具有6個環原子之雜環基，其中1-2個(例如一個)環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中雜環基視情況經1-4個獨立地選自由 R ^c7 組成之群之取代基取代，其中每一 R ^c7 係獨立選擇之 R ^c 。 97.如條款96之化合物，其中 R ⁷ 係下式之基團：

，其中 X ⁷ 係CH、C R ⁷ 或N，例如CH或N。 98.如條款96或97之化合物，其中存在兩個 R ^c7 基團。 99.如條款76至98中任一項之化合物，其中 R ⁷ 係下式之基團：

，其中 X ⁷ 係N或CH；且每一 R ^c7 係獨立選擇之 R ^c 。 100.如條款96至99中任一項之化合物，其中每一 R ^c7 係獨立選擇之鹵基或視情況經1-6個 R ^a (例如1-6個獨立選擇之鹵基)取代之C _1-3烷基。 101.如條款96至100中任一項之化合物，其中每一 R ^c7 獨立地係鹵基，例如-F。 102.如條款76至101中任一項之化合物，其中 R ⁷ 係

，其中 X ⁷ 係N或CH，例如

或

。 103.如條款1之化合物，其中該化合物係選自由 表 C1中所描述化合物或其醫藥上可接受之鹽組成之群。 104.一種醫藥組合物，其包括如條款1至103之化合物及一或多種醫藥上可接受之賦形劑。 105.一種抑制STING活性之方法，該方法包括使STING與如條款1至103中任一項之化合物或其醫藥上可接受之鹽或如條款104之醫藥組合物接觸。 106.如條款105之方法，其中該抑制包括拮抗STING。 107.如條款105至106中任一項之方法，其係在活體外實施。 108.如條款107之方法，其中該方法包括使包括一或多種包括STING之細胞之試樣與該化合物接觸。 109.如條款107或108之方法，其中該一或多種細胞係一或多種癌細胞。 110.如條款108或109之方法，其中該試樣進一步包括一或多種癌細胞，其中該癌症係選自由以下組成之群：黑色素瘤、子宮頸癌、乳癌、卵巢癌、前列腺癌、睪丸癌、尿路上皮癌、膀胱癌、非小細胞肺癌、小細胞肺癌、肉瘤、結腸直腸腺癌、胃腸道基質腫瘤、胃食道癌、結腸直腸癌、胰臟癌、腎癌、肝細胞癌、惡性間皮瘤、白血病、淋巴瘤、骨髓發育不良症候群、多發性骨髓瘤、移行細胞癌、神經母細胞瘤、漿細胞贅瘤、維爾姆斯氏腫瘤或肝細胞癌。 111.如條款105或106之方法，其係在活體內實施。 112.如條款111之方法，其中該方法包括將該化合物投與患有其中增加(例如過度)之STING信號傳導有助於疾病之病理學及/或症狀及/或進展之疾病的個體。 113.如條款112之方法，其中該個體係人類。 114.如條款113之方法，其中該疾病係癌症。 115.如條款114之方法，其中該癌症係選自由以下組成之群：黑色素瘤、子宮頸癌、乳癌、卵巢癌、前列腺癌、睪丸癌、尿路上皮癌、膀胱癌、非小細胞肺癌、小細胞肺癌、肉瘤、結腸直腸腺癌、胃腸道基質腫瘤、胃食道癌、結腸直腸癌、胰臟癌、腎癌、肝細胞癌、惡性間皮瘤、白血病、淋巴瘤、骨髓發育不良症候群、多發性骨髓瘤、移行細胞癌、神經母細胞瘤、漿細胞贅瘤、維爾姆斯氏腫瘤或肝細胞癌。 116.如條款114或115之方法，其中該癌症係難治性癌症。 117.如條款112之方法，其中該化合物係與一或多種其他癌症療法組合投與。 118.如條款117之方法，其中該一或多種其他癌症療法包括手術、放射療法、化學療法、毒素療法、免疫療法、冷療法或基因療法或其組合。 119.如條款118之方法，其中化學療法包括投與一或多種其他化學治療劑。 120.如條款119之方法，其中該一或多種其他化學治療劑係選自烷基化劑(例如順鉑(cisplatin)、卡鉑(carboplatin)、雙氯乙基甲胺(mechlorethamine)、環磷醯胺(cyclophosphamide)、氮芥苯丁酸(chlorambucil)、異環磷醯胺(ifosfamide)及/或奧沙利鉑(oxaliplatin))；抗代謝物(例如硫唑嘌呤(azathioprine)及/或巰嘌呤(mercaptopurine))；類萜(例如長春花生物鹼及/或紫杉烷(taxane)；例如長春新鹼(Vincristine)、長春鹼(Vinblastine)、長春瑞濱(Vinorelbine)及/或長春地辛(Vindesine)、紫杉醇(Taxol)、太平洋紫杉醇(Pacllitaxel)及/或多西他賽(Docetaxel))；拓撲異構酶(例如I型拓撲異構酶及/或2型拓撲異構酶；例如喜樹鹼(camptothecin),例如伊立替康(irinotecan)及/或托泊替康(topotecan)；安吖啶(amsacrine)、依託泊苷(etoposide)、磷酸依託泊苷及/或替尼泊苷(teniposide))；細胞毒性抗生素(例如放線菌素(actinomycin)、蒽環、多柔比星(doxorubicin)、柔紅黴素(daunorubicin)、戊柔比星(valrubicin)、伊達比星(idarubicin)、表柔比星(epirubicin)、博來黴素(bleomycin)、普卡黴素(plicamycin)及/或絲裂黴素(mitomycin))；激素(例如黃體激素釋放激素激動劑；例如亮丙瑞林(leuprolidine)、戈舍瑞林(goserelin)、曲普瑞林(triptorelin)、組胺瑞林(histrelin)、比卡魯胺(bicalutamide)、氟他胺(flutamide)及/或尼魯米特(nilutamide))；抗體(例如阿昔單抗(Abciximab)、阿達木單抗(Adalimumab)、阿倫單抗(Alemtuzumab)、阿利珠單抗(Atlizumab)、巴利昔單抗(Basiliximab)、貝利木單抗(Belimumab)、貝伐珠單抗(Bevacizumab)、維布妥昔單抗(Bretuximab vedotin)、卡那單抗(Canakinumab)、西妥昔單抗(Cetuximab)、培塞利珠單抗(Ceertolizumab pegol)、達克珠單抗(Daclizumab)、地諾單抗(Denosumab)、依庫珠單抗(Eculizumab)、依法利珠單抗(Efalizumab)、吉妥珠單抗(Gemtuzumab)、戈利木單抗(Golimumab)、戈利木單抗、替伊莫單抗(Ibritumomab tiuxetan)、英夫利昔單抗(Infliximab)、伊匹單抗(Ipilimumab)、莫羅單抗(Muromonab)-CD3、那他珠單抗(Natalizumab)、奧法木單抗(Ofatumumab)、奧馬佐單抗(Omalizumab)、帕利珠單抗(Palivizumab)、帕尼單抗(Panitumuab)、雷珠單抗(Ranibizumab)、利妥昔單抗(Rituximab)、托珠單抗(Tocilizumab)、托西莫單抗(Tositumomab)及/或曲妥珠單抗(Trastuzumab))；抗血管生成劑；細胞介素；血栓劑；生長抑制劑；抗蠕蟲劑；及靶向選自由以下組成之群之免疫檢查點受體之免疫檢查點抑制劑：CTLA-4、PD-1、PD-L1、PD-1 - PD-L1、PD-1 - PD-L2、介白素-2 (IL-2)、吲哚胺2,3-二氧合酶(IDO)、IL-10、轉變生長因子-β (TGFβ)、T細胞免疫球蛋白及黏蛋白3 (TIM3或HAVCR2)、半乳糖凝集素9 - TIM3、磷脂醯絲胺酸- TIM3、淋巴球活化基因3蛋白(LAG3)、MHC II類- LAG3、4-1BB-4-1BB配體、OX40-OX40配體、GITR、GITR配體- GITR、CD27、CD70-CD27、TNFRSF25、TNFRSF25-TL1A、CD40L、CD40-CD40配體、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配體、B7-H3、B7-H4、VISTA、TMIGD2、HHLA2-TMIGD2、嗜乳脂蛋白(Butyrophilin) (包含BTNL2)、Siglec家族、TIGIT及PVR家族成員、KIR、ILT及LIR、NKG2D及NKG2A、MICA及MICB、CD244、CD28、CD86 - CD28、CD86 - CTLA、CD80 - CD28、CD39、CD73腺苷-CD39-CD73、CXCR4-CXCL12、磷脂醯絲胺酸、TIM3、磷脂醯絲胺酸- TIM3、SIRPA-CD47、VEGF、神經纖毛蛋白(Neuropilin)、CD160、CD30及CD155 (例如CTLA-4或PD1或PD-L1)。 121.如條款112至120中任一項之方法，其中該化合物係經腫瘤內投與。 122.一種治療癌症之方法，其包括向需要該治療之個體投與有效量之如條款1至103中任一項之化合物或如條款104之醫藥組合物。 123.如條款122之方法，其中該癌症係選自由以下組成之群：黑色素瘤、子宮頸癌、乳癌、卵巢癌、前列腺癌、睪丸癌、尿路上皮癌、膀胱癌、非小細胞肺癌、小細胞肺癌、肉瘤、結腸直腸腺癌、胃腸道基質腫瘤、胃食道癌、結腸直腸癌、胰臟癌、腎癌、肝細胞癌、惡性間皮瘤、白血病、淋巴瘤、骨髓發育不良症候群、多發性骨髓瘤、移行細胞癌、神經母細胞瘤、漿細胞贅瘤、維爾姆斯氏腫瘤或肝細胞癌。 124.如條款122或123之方法，其中該癌症係難治性癌症。 125.如條款122之方法，其中該化合物係與一或多種其他癌症療法組合投與。 126.如條款125之方法，其中該一或多種其他癌症療法包括手術、放射療法、化學療法、毒素療法、免疫療法、冷療法或基因療法或其組合。 127.如條款126之方法，其中化學療法包括投與一或多種其他化學治療劑。 128.如條款126之方法，其中該一或多種其他化學治療劑係選自烷基化劑(例如順鉑、卡鉑、雙氯乙基甲胺、環磷醯胺、氮芥苯丁酸、異環磷醯胺及/或奧沙利鉑)；抗代謝物(例如硫唑嘌呤及/或巰嘌呤)；類萜(例如長春花生物鹼及/或紫杉烷；例如長春新鹼、長春鹼、長春瑞濱及/或長春地辛、紫杉醇、太平洋紫杉醇及/或多西他賽)；拓撲異構酶(例如I型拓撲異構酶及/或2型拓撲異構酶；例如喜樹鹼,例如伊立替康及/或托泊替康；安吖啶、依託泊苷、磷酸依託泊苷及/或替尼泊苷)；細胞毒性抗生素(例如放線菌素、蒽環、多柔比星、柔紅黴素、戊柔比星、伊達比星、表柔比星、博來黴素、普卡黴素及/或絲裂黴素)；激素(例如黃體激素釋放激素激動劑；例如亮丙瑞林、戈舍瑞林、曲普瑞林、組胺瑞林、比卡魯胺、氟他胺及/或尼魯米特)；抗體(例如阿昔單抗、阿達木單抗、阿倫單抗、阿利珠單抗、巴利昔單抗、貝利木單抗、貝伐珠單抗、維布妥昔單抗、卡那單抗、西妥昔單抗、培塞利珠單抗、達克珠單抗、地諾單抗、依庫珠單抗、依法利珠單抗、吉妥珠單抗、戈利木單抗、戈利木單抗、替伊莫單抗、英夫利昔單抗、伊匹單抗、莫羅單抗-CD3、那他珠單抗、奧法木單抗、奧馬佐單抗、帕利珠單抗、帕尼單抗、雷珠單抗、利妥昔單抗、托珠單抗、托西莫單抗及/或曲妥珠單抗)；抗血管生成劑；細胞介素；血栓劑；生長抑制劑；抗蠕蟲劑；及靶向選自由以下組成之群之免疫檢查點受體之免疫檢查點抑制劑：CTLA-4、PD-1、PD-L1、PD-1 - PD-L1、PD-1 - PD-L2、介白素-2 (IL-2)、吲哚胺2,3-二氧合酶(IDO)、IL-10、轉變生長因子-β (TGFβ)、T細胞免疫球蛋白及黏蛋白3 (TIM3或HAVCR2)、半乳糖凝集素9 - TIM3、磷脂醯絲胺酸- TIM3、淋巴球活化基因3蛋白(LAG3)、MHC II類- LAG3、4-1BB-4-1BB配體、OX40-OX40配體、GITR、GITR配體- GITR、CD27、CD70-CD27、TNFRSF25、TNFRSF25-TL1A、CD40L、CD40-CD40配體、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配體、B7-H3、B7-H4、VISTA、TMIGD2、HHLA2-TMIGD2、嗜乳脂蛋白(包含BTNL2)、Siglec家族、TIGIT及PVR家族成員、KIR、ILT及LIR、NKG2D及NKG2A、MICA及MICB、CD244、CD28、CD86 - CD28、CD86 - CTLA、CD80 - CD28、CD39、CD73腺苷-CD39-CD73、CXCR4-CXCL12、磷脂醯絲胺酸、TIM3、磷脂醯絲胺酸- TIM3、SIRPA-CD47、VEGF、神經纖毛蛋白、CD160、CD30及CD155 (例如CTLA-4或PD1或PD-L1)。 129.如條款122至128中任一項之方法，其中該化合物係經腫瘤內投與。 130.一種誘導有需要之個體中之免疫反應之方法，該方法包括向該個體投與有效量之如條款1至103中任一項之化合物或如條款104之醫藥組合物。 131.如條款130之方法，其中該個體患有癌症。 132.如條款131之方法，其中該個體已經受及/或正經受及/或將經受一或多種癌症療法。 133.如條款131之方法，其中該癌症選自由以下組成之群：黑色素瘤、子宮頸癌、乳癌、卵巢癌、前列腺癌、睪丸癌、尿路上皮癌、膀胱癌、非小細胞肺癌、小細胞肺癌、肉瘤、結腸直腸腺癌、胃腸道基質腫瘤、胃食道癌、結腸直腸癌、胰臟癌、腎癌、肝細胞癌、惡性間皮瘤、白血病、淋巴瘤、骨髓發育不良症候群、多發性骨髓瘤、移行細胞癌、神經母細胞瘤、漿細胞贅瘤、維爾姆斯氏腫瘤或肝細胞癌。 134.如條款131至133中任一項之方法，其中該癌症係難治性癌症。 135.如條款130之方法，其中該免疫反應係先天性免疫反應。 136.如條款135之方法，其中該至少一種或多種癌症療法包括手術、放射療法、化學療法、毒素療法、免疫療法、冷療法或基因療法或其組合。 137.如條款136之方法，其中化學療法包括投與一或多種其他化學治療劑。 138.如條款137之方法，其中該一或多種其他化學治療劑係選自烷基化劑(例如順鉑、卡鉑、雙氯乙基甲胺、環磷醯胺、氮芥苯丁酸、異環磷醯胺及/或奧沙利鉑)；抗代謝物(例如硫唑嘌呤及/或巰嘌呤)；類萜(例如長春花生物鹼及/或紫杉烷；例如長春新鹼、長春鹼、長春瑞濱及/或長春地辛、紫杉醇、太平洋紫杉醇及/或多西他賽)；拓撲異構酶(例如I型拓撲異構酶及/或2型拓撲異構酶；例如喜樹鹼,例如伊立替康及/或托泊替康；安吖啶、依託泊苷、磷酸依託泊苷及/或替尼泊苷)；細胞毒性抗生素(例如放線菌素、蒽環、多柔比星、柔紅黴素、戊柔比星、伊達比星、表柔比星、博來黴素、普卡黴素及/或絲裂黴素)；激素(例如黃體激素釋放激素激動劑；例如亮丙瑞林、戈舍瑞林、曲普瑞林、組胺瑞林、比卡魯胺、氟他胺及/或尼魯米特)；抗體(例如阿昔單抗、阿達木單抗、阿倫單抗、阿利珠單抗、巴利昔單抗、貝利木單抗、貝伐珠單抗、維布妥昔單抗、卡那單抗、西妥昔單抗、培塞利珠單抗、達克珠單抗、地諾單抗、依庫珠單抗、依法利珠單抗、吉妥珠單抗、戈利木單抗、戈利木單抗、替伊莫單抗、英夫利昔單抗、伊匹單抗、莫羅單抗-CD3、那他珠單抗、奧法木單抗、奧馬佐單抗、帕利珠單抗、帕尼單抗、雷珠單抗、利妥昔單抗、托珠單抗、托西莫單抗及/或曲妥珠單抗)；抗血管生成劑；細胞介素；血栓劑；生長抑制劑；抗蠕蟲劑；及靶向選自由以下組成之群之免疫檢查點受體之免疫檢查點抑制劑：CTLA-4、PD-1、PD-L1、PD-1 - PD-L1、PD-1 - PD-L2、介白素-2 (IL-2)、吲哚胺2,3-二氧合酶(IDO)、IL-10、轉變生長因子-β (TGFβ)、T細胞免疫球蛋白及黏蛋白3 (TIM3或HAVCR2)、半乳糖凝集素9 - TIM3、磷脂醯絲胺酸- TIM3、淋巴球活化基因3蛋白(LAG3)、MHC II類- LAG3、4-1BB-4-1BB配體、OX40-OX40配體、GITR、GITR配體- GITR、CD27、CD70-CD27、TNFRSF25、TNFRSF25-TL1A、CD40L、CD40-CD40配體、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配體、B7-H3、B7-H4、VISTA、TMIGD2、HHLA2-TMIGD2、嗜乳脂蛋白(包含BTNL2)、Siglec家族、TIGIT及PVR家族成員、KIR、ILT及LIR、NKG2D及NKG2A、MICA及MICB、CD244、CD28、CD86 - CD28、CD86 - CTLA、CD80 - CD28、CD39、CD73腺苷-CD39-CD73、CXCR4-CXCL12、磷脂醯絲胺酸、TIM3、磷脂醯絲胺酸- TIM3、SIRPA-CD47、VEGF、神經纖毛蛋白、CD160、CD30及CD155 (例如CTLA-4或PD1或PD-L1)。 139.一種治療其中增加(例如過度)之STING信號傳導有助於疾病之病理學及/或症狀及/或進展之疾病之方法，其包括向需要該治療之個體投與有效量之如條款1至103中任一項之化合物或如條款104之醫藥組合物。 140.一種治療方法，其包括向患有其中增加(例如過度)之STING信號傳導有助於疾病之病理學及/或症狀及/或進展之疾病的個體投與有效量之如條款1至103中任一項之化合物或如條款104之醫藥組合物。 141.一種治療方法，其包括向個體投與如條款1至103中任一項之化合物或如條款104之醫藥組合物，其中該化合物或組合物係以有效治療其中增加(例如過度)之STING信號傳導有助於疾病之病理學及/或症狀及/或進展之疾病的量來投與，由此治療該疾病。 142.如條款139至141中任一項之方法，其中該疾病係癌症。 143.如條款142之方法，其中該癌症係選自由以下組成之群：黑色素瘤、子宮頸癌、乳癌、卵巢癌、前列腺癌、睪丸癌、尿路上皮癌、膀胱癌、非小細胞肺癌、小細胞肺癌、肉瘤、結腸直腸腺癌、胃腸道基質腫瘤、胃食道癌、結腸直腸癌、胰臟癌、腎癌、肝細胞癌、惡性間皮瘤、白血病、淋巴瘤、骨髓發育不良症候群、多發性骨髓瘤、移行細胞癌、神經母細胞瘤、漿細胞贅瘤、維爾姆斯氏腫瘤或肝細胞癌。 144.如條款142或143之方法，其中該癌症係難治性癌症。 145.如條款142至144中任一項之方法，其中該化合物係與一或多種其他癌症療法組合投與。 146.如條款145之方法，其中該一或多種其他癌症療法包括手術、放射療法、化學療法、毒素療法、免疫療法、冷療法或基因療法或其組合。 147.如條款146之方法，其中化學療法包括投與一或多種其他化學治療劑。 148.如條款147之方法，其中該一或多種其他化學治療劑係選自烷基化劑(例如順鉑、卡鉑、雙氯乙基甲胺、環磷醯胺、氮芥苯丁酸、異環磷醯胺及/或奧沙利鉑)；抗代謝物(例如硫唑嘌呤及/或巰嘌呤)；類萜(例如長春花生物鹼及/或紫杉烷；例如長春新鹼、長春鹼、長春瑞濱及/或長春地辛、紫杉醇、太平洋紫杉醇及/或多西他賽)；拓撲異構酶(例如I型拓撲異構酶及/或2型拓撲異構酶；例如喜樹鹼,例如伊立替康及/或托泊替康；安吖啶、依託泊苷、磷酸依託泊苷及/或替尼泊苷)；細胞毒性抗生素(例如放線菌素、蒽環、多柔比星、柔紅黴素、戊柔比星、伊達比星、表柔比星、博來黴素、普卡黴素及/或絲裂黴素)；激素(例如黃體激素釋放激素激動劑；例如亮丙瑞林、戈舍瑞林、曲普瑞林、組胺瑞林、比卡魯胺、氟他胺及/或尼魯米特)；抗體(例如阿昔單抗、阿達木單抗、阿倫單抗、阿利珠單抗、巴利昔單抗、貝利木單抗、貝伐珠單抗、維布妥昔單抗、卡那單抗、西妥昔單抗、培塞利珠單抗、達克珠單抗、地諾單抗、依庫珠單抗、依法利珠單抗、吉妥珠單抗、戈利木單抗、戈利木單抗、替伊莫單抗、英夫利昔單抗、伊匹單抗、莫羅單抗-CD3、那他珠單抗、奧法木單抗、奧馬佐單抗、帕利珠單抗、帕尼單抗、雷珠單抗、利妥昔單抗、托珠單抗、托西莫單抗及/或曲妥珠單抗)；抗血管生成劑；細胞介素；血栓劑；生長抑制劑；抗蠕蟲劑；及靶向選自由以下組成之群之免疫檢查點受體之免疫檢查點抑制劑：CTLA-4、PD-1、PD-L1、PD-1 - PD-L1、PD-1 - PD-L2、介白素-2 (IL-2)、吲哚胺2,3-二氧合酶(IDO)、IL-10、轉變生長因子-β (TGFβ)、T細胞免疫球蛋白及黏蛋白3 (TIM3或HAVCR2)、半乳糖凝集素9 - TIM3、磷脂醯絲胺酸- TIM3、淋巴球活化基因3蛋白(LAG3)、MHC II類- LAG3、4-1BB-4-1BB配體、OX40-OX40配體、GITR、GITR配體- GITR、CD27、CD70-CD27、TNFRSF25、TNFRSF25-TL1A、CD40L、CD40-CD40配體、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配體、B7-H3、B7-H4、VISTA、TMIGD2、HHLA2-TMIGD2、嗜乳脂蛋白(包含BTNL2)、Siglec家族、TIGIT及PVR家族成員、KIR、ILT及LIR、NKG2D及NKG2A、MICA及MICB、CD244、CD28、CD86 - CD28、CD86 - CTLA、CD80 - CD28、CD39、CD73腺苷-CD39-CD73、CXCR4-CXCL12、磷脂醯絲胺酸、TIM3、磷脂醯絲胺酸- TIM3、SIRPA-CD47、VEGF、神經纖毛蛋白、CD160、CD30及CD155 (例如CTLA-4或PD1或PD-L1)。 149.如條款139至148中任一項之方法，其中該化合物係經腫瘤內投與。 150.一種治療與STING相關之疾病、病症或病狀之方法，其包括向需要該治療之個體投與有效量之如條款1至103中任一項之化合物或如條款104之醫藥組合物。 151.如條款150之方法，其中該疾病、病症或病狀係選自I型干擾素病變、艾卡迪-古蒂雷斯症候群(AGS)、遺傳狼瘡形式、發炎相關病症及類風濕性關節炎。 152.如條款151之方法，其中該疾病、病症或病狀係I型干擾素病變(例如嬰兒期發作之STING相關血管病變(SAVI))。 153.如條款152之方法，其中該I型干擾素病變係嬰兒期發作之STING相關血管病變(SAVI))。 154.如條款151之方法，其中該疾病、病症或病狀係艾卡迪-古蒂雷斯症候群(AGS)。 155.如條款151之方法，其中該疾病、病症或病狀係遺傳狼瘡形式。 156.如條款151之方法，其中該疾病、病症或病狀係發炎相關病症。 157.如條款156之方法，其中該發炎相關病症係全身性紅斑狼瘡。 158.一種組合，其包括如條款1至103中任一項之化合物或其醫藥上可接受之鹽或互變異構體及一或多種治療活性劑。 159.如條款1至103中任一項之化合物或其醫藥上可接受之鹽或互變異構體或如條款104之醫藥組合物，其用作藥劑。 160.如條款1至103中任一項之化合物或其醫藥上可接受之鹽或互變異構體或如條款104之醫藥組合物，其用於治療藉由STING抑制來調節之疾病、病狀或病症。 161.如條款1至103中任一項之化合物或其醫藥上可接受之鹽或互變異構體或如條款104之醫藥組合物，其用於治療如條款105至157中任一項所提及之疾病。 162.一種如條款1至103中任一項之化合物或其醫藥上可接受之鹽或互變異構體或如條款104之醫藥組合物之用途，其用以製造用於治療如條款105至157中任一項所提及之疾病之藥劑。 163.如條款43之化合物，其中 環 B係選自由以下組成之群：伸異噁唑基、伸噁二唑基、伸噁唑基、伸噻唑基、伸異噻唑基或伸噻二唑基，其視情況經一個 R ^cB 取代。 164.如條款163之化合物，其中 環 B係

或

，其中之每一者視情況經一個 R ^cB 取代，其中 aa 係與 (L ^A) _a1 之連結點。 165.如條款43或163之化合物，其中 環 B係

或

，其中之每一者視情況經一個 R ^cB 取代，其中 aa 係與 (L ^A) _a1 之連結點。 166.如條款43或163之化合物，其中 環 B係

或

，其中之每一者視情況經一個 R ^cB 取代，其中 aa 係與 (L ^A) _a1 之連結點。 167.如條款43或163之化合物，其中 環 B係

或

，其視情況經一個 R ^cB 取代，其中 aa 係與 (L ^A) _a1 之連結點。 168.如條款43或163之化合物，其中 環 B係

或

，其中之每一者視情況經一個 R ^cB 取代，其中 aa 係與 (L ^A) _a1 之連結點。 169.如條款43或163之化合物，其中 環 B係

或

，其中之每一者視情況經一個 R ^cB 取代，其中 aa 係與 (L ^A) _a1 之連結點。 170.如條款68之化合物，其中 R ⁷ 係選自由以下組成之群： • C _4-5環烷基，其視情況經1-4個獨立地選自由 R ^c7 組成之群之取代基取代；及 • 具有5-6個環原子之雜環基，其中1-2個(例如一個)環原子係各自獨立地選自由N、N(H)、N( R ^d )、O及S(O) _0-2組成之群之雜原子，且其中雜環基視情況經1-4個獨立地選自由 R ^c7 組成之群之取代基取代。 171.如條款68之化合物，其中 R ⁷ 係下式之基團：

或

，其中 X ⁷ 係CH、C R ^c7 或N，例如CH或N。 172.如條款68之化合物，其中 R ⁷ 係下式之基團：

或

，其中 R ^d 獨立地選自由視情況經1-3個獨立選擇之 R ^a 取代之C _1-6烷基組成之群，其中m7為0或1。 173.如條款68之化合物，其中 R ⁷ 係選自由以下組成之群：四氫吡喃基、嗎啉基、5-氮雜螺[2.5]辛烷基或2-氮雜雙環[2.2.1]庚烷，其中之每一者視情況經1-2個 R ^c7 取代。舉例而言， R ⁷ 可為：

或

。 Numbered Clauses The compounds, compositions, methods, and other subject matter described herein are further described in the following numbered clauses: 1. A compound of formula I ,

Formula I or a pharmaceutically acceptable salt or tautomer thereof, wherein: Z , Y ¹ , Y ² and Y ³ are independently selected from the group consisting of C R ¹ , C(=O), N and NR ² ; X ¹ is selected from the group consisting of: O, S, N, NR ² and CR ¹ ; X ² is selected from the group consisting of: O, S, N, NR ⁴ and CR ⁵ ; each

is independently a single bond or a double bond, provided that a 5-membered ring system heteroaryl group including ^X1 and ^X2 , and a 6-membered ring system aryl or heteroaryl group including Z , ^Y1 , ^Y2 , and ^Y3 ; Each R ¹ is independently selected from the group consisting of: H; R ^c ; R ^g ; and -(L ¹ ) _{b 1} -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 heteroaryl group having 5 ring atoms, wherein 1-4 ring atoms are each independently selected from N, NH, N( A heteroatom of the group consisting of R ^d ), O and S; wherein the heteroaryl group of ring B is optionally substituted with 1-2 substituents independently selected from the group consisting of pendant oxy and R ^c , provided that the ring B is attached to the C(=O)N R ⁶ group through a ring carbon atom; each L ^A is independently selected from the group consisting of: C _1-3 alkylene optionally substituted with 1-2 R ^a1 ; -O-; -NH-; -N R ^d ; -S(O) _0-2 ; and C(O); a1 is 0, 1, or 2; ring C is selected from the group consisting of: • C _{3- 12} cycloalkylene or _C3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of pendant oxy, ^Rc and ^Rh ; • having 3 -12 ring-atoms heterocyclylene or heterocycloalkenyl, wherein 1-3 ring atoms are each independently selected from N, N(H), N( R ^d ), O and S(O) ₀ - a heteroatom of the group consisting of ₂ , and wherein the heterocyclylene or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: pendant oxy, R ^c and R ^h ; • Heteroaryl having 5-12 ring atoms, wherein 1-3 ring atoms are each independently selected from N, N(H), N( ^Rd ), O and S(O) _0-2 A heteroatom of the group consisting of, and wherein heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of: R ^c and R ^h ; and • C _6-10 aryl, which Optionally substituted with 1-4 substituents independently selected from the group consisting of: ^Rc and ^Rh ; ^R7 is selected from the group consisting of: ^Rg and -( ^L7 ) _b7 - ^Rg ; R ^a and R ^a1 are at each occurrence independently selected from the group consisting of: -OH; -halo; -N R ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; (=O)O(C _1-4 alkyl); -C(=O)(C _{1- 4} alkyl);-C(=O)OH;-CON R'R'' ;-S(O) _1-2N R'R'' ;-S(O) _1-2 ( _C1-4alkane and cyano; R ^c is at each occurrence independently selected from the group consisting of: halo; cyano; C _1-10 alkyl optionally substituted with 1-6 independently selected R ^a ; C _2-6 alkenyl; C _2-6 alkynyl; C _1-4 alkoxy; C _1-4 haloalkoxy; -S(O) _1-2 (C _1-4 alkyl); -S( O)(=NH)(C _1-4 alkyl); -N R ^e R ^f ; -OH; -S(O) _1-2 N R'R'' ; -C _1-4 thioalkoxy ;-NO ₂ ;-C(=O)(C _1-10 alkyl);-C(=O)O(C _1-4 alkyl);-C(=O)OH;-C(=O) N R'R'' ; and -SF ₅ ; R ^d at each occurrence is independently selected from the group consisting of: C _1-6 alkyl optionally substituted with 1-3 independently selected ^Ra ; - C(O)(C _1-4 alkyl); -C(O)O(C _1-4 alkyl); -CON R'R'' ; -S(O) _1-2 N R'R'' -S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; ^Re and R ^f at each occurrence are independently selected from the group consisting of: H ; C _1-6 alkyl, optionally substituted with 1-3 substituents each independently selected from the group consisting of NR'R'' , -OH and ^Ri ; -C(O)(C _{1- 4} alkyl);-C(O)O(C _1-4 alkyl);-CON R'R'' ;-S(O) _1-2N R'R'' ;-S(O) _{1- 2} (C _1-4 alkyl); -OH; and C _1-4 alkoxy; R ^g at each occurrence is independently selected from the group consisting of: • C _3-12 cycloalkyl or C _{3- 12} cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of pendant oxy, ^Rc , ^Rh , and -( ^Lg ) _bg - ^Rh ; • Heterocyclyl or heterocycloalkenyl having 3-12 ring atoms, wherein 1-3 ring atoms are each independently selected from N, N(H), N( ^Rd ), O and S(O) A heteroatom of the group consisting of _0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: pendant oxy, R ^c , R ^h and -( ^Lg ) _bg - ^Rh ; • Heteroaryl groups having 5-12 ring atoms, wherein 1-3 ring atoms are each independently selected from N, N(H), N( ^Rd ), O And the heteroatom of the group consisting of S(O) _0-2 , and wherein the heteroaryl group is independently selected from 1-4 according to the situation Substituted by substituents of the group consisting of: R ^c , R ^h and -( L ^g ) _bg -R ^h ; and • C _6-10 aryl, optionally 1-4 independently selected from the group consisting of Substituent substitutions of the group: R ^c , R ^h and -( L ^g ) _bg -R ^h ; R ^h at each occurrence is independently selected from the group consisting of: • C _{3-12cycloalkyl} or C _{3- 12} cycloalkenyl, each of which is optionally substituted with 1-4 R ⁱ ; • a heterocyclyl or heterocycloalkenyl having 3-12 ring atoms, wherein 1-3 ring atoms are each independently A heteroatom selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 , and wherein heterocyclyl or heterocycloalkenyl optionally has 1-4 R ⁱ Substituted; Heteroaryl having 5-12 ring atoms, wherein 1-3 ring atoms are each independently selected from N, N(H), N( ^Rd ), O and S(O) _0-2 Heteroatoms of the group consisting of, and wherein heteroaryl is optionally substituted with 1-4 R ⁱ ; and • C _6-10 aryl, optionally substituted with 1-4 R ⁱ ; R ⁱ in each occurrence are 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; L ¹ , L ² , L ⁷ and L ^g are at each occurrence selected from the group consisting of -O-, -NH-, -NR ^d , -S(O) _0-2 , C(O) and optionally via 1- 3 R ^a substituted C _1-3 alkylene; b1 , b2 , b7 and bg are each independently 1, 2 or 3; and R' and R'' are independently selected at each occurrence from the group consisting of Groups: H; -OH; and C _1-4 alkyl. 2. The compound of clause 1, wherein each of Z , ^Y1 , ^Y2 and ^Y3 is independently N or ^CR1 . 3. The compound of clause 1 or 2, wherein the compound is a compound of formula ( Ia ):

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. The compound of clause 1 or 2, wherein 1-2 of Z , ^Y1 , ^Y2 , and ^Y3 (eg, 1) are N; and the remainder of each of Z , ^Y1 , ^Y2 , and ^Y3 which is an independently selected C R ¹ . 5. The compound of any one of clauses 1 to 2 or 4, wherein the compound is selected from the group consisting of compounds of the following formulae:

or a pharmaceutically acceptable salt thereof, wherein: R ^1a , R ^1b , R ^1c and R ^1d are each independently selected R ¹ . 6. The compound of any one of clauses 1 to 5, wherein ^X1 is ^NR2 . 7. A compound according to any of clauses 1 to 6, wherein ^X1 is NH. 8. The compound of any one of clauses 1 to 7, wherein ^X2 is ^CR5 . 9. The compound of any one of clauses 1 to 8, wherein ^X2 is CH. 10. The compound of any one of clauses 1 to 5, wherein ^X1 is ^NR2 ; and ^X2 is ^CR5 . 11. The compound of any one of clauses 1 to 5 or 10, wherein ^X1 is NH; and ^X2 is CH. 12. The compound of clause 1, wherein the compound is a compound of formula ( Ia-1 ):

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 compound of clause 1, wherein the compound is selected from the group consisting of compounds of the following formulae:

or a pharmaceutically acceptable salt thereof, wherein: R ^1a , R ^1b , R ^1c and R ^1d are each independently selected R ¹ . 14. The compound of clause 12 or 13, wherein ^R2 is H. 15. The compound of any one of clauses 12 to 14, wherein ^R5 is H. 16. The compound of any one of clauses 1 to 15, wherein each ^R1 is H. 17. The compound of any one of clauses 1 to 15, wherein 1-2 R ¹ are independently selected from the group consisting of R ^c1 and R ^g1 ; and each remaining R ¹ is H, wherein R ^c1 is independently selected R ^c ; and R ^g1 is an independently selected R ^g . 18. The compound of clause 17, wherein ^R1 is independently selected from the group consisting of ^Rc1 and ^Rg1 on both occurrences; and each remaining ^R1 is H. 19. The compound of clause 17 or 18, wherein ^R1 is an independently selected ^Rc1 on both occurrences; and each remaining ^R1 is H. 20. The compound of clause 17, wherein ^R1 is selected from the group consisting of ^Rc1 and ^Rg1 at one occurrence; and each remaining ^R1 is H. 21. The compound of clause 17 or 20, wherein at one occurrence ^R1 is ^Rc1 ; and each remaining ^R1 is H. 22. The compound of clause 17 or 20, wherein ^R1 is ^Rg1 in one occurrence; and each remaining ^R1 is H. 23. The compound of any one of clauses 17 to 22, wherein each R ^c1 is an independently selected halo group, eg -F, -Cl or -Br. 24. The compound of clause 23, wherein each R ^c1 is independently -F or -Cl, eg -F. 25. The compound of any one of clauses 17 to 24, wherein each R ^g1 is independently selected from the group consisting of: Heteroaryl having 5-10 ring atoms, wherein 1-3 ring atoms are each independently Heteroatoms selected from the group consisting of N, N(H), N( ^Rd ), O, and S, and wherein the heteroaryl group is optionally substituted with 1-4 substituents independently selected from the group consisting of : R ^c , R ^h and -( L ^g ) _bg -R ^h ; and C _6-10 aryl, optionally substituted with 1-4 substituents independently selected from the group consisting of: R ^c , R ^h and -( L ^g ) _bg -R ^h . 26. The compound of clause 25, wherein each R ^g1 is independently selected from the group consisting of: Heteroaryl having 5-6 ring atoms, wherein 1-3 ring atoms are each independently selected from N, N Heteroatoms of the group consisting of (H), N( R ^d ), O, and S, and wherein heteroaryl is optionally substituted with 1-4 R ^C _; and C aryl, optionally substituted with 1-4 R ^C substituted. 27. The compound of clause 25 or 26, wherein each R ^g1 is independently a heteroaryl group having 5 ring atoms, wherein 1-3 ring atoms are each independently selected from N, N(H), N( A heteroatom of the group consisting of R ^d ), O and S, and wherein the heteroaryl is optionally substituted with 1-4 R ^c . 28. The compound of clause 27, wherein each R ^g1 is optionally pyrazolyl substituted with 1-2 R ^c , such as 1-2 independently selected optionally through 1-6 independently selected R ^a substituted (eg unsubstituted) C _1-6 (eg C _1-3 ) alkyl. 29. The compound of any of clauses 3, 5 or 12 to 13, wherein ^R1a is H. 30. The compound of any one of clauses 3, 5, 12 to 13 or 29, wherein R ^1b is H. 31. The compound of any one of clauses 3, 5, 12 to 13 or 29, wherein R ^1b is halo, eg -F or -Cl (eg -F). 32. The compound of any one of clauses 3, 5, 12 to 13 or 29, wherein R ^1b is a heteroaryl group having 5 ring atoms, wherein 1-3 ring atoms are each independently selected from N, N A heteroatom of the group consisting of (H), N( ^Rd ), O, and S, and wherein the heteroaryl group is optionally substituted with 1-2 ^Rc . 33. The compound of clause 32, wherein R ^1b is pyrazolyl optionally substituted with 1-2 R ^c , for example, each R ^c is an independently selected optionally 1-6 independently selected R ^a Substituted (eg, unsubstituted) C _1-6 (eg C _1-3 ) alkyl. 34. The compound of any one of clauses 3, 5, 12 to 13 or 29 to 33, wherein R ^1c is H. 35. The compound of any one of clauses 3, 5, 12 to 13 or 29 to 33, wherein R ^1c is halo, eg -F or -Cl (eg -F). 36. The compound of any one of clauses 3, 5, 12 to 13 or 29 to 35, wherein R ^1d is H. 37. The compound of any one of clauses 3, 5, 12 to 13 or 29 to 35, wherein R ^1d is halo, eg -F or -Cl (eg -F). 38. The compound of any one of clauses 3, 5, or 12 to 13, 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 . 39. The compound of any one of clauses 3, 5, or 12 to 13, wherein 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 Halogen, such as -F or -Cl, such as -F. 40. The compound of any one of clauses 3, 5 or 12 to 13, wherein R ^1a and R ^1d are H; R ^1c is halo or H, such as -F, -Cl or H; and R ^1b has 5 A heteroaryl group of 1 ring atoms, wherein 1-3 ring atoms are each independently selected from the group consisting of N, N(H), N( ^Rd ), O, and S, and wherein the heteroaryl group Optionally substituted with 1-4 ^Rcs . 41. The compound of any one of clauses 1 to 40, wherein ^R6 is H. 42. The compound of any one of clauses 1 to 41, wherein Ring B is a heteroaryl group having 5 ring atoms, wherein 1-3 ring atoms are each independently selected from N, NH, O, and S. A heteroatom of the group of wherein the heteroaryl of Ring B is optionally substituted with 1-2 ^RcB ; and each ^RcB is an independently selected ^Rc . 43. The compound of any one of clauses 1 to 42, wherein Ring B is a heteroaryl group having 5 ring atoms, wherein 2-3 ring atoms are each independently selected from N, NH, N( R ^d ), O, and S (e.g., N and NH) heteroatoms of the group consisting of, wherein the heteroaryl of ring B is optionally substituted with 1-2 ^RcB ; and each ^RcB is an independently selected ^Rc . 44. The compound of clause 43, wherein Ring B is selected from the group consisting of: triazolyl, triazolyl, or triazolyl (e.g., 1,2,3-triazolyl), optionally via an R ^cB substituted. 45. The compound of clause 44, wherein Ring B is optionally substituted with one R ^cB

, where aa is the junction with (L ^A ) _a1 . 46. The compound of clause 44, wherein Ring B is optionally substituted with one R ^cB

, where aa is the junction with (L ^A ) _a1 . 47. The compound of clause 44, wherein Ring B is optionally substituted with one R ^cB

, where aa is the junction with (L ^A ) _a1 . 48. The compound of clause 44, wherein Ring B is

or

, each of which is optionally substituted with an R ^cB , where aa is the point of attachment to (L ^A ) _a1 . 49. The compound of any one of clauses 42 to 48 or 163 to 169, wherein each R ^cB is independently halo or optionally C _1-3 alkyl, optionally 1-3 independently selected R ^a (eg, 1-3 independently selected halo groups) are substituted. 50. The compound of any one of clauses 1 to 49 or 163 to 169, wherein a1 is 0. 51. The compound of any one of clauses 1 to 49 or 163 to 169, wherein a1 is 1. 52. The compound of any one of clauses 1 to 49, 51 or 163 to 169, wherein L ^A is C _1-3 alkylene optionally substituted with 1-2 R ^a1 . 53. The compound of clause 52, wherein ^LA is _CH2 or CH(Me), eg _CH2 . 54. The compound of any one of clauses 1 to 53 or 163 to 169, wherein Ring C is selected from the group consisting of: • Heteroaryl having 5-10 ring atoms, of which 1-3 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 , and wherein heteroaryl is optionally represented by 1-4 independently substituted with a substituent selected from the group consisting of R ^cC and R ^hC ; and • C _6-10 aryl, optionally substituted with 1-4 substituents independently selected from the group consisting of R ^cC and R ^hC , wherein each R ^cC is an independently selected R ^c ; and each R ^hC is an independently selected R ^h . 55. The compound of any one of clauses 54 or 163 to 169, wherein Ring C is selected from the group consisting of: • Heteroaryl having 5-6 (for example 6) ring atoms, wherein 1-3 ( For example 1-2) ring atoms are each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 heteroatoms, and wherein heteroaryl is regarded as substituted with 1-4 substituents independently selected from the group consisting of ^RcC ; and • _C6 aryl, optionally substituted with 1-4 substituents independently selected from the group consisting of ^RcC . 56. The compound of any one of clauses 54, 55, or 163 to 169, wherein Ring C is selected from the group consisting of: • Pyridinyl, optionally independently selected from 1-3 (eg 1 ) Substituent substitution from the group consisting of ^RcC ; and • _C6aryl , optionally substituted with 1-4 (eg, 1-2) substituents independently selected from the group consisting of ^RcC . 57. The compound of any one of clauses 54 to 56 or 163 to 169, wherein Ring C is a group of the formula:

, where each 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 point of attachment to R ⁷ . 58. The compound of any one of clauses 57 or 163 to 169, wherein ^Q2 is CH. 59. The compound of any one of clauses 57, 58 or 163 to 169, wherein ^Q3 is CH. 60. The compound of any one of clauses 57 to 59 or 163 to 169, wherein ^Q4 is N. 61. The compound of any one of clauses 57 to 60 or 163 to 169, wherein ^Q1 is CH. 62. The compound of any one of clauses 57 to 60 or 163 to 169, wherein ^Q1 is ^CRcC . 63. The compound of any one of clauses 57 or 163 to 169, wherein Ring C is

or

,E.g

. 64. The compound of any one of clauses 54 to 63 or 163 to 169, wherein each R ^cC is independently selected from the group consisting of - halo and C _1-6 (eg C _1-3 ) alkyl, The alkyl is optionally substituted with 1-6 independently selected ^Ra (eg 1-6 independently selected halo, eg -F). 65. The compound of any one of clauses 54 to 64 or 163 to 169, wherein each ^RcC is independently halo, eg -Cl or -F, eg -F. 66. The compound of any one of clauses 1 to 65 or 170 to 173, wherein ^R7 is ^Rg . 67. The compound of any one of clauses 1 to 66 or 170 to 173, wherein R ⁷ is selected from the group consisting of: • C _3-12 cycloalkyl, which is independently selected from 1-4 as appropriate Substituent substitution from the group consisting of: pendant oxy, R ^c7 , R ^h7 and -( L ^g ) _bg -R ^h7 ; and • Heterocyclyl having 4-12 ring atoms, of which 1-3 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N( R ^d ), O, and S(O) _0-2 , and wherein heterocyclyl is independently selected from 1-4 as appropriate Substituent substitution of the group consisting of free pendant oxy, R ^c7 , R ^h7 and -( L ^g ) _bg -R ^h7 , wherein each R ^c7 is an independently selected R ^c ; and R ^h7 is an independently selected R ^h . 68. The compound of any one of clauses 67 or 170 to 173, wherein R ⁷ is selected from the group consisting of: • C _4-8 cycloalkyl, optionally independently selected from pendant oxygen through 1-4 and • ^Heterocyclyl having 4-8 ring atoms, ^wherein 1-3 ring atoms are each independently selected from N, N(H), N ( R ^d ), O, and S(O) _0-2 of the group consisting of heteroatoms, and wherein the heterocyclyl group is optionally substituted with 1-4 substituents independently selected from the group consisting of: pendant oxy, R ^c7 and R ^h7 . 69. The compound of any one of clauses 68 or 170 to 173, wherein R ⁷ is selected from the group consisting of: • C ₆ cycloalkyl, optionally independently selected from the group consisting of ^R c 7 through 1-4 Substituent substitution of groups; and • Heterocyclyl having 6 ring atoms, wherein 1-2 (eg, one) ring atoms are each independently selected from N, N(H), N( ^Rd ), O, and A heteroatom of the group consisting of S(O) _0-2 , and wherein the heterocyclyl group is optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c7 . 70. The compound of any one of clauses 69 or 170 to 173, wherein R ⁷ is a group of the formula:

, wherein X ⁷ is CH, ^{CR c7} or N, such as CH or N. 71. The compound of any of clauses 69, 70 or 170 to 173, wherein two ^Rc7 groups are present. 72. The compound of any one of clauses 1 to 71 or 170 to 173, wherein R ⁷ is a group of the formula:

, where X ⁷ is N or CH; and each R ^c7 is an independently selected R ^c . 73. The compound of any one of clauses 67 to 72 or 170 to 173, wherein each R ^c7 is an independently selected halo group or optionally through 1-6 R ^a (such as 1-6 independently selected halo groups ) substituted C _1-3 alkyl. 74. The compound of any one of clauses 67 to 73 or 170 to 173, wherein each R ^c7 is independently halo, eg -F. 75. The compound of any one of clauses 1 to 74 or 170 to 173, wherein R ⁷ is

, where X ⁷ is N or CH. 76. The compound of clause 1, wherein the compound is a compound of formula (I-a1-1) :

Formula (I-a1-1) or a pharmaceutically acceptable salt thereof, wherein: each of R ^1a , R ^1b , R ^1c and R ^1d is an 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 Groups: N, CH, and C R ^cC ; R ^cB and R ^cC are independently selected R ^c at each occurrence; and each

is independently a single bond or a double bond, provided that the ring comprising B ¹ -B ⁴ is a heteroaryl group. 77. The compound of clause 76, wherein ^R1a and ^R1d are H; and ^R1b and ^R1c are independently H or halo, eg, halo (eg -F or -Cl, eg -F). 78. The compound of clause 76, wherein each of R ^1a , R ^1b , R ^1c and R ^1d is H. 79. The compound of clause 76, wherein 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 group having 5 ring atoms, wherein 1 - 3 ring atoms are each independently selected from the group consisting of N, N(H), N( ^Rd ), O, and S heteroatoms, and wherein the heteroaryl is optionally 1-4 independently selected Substituent substitution of the group consisting of free R ^c . 80. The compound of any one of clauses 76 to 79, wherein ^R2 is H. 81. The compound of any one of clauses 76 to 80, wherein ^R5 is H. 82. The compound of any one of clauses 76 to 81, wherein ^R6 is H. 83. The compound of any one of clauses 76 to 82, wherein ^R2 is H; ^R5 is H; and ^R6 is H. 84. The compound of any one of clauses 76 to 83, wherein ^B4 is N; ^B1 is N; ^B3 is CH; and ^B2 is CH. 85. The compound of any one of clauses 76 to 83, wherein ^B4 is N; ^B1 is N; ^B3 is CH; and ^B2 is N. 86. The compound of any one of clauses 76 to 83, wherein ^B4 is N; ^B1 is N; ^B3 is CH; and ^B2 is ^CRcB . 87. The compound of any one of clauses 76 to 83, wherein ^B4 is N; ^B1 is CH; ^B3 is CH; and ^B2 is N. 88. The compound of any one of clauses 76 to 83, wherein ^B4 is N; ^B1 is CH; ^B3 is N; and ^B2 is CH. 89. The compound of any one of clauses 76 to 88, wherein a1 is zero. 90. The compound of any one of clauses 76 to 88, wherein a1 is 1 . 91. The compound of any one of clauses 76 to 88 or 90, wherein ^LA is _CH2 or CH(Me). 92. The compound of any one of clauses 76 to 91, wherein ^Q1 and ^Q3 are CH. 93. The compound of any one of clauses 76 to 92, wherein ^Q4 is N; and ^Q2 is CH or ^CRcC , eg ^CRcC . 94. The compound of any one of clauses 76 to 93, comprising the ring system of Q ¹ -Q ⁴ :

, where bb is the junction with R ⁷ . 95. The compound of any one of clauses 76 to 94, wherein ^RcC is halo, eg -F or -Cl, eg -F. 96. The compound of any one of clauses 76 to 95, wherein R ⁷ is selected from the group consisting of: • C ₆ cycloalkyl, optionally 1-4 independently selected from the group consisting of R ^c7 Substituent substitution; and • Heterocyclyl having 6 ring atoms, wherein 1-2 (eg, one) ring atoms are each independently selected from N, N(H), N( ^Rd ), O, and S( O) a heteroatom of the group consisting of _0-2 , and wherein the heterocyclyl group is optionally substituted with 1-4 substituents independently selected from the group consisting of ^Rc7 , wherein each ^Rc7 is an independently selected ^Rc . 97. The compound of clause 96, wherein R ⁷ is a group of the formula:

, wherein X ⁷ is CH, C R ⁷ or N, such as CH or N. 98. The compound of clause 96 or 97, wherein two ^Rc7 groups are present. 99. The compound of any one of clauses 76 to 98, wherein R ⁷ is a group of the formula:

, where X ⁷ is N or CH; and each R ^c7 is an independently selected R ^c . 100. The compound of any one of clauses 96 to 99, wherein each R ^c7 is an independently selected halo group or a C optionally substituted with 1-6 R ^a (such as 1-6 independently selected halo groups) _1-3 alkyl. 101. The compound of any one of clauses 96 to 100, wherein each R ^c7 is independently halo, eg -F. 102. The compound of any one of clauses 76 to 101, wherein R ⁷ is

, where X ⁷ is N or CH, for example

or

. 103. The compound of clause 1, wherein the compound is selected from the group consisting of a compound described in Table C1 or a pharmaceutically acceptable salt thereof. 104. A pharmaceutical composition comprising a compound of clauses 1 to 103 and one or more pharmaceutically acceptable excipients. 105. A method of inhibiting the activity of STING, the method comprising contacting STING with a compound of any one of clauses 1 to 103, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of clause 104. 106. The method of clause 105, wherein the inhibiting comprises antagonizing STING. 107. The method of any one of clauses 105 to 106, which is performed in vitro. 108. The method of clause 107, wherein the method comprises contacting a sample comprising one or more cells comprising STING with the compound. 109. The method of clause 107 or 108, wherein the one or more cells are one or more cancer cells. 110. The method of clause 108 or 109, wherein the sample further comprises one or more cancer cells, wherein the cancer is selected from the group consisting of: melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer , urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular carcinoma, malignant Mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasia, Wilms' tumor, or hepatocellular carcinoma. 111. The method of clause 105 or 106, which is performed in vivo. 112. The method of clause 111, wherein the method comprises administering the compound to an individual having a disease in which increased (eg, excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease. 113. The method of clause 112, wherein the system is human. 114. The method of clause 113, wherein the disease is cancer. 115. The method of clause 114, wherein the cancer is selected from the group consisting of: melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, Small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, Multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms' tumor, or hepatocellular carcinoma. 116. The method of clause 114 or 115, wherein the cancer is a refractory cancer. 117. The method of clause 112, wherein the compound is administered in combination with one or more other cancer therapies. 118. The method of clause 117, wherein the one or more other cancer therapies comprises surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cold therapy, or gene therapy, or a combination thereof. 119. The method of clause 118, wherein the chemotherapy comprises administration of one or more other chemotherapeutic agents. 120. The method of clause 119, wherein the one or more other chemotherapeutic agents are selected from alkylating agents (eg, cisplatin, carboplatin, mechlorethamine, cyclophosphine) cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); antimetabolites (eg azathioprine and/or sulfhydryl) mercaptopurine); terpenoids (e.g. vinca alkaloids and/or taxanes; e.g. Vincristine, Vinblastine, Vinorelbine and/or Vindesine (Vindesine), Taxol (Taxol), Paclitaxel (Paclitaxel) and/or Docetaxel (Docetaxel); topoisomerase (eg type I topoisomerase and/or type 2 topoisomerase; Camptothecins such as irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide ( teniposide); cytotoxic antibiotics (eg actinomycin, anthracycline, doxorubicin, daunorubicin, valrubicin, idarubicin, Epirubicin, bleomycin, plicamycin, and/or mitomycin); hormones (eg, LH agonists; eg, leuprolide (leuprolidine), goserelin (goserelin), triptorelin (triptorelin), histrelin (histrelin), bicalutamide (bicalutamide), flutamide (flutamide) and/or nilutamide ( nilutamide); antibodies (e.g. Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Beli Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, efalizumab Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipil Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab , Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab, and/or Trastuzumab (Trastuzumab); anti-angiogenic agents; interferons; thrombotic agents; growth inhibitors; anti-helminths; and immune checkpoint inhibitors targeting immune checkpoint receptors selected from the group consisting of: CTLA- 4. PD-1, PD-L1, PD-1 - PD-L1, PD-1 - PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO) ), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9 - TIM3, phosphatidylserine - TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II - LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand - GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 Ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligands, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilin (including BTNL2), Siglec family, TIGIT and PVR family 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, phospholipid filaments amino acids, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30 and CD155 (eg CTLA-4 or PD1 or PD-L1). 121. The method of any one of clauses 112 to 120, wherein the compound is administered intratumorally. 122. A method of treating cancer comprising administering to an individual in need of such treatment an effective amount of a compound of any one of clauses 1 to 103 or a pharmaceutical composition of clause 104. 123. The method of clause 122, wherein the cancer is selected from the group consisting of: melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, Small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, Multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms' tumor, or hepatocellular carcinoma. 124. The method of clause 122 or 123, wherein the cancer is a refractory cancer. 125. The method of clause 122, wherein the compound is administered in combination with one or more other cancer therapies. 126. The method of clause 125, wherein the one or more other cancer therapies comprises surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cold therapy or gene therapy or a combination thereof. 127. The method of clause 126, wherein the chemotherapy comprises administration of one or more other chemotherapeutic agents. 128. The method of clause 126, wherein the one or more other chemotherapeutic agents are selected from alkylating agents (eg, cisplatin, carboplatin, diclofenac, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); antimetabolites (eg, azathioprine and/or mercaptopurine); terpenoids (eg, vinca alkaloids and/or taxanes; eg, vincristine, vinca base, vinorelbine and/or vindesine, paclitaxel, paclitaxel and/or docetaxel); topoisomerases (e.g. topoisomerase type I and/or topoisomerase type 2; e.g. Camptotheca Bases, such as irinotecan and/or topotecan; amacridine, etoposide, etoposide phosphate and/or teniposide); cytotoxic antibiotics (e.g. actinomycin, anthracycline, doxorubicin) star, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, prucamycin, and/or mitomycin); hormones (e.g., luteinizing hormone-releasing hormone agonists; e.g. leuprolide, goserelin, triptorelin, histaminerelin, bicalutamide, flutamide, and/or nilutamide); antibodies (eg, abciximab, adalimumab, Alemtuzumab, Alemtuzumab, Basiliximab, Belimumab, Bevacizumab, Velbutuximab, Canakinumab, Cetuximab, Perselizub Monoclonal antibody, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, golimumab, tiimumab, Infliximab, ipilimumab, muromumab-CD3, natalizumab, ofatumumab, omazumab, palivizumab, panitumumab, ranibizumab , rituximab, tocilizumab, tositumumab, and/or trastuzumab); anti-angiogenic agents; interferons; thrombotic agents; growth inhibitors; anthelmintics; and targets Immune checkpoint inhibitors to immune checkpoint receptors selected from the group consisting of: CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin Indole-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-beta (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 - C D244, CD244, ICOS, ICOS-ICOS ligands, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, butyrophilin (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 Amino acids - TIM3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30 and CD155 (eg CTLA-4 or PD1 or PD-L1). 129. The method of any one of clauses 122 to 128, wherein the compound is administered intratumorally. 130. A method of inducing an immune response in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound of any one of clauses 1 to 103 or a pharmaceutical composition of clause 104. 131. The method of clause 130, wherein the individual has cancer. 132. The method of clause 131, wherein the individual has and/or is undergoing and/or will undergo one or more cancer therapies. 133. The method of clause 131, wherein the cancer is selected from the group consisting of: melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small Cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasia, Wilms' tumor, or hepatocellular carcinoma. 134. The method of any one of clauses 131 to 133, wherein the cancer is a refractory cancer. 135. The method of clause 130, wherein the immune response is an innate immune response. 136. The method of clause 135, wherein the at least one or more cancer therapies comprises surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cold therapy or gene therapy or a combination thereof. 137. The method of clause 136, wherein the chemotherapy comprises administration of one or more other chemotherapeutic agents. 138. The method of clause 137, wherein the one or more other chemotherapeutic agents are selected from alkylating agents (eg, cisplatin, carboplatin, diclofenac, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); antimetabolites (eg, azathioprine and/or mercaptopurine); terpenoids (eg, vinca alkaloids and/or taxanes; eg, vincristine, vinca base, vinorelbine and/or vindesine, paclitaxel, paclitaxel and/or docetaxel); topoisomerases (e.g. topoisomerase type I and/or topoisomerase type 2; e.g. Camptotheca Bases, such as irinotecan and/or topotecan; amacridine, etoposide, etoposide phosphate and/or teniposide); cytotoxic antibiotics (e.g. actinomycin, anthracycline, doxorubicin) star, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, prucamycin, and/or mitomycin); hormones (e.g., luteinizing hormone-releasing hormone agonists; e.g. leuprolide, goserelin, triptorelin, histaminerelin, bicalutamide, flutamide, and/or nilutamide); antibodies (eg, abciximab, adalimumab, Alemtuzumab, Alemtuzumab, Basiliximab, Belimumab, Bevacizumab, Velbutuximab, Canakinumab, Cetuximab, Perselizub Monoclonal antibody, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, golimumab, tiimumab, Infliximab, ipilimumab, muromumab-CD3, natalizumab, ofatumumab, omazumab, palivizumab, panitumumab, ranibizumab , rituximab, tocilizumab, tositumumab, and/or trastuzumab); anti-angiogenic agents; interferons; thrombotic agents; growth inhibitors; anthelmintics; and targets Immune checkpoint inhibitors to immune checkpoint receptors selected from the group consisting of: CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin Indole-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-beta (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 - C D244, CD244, ICOS, ICOS-ICOS ligands, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, butyrophilin (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 Amino acids - TIM3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30 and CD155 (eg CTLA-4 or PD1 or PD-L1). 139. A method of treating a disease in which increased (eg, excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease, comprising administering to an individual in need of such treatment an effective amount of as clause 1 The compound of any one of to 103 or the pharmaceutical composition of clause 104. 140. A method of treatment comprising administering an effective amount of as clause 1 to 103 to an individual suffering from a disease in which increased (for example excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease The compound of any one or the pharmaceutical composition of clause 104. 141. A method of treatment comprising administering to an individual a compound as in any one of clauses 1 to 103 or a pharmaceutical composition as in clause 104, wherein the compound or composition is effective for the treatment of increased (eg excessive) STING therein Signaling is administered in an amount that contributes to the pathology and/or symptoms and/or progression of the disease, thereby treating the disease. 142. The method of any one of clauses 139 to 141, wherein the disease is cancer. 143. The method of clause 142, wherein the cancer is selected from the group consisting of: melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, Small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, Multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms' tumor, or hepatocellular carcinoma. 144. The method of clause 142 or 143, wherein the cancer is a refractory cancer. 145. The method of any one of clauses 142 to 144, wherein the compound is administered in combination with one or more other cancer therapies. 146. The method of clause 145, wherein the one or more other cancer therapies comprises surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cold therapy or gene therapy or a combination thereof. 147. The method of clause 146, wherein the chemotherapy comprises administration of one or more other chemotherapeutic agents. 148. The method of clause 147, wherein the one or more other chemotherapeutic agents are selected from alkylating agents (eg, cisplatin, carboplatin, diclofenac, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); antimetabolites (eg, azathioprine and/or mercaptopurine); terpenoids (eg, vinca alkaloids and/or taxanes; eg, vincristine, vinca base, vinorelbine and/or vindesine, paclitaxel, paclitaxel and/or docetaxel); topoisomerases (e.g. topoisomerase type I and/or topoisomerase type 2; e.g. Camptotheca Bases, such as irinotecan and/or topotecan; amacridine, etoposide, etoposide phosphate and/or teniposide); cytotoxic antibiotics (e.g. actinomycin, anthracycline, doxorubicin) star, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, prucamycin, and/or mitomycin); hormones (e.g., luteinizing hormone-releasing hormone agonists; e.g. leuprolide, goserelin, triptorelin, histaminerelin, bicalutamide, flutamide, and/or nilutamide); antibodies (eg, abciximab, adalimumab, Alemtuzumab, Alemtuzumab, Basiliximab, Belimumab, Bevacizumab, Velbutuximab, Canakinumab, Cetuximab, Perselizub Monoclonal antibody, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, golimumab, tiimumab, Infliximab, ipilimumab, muromumab-CD3, natalizumab, ofatumumab, omazumab, palivizumab, panitumumab, ranibizumab , rituximab, tocilizumab, tositumumab, and/or trastuzumab); anti-angiogenic agents; interferons; thrombotic agents; growth inhibitors; anthelmintics; and targets Immune checkpoint inhibitors to immune checkpoint receptors selected from the group consisting of: CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin Indole-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-beta (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 - C D244, CD244, ICOS, ICOS-ICOS ligands, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, butyrophilin (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 Amino acids - TIM3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30 and CD155 (eg CTLA-4 or PD1 or PD-L1). 149. The method of any one of clauses 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 an individual in need of such treatment an effective amount of a compound of any one of clauses 1 to 103 or a pharmaceutical composition of clause 104. 151. The method of clause 150, wherein the disease, disorder or condition is selected from the group consisting of Type I interferonopathy, Icardi-Gutierrez Syndrome (AGS), hereditary forms of lupus, inflammation-related disorders and rheumatoid joints inflammation. 152. The method of clause 151, wherein the disease, disorder or condition is type I interferonopathy (eg, STING-associated vasculopathy of infancy (SAVI)). 153. The method of clause 152, wherein the type I interferon lesion is infant-onset STING-associated vasculopathy (SAVI)). 154. The method of clause 151, wherein the disease, disorder or condition is Icardi-Gutierrez Syndrome (AGS). 155. The method of clause 151, wherein the disease, disorder or condition is an inherited form of lupus. 156. The method of clause 151, wherein the disease, disorder or condition is an inflammation-related disorder. 157. The method of clause 156, wherein the inflammation-related disorder is systemic lupus erythematosus. 158. A combination comprising a compound of any one of clauses 1 to 103, or a pharmaceutically acceptable salt or tautomer thereof, and one or more therapeutically active agents. 159. A compound of any one of clauses 1 to 103, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition of clause 104, for use as a medicament. 160. A compound according to any one of clauses 1 to 103, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition according to clause 104, for use in the treatment of a disease, condition modulated by STING inhibition or disease. 161. A compound according to any one of clauses 1 to 103, or a pharmaceutically acceptable salt or tautomer thereof or a pharmaceutical composition according to clause 104, for use in therapy as mentioned in any one of clauses 105 to 157 and diseases. 162. Use of a compound according to any one of clauses 1 to 103 or a pharmaceutically acceptable salt or tautomer thereof or a pharmaceutical composition according to clause 104 for the manufacture of a compound according to clause 105 to 157 Medicines for the diseases mentioned in any one of them. 163. The compound according to clause 43, wherein Ring B is selected from the group consisting of: ethoxazolyl, ethoxadiazolyl, ethoxazolyl, eththiazolyl, eththiazolyl or ethadiazolyl , which is optionally substituted with an R ^cB . 164. The compound of clause 163, wherein Ring B is

or

, each of which is optionally substituted with an R ^cB , where aa is the point of attachment to (L ^A ) _a1 . 165. The compound of clause 43 or 163, wherein Ring B is

or

, each of which is optionally substituted with an R ^cB , where aa is the point of attachment to (L ^A ) _a1 . 166. The compound of clause 43 or 163, wherein Ring B is

or

, each of which is optionally substituted with an R ^cB , where aa is the point of attachment to (L ^A ) _a1 . 167. The compound of clause 43 or 163, wherein Ring B is

or

, optionally substituted with an R ^cB , where aa is the point of attachment to (L ^A ) _a1 . 168. The compound of clause 43 or 163, wherein Ring B is

or

, each of which is optionally substituted with an R ^cB , where aa is the point of attachment to (L ^A ) _a1 . 169. The compound of clause 43 or 163, wherein Ring B is

or

, each of which is optionally substituted with an R ^cB , where aa is the point of attachment to (L ^A ) _a1 . 170. The compound of clause 68, wherein R ⁷ is selected from the group consisting of: • C _4-5 cycloalkyl, optionally substituted with 1-4 substituents independently selected from the group consisting of R ^c7 ; and • Heterocyclyl having 5-6 ring atoms, wherein 1-2 (eg, one) ring atoms are each independently selected from N, N(H), N( ^Rd ), O, and S(O) A heteroatom of the group consisting of _0-2 , and wherein the heterocyclyl group is optionally substituted with 1-4 substituents independently selected from the group consisting of ^Rc7 . 171. The compound of clause 68, wherein R ⁷ is a group of the formula:

or

, wherein X ⁷ is CH, ^{CR c7} or N, such as CH or N. 172. The compound of clause 68, wherein R ⁷ is a group of the formula:

or

, wherein R ^d is independently selected from the group consisting of C _1-6 alkyl optionally substituted with 1-3 independently selected R ^a , wherein m7 is 0 or 1. 173. The compound of clause 68, wherein R ⁷ is selected from the group consisting of tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octyl or 2-azabicyclo[2.2.1 ]heptane, each of which is optionally substituted with 1-2 R ^c7 . For example, ^R7 can be:

or

.

Claims (17)

a compound of formula I ,

Formula I or a pharmaceutically acceptable salt or tautomer thereof, wherein: Z , Y ¹ , Y ² and Y ³ are independently selected from the group consisting of C R ¹ , C(=O), N and NR ² ; X ¹ is selected from the group consisting of: O, S, N, NR ² and CR ¹ ; X ² is selected from the group consisting of: O, S, N, NR ⁴ and CR ⁵ ; each

is independently a single bond or a double bond, provided that a 5-membered ring system heteroaryl group including ^X1 and ^X2 , and a 6-membered ring system aryl or heteroaryl group including Z , ^Y1 , ^Y2 , and ^Y3 ; Each R ¹ is independently selected from the group consisting of: H; R ^c ; R ^g ; and -(L ¹ ) _{b 1} -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 heteroaryl group having 5 ring atoms, wherein 1 to 4 ring atoms are each independently selected from N, NH, N( A heteroatom of the group consisting of R ^d ), O and S; wherein the heteroaryl of ring B is optionally substituted with 1 to 2 substituents independently selected from the group consisting of pendant oxy and R ^c , provided that Ring B is attached to the C(=O)N R ⁶ group via a ring carbon atom; each ^LA is independently selected from the group consisting of: C _1-3 alkylene optionally substituted with 1 to 2 R ^a1 and C(O); ^a1 is ₀ , 1 or 2; Ring C is selected from the group consisting of: C _{3- 12} cycloalkylene or _C3-12 cycloalkenyl, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of pendant oxy, ^R and ^R ; having 3 to A 12-ring-atom extended or heterocycloalkenyl group, wherein 1 to 3 ring atoms are each independently selected from N, N(H), N( R ^d ), O and S(O) _0- A heteroatom of the group consisting of ₂ , and wherein the heterocyclylene or heterocycloalkenyl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of pendant oxy, ^R and ^R ; A heteroaryl group having 5 to 12 ring atoms, wherein 1 to 3 ring atoms are each independently selected from N, N(H), N( R ^d ), O and S(O) _0-2 . A heteroatom of the group of R, and wherein the _heteroaryl group is optionally substituted with 1 to 4 substituents independently selected from the group consisting of: R ^c and R ^h ; is 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 ; R ^a and R ^a1 at each occurrence is independently selected from the group consisting of: -OH; -halo; -N R ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; =O)O(C _1-4 alkyl);-C(=O)(C _1-4 alkyl);-C(=O)OH ;-CON R'R'' ;-S(O) _1-2N R'R'' ;-S(O) _1-2 ( _C1-4 alkyl); and cyano; R ^c in each When present, independently selected from the group consisting of: halo; cyano; _C1-10 alkyl optionally substituted with 1 to 6 independently selected ^Ra ; _C2-6 alkenyl; _C2-6 alkyne base; C _1-4 alkoxy; C _1-4 haloalkoxy; -S(O) _1-2 (C _1-4 alkyl); -S(O)(=NH)(C _1-4 alkane -N R ^e R ^f ; -OH; -S(O) _1-2 N R'R'' ; -C _1-4 thioalkoxy; -NO ₂ ; -C(=O)( -C(=O)O( _C1-4 alkyl); _-C (=O)OH; -C(=O)N R'R'' ; and _-SF5 ; ^Rd at each occurrence is independently selected from the group consisting of: _C1-6 alkyl optionally substituted with 1 to 3 independently selected R ^a ; -C(O)( _C1-4 alkyl) ;-C(O)O(C _1-4 alkyl);-CON R'R'' ;-S(O) _1-2N R'R'' ;-S(O) _1-2 (C _{1 -4} alkyl); -OH; and C _1-4 alkoxy; R ^e and R ^f at each occurrence are independently selected from the group consisting of: H; C _1-6 alkyl, optionally modified by 1 to 3 substituents independently selected from the group consisting of NR'R'' , -OH and ^Ri ; -C(O)(C _1-4 alkyl); -C(O)O( C _1-4 alkyl); -CON R'R'' ; -S(O) _1-2 N R'R'' ; -S(O) _1-2 (C _1-4 alkyl); -OH and C _1-4 alkoxy; R ^g is independently selected at each occurrence from the group consisting of C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each of which is optionally 1 to 4 substituents independently selected from the group consisting of pendant oxy, R ^c , R ^h and -( L ^g ) _bg -R ^h ; Heterocyclyl or heterocyclyl having 3 to 12 ring atoms Cycloalkenyl, wherein 1 to 3 ring atoms are each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 heteroatoms, and wherein the heteroatom Cyclo or heterocycloalkenyl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of pendant oxy, ^Rc , ^Rh , and -( ^Lg ) _bg - ^Rh ; with 5 to Heteroaryl groups of 12 ring atoms, wherein 1 to 3 ring atoms are each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 heteroatoms , and wherein the heteroaryl group 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 ; and 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 ; R ^h is independently selected at each occurrence from the group consisting of: C _3-12 cycloalkyl or C _3-12 cycloalkenyl, each of which is optionally modified from 1 to 4 R ⁱ substitution; heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are each independently selected from N, N(H), N( ^Rd ), O, and A heteroatom of the group consisting of S(O) _0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by 1 to 4 R ⁱ ; a heteroaryl group having 5 to 12 ring atoms, wherein 1 to 3 ring atoms are each independently a heteroatom selected from the group consisting of N, N(H), N( ^Rd ), O, and S(O) _0-2 , and wherein the heteroaryl is optionally substituted with 1 and C _6-10 aryl, optionally substituted with 1 to 4 ^{R i} ; R ⁱ at each occurrence 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; L ¹ , L ² , L ⁷ and L ^g at each occurrence are selected from the group consisting of : -O-, -NH-, -N R ^d , -S(O) _0-2 , C(O) and optionally C _1-3 alkylene substituted with 1 to 3 R ^a ; b1 , b2 , b7 , and bg are each independently 1, 2, or 3; and R' and R'' are, at each occurrence, independently selected from the group consisting of: H; -OH; and _C1-4 alkyl. The compound of claim 1, wherein the compound is a compound of formula ( Ia ):

Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein: R ^1a , R ^1b , R ^1c and R ^1d are each independently selected R ¹ . The compound of claim 1, wherein one of Z , ^Y1 , ^Y2 , and ^Y3 is N; and each remaining of Z , ^Y1 , ^Y2 , and ^Y3 is an independently selected C ^R1 . A compound as claimed in any one of claims 1 to 3, wherein ^X1 is NR2 and ^X2 is ^CR5 ; optionally wherein ^X1 is NH and ^X2 is ^CH . The compound of 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. The compound of any one of claims 1 to 5, wherein each R ^c is independently selected halo, such as -F, -Cl or -Br, such as wherein each R ^c is independently -F or -Cl, and each R ^g is independently a heteroaryl group having 5 ring atoms, wherein 1 to 3 ring atoms are each independently selected from N, N(H), N( ^Rd ), O, and A heteroatom of the group consisting of S, and wherein the heteroaryl is optionally substituted with 1 to 4 ^Rc . The compound of claim 2 or claims 4 to 6 dependent on claim 2, wherein R ^1a and R ^1d are H; and R ^1b and R ^1c are independently selected halo groups, such as -F or -Cl, such as - F; or wherein 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; or wherein 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 group having 5 ring atoms, wherein 1 to 3 ring atoms are each A heteroatom independently selected from the group consisting of N, N(H), N( ^Rd ), O, and S, and wherein the heteroaryl is optionally substituted with 1 to 4 ^Rc . The compound of any one of claims 1 to 7, wherein Ring B is a heteroaryl group having 5 ring atoms, wherein 2 to 3 ring atoms are each independently selected from N, NH, N( R ^d ) Heteroatoms of the group consisting of , O and S, such as N and NH, wherein the heteroaryl of ring B is optionally substituted with 1 to 2 R ^c , for example: wherein ring B is selected from the group consisting of: imidazolyl, triazolyl, or triazolyl, such as 1,2,3-triazolyl, each of which is optionally substituted with one ^R ; for example: wherein the heteroaryl of ring B is selected from :

or

, each of which is optionally substituted with an R ^c ; where aa is the point of attachment to ⁽ LA ) _a1 . The compound of any one of claims 1 to 8, wherein a1 is 0; or wherein a1 is 1, and optionally ^LA is a C _1-3 alkylene group optionally substituted with 1 to 2 R ^a1 , such as Wherein L ^A is CH ₂ or CH(Me). The compound of any one of claims 1 to 9, wherein Ring C is selected from the group consisting of: Heteroaryl having 5 to 10 ring atoms, wherein 1 to 3 ring atoms are each independently selected from A heteroatom of the group consisting of N, N(H), N( R ^d ), O, and S(O) _0-2 , and wherein the heteroaryl group is optionally 1 to 4 independently selected from the group consisting of Substituent substitutions of the group: R ^c and R ^h ; and C _6-10 aryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: R ^c and R ^h ; for example: wherein Ring C is selected from the group consisting of: Heteroaryl having 5 to 6, such as 6 ring atoms, wherein 1 to 3, such as 1 to 2 ring atoms are each independently selected from N, N(H ), N( R ^d ), O, and S(O) _0-2 a heteroatom of the group consisting of, and wherein the heteroaryl group is optionally substituted with 1 to 4 substituents independently selected from the group consisting of R ^c substituted; and C _arylidene , which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of ^R ; for example: wherein Ring C is selected from the group consisting of: pyridyl, which is considered substituted with 1 to 3, such as 1, substituents independently selected from the group consisting of ^Rc ; and C _arylidene , optionally substituted with 1 to 4, such as 1 to 2, independently selected from the group consisting of ^Rc Substituents of the group of ; for example: wherein Ring C is a group of the following formula:

, where each 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 point of attachment to R ⁷ . The compound of any one of claims 1 to 10, wherein R ⁷ is selected from the group consisting of: C _3-12 cycloalkyl, optionally substituted with 1 to 4 independently selected from the group consisting of group substitution: pendant oxy, R ^c7 , R ^h and -( L ^g ) _bg -R ^h ; and heterocyclyl groups having 4 to 12 ring atoms, wherein 1 to 3 ring atoms are each independently selected from N , N(H), N( R ^d ), O, and S(O) _0-2 heteroatoms of the group consisting of 0-2, and wherein the heterocyclyl group is optionally selected from 1 to 4 independently from pendant oxy, R Substituent substitution of the group consisting of ^c7 , ^Rh and -( ^Lg ₎ ^bg -Rh, wherein each ^Rc7 is an independently selected ^Rc ; for example: wherein ^R7 is selected from the group consisting of: _{C4- 8} cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of pendant oxy, ^R and ^R ; and heterocyclyl having 4 to 8 ring atoms, wherein 1 to The 3 ring atoms are each independently a heteroatom selected from the group consisting of N, N(H), N( ^Rd ), O and S(O) _0-2 , and wherein the heterocyclyl group is optionally modified from 1 to substituted with 4 substituents independently selected from the group consisting of: pendant oxy, R ^c7 and R ^h ; for example: wherein R ⁷ is selected from the group consisting of: C ₆ cycloalkyl, optionally through 1 to 4 substituents independently selected from the group consisting of R ^c7 are substituted; and a heterocyclyl group having 6 ring atoms, wherein 1 to 2, such as one ring atom, are each independently selected from N, N(H), A heteroatom of the group consisting of N( ^Rd ), O, and S(O) _0-2 , and wherein the heterocyclyl group is optionally substituted with 1 to 4 substituents independently selected from the group consisting of ^Rc7 ; for example : wherein R ⁷ is a group of the following formula:

, wherein X ⁷ is CH, C R ^c7 or N, such as CH or N; for example: R ⁷ is a group of the following formula:

, wherein X ⁷ is N or CH; and each R ^c7 is an independently selected R ^c ; and optionally, wherein each R ^c7 is an independently selected halo or optionally C ₁ substituted with 1 to 6 R ^a _-3 alkyl, such as halo or _C1-3 alkyl optionally substituted with 1 to 6 independently selected halo. The compound of claim 1, wherein the compound is a compound of formula (I-a1-1) :

Formula (I-a1-1) or a pharmaceutically acceptable salt thereof, wherein: each of R ^1a , R ^1b , R ^1c and R ^1d is an 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 Groups: N, CH, and C R ^cC ; R ^cB and R ^cC are independently selected R ^c at each occurrence; and each

is independently a single bond or a double bond, provided that the ring comprising ^B1 to ^B4 is a heteroaryl group. The compound of claim 1, wherein the compound is selected from the group consisting of the compounds described in Table C1 or pharmaceutically acceptable salts thereof. A pharmaceutical composition comprising a compound of claims 1 to 13 and one or more pharmaceutically acceptable excipients. A method of inhibiting the activity of STING, the method comprising contacting STING with a compound as claimed in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 14. A method of inducing an immune response in an individual in need, the method comprising administering to the individual an effective amount of a compound as claimed in any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or as claimed in claim 14 Pharmaceutical composition. A method of treating a disease, disorder or condition associated with STING, such as where increased STING signaling, such as excessive STING signaling contributes to the pathology and/or symptoms of the disease and/or or progression of a disease, disorder or condition, such as cancer, the method comprising administering to an individual in need of such treatment an effective amount of a compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof or as claimed The pharmaceutical composition of item 14.