CN116528862A

CN116528862A - Compounds and compositions for the treatment of diseases associated with STING activity

Info

Publication number: CN116528862A
Application number: CN202180063054.0A
Authority: CN
Inventors: S·范卡彻曼; J·卡茨; W·R·劳世; H·M·塞德尔
Original assignee: Afumdeyou Co ltd
Current assignee: Afumdeyou Co ltd
Priority date: 2020-07-15
Filing date: 2021-07-15
Publication date: 2023-08-01
Also published as: TW202216685A; AR122976A1; WO2022015957A1; EP4182028A1; JP2023540672A; UY39328A

Abstract

The present invention provides chemical entities (e.g., compounds or pharmaceutically acceptable salts and/or hydrates and/or co-crystals and/or pharmaceutical combinations of the compounds) that inhibit (e.g., antagonize) the interferon gene Stimulus (STING). The chemical entities may be used, for example, to treat a condition, disease or disorder in which an increase (e.g., excess) in STING activation (e.g., STING signaling) promotes the etiology/symptoms and/or progression of a condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). The invention also provides compositions comprising the chemical entities and methods of using and making the compositions.

Description

Compounds and compositions for the treatment of diseases associated with STING activity

Cross Reference to Related Applications

The present application claims the benefit of U.S. provisional patent application serial No. 63/052,117, filed 7/15/2020, the disclosure of which is incorporated herein by reference in its entirety.

Technical Field

The present invention provides chemical entities (e.g., compounds or pharmaceutically acceptable salts and/or hydrates and/or co-crystals and/or pharmaceutical combinations of the compounds) that inhibit (e.g., antagonize) the interferon gene Stimulus (STING). The chemical entities may be used, for example, to treat a condition, disease or disorder in which an increase (e.g., excess) in STING activation (e.g., STING signaling) promotes pathology and/or symptoms and/or progression of a condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). The invention also provides compositions comprising the chemical entities and methods of using and making the compositions.

Background

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

STING pathway is critical in mediating recognition of cytoplasmic DNA. In this case STING is a transmembrane protein located in the Endoplasmic Reticulum (ER) and acts as a second messenger receptor for 2',3' cyclic GMP-AMP (hereinafter cGAMP), which is produced by cGAS after dsDNA binding. Furthermore, STING can also be used as a primary pattern recognition receptor for bacterial Cyclic Dinucleotides (CDNs) and small molecule agonists. Recognition of endogenous or prokaryotic CDNs occurs through the carboxy-terminal domain of STING, which faces the cytoplasm and creates a V-shaped binding pocket formed by STING homodimers. Ligand-induced STING activation triggers its relocation to the golgi apparatus, a process essential for promoting STING interaction with TBK 1. This protein complex in turn signals through the transcription factor IRF-3, thereby inducing type I Interferons (IFNs) and other co-regulated antiviral factors. Furthermore, STING was shown to trigger NF- κb and MAP kinase activation. After initiation of signal transduction STING rapidly degrades, which is important in terminating inflammatory responses.

Overactivation of STING is associated with a subset of monogenic autoinflammatory disorders (i.e. so-called type I interferon disease). Examples of such diseases include the clinical syndrome known as STING-related vascular disease (SAVI), which is caused by a functionally acquired mutation in TMEM173 (gene name of STING). Furthermore, STING is involved in the pathogenesis and inherited forms of lupus in the Aicadi-Gu Di Ras Syndrome (Aicadi-Gouti res Syndrome, AGS). Unlike SAVI, continuous innate immune activation in AGS is the basis for deregulation of nucleic acid metabolism. In addition to these genetic diseases, emerging evidence suggests that STING has a more general pathogenic role in a range of diseases associated with inflammation (e.g., systemic lupus erythematosus, rheumatoid arthritis, and cancer). Thus, small molecule-based pharmacological intervention in STING signaling has great potential in the treatment of a variety of diseases.

Disclosure of Invention

"antagonists" of STING include compounds that bind or modify STING directly at the protein level such that STING activity is reduced, e.g., by inhibiting, blocking or attenuating an agonist-mediated response, altering distribution or otherwise. STING antagonists include chemical entities that interfere with or inhibit STING signaling.

In one aspect, the disclosure features a compound of formula I:

therein, Z, Y ¹ 、Y ² 、Y ³ 、X ¹ 、X ² 、R ⁶ Ring B, L ^A A1, ring C and R ⁷ May be as defined at any location herein.

In one aspect, the invention provides pharmaceutical compositions comprising a chemical entity described herein (e.g., a compound, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound, as generally or specifically described herein) and one or more pharmaceutically acceptable excipients.

In one aspect, the invention provides methods of inhibiting (e.g., antagonizing) STING activity, comprising contacting STING with a chemical entity described herein (e.g., a compound as generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound). Methods include in vitro methods, such as contacting a sample comprising one or more cells comprising STING (e.g., innate immune cells, such as mast cells, macrophages, dendritic Cells (DCs), and natural killer cells) with the chemical entity. The method may further comprise an in vivo method; for example, the chemical entity is administered to a subject (e.g., a human) suffering from a disease in which STING signaling is increased (e.g., excessive) resulting in pathology and/or symptoms and/or progression of the disease.

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

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

In another aspect, the invention provides methods of treating other STING-related diseases, such as type I interferon diseases (e.g., STING-related vascular diseases (SAVI) in infancy), akadi-Gu Di rad Syndrome (AGS), hereditary forms of lupus, and inflammatory related diseases, such as systemic lupus erythematosus and rheumatoid arthritis. The method comprises administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound, a pharmaceutically acceptable salt thereof, or a composition comprising the same, as generally or specifically described herein).

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

In another aspect, the invention provides methods of treating a disease, wherein an increase (e.g., an excess) in STING activation (e.g., STING signaling) promotes the disease's morbidity and/or symptoms and/or progression. The method comprises administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound, a pharmaceutically acceptable salt thereof, or a composition comprising the same, as generally or specifically described herein).

In another aspect, the invention provides methods of treatment comprising administering to a subject an effective amount of a chemical entity described herein (e.g., a compound as generally or specifically described herein or a pharmaceutically acceptable salt thereof or a composition comprising the same); wherein the subject suffers from (or is predisposed to suffering from) a disease in which an increase (e.g., an excess) in STING activation (e.g., STING signaling) promotes the disease's etiology/symptoms and/or progression.

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

In another aspect, provided herein are compounds as described herein, or pharmaceutically acceptable salts or tautomers thereof, for use in the treatment of a disease, condition, or disorder modulated by STING inhibition.

In another aspect, provided herein are compounds as described herein, or pharmaceutically acceptable salts or tautomers thereof, for use in treating a condition, disease, or disorder associated with increased (e.g., excessive) STING activation.

In another aspect, provided herein are compounds, or pharmaceutically acceptable salts or tautomers thereof, as described herein for use in treating cancer.

In another aspect, provided herein is a compound as described herein, or a pharmaceutically acceptable salt or tautomer thereof, for use in treating a cancer 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, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, wilms' tumor, or hepatocellular carcinoma.

In another aspect, provided herein are compounds as described herein, or pharmaceutically acceptable salts or tautomers thereof, for use in the treatment of type I interferon disease.

In another aspect, provided herein is a compound as described herein, or a pharmaceutically acceptable salt or tautomer thereof, for use in treating a type I interferon disease selected from: STING-related vascular disease (SAVI), akadi-Gu Di rass Syndrome (AGS), hereditary forms of lupus, and inflammatory related diseases such as systemic lupus erythematosus and rheumatoid arthritis.

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

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

In another aspect, provided herein is the use of a compound as described herein, or a pharmaceutically acceptable salt or tautomer thereof, in the manufacture of a medicament for treating cancer 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, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, wilms' tumor, or hepatocellular carcinoma.

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

In another aspect, provided herein is the use of a compound as described herein, or a pharmaceutically acceptable salt or tautomer thereof, in the manufacture of a medicament for the treatment of a type I interferon disease selected from the group consisting of: STING-related vascular disease (SAVI), akadi-Gu Di rass Syndrome (AGS), hereditary forms of lupus, and inflammatory related diseases such as systemic lupus erythematosus and rheumatoid arthritis.

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

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

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

In another aspect, provided herein is the use of a compound as described herein, or a pharmaceutically acceptable salt or tautomer thereof, for treating cancer 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, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, wilms' tumor, or hepatocellular carcinoma.

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

In another aspect, provided herein is the use of a compound as described herein, or a pharmaceutically acceptable salt or tautomer thereof, in the treatment of a type I interferon disease selected from: STING-related vascular disease (SAVI), akadi-Gu Di rass Syndrome (AGS), hereditary forms of lupus, and inflammatory related diseases such as systemic lupus erythematosus and rheumatoid arthritis.

Implementations may include one or more of the following features.

The chemical entity may 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 (e.g., two, three, four, five, six or more) other agents.

The chemical entity may be administered in combination with one or more other therapeutic agents and/or regimens useful in the treatment of other STING-related diseases, such as type I interferon diseases (e.g., STING-related vascular diseases (SAVI) of infancy), ai-Gu Di rad Syndrome (AGS), genetic forms of lupus, and inflammatory related diseases such as systemic lupus erythematosus and rheumatoid arthritis.

The chemical entity may be administered in combination with one or more additional cancer therapies (e.g., surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy, or a combination thereof); for example, chemotherapy comprising the administration of one or more (e.g., two, three, four, five, six or more) other chemotherapeutic agents. Non-limiting examples of other chemotherapeutic agents are selected from: alkylating agents (e.g., cisplatin, carboplatin, nitrogen mustard, cyclophosphamide, chlorambucil, ifosfamide, and/or oxaliplatin); antimetabolites (e.g., azathioprine and/or mercaptopurine); terpenoids (e.g., vinca alkaloids (vincaalloids) and/or taxanes; e.g., vincristine (vinbristine), vinblastine (vinblastine), vinorelbine (vinorelbine) and/or vindesine (vindeline), taxol (taxol), paclitaxel (paclitaxel) and/or docetaxel); topoisomerase (e.g., type I topoisomerase and/or type 2 topoisomerase; e.g., camptothecin, e.g., irinotecan (irinotecan) and/or topotecan (topotecan); amsacrine (amacrine), etoposide (etoposide), etoposide phosphate and/or teniposide (teniposide)); cytotoxic antibiotics (e.g., actinomycin, anthracycline, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); hormones (e.g., luteinizing hormone-releasing hormone agonists; e.g., leuprolide (leuprolide), goserelin (goserelin), triptorelin (triporelin), histrelin (histrelin), bicalutamide (bicalutamide), flutamide (flutamide) and/or nilutamide); antibodies (e.g., acipimab (Abciximab), adalimumab (Adaliumab), alemtuzumab (Alemuzumab), alizumab (Atlizumab), basiliximab (Basiliximab), belimumab (Bellimumab), bevacizumab (Bevacizumab), present tuximab (Brentuximab Vedotin), kanlizumab (Canadumab), cetuximab (Cetuximab), peziumab (Certolizumab pegol), daclizumab (Daclizumab), denosumab (Denosumab), elkuzumab (Eculizumab), ai Fazhu monoclonal antibody (Efazumab), getuzumab (Gefamzumab), golimumab (Golimumab), tituzumab (Ibtuzumab), inoxitimab (Uxyab), inframab (Itimab), umamab (Pauzumab-1, otuzumab-2, and (Otuzumab-1, otutimuzumab-1, otuzumab-2-Otuzumab) are selected from the group consisting of the following, and Ratuzumab-1, otuzumab-1-Otuzumab, otuzumab (Otuab-1-Otuzumab, otuab-2-Otuzumab, otuzumab and Otulizumab (Otuzumab) and (Otulizumab) respectively, interleukin-2 (IL-2), indoleamine 2, 3-dioxygenase (IDO), IL-10, transforming growth factor-beta (TGF beta), T-cell immunoglobulin and mucin 3 (TIM 3 or HAVCR 2), galectin 9-TIM3, phosphatidylserine-TIM 3, lymphocyte activator gene 3 protein (LAG 3), MHC class II-LAG 3,4-1BB-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, HHA 2-TMIGD2, milk fat philins including BTNL2, siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 adenosine-CD 39-CD73, CXCR4-CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM 3, SIRPA-CD47, VEGF, neuropilin (Neuropilin), CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

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

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, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, wilms' tumor, or hepatocellular carcinoma. In some embodiments, the cancer may be refractory cancer.

The chemical entity may be administered intratumorally.

The method may further include identifying the object.

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

Other definitions

In order to facilitate an understanding of the disclosure set forth herein, a number of other terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, pharmaceutical chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Each patent, application, published application, and other publication mentioned throughout this specification is incorporated herein by reference in its entirety.

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

As used herein, the term "acceptable" with respect to a formulation, composition or ingredient means that there is no sustained detrimental effect on the overall health of the subject being treated.

"API" refers to the active pharmaceutical ingredient.

As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a chemical entity sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent. Results include reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is an amount necessary to include a compound disclosed herein to provide clinically significant relief from symptoms of a disease. In any event, any suitable technique (e.g., dose escalation studies) can be used to determine the appropriate "effective" amount.

The term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or carrier, 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 is suitable for contact with tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit/risk ratio. See, for example, remington pharmaceutical science and practice (Remington: the Science and Practice of Pharmacy), 21 st edition; LWW publishing company (Lippincott Williams & Wilkins): philadelphia, pa, 2005; handbook of pharmaceutical excipients (Handbook of Pharmaceutical Excipients), 6 th edition; rowe et al, pharmaceutical Press and American society of pharmacy (The Pharmaceutical Press and the American Pharmaceutical Association): 2009: handbook of pharmaceutical additives (Handbook of Pharmaceutical Additives), 3 rd edition; ash and Ash editions, golgi publishing company (Gower Publishing Company): 2007; pharmaceutical preformulation and formulation (Pharmaceutical Preformulation and Formulation), 2 nd edition, gibson, CRC Press LLC:

Bocarton, florida, 2009).

The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some cases, the pharmaceutically acceptable salts are obtained by reacting the compounds described herein with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In some cases, salts are formed by reacting the compounds described herein having an acidic group with a base, 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 amino acids, such as arginine, lysine, and the like, or by other methods previously identified. The pharmaceutically acceptable salt is not particularly limited as long as it can be used for a drug. Examples of salts of the compounds described herein with bases include the following: salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salts with organic bases such as methylamine, ethylamine and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salt may be an acid addition salt, specific examples of which are the following acid addition salts: inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid: organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersants, suspending agents, and/or thickeners. The pharmaceutical compositions facilitate administration of the compounds to organisms. There are a variety of techniques in the art for administering compounds including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary and topical administration.

The term "subject" may refer to an animal, including but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, e.g., to refer to a mammalian subject, e.g., a human subject.

In the context of treating a disease, disorder, or condition, the terms "treating," "treating," and "therapy" are intended to include alleviating or eliminating the disease, disorder, or condition or one or more symptoms associated with the disease, disorder, or condition; or slowing the progression, spread or worsening of a disease, disorder or condition, or one or more symptoms thereof. "cancer treatment" refers to one or more of the following actions: (1) To some extent, inhibit tumor growth, including (i) slowing down and (ii) complete growth arrest; (2) reducing the number of tumor cells; (3) maintaining tumor size; (4) reducing tumor size; (5) Inhibition, including (i) reduction, (ii) slowing down or (iii) completely preventing infiltration of tumor cells into peripheral organs; (6) Inhibition, including (i) reduction, (ii) slowing or (iii) total prevention of metastasis; (7) Enhancing an anti-tumor immune response that may (i) maintain tumor size, (ii) reduce tumor size, (iii) slow down tumor growth, (iv) reduce, slow down or prevent invasion and/or (8) reduce to some extent the severity or number of one or more symptoms associated with the disorder.

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

The term "alkyl" refers to an acyclic saturated hydrocarbon chain, which may be straight or branched, containing the indicated number of carbon atoms. For example, C _1-10 Meaning that the group may have from 1 to 10 carbon atoms (inclusive). The alkyl group may be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, n-hexyl. The terminology used herein"saturated" refers to a single bond that exists only between the constituent carbon atoms and other available valences 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 are replaced with independently selected halogens.

The term "alkoxy" refers to-O-alkyl (e.g., -OCH) ₃ )。

The term "alkylene" refers to a divalent alkyl group (e.g., -CH ₂ -)。

The term "alkenyl" refers to acyclic hydrocarbon chains that may be straight or branched with one or more carbon-carbon double bonds. Alkenyl moieties contain the indicated number of carbon atoms. For example, C _2-6 Meaning that the group may have 2 to 6 carbon atoms (inclusive). Alkenyl groups may 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. Alkynyl moieties contain the indicated number of carbon atoms. For example, C _2-6 Meaning that the group may have 2 to 6 carbon atoms (inclusive). Alkynyl groups may be unsubstituted or substituted with one or more substituents.

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

The term "cycloalkyl" as used herein refers to a cyclic saturated hydrocarbon group having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups may include multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl groups include: bicyclo [1.1.0] butanoyl, bicyclo [2.1.0] pentanoyl, bicyclo [1.1.1] pentanoyl, bicyclo [3.1.0] hexanoyl, bicyclo [2.1.1] hexanoyl, bicyclo [3.2.0] heptanyl, bicyclo [4.1.0] heptanyl, bicyclo [2.2.1] heptanyl, bicyclo [3.1.1] heptanyl, bicyclo [4.2.0] octanyl, bicyclo [3.2.1] octanyl, bicyclo [2.2.2] octanyl, and the like. Cycloalkyl also includes spiro rings (e.g., spiro bicyclic rings in which two rings are connected by only one atom). Non-limiting examples of spirocycloalkyl groups include: spiro [2.2] pentyl, spiro [2.5] octyl, spiro [3.5] nonyl, spiro [4.4] nonyl, spiro [2.6] nonyl, spiro [4.5] decyl, spiro [3.6] decyl, spiro [5.5] undecyl, and the like. The term "saturated" as used herein refers to single bonds that exist only between constituent carbon atoms.

The term "cycloalkenyl" as used herein means a partially unsaturated cyclic hydrocarbon group having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the alkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As a partially unsaturated cyclic hydrocarbon group, cycloalkenyl groups 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 cycloalkenyl groups are generally not fully saturated. The cycloalkenyl group may include a plurality of fused and/or bridged and/or spiro rings.

The term "heteroaryl" as used herein refers to a mono-, bi-, tri-or polycyclic group having 5 to 20 ring atoms, or 5, 6, 9, 10 or 14 ring atoms; and sharing 6, 10 or 14 pi electrons in a circular array; wherein at least one ring in the system is aromatic and at least one ring in the system comprises one or more heteroatoms independently selected from N, O and S (but not necessarily a heteroatom-containing ring, such as tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups may be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include: thienyl, pyridyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido [2,3-d ] pyrimidinyl, pyrrolo [2,3-b ] pyridinyl, quinazolinyl, quinolinyl, thieno [2,3-c ] pyridinyl, pyrazolo [3,4-b ] pyridinyl, pyrazolo [3,4-c ] pyridinyl, pyrazolo [4,3-b ] pyridinyl, tetrazolyl, chromane, 2, 3-dihydrobenzo [1,4] dioxol [1, 3-d ] [1, 3-dioxanyl, 1, 3-dioxa [2,3-b ] pyridinyl, 1, 3-dioxa [2,3-d ] benzo [1, 3-d ] pyridinyl, and the like. In some embodiments, heteroaryl is selected from: thienyl, pyridyl, furyl, pyrazolyl, imidazolyl, isoindolyl, pyranyl, pyrazinyl and pyrimidinyl.

The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic or polycyclic saturated ring system having 3 to 16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic), having 1 to 3 heteroatoms (if monocyclic), 1 to 6 heteroatoms (if bicyclic), or 1 to 9 heteroatoms (if tricyclic or polycyclic) selected from O, N, or S (e.g., if monocyclic, bicyclic, or tricyclic, respectively), having carbon atoms and 1 to 3, 1 to 6, or 1 to 9 heteroatoms selected from N, O or S, wherein 0, 1, 2, or 3 atoms of each ring may be substituted with substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. The heterocyclyl may include a plurality of fused and/or bridged rings. Non-limiting examples of fused/bridged heterocyclyl groups include: 2-azabicyclo [1.1.0] butyl, 2-azabicyclo [2.1.0] pentyl, 2-azabicyclo [1.1.1] pentyl, 3-azabicyclo [3.1.0] hexyl, 5-azabicyclo [2.1.1] hexyl, 3-azabicyclo [3.2.0] heptyl, octahydrocyclopenta [ c ] pyrrolyl, 3-azabicyclo [4.1.0] heptyl, 7-azabicyclo [2.2.1] heptyl, 6-azabicyclo [3.1.1] heptyl, 7-azabicyclo [4.2.0] octyl, 2-azabicyclo [2.2.2] octyl, 3-azabicyclo [3.2.1] octyl, 2-oxabicyclo [1.1.0] butyl, 2-oxabicyclo [2.1.0] pentyl, 2-oxabicyclo [1.1.1] pentyl, 3-oxabicyclo [3.1.0] hexyl, 5-oxabicyclo [ 2.2.1.1 ] octyl, 2.0] octyl, 2-oxabicyclo [ 2.1.1.1.0 ] octyl, 2-oxabicyclo [ 3.1.1.1.0 ] octyl, 2.2.1-oxabicyclo [3.1.0] octyl, 2.1.2.0 ] heptyl. Heterocyclyl also includes spiro rings (e.g., spiro bicyclic rings in which two rings are connected by only one atom). Non-limiting examples of spiro heterocyclyl groups include: 2-azaspiro [2.2] pentyl, 4-azaspiro [2.5] octyl, 1-azaspiro [3.5] nonyl, 2-azaspiro [3.5] nonyl, 7-azaspiro [3.5] nonyl, 2-azaspiro [4.4] nonyl, 6-azaspiro [2.6] nonyl, 1, 7-diazaspiro [4.5] decyl, 7-azaspiro [4.5] decyl, 2, 5-diazaspiro [3.6] decyl, 3-azaspiro [5.5] undecyl, 2-oxaspiro [2.2] pentyl, 4-oxaspiro [2.5] octyl, 1-oxaspiro [3.5] nonyl, 2-oxaspiro [3.5] nonyl, 7-oxaspiro [3.5] nonyl, 2-oxaspiro [4.4] nonyl, 6-oxaspiro [2.6] decyl, 1, 7-dioxaspiro [3.5] undecyl, 2-oxaspiro [3.5] decyl, 3.5-oxaspiro [3.5] undecyl, etc. The term "saturated" as used herein refers to a single bond that exists only between the constituent ring atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.

The term "heterocycloalkenyl" as used herein refers to a partially unsaturated ring system having 3-16 ring atoms (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system), 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic), selected from O, N or S (e.g., carbon atoms and 1-3, 1-6 or 1-9N, O or S heteroatoms corresponding to monocyclic, bicyclic or tricyclic rings, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted with substituents. Examples of heterocycloalkenyl groups include, but are not limited to, tetrahydropyridinyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl. As partially unsaturated cyclic groups, heterocyclenyl groups 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 heterocyclenyl groups are generally not fully saturated. Heterocycloalkenyl groups can include multiple fused and/or bridged and/or spiro rings.

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

As used herein, when a ring is described as "partially unsaturated" it is meant that the ring has one or more additional unsaturations (in addition to the unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between the atoms making up the ring), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

For the avoidance of doubt, unless otherwise indicated, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocyclenyl, cycloalkenyl, cycloalkyl, etc., as described herein) containing a sufficient number of ring atoms to form a bicyclic or higher ring system (e.g., tricyclic, polycyclic system), it is to be understood that such rings and cyclic groups include those having fused rings, including the following: (i) The condensed sites being located on adjacent ring atoms (e.g., [ x.x.0)]Ring systems in which 0 represents a zero-atom bridge (e.g) The method comprises the steps of carrying out a first treatment on the surface of the (ii) The condensed sites being located on a single ring atom (spiro condensed ring system) (e.g.) Or (iii) the condensed sites are located in a continuous array of ring atoms (all bridges long>0) (e.g.)

)。

In addition, the atoms making up the compounds of this embodiment are intended to include all isotopic forms of such atoms. Isotopes used herein include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium, while isotopes of carbon include ¹³ C and C ¹⁴ C。

In addition, compounds disclosed herein, either generically or specifically, are intended to include all tautomeric forms. Thus, for example, a portion is containedThe compounds of (1) comprise a part comprising->Is a tautomeric form of (a). Similarly, pyridinyl or pyrimidinyl moieties described as optionally substituted with hydroxy include pyridone or pyrimidinone tautomeric forms.

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

Detailed Description

The present invention provides chemical entities (e.g., compounds or pharmaceutically acceptable salts and/or hydrates and/or co-crystals and/or pharmaceutical combinations of compounds) that inhibit (e.g., antagonize) interferon gene Stimulators (STING). The chemical entities may be used, for example, to treat a condition, disease or disorder in which an increase (e.g., excess) in STING activation (e.g., STING signaling) promotes the etiology/symptoms and/or progression of a condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). The invention also provides compositions comprising the chemical entities and methods of using and making the compositions.

Compounds of formula I

In one aspect, the invention provides a compound of formula I, or a pharmaceutically acceptable salt or tautomer thereof:

wherein:

Z、Y ¹ 、Y ² and Y ³ Independently selected from the group consisting of: CR (computed radiography) ¹ , (=o), N and NR ² ；

X ¹ Selected from the group consisting of: o, S, N, NR ² And CR (CR) ¹ ；

X ² Selected from the group consisting of: o, S, N, NR ⁴ And CR (CR) ⁵ ；

Each of which is provided withIs independently a single bond or a double bond, provided that X is contained ¹ And X ² Is heteroaryl and comprises Z, Y ¹ 、Y ² And Y ³ Is aryl or heteroaryl;

each R is ¹ Independently selected from the group consisting of: h is formed; r is R ^c ；R ^g The method comprises the steps of carrying out a first treatment on the surface of the And- (L) ¹ ) _b1 -R ^g ；

Each R is ² Independently selected from the group consisting of: h is formed; r is R ^d ；R ^g The method comprises the steps of carrying out a first treatment on the surface of the And- (L) ² ) _b2 -R ^g ；

R ⁴ Selected from the group consisting of: h and R ^d ；

R ⁵ Selected from the group consisting of: h is formed; r is R ^c The method comprises the steps of carrying out a first treatment on the surface of the And R is ^h ；

R ⁶ Selected from the group consisting of: h is formed; r is R ^d The method comprises the steps of carrying out a first treatment on the surface of the And R is ^h ；

Ring B is a heteroarylene group having 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: n, NH, N (R) ^d ) O and S; wherein the heteroarylene of ring B is optionally substituted with 1-2 substituents independently selected from the group consisting of: oxo and R ^c Provided that ring B is bound to C (=O) NR via a ring carbon atom ⁶ A group connection;

each L ^A Independently selected from the group consisting of: c (C) _1-3 Alkylene, which is optionally substituted with 1-2R ^a1 Substitution; -O-; -NH-; -NR ^d ；-S(O) _0-2 The method comprises the steps of carrying out a first treatment on the surface of the And C (O);

a1 is 0, 1 or 2;

ring C is selected from the group consisting of:

C _3-12 cycloalkylene or C _3-12 A cycloalkenyl ene group, each optionally substituted with 1-4 substituents independently selected from the group consisting of: oxo, R ^c And R is ^h ；

Heterocyclylene or heterocyclylene having 3 to 12 ring atoms, wherein 1 to 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 the heterocyclylene or heterocyclylene is optionally substituted with 1-4 substituents independently selected from the group consisting of: oxo, R ^c And R is ^h ；

Heteroarylene having 5 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c And R is ^h The method comprises the steps of carrying out a first treatment on the surface of the And

C _6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c And R is ^h ；

R ⁷ Selected from the group consisting of: r is R ^g And- (L) ⁷ ) _b7 -R ^g ；

R in each occurrence ^a And R is ^a1 Independently selected from the group consisting of: -OH; -halogen; -NR ^e R ^f ；C _1-4 An alkoxy group; c (C) _1-4 Haloalkoxy groups; -C (=o) O (C _1-4 An alkyl group); -C (=o) (C _1-4 An alkyl group); -C (=o) OH; -CONR' R "; s (O) _1-2 NR’R”；-S(O) _1-2 (C _1-4 An alkyl group); and cyano;

r in each occurrence ^c Independently selected from the group consisting of: halogen; cyano group; c (C) _1-10 Alkyl, optionally substituted with 1-6 independently selected R ^a Substitution; c (C) _2-6 Alkenyl groups; c (C) _2-6 Alkynyl; c (C) _1-4 An alkoxy group; c (C) _1-4 Haloalkoxy groups; s (O) _1-2 (C _1-4 An alkyl group); -S (O) (=nh) (C _1-4 An alkyl group); -NR ^e R ^f ；–OH；-S(O) _1-2 NR’R”；-C _1-4 Thioalkoxy; -NO ₂ ；-C(＝O)(C _1-10 An alkyl group); -C (=o) O (C _1-4 An alkyl group); -C (=o) OH; -C (=o) NR' R "; and-SF ₅ ；

R in each occurrence ^d Independently selected from the group consisting of: c (C) _1-6 Alkyl, optionally substituted with 1-3 independently selected R ^a Substitution; -C (O) (C _1-4 An alkyl group); -C (O) O (C) _1-4 An alkyl group); -CONR' R "; s (O) _1-2 NR’R”；-S(O) _1-2 (C _1-4 An alkyl group); -OH; and C _1-4 An alkoxy group;

r in each occurrence ^e And R is ^f Independently selected from the group consisting of: h is formed; c (C) _1-6 Alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of: NR 'R', -OH and R ⁱ ；-C(O)(C _1-4 An alkyl group); -C (O) O (C) _1-4 An alkyl group); -CONR' R "; s (O) _1- ₂ NR’R”；-S(O) _1-2 (C _1-4 An alkyl group); -OH; and C _1-4 An alkoxy group;

r in each occurrence ^g Independently selected from the group consisting of:

C _3-12 cycloalkyl or C _3-12 Cycloalkenyl groups, each optionally substituted with 1-4 substituents independently selected from the group consisting of: oxo, R ^c 、R ^h And- (L) ^g ) _bg -R ^h ；

A heterocyclyl or heterocycloalkenyl group having 3-12 ring atoms in 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 the heterocyclyl or heterocyclenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: oxo, R ^c 、R ^h And- (L) ^g ) _bg -R ^h ；

Heteroaryl groups having 5 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from Group: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c 、R ^h And- (L) ^g ) _bg -R ^h The method comprises the steps of carrying out a first treatment on the surface of the And

C _6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c 、R ^h And- (L) ^g ) _bg -R ^h ；

R in each occurrence ^h Independently selected from the group consisting of:

C _3-12 cycloalkyl or C _3-12 Cycloalkenyl groups, each optionally substituted with 1-4R ⁱ Substitution;

a heterocyclyl or heterocycloalkenyl group having 3-12 ring atoms in 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 the heterocyclyl or heterocyclenyl is optionally substituted with 1-4R ⁱ Substitution;

heteroaryl groups having 5 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heteroaryl is optionally substituted with 1-4R ⁱ Substitution; and

C _6-10 aryl, optionally substituted with 1-4R ⁱ Substitution;

r in each occurrence ⁱ Independently selected from the group consisting of: c (C) _1-6 An alkyl group; c (C) _1-4 A haloalkyl group; c (C) _1-4 An alkoxy group; c (C) _1-4 Haloalkoxy and halogen;

l per occurrence ¹ 、L ² 、L ⁷ And L ^g Selected from the group consisting of:

-O-、-NH-、-NR ^d 、-S(O) _0-2 c (O) and optionally 1-3R ^a Substituted C _1-3 An alkylene group;

b1, b2, b7 and bg are each independently 1, 2 or 3; and

Each occurrence of R 'and R' is independently selected from the group consisting of: h is formed; -OH; and C _1-4 An alkyl group.

¹ ² ³ ¹ ² Variables Z, Y, Y, Y, X and X

In some embodiments, Z, Y ¹ 、Y ² And Y ³ Each independently is N or CR ¹ 。

In some embodiments, Z, Y ¹ 、Y ² And Y ³ CR each independently selected ¹ 。

In certain embodiments, the compound is a compound having formula (Ia):

wherein: r is R ^1a 、R ^1b 、R ^1c And R is ^1d Each independently selected R ¹ 。

In some embodiments, Z, Y ¹ 、Y ² And Y ³ Wherein 1-2 (e.g., 1) are N; and Z, Y ¹ 、Y ² And Y ³ The remainder of each being independently selected CR ¹ 。

In certain of these embodiments, the compound is selected from the group consisting of compounds having the formula:

In certain embodiments, the compound is a compound having formula (Ib):

wherein: r is R ^1a 、R ^1b And R is ^1c Each is thatR independently selected ¹ 。

In certain embodiments, the compound is a compound having formula (Ic):

wherein: r is R ^1a 、R ^1b And R is ^1d Each independently selected R ¹ 。

In certain embodiments, the compound is a compound having formula (Id):

wherein: r is R ^1a 、R ^1c And R is ^1d Each independently selected R ¹ 。

In certain embodiments, the compound is a compound having formula (Ie):

wherein: r is R ^1b 、R ^1c And R is ^1d Each independently selected R ¹ 。

In some embodiments, X ¹ Is NR (NR) ² . In some of these embodiments, X ¹ Is NH.

In some embodiments, X ² Is CR (CR) ⁵ . In some of these embodiments, X ² Is CH.

In some embodiments, X ¹ Is NR ² The method comprises the steps of carrying out a first treatment on the surface of the And X is ² Is CR (CR) ⁵ . In certain embodiments, X ¹ Is NR ² The method comprises the steps of carrying out a first treatment on the surface of the And X is ² Is CH. In certain embodiments, X ¹ Is NH; and X is ² Is CR (CR) ² . In certain embodiments, X ¹ Is NH; and X is ² Is CH.

In some embodiments, the compound is a compound having formula (Ia-1) or a pharmaceutically acceptable salt thereof:

wherein: r is R ^1a 、R ^1b 、R ^1c And R is ^1d 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 is ⁵ Is H.

In some embodiments, the compound is selected from a compound having the formula:

In certain embodiments, the compound is a compound having formula (Ib-1):

Wherein: r is R ^1a 、R ^1b And R is ^1c 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 is ⁵ Is H.

In certain embodiments, the compound is a compound having formula (Ic-1) or a pharmaceutically acceptable salt thereof:

wherein: r is R ^1a 、R ^1b And R is ^1d 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 is ⁵ Is H.

In certain embodiments, the compound is a compound having the formula (Id-1):

wherein: r is R ^1a 、R ^1c And R is ^1d Each independently selected R ¹ . In certain embodiments of formula (Id-1), R ² Is H. In certain embodiments of formula (Id-1), R ⁵ Is H. In certain embodiments of formula (Id-1), R ² Is H; and R is ⁵ Is H.

In certain embodiments, the compound is a compound having the formula (Ie-1):

wherein: r is R ^1b 、R ^1c And R is ^1d 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 is ⁵ Is H.

¹ Variable R

In some embodiments, each R ¹ Is H.

In some embodiments, 1-2R ¹ Is independently selected notHydrogen substituents, with each remaining R ¹ Is H. In certain embodiments, 1-2R ¹ Each independently selected from the group consisting of: r is R ^c1 And R is ^g1 The method comprises the steps of carrying out a first treatment on the surface of the And each remaining R ¹ Is H, wherein R ^c1 R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And R is ^g1 R is independently selected ^g 。

In some of these embodiments, R ^a Independently selected from the group consisting of: r is R ^c1 And R is ^g1 The method comprises the steps of carrying out a first treatment on the surface of the And each remaining R ¹ Is H.

For example, R ¹ Is R independently selected for two occurrences of ^c1 The method comprises the steps of carrying out a first treatment on the surface of the And each remaining R ¹ Is H. In some of these embodiments, each R ^c1 Is an independently selected halogen, such as-F or-Cl.

In certain embodiments (wherein 1-2R' s ¹ Independently selected from the group consisting of: r is R ^c1 And R is ^g1 The method comprises the steps of carrying out a first treatment on the surface of the And each remaining R ¹ Is H, wherein R ^c1 R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And R is ^g1 R is independently selected ^g ) Wherein R is ¹ Is selected from the group consisting of: r is R ^c1 And R is ^g1 The method comprises the steps of carrying out a first treatment on the surface of the And each remaining R ¹ Is H. In some of these embodiments, R ¹ Is R ^c1 The method comprises the steps of carrying out a first treatment on the surface of the And each remaining R ¹ Is H. In some of these embodiments, R ^c1 Halogen, for example-F or-Cl, for example-F.

In certain embodiments (wherein 1-2R' s ¹ Independently selected from the group consisting of: r is R ^c1 And R is ^g1 The method comprises the steps of carrying out a first treatment on the surface of the And each remaining R ¹ Is H, wherein R ^c1 R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And R is ^g1 R is independently selected ^g ) Wherein R is ¹ Is R ^g1 The method comprises the steps of carrying out a first treatment on the surface of the And each remaining R ¹ Is H.

In certain embodiments (wherein 1-2R' s ¹ Independently selected from the group consisting of: r is R ^c1 And R is ^g1 The method comprises the steps of carrying out a first treatment on the surface of the And each remaining R ¹ Is H, wherein R ^c1 R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And R is ^g1 R is independently selected ^g ) Wherein each R is ^c1 Is an independently selected halogen, eSuch as-F, -Cl or-Br. In some of these embodiments, each R ^c1 independently-F or-Cl, such as-F.

In certain embodiments (wherein 1-2R' s ¹ Independently selected from the group consisting of: r is R ^c1 And R is ^g1 The method comprises the steps of carrying out a first treatment on the surface of the And each remaining R ¹ Is H, wherein R ^c1 R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And R is ^g1 R is independently selected ^g ) Wherein each R is ^g1 Independently selected from the group consisting of: heteroaryl groups having 5 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c 、R ^h And- (L) ^g ) _bg -R ^h The method comprises the steps of carrying out a first treatment on the surface of the And C _6-10 Aryl optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c 、R ^h And- (L) ^g ) _bg -R ^h 。

In some of these embodiments, each R ^g1 Independently selected from the group consisting of: heteroaryl groups having 5 to 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S, and wherein the heteroaryl is optionally substituted with 1-4R ^c Substitution; and optionally is substituted with 1-4R ^c Substituted C ₆ Aryl groups.

In some of the foregoing embodiments, each R ^g1 Independently is a heteroaryl group having 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S, and wherein the heteroaryl group is optionally substituted with 1-4R ^c And (3) substitution. As a non-limiting example of the foregoing embodiment, each R ^g1 Can be optionally substituted with 1-2R ^c (e.g. 1-2 independently selected C _1-6 (e.g., C _1-3 ) Alkyl) substituted pyrazolyl, the C _1-6 Alkyl is optionally substituted with 1-6 independently selected R ^a Substituted (e.g., unsubstituted).

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

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

In some embodiments, the compound is a compound having formula (Ia), (Ia-1), (Ib-1), (Ic-1), (Ie) or (Ie-1); and R is ^1b Halogen, such as-F or-Cl (e.g., -F).

In some embodiments, the compound is a compound having formula (Ia), (Ia-1), (Ib-1), (Ic-1), (Ie) or (Ie-1); and R is ^1b Is a heteroaryl group having 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S, and wherein the heteroaryl group is optionally substituted with 1-2R ^c And (3) substitution. In some of these embodiments, R ^1b Is optionally substituted with 1-2R ^c Substituted pyrazolyl radicals, e.g. each R ^c Is independently selected C _1-6 (e.g., C _1-3 ) Alkyl, optionally substituted with 1-6 independently selected R ^a Substituted (e.g., unsubstituted).

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

In some embodiments, the compound is a compound having formula (Ia), (Ia-1), (Ib-1), (Id-1), (Ie) or (Ie-1); and R is ^1c Halogen, such as-F or-Cl (e.g., -F).

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

In some embodiments, the compound is a compound having formula (Ia), (Ia-1), (Ic-1), (Id-1), (Ie) or (Ie-1); and R is ^1d Halogen, such as-F or-Cl (e.g., -F).

In some embodiments, the compound is of formula (Ia), (Ia-1), (Ib-1), (Ic),A compound of (Ic-1), (Id-1), (Ie) or (Ie-1); r is R ^1a And R is ^1d When present is H; and R is ^1b And R is ^1c Halogen, such as-F or-Cl, such as-F, when present, is independently selected.

In some embodiments, the compound is a compound having formula (Ia), (Ia-1), (Ib-1), (Ic-1), (Id-1), (Ie) or (Ie-1); r is R ^1a And R is ^1d When present is H; r is R ^1b And R is ^1c One of which when present is H; and R is ^1b And R is ^1c The other, when present, is halogen, such as-F or-Cl, such as-F.

In some embodiments, the compound is a compound having formula (Ia), (Ia-1), (Ib-1), (Ic-1), (Id-1), (Ie) or (Ie-1); r is R ^1a And R is ^1d When present is H; r is R ^1c Halogen or H when present, e.g., -F, -Cl or H; and R is ^1b Heteroaryl groups having 5 ring atoms, where 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S, and wherein the heteroaryl group is optionally substituted with 1-4R ^c And (3) substitution.

⁶ Variable R

In some embodiments, R ⁶ Is H.

Variable ring B

In some embodiments, ring B is a heteroarylene group having 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, NH, O and S, wherein the heteroarylene of ring B is optionally substituted with 1-2R ^cB Substitution; and each R is ^cB R is independently selected ^c 。

In some embodiments, ring B is a heteroarylene group having 5 ring atoms, wherein 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, NH, N (R) ^d ) And S, wherein the heteroarylene of ring B is optionally substituted with 1-2R ^cB Substitution; and each R is ^cB R is independently selected ^c 。

In one placeIn some embodiments, ring B is a heteroarylene group having 5 ring atoms, wherein 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of: n and NH, wherein the heteroarylene of ring B is optionally substituted with 1-2R ^cB Substitution; and each R is ^cB R is independently selected ^c . As non-limiting examples of the foregoing embodiments, ring B is selected from the group consisting of: imidazolylene (imidazolylene), pyrazolylene (pyrazolylene) or triazolylene (triazolylene) (e.g. 1,2, 3-triazolylene), optionally substituted with one R ^cB And (3) substitution.

In certain embodiments, ring B is an imidazolylene group, optionally substituted with one R ^cB And (3) substitution.

In certain embodiments, ring B isWhich is optionally substituted with one R ^cB Substitution, wherein aa is a group similar to (L ^A ) _a1 Is connected to the connecting point of (c).

In certain embodiments, ring B isWhich is optionally substituted with one R ^cB Substitution, wherein aa is a group similar to (L ^A ) _a1 Is connected to the connecting point of (c). />

In certain embodiments, ring B is a triazolylene group (e.g., 1,2, 3-triazolylene) optionally substituted with one R ^cB And (3) substitution.

In certain embodiments, ring B is pyrazolylene, optionally substituted with one R ^cB And (3) substitution.

In certain embodiments, ring B isWhich is optionally covered withR ^cB Substitution, wherein aa is a group similar to (L ^A ) _a1 Is connected to the connecting point of (c).

In certain embodiments, each R ^cB Independently is halogen or C _1-3 Alkyl, optionally substituted with 1-3 independently selected R ^a (e.g., 1-3 independently selected halogens).

In some embodiments, ring B is selected from the group consisting of: isoxazolylene, oxadiazolylene, oxazolylene, thiazolylene, isothiazolylene or thiadiazolylene, optionally substituted with one R ^cB And (3) substitution.

In certain embodiments, ring B isEach of which is optionally covered with one R ^cB Substitution, wherein aa is a group similar to (L ^A ) _a1 Is connected to the connecting point of (c).

^A Variables a1 and L

In some embodiments, a1 is 0. In some other embodiments, a1 is 1.

In some embodiments, L ^A Is optionally substituted with 1-2R ^a1 Substituted C _1-3 An alkylene group. In some of these embodiments, L ^A Is CH ₂ Or CH (Me), e.g. CH ₂ 。

In some embodiments, a1 is 1; and L is ^A Is optionally substituted with 1-2R ^a1 Substituted C _1-3 An alkylene group. In some of these embodiments, L ^A Is CH ₂ Or CH (Me), e.g. CH ₂ 。

Variable ring C

In some embodiments, ring C is selected from the group consisting of:

heteroarylene having 5 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heteroarylene isThe radicals being optionally substituted by 1 to 4 substituents independently selected from the group consisting of: r is R ^cC And R is ^hC The method comprises the steps of carrying out a first treatment on the surface of the And

C _6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^cC And R is ^hC ；

Wherein each R is ^cC R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And each R is ^hC R is independently selected ^h 。

In some of these embodiments, ring C is selected from the group consisting of:

heteroarylene having 5 to 6 (e.g., 6) ring atoms, wherein 1 to 3 (e.g., 1 to 2) ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^cC The method comprises the steps of carrying out a first treatment on the surface of the And

C ₆ arylene optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^cC 。

In certain embodiments (wherein ring C is selected from the group consisting of heteroarylenes having 5 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^cC And R is ^hC The method comprises the steps of carrying out a first treatment on the surface of the And C _6-10 Arylene optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^cC And R is ^hC Wherein each R is ^cC R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And each R ^hC R is independently selected ^h ) Wherein ring C is selected from the group consisting of:

a pyridinyl group optionally substituted with 1-3 (e.g., 1) substituents independently selected from the group consisting of: r is R ^cC The method comprises the steps of carrying out a first treatment on the surface of the And

C ₆ arylene optionally substituted with 1-4 (e.g., 1-2) substituents independently selected from the group consisting of: r is R ^cC 。

In certain embodiments, ring C is a group having the formula:wherein Q is ¹ 、Q ² 、Q ³ And Q ⁴ Each independently selected from the group consisting of: n, CH and CR ^cC The method comprises the steps of carrying out a first treatment on the surface of the And bb is with R ⁷ Wherein each R is ^cC R is independently selected ^c 。

In certain embodiments, Q ¹ 、Q ² 、Q ³ And Q ⁴ One is each independently CH or CR ^cC . In certain other embodiments, Q ¹ 、Q ² 、Q ³ And Q ⁴ From 1 to 2 (e.g., 1) of (a) are N; and Q is ¹ 、Q ² 、Q ³ And Q ⁴ Each of the remainder of (a) is independently CH or CR ^cC 。

In certain embodiments, Q ² Is CH. In certain embodiments, Q ³ Is CH. In certain embodiments, Q ⁴ Is N. In certain embodiments, Q ¹ Is CH. In certain other embodiments, Q ¹ Is CR (CR) ^cC 。

In certain embodiments, ring C isFor example->

In certain embodiments, each R ^cC Independently selected from the group consisting of: halogen and C _1-6 (e.g. C _1-3 ) Alkyl, optionally R independently selected by 1-6 each ^a (e.g., 1-6 independently selected halogens, such as-F).

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

⁷ Variable R

In some embodiments, R ⁷ Is R ^g 。

In some embodiments, R ⁷ Selected from the group consisting of:

C _3-12 cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of: oxo, R ^c7 、R ^h7 And- (L) ^g ) _bg -R ^h7 The method comprises the steps of carrying out a first treatment on the surface of the And

heterocyclyl having 4 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: oxo, R ^c7 、R ^h7 And- (L) ^g ) _bg -R ^h7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein each R is ^c7 R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And R is ^h7 R is independently selected ^h 。

In some of these embodiments, R ⁷ Selected from the group consisting of:

C _4-8 (e.g. C ₄ 、C ₅ Or C ₆ ) Cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of: oxo, R ^c7 And R is ^h7 The method comprises the steps of carrying out a first treatment on the surface of the And

heterocyclyl having 4-8 (e.g., 4, 5, or 6) ring atoms, wherein 1-3 ring atoms are heteroatoms each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: oxo, R ^c7 And R is ^h 。

In some of the foregoing embodiments, R ⁷ Selected from the group consisting of:

C ₆ cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c7 The method comprises the steps of carrying out a first treatment on the surface of the And

heterocyclyl having 6-8 ring atoms, wherein 1-2 (e.g., 1) ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c7 。

In some of these embodiments, R ⁷ Is a group having the formula:wherein X is ⁷ Is CH, CR ^c7 Or N, such as CH or N. In certain embodiments (when R ⁷ Is->When) there are two R ^c7 A group.

In certain embodiments, R ⁷ Is a group having the formula:wherein X is ⁷ Is N or CH; and each R is ^c7 R is independently selected ^c . In certain embodiments, R ⁷ Is->Wherein X is ⁷ Is N or CH; for example->

C ₄ cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c7 The method comprises the steps of carrying out a first treatment on the surface of the And

heterocyclyl having 4-8 ring atoms, wherein 1-2 (e.g., 1) ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c7 。

In certain embodiments, R ⁷ Selected from the group consisting of: tetrahydropyranyl, morpholinyl, 5-azaspiro [2.5 ]]Octyl or 2-azabicyclo [2.2.1]Heptyl groups, each optionally substituted with 1-2R ^c7 And (3) substitution. For example, R7 may be:

in certain embodiments, each R ^c7 Is independently selected halogen or C _1-3 Alkyl, optionally substituted with 1-6 each R ^a Substitution (e.g., 1-6 independently selected halogens). In some of these embodiments, each R ^c7 Independently is halogen, e.g., -F.

In some embodiments, R ⁷ Selected from the group consisting of:

C _4-5 cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c7 The method comprises the steps of carrying out a first treatment on the surface of the And

heterocyclyl having 5-6 ring atoms, wherein 1-2 (e.g., 1) ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl is optionally independently selected from1-4 substituents of the group: r is R ^c7 。

In certain embodiments, R ⁷ Is a group having the formula:wherein X is ⁷ Is CH, CR ^c7 Or N, alternatively CH or N.

In certain embodiments, R ⁷ Is a group having the formula:wherein R is ^d Independently selected from the group consisting of: c (C) _1-6 Alkyl, optionally substituted with 1-3 independently selected R ^a And (3) substitution.

non-limiting combinations

In some embodiments, the compound is a compound having formula (I-a 1-1):

wherein:

R ^1a 、R ^1b and R is ^1c Each independently selected R ¹ ；

B ⁴ Is C or N;

B ¹ 、B ² and B ³ Each independently is CH, CR ^cB 、NH、N(R ^d ) N, O or S;

Q ¹ 、Q ² 、Q ³ and Q ⁴ Each independently selected from the group consisting of: n, CH and CR ^cC ；

R in each occurrence ^cB And R is ^cC R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And

each of which is provided withIs independently a single bond or a double bond, provided that B is contained ¹ -B ⁴ Is heteroaryl.

In some embodiments of formula (I-a 1-1), R ^1a And R is ^1d Is H; and R is ^1b And R is ^1c Independently H or halogen.

In some embodiments of formula (I-a 1-1), R ^1a And R is ^1d Is H; and R is ^1b And R is ^1c Is an independently selected halogen, such as-F or-Cl, such as-F.

In some embodiments of formula (I-a 1-1), R ^1a 、R ^1b 、R ^1c And R is ^1d Is H.

In some embodiments of formula (I-a 1-1), R ^1a And R is ^1d Is H; r is R ^1c Halogen or H, for example-F, -Cl or H; and R is ^1b Is a heteroaryl group having 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c 。

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

In some embodiments of formula (I-a 1-1), R ⁶ Is H.

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

In some embodiments of formula (I-a 1-1), B ⁴ Is N; b (B) ¹ Is N; b (B) ³ Is CH or CR ^cB The method comprises the steps of carrying out a first treatment on the surface of the And B ² Is CH or CR ^cB . In certain embodiments, B ⁴ Is N; b (B) ¹ Is N; b (B) ³ Is CH; and B ² Is CH. In certain embodiments, B ⁴ Is N; b (B) ¹ Is N; b (B) ³ Is CH; and B ² Is CR (CR) ^cB 。

In some embodiments of formula (I-a 1-1), B ⁴ Is N; b (B) ¹ Is N; b (B) ³ Is CH or CR ^cB The method comprises the steps of carrying out a first treatment on the surface of the And B ² Is N. In certain embodiments, B ⁴ Is N; b (B) ¹ Is N; b (B) ³ Is CH; and B ² Is N.

In some embodiments of formula (I-a 1-1), B ⁴ Is N; b (B) ¹ Is CH or CR ^cB ；B ³ Is CH or CR ^cB The method comprises the steps of carrying out a first treatment on the surface of the And B ² Is N. In certain embodiments, B ⁴ Is N; b (B) ¹ Is CH; b (B) ³ Is CH; and B ² Is N.

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

In some embodiments of formula (I-a 1-1), B ⁴ Is C; b (B) ¹ Is N, B ³ Is CR (CR) ^cB The method comprises the steps of carrying out a first treatment on the surface of the And B ² Is O. In certain embodiments, B ⁴ Is C; b (B) ¹ Is N; b (B) ³ Is CH; and B ² Is O. In other embodiments, B ⁴ Is C; b (B) ¹ Is O; b (B) ³ Is CH; and B ² Is N.

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

Some of the examples of the compounds of the formula (I-a 1-1)In embodiments, Q ¹ And Q ³ Is CH or CR ^cC (e.g., CH). In some embodiments of formula (I-a 1-1), Q ⁴ Is N; and Q is ² Is CH or CR ^cC For example CR ^cC 。

In some embodiments of formula (I-a 1-1), Q is included ¹ -Q ⁴ The ring of (2) is:wherein bb is with R ⁷ Is connected to the connecting point of (c).

In some embodiments of formula (I-a 1-1), R ^cC Halogen, for example-F or-Cl, for example-F.

In some embodiments of formula (I-a 1-1), R ⁷ Selected from the group consisting of:

heterocyclyl having 6-8 ring atoms, wherein 1-2 (e.g., 1) ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c7 Wherein each R is ^c7 R is independently selected ^c 。

In some embodiments of formula (I-a 1-1), R ⁷ Is a group having the formula:wherein X is ⁷ Is CH, CR ⁷ Or N, such as CH or N. In certain embodiments, there are two R ^c7 A group.

In some embodiments of formula (I-a 1-1), R ⁷ Is a group having the formula:wherein X is ⁷ Is N or CH; and each R is ^c7 R is independently selected ^c . In certain embodiments, R ⁷ Is->Wherein X is ⁷ Is N or CH; for example

In some embodiments of formula (I-a 1-1), R ⁷ Is a group having the formula:wherein X is ⁷ Is CH, CR ^c7 Or N, such as CH or N. In certain embodiments (when R ⁷ Is->When) there are two R ^c7 A group.

In some embodiments of formula (I-a 1-1), R ⁷ Is a group having the formula:wherein X is ⁷ Is N or CH; and each R is ^c7 R is independently selected ^c . In certain embodiments, R ⁷ Is->Wherein X is ⁷ Is N or CH; for example->

In some embodiments of formula (I-a 1-1), R ⁷ Selected from the group consisting of: tetrahydropyranyl, morpholinyl, 5-azaspiro [2.5 ]]Octyl or 2-azabicyclo [2.2.1]Heptyl groups, each optionally substituted with 1-2R ^c7 And (3) substitution. For example, R7 may be:

in some embodiments of formula (I-a 1-1), each R ^c7 Is independently selected halogen or C _1-3 Alkyl, optionally substituted with 1-6 each R ^a Substitution (e.g., 1-6 independently selected halogens). In some of these embodiments, each R ^c7 Independently is halogen, e.g., -F.

In some embodiments, the compound is a compound having formula (I-a 1-1), wherein:

R ^1a and R is ^1d Is H;

R ^1b 、R ^1c each independently selected from: h is formed; and R is ^c ，

R ² 、R ⁵ 、R ⁶ Each independently is H;

B ¹ selected from CH and N;

B ² and B ⁴ Each independently is N;

B ³ is CH;

Q ¹ is N; q (Q) ² And Q ³ Each independently is CH; q (Q) ⁴ Is CR (CR) ^c The method comprises the steps of carrying out a first treatment on the surface of the And

each of which is provided withIs independently a single bond or a double bond, provided that B is contained ¹ -B ⁴ Is heteroaryl;

R ⁷ is thatWherein X is ⁷ Is N or CH, and is not limited to the above,

wherein each occurrence of R ^c Independently selected from the group consisting of: halogen; c (C) _1-10 Alkyl, optionally R independently selected by 1-6 each ^a Substitution;

wherein each occurrence of R ^a Independently selected from the group consisting of: -OH; halogen; c (C) _1-4 An alkoxy group; c (C) _1-4 Haloalkoxy groups.

In some embodiments, the compound is a compound having formula (I-f 1-1) or a pharmaceutically acceptable salt thereof:

wherein:

z is N or CR ^1a ；Y ¹ Is N or CR ^1b ；Y ² Is N or CR ^1c ；Y ³ Is N or CR ^1d Provided that it is Z, Y ¹ 、Y ² And Y ³ From 1 to 2 (e.g., 1) of (a) are N;

R ^1a 、R ^1b and R is ^1c Each independently selected R ¹ ；

B ⁴ Is C or N;

In some embodiments of formula (I-f 1-1), Z, Y ¹ 、Y ² And Y ³ One of which is N.

In some embodiments of formula (I-f 1-1), the compound is a compound having formula (I-b 1-1):

or a pharmaceutically acceptable salt thereof.

In some embodiments of formula (I-f 1-1), the compound is a compound having formula (I-c 1-1):

or a pharmaceutically acceptable salt thereof.

In some embodiments of formula (I-f 1-1), the compound is a compound having formula (I-d 1-1):

or a pharmaceutically acceptable salt thereof.

In some embodiments of formula (I-f 1-1) (e.g., formula (I-b 1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), R ^1a And R is ^1d Is H when present; and R is ^1b And R is ^1c And when present is H or halogen.

In some embodiments of formula (I-f 1-1) (e.g., formula (I-b 1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), R ^1a And R is ^1d Is H when present; and R is ^1b And R is ^1c Independently selected from halogen, such as-F or-Cl, such as-F, when present.

In the formula (I-f 1)1) In some embodiments of (e.g., formula (I-b 1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), R ^1a 、R ^1b 、R ^1c And R is ^1d Is H when present.

In some embodiments of formula (I-f 1-1) (e.g., formula (I-b 1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), R ^1a And R is ^1d Is H; r is R ^1c Halogen or H, for example-F, -Cl or H; and R is ^1b Heteroaryl groups having 5 ring atoms, where 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c 。

In some embodiments of formula (I-f 1-1) (e.g., formula (I-b 1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), R ^1d Halogen, such as-F or-Cl, when present, is independently selected. In some of these embodiments, R ^1a 、R ^1b And R is ^1c Is H when present.

In some embodiments of formula (I-f 1-1) (e.g., formula (I-b 1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), R ² Is H. In some embodiments of formula (I-a 1-1), R ⁵ Is H. In some embodiments of formula (I-a 1-1), R ² Is H; and R is ⁵ Is H.

In some embodiments of formula (I-f 1-1) (e.g., formula (I-b 1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), R ⁶ Is H.

In some embodiments of formula (I-f 1-1) (e.g., formula (I-b 1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), R ² Is H; r is R ⁵ Is H; and R is ⁶ Is H.

In some embodiments of formula (I-f 1-1) (e.g., formula (I-B1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), B ⁴ Is N; b (B) ¹ Is N; b (B) ³ Is CH or CR ^cB The method comprises the steps of carrying out a first treatment on the surface of the And B ² Is CH or CR ^cB . In certain embodiments, B ⁴ Is N; b (B) ¹ Is N; b (B) ³ Is CH; and B ² Is CH. In certain embodiments, B ⁴ Is N; b (B) ¹ Is N; b (B) ³ Is CH; and B ² Is CR (CR) ^cB 。

In some embodiments of formula (I-f 1-1) (e.g., formula (I-B1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), B ⁴ Is N; b (B) ¹ Is N; b (B) ³ Is CH or CR ^cB The method comprises the steps of carrying out a first treatment on the surface of the And B ² Is N. In certain embodiments, B ⁴ Is N; b (B) ¹ Is N; b (B) ³ Is CH; and B ² Is N.

In some embodiments of formula (I-f 1-1) (e.g., formula (I-B1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), B ⁴ Is N; b (B) ¹ Is CH or CR ^cB ；B ³ Is CH or CR ^cB The method comprises the steps of carrying out a first treatment on the surface of the And B ² Is N. In certain embodiments, B ⁴ Is N; b (B) ¹ Is CH; b (B) ³ Is CH; and B ² Is N.

In some embodiments of formula (I-f 1-1) (e.g., formula (I-B1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), B ⁴ Is N; b (B) ¹ Is CH or CR ^cB ；B ³ Is N; and B ² Is CH or CR ^cB . In certain embodiments, B ⁴ Is N; b (B) ¹ Is CH; b (B) ³ Is N; and B ² Is CH.

In some embodiments of formula (I-f 1-1) (e.g., formula (I-b 1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), a1 is 0. In some embodiments of formula (I-a 1-1), a1 is 1. In some embodiments of formula (I-f 1-1), L ^A Is CH ₂ Or CH (Me).

In some embodiments of formula (I-f 1-1) (e.g., formula (I-b 1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), Q ¹ And Q ³ Is CH or CR ^cC (e.g., CH). In some embodiments of formula (I-f 1-1), Q ⁴ Is N; and Q is ² Is CH or CR ^cC For example CR ^cC 。

In some embodiments of formula (I-f 1-1) (e.g., formula (I-b 1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), Q is included ¹ -Q ⁴ The ring of (2) is:wherein bb is withR ⁷ Is connected to the connecting point of (c).

In some embodiments of formula (I-f 1-1) (e.g., formula (I-b 1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), R ^cC Halogen, for example-F or-Cl, for example-F.

In some embodiments of formula (I-f 1-1) (e.g., formula (I-b 1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), R ⁷ Selected from the group consisting of:

In some embodiments of formula (I-f 1-1) (e.g., formula (I-b 1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), R ⁷ Is a group having the formula:wherein X is ⁷ Is CH, CR ⁷ Or N, such as CH or N. In certain embodiments, there are two R ^c7 A group.

In some embodiments of formula (I-f 1-1) (e.g., formula (I-b 1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), R ⁷ Is a group having the formula:wherein X is ⁷ Is N or CH; and each R is ^c7 R is independently selected ^c . In certain embodiments, R ⁷ Is->Wherein X is ⁷ Is N or CH; for example->

In some embodiments of formula (I-f 1-1) (e.g., formula (I-b 1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), R ⁷ Is a group having the formula:wherein X is ⁷ Is CH, CR ^c7 Or N, such as CH or N. In certain embodiments (when R ⁷ Is->When) there are two R ^c7 A group.

In formula (I-f 1-1) (e.g. formula (I-b 1-1), (I-c 1-1), (I-d 1-1) or(I-e 1-1)) and R ⁷ Selected from the group consisting of: tetrahydropyranyl, morpholinyl, 5-azaspiro [2.5 ]]Octyl or 2-azabicyclo [2.2.1]Heptyl groups, each optionally substituted with 1-2R ^c7 And (3) substitution. For example, R7 may be:

in some embodiments of formula (I-f 1-1) (e.g., formula (I-b 1-1), (I-c 1-1), (I-d 1-1), or (I-e 1-1)), each R ^c7 Is independently selected halogen or C _1-3 Alkyl, optionally substituted with 1-6R ^a (e.g., 1-6 independently selected halogens). In some of these embodiments, each R ^c7 Independently is halogen, e.g., -F.

Non-limiting exemplary Compounds

In some embodiments, the compound is selected from the compounds described in table C1 or a pharmaceutically acceptable salt thereof.

Table C1

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Pharmaceutical composition and administration

SUMMARY

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

In some embodiments, the chemical entity may be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), such as d-alpha-tocopheryl polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as tween (Tweens), poloxamers or other similar polymer delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphates, tris (tris), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or dielectrics, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and lanolin. Cyclodextrins such as alpha-, beta-and gamma-cyclodextrins, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2-and 3-hydroxypropyl-beta-cyclodextrins, or other solubilized derivatives, may also be used to provide delivery of the compounds described herein. Dosage forms or compositions may be prepared comprising in the range of 0.005% to 100% of the chemical entity described herein, the balance being complemented by non-toxic excipients. Contemplated compositions may comprise from 0.001% to 100% of the chemical entities provided herein, in one embodiment from 0.1% to 95%, in another embodiment from 75% to 85%, and in yet another embodiment from 20% to 80%. The actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, ramington: pharmaceutical science and practice (Remington: the Science and Practice of Pharmacy), 22 nd edition (pharmaceutical press in london, uk (Pharmaceutical Press), 2012).

Route of administration and composition Components

In some embodiments, a chemical entity described herein or a pharmaceutical composition thereof may be administered to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to: oral, transdermal, cervical, intranasal, intratnasal, intratracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intracapsular (intraburst), intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, endocranial, intraepidermal, esophageal, intragastric, gingival, intraileal, intralymphatic, intramedullary, intrathecal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, sinus, intraspinal, intrasynovial, intrathecal, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, transdermal, epidural (peridial), rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In some embodiments, the preferred route of administration is parenteral (e.g., intratumoral).

The compositions may be formulated for parenteral administration, for example, for injection by intravenous, intramuscular, subcutaneous or even intraperitoneal routes. Typically, such compositions may be formulated as injectables, either as liquid solutions or suspensions; solid forms suitable for addition to a liquid prior to injection to prepare a solution or suspension may also be prepared; furthermore, the formulation may also be emulsified. The preparation of such formulations is known to those skilled in the art in light of the present disclosure.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; including sesame oil, peanut oil or propylene glycol aqueous formulations; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, this form must be sterile and must be fluid to the extent that easy injection is possible. It should also be stable under the conditions of manufacture and storage and must be resistant to the contaminating action of microorganisms such as bacteria and fungi during storage.

The carrier may also be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycols, and the like), and suitable mixtures thereof, as well as vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars or sodium chloride. Absorption of the injectable composition may be prolonged by the use in the composition of agents which delay 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 various of the other above-described ingredients and then filter-sterilizing as required. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains an alkaline dispersion medium and the other required ingredients described above. When preparing sterile injectable solutions to prepare the desired sterile powders, the preferred methods of preparation are vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Intratumoral injection is described, for example, in Lammers et al, "effect of intratumoral injection on biodistribution and therapeutic potential of HPMA copolymer-based drug delivery systems" ("Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems") neoplasia.2006,10,788-795.

Pharmaceutically acceptable excipients that may be used as gels, creams, enemas, or rectal suppositories in rectal compositions include, but are not limited to, one or more of the following: cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerol, glycerogelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols and fatty acid esters of polyethylene glycols of various molecular weights, petrolatum, anhydrous lanolin, shark liver oil, saccharin sodium, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosols, parabens in phenoxyethanol, sodium methylparaben, sodium propylparaben, diethylamine, carbomers, carbopol, methoxybenzoate, polyethylene glycol cetostearyl ether, decyl cocoate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-pyrosulfite, sodium ethylenediamine tetraacetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins (e.g., vitamins a and E), and potassium acetate.

In some embodiments, suppositories may be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycols or suppository waxes, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, 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 tract or gastrointestinal tract by oral administration (e.g., solid or liquid dosage forms).

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the chemical entity is admixed with one or more pharmaceutically acceptable excipients (e.g., 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 (acacia); c) Humectants, such as glycerol; d) Disintegrants, for example agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; e) Solution retarders, such as paraffin; f) Absorption promoters, such as quaternary ammonium compounds; g) Wetting agents, such as acetyl alcohol and glycerol monostearate; h) Adsorbents such as kaolin and bentonite; and i) a lubricant, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, high molecular weight polyethylene glycols and the like.

In one embodiment, the composition may take the form of a unit dosage form such as a pill or tablet, and thus the composition may comprise, in addition to the chemical entities provided herein: diluents such as lactose, sucrose, dicalcium phosphate and the like; lubricants such as magnesium stearate and the like; binding agents such as starch, acacia, polyvinylpyrrolidone, gelatin, cellulose derivatives and the like. In another solid dosage form, a powder, pill, solution or suspension (e.g., in propylene carbonate, vegetable oil, PEG agent, poloxamer 124, or triglycerides) is encapsulated within a capsule (gelatin or cellulose-based capsule). Unit dosage forms in which one or more chemical entities or other active agents provided herein are physically separated, such as capsules (or tablets in capsules) containing individual drug particles, are also contemplated; bilayer tablets; double-chamber gel capsules, and the like. 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 particularly useful for avoiding microbial growth or action. Various preservatives are well known and include, for example, phenol and ascorbic acid.

In certain embodiments, the excipient is sterile and generally free of undesirable substances. The composition may be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients, such as tablets and capsules, no sterility is required. The USP/NF standard is generally sufficient.

In some embodiments, the solid oral dosage form may further include one or more components that chemically and/or structurally facilitate the composition to deliver a chemical entity to the stomach or lower GI; for example, the ascending and/or transverse and/or distal colon and/or small intestine. Exemplary formulation techniques are described, for example, in Filipski, K.J. et al, current Topics in Medicinal Chemistry,2013,13,776-802, which is incorporated herein by reference in its entirety.

Examples include upper GI targeting techniques such as Accordion Pill (intel Pharma corporation), floating capsules and materials that can adhere to mucosal walls.

Other examples include lower GI targeting techniques. To target various regions of the intestinal tract, several enteric/pH-responsive coatings and excipients may be used. These materials are typically polymers designed to dissolve or erode over a specific pH range, selected based on the GI region of desired drug release. In cases where the active ingredient may stimulate the upper GI, these materials also function to protect the acid labile drug from gastric erosion or limit exposure (e.g., hydroxypropyl methylcellulose phthalate series, coaterics (vinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate series (methacrylic acid-methyl methacrylate copolymers) and Marcoat. Other techniques include dosage forms responsive to the local flora of the gastrointestinal tract, pressure controlled colon delivery capsules and Pulsincap.

The ophthalmic composition may comprise, but is not limited to, any one or more of the following: collagen (viscons) (e.g., carboxymethyl cellulose, glycerol, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., pluronic (triblock copolymers), cyclodextrins); preservatives (e.g., benzalkonium chloride, ETDA, softzia (boric acid, propylene glycol, sorbitol, and zinc chloride; elkang laboratories (Alcon Laboratories inc.)), purite (stable chlorooxide complex; allergan, inc.).

Topical compositions may include ointments and creams. Ointments are semisolid preparations, usually based on petrolatum or other petroleum derivatives. The cream containing the selected active agent is typically a viscous liquid or semi-solid emulsion, typically oil-in-water or water-in-oil. The cream base is typically water washable and contains an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes referred to as the "internal" phase, is typically composed of petrolatum and a fatty alcohol (such as cetyl or stearyl alcohol); although not necessarily, the aqueous phase typically exceeds the volume of the oil phase and typically contains a humectant. The emulsifier in the cream formulation is typically a nonionic, anionic, cationic or amphoteric surfactant. Like other carriers or vehicles, the ointment base should be inert, stable, non-irritating and insensitive.

In any of the foregoing embodiments, the pharmaceutical compositions described herein may comprise one or more of the following: lipid, multilamellar vesicles crosslinked between bilayers, biodegradable poly (D, L-lactic-co-glycolic acid) [ PLGA ] based or polyanhydride based nanoparticles or microparticles, and nanoporous particle supported lipid bilayers.

Dosage of

The dosage may vary depending on the patient's needs, the severity of the disease being treated and the particular compound being used. The determination of the appropriate dosage for a particular situation may be determined by one skilled in the medical arts. The total daily dose may be divided and administered in portions throughout the day or by providing continuous delivery.

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

Dosing regimen

The aforementioned doses may be administered daily (e.g., as a single dose or as two or more divided doses) or non-daily (e.g., every other day, every second day, every third day, once a week, twice a week, once every second week, once a month).

In some embodiments, the compounds described herein are administered for a period of time of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In another embodiment, the dosing is stopped for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In one embodiment, the therapeutic compound is administered to the subject for a period of time, followed by a separate period of time. In another embodiment, the therapeutic compound is administered for a first period of time, the administration is stopped for a second period of time after the first period of time, then the administration of the therapeutic compound is restarted for a third period of time, and then the administration is stopped for a fourth period of time after the third period of time. In one aspect of this embodiment, the period of administration of the therapeutic compound and the subsequent period of discontinuation of administration are repeated for a defined or indeterminate period of time. In another embodiment, the administration time 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 dosing is stopped for a period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more.

Therapeutic method

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

Indication of disease

In some embodiments, the condition, disease, or disorder is cancer. Non-limiting examples of cancers include: melanoma, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific examples of such cancers include: breast cancer, colon cancer, rectal cancer, large intestine cancer, kidney cancer, clear cell carcinoma lung cancer including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and lung squamous carcinoma, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), cervical cancer, ovarian cancer, prostate tumor, liver cancer, bladder cancer, peritoneal cancer, hepatocellular carcinoma, stomach cancer including gastrointestinal cancer, gastrointestinal stromal tumor, pancreatic cancer, head and neck cancer, glioblastoma, retinoblastoma, astrocytoma, follicular carcinoma, nephroblastoma, liver cancer (hepatoma), hematological malignancies including non-hodgkin lymphoma (NHL), multiple myeloma, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia, and acute hematological malignancies, endometrial or uterine cancer, endometriosis, endometrial sarcoma, fibrosarcoma, choriocarcinoma, salivary gland carcinoma, vulvar cancer, thyroid cancer, esophageal cancer, liver cancer (hepatic carcinoma), anal cancer, penile cancer, nasopharyngeal cancer, laryngeal cancer, kaposi's sarcoma, mast cell sarcoma, ovarian sarcoma, uterine sarcoma, melanoma, malignant mesothelioma, skin cancer, schwannoma (Schwannoma), glioma, neuroblastoma, neuroectodermal tumor, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcoma, ewing's sarcoma, peripheral primitive neuroectodermal tumor, urinary tract cancer, thyroid cancer, wilms ' tumor, abnormal vascular proliferation associated with phagocytosis, edema (e.g., edema associated with brain tumor), and Meger syndrome. In some cases, the cancer is melanoma.

In some embodiments, the condition, disease or disorder is a neurological disease, including diseases involving the central nervous system (brain, brain stem and cerebellum), the peripheral nervous system (including cranial nerves) and the autonomic nervous system (portions of which are located in the central and peripheral nervous systems). Non-limiting examples of neurological disorders include: acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; age-related macular degeneration; hypoplasia of the corpus callosum; disability syndrome; the akadine syndrome (aicodi syndrome); alexander disease (Alexander dis)an enzyme); alpers' disease; alternating hemiplegia; alzheimer's disease; vascular dementia; amyotrophic lateral sclerosis; no brain deformity; an Geman syndrome (Angelman syndrome); hemangiomatosis; hypoxia; aphasia; disuse; spider-web cysts; arachnoiditis; a malformation of a-Cai Ershi (Anronl-Chiari malformation); arteriovenous malformation; ai Siba lattice syndrome (Asperger syndrome); ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; white disease (Batten disease); behcet's disease; bell palsy (Bell's palsy); benign essential blepharospasm; benign localized muscular atrophy; intracranial benign hypertension; binswanger's disease; blepharospasm; brueck-sozbek syndrome (Bloch Sulzberger syndrome); brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal column tumor; brown-Sequard syndrome; kanavan disease (kanavan disease); carpal tunnel syndrome; causalgia (causalgia); central pain syndrome; central pontine myelination; headache; cerebral aneurysms; cerebral arteriosclerosis; brain atrophy; cerebral megaly; cerebral palsy; summer-horse-figure three disease (Charcot-Marie-Tooth); chemotherapy-induced neuropathy and neuropathic pain; QIANLIZHENG (Chiari malformation); chorea; chronic inflammatory demyelinating polyneuropathy; chronic pain; chronic local pain syndrome; kemelier's syndrome (Coffin Lowry syndrome); coma, including persistent plant states; congenital facial paralysis; degeneration of cortical basal; craniofacial arteritis; a skull anterior process; creutzfeldt-Jakob disease (Creutzfeldt-Jakob disease); cumulative traumatic disease; cushing's syndrome; megacell inclusion body disease; cytomegalovirus infection; dancing eye dancing foot syndrome; dandy-wok syndrome (Dandy-Walker syndrome); dawson disease (Dawson disease); de Mo Xiye syndrome (De Morsier's syndrome); jie Lin-Klumke palsy (Dejerine-Klumke palsy); dementia; dermatomyositis; diabetic neuropathy; diffuse hardening; autonomic nerve abnormalities; difficulty of writing (dysgraphia); a reading disorder; dystonia; early epileptic encephalopathy of infants; hollow butterfly saddle Syndrome; encephalitis; cerebral bulge; cerebral trigeminal hemangiomatosis (encephalotrigeminal angiomatosis); epilepsy; erb paralysis (Erb's palsy); essential tremor; fabry's disease; fire's syndrome; faint; familial spastic paralysis; febrile convulsion; fischer syndrome; friedrich's ataxia; frontotemporal dementia and other "tauopathies"; gaucher's disease; gerstmann syndrome (Gerstmann's syndrome); giant cell arteritis; giant cell inclusion body disease; globular cell white matter dystrophy; guillain-Barre syndrome; HTLV-1 related myelopathy; hallervorden-Spatz disease; head injury; headache; facial spasm; hereditary spastic paraplegia; hereditary ataxia polyneuritis-like disease (heredopathia atactica polyneuritiformis); herpes zoster of ear; herpes zoster; mountain-level syndrome (Hirayama syndrome); HIV-associated dementia and neuropathy (also the nervous system manifestations of AIDS); full forebrain deformity (holoprosencephaly); huntington's disease and other polyglutamine repeat diseases; hydrocephalus (hydrocephalus); hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; pigment incontinence (incontinentia pigmenti); infant phytic acid storage disease; infant raffinose disease (infantile refsum disease); cramping of the infant; inflammatory myopathy; intracranial cyst; intracranial hypertension; qiao Bate syndrome (Joubert syndrome); kearns-Sayre syndrome; kennedy disease Jin Siben syndrome (Kinsbourne syndrome); klippel Feil syndrome; keabbe disease (Krabbe disease); kugelberg-valands disease (Kugelberg-Welander disease); kuru (kuru); lafora disease (Lafora disease); lambert-eaton muscle weakness syndrome (Lambert-Eaton myasthenic syndrome); landa-Crabner syndrome (Landau-Kleffner syndrome); lateral bulbar (Wallenberg) syndrome; learning disabilities; leigh's disease; lunox-gaustat syndrome (Lennox-gusbaut syndrome); lesch-Nyhan syndrome; white matter malnutrition; dementia with lewy bodies; plagiocephaly (Lissencephaly); locking heald Syndrome; legrignard disease (Lou Gehrig's disease) (i.e., motor neuron disease or amyotrophic lateral sclerosis); lumbar intervertebral disc disease; lyme disease-neurological sequelae; marchado-Joseph disease (Machado-Joseph disease); brain deformity (macrodeformity); megabrain deformity (megacephaly); melsen-rosenstar syndrome (Melkersson-Rosenthal syndrome); meniere disease (meniere diseases); meningitis; a Menkes disease; metachromatic leukodystrophy (metachromatic leukodystrophy); small head deformity; migraine; mi Le Fisher syndrome (Miller Fisher syndrome); small stroke; mitochondrial myopathy; mobius syndrome (Mobius syndrome); monomer muscular atrophy; motor neuron disease; abnormal vascular network disease of brain bottom; mucopolysaccharidoses (mucopolysaccharidoses); multi-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating diseases; multiple system atrophy with orthostatic hypotension; p-muscular dystrophy; myasthenia gravis; diffuse sclerosis of bone marrow fragmentation; infantile myoclonus encephalopathy; myoclonus; myopathy; congenital myotonia; narcolepsy; neurofibromatosis; malignant syndrome of nerve blocking agent (neuroleptic malignant syndrome); the neurological manifestations of AIDS; neurological sequelae of lupus; neuromuscular rigidity; neuronal ceroid lipofuscinosis (neuronal ceroid lipofuscinosis); a neuronal migration disorder; niemann-Pick disease (Niemann-Pick disease); oxalis-Maclaude syndrome (O' Sullivan-McLeod syndrome); occipital neuralgia; recessive spinal neural tube insufficiency signs (occult spinal dysraphism sequence); primary field syndrome (Ohtahara syndrome); oleuropeia cerebellar atrophy (olivopontocerebelaratophy); ocular clonic-myoclonus (opsoclonus myoclonus); optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; parkinson's disease; congenital myotonia; paraneoplastic disease; paroxysmal onset; parylene Long Bage syndrome (Parry Romberg syndrome); beli Niu Si-Muzhibach disease (Pelizaeus-Merzbacher disease); periodic paralysis; peripheral neuropathy; painful neuropathy and neuropathic pain; a persistent plant human state; a pervasive developmental disorder; strong sneeze reflex (photic sneeze reflex); phytic acid storage disease The method comprises the steps of carrying out a first treatment on the surface of the Pick disease; pinching the nerve; pituitary tumor; polymyositis; brain punch-through (pore phaly); post-polio syndrome; post herpetic neuralgia; encephalomyelitis after infection; orthostatic hypotension; prader-Willi syndrome (Prader-Willi syndrome); primary lateral cord hardening; prion diseases; progressive hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliomyelitis; progressive supranuclear palsy; pseudobrain tumor; ramsay-Hunt syndrome (types I and II); las Mu Sen encephalitis (Rasmessen's encephilitis); reflex sympathetic dystrophy syndrome; refsum disease (Refsum disease); repetitive movement disorders; repetitive stress injury; restless legs syndrome; retrovirus-associated myelopathy; rett syndrome (Rett syndrome); lehr's syndrome (Reye); a Saint Vital dance (Saint Vitus dance); sang Huofu disease (Sandhoff disease); hilder's disease; schizophrenia; dysplasia (septo-optic dysplasia); infant shake syndrome; herpes zoster (shingles); shy-Drager syndrome; sicca syndrome @ syndrome); sleep apnea; soto's syndrome (Soto's syndrome); cramps; spinal column fracture; spinal cord injury; spinal cord tumor; spinal muscular atrophy; stiff Person syndrome (Stiff-Person syndrome); stroke; stutch-Weber syndrome; subacute sclerotic encephalitis; subcortical arteriosclerotic encephalopathy; xue Denghan chorea (Sydenham chorea); syncope; syringomyelia; tardive dyskinesia; tay-Sachs disease; temporal arteritis; spinal cord tethering syndrome; thomson disease (Thomsen disease); thoracic outlet syndrome; cramps (Tic Douloureux); tropenia (Todd's paralysis); tourette syndrome (Tourette syndrome); transient ischemic attacks; infectious spongiform encephalopathy; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; spastic flaccid paralysis of tropical zone; nodular hardening; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; fengxi Pel. Lin Daobing (Von Hip)pel-Lindau disease); valenberg syndrome (Wallenberg's syndrome); werdnig-Hoffman disease; westerr syndrome (West syndrome); whiplash (whislash); williams syndrome (Williams syndrome); huai Erdu (Wildon's disease); amyotrophic lateral sclerosis and jersey's disease (Zellweger syndrome).

In some embodiments, the condition, disease or disorder is a condition associated with STING, for example, type I interferon disease (e.g., STING-associated vascular disease (SAVI) of infancy), heart-gate Syndrome (AGS), genetic forms of lupus and inflammation-related diseases, for example, systemic lupus erythematosus and rheumatoid arthritis. In some embodiments, the condition, disease, or disorder is an autoimmune disease (e.g., 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), which is a chronic inflammatory disease with polygenic susceptibility. In some embodiments, the disorder is inflammatory bowel disease. In some embodiments, the condition is crohn's disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated with one or more alloimmune diseases (e.g., graft versus host disease, such as acute graft versus host disease and chronic graft versus host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In some of these embodiments, the condition is an alloimmune disease (e.g., graft versus host disease, such as acute graft versus host disease and chronic graft versus host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis, or intestinal mucositis).

In some embodiments, modulation of the immune system by STING provides treatment of diseases, including diseases caused by foreign factors. Exemplary infections of foreign factors that may be treated and/or prevented by the methods of the invention include: bacterial (e.g., gram positive or gram negative), fungal, parasitic, and viral infections. In one embodiment of the invention, the infection is a bacterial infection (e.g., an infection with escherichia coli, klebsiella pneumoniae (Klebsiella pneumonia), pseudomonas aeruginosa (Pseudomonas aeruginosa), salmonella (Salmonella spp.), staphylococcus aureus (Staphylococcus aureus), streptococcus or vancomycin-resistant enterococci) or sepsis. In another embodiment, the infection is a fungal infection (e.g., a mold, yeast, or higher fungal infection). In another embodiment, the infection is a parasitic infection (e.g., an infection caused by a single or multicellular parasite, including giardia duodenum (Giardia duodenalis), cryptosporidium parvum (Cryptosporidium parvum), sporozoon (Cyclospora cayetanensis) and toxoplasma (Toxoplasma gondiz)). In yet another embodiment, the infection is a viral infection (e.g., an AIDS-related viral infection, avian influenza, varicella, herpes labialis, common cold, gastroenteritis, adenofever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, and lower or upper respiratory tract infection (e.g., respiratory syncytial virus).

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

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

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

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

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

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

Other examples may include those indications discussed herein and below in contemplated combination treatment regimens.

Combination therapy

The present disclosure encompasses monotherapy regimens and combination therapy regimens.

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

In some embodiments, the methods described herein may further comprise administering one or more additional cancer therapies.

One or more additional cancer therapies may include, but are not limited to: surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine, hepatitis b vaccine, oncophage, provinge) and gene therapy, and combinations thereof. Immunotherapy, including but not limited to adoptive cell therapy, derivatization of stem cells and/or dendritic cells, transfusion, lavage and/or other therapies, including but not limited to frozen tumors.

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

In some embodiments, the other chemotherapeutic agent is an immunomodulatory molecule, such as an immune checkpoint inhibitor. In some of these embodiments, the immune checkpoint inhibitor targets an immune checkpoint receptor selected from the group consisting of: CTLA-4, PD-1, PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2, 3-dioxygenase (IDO), IL-10, transforming growth factor- β (tgfβ), T-cell immunoglobulin and mucin 3 (TIM 3 or HAVCR 2), galectin 9-TIM3, phosphatidylserine-TIM 3, lymphocyte activating gene 3 protein (LAG 3), MHC class II-LAG 3,4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDCL 2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHTA 2-TMIGD2, milk philins (including BTNL2, siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 adenosine-CD 39-CD73, CXCR4-CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM 3, PA-CD47, VEGF, neuropilin (Neuropilin), CD160, CD30, and CD155; for example, CTLA-4 or PD1 or PD-L1). See, e.g., poston, M.J. Clin. Oncol.2015,33,1.

In some of these embodiments, the immune checkpoint inhibitor is selected from the group consisting of: wu Lushan anti (Urilumab), PF-05082566, MEDI6469, TRX518, varilumab (Varlilumab), CP-870893, pembrolizumab (Pembrolizumab) (PD 1), nawuzumab (Nivolumab) (PD 1), atlantana Zhu Shankang (Atezolizumab) (formerly MPDL 3280A) (PDL 1), MEDI4736 (PD-L1), avelumab (Avelumab) (PD-L1), PDR001 (PD 1), BMS-986, MGA271, li Lushan anti (Lirillumab), IPH2201, yin Make tobulab (Emactuzumab), INCB 360, gao Luni alternative (Galunoisentib), wu Kepu rutuzumab (Ulocupumaab), BKT140, bavisuximab (Bavituximab), CC-90002, bevacizumab (Bevacizumab), 6015A and MGRP.

In some embodiments, the other chemotherapeutic agent is an alkylating agent. Alkylating agents are so named because they are capable of alkylating many nucleophilic functional groups in the presence of cells, including but not limited to cancer cells. In another embodiment, alkylating agents include, but are not limited to: cisplatin, carboplatin, methylethylamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin. In one embodiment, alkylating agents may act by forming covalent bonds with amino, carboxyl, sulfhydryl and phosphate groups in biologically important molecules to disrupt cell function, or they may act by modifying the DNA of a cell. In another embodiment, the alkylating agent is synthetic, semi-synthetic or a derivative.

In some embodiments, the other chemotherapeutic agent is an antimetabolite. Antimetabolites can camouflage as purines or pyrimidines, which are fundamental components of DNA, and generally prevent incorporation of these substances into DNA during the "S" phase (cell cycle), thereby preventing normal development and division. Antimetabolites also affect RNA synthesis. In one embodiment, antimetabolites include, but are not limited to: azathioprine and/or mercaptopurine. In another embodiment, the antimetabolite is synthetic, semisynthetic or a derivative.

In some embodiments, the other chemotherapeutic agent is a plant alkaloid and/or a terpene. These alkaloids are usually derived from plants and prevent cell division by preventing microtubule function. In one embodiment, the plant alkaloid and/or terpenoid is a vinca alkaloid, podophyllotoxin and/or taxane. Generally, vinca alkaloids bind to specific sites on tubulin, usually during the M phase of the cell cycle, inhibiting the assembly of tubulin into microtubules. In one embodiment, the vinca alkaloids are not limited to: motor gas lengthened spring flowers (Madagascar periwinkle), chang Chunhua (Catharanthus roseus) (formerly known as vina rosea). In one embodiment, 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: taxol, taxol and/or docetaxel. In another embodiment, the plant alkaloid or terpenoid organism is a synthetic, semisynthetic 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 octreotide. [021] In one embodiment, the cancer therapeutic is a topoisomerase. Topoisomerase is an essential enzyme for maintaining the DNA topology. Inhibition of type I or type II topoisomerase interferes with transcription and replication of DNA by disrupting the appropriate DNA supercoils. In another embodiment, the topoisomerase is, but is not limited to, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In one embodiment, the type I topoisomerase inhibitor is, but is not limited to, camptothecin. In another embodiment, the camptothecin is, but is not limited to, irinotecan (execan), irinotecan, lu Tuo, topotecan, BNP 1350,CKD 602,DB 67 (AR 67) and/or ST1481. In one embodiment, the type II topoisomerase inhibitor is, but is not limited to, an epipodophyllotoxin. In another embodiment, the epipodophyllotoxin is, but is not limited to, amitriptin (amacrine), etoposide phosphate and/or teniposide. In another embodiment, the topoisomerase is a synthetic, semisynthetic or derivative, including those found in nature, such as, but not limited to, an epipodophyllotoxin, a substance naturally found in the root of the fruit of the fifth lunar bearing (American Mayapple) (epipodophyllum (Podophyllum peltatum)) in north america.

In some embodiments, the other chemotherapeutic agent is stilbene. In further embodiments, stilbenes include, but are not limited to: resveratrol, piceatannol (Piceatannol), pinosylvin (Pinosylvin), pterostilbene (Pterosporilbene), alpha-glucopyranosin (Alpha-Viniferin), ampelopsin (Ampelopsin) A, ampelopsin E, didanosine (Diptoindonesin) C, didanosine F, epsilon-glucopyranosin (Epsilon-Vinferin), frexol (Flexuosol) A, ge Naining (Gnettinns) D, mattebucol (Hopeaphenol), trans-didanosine B, acitretin (Astringin), spruce neoside (Piceid) and didanosine A. In another embodiment, the stilbenes are synthetic, semisynthetic or derivatives.

In some embodiments, the other chemotherapeutic agent is a cytotoxic antibiotic. In one embodiment, the cytotoxic antibiotic is, but is not limited to: actinomycin, anthracenedione, anthracyclines, thalidomide, dichloroacetic acid, niacin, 2-deoxyglucose and/or chlorofazine (chlorofazine). In one embodiment, the actinomycin is but is not limited to: actinomycin D, bacitracin, colistin (polymyxin E) and/or polymyxin B. In another embodiment, the anthraquinones are, but are not limited to, mitoxantrone and/or pitaxron (pixantrone). In another embodiment, the anthracycline is, but is not limited to, bleomycin, doxorubicin (Adriamycin), daunorubicin (daunorubicin), epirubicin, idarubicin, mitomycin, pristinamycin, and/or valsarcin. In another embodiment, the cytotoxic antibiotic is a synthetic, semi-synthetic or derivative.

In some embodiments, the additional chemotherapeutic agent is selected from the group consisting of: endostatin, angiogenin, angiostatin, chemokine, angiostatin rest (angiarrstin), angiostatin (plasminogen fragment), basement membrane collagen-derived anti-angiogenic factor (tumstatin), compstatin (canstatin) or inhibitor protein (arestin)), anti-angiogenic antithrombin III, signal transduction inhibitors, cartilage Derived Inhibitors (CDI), CD59 complement fragments, fibronectin fragments, gro-beta, heparinase, heparin hexasaccharide fragments, human chorionic gonadotrophin (hCG), interferon alpha/beta/gamma, interferon inducible protein (IP-10), interleukin 12, kringle 5 (plasminogen fragment), metalloprotease inhibitors (TIMP), 2-methoxyestradiol, placental ribonuclease inhibitors, plasminogen activator inhibitors, platelet factor-4 (PF 4), prolactin 16kD fragments, protein associated with proliferative proteins (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin 1 (TSP-1), TSP-beta, vascular growth factor (TSP-1), and the like.

In some 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-valyl-N-methyl-L-valyl-L-prolyl-1-L-proline t-butyramide, cachetin (cachectin), cimadotin (cemadectin), chlorambucil, cyclophosphamide, vinorelbine tartrate (3 ',4' -didehydro-4'-deoxy-8' -norvin-calukoblatine), docetaxel, docetaxel (doxetaxel), cyclophosphamide, carboplatin, carmustine (carmustine), cisplatin, cryptophycin (cryptosporidium), cyclophosphamide, cytarabine, dacarbazine (DTIC), actinomycin, daunorubicin, decitabine (docitastatin), doxorubicin (doxorubicin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyurea taxane, ifosfamide (ifosfamide), li La (liarozole), lonidamine (lomustine), lomustine (lomustine) (CCNU), MDV3100, mechlorethamine (nitrogen), hydroxyethane sulfonate (mivobulin isethionate), rhizobiamine (rhizoxin), sertib (sertenef), streptococci (streptozocin), mitomycin, methotrexate, taxanes, nilutamide (nilutamide), onapristone (onapristone), paclitaxel, prednisone mustard (prednimustine), procarbazine (procarbazine), RPR109881, estramustine phosphate (stramustine phosphate), tamoxifen, tamonamine (tasonermin), paclitaxel, retinoic acid, vinblastine, vincristine, vindesine sulfate and vinflunine.

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

In other embodiments, the other chemotherapeutic agents may be selected from those described in U.S. patent 7,927,613, which is incorporated herein by reference in its entirety.

In some embodiments, the additional therapeutic agents and/or regimens may be used to treat other STING-related conditions, such as type I interferon diseases, e.g., STING-related vascular diseases (SAVI) of infancy, heart-gate-pedicle syndrome (AGS), hereditary forms of lupus, inflammation-related conditions, e.g., systemic lupus erythematosus, and rheumatoid arthritis, among others.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating rheumatoid arthritis include: non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g., prednisone), disease-modifying antirheumatic drugs (DMARDs; e.g., methotrexate) Leflunomide->Hydroxychloroquine (Plaquenil), PF-06650833, iguratimod (Iguratimmod), tofacitinib (tofacitinib)>ABBV-599, evobrutinib and sulfasalazine (sulfasalazine) are added>And biological agents (e.g., abatacept)Adalimumab (adalimumab)>Anakinra (anakinra)>Certolizumab (certolizumab)

Etanercept (etanercept) is added to the mixture>Golimumab (golimumab)

Infliximab (infliximab) is added>Rituximab (rituximab)>Tozulizumab (tocilizumab) in the presence of a drug>Wobulizumab (vobarlizumab), as well as anti-sarilumab (sarilumab) by spreading Li Lushan>Sukunmab (Secukinumab), ABP 501, CHS-0214, ABC-3373, and tobalizumab (tocilizumab)>)。

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating lupus include: steroids, local immunomodulators (e.g., tacrolimusOintment for treating common coldAnd pimecrolimus cream- >) Thalidomide->Non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarial drugs (e.g., hydroxychloroquine (Plaquenil)), corticosteroids (e.g., prednisone), immunomodulators (e.g., ibrutinib (evobrinib), iberdomide, wo Lvpu octyl (voclosporin), cerimimod (cenerimod), azathioprine (azathioprine)>Cyclophosphamide->Cyclosporin (Neoral,)>) Mycophenolate mofetil), barytropinib (baricinib), iguratimode (iguratimmod), filototinib (filototinib), GS-9876, rapamycin, and PF-06650833), biologicals (e.g., belimumab)>Alfluromumab (anifloumab), melitumomab (prezalumab), MEDI0700, obabine You Tuozhu mab (obinutuzumab), vobarilizumab (vobarilizumab), lu Lizhu mab (lulizumab), asenaproxen (atacicept), PF-06823859, and Lu Pi mol (lupizor), rituximab (rituximab), BT063, BI655064, BIIB059, aldesinterleukin (aldeslickin)>Dapipi Luo Shankang (dapirolizumab),according to Qu Tai (edge), IFN-alpha-kinoid, OMS721, RC18, RSLV-132, cetrimab, xmAb5871, and Uterimab (Utekinumab) >For example, non-limiting treatment methods for systemic lupus erythematosus include: non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarial drugs (e.g., hydroxychloroquine (Plaquenil)), corticosteroids (e.g., prednisone) and immunomodulators ((e.g., iberdomide), wo Lvpu octyl (voclosporin), azathioprine (azathioprine)>Cyclophosphamide->And cyclosporin (Neoral, </i >>) And mycophenolate mofetil, barricitinib, filototinib, and PF-06650833), and biologicals (e.g., belimumab)Alflozumab, plalumab, MEDI0700, vobarizumab, lu Lizhu mab, alexidine, PF-06823859, lu Pi mol (lupizor), rituximab, BT063, BI655064, BIIB059, aldeluxin>Dapirolizumab, IFN- α -kineid, RC18, RSLV-132, cetrimab, xmAb5871, and Utekey mab (Utekamiab)>). As another aspectOne example, non-limiting examples of treatments for cutaneous lupus include: steroids, immunomodulators (e.g., tacrolimus ointment +) >And pimecrolimus cream->) GS-9876, filototinib and thalidomide>Agents and regimens for treating drug-induced and/or neonatal lupus may also be administered.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating STING-related vascular disease (SAVI) in infancy include JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgitinib, and baritinib).

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating the ecardi-Gu Di rass syndrome (AGS) include: physical therapy, treatment of respiratory complications, anticonvulsant therapy of seizures, gavage, nucleoside reverse transcriptase inhibitors (e.g., emtricitabine) (e.g., emtricitabine) Tenofovir (tenofovir) (e.g.)) Emtricitabine/tenofovir (e.g.. About->) Zidovudine (zidovudine), lamivudine (lamivudine) and abacavir (abacavir)), and JAK inhibitors (e.g., tofacitinib, ruxolitinib, phenanthrotinib, and baratinib).

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating IBD include: 6-mercaptopurine, abGn-168H, ABX464, ABT-494, adalimumab (Adaliumab), AJM300, a Li Kashan antibody (aliaforsen), AMG139, an Lujin bead monoclonal antibody (anarukinzumab), apremilast (apremilast), ATR-107 (PF 0530900), autologous CD34 selected peripheral blood stem cell transplantation, azathioprine (azathioprine), bettuzumab (bertilimumab), BI 655066, BMS-936557, cetuximab (certolizumab pegol) Silbimod (cobbitimod), corticosteroids (e.g., prednisone, methylprednisolone, prednisone), CP-690,550, ct-P13, cyclosporin, DIMS0150, E6007, E6011, angstrom Qu Ximo T (etaimod), ertrozumab (etrolizumab), fecal microorganism transplantation, fei Luoti ni (figlotinib), fingolimod (fingolimod), filassist (firategrast) (SB-683699) (formerly T-0047), GED0301, GLPG0634, GLPG0974, antikukumab (guselkumab), golimumab), GSK1399686, HMPL-004 (extract of andrographis paniculata (Andrographis paniculata), IMU-838, infliximab), interleukin 2 (IL-2), janus kinase (JAK) inhibitors, laquinimod (Laquinmod), mosatinib (pefitinib) (AB 1010), matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, me Sha Lamin (mesalamine), methotrexate, milbezumab (LY 3074828), natalizumab (natalizumab), NNC 0142-0000-0002, NNC0114-0006, ozanimod (ozanimod), pefitinib (JNJ-54781532), PF-00547659, PF-04236921, PF-06687234, QAX576, RHB-104, rifaximin (rifaximin), rituximab (risanizumab), RPC1063, SB012, SHP647, sulfasalazine (SUSAZIne), TD-3, thalidomide, telaprizumab (MK 3222), TJ301, TNF- >Tofacitinib (tofacitinib), tralokinumab (TRK-170, apatinib (upadaciti)nib), ulipristinab, UTTR1147A, V565, vallizumab (vatelizumab), VB-201, vedolizumab (vedolizumab), and vedofludim (vidofludimus).

Non-limiting examples of other therapeutic agents and/or treatment regimens for treating irritable bowel syndrome include: alosetron (alosetron), bile acid sequestrants (e.g., cholestyramine (cholestipol), colesevelam (colesevelam), chloride ion channel activators (e.g., lubiprostone (lubiprostone)), coated peppermint oil capsules, desipramine (desipramine), dicyclopramide (dicyclopramine), ebastine (ebastine), efadoline (elupoline), farnesol X receptor agonists (e.g., obeticholic acid), fecal microorganism transplantation, fluoxetine (fluoxetine), gabapentine (gabapentin), guanylate cyclase C agonists (e.g., linaclotide), procaterol (plectalide), epothilone (ibustan), promethazine (im), JCM-21, lopamitriptyline (lopirox), protamine (protamine), and other drugs (protamine), paroxetine (protamine), and other drugs (protamine).

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating scleroderma include: non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g., prednisone), immunomodulators (e.g., azathioprine, methotrexate) Cyclophosphamide (cyclophosphamide)And cyclosporin->Anti-thymocyte globulin, mycophenolate mofetil, intravenous immunoglobulins, rituximab, sirolimus and alefacept, calcium channel blockers (e.g., nifedipine), alpha blockers, serotonin receptor antagonists, angiotensin II receptor inhibitors, statins, topical nitrates, iloprost (ilopost), phosphodiesterase 5 inhibitors (e.g., sildenafil), bosentan (bosentan), tetracycline antibiotics, endothelin receptor antagonists, prostaglandins, and tyrosine kinase inhibitors (e.g., imatinib, nilotinib and dasatinib).

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating Crohn's Disease (CD) include: adalimumab, autologous CD34 selected peripheral blood stem cell transplantation, 6-mercaptopurine, azathioprine, polyethylene glycol cetuximabCorticosteroids (e.g., prednisone), erterelizumab (etrolizumab), E6011, fecal microorganism transplantation, fei Luoti ni (figlotinib), archakutikuzumab (guselkumab), infliximab (Infliximab), IL-2, jak inhibitors, matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, me Sha Lamin, methotrexate, natalizumab, ozanimod (ozanimod), RHB-104, rifaximin (rifaximin), rituximab (risanizumab), SHP647, sulfasalazine, thalidomide, apazitinib (upadatinib), V565, and vedolizumab.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating UC include: abGn-168H, ABT-494, ABX464, apremilast (apremilast), PF-00547659, PF-06687234, 6-mercaptopurine, adalimumab, azathioprine, belitemumab, brazikumab (MEDI 2070), cobratimod (cobitemod), polyethylene glycol cetuximabCP-690,550, corticosteroids (e.g., multifunctional budesonide (multimax budesonide)) Methylprednisolone (Methylprednisolone)), cyclosporin, E6007, etrexed, erteremomab, fecal microorganism transplantation, filotinib, gu Saiku mab (guselkumab), golimumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), mei Sha Lamin, mei Sha Lamin, milbezumab (mirikizumab)

(LY 3074828), RPC1063, rituximab (BI 6555066), SHP647, sulfasalazine, TD-1473, TJ301, tildrakizumab (MK 3222), tofacitinib (Tofacitinib), utezomib (ustekinumab), UTTR1147A and vedolizumab (vedolizumab).

Non-limiting examples of other therapeutic agents and/or treatment regimens for treating autoimmune colitis include: corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), benzodragline/atropine, infliximab, loperamide, methamphetamine, mep Sha Lamin, TIP60 inhibitors (see, e.g., U.S. patent application publication No. 2012/0202848) and vedolizumab.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for the treatment of iatrogenic autoimmune colitis include: corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), benzomarital/atropine, infliximab, loperamide (loperamide), TIP60 inhibitors (see, e.g., U.S. patent application publication No. 2012/0202848) and vedolizumab.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating colitis induced by one or more chemotherapeutic agents include: corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), benzodragline/atropine, infliximab, loperamide, methamphetamine, mep Sha Lamin, TIP60 inhibitors (see, e.g., U.S. patent application publication No. 2012/0202848) and vedolizumab.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating colitis caused by adoptive cell therapy include: corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), benzomarital/atropine, infliximab, loperamide (loperamide), TIP60 inhibitors (see, e.g., U.S. patent application publication No. 2012/0202848) and vedolizumab.

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

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating radiation enteritis include: tedulcitide, amifostine, angiotensin Converting Enzyme (ACE) inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, moxidecpril, perindopril, quinapril, ramipril, and trandolapril), probiotics, selenium supplements, statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin), sucralfate, and vitamin E.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating collagenous colitis include: 6-mercaptopurine, azathioprine (azathaiporine), bismuth subate (bismuth subsalicate), boswellia serrata (Boswellia serrata) extracts, cholestyramine (cholestipol), corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), me Sha Lamin, methotrexate, probiotics and sulfasalazine.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating lymphocytic colitis include: 6-mercaptopurine, azathioprine (azathaiporine), bismuth subsalicylate (bismuth subsalicylate), cholestyramine (colestipol), cholesterol (colestipol), corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), methotrexate and sulfasalazine.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating microbial colitis include: 6-mercaptopurine, azathioprine (azathioprine), bismuth hydroxide (bismuth subsalicate), boswellia serrata (Boswellia serrata) extracts, cholestyramine (cholestipol), colestipol (colestipol), corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), fecal microorganism transplantation, loperamide (loperamide), me Sha Lamin, methotrexate, probiotics and sulfasalazine.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating an alloimmune disorder include: intrauterine platelet infusion, intravenous immunoglobulin, maternal steroids, albazept, alemtuzumab (alemtuzumab), alpha 1-antitrypsin, AMG592, anti-thymocyte globulin, baratinib (barcitinib), basiliximab (basiliximab), bortezomib (bortezomib), bentuximab (brentuximab), cannabidiol (cannabidil), corticosteroids (e.g., methylprednisone, prednisone), cyclosporin, daclizumab (dacilzumab), defibrinoxidin (defrobotide), a dimesleukin-toxin linker (denileukin diftitox), granatinib (glastinib), ibrutinib (britinib), IL-2, infliximab, itatinib (itatinib), LBH589, maraviroc acid (marovide), neomycin (gefitinib), and dispensing of light.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating Multiple Sclerosis (MS) include: albumabALKS 8700, AMiloride (amiloride), ATX-MS-1467, azathioprine, baclofen (baclofen)>Interferon beta (e.g., IFN-beta-1 a, IFN-beta-1 b), cladribine (cladribine), corticosteroids (e.g., methylprednisolone), daclizumab (daclizumab), dimethyl fumarateFingolimod (fingolimod)>Fluoxetine, glatiramer acetate (glatiramer acetate)

Hydroxychloroquine, ibudilast (ibudilast), idebenone (idebenone), laquinimod (laquinimod), lipoic acid, losartan (losartan), mositinib (masitinib), MD1003 (biotin), mitoxantrone, montelukast (montelukast), natalizumab>NeuroVax ^TM Orelizumab (ocrelizumab), ofatumumab, pioglitazone (pioglitazone) and RPC1063.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating graft versus host disease include: albazipran (abaatacept), alemtuzumab (alemtuzumab), α1-antitrypsin, AMG592, anti-thymocyte globulin, baroretinib (barbitinib), basiliximab (basiliximab), bortezomib (bortezomib), bentuximab (brentuximab), cannabidiol (cannabimol), corticosteroids (e.g., methylprednisone, prednisone), cyclosporin, daclizumab (dacilzumab), defibrinoxidin (defrobrotide), deniinterleukin-toxin conjugate (denileukin diftitox), garamib (glastuib), ibrutinib (ibretinib), IL-2, imatinib (imatinib), infliximab (itumomab), italopirox, lborotidine (imab), LBH589, maceramide, dacarbamate (dacarbazone), cilazapirtine (vanab), desipramipexolone (vandulatinib), desipramipexole (vanadzuab), desipramipexole (vant), and vandulatinib (vantagatodine).

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating acute graft versus host disease include: alemtuzumab (alemtuzumab), α1-antitrypsin, anti-thymus cytoglobulin, basiliximab (basiliximab), bentuximab (brentuximab), corticosteroids (e.g., methylprednisone, prednisone), cyclosporin, daclizumab (dacilzumab), defibrinated (defibrutinide), diniinterleukin-toxin conjugate (denileukin diftitox), ibrutinib (ibrutinib), infliximab, itaitinib (itacitiinib), LBH589, mycophenolic acid ester, natalizumab (neihulizumab), pencytarabine, photo-hemolysis, ruxotinib (ruxolitinib), sirolimus (sirolimus), tacrolimus and tacrolimus (tocilizumab).

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating chronic graft versus host disease include: abarubip (abatacept), alemtuzumab (alemtuzumab), AMG592, anti-thymus cytoglobulin, basiliximab (basiliximab), bortezomib (bortezomib), corticosteroids (e.g., methylprednisone, prednisone), cyclosporin, daclizumab (dacilzumab), a deniinterleukin-toxin linker (denileukin diftitox), glageb (glasdigib), ibrutinib (ibrutinib), IL-2, imatinib (imatinib), infliximab, mycophenolate, penstin, photobiometune, ruxotinib (ruxolitinib), sirolimus (sirolimus), sonidegib (sonidegib), tac, tacrolimab (tocilizumab) and valimod (smoigib).

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating celiac disease include: AMG 714, AMY01, aspergillus niger (Aspergillus niger) prolyl endoprotease, BL-7010, CALY-002, GBR 830, hu-Mik-Beta-1, IMGX003, kumamax, laprazosin acetate (Larazotide Acetate),pancreatic lipase, TIMP-GLIA, vedolizumab and ZED1227.

Non-limiting examples of additional therapeutic agents and/or regimens for treating psoriasis include: topical corticosteroids, topical croiborone/AN 2728, topical SNA-120, topical SAN021, topical benomyl (tapinaof), topical tokafinib (tocafinib), topical IDP-118, topical M518101, topical calcipotriene (calcipotriene) and betamethasone dipropionate (e.g., MC2-01 cream and) Local P-3073, local LEO 90100 +.>Topical betamethasone dipropionate +.>Betaxolol propionateVitamin D analogues (e.g. calcipotriene +.>And calcitriol->) Anthralin (e.g. Dritho-/->And Dritho- & gt>) Topical retinoids (e.g., tazarotene) (e.g., +.>And->) Calcineurin inhibitors (e.g., tacrolimus)And pimecrolimus- >) Salicylic acid, tar (coral tar), moisturizers, phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrowband UVB phototherapy, gossaman therapy (Goeckerman therapy), psoralen plus ultraviolet a (PUVA) therapy and excimer laser (eximer laser)), retinoids (e.g., acitretin)Methotrexate> Apo805K1, baratinib (baricitinib), FP187, KD025, prurisol (Prurisol), VTP-43742, XP23829, ZPL-389, CF101 (Picipidenoson)), LAS41008, VPD-737 (Se Luo Pi he (servopitant)), apatinib (upadacritinib) (ABT-494), apipulet (apremilast), tofacitinib (tofacitinib), cyclosporine (Cyclosporin)>Biological agents (e.g., etanercept->Etanercept-szzs->Inliximab->Adalimumab->Adalimumab-adbm->Utekumab (Utekuumab) in the presence of a drug>Golimumab->Apremilast (apremilast)>Sukunmab (sekukunuumab)>Polyethylene glycol cetuximab, secukinumab (tildrakizumab), telaprizumab-asmn, infliximab-dyyb, abatacept, elcatuzumab (ixekizumab)>ABP 710, bcd-057, BI695501, bimetalizumab (UCB 4940), CHS-1420, gp2017, gulickumab (guselkumab) (CNTO 1959), HD203, M923, MSB11022, mi Lizhu mab (micikizumab) (LY 3074828), PF-06410293, PF-06438179, risazomumab (risankizumab) (BI 655066), SB2, SB4, SB5, siliq (cloth Luo Lushan anti (brodalumab)), nalmeuzumab (namimumab) (MT 203, tiramelizumab (tidrakuumab) (MK-3222), and exelizumab (ixekizumab) are described >) Thioguanine, and hydroxyurea (e.g.,/->And->)。

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating cutaneous T cell lymphoma include: phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrowband UVB phototherapy, goldman therapy, psoralen plus ultraviolet a (PUVA) therapy and excimer laser), in vitro photopuncturing (extracorporeal photopheresis), radiotherapy (e.g., spot radiation and whole body skin e-beam therapy), stem cell transplantation, corticosteroids, imiquimod, bexarotene (bexarotene) gel, topical bischloroethyl-nitrourea, methoxyethylamine gel, vorinostat (vorinostat)Romidepsin (romidepsin) is added to the mixture>Pralatrexate (pralatrexate)>Biological agents (e.g., alemtuzumab)>Velocinobacizumab (brentuximab vedotin) (SGN-35), mogamulizumab (mogamulizumab) and IPH 4102).

Non-limiting examples of additional therapeutic agents and/or regimens for treating uveitis include: corticosteroids (e.g., triamcinolone acetonide injection in the vitreous), antibiotics, antivirals (e.g., acyclovir), dexamethasone, immunomodulators (e.g., tacrolimus, leflunomide, cyclophosphamide) And cyclosporin->Chlorambucil (chloramucil), azathioprine, methotrexate, and mycophenolate), biologicals (e.g., infliximab->AdalimumabEtanercept->Golimumab->Cetuximab (certolizumab)>Rituximab->Arbazedox->Basiliximab->Anakinra (anakinra)>Kanagamab (Canakiumab)Govorexant (gevokixumab) (XOMA 052), tolizumab (tocilizumab) is->Alemtuzumab->Ai Fazhu mab (Efalizumab) in the presence of a drug>LFG316, sirolimusArbazedox, spill Li Lushan anti (sarilumab)/(A)>And daclizumab (daclizumab)/(d.k.b)>) Cytotoxic drugs, surgical implants (e.g., fluocinolone acetonide tab), and vitrectomy.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating mucositis include: AG013, SGX942 (up to Shu Kuitai (dusquetide)), amifostineCryotherapy, siberian pastille (lonzees), mucoadhesive (e.g., jersey)>) Oral diphenhydramine (e.g.,. About.>Elixir), bioadhesives for oral administration (e.g., polyvinylpyrrolidone-sodium hyaluronate gel +.>) An Oral lubricant (e.g., oral +.>)，Kang Pushu (caphosol), chamomile (chamomilla recutita) mouthwash, edible grape plant exosomes, antiseptic mouthwashes (e.g., chlorhexidine gluconate (e.g.) >Or->) Local analgesics (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylencaine (e.g., viscous xylencaine 2%), and(0.6% phenol), corticosteroids (e.g., prednisone), analgesics (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifemin (keratinocyte growth factor;) ATL-104, clonidine) Lorentided (lauriad), IZN-6N4, SGX942, rebamipide (rebamipide), nepidermin (nepidermin), soluble beta-1, 3/1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, particles containing Vaccinium myrtillus (vaccinium myrtillus) extract, macleaya (cord) alkaloids and Echinacea (echinacea angustifolia) extract (e.g.,) And gastrointestinal tract mixtures (an acid reducing agent such as aluminum hydroxide and magnesium hydroxide (e.g., maalox), antifungal agents (e.g., nystatin), and analgesic agents (e.g., hurricane liquid)). For example, non-limiting examples of additional therapeutic agents and/or treatment regimens for treating oral mucositis include: AG013, amifostine- >Cryotherapy, sibirac (cepacol) troches (l)onzenges), mucoadhesives (e.g., +.>) Oral diphenhydramine (e.g.,. About.>Elixir), bioadhesives for oral administration (e.g., polyvinylpyrrolidone-sodium hyaluronate gel +.>) An Oral lubricant (e.g., oral +.>) Kang Pushu (caphosol), chamomile (chamomilla recutita) mouthwash, edible grape plant exosomes, antiseptic mouthwashes (e.g., chlorhexidine gluconate (e.g., ->Or->) Local analgesics (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylencaine (e.g., viscous xylencaine 2%), and +.>(0.6% phenol), corticosteroids (e.g., prednisone), analgesics (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, paliferomin (paliferomin) (keratinocyte growth factor; (R); C/F)>) ATL-104, clonidine) Lorentided (lauriad), IZN-6N4, SGX942, rebamipide (rebamipide), nepidermin (nepidermin), soluble beta-1, 3/1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, and gastrointestinal mixtures (an acid reductionAgents such as aluminum hydroxide and magnesium hydroxide (e.g., maalox), antifungal agents (e.g., nystatin), and analgesic agents (e.g., hurricane liquid). As another example, non-limiting examples of treatment of esophageal mucositis include: xylene-caline (e.g., gel-viscous xylene-caline 2%). As another example, the treatment of intestinal mucositis, the treatment of altering intestinal mucositis and the treatment of signs and symptoms of intestinal mucositis include: gastrointestinal tract mixtures (an acid reducing agent such as aluminum hydroxide and magnesium hydroxide (e.g., maalox), antifungal agents (e.g., nystatin), and analgesics (e.g., hurricane liquid).

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

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

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

Patient selection

In some embodiments, the methods described herein further comprise the step of identifying a subject (e.g., a patient) in need of such treatment (e.g., by biopsy, endoscopy, or other conventional methods known in the art). In some embodiments, STING proteins may be used as biomarkers for some types of cancer, such as colon and prostate cancer. In other embodiments, identifying the subject may include analyzing a patient's tumor microenvironment (e.g., with one or more cold tumors) for the presence of T cells and/or for the presence of depleted T cells. Such patients may include patients that are resistant to treatment with checkpoint inhibitors. In some embodiments, such patients may be treated with the chemical entities herein, e.g., to recruit T cells into a tumor, and in some cases, e.g., once the T cells are depleted, further treated with one or more checkpoint inhibitors.

In some embodiments, the chemical entities, methods and compositions described herein can be administered to a population of patients that are resistant to treatment (e.g., patients that are resistant to checkpoint inhibitors; e.g., patients with one or more cold tumors (e.g., tumors that lack T cells or are depleted of T cells)).

Preparation of Compounds

As will be appreciated by those skilled in the art, methods of synthesizing the compounds of the formulae described herein will be apparent to those of ordinary skill in the art. Synthetic chemical transformations and protecting group methods (protection and deprotection) useful for synthesizing the compounds described herein are known in the art and include, for example, those described in r.larock, integrated organic transformation (Comprehensive Organic Transformations), VCH publishers (1989); T.W.Greene and RGM.Wuts, protecting groups in organic Synthesis, 2 nd edition, john Willi parent company (John Wiley and Sons) (1991); fieser and M.Fieser, organic Synthesis reagents of Fieser and Fieser, john Willi father-son company (1994); the "organic synthetic reagents encyclopedia", code l.paquette, john wili father-son company (1995), and subsequent versions thereof. The starting materials for preparing the compounds of the present invention are known, can be prepared by known methods, or are commercially available. Those skilled in the art will also recognize that the conditions and reagents described herein may be interchanged with alternative art-recognized equivalents. For example, in many reactions, triethylamine may be exchanged with other bases, such as non-nucleophilic bases (e.g., diisopropylamine, 1, 8-diazabicycloundec-7-ene, 2, 6-di-tert-butylpyridine, or tetrabutylphosphazene).

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

To further illustrate the foregoing, the following non-limiting exemplary synthetic schemes are included. Variations of these embodiments within the scope of the claims are within the knowledge of a person skilled in the art and should be considered to fall within the scope of the described claimed invention. The reader will recognize that one of ordinary skill in the art, based on this disclosure, could make and use the invention without an exhaustive example.

The following abbreviations have the indicated meanings:

ac=acetyl group

Acn=acetonitrile

Boc ₂ O=di-tert-butyl pyrocarbonate

Bu=butyl

Dcm=dichloromethane

Diea=n, N-diisopropylethylamine

Dmf=n, N-dimethylformamide

DMSO = dimethylsulfoxide

Dppa=diphenyl azide phosphate

Dppf = bis (diphenylphosphine) ferrocene

HATU = 2- (7-azotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate

HPLC = high performance liquid chromatography

LC-ms=liquid chromatography-mass spectrometry

Me=methyl group

Nmr=nuclear magnetic resonance

RT = residence time

Tea=triethylamine

THF = tetrahydrofuran

Tms=tetramethylsilane

T ₃ P=2, 4, 6-tripropyl-2, 4, 6-trioxo-1,3,5,2,4,6-trioxatriphosphine cycloalkane

Xphos= (2- (2, 4, 6-triisopropylphenethyl) phenyl) dicyclohexylphosphine

DCC = N, N' -dicyclohexylcarbodiimide

DCE = dichloroethane

DMAP = dimethylaminopyridine

Ir [ dF (CF 3) ppy ]2 (dtbpy) PF 6=Iridium (1+), [4,4' -bis (1, 1-dimethylethyl) -2,2' -bipyridyl-. Kappa.N 1,. Kappa.N 1' ] bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridinyl-. Kappa.N ] phenyl-. Kappa.C ] -, (OC-6-33) -, hexafluorophosphate (1-) (1:1)

NBS = N-bromosuccinimide

Ncs=n-chlorosuccinimide

Nmm=n-methylmorpholine pybop=benzotriazol-1-yl-oxy-tripyrroline hexafluorophosphate (oxytripyrrolininophosphomium hexafluorophosphate)

SelectFluor=1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate)

TFA = trifluoroacetic acid

Ts=p-toluenesulfonyl

t-AmOH=tert-amyl alcohol

Tes=triethylsilane

AcOH = acetic acid

SOCl ₂ =thionyl 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=methanesulfonic acid (2-dicyclohexylphosphino-2, 6-diisopropyloxy-1, 1-biphenyl) (2-amino-1, 1-biphenyl-2-yl) palladium (II)

XPhos Pd G3=methanesulfonic acid (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) (2-amino-1, 1-biphenyl-2-yl) palladium (II)

K ₃ PO ₄ =potassium phosphate

EtOAc = ethyl acetate

Na ₂ SO ₄ Sodium sulfate =

FA = formic acid

Meoh=methanol

SpeedVac = Savant SC250EXP SpeedVac concentrator

Examples

Materials and methods

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

LCMS method a: kineex EVO C18 100a,30 x 3mm,0.5 μl sample introduction, 1.2 mL/min flow rate, 90-900amu scan range, 254nm UV detection. Mobile Phase A (MPA): water/5 mM NH ₄ HCO ₃ And Mobile Phase B (MPB): acetonitrile. 10% MPB eluted to 95% in 2.00 minutes, and was maintained at 95% MPB for 0.30 minutes, and 95% MPB eluted to 10% in 0.10 minutes.

LCMS method B: xselect CSH C18, 50 x 3mm,1.0 μl sample, 1.2 mL/min flow rate, 90-900amu scan range, 254nm UV detection. Mobile Phase A (MPA): water/0.1% FA and Mobile Phase B (MPB): acetonitrile/0.1% FA. 5% MPB eluted to 100% in 2.00 minutes, was held at 100% MPB for 0.70 minutes, 100% MPB to 5% in 0.05 minutes, and then equilibrated at 5% MPB for 0.15 minutes.

LCMS method C: XBridge Shield RP18, 50X 4.6mm, 0.5. Mu.L of sample introduction, 1.2 mL/min flow rate, 90-900amu scan range, 254nm UV detection. Mobile Phase A (MPA): water/0.04% nh3.h2o and Mobile Phase B (MPB): acetonitrile. 10% MPB eluted to 95% in 2.00 minutes, was held at 95% MPB for 0.79 minutes, was equilibrated at 10% MPB for 0.15 minutes, and was eluted at 95% MPB for 0.06 minutes.

LCMS method D: shim-pack XR-ODS, 50X 3mm, 0.3. Mu.L of sample, 1.2 mL/min flow rate, 30-2000amu scan range, 254nm UV detection. Mobile Phase A (MPA): water/0.05% tfa and Mobile Phase B (MPB): acetonitrile/0.05% TFA. 5% MPB eluted to 100% in 1.10 minutes, was held at 100% MPB for 0.60 minutes, 100% MPB to 5% in 0.05 minutes, and then equilibrated at 5% MPB for 0.25 minutes.

LCMS method E: xbridge BEH C18, 50 x 3mm,4.0 μl sample injection, 1.2 mL/min flow rate, 30-2000amu scan range, 254nm UV detection. Mobile Phase A (MPA): water/5 mM NH ₄ HCO ₃ And Mobile Phase B (MPB): acetonitrile. 5% MPB eluted to 95% in 2.00 minutes, was held at 95% MPB for 0.70 minutes, 95% MPB to 5% in 0.05 minutes, and then equilibrated at 5% MPB for 0.25 minutes.

LCMS method F: kineex 2.6um EVO C18 100A,50*3mm,0.6 μl sample, flow rate 1.2 mL/min, scanning range 30-2000amu, UV detection 254 nm. Mobile Phase A (MPA): water/5 mM NH ₄ HCO ₃ And Mobile Phase B (MPB): acetonitrile. 10% MPB eluted to 95% in 1.20 minutes, was held at 95% MPB for 0.50 minutes, 95% MPB to 10% in 0.05 minutes, and then equilibrated at 10% MPB for 0.10 minutes.

LCMS method G: kineex 2.6um EVO,50*3mm,0.5 μl sample, flow rate 1.2 mL/min, scanning range 30-2000amu, UV detection 254 nm. Mobile Phase A (MPA): water/5 mM NH ₄ HCO ₃ And Mobile Phase B (MPB): acetonitrile. 10% MPB eluted to 95% in 2.00 minutes, was held at 95% MPB for 0.70 minutes, 95% MPB to 10% in 0.05 minutes, and then equilibrated at 10% MPB for 0.25 minutes.

LCMS method H: titank C18, 50 x 3mm, 0.5. Mu.L sample introduction, 1.5 mL/min flow rate, 30-2000amu scan range, 254nm UV detection. Mobile Phase A (MPA): water/5 mM NH ₄ HCO ₃ And Mobile Phase B (MPB): acetonitrile. 10% MPB eluted to 95% in 1.80 minutes, was held at 95% MPB for 0.80 minutes, 95% MPB to 10% in 0.15 minutes, and then equilibrated at 10% MPB for 0.25 minutes.

LCMS method I: xbridge BEH C18, 50 x 3mm,4.0 μl sample injection, 1.2 mL/min flow rate, 30-2000amu scan range, 254nm UV detection. Mobile Phase A (MPA): water/5 mM NH ₄ HCO ₃ And Mobile Phase B (MPB): acetonitrile. 5% MPB eluted to 95% in 2.00 minutes, was held at 95% MPB for 0.70 minutes, 95% MPB to 5% in 0.05 minutes, and then equilibrated at 5% MPB for 0.25 minutes.

LCMS method J: HALOC18, 30 x 3mm, 0.5. Mu.L of sample introduction, 1.5 mL/min flow rate, 30-2000amu scan range, 254nm UV detection. Mobile Phase A (MPA): water/0.05% TFA and Mobile Phase B (MPB): acetonitrile/0.05% TFA. The 5% MPB eluted to 100% in 1.20 minutes, remained at 100% MPB for 0.60 minutes, 100% MPB to 5% in 0.02 minutes, and then equilibrated at 5% MPB for 0.18 minutes.

LCMS method K: ascentis Express C18, 50X 3mm, 0.5. Mu.L of sample introduction, 1.5 mL/min flow rate, 30-2000amu scan range, 254nm UV detection. Mobile Phase A (MPA): water/0.05% tfa and Mobile Phase B (MPB): acetonitrile/0.05% TFA. 5% MPB eluted to 100% in 2.00 minutes, was held at 100% MPB for 0.70 minutes, 100% MPB to 5% in 0.05 minutes, and then equilibrated at 5% MPB for 0.25 minutes.

In BRUKER NMR 300.03Mz, DUL-C-H, ULTRASHIELD ^TM 300，AVANCE II 300B-ACS ^TM 120 or BRUKER NMR 400.13Mz, BBFO, ULTRASHIELD ^TM 400，AVANCE III 400，B-ACS ^TM NMR was recorded at 120.

Preparation examples

Scheme for preparing key intermediates: the following schemes show the preparation of key intermediates.

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

Step 1:2- (4, 4-difluoropiperidin-1-yl) -3-methyl-5-nitropyridine

2-chloro-2-methyl-3-nitropyridine (5.0 g,28.9mmol,1.0 eq.) was dissolved in ACN (100 mL) followed by the addition of piperazine 4.4-difluoropiperidine (4.2 g,34.7mmol,1.2 eq.) and Cs ₂ CO ₃ (18.8 g,57.9mmol,2.0 eq.). The resulting mixture was heated to 80 ℃ for 16 hours and then cooled to room temperature. After filtration and washing of the solid with MeOH, the filtrate was concentrated in vacuo to give 2- (4, 4-difluoropiperidin-1-yl) -3-methyl-5-nitropyridine (6 g) as a brown solid. LCMS method B: [ M+H ]] ⁺ ＝258。

Step 2:6- (4, 4-difluoropiperidin-1-yl) -5-methylpyridin-3-amine

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

Step 3-4:1- [6- (4, 4-Difluoropiperidin-1-yl) -5-methylpyridin-3-yl ] imidazole-4-carboxylic acid ethyl ester

6- (4, 4-Difluoropiperidin-1-yl) -5-methylpyridin-3-amine (2.0 g,8.8mmol,1.0 eq.) was dissolved in EtOH (20 mL) and AcOH (1 mL) followed by the addition of ethyl 2-nitroacetate (1.1 g,8.8mmol,1.0 eq.). The reaction mixture was heated to 80 ℃ for 30 minutes and then cooled to ambient temperature. Triethoxymethane (6.5 g,44.0mmol,5.0 eq.) was then added and the resulting solution was heated at 80℃for 2 hours. After cooling to ambient temperature, acOH (10 mL) and triethyloxymethane (10 mL) were added followed by dropwise addition of Fe (0.3 g,5.4mmol,1.0 eq). The reaction mixture was heated to 80 ℃ 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-difluoropiperidin-1-yl) -5-methylpyridin-3-yl as an off-white solid ]Imidazole-4-carboxylic acid ethyl ester (600 mg). Method A: [ M+H ]] ⁺ ＝351。

Step 5:1- [6- (4, 4-difluoropiperidin-1-yl) -5-methylpyridin-3-yl ] imidazole-4-carboxylic acid

1- [6- (4, 4-difluoropiperidin-1-yl) -5-methylpyridin-3-yl]Imidazole-4-carboxylic acid ethyl ester (500.0 mg,1.4mmol,1.0 eq.) in MeOH/H ₂ O (5:1, 12 mL) was dissolved and then NaOH (85.6 mg,2.1mmol,1.5 eq.) was added. The reaction mixture was heated to 50 ℃ for 2 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and the solution was then adjusted to pH 2 with aqueous HCl (6M). The solid was collected by filtration and then dried to give 1-[6- (4, 4-difluoropiperidin-1-yl) -5-methylpyridin-3-yl]Imidazole-4-carboxylic acid (300 mg). Method A: [ M+H ]] ⁺ ＝323。

The following intermediates were prepared using the same procedure as described for intermediate 1.

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

Step 1:1- [ [6- (4, 4-difluorocyclohexyl) -5-fluoropyridin-3-yl ] methyl ] pyrazole-4-carboxylic acid ethyl ester

5- (bromomethyl) -2- (4, 4-difluorocyclohexyl) -3-fluoropyridine (500.0 mg,1.6mmol,1.0 eq.) was dissolved in ACN (20 mL) and K was then added ₂ CO ₃ (704.9 mg,5.1mmol,3.0 eq.) and ethyl 1H-pyrazole-4-carboxylate (238.2 mg,1.7mmol,1.0 eq.). The reaction mixture was stirred at ambient temperature for 16 hours. The solids were removed by filtration and the filtrate 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-difluorocyclohexyl) -5-fluoropyridin-3-yl as a white solid ]Methyl group]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

1- [ [6- (4, 4-difluorocyclohexyl) -5-fluoropyridin-3-yl ]]Methyl group]Pyrazole-4-carboxylic acid ethyl ester (300.0 mg,0.8mmol,1.0 eq.) was dissolved in MeOH (2 mL) and water (2 mL), followed by addition of NaOH (65.3 mg,1.6mmol,2.0 eq.). The reaction mixture was heated to 80 ℃ for 1 hour, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and the solution was then adjusted to pH 5 with aqueous HCl (6M). The solid was collected by filtration and then dried to give 1- [ [6- (4, 4-difluorocyclohexyl) -5-fluoropyridine-3 as a white solid-base group]Methyl group]Pyrazole-4-carboxylic acid (250 mg). LCMS method B: [ M+H ]] ⁺ ＝340。

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

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,2.6mmol,1.0 eq.) was dissolved in ACN (15 mL) and K was then added ₂ CO ₃ (1.1 g,7.8mmol,3.0 eq.) and ethyl 1H-imidazole-4-carboxylate (363.8 mg,2.6mmol,1.0 eq.). The reaction mixture was heated to 80 ℃ for 2 hours. After filtration and washing with MeOH, the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:10-1:1) to give 1- [ [6- (4, 4-difluorocyclohexyl) -5-fluoropyridin-3-yl as a pale yellow solid]Methyl group]Imidazole-4-carboxylic acid ethyl ester (Compound 8A,350 mg) and 3- [ [6- (4, 4-difluorocyclohexyl) -5-fluoropyridin-3-yl ] as a white solid]Methyl group]Imidazole-4-carboxylic acid ethyl ester (compound 8b,370 mg). LCMS of compound 8A, method B: [ M+H ]] ⁺ =368. Compound 8A ¹ H NMR(400MHz,DMSO-d ₆ ): delta 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. Compound 8B ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.27(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

1- [ [6- (4, 4-difluorocyclohexyl) -5-fluoropyridin-3-yl ]]Methyl group]Imidazole-4-carboxylic acid ethyl ester (200.0 mg,0.5mmol,1.0 eq.) was dissolved in MeOH (4 mL) and water (4 mL), followed by addition of NaOH (65.3 mg,1.6mmol,3.0 eq.). The reaction mixture was stirred at 80 ℃ for 2 hours and then concentrated in vacuo. The residue was diluted with water and then adjusted to pH 5 with aqueous HCl (6M). The resulting solid was collected by filtration and filtered by flash prep-HPLC under the following conditions: column, C18; mobile phase, ACN/H ₂ O increases from 0 to 100% in 30 minutes; detector, 254nm. This gives 1- [ [6- (4, 4-difluorocyclohexyl) -5-fluoropyridin-3-yl as a white solid]Methyl group]Imidazole-4-carboxylic acid (160 mg). LCMS method B: [ M+H ]] ⁺ ＝340。

Step 3:1- ((6- (4, 4-difluorocyclohexyl) -5-fluoropyridin-3-yl) methyl) -1H-imidazole-5-carboxylic acid

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

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

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

Step 1:2- (4, 4-difluorocyclohexyl) -3-fluoro-5-iodopyridine

6- (4, 4-Difluorocyclohexyl) -5-fluoropyridin-3-amine (400.0 mg,1.7mmol,1.0 eq.) was dissolved in aqueous HCl (6M, 10 mL) and cooled to 0deg.C, then NaNO was added dropwise ₂ (179.8 mg,2.6mmol,1.5 eq.) in water (0.5 mL) the reaction mixture was maintained at 0deg.C. After the addition was complete, the solution was stirred at 0 ℃ for an additional 2 hours. After quenching with water, the resulting solution was extracted with ethyl acetate and concentrated in vacuo. Purification by flash column chromatography on silica gelThe residue was eluted with ethyl acetate/petroleum ether (1:1) to give 2- (4, 4-difluorocyclohexyl) -3-fluoro-5-iodopyridine (120 mg) as a pale yellow solid. LCMS method a:

[M+H] ⁺ ＝342。

Step 2:1- (6- (4, 4-Difluorocyclohexyl) -5-fluoropyridin-3-yl) -1H-pyrazole-4-carboxylic acid ethyl ester

2- (4, 4-Difluorocyclohexyl) -3-fluoro-5-iodopyridine (500.0 mg,1.5mmol,1.0 eq.) was dissolved in DMF (5 mL) and Cs was then added ₂ CO ₃ (1.4 g,4.4mmol,3.0 eq.) 1H-pyrazole-4-carboxylic acid ethyl ester (246.5 mg,1.8mmol,1.2 eq.) N ₁ ,N ₂ Dimethylcyclohexane-1, 2-diamine (0.1 mL,0.7mmol,0.5 eq.) and CuI (57.3 mg,0.3mmol,0.2 eq.). The resulting solution was heated to 80 ℃ for 8 hours, then cooled to ambient temperature and quenched by the 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-difluorocyclohexyl) -5-fluoropyridin-3-yl as a pale yellow solid]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

1- [6- (4, 4-difluorocyclohexyl) -5-fluoropyridin-3-yl]Pyrazole-4-carboxylic acid ethyl ester (110.0 mg,0.3mmol,1.0 eq.) was dissolved in MeOH (5 mL) followed by the addition of aqueous NaOH (2 mL, 2M). The reaction mixture was stirred at ambient temperature for 2 hours and then diluted with 5mL of water. The solution was adjusted to pH 5 with aqueous HCl (2M) and dried in vacuo. The crude product was purified by flash prep-HPLC under the following conditions: column, silica gel; the mobile phase, ACN/water, increased from 0 to 70% in 25 minutes. This gives 1- [6- (4, 4-difluorocyclohexyl) -5-fluoropyridin-3-yl as a pale yellow solid ]Pyrazole-4-carboxylic acid (70 mg). LCMS method a: [ M+H ]] ⁺ ＝326。

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,163.3mmol,1.0 eq.) was dissolved in ACN (300 mL) and cooled to 0deg.C, then AgNO was added ₃ (33.3 g,195.9mmol,1.2 eq.). The resulting mixture was stirred for 15 minutes, then benzoyl chloride (27.5 g,195.9mmol,1.2 eq.) was added in portions and the reaction mixture was maintained at 0 ℃. After an additional 3 hours at 0 ℃, the reaction mixture was quenched by addition of ice water. The reaction mixture was treated with saturated aqueous NaHCO ₃ The pH was adjusted to 8, then extracted with DCM and the organic layer concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (2:1) to give 5, 6-difluoro-3-nitro-1H-indole (24 g) as a brown solid. LCMS method a: [ M+H ]] ⁺ ＝199。

Step 2: n- (5, 6-difluoro-1H-indol-3-yl) carbamic acid tert-butyl ester

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

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

Tert-butyl N- (5, 6-difluoro-1H-indol-3-yl) carbamate (17.0 g,63.4mmol,1.0 eq.) is 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-1H-indol-3-amine hydrochloride (12 g) as a yellow solid. LCMS method C: [ M+H ]] ⁺ ＝169。

The intermediates in the following table were prepared using the same procedure as described for intermediate 11.

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-carbonyl azide

5-fluoro-1H-pyrrolo [2,3-b]Pyridine-3-carboxylic acid (1.0 g,5.6mmol,1.0 eq.) and DPPA (3.0 g,11.1mmol,2.0 eq.) were dissolved in THF (10.0 mL) and TEA (1.6 mL,11.1mmol,2.0 eq.) was added. The resulting mixture was stirred at ambient temperature overnight and then concentrated in vacuo. The residue was diluted with water, extracted with ethyl acetate, and taken up in anhydrous Na ₂ SO ₄ Drying above, and concentrating under vacuum to give 5-fluoro-1H-pyrrolo [2,3-b ] as a white solid]Pyridine-3-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-1H-pyrrolo [2,3-b]Pyridine-3-carbonyl azide (300.0 mg,1.5mmol,1.0 eq.) was added to t-BuOH (8.0 mL). The resulting mixture was stirred at 100 ℃ 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 [2,3-b ] as a yellow solid]Pyridin-3-yl]Tert-butyl carbamate (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 ]]Pyridin-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 ] as a yellow solid]Pyridin-3-amine hydrochloride (350 mg). LCMS method E: [ M+H ]] ⁺ ＝151。

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,4.2mmol,1.0 eq.) was dissolved in THF (10.0 mL) and DPPA (2.3 g,8.3mmol,2.0 eq.) and TEA (1.8 mL,12.5mmol,3.0 eq.) 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-1H-indole-3-carbonyl azide (900 mg) as a white solid. LCMS method E: [ M+H ] ] ⁺ ＝265。

Step 2: n- (5-bromo-1H-indol-3-yl) carbamic acid tert-butyl ester

5-bromo-1H-indole-3-carbonyl azide (900.0 mg,3.4mmol,1.0 eq.) was dissolved in t-BuOH (6 mL). The resulting mixture was heated at 80 ℃ 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 tert-butyl N- (5-bromo-1H-indol-3-yl) carbamate (910 mg) as a yellow solid. LCMS method E: [ M+H ]] ⁺ ＝311。

Step 3: n- [5- (1-Isopropylpyrazol-4-yl) -1H-indol-3-yl ] carbamic acid tert-butyl ester

Tert-butyl N- (5-bromo-1H-indol-3-yl) carbamate (500.0 mg,1.6mmol,1.0 eq) is dissolved in 1, 4-dioxane (6 mL) and water (0.6 mL), then 1-isopropyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (417.3 mg,1.8mmol,1.1 eq), xphos Pd G3 (136.0 mg,0.2mmol,0.1 eq) and Cs are added under nitrogen atmosphere ₂ CO ₃ (1.0 g,3.2mmol,2.0 eq.). The solution was heated at 100 ℃ overnight and then quenched by the 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-isopropylpyrazol-4-yl) -1H-indol-3-yl as a white solid ]Tert-butyl carbamate (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]Tert-butyl carbamate (400.0 mg,1.2mmol,1.0 eq.) was dissolved in HCl in 1, 4-dioxane (4 m,8.0 ml). The resulting solution was stirred at ambient temperature for 4 hours, then concentrated in vacuo to give crude 5- (1-isopropylpyrazol-4-yl) -1H-indol-3-amine hydrochloride (400 mg) as a gray solid. LCMS method E: [ M+H ]] ⁺ ＝241。

The following intermediates were prepared using the same procedure as described for intermediate 15.

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

Step 1:6- (4, 4-difluorocyclohex-1-en-1-yl) -5-fluoropyridin-3-amine

6-bromo-5-fluoropyridin-3-amine (500.0 mg,2.6mmol,1.00 eq.) was dissolved in 1, 4-dioxane (10 mL) and water (1 mL), then K was added under nitrogen ₂ CO ₃ (1.1 g,7.9mmol,3.0 eq.) 2- (4, 4-difluorocyclohex-1-en-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (766.8 mg,3.1mmol,1.2 eq.) and Pd (dppf) Cl ₂ (383.1 mg,0.5mmol,0.2 eq.). The reaction mixture was heated to 90 ℃ 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-en-1-yl) -5-fluoropyridin-3-amine as an off-white solid (420 mg). LCMS method C: [ M+H ] ] ⁺ ＝229。

Step 2:6- (4, 4-difluorocyclohexyl) -5-fluoropyridin-3-amine

6- (4, 4-Difluorocyclohex-1-en-1-yl) -5-fluoropyridin-3-amine (400.0 mg,1.8 m)mol,1.0 eq.) in MeOH (20 mL) and Pd/C (93.3 mg,0.9mmol,0.5 eq.) was added. The mixture was sprayed with nitrogen, placed under an atmosphere of hydrogen (balloon) and then 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。

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

Step 1:2- (4, 4-difluoropiperidin-1-yl) -3-fluoro-5-nitropyridine

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

Step 2:6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-amine

2- (4, 4-Difluoropiperidin-1-yl) -3-fluoro-5-nitropyridine (13.2 g,50.5mmol,1.0 eq.) was dissolved in MeOH (100 mL) followed by Pd/C (2.0 g,18.8mmol,0.4 eq.) added. The mixture was sprayed with nitrogen, placed under an atmosphere of hydrogen (balloon) and then stirred at ambient temperature for 15 hours. The solids were removed by filtration and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography on silica eluting with methylene chloride/methanol (97:3) to give 6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-amine (11.4 g) as a yellow solid. LCMS method D: [ M+H ]] ⁺ ＝232。

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

Step 1:6- (4, 4-Difluorocyclohex-1-en-1-yl) -5-fluoropyridine-3-carboxylic acid methyl ester

6-bromo-5-fluoropyridine-3-carboxylic acid methyl ester (2.0 g,8.5mmol,1.0 eq) was dissolved in 1, 4-dioxane (2 mL) and water (2 mL), then Cs was added under nitrogen atmosphere ₂ CO ₃ (5.6 g,17.1mmol,2.0 eq.) 2- (4, 4-difluorocyclohex-1-en-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (2.1 g,8.5mmol,1.0 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (1.4 g,1.7mmol,0.2 eq.). The reaction mixture was heated at 90 ℃ 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 methyl 6- (4, 4-difluorocyclohex-1-en-1-yl) -5-fluoropyridine-3-carboxylate (2.2 g) as a yellow solid. LCMS method a: [ M+H ] ] ⁺ ＝272。

Step 2:6- (4, 4-Difluorocyclohexyl) -5-fluoropyridine-3-carboxylic acid methyl ester

6- (4, 4-Difluorocyclohex-1-en-1-yl) -5-fluoropyridine-3-carboxylic acid methyl ester (2.0 g,7.4mmol,1.0 eq.) was dissolved in DCM (80 mL) and PtO was then added ₂ (837.2 mg,3.7mmol,0.5 eq.). The mixture was sprayed with nitrogen, placed under an atmosphere of hydrogen (balloon), and then 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 solid. LCMS method I: [ M+H ]] ⁺ ＝274。

Step 3: [6- (4, 4-difluorocyclohexyl) -5-fluoropyridin-3-yl ] methanol

6- (4, 4-Difluorocyclohexyl) -5-fluoropyridine-3-carboxylic acid methyl ester (2.0 g,7.3mmol,1.0 eq.) was dissolved in THF (20 mL) and cooled to 0deg.C, then LiAlH was added in portions ₄ (0.6 g,14.6mmol,2.0 eq.). The resulting solution was stirred at 0 ℃ for 30 minutes, then by adding Na ₂ SO ₄ ·10H ₂ O is quenched. After removal of solids by filtration, the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using dichloroMethane/methanol (10:1) elution to give [6- (4, 4-difluorocyclohexyl) -5-fluoropyridin-3-yl ] as a white solid]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-fluoropyridin-3-yl]Methanol (1.0 g,4.1mmol,1.0 eq.) was dissolved in DCM (10 mL) and cooled to 0deg.C, then PBr3 (0.4 mL,4.1mmol,1.0 eq.) was added and the mixture maintained at 0deg.C. The reaction mixture was stirred at 0deg.C for 1 hour, then was prepared by adding saturated aqueous NaHCO ₃ Quenching. 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. 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,163.3mmol,1.0 eq.) was dissolved in ACN (300 mL) and cooled to 0deg.C, then AgNO was added ₃ (33.3 g,195.9mmol,1.2 eq.). The resulting mixture was stirred for 15 minutes, then benzoyl chloride (27.5 g,195.9mmol,1.2 eq.) was added in portions and the reaction mixture was maintained at 0 ℃. After an additional 3 hours at 0 ℃, the reaction mixture was quenched by addition of ice water. The reaction mixture was treated with saturated aqueous NaHCO ₃ The pH was adjusted to 8, then extracted with DCM and the organic layer concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (2:1) to give 5, 6-difluoro-3-nitro-1H-indole (24 g) as a brown solid. LCMS method a: [ M+H ] ] ⁺ ＝199。

Step 2: n- (5, 6-difluoro-1H-indol-3-yl) carbamic acid tert-butyl ester

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

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

Tert-butyl N- (5, 6-difluoro-1H-indol-3-yl) carbamate (17.0 g,63.4mmol,1.0 eq.) is dissolved in HCl/1, 4-dioxane (4N, 200 mL). The resulting mixture was stirred at ambient temperature for 30 minutes and then concentrated in vacuo to give 5, 6-difluoro-1H-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 procedure as described for intermediate 1B.

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

Step 1:6- (4, 4-difluorocyclohex-1-en-1-yl) -5-fluoropyridin-3-amine

6-bromo-5-fluoropyridin-3-amine (500.0 mg,2.6mmol,1.00 eq.) was dissolved in 1, 4-dioxane (10 mL) and water (1 mL), then K was added under nitrogen ₂ CO ₃ (1.1 g,7.9mmol,3.0 eq.) 2- (4, 4-difluorocyclohex-1-en-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (766.8 mg,3.1mmol,1.2 eq.) and Pd (dppf) Cl ₂ (383.1 mg,0.5mmol,0.2 eq.). The reaction mixture was heated to 90 ℃ for 2 hoursThen 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-en-1-yl) -5-fluoropyridin-3-amine as an off-white solid (420 mg). LCMS method C: [ M+H ]] ⁺ ＝229。

Step 2:6- (4, 4-difluorocyclohexyl) -5-fluoropyridin-3-amine

6- (4, 4-Difluorocyclohex-1-en-1-yl) -5-fluoropyridin-3-amine (400.0 mg,1.8mmol,1.0 eq.) was dissolved in MeOH (20 mL) followed by Pd/C (10% wt.,93.3 mg). The mixture was sprayed with nitrogen, placed under an atmosphere of hydrogen (balloon) and then 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 procedure as described for intermediate 6B.

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

Step 1:2- (4, 4-difluoropiperidin-1-yl) -3-fluoro-5-nitropyridine

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

Step 2:6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-amine

2- (4, 4-Dihalopiperidin-1-yl) -3-fluoro-5-nitropyridine (13.2 g,50.5mmol,1.0 eq.) was dissolved in MeOH (100 mL) followed by Pd/C (10% wt.,2.0 g). The mixture was sprayed with nitrogen, placed under an atmosphere of hydrogen (balloon) and then stirred at ambient temperature for 15 hours. The solids were removed by filtration and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography on silica eluting with methylene chloride/methanol (97:3) to give 6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-amine (11.4 g) as a yellow solid. LCMS method D: [ M+H ] ] ⁺ ＝232。

The following intermediates were prepared using the same procedure as described for intermediate 12B.

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

Step 1: 3-chloro-2- (4, 4-difluoropiperidin-1-yl) -5-nitropyridine

2-bromo-3-chloro-5-nitropyridine (10.0 g,42.1mmol,1.0 eq.) and 4, 4-difluoropiperidine (5.6 g,46.3mmol,1.1 eq.) were dissolved in DMF (100 mL) and Cs was then added ₂ CO ₃ (27.4 g,84.2mmol,2.0 eq.). The reaction mixture was heated to 90 ℃ overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Drying the above, and concentrating in vacuum to obtain3-chloro-2- (4, 4-difluoropiperidin-1-yl) -5-nitropyridine (9.5 g) was obtained as a brown solid. LCMS method a: [ M+H ]] ⁺ ＝278。

Step 2: 5-chloro-6- (4, 4-difluoropiperidin-1-yl) pyridin-3-amine

3-chloro-2- (4, 4-difluoropiperidin-1-yl) -5-nitropyridine (9.0 g,32.4mmol,1.0 eq.) was dissolved in EtOH (90 mL) followed by dropwise addition of SnCl ₂ (30.7 g,162.1mmol,5.0 eq.). The reaction mixture was heated to 60 ℃ overnight, then cooled to ambient temperature and quenched by the addition of water. The dissolution was adjusted to pH 12 with solid NaOH, extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ The above was dried and concentrated in vacuo to give 5-chloro-6- (4, 4-difluoropiperidin-1-yl) pyridin-3-amine (7.1 g) as a black solid. LCMS method E: [ M+H ] ] ⁺ ＝248。

The following intermediates were prepared using the same procedure as described for intermediate 21B.

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

Step 1:1- (4-nitropyridin-2-yl) -4- (2, 2-trifluoroethyl) piperazine

2-chloro-4-nitropyridine (2.0 g,12.6mmol,1.0 eq.) and 1- (2, 2-trifluoroethyl) piperazine (2.5 g,15.1mmol,1.2 eq.) were dissolved in 1, 4-dioxane (20 mL) and Cs was then added under nitrogen atmosphere ₂ CO ₃ (12.3G, 37.8mmol,3.0 eq.) and XPhos Pd G3 (1.1G, 1.3mmol,0.1 eq.). The reaction mixture was heated to 80 ℃ for 12 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried over 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 yellow1- (4-nitropyridin-2-yl) -4- (2, 2-trifluoroethyl) piperazine (1.2 g) as a coloured solid. LCMS method a: [ M+H ]] ⁺ ＝291。

Step 2:2- (4- (2, 2-trifluoroethyl) piperazin-1-yl) pyridin-4-amine

1- (4-nitropyridin-2-yl) -4- (2, 2-trifluoroethyl) piperazine (1.0 g,3.4mmol,1.0 eq.) was dissolved in MeOH (15 mL) and Pd/C (10% wt.,36.7 mg) was added under a nitrogen atmosphere. The mixture was sprayed with nitrogen, placed under an atmosphere of hydrogen (balloon), and then 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-trifluoroethyl) piperazin-1-yl) pyridin-4-amine (560.0 mg) as a brown solid, which was used in the next step without further purification. LCMS method E: [ M+H ] ] ⁺ ＝261。

The following intermediates were prepared using the same procedure as described for intermediate 23B.

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

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

4, 4-Difluorocyclohexane-1-one (10.0 g,74.6mmol,1.0 eq.) was dissolved in Et2O (100.0 mL) and cooled to 0deg.C, then MeMgBr (3M in THF,80.0mL,240mmol,3.0 eq.) was added dropwise and the solution maintained at 0deg.C. The reaction mixture was stirred at 0 ℃ for 2 hours and then quenched by adding ice water. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ The above was dried and concentrated in vacuo to give 4, 4-difluoro-1-methylcyclohexane-1-ol (9.5 g) as a yellow solid. LCMS method a: [ M+H ]] ⁺ ＝151。

Step 2: oxalic acid 4, 4-difluoro-1-methylcyclohexyl methyl ester

4, 4-difluoro-1-methyl esterMethylcyclohexane-1-ol (10.0 g,66.6mmol,1.0 eq.) and DMAP (0.8 g,6.7mmol,0.1 eq.) were dissolved in DCM (200 mL) and TEA (18.7 mL,133.2mmol,2.0 eq.) was added. After that, clomazone methyl (methyl oxalochloridate) (6.1 mL,67.3mmol,1.0 eq.) was 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-methylcyclohexylmethyl oxalate (11.2 g) as a yellow oil. LCMS method a: [ M+H ] ] ⁺ ＝237。

Step 3:2- ((4, 4-difluoro-1-methylcyclohexyl) oxy) -2-oxocesium acetate

Oxalic acid 4, 4-difluoro-1-methylcyclohexylmethyl ester (5.0 g,21.2mmol,1.0 eq.) was dissolved in THF (50 mL) and water (50 mL), followed by the addition of CsOH (3.2 g,20.9mmol,1.0 eq.). The reaction mixture was stirred at ambient temperature for 1 hour, then concentrated in vacuo to give cesium 2- ((4, 4-difluoro-1-methylcyclohexyl) oxy) -2-oxoacetate (5.2 g) as a white solid. LCMS method a: [ M+H ]] ⁺ ＝272。

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

Cesium 2- ((4, 4-difluoro-1-methylcyclohexyl) oxy) -2-oxoacetate (5.0 g,14.1mmol,1.0 eq.) was dissolved in DMSO (30 mL), followed by addition of (NH ₄ ) ₂ S ₂ O ₈ (2.3 g,9.9mmol,0.7 eq.) Ir [ dF (CF) ₃ )ppy] ₂ (dtbpy)PF ₆ (1.6 g,1.4mmol,0.1 eq.) and methyl 5-fluoropyridine-3-carboxylate (1.8 g,11.3mmol,0.8 eq.). The resulting solution was irradiated with Royal Blue (450 nm) LED light for 3 hours and stirred at 1000rpm and then quenched by the addition of water. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:10) to give methyl 6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridine-3-carboxylate (2.5 g) as a yellow oil. LCMS method a: [ M+H ] ] ⁺ ＝272。

Step 5:6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridine-3-carboxylic acid (2.5 g)

6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridine-3-carboxylic acid methyl ester (2.5 g,8.7mmol,1.0 eq)) Dissolved in MeOH (25 mL) and water (25 mL), then NaOH (1.0 g,26.0mmol,3.0 eq.) was added. The reaction mixture was heated to 80 ℃ for 1 hour, then cooled to ambient temperature and concentrated in vacuo. The residue was purified by flash prep-HPLC under the following conditions: column, C18 silica gel; mobile phase, ACN/H ₂ O=0% increase to ACN/H ₂ O=100%, within 30 minutes; detector, 254nm. 6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridine-3-carboxylic acid (2.1 g) was produced as a yellow oil. LCMS method C: [ M+H ]] ⁺ ＝274。

Step 6:6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridine-3-carbonyl azide

6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridine-3-carboxylic acid (1.0 g,3.7mmol,1.0 eq.) was dissolved in THF (20 mL) then TEA (1.0 mL,7.3mmol,2.0 eq.) and DPPA (1.5 g,5.5mmol,1.5 eq.) were added. 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-methylcyclohexyl) -5-fluoropyridine-3-carbonyl azide (900.0 mg) as a white oil. LCMS method E: [ M+H ] ] ⁺ ＝299。

Step 7: n- [6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridin-3-yl ] carbamic acid tert-butyl ester

6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridine-3-carbonyl azide (1.0 g,3.4mmol,1.0 eq.) was dissolved in t-BuOH (20 mL). The reaction mixture was heated to 80 ℃ for 2 hours, then cooled to ambient temperature and concentrated in vacuo. This gives N- [6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridin-3-yl as a white solid]Tert-butyl carbamate (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) -5-fluoropyridin-3-yl]Tert-butyl carbamate (900.0 mg,2.6mmol,1.0 eq.) 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 procedure as described for intermediate 25B.

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

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

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

Step 1: 3-fluoro-5-nitro-5, 6-dihydro-2H- [2, 3-bipyridine ] -1-carboxylic acid tert-butyl ester

2-chloro-3-fluoro-5-nitropyridine (2.0 g,11.3mmol,1.0 eq) and 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.3 g,17.0mmol,1.5 eq) were dissolved in 1, 4-dioxane (30 mL) and water (3 mL) and Cs was then added under nitrogen atmosphere ₂ CO ₃ (11.1G, 34.0mmol,3.0 eq.) and Xphos Pd G3 (959.0 mg,1.1mmol,0.1 eq.). The reaction mixture is heated toOvernight at 60 ℃, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated 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-dihydro-2H- [2, 3-bipyridine as a yellow solid]Tert-butyl 1-carboxylate (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-2H- [2, 3-bipyridine]Tert-butyl 1-carboxylate (600.0, 1.9mmol,1.0 eq.) was dissolved in HCl/1, 4-dioxane (4N, 15 mL). The reaction mixture was stirred at ambient temperature overnight and then concentrated in vacuo to give 3-fluoro-5-nitro-1, 2,5, 6-tetrahydro-2, 3-bipyridine hydrochloride (315.2 mg) LCMS method a as a pale yellow solid: [ M+H ] ] ⁺ ＝224。

Step 3: 3-fluoro-5-nitro-1- (2, 2-trifluoroethyl) -5, 6-dihydro-2H-2, 3-bipyridine

3-fluoro-5-nitro-1, 2,5, 6-tetrahydro-2, 3-bipyridine hydrochloride (467.5 mg,1.8mmol,1.0 eq.) and 2, 2-trifluoroethyl triflate (499.1 mg,2.2mmol,1.2 eq.) were dissolved in ACN (10 mL) and K was then added ₂ CO ₃ (495.3 mg,3.6mmol,2.0 eq.). The reaction mixture was stirred at ambient temperature for 3 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash prep-HPLC using the following conditions: column, C18 silica gel; mobile phase, H2O/mecn=90:10 increased to H2O/mecn=10:90, within 30 minutes; detector, 254nm. This gave 3-fluoro-5-nitro-1- (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-trifluoroethyl) piperidin-3-yl ] pyridin-3-amine

3-fluoro-5-nitro-1- (2, 2-trifluoroethyl) -5, 6-dihydro-2H-2, 3-bipyridine (250.0 mg,0.8mmol,1.0 eq.) was dissolved in MeOH (6 mL) and Pd/C (10% w%,25.3 mg) was then added under nitrogen. The mixture was sprayed with nitrogen and placed under hydrogenUnder atmosphere (balloon) and then stirred at ambient temperature overnight. The solids were removed by filtration and the filtrate 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-fluoro-6- [1- (2, 2-trifluoroethyl) piperidin-3-yl as a yellow oil ]Pyridin-3-amine (198.2 mg). LCMS method E: [ M+H ]] ⁺ ＝278。

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

Step 1:4- (3-fluoro-5-nitropyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester

2-chloro-3-fluoro-5-nitropyridine (2.0 g,11.3mmol,1.0 eq.) was dissolved in ACN (20 mL) and piperazine-1-carboxylic acid tert-butyl ester (2.0 g,11.3mmol,1.5 eq.) and K were then added ₂ CO ₃ (6.3 g,45.3mmol,4.0 eq.). The reaction mixture was heated to 80 ℃ overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl 4- (3-fluoro-5-nitropyridin-2-yl) piperazine-1-carboxylate (2.1 g) as a yellow solid. LCMS method a: [ M+H ]] ⁺ ＝327。

Step 2:1- (3-fluoro-5-nitropyridin-2-yl) piperazine

4- (3-fluoro-5-nitropyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (2.1 g,6.4mmol,1.0 eq.) was dissolved in HCl/1, 4-dioxane (4N, 40 mL). The reaction mixture was stirred at ambient temperature overnight and then concentrated in vacuo. The residue was purified by flash prep-HPLC using the following conditions: column, C18 silica gel; mobile phase, H2O/mecn=90:10 increased to H2O/mecn=10:90, within 30 minutes; detector, 254nm. This gave 1- (3-fluoro-5-nitropyridin-2-yl) piperazine (1.1 g) as a yellow oil. LCMS method a: [ M+H ] ] ⁺ ＝227。

Step 3:1- (3-fluoro-5-nitropyridin-2-yl) -4- (2-methoxyethyl) piperazine

1- (3-fluoro-5-nitropyridin-2-yl) piperazine (1.0 g,4.4mmol,1.0 eq.) and 2-bromoethyl methyl ether (0.9 g,6.6mmol,1.5 eq.) were dissolved in ACN (20 mL) and K was then added ₂ CO ₃ (1.2 g,8.8mmol,2.0 eq.). The reaction mixture was heated to 80 ℃ overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated 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-nitropyridin-2-yl) -4- (2-methoxyethyl) piperazine (1.0 g) as a yellow solid. LCMS method a:

[M+H] ⁺ ＝285。

step 4: 5-fluoro-6- [4- (2-methoxyethyl) piperazin-1-yl ] pyridin-3-amine

1- (3-fluoro-5-nitropyridin-2-yl) -4- (2-methoxyethyl) piperazine (1.1 g,3.9mmol,1.0 eq.) was dissolved in MeOH (20 mL) and Pd/C (10% wt.,110.1 mg) was added under nitrogen. The mixture was sprayed with nitrogen, placed under an atmosphere of hydrogen (balloon), and then stirred at ambient temperature overnight. The solids were removed by filtration and the filtrate concentrated in vacuo. The residue was purified by flash prep-HPLC using the following conditions: column, C18 silica gel; mobile phase, H2O/mecn=90:10 increased to H2O/mecn=10:90, within 30 minutes; detector, 254nm. This gives 5-fluoro-6- [4- (2-methoxyethyl) piperazin-1-yl as a yellow solid ]Pyridin-3-amine (805.2 mg). LCMS method D: [ M+H ]] ⁺ ＝255。

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

Step 1:6- (3, 3-Difluorocyclobutyl) -5-fluoropyridine-3-carboxylic acid methyl ester

Methyl 5-fluoropyridine-3-carboxylate (6.0 g,38.7mmol,1.0 eq.) was dissolved in DCE (60 mL) and water (60 mL) followed by addition of AgNO ₃ (1.3 g,7.7mmol,0.2 eq.) fluorous reagent (SelectFluor) (27.4 g,77.4mmol,2.0 eq.), TFA (4.4 g,38.7mmol,1.0 eq.) and 3, 3-difluorocyclobutane-1-carboxylic acidAcid (10.5 g,77.4mmol,2.0 eq.). The reaction mixture was heated to 50 ℃ for 24 hours and then cooled to ambient temperature. The solids were removed by filtration and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:1) to give methyl 6- (3, 3-difluorocyclobutyl) -5-fluoropyridine-3-carboxylate (1.4 g) as a white solid. LCMS method a: [ M+H ]] ⁺ ＝246。

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

Methyl 6- (3, 3-difluorocyclobutyl) -5-fluoropyridine-3-carboxylate (2.0 g,8.2mmol,1.0 eq.) was dissolved in MeOH (10 mL) and water (10 mL) followed by addition of LiOH (390.7 mg,16.3mmol,2.0 eq.). The reaction mixture was heated to 80 ℃ for 30 minutes, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water, adjusted to pH 5 with aqueous HCl (2M), extracted with ethyl acetate, and concentrated in vacuo to give 6- (3, 3-difluorocyclobutyl) -5-fluoropyridine-3-carboxylic acid (1.5 g) as a white solid. LCMS method D: [ M+H ] ] ⁺ ＝232。

Step 3:6- (3, 3-difluorocyclobutyl) -5-fluoropyridine-3-carbonyl azide

6- (3, 3-Difluorocyclobutyl) -5-fluoropyridine-3-carboxylic acid (2.0 g,8.7mmol,1.0 eq.) and TEA (2.4 mL,17.3mmol,2.0 eq.) were dissolved in THF (100 mL) and DPPA (3.6 g,13.0mmol,1.5 eq.) 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) -5-fluoropyridine-3-carbonyl azide (1.5 g) as a white solid. LCMS method a: [ M+H ]] ⁺ ＝257。

Step 4: n- [6- (3, 3-difluorocyclobutyl) -5-fluoropyridin-3-yl ] carbamic acid tert-butyl ester

6- (3, 3-Difluorocyclobutyl) -5-fluoropyridine-3-carbonyl azide (1.5 g,5.9mmol,1.0 eq.) was dissolved in t-BuOH (50 mL). The reaction mixture was heated to 80 ℃ for 16 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 (1:1) to give N- [6- (3, 3-difluorocyclobutyl) -5-fluoropyridin-3-yl as a white solid]Carbamic acidTert-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-yl ]Tert-butyl carbamate (1.5 g,5.0mmol,1.0 eq.) was dissolved in HCl/1, 4-dioxane (4N, 40 mL). The reaction mixture was stirred at ambient temperature for 16 hours and concentrated in vacuo to give 6- (3, 3-difluorocyclobutyl) -5-fluoropyridin-3-amine hydrochloride as a white solid. LCMS method C: [ M+H ]] ⁺ ＝203。

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

Step 1:6- [ 6-azaspiro [2.5] oct-6-yl ] -5-fluoropyridine-3-carboxylic acid methyl ester

6-bromo-5-fluoropyridine-3-carboxylic acid methyl ester (5.0 g,21.4mmol,1.0 eq.) was dissolved in DMF (50 mL) and K was then added ₂ CO ₃ (8.9 g,64.1mmol,3.0 eq.) and 6-azaspiro [2.5]]Octane (2.9 g,25.6mmol,1.2 eq.). The reaction mixture was heated to 80 ℃ overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na ₂ SO ₄ Dried above, and concentrated in vacuo to give 6- [ 6-azaspiro [2.5] as a pale yellow solid]Octane-6-yl]-5-fluoropyridine-3-carboxylic acid methyl ester (5.5 g). LCMS method a: [ M+H ]] ⁺ ＝265。

Step 2:6- [ 6-azaspiro [2.5] oct-6-yl ] -5-fluoropyridine-3-carboxylic acid

Methyl 6- [ 6-azaspiro [2.5] oct-6-yl ] -5-fluoropyridine-3-carboxylate (5.5 g,20.8mmol,1.0 eq.) was dissolved in MeOH (50 mL) and water (50 mL), followed by addition of LiOH (12.0 g,83.2mmol,4.0 eq.). The reaction mixture was stirred at ambient temperature overnight and then concentrated in vacuo. The residue was diluted with water and then adjusted to pH 5 with concentrated HCl. The precipitated solid was collected by filtration and washed with water to give 6- [ 6-azaspiro [2.5] oct-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 procedure as described for intermediate 31B.

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

Step 1: 3-chloro-1 ' - (2, 2-trifluoroethyl) -3',6' -dihydro-2 ' H- [2,4' -bipyridine ] -5-carboxylic acid methyl ester

6-bromo-5-chloropyridine-3-carboxylic acid methyl ester (1.0 g,4.0mmol,1.0 eq) and 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- (2, 2-trifluoroethyl) -3, 6-dihydro-2H-pyridine (2.3 g,7.9mmol,2.0 eq) were dissolved in 1, 4-dioxane (10 mL) and water (1 mL), then Cs was added under nitrogen atmosphere ₂ CO ₃ (2.6 g,8.0mmol,2.0 eq.) and Pd (dppf) Cl ₂ (292.1 mg,0.4mmol,0.1 eq.). The reaction mixture was heated to 90 ℃ for 16 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 (1:1) to give 3-chloro-1 ' - (2, 2-trifluoroethyl) -3',6' -dihydro-2 ' h- [2,4' -bipyridine as a white solid]-methyl 5-carboxylate (1.0 g). LCMS method a: [ M+H ]] ⁺ ＝335。

Step 2: 5-chloro-6- [1- (2, 2-trifluoroethyl) piperidin-4-yl ] pyridine-3-carboxylic acid methyl ester

Methyl 3-chloro-1 (1.0 g,3.0mmol,1.0 eq.) was dissolved in DCM (20 mL) and PtO was then added ₂ (67.8 mg,0.3mmol,0.1 eq.). The mixture was sprayed with nitrogen, placed under an atmosphere of hydrogen (balloon) and then stirred at ambient temperature for 16 hours. By passing through The solids were removed by filtration and the filtrate was concentrated in vacuo to give 5-chloro-6- [1- (2, 2-trifluoroethyl) piperidin-4-yl as a white solid]Pyridine-3-carboxylic acid methyl ester (812.2 mg). LCMS method E: [ M+H ]] ⁺ ＝337。

Step 3: 5-chloro-6- [1- (2, 2-trifluoroethyl) piperidin-4-yl ] pyridine-3-carboxylic acid

5-chloro-6- [1- (2, 2-trifluoroethyl) piperidin-4-yl]Pyridine-3-carboxylic acid methyl ester (800.0 mg,2.4mmol,1.0 eq.) was dissolved in MeOH (5 mL) and water (5 mL), followed by NaOH (190.0 mg,4.8mmol,2.0 eq.) added. The reaction mixture was heated to 80 ℃ for 30 minutes, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and adjusted to pH 5 with aqueous HCl (4M). The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried over and concentrated in vacuo to give 5-chloro-6- [1- (2, 2-trifluoroethyl) piperidin-4-yl as a white solid]Pyridine-3-carboxylic acid (585.5 mg). LCMS method C: [ M+H ]] ⁺ ＝323。

The following intermediates were prepared using the same procedure as described for intermediate 38B.

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

Step 1:2- (4, 4-difluoropiperidin-1-yl) -3-fluoro-5-iodopyridine

6- (4, 4-Difluoropiperidin-1-yl) -5-fluoropyridin-3-amine (3.0 g,13.0mmol,1.0 eq.) was dissolved in aqueous HCl (6M, 50 mL) and cooled to 0deg.C, then NaNO was added dropwise ₂ (1.3 g,19.5mmol,1.5 eq.) in water (2 mL) the mixture was maintained at 0deg.C. KI (4.3 g,26.0mmol,2.0 eq.) was added dropwise at 0deg.C for 30 min, and maintained at 0deg.C. After the addition was completed, the solution was stirred at 0 ℃ for an additional 2 hours. After quenching with water, the resulting solution was extracted with ethyl acetateTaken 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- (4, 4-difluoropiperidin-1-yl) -3-fluoro-5-iodopyridine (2.0 g) as a yellow solid. LCMS method a: [ M+H ]] ⁺ ＝343。

Step 2:1- [6- (4, 4-Difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] pyrazole-4-carboxylic acid ethyl ester

2- (4, 4-Difluoropiperidin-1-yl) -3-fluoro-5-iodopyridine (2.0 g,5.8mmol,1.0 eq.) was dissolved in DMF (20 mL) followed by the addition of Cs ₂ CO ₃ (5.7 g,17.5mmol,3.0 eq.), 1H-pyrazole-4-carboxylic acid ethyl ester (1.0 g,7.0mmol,1.2 eq.), N ₁ ,N ₂ Dimethylcyclohexane-1, 2-diamine (0.5 mL,2.9mmol,0.5 eq.) and CuI (220.9 mg,0.3mmol,0.2 eq.). The resulting solution was heated to 80 ℃ overnight, then cooled to ambient temperature and quenched by the 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-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as a yellow solid ]Pyrazole-4-carboxylic acid ethyl ester (1.0 g). LCMS method a: [ M+H ]] ⁺ ＝355。

Step 3:1- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] pyrazole-4-carboxylic acid

1- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl]Pyrazole-4-carboxylic acid ethyl ester (1.0 g,2.8mmol,1.0 eq.) was dissolved in MeOH (5 mL) and water (5 mL), followed by addition of NaOH (225.8 mg,5.6mmol,2.0 eq.). The reaction mixture was heated to 60 ℃ 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 (1M). The precipitated solid was collected by filtration, washed with water and dried to give 1- [6- (4, 4-difluoropiperidin-1-yl) -5-methylpyridin-3-yl as a white solid]Imidazole-4-carboxylic acid (510.0 mg). LCMS method E: [ M+H ]] ⁺ ＝327。

The following intermediates were prepared using the same procedure as described for intermediate 40B.

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

Step 1: 5-azido-2- (4, 4-difluoropiperidin-1-yl) -3-fluoropyridine

6- (4, 4-Difluoropiperidin-1-yl) -5-fluoropyridin-3-amine (400.0 mg,1.7mmol,1.0 eq.) was dissolved in ACN (10 mL) and cooled to 0℃before t-BuNO was added dropwise ₂ (0.3 mL,2.7mmol,1.6 eq.) the solution was maintained at 0deg.C. The reaction mixture was stirred at 0℃for 30 min. Then TMSN is added dropwise at 0 DEG C ₃ (0.3 mL,2.5mmol,1.5 eq.). The resulting mixture was stirred at ambient temperature for an additional 2 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried over 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-difluoropiperidin-1-yl) -3-fluoropyridine (380.0 mg) as a yellow oil. LCMS method a: [ M+H ]] ⁺ ＝258。

Step 2:1- [6- (4, 4-Difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1,2, 3-triazole-4-carboxylic acid methyl ester

5-azido-2- (4, 4-difluoropiperidin-1-yl) -3-fluoropyridine (350.0 mg,1.4mmol,1.0 eq.) was dissolved in 1, 4-dioxane (3.6 mL) and water (0.4 mL), then methacrylate (228.8 mg,2.7mmol,2.0 eq.) (R) -2- ((S) -1, 2-dihydroxyethyl) -4-hydroxy-5-oxo-2, 5-dihydrofuran-3-oleic acid sodium (53.9 mg,0.3mmol,0.2 eq.) and CuSO were added ₄ (21.7 mg,0.1mmol,0.1 eq.). The reaction mixture was stirred at ambient temperature overnight and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried over 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-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as a yellow solid ]-methyl 1,2, 3-triazole-4-carboxylate (150.0 mg). LCMS method G: [ M ]+H] ⁺ ＝341。

Step 3:1- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1,2, 3-triazole-4-carboxylic acid

1- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl]1,2, 3-triazole-4-carboxylic acid methyl ester (300.0 mg,0.9mmol,1.0 eq.) was dissolved in MeOH (3 mL) and water (7 mL), followed by addition of NaOH (70.3 mg,1.8mmol,2.0 eq.). The reaction mixture was heated to 80 ℃ 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 dried over anhydrous Na ₂ SO ₄ Dried over and concentrated in vacuo to afford 1- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as a yellow solid]-1,2, 3-triazole-4-carboxylic acid (200.1 mg). LCMS method E: [ M+H ]] ⁺ ＝328。

The following intermediates were prepared using the same procedure as described for intermediate 43B.

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

Step 1:1- [ (4-bromo-2-fluorophenyl) methyl ] -3, 3-difluoroazetidine

4-bromo-1- (bromomethyl) -2-fluorobenzene (1.0 g,3.7mmol,1.0 eq.) was dissolved in ACN (20 mL) and K was added ₂ CO ₃ (1.6 g,11.2mmol,3.0 eq.) and 3, 3-difluoroazetidine (347.4 mg,3.7mmol,1.0 eq.). The reaction mixture was stirred at ambient temperature overnight and then concentrated in vacuo. The residue was diluted with water, extracted with ethyl acetate and brine Washing with water, in anhydrous Na ₂ SO ₄ Dried above, and concentrated in vacuo to give 1- [ (4-bromo-2-fluorophenyl) methyl ] as a yellow oil]-3, 3-difluoroazetidine (821.2 mg). LCMS method a: [ M+H ]] ⁺ ＝280。

Step 2:1- [ (4-azido-2-fluorophenyl) methyl ] -3, 3-difluoroazetidine

1- [ (4-bromo-2-fluorophenyl) methyl group]-3, 3-Difluoroazetidine (800.0 mg,2.9mmol,1.0 eq.) was dissolved in DMF (10 mL) and then methyl [2- (methylamino) ethyl ] was added under nitrogen]Amine (0.6 mL,5.7mmol,2.0 eq.), sodium ascorbate (56.9 mg,0.3mmol,0.1 eq.), cuI (54.4 mg,0.3mmol,0.1 eq.) and NaN ₃ (371.4 mg,5.7mmol,2.0 eq.). The reaction mixture was heated to 80 ℃ overnight, then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with brine, dried over anhydrous Na ₂ SO ₄ Dried over 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- [ (4-azido-2-fluorophenyl) methyl ] as a yellow oil]-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 group]3, 3-Difluoroazetidine (500.0 mg,2.1mmol,1.0 eq.) was dissolved in 1, 4-dioxane (7 mL) and water (3 mL), followed by the addition of methacrylate (260.3 mg,3.1mmol,1.5 eq.), sodium ascorbate (41.1 mg,0.2mmol,0.1 eq.) and CuSO ₄ (33.0 mg,0.2mmol,0.1 eq.). The reaction mixture was stirred at ambient temperature overnight and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried above, and concentrated in vacuo to give 1- [4- [ (3, 3-difluoroazetidin-1-yl) methyl ] as a yellow solid]-3-fluorophenyl group]-methyl 1,2, 3-triazole-4-carboxylate (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

1- [4- [ (3, 3-difluoroaza) 1Cyclobutan-1-yl) methyl]-3-fluorophenyl group]1,2, 3-triazole-4-carboxylic acid methyl ester (500.0 mg,1.5mmol,1.0 eq.) was dissolved in MeOH (5 mL) and water (10 mL), followed by addition of NaOH (122.6 mg,3.1mmol,2.0 eq.). The reaction mixture was heated to 80 ℃ 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 afford 1- [4- [ (3, 3-difluoroazetidin-1-yl) methyl ] as a yellow solid]-3-fluorophenyl group]-1,2, 3-triazole-4-carboxylic acid (285.2 mg). LCMS method E: [ M+H ]] ⁺ ＝313。

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

Step 1:1- [6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridin-3-yl ] -1,2, 3-triazole-4-carboxylic acid ethyl ester

6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridin-3-amine (300.0 mg,1.2mmol,1.0 eq.) was dissolved in EtOH (3 mL) and AcOH (3 mL), followed by the addition of ethyl 2-diazo-3-oxopropionate (261.8 mg,1.8mmol,1.5 eq.). The reaction mixture was heated to 50 ℃ overnight, then cooled to ambient temperature and concentrated in vacuo. This gives 1- [6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridine-3 ]

Base group]-ethyl 1,2, 3-triazole-4-carboxylate (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

1- [6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridin-3-yl]Ethyl-1, 2, 3-triazole-4-carboxylate (400.0 mg,1.1mmol,1.0 eq.) was dissolved in MeOH (4 mL) and water (4 mL), followed by the addition of NaOH (86.9 mg,2.2mmol,2.0 eq.). The reaction mixture was heated to 80 ℃ 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 gel; mobile phase, ACN/H ₂ O=0% increaseAdded to ACN/H ₂ O=100%, 15 minutes; detector, 254nm. This gives 1- [6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridin-3-yl as a yellow solid ]-1,2, 3-triazole-4-carboxylic acid (295.2 mg). LCMS method E: [ M+H ]] ⁺ ＝341。

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

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

Step 1:1- (6-bromo-5-fluoropyridin-3-yl) -1,2, 3-triazole-4-carboxylic acid ethyl ester

6-bromo-5-fluoropyridin-3-amine (1.0 g,5.2mmol,1.0 eq) was dissolved in EtOH (30 mL) and HOAc (20 mL), followed by the addition of ethyl 2-diazo-3-oxopropionate (1.1 g,7.7mmol,1.5 eq). The reaction mixture was heated to 50 ℃ for 16 hours, then cooled to ambient temperature and concentrated in vacuo. 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 (1.2 g) as a yellow solid. LCMS method a: [ M+H ]] ⁺ ＝315。

Step 2:1- [6- [1- (tert-Butoxycarbonyl) -2, 5-dihydropyrrol-3-yl ] -5-fluoropyridin-3-yl ] -1,2, 3-triazole-4-carboxylic acid ethyl ester

1- (6-bromo-5-fluoropyridin-3-yl) -1,2, 3-triazole-4-carboxylic acid ethyl ester (1.0 g,3.2mmol,1.0 eq) and tert-butyl 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydropyrrole-1-carboxylate (1.1 g,3.8mmol,1.2 eq) were dissolved in 1, 4-dioxane (20 mL) and water (2 mL), then Pd (dppf) Cl was added ₂ (232.2 mg,0.3mmol,0.1 eq.) and Cs ₂ CO ₃ (4.1 g,12.7mmol,4.0 eq.). The reaction mixture was heated to 80 ℃ for 6 hours, then cooled to ambient temperature and quenched by the addition of waterAnd (5) extinguishing. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried over 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-butoxycarbonyl) -2, 5-dihydropyrrol-3-yl as an off-white solid]-5-fluoropyridin-3-yl]-ethyl 1,2, 3-triazole-4-carboxylate (612.2 mg). LCMS method E: [ M+H ]] ⁺ ＝404。

Step 3:1- [6- [1- (tert-Butoxycarbonyl) pyrrolidin-3-yl ] -5-fluoropyridin-3-yl ] -1,2, 3-triazole-4-carboxylic acid ethyl ester

1- [6- [1- (tert-Butoxycarbonyl) -2, 5-dihydropyrrol 3-yl]-5-fluoropyridin-3-yl]Ethyl-1, 2, 3-triazole-4-carboxylate (900.0 mg,2.2mmol,1.0 eq.) was dissolved in MeOH (15 mL) and Pd/C (10% wt.,90.0 mg) was added under a nitrogen atmosphere. The mixture was sprayed with nitrogen, placed under an atmosphere of hydrogen (balloon), and then stirred at ambient temperature overnight. The solids were removed by filtration and the filtrate 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-butoxycarbonyl) pyrrolidin-3-yl ] as an off-white solid ]-5-fluoropyridin-3-yl]-ethyl 1,2, 3-triazole-4-carboxylate (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

1- [6- [1- (tert-Butoxycarbonyl) pyrrolidin-3-yl]-5-fluoropyridin-3-yl]Ethyl-1, 2, 3-triazole-4-carboxylate (500.0 mg,1.2mmol,1.0 eq.) was dissolved in DCM (3 mL) and TFA (10 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched by the addition of water. Saturated aqueous Na ₂ CO ₃ Adjust to pH 7. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous MgSO ₄ Dried over and concentrated in vacuo to give 1- [ 5-fluoro-6- (pyrrolidin-3-yl) pyridin-3-yl) as an off-white solid]-ethyl 1,2, 3-triazole-4-carboxylate (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-trifluoroethyl) pyrrolidin-3-yl ] pyridin-3-yl ] -1,2, 3-triazole-4-carboxylic acid ethyl ester

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

Step 6:1- [ 5-fluoro-6- [1- (2, 2-trifluoroethyl) pyrrolidin-3-yl ] pyridin-3-yl ] -1,2, 3-triazole-4-carboxylic acid

1- [ 5-fluoro-6- [1- (2, 2-trifluoroethyl) pyrrolidin-3-yl]Pyridin-3-yl]Ethyl-1, 2, 3-triazole-4-carboxylate (100.0 mg,0.3mmol,1.0 eq.) was dissolved in MeOH (5 mL) and water (5 mL), followed by the addition of NaOH (62.0 mg,1.5mmol,6.0 eq.). 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, and taken up in anhydrous Na ₂ SO ₄ Drying and vacuum concentrating to obtain crude 1- [ 5-fluoro-6- [1- (2, 2-trifluoroethyl) pyrrolidin-3-yl ] as off-white solid]Pyridin-3-yl]-1,2, 3-triazole-4-carboxylic acid (83.2 mg). LCMS method E: [ M+H ]] ⁺ ＝360。

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

Step 1:6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoro-N-methoxy-N-methylpyridine-3-carboxamide

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

Step 2:1- [6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridin-3-yl ] ethanone

6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoro-N-methoxy-N-methylpyridine-3-carboxamide (1.7 g,5.4mmol,1.0 eq.) was dissolved in THF (15 mL) and cooled to 0deg.C, then MeMgBr (3M in THF,3.2mL,9.6mmol,1.5 eq.) was added dropwise, maintaining the solution at 0deg.C. The reaction mixture was stirred at 0 ℃ for 1 hour and then quenched by adding ice water. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ The above was dried and concentrated in vacuo to give 1- [6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridin-3-yl as a yellow oil ]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-dioxobutanoic acid ethyl ester

1- [6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridin-3-yl]Ethanone (1.4 g,5.2mmol,1.0 eq.) was dissolved in EtOH (14 mL) and sodium ethoxide (351.2 mg,5.2mmol,1.0 eq.) was added. After that, ethyl oxalate (1.0 mL,7.7mmol,1.5 eq.) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours, then cooled to 0 ℃ and quenched by the addition of water. The resulting solution was adjusted to pH 5 with aqueous HCl (4M), extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried over and concentrated in vacuo to give 4- [6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridin-3-yl as a brown oil]-ethyl 2, 4-dioxobutyrate (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

4- [6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridin-3-yl]Ethyl-2, 4-dioxobutyrate (1.5 g,4.0mmol,1.0 eq.) was dissolved in EtOH (15 mL) followed by hydroxylamine hydrochloride (0.4 g,6.0mmol,1.5 eq.) was added. The reaction mixture was heated to 80 ℃ for 2 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated 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-1-methylcyclohexyl) -5-fluoropyridin-3-yl as a brown oil ]-ethyl 1, 2-oxazole-3-carboxylate (1.2G) 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

5- [6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridin-3-yl]-1, 2-oxazole-3-carboxylic acid ethyl ester (1.2 g,3.3mmol,1.0 eq.) was dissolved in MeOH (10 mL) and water (10 mL), followed by NaOH (260.6 mg,6.5mmol,2.0 eq.) added. The reaction mixture was heated to 80 ℃ 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 gel; mobile phase, ACN/H ₂ O=0% increase to ACN/H ₂ O=100%, within 25 minutes; detector, 254nm. This gives 5- [6- (4, 4-difluoro-1-methylcyclohexyl) -5-fluoropyridin-3-yl as a brown solid]-1, 2-oxazole-3-carboxylic acid (1.0 g). LCMS method a: [ M+H ]] ⁺ ＝341。

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

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

Step 1: 5-chloro-N-methoxy-N-methyl-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl ] pyridine-3-carboxamide

5-chloro-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl]Pyridine-3-carboxylic acid (1.8 g,5.6mmol,1.0 eq.) and N, O-dimethylhydroxylamine hydrochloride (813.6 mg,8.3mmol,1.5 eq.) were dissolved in DMF (18 mL) and HATU (4.2 g,11.1mmol,2.0 eq.) and DIEA (3.9 mL,22.2mmol,4.0 eq.) were added. The reaction mixture was stirred at ambient temperature overnight and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried over 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-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl as a yellow solid]Pyridine-3-carboxamide (1.8 g). LCMS method a: [ M+H ]] ⁺ ＝367。

Step 2: 5-chloro-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl ] pyridine-3-carbaldehyde

5-chloro-N-methoxy-N-methyl-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl]Pyridine-3-carboxamide (1.5 g,4.1mmol,1.0 eq.) was dissolved in THF (17 mL) and cooled to 0deg.C. Then, liAlH is added dropwise ₄ (155.2 mg,4.1mmol,1.0 eq.) and the solution was maintained at 0deg.C. The reaction mixture was stirred at 0 ℃ for 2 hours, then by addition of saturated aqueous NH ₄ And (5) quenching Cl. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried over 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-trifluoroethyl) piperazin-1-yl as a yellow solid]Pyridine-3-carbaldehyde (1.0 g). LCMS method E: [ M+H ]] ⁺ ＝308。

Step 3: (E) -N- ([ 5-chloro-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl ] pyridin-3-yl ] methylene) hydroxylamine

5-chloro-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl ]Pyridine-3-carbaldehyde (1.0 g,3.3mmol,1.0 eq.) and hydroxylamine hydrochloride (271.0 mg,3.9mmol,1.2 eq.) were added to a solution of EtOH (10 mL) and water (10 mL), followed by NaOH (195.0 mg,4.9mmol,1.5 eq.). The reaction mixture was heated to 90 ℃ for 2 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried over and concentrated in vacuo. 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 30 minutes; detector, UV 254nm. This gives (E) -N- ([ 5-chloro-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl) as a brown solid]Pyridin-3-yl]Methylene) hydroxylamine (800.0 mg). LCMS method a: [ M+H ]] ⁺ ＝323。

Step 4:3- [ 5-chloro-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl ] pyridin-3-yl ] -1, 2-oxazole-5-carboxylic acid methyl ester

(E) -N- ([ 5-chloro-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl)]Pyridin-3-yl]Methylene) hydroxylamine (1.0 g,3.1mmol,1.0 eq.) and methacrylate (260.5 mg,3.1mmol,1.0 eq.) were dissolved in CHCl ₃ (10 mL) and then NaHCO was added ₃ (390.5 mg,4.6mmol,1.5 eq.) and NCS (413.8 mg,3.1mmol,1.0 eq.). The reaction mixture was stirred at ambient temperature overnight and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried over and concentrated in vacuo to afford 3- [ 5-chloro-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl as a yellow solid]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-trifluoroethyl) piperazin-1-yl ] pyridin-3-yl ] -1, 2-oxazole-5-carboxylic acid

3- [ 5-chloro-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl]Pyridin-3-yl]-methyl 1, 2-oxazole-5-carboxylate (500.0 mg,1.2mmol,1.0 eq.) was dissolved in MeOH (5.0 mL) and water (5.0 mL) followed by addition of LiOH (118.3 mg,4.9mmol,4.0 eq.). 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 gel; mobile phase, ACN/water, gradient 0% to 100% in 30 minutes; detector, UV 254nm. This gives 3- [ 5-chloro-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl as an off-white solid]Pyridin-3-yl]-1, 2-oxazole-5-carboxylic acid (295.4 mg). LCMS method B: [ M+H ]] ⁺ ＝391。

The following intermediates were prepared using the same procedure as described for intermediate 66B.

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

Step 1: 5-bromo-2- (4, 4-difluoropiperidin-1-yl) -3-fluoropyridine

2, 5-dibromo-3-fluoropyridine (10.0 g,39.2mmol,1.0 eq.) was dissolved in DMF (100 mL) and Cs was then added ₂ CO ₃ (25.7 g,78.5mmol,2.0 eq.) and 4, 4-difluoropiperidine (7.1 g,58.8mmol,1.5 eq.). The reaction mixture was heated to 80 ℃ for 48 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried over and concentrated in vacuo. The residue was purified by flash prep-HPLC using the following conditions: column, C18 silica gel; mobile phase, ACN/H ₂ O=60% increase to ACN/H ₂ O=100%, within 20 minutes; detector, 254nm. This gave 5-bromo-2- (4, 4-difluoropiperidin-1-yl) -3-fluoropyridine (2.0 g) as a yellow solid. LCMS method a: [ M+H ]] ⁺ ＝295。

Step 2:2- (4, 4-difluoropiperidin-1-yl) -3-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine

5-bromo-2- (4, 4-difluoropiperidin-1-yl) -3-fluoropyridine (2.0 g,6.8mmol,1.0 eq.) was dissolved in DMSO (30 mL) and then AcOK (1.3 g,13.6mmol,2.0 eq.), bis (pinacolato) diboron (3.4 g,13.5mmol,2.0 eq.) and Pd (dppf) Cl were added under a nitrogen atmosphere ₂ (495.9 mg,0.7mmol,0.1 eq.). Reaction mixingThe material was heated to 90 ℃ overnight, then cooled to ambient temperature and quenched by the 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-difluoropiperidin-1-yl) -3-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine as a yellow oil. LCMS method a: [ M+H ] ] ⁺ ＝343。

Step 3:2- [6- (4, 4-Difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1, 3-thiazole-5-carboxylic acid methyl ester

2- (4, 4-Dihalopiperidin-1-yl) -3-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (300.0 mg,0.9mmol,1.0 eq) and methyl 2-bromo-1, 3-thiazole-5-carboxylate (233.6 mg,1.1mmol,1.2 eq) were dissolved in 1, 4-dioxane (5 mL) and water (5 mL) and Cs was then added under nitrogen atmosphere ₂ CO ₃ (857.0 mg,2.6mmol,3.0 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (71.4 mg,0.09mmol,0.1 eq.). The reaction mixture was heated to 90 ℃ for 6 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated 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-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as an off-white solid]-1, 3-thiazole-5-carboxylic acid methyl ester (200.0 mg). LCMS method a:

[M+H] ⁺ ＝358。

step 4:2- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1, 3-thiazole-5-carboxylic acid

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

The following intermediates were prepared using the same procedure as described for intermediate 70B.

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

Step 1:6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridine-3-carbonyl chloride

6- (4, 4-Dihaloperidin-1-yl) -5-fluoropyridine-3-carboxylic acid (1.7 g,6.5mmol,1.0 eq.) is dissolved in DCM (17 mL) and cooled to 0deg.C, then oxalyl chloride (0.8 mL,9.8mmol,1.5 eq.) and DMF (0.1 mL) are added dropwise and the solution maintained at 0deg.C. The reaction mixture was stirred at 0 ℃ for 2 hours, then concentrated in vacuo to give 6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridine-3-carbonyl chloride (1.5 g) as a white solid.

Step 2: [ (E) -N- [ (E) -6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridine-3-carbonyloxy ] carbamimidoyl ] carboxylic acid ethyl ester

6- (4, 4-Difluoropiperidin-1-yl) -5-fluoropyridine-3-carbonyl chloride (1.4 g,5.0mmol,1.0 eq.) was dissolved in THF (14 mL) and cooled to 0deg.C, then [ (E) -N' -hydroxycarbamimimido was added]Ethyl formate (663.8 mg,5.0mmol,1.0 eq). The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried above, and concentrated in vacuo to give [ (E) -N- [ (E) -6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridine-3-carbonyloxy) as a white solid]Carbamoyl imino group]Ethyl formate (1.0 g). LCMS method a: [ M+H ]] ⁺ ＝375。

Step 3:5- [6- (4, 4-Difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1,2, 4-oxadiazole-3-carboxylic acid ethyl ester

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

Step 4:5- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1,2, 4-oxadiazole-3-carboxylic acid

5- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl]-1,2, 4-oxadiazole-3-carboxylic acid ethyl ester (600.0 mg,1.7mmol,1.0 eq.) was dissolved in MeOH (6 mL) and water (6 mL), followed by addition of LiOH (161.3 mg,6.7mmol,4.0 eq.). The reaction mixture was stirred at ambient temperature for 3 hours and then concentrated in vacuo. The resulting solution was adjusted to pH 5 with concentrated HCl. The crude product was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN/water, gradient 0% to 100% in 30 minutes; detector, UV 254nm. This gives 5- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as a red solid]-1,2, 4-oxadiazole-3-carboxylic acid (505.1 mg). LCMS method B: [ M+H ]] ⁺ ＝329。

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

Step 1:6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridine-3-carboxamide

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

Step 2:5- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1,3, 4-oxathiazol-2-one

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

Step 3:3- [6- (4, 4-Difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1,2, 4-thiadiazole-5-carboxylic acid ethyl ester

5- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl]-1,3, 4-oxathiazol-2-one (3.0 g,9.5mmol,1.0 eq.) was dissolved in dodecane (10 mL) followed by the addition of ethyl cyanoformate (ethyl carbonocyanidate) (1.4 g,14.2mmol,1.5 eq.). The reaction mixture was heated to 130 ℃ for 16 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 (1:1) to give 3- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as a yellow solid]-ethyl 1,2, 4-thiadiazole-5-carboxylate (1.2 g). LCMS method a: [ M+H ] ] ⁺ ＝260。

Step 4:3- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1,2, 4-thiadiazole-5-carboxylic acid

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

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

Step 1:3- [6- (4, 4-Difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1, 2-thiazole-5-carboxylic acid methyl ester

5- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl]-1,3, 4-oxathiazol-2-one (1.0 g,3.2mmol,1.0 eq.) was dissolved in o-dichlorobenzene (10 mL) followed by the addition of methacrylate (1.6 g,19.0mmol,6.0 eq.). The reaction mixture was heated to 135 ℃ 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-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as a yellow solid ]-methyl 1, 2-thiazole-5-carboxylate (350.0 mg). LCMS method a: [ M+H ]] ⁺ ＝358。

Step 2:3- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1.2-thiazole-5-carboxylic acid

3- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl]Methyl-1, 2-thiazole-5-carboxylate (330.0 mg,0.9mmol,1.0 eq.) was dissolved in MeOH (2 mL) and water (2 mL), followed by the addition of NaOH (55.4 mg,1.4mmol,1.5 eq.). 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 (6M). The precipitated solid was collected by filtration and washed with water to give 3- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as a yellow solid]-1, 2-thiazole-5-carboxylic acid (250.0 mg). LCMS method G: [ M+H ]] ⁺ ＝344。

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

Step 1:6- (4, 4-difluoropiperidin-1-yl) -5-fluoro-N-methoxy-N-methylpyridine-3-carboxamide

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

Step 2:1- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] ethanone

6- (4, 4-Dihalopiperidin-1-yl) -5-fluoro-N-methoxy-N-methylpyridine-3-carboxamide (1.6 g,5.3mmol,1.0 eq.) is dissolved in THF (20 mL) and cooled to 0deg.C, then MeMgBr (3M in THF,2.7mL,8.1mmol,1.5 eq.) is added dropwise under nitrogen atmosphere, maintaining the solution at 0deg.C. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ The above was dried and concentrated in vacuo to give 1- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as a yellow oil]Ketene (900.0 mg). LCMS method a: [ M+H ]] ⁺ ＝259。

Step 3: 2-bromo-1- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] ethanone

1- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl]Ethanone (3.0 g,11.6mmol,1.0 eq.) was dissolved in ACN (15 mL) followed by the addition of NBS (3.1 g,17.4mmol,1.5 eq.) and TsOH (3.0 g,17.4mmol,1.5 eq.). The reaction mixture was heated to 100 ℃ overnight, then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with brine, and dried over saturated aqueous NaHCO ₃ Dried over and concentrated in vacuo. Through siliconThe residue was purified by flash column chromatography eluting with ethyl acetate/petroleum ether (1:4) to give 2-bromo-1- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as a yellow solid]Ethanone (2.0 g). LCMS method a: [ M+H ]] ⁺ ＝337。

Step 4: acetic acid 2- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -2-oxoethyl ester

2-bromo-1- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl]Ethanone (2.0 g,5.9mmol,1.0 eq.) and acetic acid (0.5mL g,8.9mmol,1.5 eq.) were dissolved in MeOH (6 mL) and water (14 mL) and K was added ₂ CO ₃ (0.8 g,5.9mmol,1.0 eq.). The reaction mixture was heated to 70 ℃ for 3 hours, then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was saturated with NaHCO ₃ Washing with solution in anhydrous Na ₂ SO ₄ Dried over and concentrated in vacuo to afford 2- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl acetate as a yellow solid]-2-oxoethyl ester (1.5 g). LCMS method E: [ M+H ]] ⁺ ＝317。

Step 5:4- [6- (4, 4-Difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1, 3-oxazole-2-carboxylic acid ethyl ester

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

Step 6:4- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1, 3-oxazole-2-carboxylic acid

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

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

Step 1:4- [6- (4, 4-Difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -2, 4-dioxobutanoic acid ethyl ester

1- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl]Ketene (600.0 mg,2.3mmol,1.0 eq.) and EtONa (158.1 mg,2.3mmol,1.0 eq.) were dissolved in EtOH (6 mL) followed by the dropwise addition of ethyl oxalate (0.3 mL,2.3mmol,1.0 eq.). The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of water. The resulting solution was adjusted to pH 6 with aqueous HCl (4M), extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Drying and concentrating in vacuo to give 4- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as a yellow solid]-ethyl 2, 4-dioxobutyrate (610.0 mg). LCMS method a: [ M+H ]] ⁺ ＝359。

Step 2:5- [6- (4, 4-Difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1H-pyrazole-3-carboxylic acid ethyl ester

4- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl]-ethyl 2, 4-dioxobutyrate (900.0 mg,2.5mmol,1.0 eq.) and NH ₂ NH ₂ ·H ₂ O (0.2 mL,2.5mmol,1.0 eq.) 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-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as a yellow solid]-1H-pyrazole-3-carboxylic acid ethyl ester (450.0 mg). LCMS method a: [ M+H ] ] ⁺ ＝355。

Step 3:5- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1H-pyrazole-3-carboxylic acid

5- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl]Ethyl-1H-pyrazole-3-carboxylate (450.0 mg,1.3mmol,1.0 eq.) was dissolved in MeOH (5 mL) and water (5 mL), followed by the addition of NaOH (101.6 mg,2.5mmol,2.0 eq.). The reaction mixture was heated to 80 ℃ 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 (2M) and concentrated in vacuo. 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 30 minutes; detector, UV 254nm. This gives 5- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as a white solid]-1H-pyrazole-3-carboxylic acid (320.0 mg). LCMS method B: [ M+H ]] ⁺ ＝327。

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

Step 1:5- [6- (4, 4-Difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1-methylpyrazole-3-carboxylic acid ethyl ester

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

Step 2:5- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1-methylpyrazole-3-carboxylic acid

5- [6- (4, 4-difluoropiperazine)Pyridin-1-yl) -5-fluoropyridin-3-yl]Ethyl-1-methylpyrazole-3-carboxylate (150.0 mg,0.4mmol,1.0 eq.) was dissolved in MeOH (2 mL) and water (2 mL), followed by the addition of NaOH (32.6 mg,0.8mmol,2.0 eq.). The reaction mixture was heated to 80 ℃ 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 (2M). The resulting solution was concentrated in vacuo 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 minutes; detector, UV 254nm. This gives 5- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as a white solid]-1-methylpyrazole-3-carboxylic acid (105.2 mg). LCMS method C: [ M+H ]] ⁺ ＝341。

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

Step 1:1- [6- (4, 4-Difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] pyrazole-3-carboxylic acid methyl ester

5-bromo-2- (4, 4-difluoropiperidin-1-yl) -3-fluoropyridine (1.0 g,3.4mmol,1.0 eq.) and methyl 1H-pyrazole-3-carboxylate (514.1 mg,4.1mmol,1.2 eq.) were dissolved in DMF (15 mL) and then (1S, 2S) -N was added ₁ ,N ₂ Dimethylcyclohexane-1, 2-diamine (96.4 mg,0.7mmol,0.2 eq.) CuI (129.1 mg,0.7mmol,0.2 eq.) and K ₂ CO ₃ (1.4 g,10.1mmol,3.0 eq.). The reaction mixture was heated to 80 ℃ overnight, then cooled to ambient temperature and diluted with ethyl acetate. The resulting solution was washed with brine 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 1- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as a yellow solid]Pyrazole-3-carboxylic acid methyl ester. LCMS method a: [ M+H ]] ⁺ ＝341。

Step 2:1- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] pyrazole-3-carboxylic acid

1- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl]Pyrazole-3-carboxylic acid methyl ester (600.0 mg, 1).8mmol,1.0 eq.) in MeOH (5 mL) and water (5 mL) then NaOH (141.0 mg,3.5mmol,2.0 eq.) was added. The reaction mixture was heated to 60 ℃ for 2 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and then adjusted to pH 6 with aqueous HCl (6M). The precipitated solid was collected by filtration, washed with water and dried to give 1- [6- (4, 4-difluoropiperidin-1-yl) -5-methylpyridin-3-yl as a white solid]Imidazole-3-carboxylic acid (421.5 mg). LCMS method E: [ M+H ] ] ⁺ ＝327。

The following intermediates were prepared using the same procedure as described for intermediate 86B.

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

Step 1:6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridine-3-carboxylic acid hydrazine

6- (4, 4-Difluoropiperidin-1-yl) -5-fluoropyridine-3-carboxylic acid methyl ester (2.0 g,7.3mmol,1.0 eq.) was dissolved in EtOH (30 mL) followed by NH addition ₂ NH ₂ ·H ₂ O (3.5 mL,70.0mmol,10.0 eq.). The reaction mixture was heated to 90 ℃ for 16 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and the solid was collected by filtration to give 6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridine-3-carboxylic acid hydrazine (1.3 g) as a white solid. LCMS method a: [ M+H ]] ⁺ ＝275。

Step 2:2- [ [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] formylhydrazine ] -2-oxoacetic acid ethyl ester

6- (4, 4-Difluoropiperidin-1-yl) -5-fluoropyridine-3-carboxylic acid hydrazine (1.3 g,4.7mmol,1.0 eq.) and TEA (2.0 mL,14.2mmol,3.0 eq.) were dissolved in DCM (20 mL) and then oxalyl chloride ethyl ester (0.5 mL,5.0mmol,1.0 eq.) was added. The reaction mixture was stirred at ambient temperature for 2 hours, then by addition ofThe water was quenched. 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-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as a white solid ]Formylhydrazines]-ethyl 2-oxoacetate (1.1 g). LCMS method D: [ M+H ]] ⁺ ＝375。

Step 3:5- [6- (4, 4-Difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1.3,4-oxadiazole-2-carboxylic acid ethyl ester

2- [ [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl]Formylhydrazines]Ethyl 2-oxoacetate (1.0 g,2.7mmol,1.0 eq.) and TEA (1.1 mL,8.0mmol,3.0 eq.) were dissolved in DCM (20 mL) and TsCl (764.0 mg,4.0mmol,1.5 eq.) 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-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as a white solid]-ethyl 1,3, 4-oxadiazole-2-carboxylate (506.2 mg). LCMS method a: [ M+H ]] ⁺ ＝357。

Step 4:5- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl ] -1.3,4-oxadiazole-2-carboxylic acid

5- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl]-1,3, 4-oxadiazole-2-carboxylic acid ethyl ester (500.0 mg,1.4mmol,1.0 eq.) was dissolved in MeOH (3 mL) and water (3 mL), followed by NaOH (112.3 mg,2.8mmol,2.0 eq.). The reaction mixture was heated to 80 ℃ for 30 minutes, then cooled to ambient temperature and concentrated in vacuo to afford crude 5- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as a white solid ]-1,3, 4-oxadiazole-2-carboxylic acid (212.2 mg) was used in the next step without further purification. . LCMS method E: [ M+H ]] ⁺ ＝329。

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

Step 1-step 4:

step 1: 2-diazonium-3-oxopropionic acid ethyl ester

DMF (32.0 g,438.2mmol,33.7mL,0.50 eq.) and SOCl ₂ The mixture of (52.1 g,438.2mmol,31.8mL,0.5 eq.) was heated to 40℃for 2 hours. The reaction mixture was concentrated under reduced pressure to give a solid, which was then dissolved in CHCl ₃ (250 mL) and cooled to 0deg.C. Ethyl 2-diazonium acetate (100 g,876.4mmol,1 eq.) was added dropwise over 1 hour, maintaining the temperature at 0 ℃. After the addition was complete, the mixture was stirred at 25 ℃ for 12 hours. The solvent was removed under reduced pressure, and then MTBE (800.0 mL) was added to give a slurry. The yellow precipitate was collected by filtration, dissolved in aqueous acetic acid, and then extracted with MTBE (3X 300 mL). The combined organic extracts were extracted with aqueous sodium bicarbonate (2M; 3X 300 mL), hydrochloric acid (110%; 3X 300 mL), water (3X 300 mL) and brine (3X 300 mL). Organic layer in anhydrous Na ₂ SO ₄ The reaction mixture was dried and concentrated under reduced pressure to give ethyl 2-diazonium-3-oxo-propionate (15.0 g,95.0mmol,11% yield, 90% purity) as a yellow oil.

Step 2:1- (6-bromo-5-fluoropyridin-3-yl) -1H-1,2, 3-triazole-4-carboxylic acid ethyl ester

6-bromo-5-fluoro-pyridin-3-amine (12.1 g,63.4mmol,1.0 eq) and ethyl 2-diazo-3-oxo-propionate (15.0 g,95.0mmol,90% purity, 1.5 eq) were dissolved in EtOH (300 mL). AcOH (210.0 g,3.5mol,200mL,55.2 eq.) was then added and the mixture was heated at 50deg.C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with cold water and the resulting solid was collected by filtration to give ethyl 1- (6-bromo-5-fluoro-3-pyridinyl) triazole-4-carboxylate (16.0 g,50.8mmol,80% yield) as a yellow solid.

Step 3:1- (6-bromo-5-fluoropyridin-3-yl) -1H-1,2, 3-triazole-4-carboxylic acid

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

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

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

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

1- [ [6- (4, 4-difluorocyclohexyl) -5-fluoropyridin-3-yl ]]Methyl group]Imidazole-4-carboxylic acid (200.0 mg,0.6mmol,1.0 eq.) was dissolved in DMF (5 mL) followed by the addition of 5, 6-difluoro-1H-indol-3-amine hydrochloride (120.5 mg,0.6mmol,1.0 eq.), HATU (336.2 mg,0.9mmol,1.5 eq.) and DIEA (0.3 mL,1.8mmol,3.0 eq.). The reaction mixture was stirred at ambient temperature for 2 hoursAt this time, and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions: column, YMC-act three C18,30 x 250,5 μm; mobile phase, water (10 mM NH) ₄ HCO ₃ +0.1％ NH ₃ .H ₂ O) and ACN (38% phase B rises to 60% in 10 minutes); detector, uv 254nm. This gives N- (5, 6-difluoro-1H-indol-3-yl) -1- [ [6- (4, 4-difluorocyclohexyl) -5-fluoropyridin-3-yl ] as a white solid]Methyl group]Imidazole-4-carboxamide (17.1 mg). LCMS method D: [ M+H ]] ⁺ ＝490。 ¹ H NMR(300MHz,DMSO-d ₆ ):δ11.02(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 analogues in the following table were prepared using the same procedure as described in example 1.

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

1- (6- (4, 4-Difluoropiperidin-1-yl) -5-fluoropyridin-3-yl) -1H-imidazole-4-carboxylic acid (129.5 mg,0.4mmol,1.0 eq.) was dissolved in THF (10 mL) and 5-fluoro-1H-pyrrolo [2,3-b ] was then added]Pyridin-3-amine hydrochloride (74.7 mg,0.4mmol,1.0 eq.), TEA (0.6 mL,4.0mmol,10.0 eq.) and T ₃ P (189.5 mg,0.6mmol,1.5 eq.). Reaction mixtureThe mixture was stirred at ambient temperature overnight and then quenched by the 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, 30×150mm 5 μm; mobile phase a: water (0.05% FA), mobile phase B: CAN; flow rate: 50 mL/min; gradient: 35% B to 65% B in 7 minutes; 254nm. This gives 1- (6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl) -N- (5-fluoro-1H-pyrrolo [2, 3-b) as a white solid ]Pyridin-3-yl) -1H-imidazole-4-carboxamide (41.4 mg). LCMS method J: [ M+H ]] ⁺ ＝460。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.63(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 analogues in the following table were prepared using the same procedure as described in example 12.

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

Step 1: n- (5, 6-difluoro-1H-indol-3-yl) propynyl amide

5,6-difluoro-1H-indol-3-amine hydrochloride (730.0 mg,3.6mmol,1.0 eq.) was dissolved in THF (30 mL) and cooled to 0deg.C, then propiolic acid (499.9 mg,7.1mmol,2.0 eq.), TEA (1.5 mL,10.7mmol,3.0 eq.) and T were added at 0deg.C ₃ P (6.8 g,10.7mmol,3.0 eq.). The resulting solution was stirred at ambient temperature for 3 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated 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-1H-indol-3-yl) prop-2-ynonamide as a pale yellow solid (350 mg). LCMS method a: [ M+H ]] ⁺ ＝221。

Step 2: 5-azido-2- (4, 4-difluoropiperidin-1-yl) -3-fluoropyridine

6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-amine (400.0 mg,1.7mmol,1.0 eq.) was dissolved in ACN (10 mL) and cooled to 0deg.C, then t-BuNO2 (0.3 mL,2.7mmol,1.6 eq.) was added dropwise and the solution maintained at 0deg.C. Dropwise adding TMSN at 0deg.C for 30 min ₃ (0.3 mL,2.5mmol,1.5 eq.). The reaction mixture was stirred at ambient temperature for an additional 2 hours and then quenched by the 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-difluoropiperidin-1-yl) -3-fluoropyridine (380 mg) as a yellow oil.

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

5-azido-2- (4, 4-difluoropiperidin-1-yl) -3-fluoropyridine (150.0 mg,0.6mmol,1.0 eq.) was dissolved in dioxane/water (5/0.5 mL) and then N- (5, 6-difluoro-1H-indol-3-yl) propynylamide (130.0 mg,0.6mmol,1.0 eq.), (R) -2- ((S) -1, 2-dihydroxyethyl) -4-hydroxy-5-oxo-2, 5-dihydrofuran-3-oleic acid sodium (24.0 mg,0.1mmol,0.2 eq.) and CuSO were added ₄ (19.0 mg,0.1mmol,0.2 eq.). The resulting solution was stirred at ambient temperature for 15 hours and then quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. By using the following conditionsPreparative HPLC further purified the residue: XBridge Prep OBD C18 column, 30×150mm 5 μm; mobile phase a: water (0.05% FA), mobile phase B: ACN; flow rate: 50 mL/min; gradient: 35% B to 80% B in 7 minutes; 254nm; RT1:6.95 min. This gave N- (5, 6-difluoro-1H-indol-3-yl) -1- (6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide (135.5 mg) as an off-white solid. LCMS method H: [ M-H ] ] ^- ＝476. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.14(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 23: n- (5, 6-difluoro-1H-indol-3-yl) -5- (6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl) isoxazole-3-carboxamide (compound 208)

5- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl]-1, 2-oxazole-3-carboxylic acid (250.0 mg,0.8mmol,1.0 eq.) was dissolved in DMF (3 mL) followed by the addition of 5, 6-difluoro-1H-indol-3-amine hydrochloride (223.1 mg,1.1mmol,1.5 eq.) and HATU (435.7 mg,1.1mmol,1.5 eq.). DIEA (0.5 mL,2.9mmol,4.0 eq.) was then added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried over and concentrated in vacuo. 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 20 minutes; detector, UV 254nm. This gives N- (5, 6-difluoro-1H-indol-3-yl) -5- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as a pink solid]-1, 2-oxazole-3-carboxamide (127.2 mg). LCMS method J: [ M+H ]] ⁺ ＝478. ¹ H NMR(400MHz,CD ³ OD-d ₄ ):δ8.54(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 analogues in the following table were prepared using the same procedure as described in example 23.

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

3- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl]-1, 2-oxazole-5-carboxylic acid (200.0 mg,0.6mmol,1.0 eq.) in DMF (2 mL)5, 6-difluoro-1H-indol-3-amine hydrochloride (186.2 mg,0.9mmol,1.5 eq.) and HATU (348.6 mg,0.9mmol,1.5 eq.) are then added. DIEA (0.4 mL,2.4mmol,4.0 eq.) was then added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried over and concentrated in vacuo. 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 20 minutes; detector, UV 254nm. This gives N- (5, 6-difluoro-1H-indol-3-yl) -3- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl as an off-white solid]-1, 2-oxazole-5-carboxamide (145.8 mg). LCMS method H: [ M+H ]] ⁺ ＝478。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.24(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 77: n- (5, 6-difluoro-1H-indol-3-yl) -4- (6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl) oxazole-2-carboxamide (compound 193)

4- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl]-1, 3-oxazole-2-carboxylic acid (200.0 mg,0.6mmol,1.0 eq.) was dissolved in DMF (5 mL) followed by the addition of T3P (50 wt% in ethyl acetate, 0.6mL,0.9mmol,1.5 eq.) and 5, 6-difluoro-1H-indol-3-amine hydrochloride (187.6 mg,0.9mmol,1.5 eq.). TEA (0.3 mL,1.8mmol,3.0 eq.) was then added dropwise at 0deg.C. The reaction mixture was stirred at ambient temperature overnight and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. 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 30 minutes; detector, UV 254nm. This gives N- (5, 6-difluoro-1H-indol-3-yl) -4- [6- (4, 4-difluoropiperidin-1-yl) -5-fluoropyridin-3-yl) as an off-white solid ]-1, 3-oxazole-2-carboxamide (25.9 mg). LCMS methodF：[M+H] ⁺ ＝478。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.17(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 analogues in the following table were prepared using the same procedure as described in example 77.

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

3- [ 5-fluoro-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl]Pyridin-3-yl]-1, 2-oxazole-5-carboxylic acid (300.0 mg,0.8mmol,1.0 eq) and 5, 6-difluoro-1H-indol-3-amine hydrochloride (196.8 mg,1.0mmol,1.2 eq) were dissolved in DMF (10 mL) followed by the addition of NMM (486.4 mg,4.8mmol,6.0 eq) and PyBOP (417.1 mg,0.8mmol,1.0 eq). The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried over and concentrated in vacuo. The residue was purified by preparative HPLC using the following conditions: column, XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase, water (10 mmol/L NH) ₄ HCO ₃ +0.1％NH ₄ OH) and ACN (50% phase B rises to 70% in 7 minutes); detector, UV 254nm. This gives N- (5, 6-difluoro-1H-indol-3-yl) -3- [ 5-fluoro-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl as a white solid]Pyridin-3-yl]-1, 2-oxazole-5-carboxamide (63.3 mg). LCMS method H: [ M+H ] ] ⁺ ＝525。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.25(s,1H),10.89(s,1H),8.61(d,J＝1.6Hz,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 analogues in the following table were prepared using the same procedure as described in example 80.

Example 82: n- (5-chloro-1H-indol-3-yl) -3- (5-fluoro-6- (4- (2, 2-trifluoroethyl) piperazin-1-yl) pyridin-3-yl) isoxazole-5-carboxamide (Compound 171)

3- [ 5-fluoro-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl]Pyridin-3-yl]-1, 2-oxazole-5-carboxylic acid (300.0 mg,0.8mmol,1.0 eq) and 5-chloro-1H-indol-3-amine (160.3 mg,1.0mmol,1.2 eq) were dissolved in DMF (10 mL) followed by addition of NMM (121.6 mg,1.2mmol,1.5 eq) and PyBOP (625.7 mg,1.2mmol,1.5 eq). The reaction mixture was stirred at ambient temperature for 3 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried over and concentrated in vacuo. The residue was purified by preparative HPLC using the following conditions: column: XBridge Prep OBD C18 column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60 mL/min; gradient: 50% B to 75% B in 8 minutes; wavelength: 220nm; RT (min) 7.82. This gives N- (5-chloro-1H-indol-3-yl) -3- [ 5-fluoro-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl as a white solid]Pyridin-3-yl]-1, 2-oxazole-5-carboxamide (65.3 mg). LCMS method H: [ M+H ] ] ⁺ ＝523。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.28(s,1H),10.88(s,1H),8.61(d,J＝1.2Hz,1H),8.06(d,J＝2.0Hz,1H),8.02(d,J＝2.0Hz,1H),7.90(d,J＝2.4Hz,1H),7.81(s,1H),7.42(d,J＝8.8Hz,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 83: n- (5, 6-difluoro-1H-indol-3-yl) -5- (5-fluoro-6- (4- (2, 2-trifluoroethyl) piperazin-1-yl) pyridin-3-yl) isoxazole-3-carboxamide (Compound 204)

5- [ 5-fluoro-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl]Pyridin-3-yl]-1, 2-oxazole-3-carboxylic acid (300.0 mg,0.8mmol,1.0 eq) and DCC (248.1 mg,1.2mmol,1.5 eq) were dissolved in DCM (30 mL) followed by addition of DMAP (146.9 mg,1.2mmol,1.5 eq) and 5, 6-difluoro-1H-indol-3-amine hydrochloride (196.8 mg,1.0mmol,1.2 eq). The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried over and concentrated in vacuo. The residue was purified by preparative HPLC using the following conditions: column, XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase, water (10 mmol/L NH) ₄ HCO ₃ +0.1％NH ₄ OH) and ACN (50% phase B rises to 75% in 7 minutes); detector, UV 254nm. This gives N- (5, 6-difluoro-1H-indol-3-yl) -5- [ 5-fluoro-6- [4- (2, 2-trifluoroethyl) piperazin-1-yl as a yellow solid]Pyridin-3-yl]-1, 2-oxazole-3-carboxamide (138.2 mg). LCMS method H: [ M+H ]] ⁺ ＝525。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.20(s,1H),10.81(s,1H),8.61(d,J＝1.6Hz,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 analogues in the following table were prepared using the same procedure as described in example 83.

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

Step 1: n- (5, 6-difluoro-1H-indol-3-yl) propynyl amide

5, 6-difluoro-1H-indol-3-amine hydrochloride (730.0 mg,3.6mmol,1.0 eq.) is dissolved in THF (30 mL) and cooled to 0deg.C, then propiolic acid (499.9 mg,7.1mmol,2.0 eq.), TEA (1.5 mL,10.7mmol,3.0 eq.) and T3P (50 wt%, 0.7mL,10.7mmol,3.0 eq.) are added at 0deg.C. The reaction mixture was stirred at ambient temperature for 3 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated 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-1H-indol-3-yl) prop-2-ynonamide as a pale yellow solid (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,1.4mmol,1.0 eq.) was dissolved in ACN (6 mL) and cooled to 0deg.C, then t-BuNO was added dropwise ₂ (0.5 mL,4.3mmol,3.0 eq.) the mixture was maintained at 0deg.C. After 30 minutes at 0 ℃, TMSN was added dropwise at 0 DEG C ₃ (0.5 mL,4.3mmol,3.0 eq.). The reaction mixture was stirred at 0 ℃ for an additional 2 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:10) to give 5-azido-3-fluoro-2- (1-methylcyclohexyl) pyridine (260.0 mg) as a yellow oil.

Step 3: n- (5, 6-difluoro-1H-indol-3-yl) -1- [ 5-fluoro-6- (1-methylcyclohexyl) pyridin-3-yl ] -1,2, 3-triazole-4-carboxamide

5-azido-3-fluoro-2- (1-methylcyclohexyl) pyridine (250.0 mg,1.1mmol,1.0 eq.) was dissolved in dioxane/water (5/0.5 mL) and then N- (5, 6-difluoro-1H-indol-3-yl) propynylamide (235.0 mg,1.1mmol,1.0 eq.), sodium ascorbate (21.2 mg,0.1mmol,0.1 eq.) and CuSO were added ₄ (17.0 mg,0.1mmol,0.1 eq.). The reaction mixture was stirred at ambient temperature for 15 hours and then quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and vacuumConcentrating. The residue was further purified by preparative HPLC using the following conditions: XBridge Prep OBD C18 column, 30×150mm 5 μm; mobile phase a: water (0.05% FA), mobile phase B: ACN; flow rate: 50 mL/min; gradient: 35% B to 80% B in 7 minutes; 254nm; RT1:6.95 min. This gives 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(400MHz,DMSO-d ₆ )δ11.16(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 analogues in the following table were prepared using the same procedure as described in example 85.

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Example 98: n- (5, 6-difluoro-1H-indol-3-yl) -1- (6- ((4, 4-difluoropiperidin-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,7.8mmol,1.0 eq.) was dissolved in THF (40 mL) and cooled to-78deg.C. Then n-BuLi (2M in THF,8.0mL,16.0mmol,1.0 eq.) was added dropwise and the solution maintained at-78 ℃. After 10 minutes, a solution of DMF (0.6 mL,7.8mmol,1.0 eq.) in THF (2 mL) was added dropwise at-78deg.C and the reaction mixture was allowed to warm to ambient temperature and stirred for an additional 2 hours. By addition of saturated aqueous NH ₄ The reaction was quenched with Cl, extracted with ethyl acetate, washed with brine, and dried over Na ₂ SO ₄ Dried over 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 (1.3 g) as a yellow oil. LCMS method C: [ M+H ]] ⁺ ＝204。

Step 2: (5-bromo-3-fluoropyridin-2-yl) methanol

5-bromo-3-fluoropyridine-2-carbaldehyde (1.3 g,6.4mmol,1.0 eq) was dissolved in THF (20 mL) and cooled to 0deg.C. Then add NaBH in portions ₄ (0.5 g,12.7mmol,2.0 eq.) the solution was maintained at 0deg.C. The resulting solution was stirred at ambient temperature overnight, then by addition of saturated aqueous NH ₄ And (5) quenching Cl. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo to give (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,4.9mmol,1.0 eq.) was dissolved in DCM (10 mL) and cooled to 0deg.C, then phosphorus tribromide (1.6 g,5.8mmol,1.2 eq.) was added and the solution maintained at 0deg.C. The reaction mixture was stirred at 0 ℃ for 2 hours, then diluted with ethyl acetate. The resulting solution was treated with saturated aqueous NaHCO ₃ Washed, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 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-difluoropiperidin-1-yl) methyl ] -3-fluoropyridine

5-bromo-2- (bromomethyl) -3-fluoropyridine (1.0 g,3.7mmol,1.0 eq.) was dissolved in ACN (10 mL) and then 4, 4-difluoropiperidine (540.5 mg,4.5mmol,1.2 eq.) and K were added ₂ CO ₃ (1.5 g,11.1mmol,3.0 eq.). The reaction mixture was heated to 60 ℃ for 4 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous Na ₂ SO ₄ Dried over and concentrated in vacuo to give crude 5-bromo-2- [ (4, 4-difluoropiperidin-1-yl) methyl as a white solid]-3-fluoropyridine (800.0 mg). LCMS method C: [ M+H ]] ⁺ ＝309。

Step 5: 5-azido-2- [ (4, 4-difluoropiperidin-1-yl) methyl ] -3-fluoropyridine

5-bromo-2- [ (4, 4-difluoropiperidin-1-yl) methyl]3-Fluoropyridine (800.0 mg,2.6mmol,1.0 eq.) was dissolved in EtOH (7 mL) and water (3 mL), then (1S, 2S) -1, 2-diethylcyclohexane (363.0 mg,2.6mmol,1.0 eq.), cuI (492.9 mg,2.6mmol,1.0 eq.) and sodium azide (336.5 mg,5.2mmol,2.0 eq.) were added under nitrogen. The reaction mixture was heated to 80 ℃ for 2 hours, then cooled to ambient temperature and diluted with ethyl acetate. After removal of the solids by filtration, the filtrate was 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 5-azido-2- [ (4, 4-difluoropiperidin-1-yl) methyl as a brown solid]-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-difluoropiperidin-1-yl) methyl ] -5-fluoropyridin-3-yl ] -1,2, 3-triazole-4-carboxamide

5-azido-2- [ (4, 4-difluoropiperidin-1-yl) methyl]-3-fluoropyridine (200.0 mg,0.7mmol,1.0 eq.) was dissolved in dioxane (10 mL) and water (1 mL), then N- (5, 6-difluoro-1H-indol-3-yl) prop-2-ynylamide (194.8 mg,0.9mmol,1.2 eq.) was added under nitrogen, cuSO ₄ (11.8 mg,0.1mmol,0.1 eq.) and sodium ascorbate (14.7 mg,0.1mmol,0.1 eq.). The resulting solution was stirred at ambient temperature overnight and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC using the following conditions: column, XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase, water (10 mmol/L NH) ₄ HCO ₃ +0.1％ NH ₄ OH) and ACN (40% phase B rises to 58% in 7 minutes); detector, UV 254nm. This gives N- (5, 6-difluoro-1H-indol-3-yl) -1- [6- [ (4, 4-difluoropiperidin-1-yl) methyl ] as a yellow solid]-5-fluoropyridin-3-yl]-1,2, 3-triazole-4-carboxamide (25.0 mg). LCMS method F: [ M+H ]] ⁺ ＝492。 ¹ H NMR(400MHz,DMSO-d ₆ )δ11.16(s,1H),10.65(s,1H),9.54(s,1H),9.12(d,J＝1.6Hz,1H),8.51–8.48(m,1H),7.93–7.88(m,1H),7.85(d,J＝2.4Hz,1H),7.42–7.38(m,1H),3.84(s,2H),2.64–2.62(m,4H),2.00–1.93(m,4H)。

Examples 99/100: (R or S) -N- (5, 6-difluoro-1H-indol-3-yl) -1- (6- (4, 4-difluoropiperidin-1-yl-3, 5-d 4) -5-fluoropyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide; compound 162 (front peak, absolute stereochemistry not confirmed) and compound 163 (second peak, absolute stereochemistry not confirmed).

Rac (N- (5, 6-difluoro-1H-indol-3-yl) -1- [ 5-fluoro-6- [3- (trifluoromethyl) pyrrolidin-1-yl)]Pyridin-3-yl]-1,2, 3-triazole-4-carboxamide (compound 200), (60.0 mg) was isolated by Prep-Chiral-HPLC using the following conditions: column: CHIRALPAK IE,2×25cm,5 μm; mobile phase a: hex (0.5% 2M NH) ₃ MeOH) -HPLC, mobile phase B: etOH-HPLC; flow rate: 20 mL/min; gradient: 50% B to 50% B in 15.5 minutes; wavelength: 220/254nm; RT1 (min): 11.16; RT2 (min): 13.16. this gave compound 162 (front peak, 27.9 mg) as a white solid and compound 163 (second peak, 25.3 mg) as a white solid.

Compound 162: (R or S) -N- (5, 6-difluoro-1H-indol-3-yl) -1- [ 5-fluoro-6- [3- (trifluoromethyl) pyrrolidin-1-yl ]Pyridin-3-yl]-1,2, 3-triazole-4-carboxamide. [ M+H ]] ⁺ ＝496。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.14(s,1H),10.56(s,1H),9.30(s,1H),8.58(d,J＝1.6Hz,1H),8.21–8.17(m,1H),7.92–7.87(m,1H),7.84(d,J＝2.4Hz,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: (R or S) -N- (5, 6-difluoro-1H-indol-3-yl) -1- [ 5-fluoro-6- [3- (trifluoromethyl) pyrrolidin-1-yl]Pyridin-3-yl]-1,2, 3-triazole-4-carboxamide. [ M+H ]] ⁺ ＝496。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.14(s,1H),10.55(s,1H),9.30(s,1H),8.58(d,J＝1.6Hz,1H),8.21–8.17(m,1H),7.92–7.87(m,1H),7.84(d,J＝2.4Hz,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 101:1- (6-cyclohexyl-5-fluoropyridin-3-yl) -N- (5, 6-difluoro-1H-indol-3-yl) -1H-1,2, 3-triazole-4-carboxamide (Compound 170)

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

1- (6-bromo-5-fluoropyridin-3-yl) -N- (5, 6-difluoro-1H-indol-3-yl) -1H-1,2, 3-triazole-4-carboxamide (130.7 mg,0.3mmol,1.0 eq.) and 2- (-cyclopent-1-en-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (124.8 mg,0.6mmol,2.0 eq.) are dissolved in dioxane (3 mL). Pd G3 (12.7 mg,0.015mmol,0.05 eq.) and aqueous K3PO4 (450. Mu.l, 2M,3.0 eq.) were then added under nitrogen. The reaction mixture was heated at 80℃for 16 hours. The reaction mixture was concentrated to give 1- (6- (-cyclopent-1-en-1-yl) -5-fluoropyridin-3-yl) -N- (5, 6-difluoro-1H-indol-3-yl) -1H-1,2, 3-triazole-4-carboxamide, which was used in the next step without purification.

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

1- (6- (-cyclopent-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, 0.2mmol,1.0 eq.) was dissolved in DCM (2 mL). Pd (AcO) was then added under nitrogen ₂ (2.2 mg,0.01mmol,0.05 eq.), acOH (50. Mu.l) and TES (200. Mu.l). The mixture was stirred at 30℃for 16 hours. The mixture was concentrated under reduced pressure to remove dioxane. Then add H ₂ O (5 mL) and extracted with EtOAc, the organic layer was dried over anhydrous Na ₂ SO ₄ Drying, filtering, concentrating under reduced pressure and purifying by HPLC to obtain 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(400MHz,DMSO-d ₆ )δppm 11.15(br s,1H),10.62(s,1H),9.47(s,1H),9.06(d,J＝1.8Hz,1H),8.39(dd,J＝10.5,2.0Hz,1H),7.97–7.78(m,2H),7.39(dd,J＝11.3,7.0Hz,1H),3.10-3.05(br t,1H),1.89–1.56(m,7H),1.45–1.22(m,3H)。

The analogues in the following table were prepared using the same procedure as described in example 101.

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

1- (6-bromo-5-fluoropyridin-3-yl) -N- (5, 6-difluoro-1H-indol-3-yl) -1H-1,2, 3-triazole-4-carboxamide (130.8 mg,0.3mmol,1.0 eq.) and 5-azaspiro [2.4]]Heptane (58.3 mg,0.6mmol,2.0 eq.) was dissolved in t-AmOH (3 mL). K is then added under nitrogen atmosphere ₃ PO ₄ (189.9 mg,0.9mmol,3.0 eq.) and RuPhos Pd G3 (12.5 mg,0.15mmol,0.05 eq.). The reaction mixture was heated at 100℃for 16 hours. The mixture was concentrated under reduced pressure to remove t-AmOH. Then add H ₂ O (5 mL) and extracted with EtOAc in anhydrous Na ₂ SO ₄ Drying above, filtering, concentrating under reduced pressure and purifying by HPLC to give N- (5, 6-difluoro-1H-indol-3-yl) -1- (5-fluoro-6- (5-azaspiro [ 2.4)]Heptane-5-yl) pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide. MS-ESI,454.2[ M+H ] ⁺ ]。

¹ H NMR(400MHz,DMSO-d ₆ )δppm 11.14(s,1H),10.55(s,1H),9.26(s,1H),8.60–8.46(m,1H),8.11(dd,J＝13.55,2.26Hz,1H),7.96–7.75(m,2H),7.50–7.30(m,1H),3.82–3.79(td,J＝6.78,2.51Hz,2H),3.56(d,J＝2.76Hz,2H),1.89(t,J＝6.90Hz,2H),0.70–0.55(m,4H)。

The analogues in the following table were prepared using the same procedure as described in example 109.

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Biological detection

Using THP1-Dual ^TM Cells (KO-IFNAR 2) measure activation of STING pathway by compounds described herein.

THP1-Dual ^TM KO-IFNAR2 cells (obtained from a living source) were stored in RPMI,10%FCS,5ml P/S,2mM L-glut,10mM Hepes and 1mM sodium pyruvate. Compounds were found in empty 384 well tissue culture plates (Greiner 781182) with Echo at final concentrations of 0.0017-100. Mu.M. Cells were seeded into TC plates at 40. Mu.L per well, 2X 10E6 cells/mL. For activation with STING ligand, 2'3' cgamp (MW 718.38, available from invitrogen) was prepared in Optimem medium.

The following solutions were prepared for each 1×384 plate:

solution a:2mL Optimem with one of the following stimuli:

60uL of 10mM 2'3' cGAMP- > 150. Mu.M stock solution

Solution B:2mL Optimem incubated with 60. Mu.L Lipofectamine 2000- > for 5 min at RT

2mL of solution A and 2mL of solution B were mixed and incubated for 20 minutes at Room Temperature (RT). mu.L of transfection solution (A+B) was added to the top of the plated cells, with a final 2'3' cGAMP concentration of 15. Mu.M. The plates were then immediately centrifuged at 340g for 1 min, then at 37℃with 5% CO ₂ 、>Incubate at 98% humidity for 24 hours. Luciferase reporter activity is then measured. EC is calculated by using standard methods known in the art ₅₀ Values.

Luciferase reporter detection: 10. Mu.L of supernatant from the assay was transferred to a white 384 plate with flat bottom and square wells. One bag of QUANTI-Luc ^TM Plus was dissolved in 25mL of water. QUANTI-Luc per 25mL ^TM Plus solution 100 μl QLC stabilizer was added. Then 50. Mu.L of QUANTI-Luc was added to each well ^TM Plus/QLC solution. Luminescence was measured on a plate reader (e.g., spectramax I3X (Molecular Devices GF 3637001)).

Luciferase reporter activity is then measured. EC is calculated by using standard methods known in the art ₅₀ Values.

Table BA shows the activity of the compounds in STING reporter assays: <0.008 μm= "++ + + and ++"; not less than 0.008 and less than 0.04 mu m= "+" ++ "; not less than 0.04 and less than 0.2 mu m= "+ ++"; not less than 0.2 and <1 mu m= "+ ++"; not less than 1 and not more than 5 mu m= "+ plus"; gtoreq 5 and <100 μm= "+".

Table BA

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Numbering clauses

The compounds, compositions, methods, and other subject matter described herein are further described in the following numbered clauses:

1. a compound of formula I or a pharmaceutically acceptable salt or tautomer thereof:

wherein:

X ¹ Selected from the group consisting of: o, S, N, NR ² And CR (CR) ¹ ；

X ² Selected from the group consisting of: o, S, N, NR ⁴ And CR (CR) ⁵ ；

each R1 is independently selected from the group consisting of: h is formed; r is R ^c ；R ^g The method comprises the steps of carrying out a first treatment on the surface of the And- (L) ¹ ) _b1 -R ^g ；

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

R5 is selected from the group consisting of: h is formed; r is R ^c The method comprises the steps of carrying out a first treatment on the surface of the And R is ^h ；

R6 is selected from the group consisting of: h is formed; r is R ^d The method comprises the steps of carrying out a first treatment on the surface of the And R is ^h ；

Ring B is a heteroarylene group having 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: n, NH, N (R) ^d ) O and S; wherein the heteroarylene of ring B is optionally independently selected from the group consisting of1-2 substituents: oxo and R ^c Provided that ring B is bound to C (=O) NR via a ring carbon atom ⁶ A group connection;

a1 is 0, 1 or 2;

ring C is selected from the group consisting of:

R7 is selected from the group consisting of: r is R ^g And- (L) ⁷ ) _b7 -R ^g ；

each time go outR at present ^c Independently selected from the group consisting of: halogen; cyano group; c (C) _1-10 Alkyl, optionally substituted with 1-6 independently selected R ^a Substitution; c (C) _2-6 Alkenyl groups; c (C) _2-6 Alkynyl; c (C) _1-4 An alkoxy group; c (C) _1-4 Haloalkoxy groups; s (O) _1-2 (C _1-4 An alkyl group); -S (O) (=nh) (C _1-4 An alkyl group); -NR ^e R ^f ；–OH；-S(O) _1-2 NR’R”；-C _1-4 Thioalkoxy; -NO ₂ ；-C(＝O)(C _1-10 An alkyl group); -C (=o) O (C _1-4 An alkyl group); -C (=o) OH; -C (=o) NR' R "; and-SF ₅ ；

r in each occurrence ^g Independently selected from the group consisting of:

Heteroaryl groups having 5 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c 、R ^h And- (L) ^g ) _bg -R ^h The method comprises the steps of carrying out a first treatment on the surface of the And

R in each occurrence ^h Independently selected from the group consisting of:

C _6-10 aryl, optionally substituted with 1-4R ⁱ Substitution;

b1, b2, b7 and bg are each independently 1, 2 or 3; and

2. The compound of clause 1, wherein each Z, Y ¹ 、Y ² And Y ³ Independently N or CR ¹ 。

3. The compound of any one of clauses 1-2, wherein the compound is a compound of formula (Ia):

4. The compound of clauses 1-2, wherein Z, Y ¹ 、Y ² And Y ³ From 1 to 2 (e.g., 1) of (a) are N; and Z, Y ¹ 、Y ² And Y ³ The remainder of each being independently selected CR ¹ 。

5. The compound of any one of clauses 1-2 or 4, wherein the compound is selected from the group of compounds having the formula:

6. The compound of any one of clauses 1-5, wherein X ¹ Is NR ² 。

7. The compound of any one of clauses 1-6, wherein X ¹ Is NH.

8. The compound of any one of clauses 1-7, wherein X ² Is CR (CR) ⁵ 。

9. The compound of any one of clauses 1-8, wherein X ² Is CH.

10. The compound of any one of clauses 1-5, wherein X ¹ Is NR ² And X is ² Is CR (CR) ⁵ 。

11. The compound of any one of clauses 1-5 or 10, wherein X ¹ Is NH and X ² Is CH.

12. The compound of clause 1, wherein the compound is of formula (Ia):

13. The compound of clause 1, wherein the compound is selected from the group of compounds having the formula:

14. The compound of clause 12 or 13, wherein R ² Is H.

15. The compound of any one of clauses 12-14, wherein R5 is H.

16. The compound of any one of clauses 1-15, wherein each R ¹ Is H.

17. The compound of any one of clauses 1-15, wherein 1-2R ¹ Independently selected from the group consisting of: r is R ^c1 And R is ^g1 The method comprises the steps of carrying out a first treatment on the surface of the And each remaining R ¹ Is H, wherein R ^c1 R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And R is ^g1 R is independently selected ^g 。

18. The compound of clause 17, wherein R is present in two occurrences ¹ Independently selected from the group consisting of: r is R ^c1 And R is ^g1 The method comprises the steps of carrying out a first treatment on the surface of the And each remaining R ¹ Is H.

19. The compound of clause 17 or 18, wherein R occurs twice ¹ R is independently selected ^c1 The method comprises the steps of carrying out a first treatment on the surface of the And each remaining R ¹ Is H.

20. The compound of clause 17, wherein R ¹ Independently selected from the group consisting of: r is R ^c1 And R is ^g1 The method comprises the steps of carrying out a first treatment on the surface of the And each remaining R ¹ Is H.

21. The compound of clause 17 or 20, wherein R is present in one occurrence ¹ Is R ^c1 The method comprises the steps of carrying out a first treatment on the surface of the And each remaining R ¹ Is H.

22. The compound of clause 17 or 20, wherein R is present in one occurrence ¹ Is R ^g1 The method comprises the steps of carrying out a first treatment on the surface of the And each remaining R ¹ Is H.

23. The compound of any one of clauses 17-22, wherein each R ^c1 Is an independently selected halogen, such as-F, -Cl or-Br.

24. The compound of clause 23, wherein each R ^c1 independently-F or-Cl, such as-F.

25. The compound of any one of clauses 17-24, wherein each R ^g1 Each independently selected from the group consisting of:

heteroaryl groups having 5 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c 、R ^h And- (L) ^g ) _bg -R ^h The method comprises the steps of carrying out a first treatment on the surface of the And

C _6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c 、R ^h And- (L) ^g ) _bg -R ^h 。

26. The compound of clause 25, wherein each R ^g1 Each independently selected from the group consisting of:

heteroaryl groups having 5 to 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S, and wherein the heteroaryl is optionally substituted with 1-4R ^c Substitution; and

C ₆ aryl, optionally substituted with 1-4R ^c And (3) substitution.

27. The compound of clause 25 or 26, wherein each R ^g1 Independently is a heteroaryl group having 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S, and wherein the heteroaryl is optionally substituted with 1-4R ^c And (3) substitution.

28. The compound of clause 27, wherein each R ^g1 Is optionally substituted with 1-2R ^c Substituted pyrazolyl groups, e.g. 1-2 independently selected C _1-6 (e.g., C _1-3 ) Alkyl, optionally substituted with 1-6 independently selected R ^a Substituted (e.g., unsubstituted).

29. The compound of any one of clauses 3, 5, or 12-13, wherein R ^1a Is H.

30. The compound of any one of clauses 3, 5, 12-13, or 29, wherein R ^1b Is H.

31. The compound of any one of clauses 3, 5, 12-13, or 29, wherein R ^1b Halogen, such as-F or-Cl (e.g., -F).

32. The compound of any one of clauses 3, 5, 12-13, or 29, wherein R ^1b Is a heteroaryl group having 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S, and wherein the heteroaryl is optionally substituted with 1-2R ^c And (3) substitution.

33. The compound of clause 32, wherein R ^1b Is optionally substituted with 1-2R ^c Substituted pyrazolyl radicals, e.g. each R ^c Is independently selected C _1-6 (e.g., C _1-3 ) Alkyl, optionally substituted with 1-6 independently selected R ^a Substituted (e.g., unsubstituted).

34. The compound of any one of clauses 3, 5, 12-13, or 29, wherein R ^1c Is H.

35. Such asThe compound of any one of clauses 3, 5, 12-13 or 29-33, wherein R ^1c Halogen, such as-F or-Cl (e.g., -F).

36. The compound of any one of clauses 3, 5, 12-13, or 29-35, wherein R ^1d Is H.

37. The compound of any one of clauses 3, 5, 12-13, or 29-35, wherein R ^1d Halogen, such as-F or-Cl (e.g., -F).

38. The compound of any one of clauses 3, 5, or 12-13, wherein R ^1a And R is ^1d Is H; and R is ^1b And R is ^1c Is an independently selected halogen, such as-F or-Cl, such as-F.

39. The compound of any one of clauses 3, 5, or 12-13, wherein R ^1a And R is ^1d Is H; r is R ^1b And R is ^1c One of which is H; and R is ^1b And R is ^1c The other of (C) is halogen, e.g. -F or-Cl, e.g. -F.

40. The compound of any one of clauses 3, 5, or 12-13, wherein R ^1a And R is ^1d Is H; r is R ^1c Halogen or H, for example-F, -Cl or H; and R is ^1b Is a heteroaryl group having 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S, and wherein the heteroaryl is optionally substituted with 1-4R ^c And (3) substitution.

41. The compound of any one of clauses 1-40, wherein R ⁶ Is H.

42. The compound of any of clauses 1-41, wherein ring B is a heteroarylene group having 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, NH, O and S, wherein the ring B heteroarylene is optionally substituted with 1-2R ^cB Substitution; and each R ^cB R is independently selected ^c 。

43. The compound of any of clauses 1-42, wherein ring B is a heteroarylene group having 5 ring atoms, wherein 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, NH, N (R) ^d ) O and S (e.g., N and NH), wherein the cyclic B heteroarylene is optionally substituted with 1-2R ^cB Substitution; and each R ^cB R is independently selected ^c 。

44. The compound of clause 43, wherein ring B is selected from the group consisting of: imidazolylene, pyrazolylene or triazolylene (e.g. 1,2, 3-triazolylene), optionally substituted with one R ^cB And (3) substitution.

45. The compound of clause 44, wherein ring B isWhich is optionally substituted with one R ^cB Substitution, wherein aa is a group similar to (L ^A ) _a1 Is connected to the connecting point of (c).

46. The compound of clause 44, wherein ring B isWhich is optionally substituted with one R ^cB Substitution, wherein aa is a group similar to (L ^A ) _a1 Is connected to the connecting point of (c).

47. The compound of clause 44, wherein ring B isWhich is optionally substituted with one R ^cB Substitution, wherein aa is a group similar to (L ^A ) _a1 Is connected to the connecting point of (c).

48. The compound of clause 44, wherein ring B isEach of which is optionally covered with one R ^cB Substitution, wherein aa is a group similar to (L ^A ) _a1 Is connected to the connecting point of (c).

49. The compound of any one of clauses 42-48 or 163-169, wherein each R ^cB Independently is halogen or C _1-3 Alkyl, optionally substituted with 1-3 independently selected R ^a (e.g., 1-3 independently selected halogens).

50. The compound of any one of clauses 1-49 or 163-169, wherein a1 is 0.

51. The compound of any one of clauses 1-49 or 163-169, wherein a1 is 1.

52. The compound of any one of clauses 1-49, 51 or 163-169, wherein L ^A Is C _1-3 Alkylene, optionally substituted with 1-2R ^a1 And (3) substitution.

53. The compound of clause 52, wherein L ^A Is CH ₂ Or CH (Me), e.g. CH ₂ 。

54. The compound of any one of clauses 1-53 or 163-169, wherein ring C is selected from the group consisting of:

Heteroarylene having 5 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^cC And R is ^hC The method comprises the steps of carrying out a first treatment on the surface of the And

C _6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^cC And R is ^hC Wherein each R is ^cC R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And each R ^hC R is independently selected ^h 。

55. The compound of any one of clauses 54 or 163-169, wherein ring C is selected from the group consisting of:

heteroarylene of 5 to 6 (e.g., 6) ring atoms, wherein 1 to 3 (e.g., 1 to 2) ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^cC The method comprises the steps of carrying out a first treatment on the surface of the And

56. The compound of any one of clauses 5455 or 163-169, wherein ring C is selected from the group consisting of:

57. The compound of any of clauses 54-56 or 163-169, wherein ring C is a group having the formula:wherein Q is ¹ 、Q ² 、Q ³ And Q ⁴ Each independently selected from the group consisting of: n, CH and CR ^cC The method comprises the steps of carrying out a first treatment on the surface of the And bb is with R ⁷ Is connected to the connecting point of (c).

58. The compound of any one of clauses 57 or 163-169, wherein Q ² Is CH.

59. The compound of any one of clauses 57, 58, or 163-169, wherein Q ³ Is CH.

60. The compound of any one of clauses 57-59 or 163-169, wherein Q ⁴ Is N.

61. The compound of any one of clauses 57-60 or 163-169, wherein Q ¹ Is CH.

62. The compound of any one of clauses 57-60 or 163-169, wherein Q ¹ Is CR (CR) ^cC 。

63. The compound of any one of clauses 57 or 163-169, wherein ring C isFor example->

64. The compound of any one of clauses 54-63 or 163-169, wherein each R ^cC Independently selected from the group consisting of: halogen and C _1-6 (e.g. C _1-3 ) Alkyl, optionally R independently selected by 1-6 each ^a (e.g., 1-6 independently selected halogens, such as-F).

65. The compound of any one of clauses 54-64 or 163-169, wherein each R ^cC Independently halogen, e.g. -Cl or-F, e.g.)F。

66. The compound of any one of clauses 1-65 or 170-173, wherein R ⁷ Is R ^g 。

67. The compound of any one of clauses 1-66 or 170-173, wherein R7 is selected from the group consisting of:

68. The compound of any one of clauses 67-66 or 170-173, wherein R ⁷ Selected from the group consisting of:

C _4-8 cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of: oxo, R ^c7 And R is ^h7 The method comprises the steps of carrying out a first treatment on the surface of the And

heterocyclyl having 4 to 8 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: oxo, R ^c7 And R is ^h7 。

69. The compound of any one of clauses 68-66 or 170-173, wherein R ⁷ Selected from the group consisting of:

heterocyclyl having 6-8 ring atoms, wherein 1-2 (e.g., 1) ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O andS(O) _0-2 and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c7 。

70. The compound of any one of clauses 69 or 170-173, wherein R ⁷ Is a group having the formula:wherein X is ⁷ Is CH, CR ^c7 Or N, alternatively CH or N.

71. The compound of any one of clauses 69, 70, or 170-173, wherein each R is present ^c7 A group.

72. The compound of any one of clauses 1-71 or 170-173, wherein R ⁷ Is a group having the formula:wherein X is ⁷ Is N or CH; and each R is ^c7 R is independently selected ^c 。

73. The compound of any one of clauses 67-72 or 170-173, wherein each R ^c7 Is independently selected halogen or C _1-3 Alkyl, optionally substituted with 1-6R ^a (e.g., 1-6 independently selected halogens).

74. The compound of any one of clauses 67-73 or 170-173, wherein each R ^c7 Independently is halogen, e.g., -F.

75. The compound of any one of clauses 1-74 or 170-173, wherein R ⁷ Is thatWherein X is ⁷ Is N or CH.

76. The compound of clause 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound having the formula (I-a 1-1):

Wherein:

R ^1a 、R ^1b and R is ^1c Each independently selected R ¹ ；

B ⁴ Is C or N;

77. The compound of clause 76, wherein R ^1a And R is ^1d Is H; and R is ^1b And R is ^1c Independently is H or halogen, such as halogen (e.g., -F or-Cl, e.g., -F).

78. The compound of clause 76, wherein R ^1a 、R ^1b 、R ^1c And R is ^1d Any one of which is H.

79. The compound of clause 76, wherein R ^1a And R is ^1d Is H; r is R ^1c Halogen or H, for example-F, -Cl or H; and R is ^1b Is a heteroaryl group having 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c 。

80. The compound of any one of clauses 76-79, wherein R ² Is H.

81. The compound of any one of clauses 76-80, wherein R ⁵ Is H.

82. The compound of any one of clauses 76-81, wherein R ⁶ Is H.

83. The compound of any of clauses 76-82, wherein R ² Is H; r is R ⁵ Is H; and R is ⁶ Is H.

84. The compound of any one of clauses 76-83, wherein B ⁴ Is N; b (B) ¹ Is N; b (B) ³ Is CH; and B ² Is CH.

85. The compound of any one of clauses 76-83, wherein B ⁴ Is N; b (B) ¹ Is N; b (B) ³ Is CH; and B ² Is N.

86. The compound of any one of clauses 76-83, wherein B ⁴ Is N; b (B) ¹ Is N; b (B) ³ Is CH; and B ² Is CR (CR) ^cB 。

87. The compound of any one of clauses 76-83, wherein B ⁴ Is N; b (B) ¹ Is CH; b (B) ³ Is CH; and B ² Is N.

88. The compound of any one of clauses 76-83, wherein B ⁴ Is N; b (B) ¹ Is CH; b (B) ³ Is N; and B ² Is CH.

89. The compound of any one of clauses 76-88, wherein a1 is 0.

90. The compound of any one of clauses 76-88, wherein a1 is 1.

91. The compound of any of clauses 76-88 or 90, wherein L ^A Is CH ₂ Or CH (Me).

92. The compound of any one of clauses 76-91, wherein Q ¹ And Q ³ Is CH.

93. The compound of any of clauses 76-92, wherein Q ⁴ Is N; and Q ² Is CH or CR ^cC For example CR ^cC 。

94. The compound of any one of clauses 76-93, wherein comprising Q ¹ -Q ⁴ The ring of (2) is:wherein bb is with R ⁷ Is connected to the connecting point of (c).

95. The compound of any of clauses 76-94, wherein R ^cC Halogen, for example-F or-Cl, for example-F.

96. The compound of any one of clauses 76-95, wherein R ⁷ Selected from the group consisting of:

97. The compound of clause 96, wherein R ⁷ Is a group having the formula:wherein X is ⁷ Is CH, CR ⁷ Or N, alternatively CH or N.

98. The compound of clause 96 or 97, wherein there are 2R ^c7 A group.

99. The compound of any one of clauses 76-98, wherein R ⁷ Is a group having the formula:wherein X is ⁷ Is N or CH; and each R is ^c7 R is independently selected ^c 。

100. The compound of any of clauses 96-99, wherein each R ^c7 Is independently selected halogen or C _1-3 Alkyl, optionally substituted with 1-6R ^a (e.g., 1-6 independently selected halogens).

101. The compound of any one of clauses 96-100, wherein each R ^c7 Independently is a halogen, such as-F.

102. The compound of any one of clauses 76-101, wherein，R ⁷ Is thatWherein X is ⁷ Is N or CH, e.g.>

103. The compound of clause 1, wherein the compound is selected from the compounds described in table C1 or a pharmaceutically acceptable salt thereof.

104. A pharmaceutical composition comprising a compound of any one of clauses 1-103 and one or more pharmaceutically acceptable excipients.

105. A method of inhibiting STING activity, the method comprising contacting STING with a compound according to any one of clauses 1-103, or a pharmaceutically acceptable salt thereof; or with the 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 105-106, wherein the method 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 clauses 108 or 109, wherein the sample further comprises one or more cancer cells, the cancer 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, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, wilms' tumor, or hepatocellular carcinoma.

111. The method of clauses 105 or 106, wherein the method is performed in vivo.

112. A method according to clause 111, wherein the method comprises administering the compound to a subject having a disease in which increased (e.g., excessive) STING signaling results in pathology and/or symptoms and/or progression of the disease.

113. The method of clause 112, wherein the object is a person.

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, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, wilms' tumor, or hepatocellular carcinoma.

116. The method of clause 114 or 115, wherein the cancer is refractory cancer.

117. The method of clause 112, wherein the compound is administered in combination with one or more additional cancer therapies.

118. The method of clause 117, wherein the one or more additional cancer therapies comprise: surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

119. The method of clause 118, wherein the chemotherapy comprises the 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 the group consisting of: alkylating agents (e.g., cisplatin, carboplatin, nitrogen mustard, cyclophosphamide, chlorambucil, ifosfamide, and/or oxaliplatin); antimetabolites (e.g., azathioprine and/or mercaptopurine); terpenes (e.g., vinca alkaloids and/or taxanes; e.g., vincristine, vinblastine, vinorelbine and/or vindesine, taxol and/or docetaxel); topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, e.g., irinotecan and/or topotecan; amsacrine, etoposide phosphate and/or teniposide); cytotoxic antibiotics (e.g., actinomycin, anthracycline, doxorubicin, daunorubicin, valubicin, idarubicin, epirubicin, bleomycin, plicamycin, and/or mitomycin); hormones (e.g., luteinizing hormone-releasing hormone agonists; e.g., leuprorelin, goserelin, triptorelin, histamine relin, bicalutamide, flutamide, and/or nilutamide); antibodies (e.g., acipimab, adalimumab, alemtuzumab, basiliximab, valitumumab, kanamemumab, cetuximab, pessary bevacizumab, daclizumab, desiuzumab, eculizumab, ai Fazhu mab, gemtuzumab, golimumab, tiimumab, infliximab, ipilimumab, moluzumab-CD 3, natalizumab, oxlimumab, omalizumab, palivizumab, panitumumab, rituximab, tozumumab, tositumumab and/or trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic active agent; a growth inhibitor; anthelmintic agents; and an immune checkpoint inhibitor targeting an immune checkpoint receptor selected from the group consisting of: CTLA-4, PD-1, PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2, 3-dioxygenase (IDO), IL-10, transforming growth factor- β (tgfβ), T-cell immunoglobulin and mucin 3 (TIM 3 or HAVCR 2), galectin 9-TIM3, phosphatidylserine-TIM 3, lymphocyte activating gene 3 protein (LAG 3), MHC class II-LAG 3,4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDCL 2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHTA 2-TMIGD2, milk philins including BTNL2, siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 adenosine-CD 39-CD73, CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM 3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., PD, CTLA-4 or PD-1 or PD-L1).

121. The method of any of clauses 112-120, wherein the compound is administered intratumorally.

122. A method of treating cancer comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of clauses 1-103 or a pharmaceutical composition according to 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, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, wilms' tumor, or hepatocellular carcinoma.

124. The method of clause 122 or 123, wherein the cancer is refractory cancer.

125. The method of clause 122, wherein the compound is administered in combination with one or more additional cancer therapies.

126. The method of clause 125, wherein the one or more additional cancer therapies comprise: surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

127. The method of clause 126, wherein the chemotherapy comprises the 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 the group consisting of: alkylating agents (e.g., cisplatin, carboplatin, nitrogen mustard, cyclophosphamide, chlorambucil, ifosfamide, and/or oxaliplatin); antimetabolites (e.g., azathioprine and/or mercaptopurine); terpenes (e.g., vinca alkaloids and/or taxanes; e.g., vincristine, vinblastine, vinorelbine and/or vindesine, taxol and/or docetaxel); topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, e.g., irinotecan and/or topotecan; amsacrine, etoposide phosphate and/or teniposide); cytotoxic antibiotics (e.g., actinomycin, anthracycline, doxorubicin, daunorubicin, valubicin, idarubicin, epirubicin, bleomycin, plicamycin, and/or mitomycin); hormones (e.g., luteinizing hormone-releasing hormone agonists; e.g., leuprorelin, goserelin, triptorelin, histamine relin, bicalutamide, flutamide, and/or nilutamide); antibodies (e.g., acipimab, adalimumab, alemtuzumab, basiliximab, valitumumab, kanamemumab, cetuximab, pessary bevacizumab, daclizumab, desiuzumab, eculizumab, ai Fazhu mab, gemtuzumab, golimumab, tiimumab, infliximab, ipilimumab, moluzumab-CD 3, natalizumab, oxlimumab, omalizumab, palivizumab, panitumumab, rituximab, tozumumab, tositumumab and/or trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic active agent; a growth inhibitor; anthelmintic agents; and an immune checkpoint inhibitor targeting an immune checkpoint receptor selected from the group consisting of: CTLA-4, PD-1, PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2, 3-dioxygenase (IDO), IL-10, transforming growth factor- β (tgfβ), T-cell immunoglobulin and mucin 3 (TIM 3 or HAVCR 2), galectin 9-TIM3, phosphatidylserine-TIM 3, lymphocyte activating gene 3 protein (LAG 3), MHC class II-LAG 3,4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDCL 2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHTA 2-TMIGD2, milk philins including BTNL2, siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 adenosine-CD 39-CD73, CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM 3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., PD, CTLA-4 or PD-1 or PD-L1).

129. The method of any of clauses 122-128, wherein the compound is administered intratumorally.

130. A method of inducing an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of clauses 1-103 or the pharmaceutical composition of clause 104.

131. The method of clause 130, wherein the subject has cancer.

132. The method of clause 131, wherein the subject has undergone 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, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, wilms' tumor, or hepatocellular carcinoma.

134. The method of any of clauses 131-133, wherein the cancer is 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 additional cancer therapies comprise: surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

137. The method of clause 136, wherein the chemotherapy comprises the 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 the group consisting of: alkylating agents (e.g., cisplatin, carboplatin, nitrogen mustard, cyclophosphamide, chlorambucil, ifosfamide, and/or oxaliplatin); antimetabolites (e.g., azathioprine and/or mercaptopurine); terpenes (e.g., vinca alkaloids and/or taxanes; e.g., vincristine, vinblastine, vinorelbine and/or vindesine, taxol and/or docetaxel); topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, e.g., irinotecan and/or topotecan; amsacrine, etoposide phosphate and/or teniposide); cytotoxic antibiotics (e.g., actinomycin, anthracycline, doxorubicin, daunorubicin, valubicin, idarubicin, epirubicin, bleomycin, plicamycin, and/or mitomycin); hormones (e.g., luteinizing hormone-releasing hormone agonists; e.g., leuprorelin, goserelin, triptorelin, histamine relin, bicalutamide, flutamide, and/or nilutamide); antibodies (e.g., acipimab, adalimumab, alemtuzumab, basiliximab, valitumumab, kanamemumab, cetuximab, pessary bevacizumab, daclizumab, desiuzumab, eculizumab, ai Fazhu mab, gemtuzumab, golimumab, tiimumab, infliximab, ipilimumab, moluzumab-CD 3, natalizumab, oxlimumab, omalizumab, palivizumab, panitumumab, rituximab, tozumumab, tositumumab and/or trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic active agent; a growth inhibitor; anthelmintic agents; and an immune checkpoint inhibitor targeting an immune checkpoint receptor selected from the group consisting of: CTLA-4, PD-1, PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2, 3-dioxygenase (IDO), IL-10, transforming growth factor- β (tgfβ), T-cell immunoglobulin and mucin 3 (TIM 3 or HAVCR 2), galectin 9-TIM3, phosphatidylserine-TIM 3, lymphocyte activating gene 3 protein (LAG 3), MHC class II-LAG 3,4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDCL 2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHTA 2-TMIGD2, milk philins including BTNL2, siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 adenosine-CD 39-CD73, CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM 3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., PD, CTLA-4 or PD-1 or PD-L1).

139. A method of treating a disease in which increased (e.g., excessive) STING signaling promotes pathology and/or symptom and/or progression of the disease, the method comprising administering to a subject in need of such treatment an effective amount of a compound of any one of clauses 1-103 or a pharmaceutical composition of clause 104.

140. A method of treatment comprising administering to a subject suffering from a disease in which increased (e.g., excessive) STING signaling promotes pathology and/or symptoms and/or progression of the disease, an effective amount of a compound according to any one of clauses 1-103 or a pharmaceutical composition according to clause 104.

141. A method of treatment comprising administering to a subject a compound according to any one of clauses 1-103 or a pharmaceutical composition according to clause 104, wherein the compound or composition is administered in an amount effective to treat a disease in which increased (e.g., excessive) STING signaling promotes pathology and/or symptoms and/or progression of the disease, thereby treating the disease.

142. The method of any of clauses 139-141, 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, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, wilms' tumor, or hepatocellular carcinoma.

144. The method of clause 142 or 143, wherein the cancer is refractory cancer.

145. The method of any of clauses 142-144, wherein the compound is administered in combination with one or more additional cancer therapies.

146. The method of clause 145, wherein the one or more additional cancer therapies comprise: surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

147. The method of clause 146, wherein the chemotherapy comprises the 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 the group consisting of: alkylating agents (e.g., cisplatin, carboplatin, nitrogen mustard, cyclophosphamide, chlorambucil, ifosfamide, and/or oxaliplatin); antimetabolites (e.g., azathioprine and/or mercaptopurine); terpenes (e.g., vinca alkaloids and/or taxanes; e.g., vincristine, vinblastine, vinorelbine and/or vindesine, taxol and/or docetaxel); topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, e.g., irinotecan and/or topotecan; amsacrine, etoposide phosphate and/or teniposide); cytotoxic antibiotics (e.g., actinomycin, anthracycline, doxorubicin, daunorubicin, valubicin, idarubicin, epirubicin, bleomycin, plicamycin, and/or mitomycin); hormones (e.g., luteinizing hormone-releasing hormone agonists; e.g., leuprorelin, goserelin, triptorelin, histamine relin, bicalutamide, flutamide, and/or nilutamide); antibodies (e.g., acipimab, adalimumab, alemtuzumab, basiliximab, valitumumab, kanamemumab, cetuximab, pessary bevacizumab, daclizumab, desiuzumab, eculizumab, ai Fazhu mab, gemtuzumab, golimumab, tiimumab, infliximab, ipilimumab, moluzumab-CD 3, natalizumab, oxlimumab, omalizumab, palivizumab, panitumumab, rituximab, tozumumab, tositumumab and/or trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic active agent; a growth inhibitor; anthelmintic agents; and an immune checkpoint inhibitor targeting an immune checkpoint receptor selected from the group consisting of: CTLA-4, PD-1, PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2, 3-dioxygenase (IDO), IL-10, transforming growth factor- β (tgfβ), T-cell immunoglobulin and mucin 3 (TIM 3 or HAVCR 2), galectin 9-TIM3, phosphatidylserine-TIM 3, lymphocyte activating gene 3 protein (LAG 3), MHC class II-LAG 3,4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDCL 2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHTA 2-TMIGD2, milk philins including BTNL2, siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 adenosine-CD 39-CD73, CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM 3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., PD, CTLA-4 or PD-1 or PD-L1).

149. The method of any of clauses 139-148, wherein the compound is administered intratumorally.

150. A method of treating a disease, disorder, or condition associated with STING comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of clauses 1-103 or a pharmaceutical composition according to clause 104.

151. The method of clause 150, wherein the disease, disorder, or condition is selected from the group consisting of: type I interferon disease, akadi-Gu Di rass syndrome (AGS), hereditary form lupus, inflammation-related disorders and rheumatoid arthritis.

152. The method of clause 151, wherein the disease, disorder, or condition is type I interferon disease (e.g., STING-related vascular disease (SAVI) of infancy).

153. The method of clause 152, wherein the type I interferon disease is STING-related vascular disease (SAVI) of infancy.

154. The method of clause 151, wherein the disease, disorder, or condition is akadine-Gu Di rass syndrome (AGS).

155. The method of clause 151, wherein the disease, disorder, or condition is a genetic 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 condition associated with inflammation is systemic lupus erythematosus.

158. A combination comprising a compound as defined in 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 as defined in any one of clauses 1 to 103, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition as defined in clause 104, for use as a medicament.

160. A compound as defined in any one of clauses 1 to 103, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition as defined in clause 104, for use in the treatment of a disease, disorder, or condition modulated by STING inhibition.

161. A compound as defined in any one of clauses 1 to 103, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition as defined in clause 104, for use in the treatment of a disease as defined in any one of clauses 105 to 278.

162. Use of a compound as defined in any one of clauses 1 to 103, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition as defined in clause 104, in the manufacture of a medicament for the treatment of a disease as defined in any one of clauses 105 to 157.

163. The compound of clause 43, wherein ring B is selected from the group consisting of: isoxazolylene, oxadiazolylene, oxazolylene, thiazolylene, isothiazolylene or thiadiazolylene, optionally substituted with one R ^cB And (3) substitution.

164. The compound of clause 163, wherein ring B isEach of which is optionally covered with one R ^cB Substitution, wherein aa is a group similar to (L ^A ) _a1 Is connected to the connecting point of (c).

165. The compound of clause 163, wherein ring B isEach of which is optionally covered with one R ^cB Substitution, wherein aa is a group similar to (L ^A ) _a1 Is connected to the connecting point of (c).

166. The compound of clause 163, wherein a ringB isEach of which is optionally covered with one R ^cB Substitution, wherein aa is a group similar to (L ^A ) _a1 Is connected to the connecting point of (c). />

167. The compound of clause 163, wherein ring B isEach of which is optionally covered with one R ^cB Substitution, wherein aa is a group similar to (L ^A ) _a1 Is connected to the connecting point of (c).

168. The compound of clause 163, wherein ring B isEach of which is optionally covered with one R ^cB Substitution, wherein aa is a group similar to (L ^A ) _a1 Is connected to the connecting point of (c).

169. The compound of clause 163, wherein ring B isEach of which is optionally covered with one R ^cB Substitution, wherein aa is a group similar to (L ^A ) _a1 Is connected to the connecting point of (c).

170. The compound of clause 68, wherein R ⁷ Selected from the group consisting of:

heterocyclyl having 5-6 ring atoms, wherein 1-2 (e.g., 1) ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c7 。

171. The compound of clause 68, wherein R ⁷ Is a group having the formula: wherein X is ⁷ Is CH, CR ^c7 Or N, alternatively CH or N.

172. The compound of clause 68, wherein R ⁷ Is a group having the formula: wherein R is ^d Independently selected from the group consisting of: c (C) _1-6 Alkyl, optionally substituted with 1-3 independently selected R ^a Substitution, wherein m7 is 0 or 1.

173. The compound of clause 68, wherein R ⁷ Selected from the group consisting of: tetrahydropyranyl, morpholinyl, 5-azaspiro [2.5 ]]Octyl or 2-azabicyclo [2.2.1]Heptyl groups, each optionally substituted with 1-2R ^c7 And (3) substitution. For example, R7 may be:

/>

Claims

wherein:

X ¹ Selected from the group consisting of: o, S, N, NR ² And CR (CR) ¹ ；

X ² Selected from the group consisting of: o, S, N, NR ⁴ And CR (CR) ⁵ ；

R ⁴ Selected from the group consisting of: h and R ^d ；

each L ^A Independently selected from the group consisting of: c (C) _1-3 Alkylene, optionally substituted with 1-2R ^a1 Substitution; -O-; -NH-; -NR ^d ；-S(O) _0-2 The method comprises the steps of carrying out a first treatment on the surface of the And C (O);

a1 is 0, 1 or 2;

ring C is selected from the group consisting of:

Having 3-12 ring atomsHeterocyclylene or heterocyclylene wherein 1-3 ring atoms are heteroatoms each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And the heterocyclylene or heterocyclylene is optionally substituted with 1-4 substituents independently selected from the group consisting of: oxo, R ^c And R is ^h ；

R in each occurrence ^d Independently selected from the group consisting of: c (C) _1-6 Alkyl group, which is optionalGround is covered by 1-3 independently selected R ^a Substitution; -C (O) (C _1-4 An alkyl group); -C (O) O (C) _1-4 An alkyl group); -CONR' R "; s (O) _1-2 NR’R”；-S(O) _1-2 (C _1-4 An alkyl group); -OH; and C _1-4 An alkoxy group;

r in each occurrence ^e And R is ^f Independently selected from the group consisting of: h is formed; c (C) _1-6 Alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of: NR 'R', -OH and R ⁱ ；-C(O)(C _1-4 An alkyl group); -C (O) O (C) _1-4 An alkyl group); -CONR' R "; s (O) _1-2 NR’R”；-S(O) _1-2 (C _1-4 An alkyl group); -OH; and C _1-4 An alkoxy group;

r in each occurrence ^g Independently selected from the group consisting of:

R in each occurrence ^h Independently selected from the group consisting of:

C _6-10 aryl, optionally substituted with 1-4R ⁱ Substitution;

b1, b2, b7 and bg are each independently 1, 2 or 3; and

2. The compound of claim 1, wherein the compound is a compound of formula (Ia):

Wherein: r is R ^1a 、R ^1b 、R ^1c And R is ^1d R each independently selected ¹ 。

3. The compound of claim 1, wherein Z, Y ¹ 、Y ² And Y ³ One of which is N; and Z, Y ¹ 、Y ² And Y ³ The remainder of each being independently selected CR ¹ 。

4. A compound according to any one of claims 1 to 3 wherein X ¹ Is NR ² The method comprises the steps of carrying out a first treatment on the surface of the And X is ² Is CR (CR) ⁵ Optionally, wherein X ¹ Is NH; and X is ² Is CH.

5. The compound of any one of claims 1-4, wherein 1-2R ¹ Independently selected from the group consisting of: r is R ^c And R is ^g The method comprises the steps of carrying out a first treatment on the surface of the And the remainder R ¹ Each is H.

6. The compound of any one of claims 1-5, wherein each R ^c Is an independently selected halogen, e.g. -F, -Cl or-Br, e.g. wherein each R ^c independently-F or-Cl, such as-F; and each R ^g Independently is a heteroaryl group having 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S, and wherein the heteroaryl is optionally substituted with 1-4R ^c And (3) substitution.

7. A compound according to claim 2 or claims 4 to 6 when dependent on claim 2, wherein R ^1a And R is ^1d Is H; and R is ^1b And R is ^1c Is an independently selected halogen, such as-F or-Cl, such as-F; or (b)

Wherein R is ^1a And R is ^1d Is H; r is R ^1b And R is ^1c One of which is H; and R is ^1b And R is ^1c The other of (a) is halogen, e.g. -F or-Cl, e.g. -F; or (b)

Wherein R is ^1a And R is ^1d Is H; r is R ^1c Halogen or H, e.g.)F. -Cl or H; and R is ^1b Is a heteroaryl group having 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S, and wherein the heteroaryl is optionally substituted with 1-4R ^c And (3) substitution.

8. The compound of any one of claims 1-7, wherein ring B is a heteroarylene group having 5 ring atoms, wherein 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, NH, N (R) ^d ) O and S, e.g. N and NH, wherein the heteroarylene of ring B is optionally substituted with 1-2R ^c Substitution, for example:

wherein ring B is selected from the group consisting of: imidazolylene, pyrazolylene or triazolylene, e.g. 1,2, 3-triazolylene, each of which is optionally substituted with 1R ^c Substitution; for example:

wherein the heteroarylene of ring B is selected from:

each of which is optionally substituted with 1R ^c Substitution;

wherein aa is a number equal to (L) ^A ) _a1 Is connected to the connecting point of (c).

9. The compound of any one of claims 1-8, wherein a1 is 0; or wherein a1 is 1, and optionally L ^A Is optionally substituted with 1-2R ^a1 Substituted C _1-3 Alkylene groups, e.g. wherein L ^A Is CH ₂ Or CH (Me).

10. The compound of any one of claims 1-9, wherein ring C is selected from the group consisting of:

heteroarylene having 5 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heteroarylene is optionally taken by 1-4 substituents independently selected from the group consisting ofAnd (3) substitution: r is R ^c And R is ^h The method comprises the steps of carrying out a first treatment on the surface of the And

C _6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c And R is ^h The method comprises the steps of carrying out a first treatment on the surface of the For example:

wherein ring C is selected from the group consisting of:

heteroarylene having 5 to 6 (e.g., 6) ring atoms, wherein 1 to 3 (e.g., 1 to 2) ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c The method comprises the steps of carrying out a first treatment on the surface of the And

c optionally substituted with 1-4 substituents independently selected from the group consisting of ₆ Arylene group: r is R ^c The method comprises the steps of carrying out a first treatment on the surface of the For example:

wherein ring C is selected from the group consisting of:

a pyridinyl group optionally substituted with 1-3 (e.g., 1) substituents independently selected from the group consisting of: r is R ^c The method comprises the steps of carrying out a first treatment on the surface of the And

c optionally substituted with 1-4 (e.g., 1-2) substituents independently selected from the group consisting of ₆ Arylene group: r is R ^c The method comprises the steps of carrying out a first treatment on the surface of the For example:

wherein ring C is a group having the formula:wherein Q is ¹ 、Q ² 、Q ³ And Q ⁴ Each independently selected from the group consisting of: n, CH and CR ^c The method comprises the steps of carrying out a first treatment on the surface of the And bb is with R ⁷ Is connected to the connecting point of (c).

11. The compound of any one of claims 1-10, wherein R ⁷ Selected from the group consisting of:

C _3-12 cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of: oxo, R ^c7 、R ^h And- (L) ^g ) _bg -R ^h The method comprises the steps of carrying out a first treatment on the surface of the And

heterocyclyl having 4 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d )、OAnd S (O) _0-2 And wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: oxo, R ^c7 、R ^h And- (L) ^g ) _bg -R ^h The method comprises the steps of carrying out a first treatment on the surface of the Wherein each R is ^c7 R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the For example:

wherein R is ⁷ Selected from the group consisting of:

C _4-8 cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of: oxo, R ^c7 And R is ^h The method comprises the steps of carrying out a first treatment on the surface of the And

heterocyclyl having 4 to 8 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: oxo, R ^c7 And R is ^h The method comprises the steps of carrying out a first treatment on the surface of the For example:

wherein R is ⁷ Selected from the group consisting of:

heterocyclyl having 6-8 ring atoms, wherein 1-2 (e.g., 1) ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of: r is R ^c7 The method comprises the steps of carrying out a first treatment on the surface of the For example:

wherein R is ⁷ Is a group having the formula:wherein X is ⁷ Is CH, CR ^c7 Or N, such as CH or N; for example:

R ⁷ is a group having the formula:wherein X is ⁷ Is N or CH; and each R is ^c7 R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And optionally, the presence of a metal salt,

wherein each R is ^c7 Is independently selected halogen or is optionally substituted with 1-6R ^a Substituted C _1-3 Alkyl groups, e.g. halogen or C optionally substituted by 1-6 independently selected halogen _1-3 An alkyl group.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound having the formula (I-a 1-1):

wherein:

R ^1a 、R ^1b and R is ^1c Each independently selected R ¹ ；

B ⁴ Is C or N;

13. The compound of claim 1, wherein the compound is selected from the compounds described in table C1 or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound of any one of claims 1-13 and one or more pharmaceutically acceptable excipients.

15. A method of inhibiting STING activity, the method comprising contacting STING with a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition according to claim 14.

16. A method of inducing an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition according to claim 14.

17. A method of treating a disease, disorder or condition associated with STING, for example a disease, disorder or condition in which increased STING signaling (e.g. excessive STING signaling) promotes pathology and/or symptoms and/or progression of the disease (e.g. cancer), comprising administering to a subject in need of such treatment an effective amount of a compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 14.