TW202043198A - Compounds and compositions for treating conditions associated with sting activity - Google Patents

Abstract

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

Description

Compounds and compositions for the treatment of conditions related to STING activity

Cross-reference of related applications

This application claims the U.S. provisional application serial number 62/793,795 filed on January 17, 2019; the U.S. provisional application serial number 62/861,865 filed on June 14, 2019; the U.S. provisional application filed on July 2, 2019 Application serial number 62/869,914; and U.S. provisional application serial number 62/955,891 filed on December 31, 2019, each case is incorporated herein by reference in its entirety.

The present disclosure is characterized by inhibiting (for example, antagonizing) a chemical entity (for example, a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or co-crystal of the interferon gene stimulating protein (STING)) of the interferon gene, and / Or drug combination). These chemical entities can be used, for example, to treat STING activation (such as STING signal transduction) increased (such as excessive) contributing to individual (such as human) disease, disease or disease (such as cancer) pathology and/or symptoms and/or disease conditions, Disease or illness. The present disclosure is also characterized by the composition containing the chemical entities and the method of use and preparation thereof.

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

The STING pathway plays a key role in mediating the recognition of cytoplasmic DNA. In this case, STING, as a transmembrane protein located in the endoplasmic reticulum (ER), acts as the second messenger receptor for 2', 3'cyclic GMP-AMP (hereinafter referred to as cGAMP), which is located in dsDNA Produced by cGAS after combination. In addition, STING can also be used as the main pattern recognition receptor for bacterial cyclic dinucleotides (CDN) and small molecule agonists. The recognition of endogenous or prokaryotic CDNs is carried out via the carboxy-terminal domain of STING, which faces the cytosol and creates a V-shaped binding pocket formed by the homodimer of STING. The ligand-induced activation of STING causes its relocation to the Golgi apparatus, which is an essential process for promoting the interaction between STING and TBK1. This protein complex transmits signals via the transcription factor IRF-3 to induce type I interferon (IFN) and other co-regulated antiviral factors. In addition, it was also shown that STING caused NF-κB and MAP kinase activation. After the initiation of signal transduction, STING is rapidly degraded, and this step is considered to be essential for stopping the inflammatory response.

Excessive activation of STING is associated with a small class of monogenic spontaneous inflammatory conditions, the so-called type I interferon pathology. Examples of these diseases include the clinical syndrome called STING-related infantile onset vascular disease (SAVI), which is caused by a gain-of-function mutation in TMEM173 (the gene name of STING). In addition, STING involves the onset of Aicardi-Goutières Syndrome (AGS) and hereditary lupus. In contrast to SAVI, nucleic acid metabolism disorders are the basis of continuous innate immune activation in AGS. In addition to these genetic disorders, emerging evidence indicates that STING has a more common pathogenic role in many inflammation-related disorders such as systemic lupus erythematosus, rheumatoid arthritis and cancer. Therefore, small molecule-based pharmacological interventions for the STING signal transduction pathway have great potential in the treatment of various diseases.

The present disclosure is characterized by inhibiting (for example, antagonizing) a chemical entity (for example, a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or co-crystal of the interferon gene stimulating protein (STING)) of the interferon gene, and / Or drug combination). These chemical entities can be used, for example, to treat STING activation (such as STING signal transduction) increased (such as excessive) contributing to individual (such as human) disease, disease or disease (such as cancer) pathology and/or symptoms and/or disease conditions, Disease or illness. The present disclosure is also characterized by the composition containing the chemical entities and the method of use and preparation thereof.

The "antagonist" of STING includes compounds that directly bind or modify STING at the protein level, thereby, for example, by inhibiting, blocking or preventing the agonist-mediated response, changing the distribution or otherwise reducing the activity of STING. STING antagonists include chemical entities that interfere with or inhibit STING signaling.

其中A 、B 、W¹ 及W² 可如本文任何地方所定義。In one aspect, the compound characterized by formula ( I ) or a pharmaceutically acceptable salt thereof:

Wherein A , B , W ¹ and W ² can be as defined anywhere in this document.

其中Z 、Y¹ 、Y² 、Y³ 、R⁶ 、B 、R^2N 、L³ 及R⁴ 可如本文任何地方所定義。In another aspect, the compound characterized by formula ( II ) or a pharmaceutically acceptable salt thereof:

Wherein Z , Y ¹ , Y ² , Y ³ , R ⁶ , B , R ^2N , L ³ and R ⁴ can be as defined anywhere in this document.

In one aspect, it is characterized by a pharmaceutical composition, which comprises a chemical entity described herein (for example, a compound described generally or specifically herein or a pharmaceutically acceptable salt or composition containing the same) and one or A variety of pharmaceutically acceptable excipients.

In one aspect, a method for inhibiting (e.g., antagonizing) the activity of STING comprises combining STING with a chemical entity described herein (e.g., a compound described generally or specifically herein or a pharmaceutically acceptable compound thereof). Salt or a composition containing it) contact. The method includes in vitro methods, such as contacting a sample with the chemical entity, the sample includes one or more cells containing STING (such as innate immune cells, such as mast cells, macrophages, dendritic cells (DC), and natural Killer cells). The methods may also include in vivo methods; for example, administering the chemical entity to an individual (such as a human) suffering from a disease in which increased (such as overdose) STING signaling contributes to disease and/or symptoms and/or progression.

In one aspect, it is characterized by a method of treating a condition, disease, or disorder that is improved by antagonizing STING, such as treating a condition, disease, or disorder in which STING activation (eg, STING signaling) increases (eg, excessive) contributes to the individual (eg, human) (Such as cancer) pathology and/or symptoms and/or progressing conditions, diseases or disorders. These methods comprise administering to an individual in need of such treatment an effective amount of a chemical entity described herein (eg, a compound described generally or specifically herein or a pharmaceutically acceptable salt or composition containing the same).

In another aspect, a method characterized by the treatment of cancer, which comprises administering to an individual in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generally or specifically herein or a pharmaceutically Acceptable salts or compositions containing them).

In another aspect, it is characterized by the treatment of other STING-related conditions, such as type I interferon lesions (such as STING-related infantile onset vascular disease (SAVI)), Icardi-Gottiers syndrome (AGS), Methods for hereditary lupus and inflammation-related disorders such as systemic lupus erythematosus and rheumatoid arthritis. These methods comprise administering to an individual in need of such treatment an effective amount of a chemical entity described herein (eg, a compound described generally or specifically herein or a pharmaceutically acceptable salt or composition containing the same).

In another aspect, a method characterized by inhibiting the production of STING-dependent type I interferon in an individual in need thereof comprises administering to the individual an effective amount of a chemical entity described herein (e.g., substantially or The specifically described compound or its pharmaceutically acceptable salt or composition containing it).

In another aspect, it is characterized by a method of treating a disease in which STING activation (such as STING signaling) is increased (such as excessive) that contributes to the disease and/or symptoms and/or progression. These methods comprise administering to an individual in need of such treatment an effective amount of a chemical entity described herein (eg, a compound described generally or specifically herein or a pharmaceutically acceptable salt or composition containing the same).

In another aspect, it is characterized by a method of treatment, which comprises administering to the individual an effective amount of a chemical entity described herein (for example, a compound described generally or specifically herein or a pharmaceutically acceptable salt thereof, or containing it The composition); wherein the individual suffers from (or is susceptible to) STING activation (such as STING signal transduction) increased (such as excessive) contributing to the disease and/or symptoms and/or progression of the disease.

In another aspect, the method of treatment comprises administering to the individual a chemical entity described herein (for example, a compound described generally or specifically herein or a pharmaceutically acceptable salt thereof or a composition containing the same), The chemical system is administered in an amount effective to treat STING activation (for example, STING signal transduction) and increase (for example, excessive) the disease and/or the symptoms and/or the progression of the disease, thereby treating the disease.

Embodiments may include one or more of the following features.

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

The chemical entity can be administered in combination with one or more additional therapeutic agents and/or regimens, which can be used to treat other STING-related conditions, such as type I interferon lesions (such as STING-related infantile Onset of vascular disease (SAVI), Alkadi-Gortiers syndrome (AGS), hereditary lupus, and inflammation-related conditions such as systemic lupus erythematosus and rheumatoid arthritis.

The chemical entity can be combined with one or more additional cancer therapies (such as surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy), or a combination thereof; for example, including administration of one or more (such as two, three , Four, five, six or more) additional chemotherapeutic agents. Non-limiting examples of additional chemotherapeutic agents are selected from alkylating agents (such as cisplatin, carboplatin) (Carboplatin), mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); antimetabolites (Such as azathioprine and/or mercaptopurine); terpenoids (such as vinca alkaloid and/or taxane); such as vincristine, vinblastine ), Vinorelbine (Vinorelbine) and/or Vindesine (Vindesine) Paclitaxel (Taxol), Paclitaxel (Pacllitaxel) and/or Docetaxel (Docetaxel); Topoisomerase (such as type I Topo Isomerase and/or type 2 topoisomerase; for example camptothecins, such as irinotecan and/or topotecan; amsacrine, etoposide (Etoposide), etoposide phosphate and/or teniposide); cytotoxic antibiotics (such as actinomycin, anthracyclines, doxorubicin, daunorubicin) Daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin (Mitomycin)); hormones (such as luteinizing hormone releasing hormone agonists; for example, leuprolidine, goserelin, triptorelin, histrelin, Bicalutamide, flutamide and/or nilutamide); antibodies (such as abciximab, adalimumab, alemtuzumab) ), Alizumab (Atl izumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab Antibodies (Cetuximab), pegylated Ceertolizumab (Ceertolizumab pegol), Daclizumab (Daclizumab), Denosumab (Denosumab), Eculizumab (Eculizumab), Ifazizumab ( Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab ), Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumumab (Panitumuab), Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); Anti-angiogenic agents; cytokines; thrombosis agents; growth inhibitors; anti-worm agents; and immune checkpoint inhibitors targeting immune checkpoint receptors selected from the group consisting of CTLA-4, PD -1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL -10. Transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9-TIM3, phospholipid serine-TIM3, lymphocyte activation gene 3 protein ( LAG3), Class II MHC-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 Ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS , ICOS-ICOS ligand, B7 -H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, lactophilin containing BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86 -CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, neuropil Vegetarian, CD160, CD30 and CD155 (such as CTLA-4 or PD1 or PD-L1).

The individual may have cancer; for example, the individual has experienced and/or is experiencing and/or is about to undergo one or more cancer therapies.

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

The chemical entity can be administered intratumorally.

The methods can further include identifying individuals.

Other embodiments include the embodiments described in the implementation mode and/or the scope of the patent application. Additional definition

To facilitate understanding of the disclosure set forth in this article, many additional terms are defined below. In general, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry and pharmacology described herein are well-known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. The patents, applications, published applications and other publications mentioned throughout this specification and in the appendix are each incorporated herein by reference in their 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, homology 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 it does not have a lasting deleterious effect on the overall health of the individual being treated.

"API" refers to active pharmaceutical ingredients.

As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a chemical entity administered to relieve one or more symptoms of the disease or condition being treated to a certain extent. The result includes alleviating and/or alleviating the signs, symptoms or causes of the disease, or any other desired changes in the biological system. For example, the "effective amount" for therapeutic use is the amount of the composition containing the compound as disclosed herein that is required to clinically significantly reduce the symptoms of the disease. The appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study.

The term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or capsule Seal material. In one embodiment, each component is "pharmaceutically acceptable" in the following sense: it is compatible with other ingredients of the pharmaceutical formulation and is suitable for use in contact with human and animal tissues or organs without excessive toxicity or irritation , Allergic reactions, immunogenicity or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, for example, "Remington: Science and Practice of Pharmacy (Remington: The Science and Practice of Pharmacy)", 21st Edition; Lippincott Williams & Wilkins: Philadelphia, PA (Philadelphia, PA), 2005; " pharmaceutical excipient Handbook (Handbook of pharmaceutical Excipients) ", 6th edition; Rowe et al., eds; pharmaceutical Press and the American Medical Association (The pharmaceutical Press and the American pharmaceutical Association): 2009;" pharmaceutical additives Handbook (Handbook of pharmaceutical additives) ", 3rd Edition ; Ash and Ash ed; Gower Publishing Company: 2007; "pre-deployment and deployment of medicine (pharmaceutical Preformulation and Formulation)", 2nd Edition; Gibson ed; CRC Press LLC: Boca Raton, Florida (Boca Raton, FL), 2009 .

The term "pharmaceutically acceptable salt" refers to a compound formulation that does not produce significant irritation to the organism to which it is administered and does not eliminate the biological activity and properties of the compound. In some cases, pharmaceutically acceptable salts are obtained by combining the compounds described herein with acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid , Salicylic acid and its analogues. In some cases, a pharmaceutically acceptable salt is obtained by reacting a compound having an acidic group described herein with a base to form a salt or by other predetermined methods, such as an ammonium salt; 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-reduced glucosamine, ginseng (hydroxymethyl) Methylamine, and salts with amino acids such as arginine, lysine and the like. The pharmacologically acceptable salt is not particularly limited as long as it can be used for medicine. Examples of the 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 ; Its salts with basic amino acids, such as lysine and ornithine; and ammonium salts. The salt may be an acid addition salt, and specific examples thereof are acid addition salts formed with: 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, propylene 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 aspartame Amino acid and glutamine acid.

The term "pharmaceutical composition" refers to the compound described herein and other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersing agents, suspending agents and/or enhancing agents. Mixture of thickeners. The pharmaceutical composition helps to administer the compound to the organism. There are many techniques for administering compounds in this technology, including but not limited to: rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

The term "individual" refers to animals, including but not limited to primates (such as humans), monkeys, cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. For, for example, mammalian individuals, such as humans, the terms "individual" and "patient" are used interchangeably herein.

In the context of treating a disease or condition, the term "Treat/treating/treatment" is intended to include alleviation or elimination of a disease, disease or condition, or one or more symptoms related to the disease, disease or condition; or slowing down the disease , The progression, spread or worsening of a disease or condition or one or more of its symptoms. "Cancer treatment" refers to one or more of the following effects: (1) inhibit tumor growth to a certain extent, including (i) slowing growth and (ii) complete growth arrest; (2) reducing the number of tumor cells; 3) Maintain tumor size; (4) Reduce tumor size; (5) Inhibit, including (i) reduce, (ii) slow down or (iii) completely prevent tumor cell infiltration into surrounding organs; (6) Inhibit, include (i) reduce, (ii) slow down, or (iii) completely prevent metastasis; (7) enhance anti-tumor immune response, which can (i) maintain tumor size, (ii) reduce tumor size, (iii) slow down Tumor growth, (iv) reducing, slowing down or preventing invasion; and/or (8) reducing the severity or number of one or more symptoms associated with the disease to a certain extent.

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

The term "alkyl" refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms. For example, C _1-10 indicates that the group can have 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, isopropyl, t-butyl, n-hexyl.

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

The term "alkoxy" refers to -O-alkyl (for example -OCH ₃ ).

The term "alkylene" refers to a divalent alkyl group (for example -CH ₂ -).

The term "alkenyl" refers to a straight or branched hydrocarbon chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the specified number of carbon atoms. For example, the C _2-6 indicator group can have 2 to 6 (inclusive) carbon atoms in it.

The term "alkynyl" refers to a straight or branched hydrocarbon chain with one or more carbon-carbon bonds. The alkynyl moiety contains the specified number of carbon atoms. For example, the C _2-6 indicator group can have 2 to 6 (inclusive) carbon atoms in it.

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

As used herein, the term "cycloalkyl" includes those 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 A cyclic hydrocarbon group with 3-6 ring carbons, in which the cycloalkyl group can be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups can include multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl groups include: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, Bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0 ]Octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane and their analogs. Cycloalkyl also includes spirocyclic rings (for example, spirocyclic bicyclic rings, where two rings are connected via only one atom). Non-limiting examples of spirocyclic cycloalkyl groups include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4] Nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane and the like.

As used herein, the term "cycloalkenyl" includes those 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 Partially unsaturated cyclic hydrocarbon groups with 3-6 ring carbons, in which cycloalkenyl groups may be substituted as appropriate. Examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. The cycloalkenyl group can have any degree of saturation, provided that none of the rings in the ring system are aromatic; and the cycloalkenyl group as a whole is not fully saturated. Cycloalkyl groups may include multiple fused rings and/or bridged rings and/or spiro rings.

As used herein, the term "heteroaryl" means having 5 to 20 ring atoms, or having 5, 6, 9, 10, or 14 ring atoms; and having 6, 10, or 14 shared in a ring array π-electron monocyclic, bicyclic, tricyclic or polycyclic group; wherein at least one ring in the system is an aromatic ring (but not necessarily a ring containing heteroatoms, such as tetrahydroisoquinolinyl, such as tetrahydroquinoline Linyl), and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O and S. Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thienyl, pyridyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazole Azolyl, piperanyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazole Group, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[ 2,3-b]pyridyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridyl, pyrazolo[3,4-b]pyridyl, pyrazolo[3,4 -c]pyridyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][ 1,4] dioxane, benzo[d][1,3] dioxol, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydro Benzo[b][1,4]oxathiolane, isoindoline, etc. In some embodiments, the heteroaryl group is selected from thienyl, pyridyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, piperanyl, pyrazinyl and pyrimidinyl.

The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic or polycyclic non-aromatic ring system with 3-16 ring atoms (e.g. 5-8 membered monocyclic ring, 8-12 membered bicyclic ring or 11-14 membered ring Tricyclic ring system), if it is a monocyclic ring, it has 1-3 heteroatoms; if it is a bicyclic ring, it has 1-6 heteroatoms, or if it is tricyclic or polycyclic, it has 1-9 Heteroatoms, which are selected from O, N or S (for example, in the case of monocyclic, bicyclic or tricyclic carbon atoms and 1-3, 1-6 or 1-9 heteroatoms respectively), Wherein 0, 1, 2, or 3 atoms of each ring may be substituted by substituents. Examples of heterocyclic groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl and the like. The heterocyclic group may include multiple fused and bridged rings. Non-limiting examples of fused/bridged heterocyclic groups include: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1] Pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c] Pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0 ]Octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1 .0]Pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo [3.2.0]Heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxo Heterobicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane and the like. Heterocyclic groups also include spirocyclic rings (for example, spirocyclic bicyclic rings, where two rings are connected via only one atom). Non-limiting examples of spirocyclic heterocyclyl groups include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[ 3.5] Nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazespiro[4.5]decane Alkane, 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4 -Oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4 ] Nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5 ]Undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane and the like.

In addition, the atoms constituting the compounds of the embodiments of the present invention are intended to include all isotopic forms of such atoms. As used herein, isotopes include atoms that have the same atomic number but different mass numbers. As a general example and not limitation, hydrogen isotopes include tritium and deuterium, and carbon isotopes include ¹³ C and ¹⁴ C.

涵蓋含有以下部分之互變異構形式：

。類似地，描述為視情況經羥基取代之吡啶基或嘧啶基部分涵蓋吡啶酮或嘧啶酮互變異構形式。In addition, the compounds disclosed generally or specifically herein are intended to include all tautomeric forms. So, for example, a compound containing:

Covers tautomeric forms containing the following parts:

. Similarly, a pyridyl or pyrimidinyl moiety described as optionally substituted with a hydroxyl group encompasses pyridone or pyrimidinone tautomeric forms.

（例如

），其中m1 =0、1、2或3；且m3 =0、1、2或3（例如m1 =0或1；且m3 =0、1或2）。This specification ends with 278 claims, the full text of which is incorporated into this disclosure. For ease of explanation, some variable definitions mention one or more specific request item numbers. For the avoidance of doubt, use phrases such as " A as defined by 25" to mean: A series:

(E.g

), where m1 =0, 1, 2 or 3; and m3 =0, 1, 2 or 3 (for example, m1 =0 or 1; and m3 =0, 1 or 2).

The details of one or more embodiments of the present invention are illustrated in the accompanying drawings and the following embodiments. Other features and advantages of the present invention will be apparent from the specification and drawings as well as the scope of the patent application.

The present disclosure is characterized by inhibiting (for example, antagonizing) a chemical entity (for example, a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or co-crystal of the interferon gene stimulating protein (STING)) of the interferon gene, and / Or drug combination). These chemical entities can be used, for example, to treat STING activation (such as STING signal transduction) increased (such as excessive) contributing to individual (such as human) disease, disease or disease (such as cancer) pathology and/or symptoms and/or disease conditions, Disease or illness. The present disclosure is also characterized by the composition containing the chemical entities and the method of use and preparation thereof. Formula I compound

或其醫藥學上可接受之鹽或其互變異構體， 其中：W¹ 及W² 中之一個係-N(H)-、-N(R^d )-（例如-N(H)-或-N(C_1-3 烷基)-）、-N(H)-(W¹² )-或-N(R^d )-(W¹² )-， 條件是W¹ 及W² 中之一個經由氮原子連接至式I 之C(=O)部分；W¹ 及W² 中之另一個係化學鍵、-O-、-O-(W¹² )-或視情況經1-3個R^a 取代之C₁ -C₆ 伸烷基（例如C₁ -C₃ ，例如CH₂ 、CHR^a 或CR^a ₂ ）； 其中W¹² 係視情況經1-3個R^a 取代之C₁ -C₆ 伸烷基，A 選自由以下組成的群組：(i) 包含5-6個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R¹ )、N(R² )、O、S及S(O)₂ ，且其中1-5個環原子係碳原子，各自獨立地選自由以下組成的群組：C、CH、CR¹ 及CR³ ；及(ii) 包含7-20個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R¹ )、N(R² )、O及S(O)_0-2 ，且其中3-19個環原子係碳原子，各自獨立地選自由以下組成的群組：C、CH、CH₂ 、CR¹ 、CHR¹ 、C(R¹ )₂ 、CR³ 、CHR³ 及C(R³ )₂ ；B 係： (a) C_1-15 烷基，其視情況經1-6個獨立選擇之R^a 取代； (b )  C_3-20 環烷基，其視情況經1-4個R^b 取代； (c )   經1-4個R^c 取代之苯基； (d )  視情況經1-4個R^c 取代之C_8-20 芳基； (e )   包含5-20個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜芳基環視情況經1-4個獨立選擇之R^c 取代；或 (f )   包含3-16個環原子之雜環基，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜環基環視情況經1-4個獨立選擇之R^b 取代；R¹ 係：(i) -(U¹ ) _q -U² ，其中： ●q 係0或1； ●U¹ 係C_1-6 伸烷基，其視情況經1-6個R^a 取代；且 ●U² 係： (a )   C_3-12 環烷基，其視情況經1-4個R^b 取代， (b )  C_6-10 芳基，其視情況經1-4個R^c 取代； (c )   包含5-20個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜芳基環視情況經1-4個獨立選擇之R^c 取代，或 (d )  包含3-12個環原子之雜環基，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜環基環視情況經1-4個獨立選擇之R^b 取代， 或 (ii ) C_1-10 烷基，其視情況經1-6個獨立選擇之R^a 取代；R² 在每次出現時獨立地選自由以下組成的群組： (i ) C_1-6 烷基，其視情況經1-4個獨立選擇之R^a 取代； (ii ) C_3-6 環烷基； (iii )包含3-10個環原子之雜環基，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ； (iv ) -C(O)(C_1-4 烷基)； (v ) -C(O)O(C_1-4 烷基)； (vi ) -CON(R')(R'')； (vii ) -S(O)_1-2 (NR'R'')； (viii ) - S(O)_1-2 (C_1-4 烷基)； (ix ) -OH；及 (x ) C_1-4 烷氧基；R³ 在每次出現時獨立地選自由以下組成的群組：鹵基、氰基、C_2-6 烯基、C_2-6 炔基、視情況經C_3-6 環烷基取代之C_1-4 烷氧基、C_1-4 鹵烷氧基、-S(O)_1-2 (C_1-4 烷基)、-NR^e R^f 、-OH、側氧基、-S(O)_1-2 (NR'R'')、-C_1-4 硫代烷氧基、-NO₂ 、-C(=O)(C_1-4 烷基)、-C(=O)O(C_1-4 烷基)、-C(=O)OH及-C(=O)N(R')(R'')；R^a 在每次出現時獨立地選自由以下組成的群組：-OH；-F；-Cl；-Br；-NR^e R^f ；C_1-4 烷氧基；C_1-4 鹵烷氧基；-C(=O)O(C_1-4 烷基)；-C(=O)(C_1-4 烷基)；-C(=O)OH；-CON(R')(R'')；-S(O)_1-2 (NR'R'')；-S(O)_1-2 (C_1-4 烷基)；氰基；及視情況經1-4個獨立選擇之C_1-4 烷基取代的C_3-6 環烷基；R^b 在每次出現時獨立地選自由以下組成的群組：視情況經1-6個獨立選擇之R^a 取代的C_1-10 烷基；C_1-4 鹵烷基；-OH；側氧基；-F；-Cl；-Br；-NR^e R^f ；C_1-4 烷氧基；C_1-4 鹵烷氧基；-C(=O)(C_1-4 烷基)；-C(=O)O(C_1-4 烷基)；-C(=O)OH；-C(=O)N(R')(R'')；-S(O)_1-2 (NR'R'')；-S(O)_1-2 (C_1-4 烷基)；氰基；及-L¹ -L² -R^h ；R^c 在每次出現時獨立地選自由以下組成的群組： (a)鹵基； (b)氰基； (c) C_1-15 烷基，其視情況經1-6個獨立選擇之R^a 取代； (d) C_2-6 烯基； (e) C_2-6 炔基； (g)視情況經C_1-4 烷氧基取代之C_1-4 烷氧基； (h) C_1-4 鹵烷氧基； (i) -S(O)_1-2 (C_1-4 烷基)； (j) -NR^e R^f ； (k) -OH； (l) -S(O)_1-2 (NR 'R '')； (m)視情況經1-4個鹵基取代之-C_1-4 硫代烷氧基； (n) -NO₂ ； (o) -C(=O)(C_1-4 烷基)； (p) -C(=O)O(C_1-4 烷基)； (q) -C(=O)OH； (r) -C(=O)N(R')(R'')；及 (s)-L¹ -L² -R^h ；R^d 選自由以下組成的群組：C_1-6 烷基；C_3-6 環烷基；-C(O)(C_1-4 烷基)；-C(O)O(C_1-4 烷基)；-CON(R')(R'')；-S(O)_1-2 (NR'R'')；-S(O)_1-2 (C_1-4 烷基)；-OH；及C_1-4 烷氧基；R^e 及R^f 在每次出現時獨立地選自由以下組成的群組：H；C_1-6 烷基；C_1-6 鹵烷基；C_3-6 環烷基；-C(O)(C_1-4 烷基)；-C(O)O(C_1-4 烷基)；-CON(R')(R'')；-S(O)_1-2 (NR'R'')；- S(O)_1-2 (C_1-4 烷基)；-OH；及C_1-4 烷氧基；或R^e 及R^f 連同其各自所連接之氮原子一起形成包含3-8個環原子之環，其中該環包含：(a ) 1-7個環碳原子，其各自經1-2個獨立地選自H及C_1-3 烷基之取代基取代；及(b ) 0-3個環雜原子（除連接至R^e 及R^f 之氮原子外），其各自獨立地選自由以下組成的群組：N(R^d )、NH、O及S； -L¹ 係化學鍵或C_1-3 伸烷基； -L² 係-O-、-N(H)-、-S-或化學鍵；R^h 選自： ●     C_3-8 環烷基，其視情況經1-4個獨立地選自由以下組成的群組之取代基取代：鹵基、C_1-4 烷基及C_1-4 鹵烷基（在某些實施例中，其條件是當R^h 係視情況經1-4個獨立選擇之C_1-4 烷基取代的C_3-6 環烷基時，-L¹ 係化學鍵，或-L² 係-O-、-N(H)-或-S-）； ●     雜環基，其中該雜環基包含3-16個環原子，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，其中該雜環基視情況經1-4個獨立地選自由以下組成的群組之取代基取代：鹵基、C_1-4 烷基及C_1-4 鹵烷基； ●     包含5-10個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜芳基環視情況經1-4個獨立地選自由以下組成的群組之取代基取代：鹵基、C_1-4 烷基及C_1-4 鹵烷基；及 ●     C_6-10 芳基，其視情況經1-4個獨立地選自由以下組成的群組之取代基取代：鹵基、C_1-4 烷基或C_1-4 鹵烷基；且R '及R ''在每次出現時獨立地選自由以下組成的群組：H、C_1-4 烷基、及視情況經1-2個選自鹵基、C_1-4 烷基及C_1-4 鹵烷基之取代基取代的C_6-10 芳基；或R '及R ''連同其各自所連接之氮原子一起形成包含3-8個環原子之環，其中該環包含：(a ) 1-7個環碳原子，其各自經1-2個獨立地選自由H及C_1-3 烷基組成的群組之取代基取代；及(b ) 0-3個環雜原子（除連接至R '及R ''之氮原子外），其各自獨立地選自由以下組成的群組：N(H)、N(R^d )、O及S。In one aspect, the compound characterized by formula ( I ) or a pharmaceutically acceptable salt thereof:

Or a pharmaceutically acceptable salt or tautomer thereof, wherein: one of W ¹ and W ² is -N(H)-, -N( R ^d )- (for example, -N(H)- or -N(C _1-3 alkyl)-), -N(H)-( W ¹² )- or -N( R ^d )-( W ¹² )-, provided that one of W ¹ and W ² passes through nitrogen atom of formula I to C (= O) portion; W ¹ and W ² in the other chemically-based, -O -, - O- (W 12) - or optionally substituted with 1-3 of R ^a C ₁ -C ₆ alkylene (e.g., C ₁ -C _3, e.g. CH _2, CH R ^a or C R ^a _2); wherein W ¹² system optionally substituted with 1-3 of R ^a C ₁ -C ₆ extends Alkyl, A is selected from the group consisting of: (i) Heteroaryl groups containing 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: N , N(H), N( R ¹ ), N( R ² ), O, S and S(O) ₂ , and 1-5 ring atoms are carbon atoms, each independently selected from the following group : C, CH, C R ¹ and C R ³ ; and (ii) a heteroaryl group containing 7-20 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of ：N, N(H), N( R ¹ ), N( R ² ), O and S(O) _0-2 , and 3-19 ring atoms are carbon atoms, each independently selected from the following Group: C, CH, CH ₂ , C R ¹ , CH R ¹ , C( R ¹ ) ₂ , C R ³ , CH R ³ and C( R ³ ) ₂ ; B series: ( a) C _1-15 alkyl, which is optionally substituted with 1-6 independently selected R ^a substituents of; (b) C _3-20 cycloalkyl, which is optionally substituted with 1-4 R ^b; (c) with 1-4 R ^c substituted phenyl; ( d ) optionally substituted by 1-4 R ^c C _8-20 aryl; ( e ) containing 5-20 ring atoms heteroaryl, of which 1-4 ring atoms are Heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O, and S(O) _0-2 , and the heteroaryl ring is optionally separated by 1-4 Alternative R ^c substitution; or ( f ) a heterocyclic group containing 3-16 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H) , N( R ^d ), O and S(O) _0-2 , and the heterocyclic ring is optionally substituted by 1-4 independently selected R ^b ; R ¹ is: (i) -( U ¹ ) _q- U ² , where: ● q is 0 or 1; ● U ¹ is C _1-6 Alkyl, which is optionally substituted with 1-6 substituents R ^a; and ● U ² system: (a) C _3-12 cycloalkyl, which is optionally substituted with 1-4 R ^{b, (b)} C _{6- 10} aryl groups, optionally substituted by 1-4 R ^c ; ( c ) Heteroaryl groups containing 5-20 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the following Group: N, N(H), N( R ^d ), O and S(O) _0-2 , and the heteroaryl ring is optionally substituted by 1-4 independently selected R ^c , or ( d ) includes Heterocyclic groups with 3-12 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S( O) _0-2 , where the heterocyclyl ring is optionally substituted by 1-4 independently selected R ^b , or ( ii ) C _1-10 alkyl, which is optionally substituted by 1-6 independently selected R ^a ; R ² at each occurrence is independently selected from the group consisting of: (i) C _1-6 alkyl, which is optionally substituted with 1-4 independently selected substituents of R ^a; (ii) C _3-6 Cycloalkyl; ( iii ) a heterocyclic group containing 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 ; ( iv ) -C(O)(C _1-4 alkyl); ( v ) -C(O)O(C _1-4 alkyl); ( vi ) -CON(R')(R''); ( vii ) -S(O) _1-2 (NR'R''); ( viii )-S(O) _1-2 (C _1-4 alkane Group); ( ix ) -OH; and ( x ) C _1-4 alkoxy; each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _2-6 alkenyl , C _2-6 alkynyl, optionally C _3-6 cycloalkyl substituted C _1-4 alkoxy, C _1-4 haloalkoxy, -S(O) _1-2 (C _1-4 Alkyl), -N R ^e R ^f , -OH, pendant oxy, -S(O) _1-2 (NR'R''), -C _1-4 thioalkoxy, -NO ₂ ,- C(=O)(C _1-4 alkyl), -C(=O)O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')( R''); R ^a is independently selected from the group consisting of: -OH; -F; -Cl; -Br; -N R ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)O(C _1-4 alkyl); -C(=O)(C _1-4 alkyl); -C(=O)OH; -CON( R')(R''); -S(O ) _1-2 (NR'R''); -S(O) _1-2 (C _1-4 alkyl); cyano; and optionally substituted with 1-4 independently selected C _1-4 alkyl the C _3-6 cycloalkyl; R ^b at each occurrence is independently selected from the group consisting of: optionally substituted with 1-6 independently selected R ^a substituents of C _1-10 alkyl; C _{1- 4-} haloalkyl; -OH; pendant oxy; -F; -Cl; -Br; -NR ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O) (C _1-4 alkyl); -C(=O)O(C _1-4 alkyl); -C(=O)OH; -C(=O)N(R')(R''); -S(O) _1-2 (NR'R''); -S(O) _1-2 (C _1-4 alkyl); cyano; and -L ¹ -L ² -R ^h ; R ^{c is} in is independently selected from the group consisting of groups at each occurrence: (a) halo; (b) cyano; (c) C _1-15 alkyl, which is optionally substituted with 1-6 independently selected R ^a of ; (D) C _2-6 alkenyl; (e) C _2-6 alkynyl; (g) optionally C _1-4 alkoxy substituted by C _1-4 alkoxy; (h) C _{1- 4} -haloalkoxy; (i) -S(O) _1-2 (C _1-4 alkyl); (j) -N R ^e R ^f ; (k) -OH; (l) -S(O) _1-2 (N R ' R ''); (m) -C _1-4 thioalkoxy substituted by 1-4 halo groups as appropriate; (n) -NO ₂ ; (o) -C( =O)(C _1-4 alkyl); (p) -C(=O)O(C _1-4 alkyl); (q) -C(=O)OH; (r) -C(=O )N(R')(R''); and (s) -L ¹ -L ² -R ^h ; R ^{d is} selected from the group consisting of: C _1-6 alkyl; C _3-6 cycloalkyl ; -C(O)(C _1-4 alkyl); -C(O)O(C _1-4 alkyl); -CON(R')(R''); -S(O) _1-2 (NR'R''); -S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; R ^e and R ^f are independently selected for each occurrence Free from the group consisting of: H; C _1-6 alkyl; C _1-6 haloalkyl; C _3-6 cycloalkyl; -C(O)(C _1-4 alkyl); -C(O )O(C _1-4 alkyl); -CON(R')(R''); -S(O) _1-2 (NR'R'');-S(O) _1-2 (C _{1 -4} alkyl); -OH; and C _1-4 alkoxy; or R ^e and R ^f together with the nitrogen atom to which they are each connected form a ring containing 3-8 ring atoms, wherein the ring comprises: ( a ) 1-7 ring carbons Atoms, each of which is substituted with 1-2 substituents independently selected from H and C _1-3 alkyl; and ( b ) 0-3 ring heteroatoms (except for the nitrogen atom connected to R ^e and R ^f ), which are each independently selected from the group consisting of N ( R ^d ), NH, O and S; -L ¹ series chemical bond or C _1-3 alkylene; -L ² series -O-, -N (H)-, -S- or chemical bond; R ^{h is} selected from: ● C _3-8 cycloalkyl, optionally substituted by 1-4 substituents independently selected from the group consisting of halo, C _1-4 alkyl and C _1-4 haloalkyl (in certain embodiments, the condition is that when R ^h is optionally substituted with 1-4 independently selected C _1-4 alkyl groups, C _{3- In the case of 6} cycloalkyl, -L ¹ is a chemical bond, or -L ² is -O-, -N(H)- or -S-); ● Heterocyclic group, wherein the heterocyclic group contains 3-16 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 , wherein the heterocyclic ring The group is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C _1-4 alkyl and C _1-4 haloalkyl; ● Hetero groups containing 5-10 ring atoms Aryl groups, in which 1-4 ring atoms are heteroatoms, are each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 , and wherein The heteroaryl ring is optionally substituted with _1-4 substituents independently selected from the group consisting of halo, C _1-4 alkyl and C _1-4 haloalkyl; and C _6-10 aryl , Which is optionally substituted with _1-4 substituents independently selected from the group consisting of halo, C _1-4 alkyl or C _1-4 haloalkyl; and R 'and R '' are in each The second occurrence is independently selected from the group consisting of: H, C _1-4 alkyl, and optionally 1-2 selected from halo, C _1-4 alkyl and C _1-4 haloalkyl A C _6-10 aryl group substituted by a substituent; or R ′ and R ″ together with the nitrogen atom to which they are each connected form a ring containing 3-8 ring atoms, wherein the ring contains: ( a ) 1-7 Ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C _1-3 alkyl groups; and ( b ) 0-3 ring heteroatoms (except connected to R'and R '' outside the nitrogen atom), which are each independently selected from the group consisting of N(H), N( R ^d ), O and S.

或其醫藥學上可接受之鹽或其互變異構體， 其中：W¹ 及W² 中之一個係-N(H)-、-N(R^d )-（例如-N(H)-或-N(C_1-3 烷基)-）、-N(H)-(W¹² )-或-N(R^d )-(W¹² )-， 條件是W¹ 及W² 中之一個經由氮原子連接至式I 之C(=O)部分；W¹ 及W² 中之另一個係化學鍵、-O-、-O-(W¹² )-或視情況經1-3個R^a 取代之C₁ -C₆ 伸烷基（例如C₁ -C₃ ，例如CH₂ 、CHR^a 或CR^a ₂ ）； 其中W¹² 係視情況經1-3個R^a 取代之C₁ -C₆ 伸烷基，A 選自由以下組成的群組：(i) 包含5-6個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R¹ )、N(R² )、O、S及S(O)₂ ，且其中1-5個環原子係碳原子，各自獨立地選自由以下組成的群組：C、CH、CR¹ 及CR³ ；及(ii) 包含7-20個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R¹ )、N(R² )、O及S(O)_0-2 ，且其中3-19個環原子係碳原子，各自獨立地選自由以下組成的群組：C、CH、CH₂ 、CR¹ 、CHR¹ 、C(R¹ )₂ 、CR³ 、CHR³ 及C(R³ )₂ ；B 係： (a) C_1-15 烷基，其視情況經1-6個獨立選擇之R^a 取代； (b )  C_3-20 環烷基，其視情況經1-4個R^b 取代； (c )   經1-4個R^c 取代之苯基； (d )  視情況經1-4個R^c 取代之C_8-20 芳基； (e )   包含5-20個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜芳基環視情況經1-4個獨立選擇之R^c 取代；或 (f )   包含3-16個環原子之雜環基，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜環基環視情況經1-4個獨立選擇之R^b 取代；R¹ 係：(i) -(U¹ ) _q -U² ，其中： ●q 係0或1； ●U¹ 係C_1-6 伸烷基，其視情況經1-6個R^a 取代；且 ●U² 係： (a )   C_3-12 環烷基，其視情況經1-4個R^b 取代， (b )  C_6-10 芳基，其視情況經1-4個R^c 取代； (c )   包含5-20個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜芳基環視情況經1-4個獨立選擇之R^c 取代，或 (d )  包含3-12個環原子之雜環基，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜環基環視情況經1-4個獨立選擇之R^b 取代， 或 (ii ) C_1-10 烷基，其視情況經1-6個獨立選擇之R^a 取代；R² 在每次出現時獨立地選自由以下組成的群組： (i ) C_1-6 烷基，其視情況經1-4個獨立選擇之R^a 取代； (ii ) C_3-6 環烷基； (iii )包含3-10個環原子之雜環基，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ； (iv ) -C(O)(C_1-4 烷基)； (v ) -C(O)O(C_1-4 烷基)； (vi ) -CON(R')(R'')； (vii ) -S(O)_1-2 (NR'R'')； (viii ) - S(O)_1-2 (C_1-4 烷基)； (ix ) -OH；及 (x ) C_1-4 烷氧基；R³ 在每次出現時獨立地選自由以下組成的群組：鹵基、氰基、C_2-6 烯基、C_2-6 炔基、C_1-4 烷氧基、C_1-4 鹵烷氧基、-S(O)_1-2 (C_1-4 烷基)、-NR^e R^f 、-OH、側氧基、-S(O)_1-2 (NR'R'')、-C_1-4 硫代烷氧基、-NO₂ 、-C(=O)(C_1-4 烷基)、-C(=O)O(C_1-4 烷基)、-C(=O)OH及-C(=O)N(R')(R'')；R^a 在每次出現時獨立地選自由以下組成的群組：-OH；-F；-Cl；-Br；-NR^e R^f ；C_1-4 烷氧基；C_1-4 鹵烷氧基；-C(=O)O(C_1-4 烷基)；-C(=O)(C_1-4 烷基)；-C(=O)OH；-CON(R')(R'')；-S(O)_1-2 (NR'R'')；-S(O)_1-2 (C_1-4 烷基)；氰基；及視情況經1-4個獨立選擇之C_1-4 烷基取代的C_3-6 環烷基；R^b 在每次出現時獨立地選自由以下組成的群組：視情況經1-6個獨立選擇之R^a 取代的C_1-10 烷基；C_1-4 鹵烷基；-OH；側氧基；-F；-Cl；-Br；-NR^e R^f ；C_1-4 烷氧基；C_1-4 鹵烷氧基；-C(=O)(C_1-4 烷基)；-C(=O)O(C_1-4 烷基)；-C(=O)OH；-C(=O)N(R')(R'')；-S(O)_1-2 (NR'R'')；-S(O)_1-2 (C_1-4 烷基)；氰基；及-L¹ -L² -R^h ；R^c 在每次出現時獨立地選自由以下組成的群組： (a)鹵基； (b)氰基； (c) C_1-15 烷基，其視情況經1-6個獨立選擇之R^a 取代； (d) C_2-6 烯基； (e) C_2-6 炔基； (g) C_1-4 烷氧基； (h) C_1-4 鹵烷氧基； (i) -S(O)_1-2 (C_1-4 烷基)； (j) -NR^e R^f ； (k) -OH； (l) -S(O)_1-2 (NR 'R '')； (m) -C_1-4 硫代烷氧基； (n) -NO₂ ； (o) -C(=O)(C_1-4 烷基)； (p) -C(=O)O(C_1-4 烷基)； (q) -C(=O)OH； (r) -C(=O)N(R')(R'')；及 (s)-L¹ -L² -R^h ；R^d 選自由以下組成的群組：C_1-6 烷基；C_3-6 環烷基；-C(O)(C_1-4 烷基)；-C(O)O(C_1-4 烷基)；-CON(R')(R'')；-S(O)_1-2 (NR'R'')；- S(O)_1-2 (C_1-4 烷基)；-OH；及C_1-4 烷氧基；R^e 及R^f 在每次出現時獨立地選自由以下組成的群組：H；C_1-6 烷基；C_1-6 鹵烷基；C_3-6 環烷基；-C(O)(C_1-4 烷基)；-C(O)O(C_1-4 烷基)；-CON(R')(R'')；-S(O)_1-2 (NR'R'')；- S(O)_1-2 (C_1-4 烷基)；-OH；及C_1-4 烷氧基；或R^e 及R^f 連同其各自所連接之氮原子一起形成包含3-8個環原子之環，其中該環包含：(a ) 1-7個環碳原子，其各自經1-2個獨立地選自H及C_1-3 烷基之取代基取代；及(b ) 0-3個環雜原子（除連接至R^e 及R^f 之氮原子外），其各自獨立地選自由以下組成的群組：N(R^d )、NH、O及S； -L¹ 係化學鍵或C_1-3 伸烷基； -L² 係-O-、-N(H)-、-S-或化學鍵；R^h 選自： ●     C_3-8 環烷基，其視情況經1-4個獨立地選自由以下組成的群組之取代基取代：鹵基、C_1-4 烷基及C_1-4 鹵烷基（在某些實施例中，其條件是當R^h 係視情況經1-4個獨立選擇之C_1-4 烷基取代的C_3-6 環烷基時，-L¹ 係化學鍵，或-L² 係-O-、-N(H)-或-S-）； ●     雜環基，其中該雜環基包含3-16個環原子，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，其中該雜環基視情況經1-4個獨立地選自由以下組成的群組之取代基取代：鹵基、C_1-4 烷基及C_1-4 鹵烷基； ●     包含5-10個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜芳基環視情況經1-4個獨立地選自由以下組成的群組之取代基取代：鹵基、C_1-4 烷基及C_1-4 鹵烷基；及 ●     C_6-10 芳基，其視情況經1-4個獨立地選自由以下組成的群組之取代基取代：鹵基、C_1-4 烷基或C_1-4 鹵烷基；且R '及R ''在每次出現時獨立地選自由以下組成的群組：H、C_1-4 烷基、及視情況經1-2個選自鹵基、C_1-4 烷基及C_1-4 鹵烷基之取代基取代的C_6-10 芳基；或R '及R ''連同其各自所連接之氮原子一起形成包含3-8個環原子之環，其中該環包含：(a ) 1-7個環碳原子，其各自經1-2個獨立地選自由H及C_1-3 烷基組成的群組之取代基取代；及(b ) 0-3個環雜原子（除連接至R '及R ''之氮原子外），其各自獨立地選自由以下組成的群組：N(H)、N(R^d )、O及S。In one aspect, the compound characterized by formula ( I ) or a pharmaceutically acceptable salt thereof:

Or a pharmaceutically acceptable salt or tautomer thereof, wherein: one of W ¹ and W ² is -N(H)-, -N( R ^d )- (for example, -N(H)- or -N(C _1-3 alkyl)-), -N(H)-( W ¹² )- or -N( R ^d )-( W ¹² )-, provided that one of W ¹ and W ² passes through nitrogen atom of formula I to C (= O) portion; W ¹ and W ² in the other chemically-based, -O -, - O- (W 12) - or optionally substituted with 1-3 of R ^a C ₁ -C ₆ alkylene (e.g., C ₁ -C _3, e.g. CH _2, CH R ^a or C R ^a _2); wherein W ¹² system optionally substituted with 1-3 of R ^a C ₁ -C ₆ extends Alkyl, A is selected from the group consisting of: (i) Heteroaryl groups containing 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: N , N(H), N( R ¹ ), N( R ² ), O, S and S(O) ₂ , and 1-5 ring atoms are carbon atoms, each independently selected from the following group : C, CH, C R ¹ and C R ³ ; and (ii) a heteroaryl group containing 7-20 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of ：N, N(H), N( R ¹ ), N( R ² ), O and S(O) _0-2 , and 3-19 ring atoms are carbon atoms, each independently selected from the following Group: C, CH, CH ₂ , C R ¹ , CH R ¹ , C( R ¹ ) ₂ , C R ³ , CH R ³ and C( R ³ ) ₂ ; B series: ( a) C _1-15 alkyl, which is optionally substituted with 1-6 independently selected R ^a substituents of; (b) C _3-20 cycloalkyl, which is optionally substituted with 1-4 R ^b; (c) with 1-4 R ^c substituted phenyl; ( d ) optionally substituted by 1-4 R ^c C _8-20 aryl ; ( e ) containing 5-20 ring atoms heteroaryl, of which 1-4 ring atoms are Heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O, and S(O) _0-2 , and the heteroaryl ring is optionally separated by 1-4 Alternative R ^c substitution; or ( f ) a heterocyclic group containing 3-16 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H) , N( R ^d ), O and S(O) _0-2 , and the heterocyclic ring is optionally substituted by 1-4 independently selected R ^b ; R ¹ is: (i) -( U ¹ ) _q- U ² , where: ● q is 0 or 1; ● U ¹ is C _1-6 Alkyl, which is optionally substituted with 1-6 substituents R ^a; and ● U ² system: (a) C _3-12 cycloalkyl, which is optionally substituted with 1-4 R ^{b, (b)} C _{6- 10} aryl groups, optionally substituted by 1-4 R ^c ; ( c ) Heteroaryl groups containing 5-20 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the following Group: N, N(H), N( R ^d ), O and S(O) _0-2 , and the heteroaryl ring is optionally substituted by 1-4 independently selected R ^c , or ( d ) includes Heterocyclic groups with 3-12 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S( O) _0-2 , where the heterocyclyl ring is optionally substituted by 1-4 independently selected R ^b , or ( ii ) C _1-10 alkyl, which is optionally substituted by 1-6 independently selected R ^a ; R ² at each occurrence is independently selected from the group consisting of: (i) C _1-6 alkyl, which is optionally substituted with 1-4 independently selected substituents of R ^a; (ii) C _3-6 Cycloalkyl; ( iii ) a heterocyclic group containing 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 ; ( iv ) -C(O)(C _1-4 alkyl); ( v ) -C(O)O(C _1-4 alkyl); ( vi ) -CON(R')(R''); ( vii ) -S(O) _1-2 (NR'R''); ( viii )-S(O) _1-2 (C _1-4 alkane Group); ( ix ) -OH; and ( x ) C _1-4 alkoxy; each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _2-6 alkenyl , C _2-6 alkynyl, C _1-4 alkoxy, C _1-4 haloalkoxy, -S(O) _1-2 (C _1-4 alkyl), -N R ^e R ^f ,- OH, pendant oxy, -S(O) _1-2 (NR'R''), -C _1-4 thioalkoxy, -NO ₂ , -C(=O)(C _1-4 alkyl ), -C(=O)O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R''); R ^a in each occurrence Independently selected from the group consisting of: -OH; -F; -Cl; -Br; -N R ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(= O)O(C _1-4 alkyl); -C(=O)(C _1-4 alkyl); -C(=O)OH; -CON(R')(R''); -S( O) _1-2 (NR'R''); -S(O) _1-2 (C _1-4 alkyl); cyano; and optionally C _3-6 cycloalkyl substituted with 1-4 independently selected C _1-4 alkyl groups; R ^{b is} in is independently selected from the group consisting of, at each occurrence the group: optionally substituted with 1-6 independently selected R ^a substituents of C _1-10 alkyl; C _1-4 haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)(C _1-4 alkyl); -C( =O)O(C _1-4 alkyl); -C(=O)OH; -C(=O)N(R')(R''); -S(O) _1-2 (NR'R ''); -S(O) _1-2 (C _1-4 alkyl); cyano; and -L ¹ -L ² -R ^h ; R ^c is independently selected from the group consisting of: group: (a) halo; (b) cyano; (c) C _1-15 alkyl, which is optionally substituted with 1-6 independently selected of R ^a; (d) C _2-6 alkenyl group; ( e) C _2-6 alkynyl; (g) C _1-4 alkoxy; (h) C _1-4 haloalkoxy; (i) -S(O) _1-2 (C _1-4 alkyl ); (j) -N R ^e R ^f ; (k) -OH; (l) -S(O) _1-2 (N R ' R ''); (m) -C _1-4 thioalkoxy Group; (n) -NO ₂ ; (o) -C(=O)(C _1-4 alkyl); (p) -C(=O)O(C _1-4 alkyl); (q)- C(=O)OH; (r) -C(=O)N(R')(R''); and (s) -L ¹ -L ² -R ^h ; R ^{d is} selected from the following group ：C _1-6 alkyl; C _3-6 cycloalkyl; -C(O)(C _1-4 alkyl); -C(O)O(C _1-4 alkyl); -CON(R')(R''); -S(O) _1-2 (NR'R''); -S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy R ^e and R ^f are independently selected from the group consisting of: H; C _1-6 alkyl; C _1-6 haloalkyl; C _3-6 cycloalkyl; -C( O)(C _1-4 alkyl); -C(O)O(C _1-4 alkyl); -CON(R')(R''); -S(O) _1-2 (NR'R ''); -S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; or R ^e and R ^f together with the nitrogen atom to which they are each connected to form the inclusion A ring of 3-8 ring atoms, wherein the ring comprises: ( a ) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from H and C _1-3 alkyl; and ( b ) 0 -3 ring heteroatoms (except the nitrogen atom connected to R ^e and R ^f ), each independently selected from the group consisting of N ( R ^d ), NH, O and S; -L ¹ is a chemical bond Or C _1-3 alkylene; -L ² is -O-, -N(H)-, -S- or chemical bond; R ^{h is} selected from: ● C _3-8 cycloalkyl, which is optionally controlled by 1- Four substituents independently selected from the group consisting of halo, C _1-4 alkyl and C _1-4 haloalkyl (in certain embodiments, the proviso is that when R ^h is optional When the C _3-6 cycloalkyl group is substituted with 1-4 independently selected C _1-4 alkyl groups, -L ¹ is a chemical bond, or -L ² is -O-, -N(H)- or -S- ); ● Heterocyclic group, wherein the heterocyclic group contains 3-16 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N ( R ^d ), O and S(O) _0-2 , wherein the heterocyclic group is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C _1-4 alkyl And C _1-4 haloalkyl; ● Heteroaryl groups containing 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H) , N( R ^d ), O and S(O) _0-2 , and the heteroaryl ring is optionally substituted with _1-4 substituents independently selected from the group consisting of halo, C _1-4 Alkyl and C _1-4 haloalkyl; and C _6-10 aryl, optionally substituted with _1-4 substituents independently selected from the group consisting of halo, C _1-4 alkane Group or C _1-4 haloalkyl; and R 'and R ″ are independently selected from the group consisting of H, C _1-4 alkyl, and optionally 1-2 selected at each occurrence. A C _6-10 aryl group substituted with substituents of halo, C _1-4 alkyl and C _1-4 haloalkyl; or R ′ and R ″ together with the nitrogen atom to which they are each connected to form a 3- A ring of 8 ring atoms, wherein the ring contains: ( a ) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C _1-3 alkyl ; And ( b ) 0-3 ring heteroatoms (except for the nitrogen atoms connected to R'and R ''), each independently selected from the group consisting of: N(H), N( R ^d ) , O and S.

Embodiments may include any one or more of the features described below and/or in the scope of the patent application.

或其醫藥學上可接受之鹽或其互變異構體， 其中：W¹ 及W² 中之一個係-N(H)-、-N(R^d )-（例如-N(H)-或-N(C_1-3 烷基)-）、-N(H)-(W¹² )-或-N(R^d )-(W¹² )-，W¹ 及W² 中之另一個係化學鍵、-O-、-O-(W¹² )-*、-(W¹² )-O-*、-(W¹² )-N(H)-*或-(W¹² ) -N(R^d )-*，或視情況經1-3個R^a 取代之C₁ -C₆ 伸烷基（例如C₁ -C₃ ，例如CH₂ 、CHR^a 或CR^a ₂ ），其中星號表示與B 之連接點； 條件是W¹ 及W² 中之一個經由氮原子連接至式I 之C(=O)部分； 其中W¹² 係視情況經1-3個R^a 取代之C₁ -C₆ 伸烷基，A 選自由以下組成的群組：(i) 包含5-6個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R¹ )、N(R² )、O、S及S(O)₂ ，且其中1-5個環原子係碳原子，各自獨立地選自由以下組成的群組：C、CH、CR¹ 及CR³ ；及(ii) 包含7-20個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R¹ )、N(R² )、O及S(O)_0-2 ，且其中3-19個環原子係碳原子，各自獨立地選自由以下組成的群組：C、CH、CH₂ 、CR¹ 、CHR¹ 、C(R¹ )₂ 、CR³ 、CHR³ 及C(R³ )₂ ；B 係： (a) C_1-15 烷基，其視情況經1-6個獨立選擇之R^a 取代； (b )  C_3-20 環烷基，其視情況經1-4個R^b 取代； (c )   經1-4個R^c 取代之苯基； (d )  視情況經1-4個R^c 取代之C_8-20 芳基； (e )   包含5-20個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜芳基環視情況經1-4個獨立選擇之R^c 取代；或 (f )   包含3-16個環原子之雜環基，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜環基環視情況經1-4個獨立選擇之R^b 取代；R¹ 係：(i) -(U¹ ) _q -U² ，其中： ●q 係0或1； ●U¹ 係C_1-6 伸烷基，其視情況經1-6個R^a 取代；且 ●U² 係： (a )   C_3-12 環烷基，其視情況經1-4個R^b 取代， (b )  C_6-10 芳基，其視情況經1-4個R^c 取代； (c )   包含5-20個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜芳基環視情況經1-4個獨立選擇之R^c 取代，或 (d )  包含3-12個環原子之雜環基，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜環基環視情況經1-4個獨立選擇之R^b 取代， 或 (ii ) C_1-10 烷基，其視情況經1-6個獨立選擇之R^a 取代；R² 在每次出現時獨立地選自由以下組成的群組： (i ) C_1-6 烷基，其視情況經1-4個獨立選擇之R^a 取代； (ii ) C_3-6 環烷基； (iii )包含3-10個環原子之雜環基，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ； (iv ) -C(O)(C_1-4 烷基)； (v ) -C(O)O(C_1-4 烷基)； (vi ) -CON(R')(R'')； (vii ) -S(O)_1-2 (NR'R'')； (viii ) - S(O)_1-2 (C_1-4 烷基)； (ix ) -OH；及 (x ) C_1-4 烷氧基；R³ 在每次出現時獨立地選自由以下組成的群組：鹵基、氰基、C_2-6 烯基、C_2-6 炔基、視情況經C_3-6 環烷基取代之C_1-4 烷氧基、C_1-4 鹵烷氧基、-S(O)_1-2 (C_1-4 烷基)、-NR^e R^f 、-OH、側氧基、-S(O)_1-2 (NR'R'')、-C_1-4 硫代烷氧基、-NO₂ 、-C(=O)(C_1-4 烷基)、-C(=O)O(C_1-4 烷基)、-C(=O)OH及-C(=O)N(R')(R'')；R^a 在每次出現時獨立地選自由以下組成的群組：-OH；-F；-Cl；-Br；-NR^e R^f ；C_1-4 烷氧基；C_1-4 鹵烷氧基；-C(=O)O(C_1-4 烷基)；-C(=O)(C_1-4 烷基)；-C(=O)OH；-CON(R')(R'')；-S(O)_1-2 (NR'R'')；-S(O)_1-2 (C_1-4 烷基)；氰基；及視情況經1-4個獨立選擇之C_1-4 烷基取代的C_3-6 環烷基；R^b 在每次出現時獨立地選自由以下組成的群組：視情況經1-6個獨立選擇之R^a 取代的C_1-10 烷基；C_1-4 鹵烷基；-OH；側氧基；-F；-Cl；-Br；-NR^e R^f ；C_1-4 烷氧基；C_1-4 鹵烷氧基；-C(=O)(C_1-4 烷基)；-C(=O)O(C_1-4 烷基)；-C(=O)OH；-C(=O)N(R')(R'')；-S(O)_1-2 (NR'R'')；-S(O)_1-2 (C_1-4 烷基)；氰基；及-L¹ -L² -R^h ；R^c 在每次出現時獨立地選自由以下組成的群組： (a)鹵基； (b)氰基； (c) C_1-15 烷基，其視情況經1-6個獨立選擇之R^a 取代； (d) C_2-6 烯基； (e) C_2-6 炔基； (g)視情況經C_1-4 烷氧基取代之C_1-4 烷氧基； (h) C_1-4 鹵烷氧基； (i) -S(O)_1-2 (C_1-4 烷基)； (j) -NR^e R^f ； (k) -OH； (l) -S(O)_1-2 (NR 'R '')； (m)視情況經1-4個鹵基取代之-C_1-4 硫代烷氧基； (n) -NO₂ ； (o) -C(=O)(C_1-4 烷基)； (p) -C(=O)O(C_1-4 烷基)； (q) -C(=O)OH； (r) -C(=O)N(R')(R'')；及 (s)-L¹ -L² -R^h ；R^d 選自由以下組成的群組：C_1-6 烷基；C_3-6 環烷基；-C(O)(C_1-4 烷基)；-C(O)O(C_1-4 烷基)；-CON(R')(R'')；-S(O)_1-2 (NR'R'')；- S(O)_1-2 (C_1-4 烷基)；-OH；及C_1-4 烷氧基；R^e 及R^f 在每次出現時獨立地選自由以下組成的群組：H；C_1-6 烷基；C_1-6 鹵烷基；C_3-6 環烷基；-C(O)(C_1-4 烷基)；-C(O)O(C_1-4 烷基)；-CON(R')(R'')；-S(O)_1-2 (NR'R'')；- S(O)_1-2 (C_1-4 烷基)；-OH；及C_1-4 烷氧基；或R^e 及R^f 連同其各自所連接之氮原子一起形成包含3-8個環原子之環，其中該環包含：(a ) 1-7個環碳原子，其各自經1-2個獨立地選自H及C_1-3 烷基之取代基取代；及(b ) 0-3個環雜原子（除連接至R^e 及R^f 之氮原子外），其各自獨立地選自由以下組成的群組：N(R^d )、NH、O及S； -L¹ 係化學鍵或C_1-3 伸烷基； -L² 係-O-、-N(H)-、-S-或化學鍵；R^h 選自： ●     C_3-8 環烷基，其視情況經1-4個獨立選擇之R^h '取代（在某些實施例中，其條件是當R^h 係視情況經1-4個獨立選擇之C_1-4 烷基取代的C_3-6 環烷基時，-L¹ 係化學鍵，或-L² 係-O-、-N(H)-或-S-）； ●     雜環基，其中該雜環基包含3-16個環原子，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，其中該雜環基視情況經1-4個獨立選擇之R^h '取代； ●     包含5-10個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜芳基環視情況經1-4個獨立選擇之R^h '取代；及 ●     C_6-10 芳基，其視情況經1-4個獨立選擇之R^h '取代； 其中各R^h '獨立地選自由以下組成的群組：鹵基；-CN；-NO₂ ；-OH；視情況經1-2個獨立選擇之R^a 取代的-C_1-4 烷基；-C_2-4 烯基；-C_2-4 炔基；-C_1-4 鹵烷基；視情況經1-2個獨立選擇之R^a 取代的-C_1-6 烷氧基；-C_1-6 鹵烷氧基；S(O)_1-2 (C_1-4 烷基)；-NR 'R ''；側氧基；-S(O)_1-2 (NR 'R '')；-C_1-4 硫代烷氧基；-C(=O)(C_1-4 烷基)；-C(=O)O(C_1-4 烷基)；-C(=O)OH；及-C(=O)N(R ')(R '')；R '及R ''在每次出現時獨立地選自由以下組成的群組：H、C_1-4 烷基、及視情況經1-2個選自鹵基、C_1-4 烷基及C_1-4 鹵烷基之取代基取代的C_6-10 芳基；或R '及R ''連同其各自所連接之氮原子一起形成包含3-8個環原子之環，其中該環包含：(a ) 1-7個環碳原子，其各自經1-2個獨立地選自由H及C_1-3 烷基組成的群組之取代基取代；及(b ) 0-3個環雜原子（除連接至R '及R ''之氮原子外），其各自獨立地選自由以下組成的群組：N(H)、N(R^d )、O及S。In one aspect, the compound characterized by formula ( I ) or a pharmaceutically acceptable salt thereof:

Or a pharmaceutically acceptable salt or tautomer thereof, wherein: one of W ¹ and W ² is -N(H)-, -N( R ^d )- (for example, -N(H)- or -N(C _1-3 alkyl)-), -N(H)-( W ¹² )- or -N( R ^d )-( W ¹² )-, the other of W ¹ and W ² is a chemical bond, -O-, -O-( W ¹² )-*, -( W ¹² )-O-*,- (W ¹² )-N(H)-* or -( W ¹² ) -N( R ^d )-* or optionally substituted with 1-3 of R ^a C ₁ -C ₆ alkylene (e.g., C ₁ -C _3, e.g. CH _2, CH R ^a or C R ^a _2), where the asterisk indicates attachment of B Point; provided that one of W ¹ and W ² is connected to the C(=O) moiety of formula I via a nitrogen atom; wherein W ¹² is ^a C ₁ -C ₆ alkylene group substituted with 1-3 R ^{a as appropriate} , A is selected from the group consisting of: (i) Heteroaryl groups containing 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N (H), N( R ¹ ), N( R ² ), O, S, and S(O) ₂ , and 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of: C , CH, C R ¹ and C R ³ ; and (ii) a heteroaryl group containing 7-20 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: N , N(H), N( R ¹ ), N( R ² ), O and S(O) _0-2 , and 3-19 ring atoms are carbon atoms, each independently selected from the following group ：C, CH, CH ₂ , C R ¹ , CH R ¹ , C( R ¹ ) ₂ , C R ³ , CH R ³ and C( R ³ ) ₂ ; B series: ( a) C _1-15 alkyl , which is optionally substituted with 1-6 independently selected of R ^a; (b) C _3-20 cycloalkyl, which is optionally substituted with 1-4 R ^b; (c) substituted with 1-4 R ^c ( D ) C _8-20 aryl group optionally substituted by 1-4 R ^c ; ( e ) Heteroaryl group containing 5-20 ring atoms, of which 1-4 ring atoms are heteroatoms , Each independently selected from the group consisting of: N, N(H), N( R ^d ), O and S(O) _0-2 , and the heteroaryl ring is optionally selected from 1-4 independently R ^c substituted; or ( f ) a heterocyclic group containing 3-16 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N ( R ^d ), O, and S(O) _0-2 , and the heterocyclic ring may optionally undergo 1 -4 independently selected R ^b substitutions; R ¹ is: (i) -( U ¹ ) _q - U ² , where: ● q is 0 or 1; ● U ¹ is a C _1-6 alkylene group, which depends on substituted with 1-6 substituents R ^a; and ● U ² system: (a) C _3-12 cycloalkyl, which is optionally substituted with 1-4 R ^{b, (b)} C _6-10 aryl group which Optionally substituted by 1-4 R ^c ; ( c ) Heteroaryl groups containing 5-20 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N( R ^d ), O and S(O) _0-2 , and the heteroaryl ring is optionally substituted with 1-4 independently selected R ^c , or ( d ) contains 3-12 rings A heterocyclic group of 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 ring is optionally substituted by 1-4 independently selected R ^b , or ( ii ) C _1-10 alkyl, which is optionally substituted by 1-6 independently selected R ^a ; R ² in each is independently selected from the group consisting of occurrences when a group: (i) C _1-6 alkyl, which is optionally substituted with 1-4 independently selected of R ^a; (ii) C _3-6 cycloalkyl; ( iii ) A heterocyclic group containing 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O And S(O) _0-2 ; ( iv ) -C(O)(C _1-4 alkyl); ( v ) -C(O)O(C _1-4 alkyl); ( vi ) -CON( R')(R''); ( vii ) -S(O) _1-2 (NR'R''); ( viii )-S(O) _1-2 (C _1-4 alkyl); ( ix ) -OH; and ( x ) C _1-4 alkoxy; R ³ is independently selected from the group consisting of: halo, cyano, C _2-6 alkenyl, C _2-6 each time it occurs Alkynyl, C _1-4 alkoxy substituted by C _3-6 cycloalkyl, C _1-4 haloalkoxy, -S(O) _1-2 (C _1-4 alkyl),- N R ^e R ^f , -OH, pendant oxy, -S(O) _1-2 (NR'R''), -C _1-4 thioalkoxy, -NO ₂ , -C(=O) (C _1-4 alkyl), -C(=O)O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R''); Each occurrence of ^Ra is independently selected from the group consisting of: -OH; -F; -Cl; -Br; -N R ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)O(C _1-4 alkyl); -C(=O)(C _1-4 alkyl); -C(=O)OH; -CON( R')(R''); -S(O) _1-2 (NR'R''); -S(O) _1-2 (C _1-4 alkyl); cyano; and optionally through 1 -4 independently selected C _1-4 alkyl substituted C _3-6 cycloalkyls; each occurrence of R ^b is independently selected from the group consisting of: 1-6 independently selected R as the case may be ^a substituted C _1-10 alkyl; C _1-4 haloalkyl; -OH; pendant oxy; -F; -Cl; -Br; -NR ^e R ^f ; C _1-4 alkoxy; C _{1 -4} haloalkoxy; -C(=O)(C _1-4 alkyl); -C(=O)O(C _1-4 alkyl); -C(=O)OH; -C(= O)N(R')(R''); -S(O) _1-2 (NR'R''); -S(O) _1-2 (C _1-4 alkyl); cyano; and -L ¹ -L ² -R ^h ; each occurrence of R ^c is independently selected from the group consisting of: (a) halo; (b) cyano; (c) C _1-15 alkyl, which optionally substituted with 1-6 independently selected substituents of R ^a; (d) C _2-6 alkenyl groups; (e) C _2-6 alkynyl groups; (G) optionally substituted with C _1-4 alkoxy of C _1-4 alkoxy; (h) C _1-4 haloalkoxy; (i) -S(O) _1-2 (C _1-4 alkyl); (j) -N R ^e R ^f ; ( k) -OH; (l) -S(O) _1-2 (N R ' R ''); (m) -C _1-4 thioalkoxy substituted with 1-4 halo groups as appropriate; (n) -NO ₂ ; (o) -C(=O)(C _1-4 alkyl); (p) -C(=O)O(C _1-4 alkyl); (q) -C( =O)OH; (r) -C(=O)N(R')(R''); and (s) -L ¹ -L ² -R ^h ; R ^{d is} selected from the group consisting of: C _1-6 alkyl; C _3-6 cycloalkyl; -C(O)(C _1-4 alkyl); -C(O)O(C _1-4 alkyl); -CON(R')( R''); -S(O) _1-2 (NR'R''); -S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; Each occurrence of R ^e and R ^f is independently selected from the group consisting of: H; C _1-6 alkyl; C _1-6 haloalkyl; C _3-6 cycloalkyl; -C(O) (C _1-4 alkyl); -C(O)O(C _1-4 alkyl); -CON(R')(R''); -S(O) _1-2 (NR'R'');-S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; or R ^e and R ^f together with the nitrogen atom to which they are each connected form a ring containing 3-8 ring atoms, wherein the ring contains: ( a ) 1-7 Ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from H and C _1-3 alkyl; and ( b ) 0-3 ring heteroatoms (except for the nitrogen connected to R ^e and R ^f Outside atoms), which are each independently selected from the group consisting of N ( R ^d ), NH, O and S; -L ¹ is a chemical bond or C _1-3 alkylene; -L ² is -O-, -N(H)-, -S- or chemical bond; R ^{h is} selected from: ● C _3-8 cycloalkyl, optionally substituted with 1-4 independently selected R ^h '(in certain embodiments, The condition is that when R ^h is a C _3-6 cycloalkyl group substituted with 1-4 independently selected C _1-4 alkyl groups as appropriate, -L ¹ is a chemical bond, or -L ² is -O-,- N(H)- or -S-); ● Heterocyclic group, wherein the heterocyclic group contains 3-16 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of : N, N(H), N( R ^d ), O and S(O) _0-2 , where the heterocyclic group is optionally substituted with 1-4 independently selected R ^h '; ● contains 5-10 Heteroaryl groups of ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _{0- 2} , and wherein the heteroaryl ring is optionally substituted by 1-4 independently selected R ^h '; and ● C _6-10 aryl, which is optionally substituted by 1-4 independently selected R ^h '; wherein each R ^h 'is independently selected from the group consisting of: halo; -CN; -NO _2; -OH; optionally substituted with 1-2 independently selected R ^a of the -C _1-4 alkyl; -C _{2 -4} alkenyl group; -C _2-4 alkynyl; -C _1-4 haloalkyl; optionally substituted with 1-2 independently selected R ^a of the -C _1-6 alkoxy; -C _1-6 Haloalkoxy; S(O) _1-2 (C _1-4 alkyl); -N R ' R ''; Pendant oxy; -S(O) _1-2 (N R ' R ''); -C _1-4 thioalkoxy; -C(=O)(C _1-4 alkyl); -C(=O)O(C _1-4 alkyl); -C(=O)OH; And -C(=O)N( R ')( R '');R'and R '' are independently selected from the group consisting of: H, C _1-4 alkyl, and depending on each occurrence. In the case of a C _6-10 aryl group substituted with 1-2 substituents selected from halo, C _1-4 alkyl and C _1-4 haloalkyl; or R ′ and R ″ together with each of them The nitrogen atoms together form a ring containing 3-8 ring atoms, wherein the ring contains: ( a ) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C _1-3 alkyl; and ( b ) 0-3 ring heteroatoms (except Connected to the nitrogen atoms of R ′ and R ″ ), which are each independently selected from the group consisting of N(H), N( R ^d ), O and S.

In some embodiments, when A is a heteroaryl group containing 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each is independently selected from the group consisting of: N, N(H), N( R ¹ ), N( R ² ), O, S, and S(O) ₂ , and 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of: C, CH, C When R ¹ and C R ^{3 are} used, at least one ring atom is substituted by R ¹ . Variable A

In some embodiments, A series: a heteroaryl group containing 7-20 (eg 8-16) ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: N , N(H), N( R ¹ ), N( R ² ), O and S(O) _0-2 , and among them 3-19 (for example 4-15) ring atoms are carbon atoms, each independently selected Free from the following groups: C, CH, CH ₂ , C R ¹ , CH R ¹ , C( R ¹ ) ₂ , C R ³ , CH R ³ and C( R ³ ) ₂ .

In some embodiments, A series: a heteroaryl group containing 8-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N( R ¹ ), N( R ² ), O and S(O) _0-2 , and 4-9 ring atoms are carbon atoms, each independently selected from the group consisting of: C, CH, CH _2. C R ¹ , CH R ¹ , C( R ¹ ) ₂ , C R ³ , CH R ³ and C( R ³ ) ₂ .

In some of these embodiments, A series: a heteroaryl group containing 8-9 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N( R ¹ ), N( R ² ), O, and S(O) _0-2 , and 4-8 ring atoms are carbon atoms, each independently selected from the group consisting of Group: C, CH, CH ₂ , C R ¹ , CH R ¹ , C( R ¹ ) ₂ , C R ³ , CH R ³ and C( R ³ ) ₂ .

其中Z 選自由以下組成的群組： 化學鍵、CH、CR¹ 、CR³ 、N、NH、N(R¹ ) 及N(R² ) ；Y¹ 、Y² 及Y³ 各自獨立地選自由以下組成的群組：O、S、CH、CR¹ 、CR³ 、N、NH、N(R¹ ) 及NR² ；Y⁴ 係C或N；X⁰ 係C或N；X¹ 選自由以下組成的群組：O、S、N、NH、NR¹ 、NR² 、CH、CR¹ 及CR³ ；X² 選自由以下組成的群組：O、S、N、NH、NR¹ 、NR² 、CH、CR¹ 及CR³ ；且 各

獨立地為單鍵或雙鍵，條件是包括Y⁴ 、X⁰ 、X¹ 及X² 之五員環係雜芳基；且 包含Z 、Y¹ 、Y² 、Y³ 及Y⁴ 之環係芳族環（亦即，碳環芳族環或雜芳族環）。In some embodiments, A series ( A-1 ):

Where Z is selected from the group consisting of: chemical bond, CH, C R ¹ , C R ³ , N, NH, N( R ¹ ), and N( R ² ) ; Y ¹ , Y ² and Y ³ are each independently selected Free from the following groups: O, S, CH, C R ¹ , C R ³ , N, NH, N( R ¹ ) and N R ² ; Y ⁴ is C or N; X ⁰ is C or N; X ^{1 is} selected from the group consisting of: O, S, N, NH, NR ¹ , NR ² , CH, C R ¹ and C R ³ ; X ^{2 is} selected from the group consisting of: O, S, N , NH, N R ¹ , N R ² , CH, C R ¹ and C R ³ ; and each

Independently a single bond or a double bond, provided that the five-membered ring system heteroaryl group including Y ⁴ , X ⁰ , X ¹ and X ² ; and the ring system including Z , Y ¹ , Y ² , Y ³ and Y ⁴ Aromatic ring (ie, carbocyclic aromatic ring or heteroaromatic ring).

In some embodiments of ( A-1 ), Z is selected from the group consisting of CH, C R ¹ , C R ³ , N, and N( R ² ) .

In some embodiments of ( A-1 ), Z is selected from the group consisting of CH, C R ¹ , C R ³ and N.

In some of these embodiments, Z is selected from the group consisting of CH, C R ¹ and C R ³ (for example, Z is CH).

In some embodiments of ( A-1 ), Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of CH, C R ¹ , C R ³ and N.

In some of these embodiments, Y ¹ , Y ^2, and Y ³ are each independently selected from the group consisting of CH, C R ¹ and C R ³ .

部分係

， 其中m1 = 0、1、2或3；且m3 = 0、1、2或3（例如m1 = 0或1；且m3 = 0、1或2）。As a non-limiting example,

Part of the department

, Where m1 = 0, 1, 2 or 3; and m3 = 0, 1, 2 or 3 (for example, m1 = 0 or 1; and m3 = 0, 1 or 2).

In certain embodiments of ( A-1 ) (when Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of CH, C R ¹ , C R ³ and N), Y ¹ , 1-2 of Y ² and Y ³ are independently N.

In some of these embodiments, one of Y ¹ , Y ² and Y ³ is independently N.

In some of the foregoing embodiments, the remaining Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of CH, C R ¹ and C R ³ , provided that Y ¹ , Y ² and One or more of Y ³ is independently CH.

部分係

，其中： 星號表示與Y⁴ 之連接點；且 m3 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。As a non-limiting example of the foregoing embodiment,

Part of the department

, Where: the asterisk indicates the connection point with Y ⁴ ; and m3 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

部分係

，其中： 星號表示與Y⁴ 之連接點；且 m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。As another non-limiting example,

Part of the department

, Where: the asterisk indicates the connection point with Y ⁴ ; and m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

In some embodiments of ( A-1 ) (for example, when Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of CH, C R ¹ , C R ³ and N), Y ^{1 Two of} Y ² and Y ³ are independently N.

部分係

，其中： 星號表示與Y⁴ 之連接點；且 m1 = 0或1；且m3 = 0或1。As a non-limiting example of the foregoing embodiment,

Part of the department

, Where: the asterisk indicates the connection point with Y ⁴ ; and m1 = 0 or 1; and m3 = 0 or 1.

In some embodiments of ( A-1 ), Y ⁴ is C.

In some embodiments of ( A-1 ), X ^{1 is} selected from the group consisting of O, S, N, CH, NH, NR ¹ and NR ² .

In some of these embodiments, X ^{1 is} selected from the group consisting of NH, NR ¹ and NR ² .

As a non-limiting example of the foregoing embodiment, X ^{1 is} selected from the group consisting of NH and NR ² (such as NH or NAc (such as NH)).

In some embodiments of ( A-1 ), X ¹ is S.

In some embodiments of ( A-1 ), X ¹ is N or CH.

In some embodiments of ( A-1 ), X ^{2 is} selected from the group consisting of N, CH, C R ¹ and C R ³ .

In certain embodiments of ( A-1 ), X ^{2 is} selected from the group consisting of N, C (C _1-3 alkyl) and CH.

As a non-limiting example of the foregoing embodiment, X ² is CH.

In some embodiments of ( A-1 ), X ⁰ is N.

In some embodiments of ( A-1 ), X ⁰ is C.

In certain embodiments of ( A-1 ), X ¹ is NH, N R ¹ or N R ² ; and X ⁰ is C.

In some of the foregoing embodiments, X ¹ is NH or NR ² (such as NH or NAc (such as NH)).

In some of the foregoing embodiments (when X ¹ is NH, NR ¹ or N R ² ; and X ⁰ is C (for example, when X ¹ is NH or N R ² (such as NH or NAc (such as NH)), X ^{2 is} selected from the group consisting of N, C (C _1-3 alkyl) and CH (for example, X ² is CH).

（例如

）， 其中m1 = 0、1、2或3；且m3 = 0、1、2或3（例如m1 = 0或1；且m3 = 0、1或2）。As a non-limiting example of the foregoing embodiment of (A-1) , Series A :

(E.g

), where m1 = 0, 1, 2 or 3; and m3 = 0, 1, 2 or 3 (for example, m1 = 0 or 1; and m3 = 0, 1 or 2).

， 其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。As an additional non-limiting example, Series A :

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

， 其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。As an additional non-limiting example, Series A :

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

， 其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。As another non-limiting example, Series A :

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

， 其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。As another non-limiting example, Series A :

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

， 其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。As another non-limiting example, Series A :

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

In some embodiments of ( A-1 ), X ¹ is N or CH; and X ⁰ is N.

In some of the foregoing embodiments, X ^{2 is} selected from the group consisting of N, C (C _1-3 alkyl), and CH (for example, X ² is CH).

， 其中m1 = 0、1、2或3；且m3 = 0、1、2或3（例如m1 = 0或1；且m3 = 0、1或2）。As a non-limiting example of the foregoing embodiment of (A-1) , Series A :

, Where m1 = 0, 1, 2 or 3; and m3 = 0, 1, 2 or 3 (for example, m1 = 0 or 1; and m3 = 0, 1 or 2).

In certain embodiments of ( A-1 ), X ¹ is S; X ^{2 is} selected from the group consisting of N, C (C _1-3 alkyl) and CH (for example, X ² is CH); and X ⁰ is C.

， 其中m1 = 0、1、2或3；且m3 = 0、1、2或3（例如m1 = 0或1；且m3 = 0、1或2）。As a non-limiting example of the foregoing embodiment of (A-1) , Series A :

, Where m1 = 0, 1, 2 or 3; and m3 = 0, 1, 2 or 3 (for example, m1 = 0 or 1; and m3 = 0, 1 or 2).

， 其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。As another non-limiting example, Series A :

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

其中：Z 選自由以下組成的群組： 化學鍵、CH、CR¹ 、CR³ 、N、NH、N(R¹ ) 及N(R² ) ；Y¹ 及Y³ 各自獨立地選自由以下組成的群組：O、S、CH、CR¹ 、CR³ 、N、NH、N(R¹ ) 及NR² ；Y⁴ 係C或N；X⁰ 選自由以下組成的群組：O、S、N、NH、NR¹ 、NR² 、CH、CR¹ 及CR³ （例如X⁰ 係CH）；X¹ 選自由以下組成的群組：O、S、N、NH、NR¹ 、NR² 、CH、CR¹ 及CR³ ；X² 選自由以下組成的群組：O、S、N、NH、NR¹ 、NR² 、CH、CR¹ 及CR³ ；且 各

獨立地為單鍵或雙鍵，條件是包括Y⁴ 、X¹ 及X² 之五員環係雜芳基；且 包含Z 、Y¹ 、Y³ 及Y⁴ 之環係芳族環（亦即，碳環芳族環或雜芳族環）。In some embodiments, A series ( A-2 ):

Among them: Z is selected from the group consisting of: chemical bond, CH, C R ¹ , C R ³ , N, NH, N( R ¹ ) and N( R ² ) ; Y ¹ and Y ³ are each independently selected from the following Group consisting of: O, S, CH, C R ¹ , C R ³ , N, NH, N( R ¹ ) and N R ² ; Y ⁴ is C or N; X ^{0 is} selected from the following groups: O, S, N, NH, N R ¹ , N R ² , CH, C R ¹ and C R ³ (for example, X ⁰ is CH); X ^{1 is} selected from the group consisting of: O, S, N, NH , N R ¹ , N R ² , CH, C R ¹ and C R ³ ; X ^{2 is} selected from the group consisting of O, S, N, NH, N R ¹ , N R ² , CH, C R ¹ And C R ³ ; and each

Independently is a single bond or a double bond, provided that the five-membered ring system heteroaryl group including Y ⁴ , X ¹ and X ² ; and the ring system aromatic ring including Z , Y ¹ , Y ³ and Y ⁴ (ie , Carbocyclic aromatic ring or heteroaromatic ring).

In some embodiments of (A-2) , Z is selected from the group consisting of CH, C R ¹ , C R ³ and N.

In some of these embodiments, Z is selected from the group consisting of CH, C R ¹ and C R ³ (for example, Z is CH).

In some embodiments of (A-2) , Y ¹ and Y ³ are each independently selected from the group consisting of CH, C R ¹ , C R ³ and N.

In some of these embodiments, Y ¹ and Y ³ are each independently selected from the group consisting of CH, C R ¹ and C R ³ .

部分係

， 其中m1 = 0、1、2或3；且m3 = 0、1、2或3（例如m1 = 0或1；且m3 = 0、1或2）；且星號表示與W¹ 之連接點。As a non-limiting example of the foregoing embodiment,

Part of the department

, Where m1 = 0, 1, 2 or 3; and m3 = 0, 1, 2 or 3 (for example, m1 = 0 or 1; and m3 = 0, 1 or 2); and the asterisk indicates the connection point with W ¹ .

In some embodiments of (A-2) , Y ⁴ is C.

In some embodiments of (A-2) , X ^{1 is} selected from the group consisting of O, S, N, CH, NH, NR ¹ and NR ² (for example, X ^{1 is} selected from NH and NR ² (For example, X ¹ is NH)).

In some embodiments of (A-2) , X ^{0 is} selected from the group consisting of CH and N (for example, X ⁰ is CH).

In some embodiments of (A-2) , X ^{2 is} selected from the group consisting of C R ¹ , CH, and N (for example, X ² is CH).

， 其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。As a non-limiting example of (A-2) , Series A :

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

In some embodiments, A is a heteroaryl group containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N ( R ¹ ), N( R ² ), O, S, and S(O) ₂ , and 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of: C, CH, C R ¹ and C R ³ ; provided that at least one ring atom is substituted by R ¹ .

In some of these embodiments, A is a heteroaryl group containing 5 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N (H), N( R ¹ ), N( R ² ), O and S, and 1-4 ring atoms are carbon atoms, each independently selected from the group consisting of: C, CH, C R ¹ And C R ³ ; with the proviso that at least one ring atom is substituted by R ¹ .

In some of the foregoing embodiments, A is a heteroaryl group containing 5 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N( H), N ( R ¹ ), N ( R ² ), O and S, and 1-4 of the ring atoms are carbon atoms, each independently selected from the group consisting of: C, CH, C R ¹ and C R ³ ; Provided that the heteroaryl group is substituted with 1-2 (for example, 1) R ¹ .

； 其中：Y⁷ 係N或C；Z² 選自CH、CR² 及N；X³ 選自O、S、N、NH、NR¹ 、NR² 、CH、CR¹ 及CR³ ；Y⁵ 及Y⁶ 各自獨立地選自O、S、CH、CR¹ 、CR³ 、 NR¹ 、NR² 、NH及N；且 各

獨立地為單鍵或雙鍵，條件是包含Y⁵ 、Y⁶ 、 Y⁷ 、X³ 及Z² 之五員環係雜芳族環。In some embodiments, A series ( A-3 ):

; Wherein: Y ⁷ is N or C; Z ^{2 is} selected from CH, C R ² and N; X ^{3 is} selected from O, S, N, NH, NR ¹ , NR ² , CH, CR ¹ and CR ³ ; Y ⁵ and Y ⁶ are each independently selected from O, S, CH, C R ¹ , C R ³ , N R ¹ , N R ² , NH and N; and each

It is independently a single bond or a double bond, provided that the five-membered ring system of Y ⁵ , Y ⁶ , Y ⁷ , X ³ and Z ² is a heteroaromatic ring.

In some embodiments of (A-3) , when X ³ is NR ¹ or CR ¹ , then Y ⁵ and Y ⁶ are each independently selected from O, S, CH, CR ³ , NR ² , NH and N; and when X ^{3 is} selected from O, S, N, NH, NR ² , CH and C R ³ , then one of Y ⁵ and Y ⁶ is C R ¹ or N R ¹ (in some In an embodiment, the other of Y ⁵ and Y ⁶ is selected from O, S, CH, C R ³ , NR ² , NH, and N).

In some embodiments of ( A-3 ), X ³ is N R ¹ or C R ¹ .

In some of these embodiments, Z ^{2 is} selected from N or CH.

In some embodiments of ( A-3 ) (for example, when X ³ is NR ¹ or C R ¹ ), Y ^{6 is} selected from S, CH, CR ³ and N.

In some embodiments, Y ^{6 is} selected from S, N, and CH (for example, Y ⁶ is CH; or Y ⁶ is S).

In some embodiments of ( A-3 ) (for example, when X ³ is N R ¹ or C R ¹ ), Y ^{5 is} selected from CH, C R ³ and N (for example, CH and N).

In some embodiments of ( A-3 ), Y ⁷ is C.

。As a non-limiting example of (A-3) , A is selected from:

.

In some embodiments of ( A-3 ), X ³ is S, N, CH, C R ³ , NH or N R ² .

In some embodiments of ( A-3 ), X ^{3 is} selected from N, CH, or NH (for example, CH or NH).

In some embodiments of ( A-3 ), Z ^{2 is} selected from N or CH (for example, Z ² is CH).

In some embodiments of ( A-3 ), Y ^{6 is} selected from CH and N (for example, Y ⁶ is N).

In some embodiments of ( A-3 ) (for example, when X ³ is S, N, CH, C R ³ , NH or N R ² ), Y ^{5 is} selected from N R ¹ and C R ¹ .

。 變數R¹ As a non-limiting example of (A-3) , A is selected from:

. Variable R ¹

In some embodiments, each occurrence of R ¹ is independently selected from: (i) -( U ¹ ) _q - U ² , where: ● q is 0 or 1; ● U ¹ is C _1-6 alkylene group, which is optionally substituted with 1-6 substituents R ^a; and ● U ² system: (a) C _3-10 cycloalkyl, which is optionally substituted with 1-4 R ^{b, (b)} C _6-10 Aryl groups, optionally substituted by 1-4 R ^c ; ( c ) heteroaryl groups containing 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of Group: N, N(H), N( R ^d ), O and S(O) _0-2 , and the heteroaryl ring is optionally substituted with 1-4 independently selected R ^c , or ( d ) contains 3 A heterocyclic group with -10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O ) _0-2 , and wherein the heterocyclyl ring is optionally substituted with 1-4 independently selected R ^b , and ( ii ) C _1-6 alkyl, which is optionally substituted with 1-6 independently selected R ^a .

In some embodiments, R ¹ is -( U ¹ ) _q - U ² .

In some of these embodiments, q is zero.

In certain embodiments (when R ¹ is -( U ¹ ) _q - U ² ), U ² is a C _6-10 aryl group, which is optionally substituted with 1-4 R ^c .

In some of the foregoing embodiments, U ² is a C _6-10 aryl group, which is optionally substituted with 1-2 R ^c .

As a non-limiting example of the foregoing embodiment, U ² is a phenyl group, which is optionally substituted with 1-2 (eg, 1) R ^c .

In certain embodiments (when R ¹ is -( U ¹ ) _q - U ² ), the R ^c substituent on U ² is selected from: (a) halo (e.g. Cl, F); (b) cyano group; (c) C _1-10 alkyl, which is optionally substituted with 1-6 independently selected of R ^a; (f) C _1-4 haloalkyl; (g) C _1-4 alkoxy; ( h) C _1-4 haloalkoxy; and (m) -C _1-4 thioalkoxy.

In some of these embodiments, each occurrence of the R ^c substituent on U ² is selected from: halo (e.g. Cl, F; e.g. F), cyano, C _1-6 alkyl And C _1-4 haloalkyl.

In certain embodiments, R ¹ is a phenyl group, which is optionally substituted with 1-2 (eg, 1) R ^c .

In some of the foregoing embodiments, each occurrence of the R ^c substituent on U ² is selected from the group consisting of : (a) halo (e.g. Cl, F); (b) cyano ; (c) C _1-10 alkyl, which is optionally substituted with 1-6 independently selected of R ^a; (f) C _1-4 haloalkyl; (g) C _1-4 alkoxy; (H ) C _1-4 haloalkoxy; and (m) -C _1-4 thioalkoxy.

In certain embodiments, each occurrence of the R ^c substituent on U ² is selected from: halo (such as Cl, F; such as F), cyano, C _1-6 alkyl, and C _1-4 halo alkyl.

In certain embodiments, R ¹ is unsubstituted phenyl.

In some embodiments, R ¹ C _1-6 alkyl-based, which is optionally substituted with 1-6 independently selected substituents of the R ^a (in some embodiments, R ¹ of each of R ^a substituents are independently selected from From: -OH; -F; -Cl; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)O(C _1-4 alkyl); -C(=O) OH, and optionally C _3-6 cycloalkyl substituted with 1-4 independently selected C _1-4 alkyl groups). Variable R ³

In some embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy, -S(O ) _1-2 (C _1-4 alkyl), -NR ^e R ^f , -OH, -S(O) _1-2 (NR'R''), -C _1-4 thioalkoxy,- C(=O)(C _1-4 alkyl), -C(=O)O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')( R'').

In some embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy, -S(O ) _1-2 (C _1-4 alkyl), -S(O) _1-2 (NR'R''), -C(=O)(C _1-4 alkyl), -C(=O) O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R'').

In some of these embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy and C _1-4 haloalkane Oxy group (such as halo or cyano).

As a non-limiting example, each occurrence of R ³ is independently halo (eg -F) or cyano. Variable R ²

In some embodiments, each occurrence of R ² is independently selected from: ( i ) C _1-6 alkyl (such as methyl); ( ii ) C _3-6 cycloalkyl; ( iv ) -C( O) (C _1-4 alkyl) (such as C(O)Me); ( v ) -C(O)O(C _1-4 alkyl); ( vi ) -CON(R')(R''); ( vii ) -S(O) _1-2 (NR'R''); and ( viii )-S(O) _1-2 (C _1-4 alkyl) (such as S(O) ₂ Me) .

In certain embodiments, each occurrence of R ² is independently selected from ( viii )-S(O) _1-2 (C _1-4 alkyl) (for example, S(O) ₂ Me) and ( iv ) -C(O)(C _1-4 alkyl) (e.g. C(O)Me). Non-limiting combination of R ¹ , R ³ and A

部分係

，其中m3 係0、1、2或3；

，其中m3 係0、1或2；

，其中m3 係0、1或2；或

，其中m3 係0、1或2，其中星號表示與Y⁴ 之連接點；且m1 = 0。舉例而言，

部分可為

，且m1 = 0。In some embodiments, when A is (A-1) ,

Part of the department

, Where m3 is 0, 1, 2 or 3;

, Where m3 is 0, 1 or 2;

, Where m3 is 0, 1 or 2; or

, Where m3 is 0, 1 or 2, where the asterisk indicates the connection point with Y ⁴ ; and m1 = 0. For example,

Part can be

, And m1 = 0.

In some of these embodiments, m3= 0.

In certain other embodiments, m3 = 1 or 2 (for example, m3 = 2).

In some of these embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkane Oxy, -S(O) _1-2 (C _1-4 alkyl), -NR ^e R ^f , -OH, -S(O) _1-2 (NR'R''), -C _1-4 Thioalkoxy, -C(=O)(C _1-4 alkyl), -C(=O)O(C _1-4 alkyl), -C(=O)OH and -C(=O )N(R')(R'').

In certain embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy, -S( O) _1-2 (C _1-4 alkyl), -S(O) _1-2 (NR'R''), -C(=O)(C _1-4 alkyl), -C(=O )O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R'').

In certain embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, and C _1-4 haloalkoxy (such as halo Or cyano).

As a non-limiting example of the foregoing embodiment, R ³ may be a halo group (such as F) or a cyano group.

部分可為

（諸如

）。For example, when the A system (A-1) ,

Part can be

(Such as

).

In some embodiments, A is as defined in any of claims 37 to 43 of U.S. Provisional Application Serial No. 62/955,891, which is incorporated herein by reference in its entirety; and m1=0.

（例如

）， 其中m1 = 0；且m3 = 0、1、2或3（例如m3 = 0、1或2）。In some embodiments, A series

(E.g

), where m1 = 0; and m3 = 0, 1, 2 or 3 (for example, m3 = 0, 1 or 2).

，其中m1 = 0；且m3 = 0、1或2（例如m3 = 0或1）。In some embodiments, A series

, Where m1 = 0; and m3 = 0, 1 or 2 (for example, m3 = 0 or 1).

，其中m1 = 0；且m3 = 0、1或2（例如m3 = 0或1）。In some embodiments, Series A :

, Where m1 = 0; and m3 = 0, 1 or 2 (for example, m3 = 0 or 1).

；且m1 =0時），m3 = 0。In some of the foregoing embodiments (when A series

; And m1 = 0), m3 = 0.

In certain other embodiments, m3=1 or 2.

In some of these embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkane Oxy, -S(O) _1-2 (C _1-4 alkyl), -NR ^e R ^f , -OH, -S(O) _1-2 (NR'R''), -C _1-4 Thioalkoxy, -C(=O)(C _1-4 alkyl), -C(=O)O(C _1-4 alkyl), -C(=O)OH and -C(=O )N(R')(R'').

In certain embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy, -S( O) _1-2 (C _1-4 alkyl), -S(O) _1-2 (NR'R''), -C(=O)(C _1-4 alkyl), -C(=O )O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R'').

In certain embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, and C _1-4 haloalkoxy (such as halo Or cyano). For example, m3 can be 2; and each R ³ can be F.

As a non-limiting example of the foregoing embodiments, R ³ may be a halo (for example, F) or a cyano group.

部分係

， 其中m1 = 0；且m3 = 0、1、2或3（例如m3 = 0、1或2）；且星號表示與W¹ 之連接點。In some embodiments, when A is (A-2) ,

Part of the department

, Where m1 = 0; and m3 = 0, 1, 2 or 3 (for example, m3 = 0, 1 or 2); and the asterisk indicates the connection point with W ¹ .

，其中m1 = 0；且m3 = 0、1或2（例如m3 = 0或1）。In some embodiments, A series

, Where m1 = 0; and m3 = 0, 1 or 2 (for example, m3 = 0 or 1).

部分係

，其中m1 = 0時；或當A 係

，其中m1 = 0時），m3 = 0。In some of these embodiments (when

Part of the department

, Where m1 = 0; or when A series

, Where m1 = 0), m3 = 0.

In certain other embodiments, m3=1 or 2.

In some of these embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkane Oxy, -S(O) _1-2 (C _1-4 alkyl), -NR ^e R ^f , -OH, -S(O) _1-2 (NR'R''), -C _1-4 Thioalkoxy, -C(=O)(C _1-4 alkyl), -C(=O)O(C _1-4 alkyl), -C(=O)OH and -C(=O )N(R')(R'').

In certain embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy, -S( O) _1-2 (C _1-4 alkyl), -S(O) _1-2 (NR'R''), -C(=O)(C _1-4 alkyl), -C(=O )O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R'').

In certain embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, and C _1-4 haloalkoxy (such as halo Or cyano).

As a non-limiting example of the foregoing embodiment, R ³ is a halogen group or a cyano group (for example, R ³ is a cyano group).

；且R¹ 如美國臨時申請案序列號62/955,891之請求項73至83中任一項中所定義，該案以全文引用之方式併入本文中（例如美國臨時申請案序列號62/955,891之請求項74至82中之任一項）。In some embodiments, A is selected from the group consisting of:

; And R ^{1 is} as defined in any one of claims 73 to 83 of U.S. Provisional Application Serial No. 62/955,891, which is incorporated herein by reference in its entirety (for example, U.S. Provisional Application Serial No. 62/955,891 Any one of claims 74 to 82).

In some of these embodiments, R ¹ is a phenyl group, which is optionally substituted with 1-2 (eg, 1) R ^c . In some of these embodiments, each occurrence of R ^c is selected from: (a) halo (e.g. Cl, F); (b) cyano; (c) C _1-10 alkyl which is optionally substituted with 1-6 independently selected substituents of R ^a; (f) C _1-4 haloalkyl; (g) C _1-4 alkoxy; (h) C _1-4 haloalkoxy; And (m) -C _1-4 thioalkoxy. For example, each occurrence of R ^c can be selected from halo (such as Cl, F; such as F), cyano, C _1-6 alkyl, and C _1-4 haloalkyl.

As a non-limiting example of the foregoing embodiments, R ¹ may be a phenyl group substituted with one R ^c as appropriate. For example, R ¹ can be an unsubstituted phenyl group.

；且R¹ 係-(U¹ ) _q -U² 。在此等實施例中之某些實施例中，q 係0；且U² 係苯基，其視情況經1-2（例如1）個R^c 取代；或U² 係包含5-6個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜芳基環視情況經1-2個獨立選擇之R^c 取代。In some embodiments, A series

; And R ¹ is -( U ¹ ) _q - U ² . In some of these embodiments, q is 0; and U ² is a phenyl group, which is optionally substituted with 1-2 (eg, 1) R ^c ; or U ² contains 5-6 rings Heteroaryl groups of atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 , And where the heteroaryl ring is optionally substituted with 1-2 independently selected R ^c .

In some of the foregoing embodiments, each occurrence of R ^c is selected from: (a) halo (e.g. Cl, F); (b) cyano; (c) C _1-10 alkyl, which is optionally substituted with 1-6 independently selected substituents of R ^a; (f) C _1-4 haloalkyl; (g) C _1-4 alkoxy; (h) C _1-4 haloalkoxy; and (m) -C _1-4 thioalkoxy. For example, each occurrence of R ^c can be selected from halo (such as Cl, F; such as F), cyano, C _1-6 alkyl, and C _1-4 haloalkyl. Variables W ¹ and W ²

In some embodiments, one of W ¹ and W ² is -N(H)- or -N( R ^d )- (eg -N(H)- or -N(C _1-3 alkyl)-) ; The other of W ¹ and W ² is a chemical bond, -O-, CH ₂ , CH R ^a or C R ^a ₂ .

In some embodiments, W ¹ is -NH-.

In some embodiments, W ¹ is CH ₂ or CH(C _1-3 alkyl) (eg, CH ₂ ).

In some embodiments, W ¹ is a chemical bond.

In some embodiments, W ² is a chemical bond.

In some embodiments, W ² is CH ₂ or CH(C _1-3 alkyl) (eg, CH ₂ ).

In some embodiments, W ² is -NH-.

In certain embodiments, W ¹ is -NH-; and W ² is a chemical bond.

In certain embodiments, W ¹ is -NH-; and W ² is CH ₂ or CH (C _1-3 alkyl) (eg, CH ₂ ).

In certain embodiments, W ¹ is -NH; and W ² is -( W ¹² )-O-*, - (W ¹² )-N(H)-* or -( W ¹² ) -N( R ^d )-*, where the asterisk indicates the connection point with B. In some of these embodiments, W ² is - (W ¹² )-N(H)-*, such as -C _1-3 alkylene-N(H)-*, such as -CH ₂ NH-*.

In certain embodiments, W ² is -NH-; and W ¹ is a chemical bond.

In certain embodiments, W ² is -NH-; and W ¹ is CH ₂ or CH (C _1-3 alkyl) (eg, CH ₂ ). Variable B

In some embodiments, B is phenyl substituted with 1-4 R ^c .

In certain embodiments, B through line 1-2 of the phenyl group substituted with R ^c, wherein R ^c 1-2 lines located in Formula I ^{- W 1 - C (= O} ) - W 2 - of the connecting portion A ring carbon in the para or meta position of the point (for example, an R ^c is at the ring carbon in the para position of the connection point).

）。As a non-limiting example of the foregoing embodiment, B is a phenyl group substituted with an R ^c at the ring carbon in the para position of the connection point of the -W ¹ -C(=O) -W ² -moiety in formula I ( that is,

).

In some embodiments, each R ^c substituent of B is independently selected from the group consisting of: (a) halo; (b) cyano; (c) C _1-10 alkyl, optionally 1-6 independently selected ^Ra substitutions; (g) C _1-4 alkoxy; (h) C _1-4 haloalkoxy; (i) -S(O) _1-2 (C _1-4 Alkyl); (m) -C _1-4 thioalkoxy; (o) -C(=O)(C _1-4 alkyl); (p) -C(=O)O(C _{1- 4} alkyl); (r) -C(=O)N(R')(R''); and (s) -L ¹ -L ² -R ^h .

In some embodiments, each R ^c substituent of B is independently selected from the group consisting of: (a) halo; (b) cyano; (c) C _1-10 alkyl, optionally 1-6 independently selected ^Ra substitutions; (g) C _1-4 alkoxy; and (h) C _1-4 haloalkoxy.

In certain embodiments, B substituents of each R ^c group independently selected from C _1-10 alkyl, which is optionally substituted with 1-6 independently selected of R ^a.

In some of the foregoing embodiments, each occurrence of R ^a is independently selected from: -halo (for example F); -OH; C _1-4 alkoxy; and C _1-4 haloalkanes Oxy.

As a non-limiting example of the foregoing embodiments, each R ^c substituent of B is C _1-10 (e.g., C _1-6 , C _1-3 , C _1-2 , C ₁ ) alkyl (for example, R ^c is CF ₃ ).

In some embodiments, each R ^c substituent of B is independently selected from unsubstituted C _1-10 (for example, C _2-10 (for example, C _3-8 )) alkyl.

In certain of these embodiments, each R ^c substituent of B is independently selected from unsubstituted C _1-6 alkyl.

In certain of the foregoing embodiments, each R ^c substituent of B is independently selected from unsubstituted C _2-6 (eg, C _2-4 , such as C ₂ or C ₄ ) alkyl.

As a non-limiting example, each R ^c substituent of B is ethyl or butyl (for example, n-butyl).

In certain embodiments, R ^c is ^a C _1-6 alkyl group optionally substituted with 1-3 independently selected Ra . In certain embodiments, the foregoing embodiments of the embodiments, R ^c line with 1-3 independently selected R ^a substituents of C _1-6 alkyl.

In some embodiments, B is C _3-20 cycloalkyl, which is optionally substituted with 1-4 R ^b .

In some embodiments, B is C _3-12 cycloalkyl, which is optionally substituted with 1-2 R ^b .

In some of these embodiments, B is C _6-12 cycloalkyl, which is optionally substituted with 1-2 R ^b .

）。As a non-limiting example of the foregoing embodiment, B is a C _6-12 cycloalkyl group (for example, B can be

).

In some embodiments, B is a heterocyclic group containing 3-16 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N ( R ^d ), O and S(O) _0-2 , and the heterocyclic ring is optionally substituted with 1-4 independently selected R ^b .

In certain embodiments, B is a heterocyclic group containing 3-12 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N( R ^d ), O and S(O) _0-2 , and the heterocyclic ring is optionally substituted with 1-4 independently selected R ^b .

In certain embodiments, B is a heterocyclic group containing 3-8 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N( R ^d ), O and S(O) _0-2 , and the heterocyclic ring is optionally substituted with 1-3 independently selected R ^b .

）。As a non-limiting example of the foregoing embodiments, B is a heterocyclic group containing 5-6 (for example, 6) ring atoms, of which 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N( R ^d ), O and S(O) _0-2 , and the heterocyclic ring is optionally substituted with 1-2 independently selected R ^b (for example, B can be

).

In some embodiments, each occurrence of R ^b is independently selected from the group consisting of: C _1-10 alkyl; C _1-4 haloalkyl; -OH; pendant oxy; -F; -Cl ; -NR ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)(C _1-4 alkyl); -C(=O)O(C _{1- 4} alkyl); -S(O) _1-2 (C _1-4 alkyl); cyano; and -L ¹ -L ² -R ^h .

In certain embodiments, each occurrence of R ^b is independently selected from the group consisting of: C _1-10 alkyl; C _1-4 haloalkyl; -OH; pendant oxy; -F;- Cl; C _1-4 alkoxy; and C _1-4 haloalkoxy. Unrestricted combination [Ia]

或其醫藥學上可接受之鹽。In some embodiments, the compound has Formula Ia :

Or its pharmaceutically acceptable salt.

In some embodiments of [ Ia] , R ^{c is} as defined in any of claims 122 to 130 of U.S. Provisional Application Serial No. 62/955,891, which is incorporated herein by reference in its entirety.

In certain embodiments of [Ia] , R ^c is optionally ^a C _1-6 alkyl group substituted with 1-3 independently selected Ra (for example, R ^c may be C _1-4 (for example, C _2-4 ) Alkyl; or R ^c can be CF ₃ ).

In some embodiments of [ Ia] , A is (A-1 ).

In some embodiments of [ Ia] , A is as defined in claim 37 of U.S. Provisional Application Serial No. 62/955,891, which is incorporated herein by reference in its entirety.

In some embodiments of [Ia] , A is as defined in claim 25.

（例如

），其中m1 = 0、1、2或3；且m3 = 0、1、2或3（例如m1 = 0或1；且m3 = 0、1或2）。In some embodiments of [ Ia] , A series:

(E.g

), where m1 = 0, 1, 2 or 3; and m3 = 0, 1, 2 or 3 (for example, m1 = 0 or 1; and m3 = 0, 1 or 2).

（例如m1 = 0；且m3 = 1或2（例如m3 =2））。As a non-limiting example of the foregoing embodiment, A can be:

(For example, m1 = 0; and m3 = 1 or 2 (for example, m3 = 2)).

In some embodiments of [ Ia] (when A is (A-1 )), A is as defined in any of claims 38 to 40 of the U.S. Provisional Application Serial No. 62/955,891, and the case is The full citation method is incorporated into this article.

，其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some of these embodiments, A is:

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

，其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some embodiments, A series

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

，其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some embodiments, A series

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

，其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some embodiments, A series

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

， 其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In certain embodiments, A series A series

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

，其中m1 = 0、1、2或3；且m3 = 0、1、2或3（例如m1 = 0或1；且m3 = 0、1或2）；或

， 其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some embodiments of [ Ia] (when A is (A-1 )), A :

, Where m1 = 0, 1, 2 or 3; and m3 = 0, 1, 2 or 3 (for example, m1 = 0 or 1; and m3 = 0, 1 or 2); or

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

In some embodiments of [ Ia] , A is ( A-2 ).

，其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some embodiments of [ Ia] , A series:

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

In some embodiments of [ Ia] , A is (A-3) .

。In some embodiments of [ Ia] , A is selected from:

.

。In some embodiments of [ Ia] , A is selected from :

.

，諸如

。In some embodiments of [ Ia] , A series

, Such as

.

時），m1 = 0。In some embodiments of [ Ia] (when A series

Hour), m1 = 0.

In some of these embodiments, m3=0.

In certain other embodiments, m3=1 or 2.

In some of these embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkane Oxy, -S(O) _1-2 (C _1-4 alkyl), -NR ^e R ^f , -OH, -S(O) _1-2 (NR'R''), -C _1-4 Thioalkoxy, -C(=O)(C _1-4 alkyl), -C(=O)O(C _1-4 alkyl), -C(=O)OH and -C(=O )N(R')(R'').

In certain embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy, -S( O) _1-2 (C _1-4 alkyl), -S(O) _1-2 (NR'R''), -C(=O)(C _1-4 alkyl), -C(=O )O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R'').

In certain embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, and C _1-4 haloalkoxy (such as halo Or cyano).

As a non-limiting example of the foregoing embodiment, R ³ is a halogen group or a cyano group (for example, R ³ is a cyano group).

時），R¹ 如美國臨時申請案序列號62/955,891之請求項73至82中任一項中所定義，該案以全文引用之方式併入本文中。In some embodiments of [ Ia] (when A series:

Hour), R ^{1 is} as defined in any of claims 73 to 82 of the US Provisional Application Serial No. 62/955,891, which is incorporated herein by reference in its entirety.

In some of these embodiments, R ¹ is a phenyl group (eg, an unsubstituted phenyl group) substituted with 1-2 independently selected R ^c as the case may be.

；且R¹ 係-(U¹ ) _q -U² 。在此等實施例中之某些實施例中，q 係0；且U² 係苯基，其視情況經1-2（例如1）個R^c 取代；或U² 係包含5-6個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜芳基環視情況經1-2個獨立選擇之R^c 取代。In some embodiments of [ Ia] , A series

; And R ¹ is -( U ¹ ) _q - U ² . In some of these embodiments, q is 0; and U ² is a phenyl group, which is optionally substituted with 1-2 (eg, 1) R ^c ; or U ² contains 5-6 rings Heteroaryl groups of atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 , And where the heteroaryl ring is optionally substituted with 1-2 independently selected R ^c .

In some of the foregoing embodiments, each occurrence of R ^c is selected from: (a) halo (e.g. Cl, F); (b) cyano; (c) C _1-10 alkyl, which is optionally substituted with 1-6 independently selected substituents of R ^a; (f) C _1-4 haloalkyl; (g) C _1-4 alkoxy; (h) C _1-4 haloalkoxy; and (m) -C _1-4 thioalkoxy. For example, each occurrence of R ^c can be selected from halo (such as Cl, F; such as F), cyano, C _1-6 alkyl, and C _1-4 haloalkyl. [Ib]

或其醫藥學上可接受之鹽， 其中：B² 係： a)包含3-8個環原子之雜環基，其中1-2個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜環基環視情況經1-3個獨立選擇之R^b 取代；或 b) C_3-12 環烷基，其視情況經1-2個R^b 取代。In some embodiments, the compound has formula Ib :

Or a pharmaceutically acceptable salt thereof, wherein: B ² series: a) a heterocyclic group containing 3-8 ring atoms, of which 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of Group: N, N(H), N( R ^d ), O and S(O) _0-2 , wherein the heterocyclic ring is optionally substituted with 1-3 independently selected R ^b ; or b) C _{3- 12} cycloalkyl, optionally substituted with 1-2 R ^b .

In some embodiments of [Ib] , B ² is a heterocyclic group containing 3-8 ring atoms, of which 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N (H), N( R ^d ), O and S(O) _0-2 , and the heterocyclic ring is optionally substituted with 1-3 independently selected R ^b .

）。In some embodiments of [Ib] , B ² is a heterocyclic group containing 5-6 ring atoms, of which 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N (H), N( R ^d ), O and S(O) _0-2 , and the heterocyclic ring is optionally substituted with 1-2 independently selected R ^b (for example, B ² may be

).

In some embodiments of [Ib] , B ² is a C _3-12 cycloalkyl group, which is optionally substituted with 1-2 R ^b .

）。In some embodiments of [Ib] , B ² is a C _6-12 cycloalkyl group, optionally substituted with 1-2 R ^b (for example, B can be

).

In some embodiments of [Ib] , A is (A-1 ).

（例如

）， 其中m1 = 0、1、2或3；且m3 = 0、1、2或3（例如m1 = 0或1；且m3 = 0、1或2）。In some embodiments of [Ib] , A is A :

(E.g

), where m1 = 0, 1, 2 or 3; and m3 = 0, 1, 2 or 3 (for example, m1 = 0 or 1; and m3 = 0, 1 or 2).

（例如m1 = 0；且m3 = 1或2（例如m3 =2））。As a non-limiting example, A can be:

(For example, m1 = 0; and m3 = 1 or 2 (for example, m3 = 2)).

In certain embodiments of [Ib] , A is defined in any of claims 38 to 43 (for example, any of claims 38-40) of the U.S. Provisional Application Serial No. 62/955,891. It is incorporated into this article by reference in its entirety.

，其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some of these embodiments, A is:

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

，其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some embodiments, A series

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

，其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some embodiments, A series

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

，其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some embodiments, A series

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

， 其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some embodiments, A series

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

時），m1 = 0。In some embodiments of [Ib] (when A series

Hour), m1 = 0.

In some of these embodiments, m3=0.

In certain other embodiments, m3=1 or 2. In some of these embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkane Oxy, -S(O) _1-2 (C _1-4 alkyl), -NR ^e R ^f , -OH, -S(O) _1-2 (NR'R''), -C _1-4 Thioalkoxy, -C(=O)(C _1-4 alkyl), -C(=O)O(C _1-4 alkyl), -C(=O)OH and -C(=O )N(R')(R'').

In certain embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy, -S( O) _1-2 (C _1-4 alkyl), -S(O) _1-2 (NR'R''), -C(=O)(C _1-4 alkyl), -C(=O )O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R'').

In certain embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, and C _1-4 haloalkoxy (such as halo Or cyano).

As a non-limiting example of the foregoing embodiment, R ³ is a halogen group or a cyano group (for example, R ³ is a cyano group). [Ic]

其中R^w 係H或C_1-3 烷基（例如H或Me（例如H））； 或其醫藥學上可接受之鹽。In some embodiments, the compound has formula Ic :

Wherein R ^w is H or C _1-3 alkyl (such as H or Me (such as H)); or a pharmaceutically acceptable salt thereof.

In some embodiments of [Ic] , R ^{c is} as defined in any of claims 122 to 130 of U.S. Provisional Application Serial No. 62/955,891, which is incorporated herein by reference in its entirety.

In certain of the foregoing embodiments, R ^c is optionally ^a C _1-6 alkyl group substituted with 1-3 independently selected Ra (for example, R ^c may be C _1-4 (for example, C _{2- 4} ) Alkyl; or R ^c can be CF ₃ ).

In some embodiments of [Ic] , A is (A-1 ).

（例如

），其中m1 = 0、1、2或3；且m3 = 0、1、2或3（例如m1 = 0或1；且m3 = 0、1或2）。In some embodiments of [Ic] , A is A :

(E.g

), where m1 = 0, 1, 2 or 3; and m3 = 0, 1, 2 or 3 (for example, m1 = 0 or 1; and m3 = 0, 1 or 2).

（例如m1 = 0；且m3 = 1或2（例如m3 =2））。As a non-limiting example of the foregoing embodiment, A can be:

(For example, m1 = 0; and m3 = 1 or 2 (for example, m3 = 2)).

In some embodiments of [Ic] , A is as defined in any of claims 38 to 40 of U.S. Provisional Application Serial No. 62/955,891, which is incorporated herein by reference in its entirety.

，其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some of these embodiments, A is:

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

，其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some embodiments, A series

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

，其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some embodiments, A series

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

，其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some embodiments, A series

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

， 其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In certain embodiments, A series A series

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

，其中m1 = 0、1、2或3；且m3 = 0、1、2或3（例如m1 = 0或1；且m3 = 0、1或2）。In some embodiments of [Ic] , A series:

, Where m1 = 0, 1, 2 or 3; and m3 = 0, 1, 2 or 3 (for example, m1 = 0 or 1; and m3 = 0, 1 or 2).

，其中m1 = 0、1、2或3；且m3 = 0、1、2或3（例如m1 = 0或1；且m3 = 0、1或2）；或

， 其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some embodiments of [ Ia] (when A is (A-1 )), A :

, Where m1 = 0, 1, 2 or 3; and m3 = 0, 1, 2 or 3 (for example, m1 = 0 or 1; and m3 = 0, 1 or 2); or

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

In some embodiments of [Ic] , A is ( A-2 ).

，其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some embodiments of [Ic] , A series:

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

In some embodiments of [Ic] , A is (A-3) .

。In some embodiments of [ Ia] , A is selected from:

.

。In some embodiments of [ Ia] , A is selected from :

.

，諸如

。In some embodiments of [ Ia] , A series

, Such as

.

時），m1 = 0。In some embodiments of [Ic] (when A series

Hour), m1 = 0.

In some of these embodiments, m3=0.

In certain other embodiments, m3=1 or 2.

In some of these embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkane Oxy, -S(O) _1-2 (C _1-4 alkyl), -NR ^e R ^f , -OH, -S(O) _1-2 (NR'R''), -C _1-4 Thioalkoxy, -C(=O)(C _1-4 alkyl), -C(=O)O(C _1-4 alkyl), -C(=O)OH and -C(=O )N(R')(R'').

In certain embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy, -S( O) _1-2 (C _1-4 alkyl), -S(O) _1-2 (NR'R''), -C(=O)(C _1-4 alkyl), -C(=O )O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R'').

In certain embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, and C _1-4 haloalkoxy (such as halo Or cyano).

As a non-limiting example of the foregoing embodiment, R ³ is a halogen group or a cyano group (for example, R ³ is a cyano group).

時），R¹ 如美國臨時申請案序列號62/955,891之請求項73至82中任一項中所定義，該案以全文引用之方式併入本文中。In some embodiments of [ Ic] , (when A series:

Hour), R ^{1 is} as defined in any of claims 73 to 82 of the US Provisional Application Serial No. 62/955,891, which is incorporated herein by reference in its entirety.

In some of these embodiments, R ¹ is a phenyl group (eg, an unsubstituted phenyl group) substituted with 1-2 independently selected R ^c as the case may be.

；且R¹ 係-(U¹ ) _q -U² 。在此等實施例中之某些實施例中，q 係0；且U² 係苯基，其視情況經1-2（例如1）個R^c 取代；或U² 係包含5-6個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜芳基環視情況經1-2個獨立選擇之R^c 取代。In some embodiments of [ Ia] , A series

; And R ¹ is -( U ¹ ) _q - U ² . In some of these embodiments, q is 0; and U ² is a phenyl group, which is optionally substituted with 1-2 (eg, 1) R ^c ; or U ² contains 5-6 rings Heteroaryl groups of atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 , And where the heteroaryl ring is optionally substituted with 1-2 independently selected R ^c .

In some of the foregoing embodiments, each occurrence of R ^c is selected from: (a) halo (e.g. Cl, F); (b) cyano; (c) C _1-10 alkyl, which is optionally substituted with 1-6 independently selected substituents of R ^a; (f) C _1-4 haloalkyl; (g) C _1-4 alkoxy; (h) C _1-4 haloalkoxy; and (m) -C _1-4 thioalkoxy. For example, each occurrence of R ^c can be selected from halo (such as Cl, F; such as F), cyano, C _1-6 alkyl, and C _1-4 haloalkyl. [Id]

或其醫藥學上可接受之鹽。In some embodiments, the compound has the formula Id :

Or its pharmaceutically acceptable salt.

In some embodiments of [Id] , R ^{c is} as defined in any of claims 122 to 130 of U.S. Provisional Application Serial No. 62/955,891, which is incorporated herein by reference in its entirety.

In certain embodiments of [Id] , R ^c is optionally ^a C _1-6 alkyl group substituted with 1-3 independently selected Ra (for example, R ^c may be C _1-4 (for example, C _2-4 ) Alkyl; or R ^c can be CF ₃ ).

In some embodiments of [Id] , A is (A-1 ).

（例如

）， 其中m1 = 0、1、2或3；且m3 = 0、1、2或3（例如m1 = 0或1；且m3 = 0、1或2）。 作為前述實施例之非限制性實例，A 可為

。In some embodiments of [Id] , A series

(E.g

), where m1 = 0, 1, 2 or 3; and m3 = 0, 1, 2 or 3 (for example, m1 = 0 or 1; and m3 = 0, 1 or 2). As a non-limiting example of the foregoing embodiment, A can be

.

In some embodiments of [Id] , A is defined in any one of claims 38 to 43 (for example, any one of claims 38-40) of the U.S. Provisional Application Serial No. 62/955,891, and the case is The full citation method is incorporated into this article.

In some embodiments of [Id] , A is ( A-2 ).

， 其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some embodiments of [Id] , A series A series:

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

In some embodiments of [Id] , A is (A-3) .

In certain embodiments of [Id] , A is as defined in any of claims 66 and 72 of U.S. Provisional Application Serial No. 62/955,891, which is incorporated herein by reference in its entirety.

In certain embodiments of [Id] (when A is any of claims 37, 38 to 43 (for example, any of claims 38-40) and 54 of the US provisional application serial number 62/955,891 As defined, m1=0 when the case is incorporated into this article by reference in its entirety.

In certain embodiments of [Id] (when A is in any of claims 37, 38 to 43 (for example, any one of claims 38-40) and 54 of the US provisional application serial number 62/955,891 As defined, m3 = 0 when the case is incorporated into this article by reference in its entirety).

In certain embodiments of [Id] (when A is in any of claims 37, 38 to 43 (for example, any one of claims 38-40) and 54 of the US provisional application serial number 62/955,891 As defined, when the case is incorporated into this article by reference in its entirety), m3 = 1 or 2.

In some of these embodiments, R ^{3 is} as defined in any one of claims 84 to 86 of U.S. Provisional Application Serial No. 62/955,891 (for example, R ³ may be a halo group (for example, F) Or cyano), the case is incorporated herein by reference in its entirety.

In some embodiments of [ Id] (when A is defined in any one of claims 66 and 72 of US provisional application serial number 62/955,891), R ^{1 is} as US provisional application serial number 62/ As defined in any one of claims 73 to 82 of 955,891, the case is incorporated herein by reference in its entirety.

In some of these embodiments, R ¹ is a phenyl group (eg, an unsubstituted phenyl group) substituted with 1-2 independently selected R ^c as the case may be. [Ie]

其中R^w 係H或C_1-3 烷基（例如H或Me（例如H））； 或其醫藥學上可接受之鹽。In some embodiments, the compound has formula Ie :

Wherein R ^w is H or C _1-3 alkyl (such as H or Me (such as H)); or a pharmaceutically acceptable salt thereof.

In some embodiments of [Ie] , R ^{c is} as defined in any of claims 122 to 130 of U.S. Provisional Application Serial No. 62/955,891, which is incorporated herein by reference in its entirety.

In certain of these embodiments, R ^c is optionally ^a C _1-6 alkyl group substituted with 1-3 independently selected Ra (e.g., R ^c can be C _1-4 (e.g. C _{2 -4} ) Alkyl; or R ^c can be CF ₃ ).

In some embodiments of [Ie] , A is (A-1 ).

（例如

）， 其中m1 = 0、1、2或3；且m3 = 0、1、2或3（例如m1 = 0或1；且m3 = 0、1或2）。In some embodiments of [Ie] , A series:

(E.g

), where m1 = 0, 1, 2 or 3; and m3 = 0, 1, 2 or 3 (for example, m1 = 0 or 1; and m3 = 0, 1 or 2).

。As a non-limiting example of the foregoing embodiment, Series A :

.

In some embodiments of [Ie] , A is defined in any one of claims 38 to 43 (for example, any one of claims 38 to 40) of the U.S. Provisional Application Serial No. 62/955,891, which is defined as The full citation method is incorporated into this article.

，In some embodiments of [Ie] , A series A series:

,

In some embodiments of [Ie] , A is ( A-2 ).

， 其中m1 = 0、1或2；且m3 = 0、1或2（例如m1 = 0或1；且m3 = 0或1）。In some embodiments of [Ie] , A is A :

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1).

In some embodiments of [Ie] , A is (A-3) .

In certain embodiments of [Ie] , A is as defined in any of claims 66 and 72 of U.S. Provisional Application Serial No. 62/955,891, which is incorporated herein by reference in its entirety.

In some embodiments of [Ie] (when A is in the US provisional application serial number 62/955,891, claims 37, 38 to 43 (for example, any one of claims 38 to 40), 41 and 54 When defined in the item), m1 = 0.

In some embodiments of [Ie] (when A is in the US provisional application serial number 62/955,891, claims 37, 38 to 43 (for example, any one of claims 38 to 40), 41 and 54 When defined in the item), m3 = 0.

In some embodiments of [Ie] (when A is in the US provisional application serial number 62/955,891, claims 37, 38 to 43 (for example, any one of claims 38 to 40), 41 and 54 When defined in the item), m3 = 1 or 2.

In some of these embodiments, R ^{3 is} as defined in any one of claims 84 to 86 of U.S. Provisional Application Serial No. 62/955,891 (for example, R ³ may be a halo group (for example, F) Or cyano), the case is incorporated herein by reference in its entirety.

In some embodiments of [ Ie] (when A is defined in any one of claims 66 and 72 of US provisional application serial number 62/955,891), R ^{1 is} as US provisional application serial number 62/ As defined in any one of claims 73 to 82 of 955,891, the case is incorporated herein by reference in its entirety.

In some of these embodiments, R ¹ is a phenyl group (eg, an unsubstituted phenyl group) substituted with 1-2 independently selected R ^c as the case may be. [If]

其中W¹ 連接至與*相鄰之碳原子或與**相鄰之碳原子；m1 係0、1、2或3；m2 係0、1、2或3；且Z^A 及Z^A 獨立地選自由以下組成的群組：N、CH、CR¹ 及CR³ 。In some embodiments, the compound has the formula If :

Wherein W ^{1 is} connected to the carbon atom adjacent to * or the carbon atom adjacent to **; m1 is 0, 1, 2 or 3; m2 is 0, 1, 2 or 3; and Z ^A and Z ^{A are} independently Choose from the group consisting of: N, CH, C R ¹ and C R ³ .

In some embodiments of [If] , one of W ¹ and W ² is -N(H)- or -N( R ^d )- (for example, -N(H)- or -N(C _1-3 alkane Group)-); and the other of W ¹ and W ² is a chemical bond or optionally ^a C ₁ -C ₆ alkylene substituted with 1-3 Ra (for example, C ₁ -C ₃ , such as CH ₂ , CH R ^a or C R ^a ₂ ).

In certain embodiments of [If] , W ¹ is -N(H)- or -N( R ^d )- (for example, -N(H)- or -N(C _1-3 alkyl)-); And W ² is a chemical bond or optionally ^a C ₁ -C ₆ alkylene substituted with 1-3 Ra (for example, C ₁ -C ₃ , such as CH ₂ , CH R ^a or C R ^a ₂ ).

In certain embodiments of [If] , W ¹ is -N(H)-; and W ² is a chemical bond or CH ₂ .

In certain embodiments of [If] , W ¹ is -N(H)-; and W ² is a chemical bond.

In certain embodiments of [If] , W ¹ is -N(H)-; and W ² is CH ₂ .

In some embodiments of [If] , W ^{1 is} connected to the carbon atom adjacent to **.

In some embodiments of [If] , Z ^A and Z ^A are each N.

In some embodiments of [If] , m1 is 0 or 1 and m2 is 1 or 2. In certain embodiments of [Ie] , m1 is 0 and m2 is 1. In some of these embodiments, Z ^B is CR ³ and one R ^{3 is} attached to the position of the indole ring between Z ^A and Z ^B C R ³ .

In some embodiments of [If] , each occurrence of R ³ is independently selected from the group consisting of halo, cyano, -N R ^e R ^f , -OH and -NO ₂ . In some of these embodiments, each occurrence of R ³ is an independently selected halo group. For example, R ³ is -F at each occurrence.

In some embodiments of [If] , B is a heteroaryl group containing 5-20 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N( H), N( R ^d ), O and S(O) _0-2 , and the heteroaryl ring is optionally substituted with 1-4 independently selected R ^c .

In certain embodiments of [If] , B is a heteroaryl group containing 5-6 ring atoms, of which 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N (H), N( R ^d ), N( R ^c ), O and S(O) _0-2 , and the heteroaryl ring is optionally substituted with 1-4 independently selected R ^c .

In some of these embodiments of [If] , B is a heteroaryl group containing 5 ring atoms, of which 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), S and N( R ^d ), N( R ^c ), and the heteroaryl ring is substituted by one independently selected R ^c as appropriate.

。In some embodiments of [If] , B is selected from the group consisting of:

.

In some of these embodiments of [If] , B is a heteroaryl group containing 6 ring atoms, two of which are heteroatoms, each independently selected from the group consisting of: N, N(H) and N( R ^d ), and the heteroaryl ring is optionally substituted with 1-2 independently selected R ^c .

。In some embodiments of [If] , B is selected from the group consisting of:

.

及吡啶基（例如2-吡啶基）。[I-g] In any of the foregoing embodiments of [If] , R ^c is ^a C _1-15 alkyl group substituted with 1-6 independently selected Ra , or -L ¹ -L ² -R ^{h as appropriate} . In some of these embodiments, R ^{c is} selected from the group consisting of isopropyl, CF ₃ , phenyl,

And pyridyl (e.g. 2-pyridyl). [Ig]

；R^2N 係H或R² ；m1 係0或1；且m3 係0、1或2；W¹ 係NH；W² 係化學鍵或C_1-3 伸烷基（例如-CH(Me)-）；且B 選自由以下組成的群組： 經1-4個R^c 取代之苯基； 包含5-6個環原子之雜芳基，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜芳基環經1-4個獨立選擇之R^c 取代； 包含9-15個環原子之雙環或三環雜芳基，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜芳基環視情況經1-4個獨立選擇之R^c 取代；及 C_5-15 烷基，其視情況經1-6個R^a 取代。In some embodiments, A is selected from the group consisting of:

; R ^2N is H or R ² ; m1 is 0 or 1; and m3 is 0, 1 or 2; W ¹ is NH; W ² is a chemical bond or a C _1-3 alkylene group (for example, -CH(Me)-) ; And B is selected from the group consisting of: phenyl substituted by 1-4 R ^c ; heteroaryl containing 5-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected Free from the group consisting of: N, N(H), N( R ^d ), O and S(O) _0-2 , and wherein the heteroaryl ring is substituted by 1-4 independently selected R ^c ; including 9 A bicyclic or tricyclic heteroaryl group with -15 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 heteroaryl ring optionally substituted with 1-4 independently selected of R ^c; and C _5-15 alkyl, which is optionally substituted with 1-6 R ^a.

In certain embodiments of [Ig] , R ^2N is H.

In certain embodiments of [Ig] , m1 is 0.

In some other embodiments of [1-g] , m1 is 1.

In certain embodiments of [Ig] , m3 is 0.

In certain other embodiments, m3 is 1 or 2.

In certain embodiments of [1-g] , m1 is 0; and m3 is 1 or 2 (for example, 2).

。舉例而言，各R³ 可為鹵基（例如F）。In certain embodiments of [1-g] , A series

. For example, each R ³ may be a halo group (for example, F).

In certain embodiments of [1-g] , each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkane Oxy, -S(O) _1-2 (C _1-4 alkyl), -S(O) _1-2 (NR'R''), -C(=O)(C _1-4 alkyl) , -C(=O)O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R'').

In certain embodiments of [1-g] , each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy and C _1-4 haloalkane Oxy group (for example, R ³ may be halo).

In certain embodiments of [1-g] , R ¹ is -( U ¹ ) _q - U ² .

In some of these embodiments, q is zero.

In certain embodiments of [1-g] (when R ¹ is -( U ¹ ) _q - U ² ), U ² is a C _6-10 aryl group, which is optionally substituted by 1-4 R ^c .

In certain of these embodiments of [1-g] , U ² is a C _6-10 aryl group, which is optionally substituted with 1-2 R ^c .

As a non-limiting example, U ² is a phenyl group, which is optionally substituted with 1-2 (for example, 1) R ^c .

In certain embodiments of [1-g] (when U ² is a C _6-10 aryl group, which is optionally substituted with 1-2 R ^c ), the R ^c substituent on U ² appears every time When is independently selected from : halo, cyano, C _1-6 alkyl and C _1-4 haloalkyl.

In certain embodiments of [1-g] (when U ² is a C _6-10 aryl group, which is optionally substituted with 1-2 R ^c ), the R ^c substituent on U ² appears every time When is independently selected from halo.

，其中各R^cA 及R^cB 係獨立選擇之R^c ；n1 係0、1或2；Q¹ 、 Q² 、 Q³ 、Q⁴ 、Q⁵ 及Q⁶ 各自獨立地選自由N及CH組成的群組，條件是Q¹ 及Q² 中之至少一個係N；且Q³ 、Q⁴ 、Q⁵ 及Q⁶ 中之至少一個係N。In some embodiments of [1-g] , B is selected from the group consisting of:

, Where each R ^cA and R ^cB is independently selected R ^c ; n1 is 0, 1 or 2; Q ¹ , Q ² , Q ³ , Q ⁴ , Q ⁵ and Q ⁶ are each independently selected from N and CH Group, the condition is that at least one of Q ¹ and Q ² is N; and at least one of Q ³ , Q ⁴ , Q ⁵ and Q ⁶ is N.

In some of these embodiments, n1 is zero.

In certain other embodiments, n1 is 1. In certain embodiments of the embodiment in such embodiments, R ^cA based halo (e.g., -F or -CI) or C _1-6 alkyl which is optionally substituted with 1-3 independently selected R ^a substituents of (e.g. Methyl or CF ₃ ).

In certain embodiments, R ^cB is ^a C _1-6 alkyl group optionally substituted with 1-6 independently selected Ra .

For example, R ^cB can be an unsubstituted C _2-10 (for example, C _2-3 , for example, C _3-4 , for example, C _4-10 ) alkyl group.

As another non-limiting example, R ^cB may be C _1-6 alkyl, which is substituted with 1-6 independently selected of R ^a. For example, each of R ^a can be halo (e.g. ^{F), N R e R f} , OH, C 1-3 alkoxy or a C _1-3 haloalkoxy.

In certain embodiments, R ^cB is -L ¹ -L ² -R ^h . In some of these embodiments, L ¹ and L ² are each a chemical bond. In certain other embodiments, L ¹ is a chemical bond; and L ² is -O-.

In certain embodiments, R ^{h is} selected from the group consisting of: C _3-6 cycloalkyl, optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C _1-4 alkyl and C _1-4 haloalkyl (in certain embodiments, the condition is that when R ^h is optionally substituted with 1-4 independently selected C _1-4 alkyl groups, C _{3- In the case of 6} cycloalkyl, -L ¹ is a chemical bond, or -L ² is -O-, -N(H)- or -S-); a heteroaryl group containing 5-6 ring atoms, of which 1-4 The 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 heteroaryl ring optionally undergoes 1- 4 substituents independently selected from the group consisting of halo, C _1-4 alkyl, and C _1-4 haloalkyl; and C ₆ aryl, which is optionally substituted by 1-4 independently Substituent substitution selected from the group consisting of halo, C _1-4 alkyl or C _1-4 haloalkyl.

In certain embodiments of [1-g] , B is a heteroaryl group containing 5 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N (H), N( R ^d ), O, and S(O) _0-2 , and the heteroaryl ring is substituted by 1-4 independently selected R ^c , provided that one R ^c appears is L ¹ -L ² -R ^h . In some of these embodiments, L ¹ and L ² are each a chemical bond. In certain other embodiments, L ¹ is a chemical bond; and L ² is -O-.

In certain embodiments, R ^{h is} selected from the group consisting of: C _3-6 cycloalkyl, optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C _1-4 alkyl and C _1-4 haloalkyl (in certain embodiments, the condition is that when R ^h is optionally substituted with 1-4 independently selected C _1-4 alkyl groups, C _{3- In the case of 6} cycloalkyl, -L ¹ is a chemical bond, or -L ² is -O-, -N(H)- or -S-); a heteroaryl group containing 5-6 ring atoms, of which 1-4 The 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 heteroaryl ring optionally undergoes 1- 4 substituents independently selected from the group consisting of halo, C _1-4 alkyl, and C _1-4 haloalkyl; and C ₆ aryl, which is optionally substituted by 1-4 independently Substituent substitution selected from the group consisting of halo, C _1-4 alkyl or C _1-4 haloalkyl. Formula II compound

或其醫藥學上可接受之鹽或其互變異構體， 其中：Z 選自由以下組成的群組：CH、CR¹ 、CR³ 、N、NH、N(R¹ ) 及N(R² ) ；Y¹ 、Y² 及Y³ 各自獨立地選自由以下組成的群組：CH、CR¹ 、CR³ 、N、NH、N(R¹ ) 及 NR² ； 各

獨立地為單鍵或雙鍵，條件是： 包括Z 、Y¹ 、Y² 及Y³ 之6員環係芳族環；R^2N 係H或R² ；R⁶ 選自由H及R^d 組成的群組；B 係包含5-6個環原子之單環雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜芳基環視情況經1-2個獨立選擇之R^c 取代；-L³ 係化學鍵或C_1-3 伸烷基；R⁴ 選自由以下組成的群組： (a ) C_3-12 環烷基，其視情況經1-4個獨立選擇之R⁴ '取代， (b )包含3-12個環原子之雜環基，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中該雜環基之一或多個環碳原子視情況經1-4個獨立選擇之R⁴ '取代；(c) 包含5-12個環原子之雜芳基，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜芳基環之一或多個環碳原子視情況經1-4個獨立選擇之R⁴ '取代；及(d) C_6-10 芳基，其視情況經1-4個獨立選擇之R⁴ '取代； 其中各R⁴ '獨立地選自由以下組成的群組： 鹵基；-CN；-NO₂ ；-OH；視情況經1-2個獨立選擇之R^a 取代的-C_1-4 烷基；-C_2-4 烯基；-C_2-4 炔基；-C_1-4 鹵烷基；視情況經1-2個獨立選擇之R^a 取代的-C_1-6 烷氧基；-C_1-6 鹵烷氧基；S(O)_1-2 (C_1-4 烷基)；-NR 'R ''；側氧基；-S(O)_1-2 (NR 'R '')；-C_1-4 硫代烷氧基；-C(=O)(C_1-4 烷基)；-C(=O)O(C_1-4 烷基)；-C(=O)OH；及-C(=O)N(R ')(R '')；R¹ 係：(i) -(U¹ ) _q -U² ，其中： ●q 係0或1； ●U¹ 係C_1-6 伸烷基，其視情況經1-6個R^a 取代；且 ●U² 係： (a )   C_3-12 環烷基，其視情況經1-4個R^b 取代， (b )  C_6-10 芳基，其視情況經1-4個R^c 取代； (c )   包含5-20個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜芳基環視情況經1-4個獨立選擇之R^c 取代，或 (d )  包含3-12個環原子之雜環基，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜環基環視情況經1-4個獨立選擇之R^b 取代， 或 (ii ) C_1-10 烷基，其視情況經1-6個獨立選擇之R^a 取代；R² 在每次出現時獨立地選自由以下組成的群組： (i ) C_1-6 烷基，其視情況經1-4個獨立選擇之R^a 取代； (ii ) C_3-6 環烷基； (iii )包含3-10個環原子之雜環基，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ； (iv ) -C(O)(C_1-4 烷基)； (v ) -C(O)O(C_1-4 烷基)； (vi ) -CON(R')(R'')； (vii ) -S(O)_1-2 (NR'R'')； (viii ) - S(O)_1-2 (C_1-4 烷基)； (ix ) -OH；及 (x ) C_1-4 烷氧基；R³ 在每次出現時獨立地選自由以下組成的群組：鹵基、氰基、C_2-6 烯基、C_2-6 炔基、視情況經C_3-6 環烷基取代之C_1-4 烷氧基、C_1-4 鹵烷氧基、-S(O)_1-2 (C_1-4 烷基)、-NR^e R^f 、-OH、側氧基、-S(O)_1-2 (NR'R'')、-C_1-4 硫代烷氧基、-NO₂ 、-C(=O)(C_1-4 烷基)、-C(=O)O(C_1-4 烷基)、-C(=O)OH及-C(=O)N(R')(R'')；R^a 在每次出現時獨立地選自由以下組成的群組：-OH；-F；-Cl；-Br；-NR^e R^f ；C_1-4 烷氧基；C_1-4 鹵烷氧基；-C(=O)O(C_1-4 烷基)；-C(=O)(C_1-4 烷基)；-C(=O)OH；-CON(R ')(R '')；-S(O)_1-2 (NR 'R '')；-S(O)_1-2 (C_1-4 烷基)；氰基；及視情況經1-4個獨立選擇之C_1-4 烷基取代的C_3-6 環烷基；R^b 在每次出現時獨立地選自由以下組成的群組：視情況經1-6個獨立選擇之R^a 取代的C_1-10 烷基；C_1-4 鹵烷基；-OH；側氧基；-F；-Cl；-Br；-NR^e R^f ；C_1-4 烷氧基；C_1-4 鹵烷氧基；-C(=O)(C_1-4 烷基)；-C(=O)O(C_1-4 烷基)；-C(=O)OH；-C(=O)N(R ')(R '')；-S(O)_1-2 (NR 'R '')；-S(O)_1-2 (C_1-4 烷基)；氰基；及-L¹ -L² -R^h ；R^c 在每次出現時獨立地選自由以下組成的群組： (a)鹵基； (b)氰基； (c) C_1-15 烷基，其視情況經1-6個獨立選擇之R^a 取代； (d) C_2-6 烯基； (e) C_2-6 炔基； (g)視情況經C_1-4 烷氧基取代之C_1-4 烷氧基； (h) C_1-4 鹵烷氧基； (i) -S(O)_1-2 (C_1-4 烷基)； (j) -NR^e R^f ； (k) -OH； (l) -S(O)_1-2 (NR 'R '')； (m)視情況經1-4個鹵基取代之-C_1-4 硫代烷氧基； (n) -NO₂ ； (o) -C(=O)(C_1-4 烷基)； (p) -C(=O)O(C_1-4 烷基)； (q) -C(=O)OH； (r) -C(=O)N(R')(R'')；及 (s)-L¹ -L² -R^h ；R^d 選自由以下組成的群組：C_1-6 烷基；C_3-6 環烷基；-C(O)(C_1-4 烷基)；-C(O)O(C_1-4 烷基)；-CON(R')(R'')；-S(O)_1-2 (NR'R'')；-S(O)_1-2 (C_1-4 烷基)；-OH；及C_1-4 烷氧基；R^e 及R^f 在每次出現時獨立地選自由以下組成的群組：H；C_1-6 烷基；C_1-6 鹵烷基；C_3-6 環烷基；-C(O)(C_1-4 烷基)；-C(O)O(C_1-4 烷基)；-CON(R')(R'')；-S(O)_1-2 (NR'R'')；- S(O)_1-2 (C_1-4 烷基)；-OH；及C_1-4 烷氧基；或R^e 及R^f 連同其各自所連接之氮原子一起形成包含3-8個環原子之環，其中該環包含：(a ) 1-7個環碳原子，其各自經1-2個獨立地選自H及C_1-3 烷基之取代基取代；及(b ) 0-3個環雜原子（除連接至R^e 及R^f 之氮原子外），其各自獨立地選自由以下組成的群組：N(R^d )、NH、O及S； -L¹ 係化學鍵或C_1-3 伸烷基； -L² 係-O-、-N(H)-、-S-或化學鍵；R^h 選自： ●     C_3-8 環烷基，其視情況經1-4個獨立地選自由以下組成的群組之取代基取代：鹵基、C_1-4 烷基及C_1-4 鹵烷基（在某些實施例中，其條件是當R^h 係視情況經1-4個獨立選擇之C_1-4 烷基取代的C_3-6 環烷基時，-L¹ 係化學鍵，或-L² 係-O-、-N(H)-或-S-）； ●     雜環基，其中該雜環基包含3-16個環原子，其中1-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，其中該雜環基視情況經1-4個獨立地選自由以下組成的群組之取代基取代：鹵基、C_1-4 烷基及C_1-4 鹵烷基； ●     包含5-10個環原子之雜芳基，其中1-4個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S(O)_0-2 ，且其中雜芳基環視情況經1-4個獨立地選自由以下組成的群組之取代基取代：鹵基、C_1-4 烷基及C_1-4 鹵烷基；及 ●     C_6-10 芳基，其視情況經1-4個獨立地選自由以下組成的群組之取代基取代：鹵基、C_1-4 烷基或C_1-4 鹵烷基；且R '及R ''在每次出現時獨立地選自由以下組成的群組：H、C_1-4 烷基、及視情況經1-2個選自鹵基、C_1-4 烷基及C_1-4 鹵烷基之取代基取代的C_6-10 芳基；或R '及R ''連同其各自所連接之氮原子一起形成包含3-8個環原子之環，其中該環包含：(a ) 1-7個環碳原子，其各自經1-2個獨立地選自由H及C_1-3 烷基組成的群組之取代基取代；及(b ) 0-3個環雜原子（除連接至R '及R ''之氮原子外），其各自獨立地選自由以下組成的群組：N(H)、N(R^d )、O及S。In another aspect, this article provides a compound of formula II :

Or a pharmaceutically acceptable salt or tautomer thereof, wherein: Z is selected from the group consisting of CH, C R ¹ , C R ³ , N, NH, N( R ¹ ), and N( R ² ) ; Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of: CH, C R ¹ , C R ³ , N, NH, N( R ¹ ), and N R ² ; each

Independently single bond or double bond, provided that: 6-membered ring system aromatic ring including Z , Y ¹ , Y ² and Y ³ ; R ^2N is H or R ² ; R ^{6 is} selected from H and R ^d Group; B is a monocyclic heteroaryl group containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N( R ^d ), O and S(O) _0-2 , and the heteroaryl ring is optionally substituted by 1-2 independently selected R ^c ; -L ³ is a chemical bond or C _1-3 alkylene; R ^{4 is} selected Free from the group consisting of: ( a ) C _3-12 cycloalkyl, optionally substituted by 1-4 independently selected R ⁴ ', ( b ) heterocyclic group containing 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 , and wherein the heterocyclic group One or more ring carbon atoms are optionally substituted with 1-4 independently selected R ⁴ '; (c) Heteroaryl groups containing 5-12 ring atoms, of which 1-3 ring atoms are heteroatoms, each Independently selected from the group consisting of: N, N(H), N( R ^d ), O and S(O) _0-2 , and one or more of the ring carbon atoms of the heteroaryl ring may be 1-4 independently selected R ⁴ 'substitutions; and (d) C _6-10 aryl, optionally substituted with 1-4 independently selected R ⁴ 's; wherein each R ⁴ ' is independently selected from the following components group: halo; -CN; -NO _2; -OH; optionally substituted with 1-2 independently selected substituents of the R ^a -C _1-4 alkyl; -C _2-4 alkenyl; -C _{2 -4} alkynyl; -C _1-4 haloalkyl; optionally substituted with 1-2 independently selected substituents of the R ^a -C _1-6 alkoxy; -C _1-6 haloalkoxy; S (O ) _1-2 (C _1-4 alkyl); -N R ' R ''; pendant oxy; -S(O) _1-2 (N R ' R ''); -C _1-4 thioalkane Oxy; -C(=O)(C _1-4 alkyl); -C(=O)O(C _1-4 alkyl); -C(=O)OH; and -C(=O)N ( R ')( R ''); R ¹ series: (i) -( U ¹ ) _q - U ² , where: ● q is 0 or 1; ● U ¹ is a C _1-6 alkylene group, which depends on substituted with 1-6 substituents R ^a; and ● U ² system: (a) C _3-12 cycloalkyl, which is optionally substituted with 1-4 R ^{b, (b)} C _6-10 aryl group which Optionally substituted by 1-4 R ^c ; ( c ) Heteroaryl groups containing 5-20 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N( R ^d ), O and S(O) _0-2 , wherein the heteroaryl ring is optionally substituted by 1-4 independently selected R ^c , or ( d ) a heterocyclic group containing 3-12 ring atoms, of which 1-3 The 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 heterocyclic ring is optionally through 1- four of independently selected R ^b substituents, or (ii) C _1-10 alkyl, which is optionally substituted with 1-6 independently selected of R ^a; R ² is independently selected at each occurrence the group consisting of group: (i) C _1-6 alkyl, which is optionally substituted with 1-4 independently selected substituents of R ^a; (ii) C _3-6 cycloalkyl; (iii) heteroaryl comprising 3-10 ring atoms Cyclic groups, in which 1-3 ring atoms are heteroatoms, are each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 ; ( iv ) -C(O)(C _1-4 alkyl); ( v ) -C(O)O(C _1-4 alkyl); ( vi ) -CON(R')(R''); ( vii ) -S(O) _1-2 (NR'R''); ( viii )-S(O) _1-2 (C _1-4 alkyl); ( ix ) -OH; and ( x ) C _{1- 4} Alkoxy; R ³ is independently selected from the group consisting of: halo, cyano, C _2-6 alkenyl, C _2-6 alkynyl, optionally through C _3-6 ring Alkyl-substituted C _1-4 alkoxy, C _1-4 haloalkoxy, -S(O) _1-2 (C _1-4 alkyl), -N R ^e R ^f , -OH, pendant oxygen Group, -S(O) _1-2 (NR'R''), -C _1-4 thioalkoxy, -NO ₂ , -C(=O)(C _1-4 alkyl), -C (=O)O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R''); R ^a is independently selected for each occurrence The group consisting of: -OH; -F; -Cl; -Br; -N R ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)O( C _1-4 alkyl); -C(=O)(C _1-4 alkyl); -C(=O)OH; -CON( R ')( R ''); -S(O) _{1- 2} (N R ' R ''); -S(O) _1-2 (C _1-4 alkyl); cyano; and optionally C substituted with 1-4 independently selected C _1-4 alkyl _3-6 cycloalkyl; R ^b at each occurrence is independently selected from the group consisting of: optionally substituted with 1-6 independently selected R ^a substituents of C _1-10 alkyl; C _1-4 halo Alkyl; -OH; pendant oxy; -F; -Cl; -Br; -NR ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)(C _1-4 alkyl); -C(=O)O(C _1-4 Alkyl); -C(=O)OH; -C(=O)N( R ')( R ''); -S(O) _1-2 (N R ' R ''); -S(O ) _1-2 (C _1-4 alkyl); cyano; and -L ¹ -L ² -R ^h ; each occurrence of R ^c is independently selected from the group consisting of: (a) halo; (b) cyano; (c) C _1-15 alkyl, which is optionally substituted with 1-6 independently selected of R ^a; (d) C _2-6 alkenyl groups; (e) C _2-6 alkynyl ; (G) C _1-4 alkoxy substituted by C _1-4 alkoxy as appropriate; (h) C _1-4 haloalkoxy; (i) -S(O) _1-2 (C _{1 -4} alkyl); (j) -N R ^e R ^f ; (k) -OH; (l) -S(O) _1-2 (N R ' R ''); (m) as appropriate through 1- -C _1-4 thioalkoxy substituted by 4 halo groups; (n) -NO ₂ ; (o) -C(=O)(C _1-4 alkyl); (p) -C(=O )O(C _1-4 alkyl); (q) -C(=O)OH; (r) -C(=O)N(R')(R''); and (s) -L ^1- L ² -R ^h ; R ^{d is} selected from the group consisting of: C _1-6 alkyl; C _3-6 cycloalkyl; -C(O)(C _1-4 alkyl); -C(O) O(C _1-4 alkyl); -CON(R')(R''); -S(O) _1-2 (NR'R''); -S(O) _1-2 (C _{1- 4} alkyl); -OH; and C _1-4 alkoxy; each occurrence of R ^e and R ^f is independently selected from the group consisting of: H; C _1-6 alkyl; C _1-6 Haloalkyl; C _3-6 cycloalkyl; -C(O)(C _1-4 alkyl); -C(O)O(C _1-4 alkyl); -CON(R')(R''); -S(O) _1-2 (NR'R''); -S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; or R ^e and R ^f together with the nitrogen atom to which they are each connected form a ring comprising 3-8 ring atoms, wherein the ring comprises: ( a ) 1-7 ring carbon atoms, each of which is independently selected from 1-2 Substitution from H and C _1-3 alkyl substituents; and ( b ) 0-3 ring heteroatoms (except for the nitrogen atoms connected to R ^e and R ^f ), each independently selected from the group consisting of Group: N ( R ^d ), NH, O and S; -L ¹ series chemical bond or C _1-3 alkylene; -L ² series -O-, -N(H)-, -S- or chemical Bond; R ^{h is} selected from : ● C _3-8 cycloalkyl, optionally substituted with _1-4 substituents independently selected from the group consisting of halo, C _1-4 alkyl and C _{1 -4} haloalkyl (in certain embodiments, the proviso is that when R ^h is a C _3-6 cycloalkyl substituted with 1-4 independently selected C _1-4 alkyl groups, -L ¹ Is a chemical bond, or -L ² is -O-, -N(H)- or -S-); ● Heterocyclic group, wherein the heterocyclic group contains 3-16 ring atoms, of which 1-3 ring atoms are Heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O, and S(O) _0-2 , where the heterocyclic group is optionally separated by 1-4 Substituent substitution selected from the group consisting of halo, C _1-4 alkyl and C _1-4 haloalkyl; ● Heteroaryl containing 5-10 ring atoms, of which 1-4 rings 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 heteroaryl ring is optionally 1-4 Substitution by one substituent independently selected from the group consisting of halo, C _1-4 alkyl and C _1-4 haloalkyl; and C _6-10 aryl, which is optionally substituted by 1-4 Substituent substitution independently selected from the group consisting of halo, C _1-4 alkyl or C _1-4 haloalkyl; and R ′ and R ″ are independently selected from the following composition at each occurrence Groups of: H, C _1-4 alkyl, and optionally C _6-10 aryl substituted with 1-2 substituents selected from halo, C _1-4 alkyl and C _1-4 haloalkyl Group; or R 'and R ” together with the nitrogen atom to which they are each connected form a ring containing 3-8 ring atoms, wherein the ring contains: ( a ) 1-7 ring carbon atoms, each of which is through 1- 2 substituents independently selected from the group consisting of H and C _1-3 alkyl; and ( b ) 0-3 ring heteroatoms (except for the nitrogen atoms connected to R ′ and R ″ ), Each is independently selected from the group consisting of N(H), N( R ^d ), O, and S.

In some embodiments, the condition is that one or more of the compound conditions (see below) apply: Compound condition

In some embodiments of formula II , the condition is that when Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of CH, C R ¹ , and C R ³ , Y ³ cannot be N; And when Z , Y ¹ , Y ^2, and Y ³ are each independently selected from the group consisting of CH, C R ¹ and C R ³ , 1-4 of Z , Y ¹ , Y ² and Y ³ Choose from the group consisting of C R ¹ and C R ³ .

，其中星號表示與R⁴ 之連接點。In some embodiments of formula II , the condition is that when Y ³ is N; and Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of CH, C R ¹ , C R ³ , Then BL ³ -is not:

, Where the asterisk indicates the connection point with R ⁴ .

In some embodiments of formula II , the condition is that when Y ³ is N; and Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of CH, C R ¹ , C R ³ , Then B is not pyrazolyl.

，其中星號表示與R⁴ 之連接點。In some embodiments of formula II , the condition is that when Y ³ is N; and Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of CH, C R ¹ , C R ³ , Then BL ^{3 is} not

, Where the asterisk indicates the connection point with R ⁴ .

In some embodiments, it is provided that -L ³ -R ^{4 is} not CH ₂ -cyclopropyl. In some embodiments, the compound is not:

In some embodiments, when Z , Y ¹ , Y ² and Y ³ are each CH, then B is not furyl, pyrazolyl, 1,2,3-triazolyl, oxazolyl, oxazolyl , Hydroxy-imidazolyl, pyrimidinyl, thiazolyl, thiophenyl, each of which is further optionally substituted with one R ^c .

In some embodiments, the compound of formula II is not the compound disclosed in WO 2013/114113, which is incorporated herein by reference in its entirety.

In some embodiments, the compound of formula II is not the compound disclosed in US Patent No. 10,000,481, which is incorporated herein by reference in its entirety.

In some embodiments, the compound of formula II is not the compound disclosed in WO 2009/140320, which is incorporated herein by reference in its entirety.

In some embodiments, the compound of formula II is not the compound disclosed in US Patent No. 8,981,085, which is incorporated herein by reference in its entirety.

In some embodiments, the compound of formula II is not the compound disclosed in WO 2003/028724, which is incorporated herein by reference in its entirety.

Embodiments may include any one or more of the features described below and/or in the scope of the patent application.

In some embodiments, Z , Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of CH, C R ¹ , C R ³ and N.

In some embodiments, Z , Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of CH, C R ¹ and C R ³ .

In some embodiments, 1-2 of Z , Y ¹ , Y ² and Y ³ are independently selected from the group consisting of C R ¹ and C R ³ ; and the remaining Z , Y ¹ , Y ² and Each Y ³ is CH.

。In some of the foregoing embodiments, the compound has formula II-a :

.

。In certain embodiments, the compound has formula II-b or II-c :

.

。In certain embodiments, the compound has formula II-d , II-e or II-f :

.

In some embodiments, one of Z , Y ¹ and Y ² is N; and the remaining Z , Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of: CH, C R ¹ and C R ³ .

In some of these embodiments, Z is N.

In some embodiments (when one of Z , Y ¹ and Y ² is N; and the remaining Z , Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of: CH, C R ¹ And C R ³ ), Y ¹ is N.

In some embodiments (when one of Z , Y ¹ and Y ² is N; and the remaining Z , Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of: CH, C R ¹ And C R ³ ), Y ² is N.

，其中m1 係0或1；且m3 係0、1或2。In some embodiments (when one of Z , Y ¹ and Y ² is N; and the remaining Z , Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of: CH, C R ¹ And C R ³ ), the compound has the formula II-g , II-h or II-i :

, Where m1 is 0 or 1; and m3 is 0, 1 or 2.

In certain embodiments of formula II-g , II-h, or II-i , m1 is zero.

In certain other embodiments, m1 is 1.

In certain embodiments of formula II-g , II-h, or II-i , m3 is zero.

In certain other embodiments, m3 is 1 or 2.

In certain embodiments of formula II-g , II-h or II-i , m1 is 0; and m3 is 1 or 2 (for example, m3 is 1).

In certain embodiments of formula II-g , II-h, or II-i , m1 is 1; and m3 is 0.

In certain embodiments of formula II-g , II-h, or II-i , m1 is 1; and m3 is 1.

In some embodiments, R ^2N is H.

In some embodiments, R ^2N is R ² , wherein the R ^{2 is} selected from the group consisting of: ( iv ) -C(O)(C _1-4 alkyl) (eg -C(O)Me); ( v ) -C(O)O(C _1-4 alkyl); ( vi ) -CON(R')(R''); ( vii ) -S(O) _1-2 (NR'R''); and ( viii )-S(O) _1-2 (C _1-4 alkyl) (for example, S(O) ₂ Me).

As a non-limiting example of the foregoing embodiment, R ^2N can be ( iv ) -C(O)(C _1-4 alkyl) (for example -C(O)Me) or ( viii ) -S(O) _{1- 2} (C _1-4 alkyl) (e.g. S(O) ₂ Me).

In some embodiments, R ¹ is C _1-6 alkyl-based, which is optionally substituted with 1-6 (e.g., 1-3) selected independently of R ^a substituents.

In certain embodiments, R ¹ is C _1-3 alkyl-based, which is optionally substituted with 1-3 independently selected of R ^a.

In some embodiments, R ¹ is -( U ¹ ) _q - U ² , wherein: q is 0 or 1, such as q is 0; U ¹ is a C _1-6 alkylene group, which may be 1-6 R ^{a is} substituted; and U ² is: (C _3-10 cycloalkyl, optionally substituted by 1-4 R ^b , (C _6-10 aryl, optionally substituted by 1-2 R ^c ; (Heteroaryl containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N( R ^d ), O And S(O) _0-2 , wherein the heteroaryl ring is optionally substituted by 1-2 independently selected R ^c , or (heterocyclic group containing 3-6 ring atoms, of which 1-3 ring atoms are Heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O, and S(O) _0-2 , and the heterocyclic ring is optionally separated by 1-4 Choose R ^{b to} replace.

In some embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy, -S(O ) _1-2 (C _1-4 alkyl), -NR ^e R ^f , -OH, -S(O) _1-2 (NR'R''), -C _1-4 thioalkoxy,- C(=O)(C _1-4 alkyl), -C(=O)O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')( R'').

In certain embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy, -S( O) _1-2 (C _1-4 alkyl), -S(O) _1-2 (NR'R''), -C(=O)(C _1-4 alkyl), -C(=O )O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R'').

In some of these embodiments, each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy and C _1-4 haloalkane Oxy.

As a non-limiting example of the foregoing embodiments, each occurrence of R ³ may be halo or cyano, such as -F or cyano.

In some embodiments, B is a monocyclic heteroaryl group containing 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(O) _0-2 , and the heteroaryl ring is optionally substituted with 1-2 independently selected R ^c .

In certain embodiments, B is a monocyclic heteroaryl group containing 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 the heteroaryl ring is optionally substituted with 1-2 independently selected R ^c .

In certain embodiments, B is a monocyclic heteroaryl group containing 5 ring atoms, of which 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N ( R ^d ), O and S, and the heteroaryl ring is optionally substituted with 1-2 independently selected R ^c .

In certain embodiments, B is a monocyclic heteroaryl group containing 5 ring atoms, wherein 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N( R ^d ), and the heteroaryl ring is optionally substituted with 1-2 independently selected R ^c .

In certain embodiments, B can be imidazolyl, pyrazolyl or triazolyl, each of which is optionally substituted with an independently selected R ^c .

As a non-limiting example of the foregoing embodiments, B can be imidazolyl or triazolyl, each of which is substituted with an independently selected R ^c as appropriate.

，其各自視情況經一個R^c 取代，其中aa 表示與L³ 之連接點。For example, B can be selected from the following groups:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ .

，其各自視情況經一個R^c 取代，其中aa 表示與L³ 之連接點。For example, B can be selected from the following groups:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ .

，其各自視情況經一個R^c 取代，其中aa 表示與L³ 之連接點。As another non-limiting example, B can be selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ .

及

，其各自視情況經一個R^c 取代，其中aa 表示與L³ 之連接點。For example, B can be selected from the following groups:

and

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ .

，其各自視情況經一個R^c 取代，其中aa 表示與L³ 之連接點。In some embodiments, B is selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ .

，其各自視情況經一個R^c 取代，其中aa 表示與L³ 之連接點。As a non-limiting example of the foregoing embodiment, B is selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ .

In certain embodiments, B is a monocyclic heteroaryl group containing 5 ring atoms, of which 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N ( R ^d ), O and S, provided that one ring atom is O or S, and the heteroaryl ring is optionally substituted with 1-2 independently selected R ^c .

In some of these embodiments, B is selected from the group consisting of oxazolyl, thiazolyl, thiadiazolyl, and oxadiazolyl, each of which is optionally substituted with one R ^c .

，其各自視情況經一個R^c 取代，其中aa 表示與L³ 之連接點。As a non-limiting example of the foregoing embodiment, B is selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ .

In certain embodiments, B is a monocyclic heteroaryl group containing 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 the heteroaryl ring is optionally substituted with 1-2 independently selected R ^c , wherein the point of attachment of the C(=O)NR ⁶ group of formula II is with L ³ between the connection point.

，其各自視情況經一個R^c 取代，其中aa 表示與L³ 之連接點。As a non-limiting example of the foregoing embodiment, B can be selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ .

In some embodiments, B is a monocyclic heteroaryl group containing 6 ring atoms, wherein 1-3 ring atoms are ring nitrogen atoms, and wherein the heteroaryl ring is optionally substituted with 1-2 independently selected R ^c .

In some of these embodiments, B is pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which is optionally substituted with 1-2 independently selected R ^c , such as R ^c substituted pyridyl.

In certain embodiments (when B is a monocyclic heteroaryl group containing 6 ring atoms, 1-3 of which are ring nitrogen atoms, and where the heteroaryl ring is optionally selected by 1-2 independently R ^{When c is} substituted), the connection point between B and the C(=O)NR ⁶ group of formula II is in the para position to the connection point of L ³ .

，其視情況經一個R^c 取代，其中aa 表示與L³ 之連接點。As a non-limiting example of the foregoing embodiment, B can be

, Which is optionally replaced by an R ^c , where aa represents the point of connection with L ³ .

In certain embodiments (when B is a monocyclic heteroaryl group containing 6 ring atoms, 1-3 of which are ring nitrogen atoms, and where the heteroaryl ring is optionally selected by 1-2 independently R ^{When c is} substituted), the connection point between B and the C(=O)NR ⁶ group of formula II is at the meta position to the connection point of L ³ .

，其各自視情況經一個R^c 取代，其中aa 表示與L³ 之連接點。As a non-limiting example of the foregoing embodiment, B can be selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ .

In some embodiments, L ³ is a chemical bond.

In some embodiments, L ³ is a C _1-3 alkylene group.

In some of these embodiments, L ³ is CH ₂ .

In some embodiments, R ⁴ is a C _6-10 aryl group optionally substituted with 1-4 independently selected R ⁴ ′.

In certain embodiments, R ⁴ is a phenyl substituted with 1-4 independently selected R ⁴ ′ as appropriate.

In certain embodiments, R ⁴ is a phenyl substituted with 1-2 independently selected R ⁴ ′ as appropriate.

As a non-limiting example, R ⁴ can be an unsubstituted phenyl group.

As another non-limiting example, R ⁴ can be a phenyl substituted with 1-2 independently selected R ⁴ ′.

。In certain embodiments, R ⁴ is a phenyl substituted with 1-2 independently selected R ⁴ ′, where one occurrence of R ⁴ ′ is in the para position to the point of attachment to L ³ , such as

.

In some embodiments, R ⁴ is a heteroaryl group containing 5-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N( R ^d ), O and S(O) _0-2 , and one or more of the ring carbon atoms of the heteroaryl ring is optionally substituted with 1-4 independently selected R ⁴ ′.

In certain embodiments, R ⁴ is a heteroaryl group containing 5-6 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 one or more of the carbon atoms of the heteroaryl ring is substituted with 1-4 independently selected R ⁴ ′ as appropriate.

In certain embodiments, R ⁴ is a heteroaryl group containing 6 ring atoms, wherein 1 to 3 ring atoms are ring nitrogen atoms, and wherein one or more ring carbon atoms of the heteroaryl ring may be controlled by 1 -4 independently selected R ⁴ 'substitutions, such as pyridyl substituted with 1-2 independently selected R ⁴ ' as appropriate.

In some embodiments, R ⁴ is a C _3-8 cycloalkyl group, which is optionally substituted with 1-4 independently selected R ⁴ ′.

In certain embodiments, R ⁴ is C _4-6 cycloalkyl, optionally substituted with 1-4 independently selected R ⁴ ′.

As a non-limiting example, R ⁴ can be unsubstituted C _4-6 cycloalkyl, such as unsubstituted cyclohexyl and unsubstituted cyclopentyl.

。As another non-limiting example, R ⁴ may be C _4-6 cycloalkyl, which is substituted with 1-3 (eg 2-3) independently selected R ⁴ ′, such as

.

In some embodiments, R ⁴ is a heterocyclic group containing 4-7 ring atoms, of which 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N( R ^d ), O and S(O) _0-2 , and wherein one or more of the ring carbon atoms of the heterocyclic group is optionally substituted with 1-4 independently selected R ⁴ ′.

In some embodiments, each R ⁴ 'are independently selected from the group consisting of: halo; -CN; optionally substituted with 1-2 independently selected substituents of the R ^a -C _1-4 alkyl; -C _1-4 haloalkyl; optionally substituted with 1-2 independently selected substituents of the R ^a -C _1-6 alkoxy; -C _{1-6 haloalkoxy; S (O) 1-2 (C} 1 _-4 alkyl); -S(O) _1-2 (N R ' R ''); -C _1-4 thioalkoxy; -C(=O)(C _1-4 alkyl);- C(=O)O(C _1-4 alkyl); and -C(=O)N( R ')( R '').

In certain embodiments, each R ⁴ 'are independently selected from the group consisting of: halo; -CN; optionally substituted with one of R ^a independently selected substituted -C _1-4 alkyl; and -C _{1 -4} haloalkyl.

As a non-limiting example of the foregoing embodiment, each R ⁴ ′ is independently selected from the group consisting of halo (such as -F), -CN, -C _1-4 alkyl, and -C _1-4 haloalkane base.

In certain embodiments, L ³ is a chemical bond or CH ₂ ; R ⁴ is a phenyl substituted with 1-2 independently selected R ⁴ ′ as appropriate; and R ⁴ ′ is independently selected from the group consisting of: halo; -CN; optionally substituted with 1-2 independently selected substituents of the R ^a -C _1-4 alkyl; -C _1-4 haloalkyl; optionally substituted with 1-2 independently selected R ^a of -C _1-6 alkoxy; -C _1-6 haloalkoxy; S(O) _1-2 (C _1-4 alkyl); -S(O) _1-2 (N R ' R ''); -C _1-4 thioalkoxy; -C(=O)(C _1-4 alkyl); -C(=O)O(C _1-4 alkyl); and -C(= O)N( R ')( R '').

，其視情況經額外R⁴ 取代。In some of these embodiments, R ⁴ is

, Which is replaced by additional R ⁴ as appropriate.

，其視情況經額外R⁴ 取代時），各R⁴ '獨立地選自由以下組成的群組：鹵基（諸如-F）、-CN、-C_1-4 烷基及-C_1-4 鹵烷基。In certain embodiments (when R ⁴ is

, When it is optionally substituted with additional R ⁴ ), each R ⁴ 'is independently selected from the group consisting of halo (such as -F), -CN, -C _1-4 alkyl, and -C _1-4 Haloalkyl.

，其視情況經額外R⁴ 取代時），位於對位之R⁴ '係-CF₃ 。In certain embodiments (when R ⁴ is

, If it is replaced by additional R ⁴ as appropriate), the R ⁴ 'at the opposite position is -CF ₃ .

In some embodiments, R ^c at each occurrence is independently selected from the group consisting of: halo; cyano; optionally substituted with 1-6 independently selected R ^a substituents of C _1-6 alkyl; Optionally C _1-4 alkoxy substituted with C _1-4 alkoxy; C _1-4 haloalkoxy; S(O) _1-2 (C _1-4 alkyl); -S(O) _1-2 (N R ' R ''); -C _1-4 thioalkoxy substituted with 1-4 halo groups as appropriate; -C(=O)(C _1-4 alkyl);- C(=O)O(C _1-4 alkyl); and -C(=O)N(R')(R'').

In certain embodiments, R ^c at each occurrence is independently selected from the group consisting of: halo; cyano; optionally substituted with 1-3 independently selected R ^a of the C _1-3 alkyl (Such as methyl or CF ₃ ); optionally C _1-4 alkoxy substituted with C _1-4 alkoxy; and C _1-4 haloalkoxy.

In certain of these embodiments, an occurrence of R ^c is ^a C _1-3 alkyl group (such as methyl or CF ₃ ) substituted with 1-3 independently selected Ra as the case may be.

m1 係0或1；m3 係0、1或2，條件是m1+m3 ＞0；且B 係包含5個環原子之單環雜芳基，其中2-3個環原子係雜原子，各自獨立地選自由以下組成的群組：N、N(H)、N(R^d )、O及S，且其中雜芳基環視情況經1-2個獨立選擇之R^c 取代。In certain embodiments, the compound of formula II having the formula II-1:

m1 is 0 or 1; m3 is 0, 1 or 2, provided that m1+m3 ＞0; and B is a monocyclic heteroaryl group containing 5 ring atoms, of which 2-3 ring atoms are heteroatoms, each independently The ground is selected from the group consisting of N, N(H), N( ^Rd ), O and S, and the heteroaryl ring is optionally substituted with 1-2 independently selected ^Rc .

In certain embodiments of formula II-1 , m3 is 1 or 2.

In some of these embodiments, m3 is 2.

In certain embodiments of formula II-1 (for example when m3 is 2), m1 is 0.

。In certain embodiments of formula II-1 , the compound has formula II-1a :

.

In certain embodiments of formula II-1 , each R ^{3 is} independently selected from the group consisting of halo and cyano. For example, each R ³ may be a halo group, such as -F.

In certain embodiments of formula II-1 , R ^2N is H.

In certain embodiments of formula II-1 , R ^2N is ( iv )-C(O)(C _1-4 alkyl) (eg -C(O)Me) or ( viii )-S(O) _{1 -2} (C _1-4 alkyl) (e.g. S(O) ₂ Me).

In certain embodiments of formula II-1 , B is a monocyclic heteroaryl group containing 5 ring atoms, of which 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N( R ^d ), O, and S, and the heteroaryl group is optionally substituted by 1-2 independently selected R ^c , where the group C(=O)NH of formula II-1 L is connected to the connection point between the point of ³ bits.

In certain embodiments, B is selected from the group consisting of imidazolyl and triazolyl, each of which is optionally substituted with one R ^c .

，其各自視情況經一個R^c 取代，其中aa 表示與L³ 之連接點。As a non-limiting example of the foregoing embodiment, B can be selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ .

In certain embodiments of formula II-1 , B is pyrazolyl optionally substituted with one R ^c .

，其各自視情況經一個R^c 取代，其中aa 表示與L³ 之連接點。As a non-limiting example, B can be

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ .

In certain embodiments of formula II-1 , B is selected from the group consisting of oxazolyl, thiazolyl, oxadiazolyl, and thiadiazolyl, wherein the oxazolyl and thiazolyl are optionally connected by one R ^c replaced.

，其各自視情況經一個R^c 取代，其中aa 表示與L³ 之連接點。As a non-limiting example, B can be selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ .

In certain embodiments of formula II-1, the time when present each R ^c is independently selected from the group consisting of: halo; cyano; optionally substituted with 1-3 independently selected R ^a of the C _{1 -3} alkyl (such as methyl or CF ₃ ); optionally C _1-4 alkoxy substituted with C _1-4 alkoxy; and C _1-4 haloalkoxy.

In certain embodiments of formula II-1 , one occurrence of R ^c is ^a C _1-3 alkyl (such as methyl or CF ₃ ) substituted with 1-3 independently selected Ra as the case.

In certain embodiments of formula II-1 , B is not substituted with R ^c .

In certain embodiments of formula II-1 , L ³ is a chemical bond.

In certain embodiments of formula II-1 , L ³ is CH ₂ .

In certain embodiments of formula II-1 , R ^{4 is} selected from the group consisting of: C _4-6 cycloalkyl, optionally substituted with 1-4 independently selected R ⁴ ′; including 6 rings A heteroaryl group of atoms, wherein 1-3 ring atoms are ring nitrogen atoms, and one or more of the ring carbon atoms of the heteroaryl ring is optionally substituted with 1-4 independently selected R ⁴ ', such as optionally Pyridyl substituted with 1-2 independently selected R ⁴ '; heterocyclic groups containing 4-7 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N( R ^d ), O, and S(O) _0-2 , and wherein one or more of the heterocyclic group's ring carbon atoms are optionally selected from 1-4 independently R ⁴ ′ Substitution; and optionally phenyl substituted with 1-2 independently selected R ⁴ '.

In certain embodiments of formula II-1 , R ⁴ is phenyl substituted with 1-2 independently selected R ⁴ ′ as appropriate.

，其視情況經額外R⁴ '取代。In certain embodiments of formula II-1 , R ⁴ is

, Which is replaced by additional R ⁴ 'as appropriate.

In certain embodiments of formula II-1 , each R ⁴ ′ is independently selected from the group consisting of halo (such as -F), -CN, -C _1-4 alkyl, and -C _1-4 Haloalkyl.

，其視情況經額外R⁴ '取代時），各R⁴ '獨立地選自由以下組成的群組：鹵基（諸如-F）、-CN、-C_1-4 烷基及-C_1-4 鹵烷基。In certain embodiments of formula II-1 (when R ⁴ is

, Which is optionally substituted with additional R ⁴ '), each R ⁴ 'is independently selected from the group consisting of halo (such as -F), -CN, -C _1-4 alkyl, and -C _{1- 4} haloalkyl.

，其視情況經額外R⁴ '取代時），位於對位之R⁴ '係-CF₃ 。In certain embodiments of formula II-1 (when R ⁴ is

, If it is replaced by additional R ⁴ 'as appropriate), the R ⁴ ' at the opposite position is -CF ₃ .

，其視情況經額外R⁴ '取代時），R⁴ 係

，其視情況經額外R⁴ 取代。In certain embodiments of formula II-1 (when R ⁴ is

, Which is replaced by additional R ⁴ 'as appropriate), R ⁴ series

, Which is replaced by additional R ⁴ as appropriate.

。 非限制性例示性式I及/或式II化合物For example, R ⁴ can be

. Non-limiting exemplary compounds of formula I and/or formula II

或其醫藥學上可接受之鹽。醫藥組合物及投與 綜述 In some embodiments, the compound is selected from the compounds in Table C1 below: Table C1

Or its pharmaceutically acceptable salt. Summary of pharmaceutical composition and administration

In some embodiments, the chemical entity (for example, a compound that inhibits (eg, antagonizes) STING, or a pharmaceutically acceptable salt, and/or hydrate, and/or co-crystal, and/or drug combination) of STING For administration in the form of a composition, the pharmaceutical composition includes a chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

In some embodiments, the chemical entity can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include but are not limited to ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 amber Acid esters; surfactants used in pharmaceutical dosage forms, such as Tweens, poloxamer (poloxamer) or other similar polymer delivery matrices; serum proteins, such as human serum albumin; buffer substances, such as phosphate, tris, glycosides Amino acid, sorbic acid, potassium sorbate; a mixture of partial glycerides of saturated plant fatty acids; water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride; zinc salt; colloidal two Silica; Magnesium Trisilicate; Polyvinylpyrrolidone; Cellulose; Polyethylene Glycol; Sodium Carboxymethylcellulose; Polyacrylate; Wax; Polyethylene-Polyoxypropylene Block Copolymer; and Wool fat. Cyclodextrins such as α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin can also be used, or chemically modified derivatives such as hydroxyalkyl cyclodextrin, including 2-hydroxypropyl-β-ring Dextrin and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives enhance the delivery of the compounds described herein. A dosage form or composition containing a chemical entity as described herein in the range of 0.005% to 100% and the remainder consisting of non-toxic excipients can be prepared. The covered composition may contain 0.001% to 100%, in one embodiment 0.1% to 95%, in another embodiment 75% to 85%, and in another embodiment 20% to 80% The chemical entities provided in this article. The actual methods for preparing such dosage forms are known or will be obvious to those familiar with the art; for example, see "Remington: Pharmaceutical Science and Practice", 22nd Edition (Pharmaceutical Press), London, UK. 2012). Dosing route and composition components

In some embodiments, the chemical entities described herein or their pharmaceutical compositions can be administered to individuals in need by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, skin, intracervix, endosinusial, intratracheal, intestinal, epidural, interstitial, intraabdominal, intraarterial, intrabronchial, Intrasac, brain, cistern, coronary artery, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileum, intralymphatic, intramedullary, meningeal Intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasine (intrasinal), intraspine, intrasynovial, intratestis, intrathecal, intratubule, intratumor, intrauterine, intravascular, intravenous , Nasal, nasogastric tube, oral, parenteral, transdermal, epidural (peridural), transrectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, surface, transdermal, transmucosal, trans Trachea, ureter, urethra and vagina. In some embodiments, the preferred route of administration is parenteral (eg, intratumor) administration.

The composition can be formulated for parenteral administration, for example, formulated for injection via intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. Generally, such compositions can be prepared in the form of injectables, such as liquid solutions or suspensions; they can also be prepared in solid forms suitable for preparing solutions or suspensions after adding liquids before injection; and the preparations can also be emulsified. According to the present disclosure, those skilled in the art will know the preparation of such formulations.

Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and, in terms of ease of injection, must be fluid. It should also be stable under manufacturing and storage conditions and must be preserved to prevent contamination by microorganisms such as bacteria and fungi.

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

Sterile injectable solutions are prepared by incorporating the active compound in the required amount, as necessary, together with the various other ingredients listed above in an appropriate solvent, followed by filter sterilization. Generally speaking, dispersions are prepared by incorporating various sterile active ingredients into a sterile vehicle that contains the basic dispersion medium and the required other ingredients from the ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation method is vacuum drying and freeze-drying techniques, which obtain a powder of the active ingredient plus any additional required ingredients from the sterile injectable solution previously sterile filtered.

Intratumoral injection is discussed in, for example, Lammers et al., " Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems "" Neoplasia ." 2006, 10 , 788-795.

The pharmacologically acceptable excipients that can be used in rectal compositions in the form of gels, creams, enemas or rectal suppositories include, but are not limited to, any one or more of the following: cocoa butter glycerides, synthetic polymers such as Polyvinylpyrrolidone, PEG (such as PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oil, poloxamer, a mixture of polyethylene glycol of various molecular weights and polyethylene glycol fatty acid esters, Vaseline, anhydrous wool Fat, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, phenoxyethanol in paraben, methyl paraben Sodium benzoate, sodium propyl p-oxybenzoate, diethylamine, carbomer, carbopol, methyloxy benzoate, polyethylene glycol cetearyl ether, coconut Oleyl decanoate decanoate, isopropanol, propylene glycol, liquid paraffin, sanxian gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed Extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, or suppository wax, which is in the environment It is solid at temperature but liquid at body temperature, and therefore melts in the rectum and releases 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 (eg, in solid or liquid dosage forms) by means of oral administration.

The solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the chemical system is mixed with one or more pharmaceutically acceptable excipients, such as 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, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; c) humectants, such as Glycerin; d) Disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) Soothing agents, such as paraffin wax; f) Absorption enhancers, such as quaternary ammonium compounds ; G) humectants, such as cetyl alcohol and glycerol monostearate; h) absorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene Glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also include buffering agents. Similar types of solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose/milk sugar and high molecular weight polyethylene glycol and the like.

In one embodiment, the composition will be in the form of a unit dosage form such as a pill or lozenge, and therefore, in addition to containing the chemical entities provided herein, the composition may also contain diluents such as lactose, sucrose, dicalcium phosphate Or its analogs; lubricants, such as magnesium stearate or its analogs; and binders, such as starch, acacia, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives, or the like. In another solid dosage form, a powder, marume, solution or suspension (for example in propylene carbonate, vegetable oil, PEG, poloxamer 124 or triglyceride) is encapsulated in a capsule (gelatin) Or cellulose capsules). It also covers the unit dosage form of one or more chemical entities or additional active agents provided herein physically separated; for example, a capsule with particles of each drug (or a lozenge in a capsule); two-layer lozenges; two-compartment gel capsules, etc. . It also covers enteric-coated or delayed-release oral dosage forms.

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

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

In certain embodiments, the solid oral dosage form may further comprise chemically and/or structurally making the composition easy to deliver the chemical entity to the stomach or lower GI, such as the ascending colon and/or transverse colon and/or distal colon and / Or one or more components of the small intestine. Exemplary formulation techniques are described in, for example, Filipski, KJ et al., " Current Topics in Medicinal Chemistry ", 2013 , 13 , 776-802, which is incorporated herein by reference in its entirety.

Examples include upper GI targeting technologies, such as Accordion Pill (Intec Pharma), floating capsules, and substances that can adhere to the mucosal wall.

Other examples include lower GI targeting technology. For targeting various areas in the intestine, several enteric/pH reactive coatings and excipients are available. It is selected based on the GI region of the desired drug release, and these substances are usually designed to dissolve or corrode polymers in a specific pH range. These substances are also used to protect acid labile drugs from gastric juice damage or to limit exposure when the active ingredient may stimulate the upper GI (such as hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate) Ester phthalate), cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymer) and Marcoat). Other technologies include dosage forms that respond to local flora in the gastrointestinal tract, pressure-controlled colonic delivery capsules, and pulse caps (Pulsincap).

The ophthalmic composition may include, but is not limited to, any one or more of the following: mucin (such as carboxymethyl cellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (such as Pluronic) (Triblock copolymer), cyclodextrin); preservatives (such as Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (Stable oxychloride complex; Allergan, Inc.)).

The topical composition may include ointments and creams. Ointments are usually semi-solid preparations based on paraffin fat or other petroleum derivatives. Creams containing selected active agents are usually viscous liquid or semi-solid emulsions, often oil-in-water or water-in-oil. The cream base is usually washable in water and contains an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes referred to as the "internal" phase, generally contains paraffin fats and fatty alcohols such as cetyl alcohol or stearyl alcohol; the volume of the water phase is usually but not necessarily larger than the oil phase, and it generally contains a humectant. The emulsifiers in cream formulations are generally nonionic, anionic, cationic or amphoteric surfactants. Like other carriers or vehicles, the ointment base should be inert, stable, non-irritating and non-sensitizing.

In any of the foregoing embodiments, the pharmaceutical composition described herein may comprise one or more of the following: lipids, cross-linked multilamellar vesicles between bilayers, biodegradable poly(D,L-lactic acid-co-glycolic acid ) [PLGA] type or polyanhydride type nanoparticle or microparticle, and nanoporous particle loaded lipid bilayer. dose

The dosage can vary depending on the needs of the patient, the severity of the condition being treated, and the particular compound used. The appropriate dosage for a particular situation can be determined by a person familiar with medical technology. The total daily dose can be divided into multiple portions and administered in portions throughout the day or by providing continuous delivery.

In some embodiments, the administration dose of the compound described herein is about 0.001 mg/Kg to about 500 mg/Kg (for example, about 0.001 mg/Kg to about 200 mg/Kg; about 0.01 mg/Kg to about 200 mg /Kg; about 0.01 mg/Kg to about 150 mg/Kg; about 0.01 mg/Kg to about 100 mg/Kg; about 0.01 mg/Kg to about 50 mg/Kg; about 0.01 mg/Kg to about 10 mg/Kg ; About 0.01 mg/Kg to about 5 mg/Kg; about 0.01 mg/Kg to about 1 mg/Kg; about 0.01 mg/Kg to about 0.5 mg/Kg; about 0.01 mg/Kg to about 0.1 mg/Kg; about 0.1 mg/Kg to about 200 mg/Kg; about 0.1 mg/Kg to about 150 mg/Kg; about 0.1 mg/Kg to about 100 mg/Kg; about 0.1 mg/Kg to about 50 mg/Kg; about 0.1 mg /Kg to about 10 mg/Kg; about 0.1 mg/Kg to about 5 mg/Kg; about 0.1 mg/Kg to about 1 mg/Kg; about 0.1 mg/Kg to about 0.5 mg/Kg). Program

The aforementioned dosage may be daily (for example, in a single dose or in two or more divided doses) or non-daily (for example, every other day, every two days, every three days, once a week, twice a week, every two weeks Once, once a month).

In some embodiments, the administration period of the compounds described herein is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 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 time period for stopping administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 Months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In one embodiment, the therapeutic compound is administered to the individual for a certain period of time, followed by a period of time. In another embodiment, the therapeutic compound is administered in the first time period and after the first time period is the second time period, wherein the administration is stopped during the second time period, and then the therapeutic compound in the third time period begins. The compound is administered, and then the administration is stopped at the fourth time period after the third time period. In one aspect of this embodiment, the time period for repeating the administration of the therapeutic compound and the subsequent time period for stopping the administration continues for a certain or undetermined time period. In another embodiment, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 Months, 9 months, 10 months, 11 months, 12 months or more. In another embodiment, the time period for stopping administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13. Days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months , 8 months, 9 months, 10 months, 11 months, 12 months or longer. Treatment methods

In some embodiments, there is provided for the treatment of diseases and/or symptoms and/or progression of a condition, disease or disorder (such as immune disorder, cancer) caused by increased (such as excessive) STING activity (such as STING signaling) Of the individual’s condition, disease or disorder. Indications

In some embodiments, the condition, disease or disorder is cancer. Non-limiting examples of cancer include melanoma, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specifically, examples of such cancers include breast cancer; colon cancer; rectal cancer, colorectal cancer; kidney or kidney cancer, clear cell carcinoma; lung cancer, including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cells Squamous cell carcinoma; squamous cell carcinoma (eg epithelial squamous cell carcinoma); cervical cancer; ovarian cancer; prostate cancer; prostate tumor; liver cancer; bladder cancer; peritoneal cancer; hepatocellular carcinoma; gastric/stomach cancer, Including gastrointestinal cancer, gastrointestinal stromal tumor; pancreatic cancer; head and neck cancer; glioblastoma; retinoblastoma; astrocytoma; follicular cell tumor; male cell tumor; hepatoma; hematological malignancies, including Non-Hodgkins lymphoma (non-Hodgkins lymphoma, NHL), multiple myeloma, myelodysplastic disorders, myelodysplastic disease, chronic myelogenous leukemia and acute hematological malignancies; endometrial or uterine cancer, intrauterine Endometriosis, endometrial stromal sarcoma; fibrosarcoma; choriocarcinoma; salivary gland cancer; vulvar cancer; thyroid cancer; esophageal cancer; liver cancer; anal cancer; penile cancer; nasopharyngeal cancer; laryngeal cancer; Kaposi's sarcoma (Kaposi's sarcoma); mast cell sarcoma; ovarian sarcoma; uterine sarcoma; melanoma; malignant mesothelioma; skin cancer; schwannoma; oligodendroglioma; neuroblastoma; neuroectodermal tumor; rhabdomyosarcoma; Osteogenic sarcoma; Leiomyosarcoma; Ewing Sarcoma; Peripheral primitive neuroectodermal tumor; Urinary tract cancer; Thyroid cancer; Wilm's tumor; and related to hamartoma Abnormal blood vessel proliferation, edema (such as edema associated with brain tumors) and Meigs’ syndrome (Meigs’ syndrome). In some cases, the cancer is melanoma.

In some embodiments, the condition, disease, or disorder is a neurological disorder, which includes the central nervous system (brain, brainstem, and cerebellum), peripheral nervous system (including cranial nerves), and autonomic nervous system (part of which are located in the central and peripheral In the nervous system). Non-limiting examples of cancers include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenal leukodystrophy; age-related macular degeneration; corpus callosum hypoplasia; dementia; Aicardi syndrome; Alexander disease; Alpers' disease; cross hemiplegia; Alzheimer's disease; vascular dementia; muscular atrophic lateral sclerosis; no brain; Anger Angelman syndrome; Hemangiomatosis; Hypoxia; Aphasia; Apraxia; Arachnoid cyst; Arachnoiditis; Anronl-Chiari malformation; Arteriovenous malformation; Asperger's syndrome (Asperger syndrome); Ataxia and microvasodilation syndrome; Attention deficit hyperactivity disorder; Autism; Autonomic dysfunction; Back pain; Batten disease; Behcet's disease (Behcet's disease); Bell's palsy; benign idiopathic blepharospasm; benign focal; muscular atrophy; benign intracranial hypertension; Binswanger's disease; blepharospasm; Bloch -Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal tumors; Brown-Sequard syndrome Canavan disease (Canavan disease); Carpal tunnel syndrome; Causal neuralgia; Central pain syndrome; Central pontine spinal cord dissolution; Head disorders; Cerebral aneurysm; Cerebral arteriosclerosis; Cerebral atrophy; Cerebral gigantism Cerebral palsy; Charcot-Marie-Tooth disease (Charcot-Marie-Tooth disease); chemotherapy-induced neuropathy and neuralgia; Chiari malformation; chorea; chronic inflammatory alopecia Myelin sheath polyneuropathy; chronic pain; chronic local pain syndrome; Coffin Lowry syndrome (Coffin Lowry syndrome); coma, including persistent vegetative state; congenital bifacial paralysis; cortical basal nucleus degeneration; cranial arteritis; Craniosynostosis; Creutzfeldt-Jakob disease; Cumulative traumatic disorder; Cushing's syndrome; Giant cell inclusion body disease; Cytomegalovirus infection; Ophthalmopod chorea syndrome; Dandy-Walker's Syndrome (Dandy-Walker syndrome); Dawson's disease (Daw son disease; De Morsier's syndrome; Dejerine-Klumke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; autonomic disorders Dyslexia; dyslexia; dystonia; early infantile epileptic encephalopathy; saddle syndrome; encephalitis; encephalocele; cerebral trigeminal neuroangiomatosis; epilepsy; Erb's palsy; idiopathic Tremor; Fabry's disease; Fahr's syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedlay Friedreich's ataxia (Friedreich's ataxia); frontotemporal dementia and other "tau protein diseases"; Gaucher's disease; Gerstmann's syndrome; giant cell arteritis; huge Cellular inclusion body disease; globular cell leukodystrophy; Guillain-Barre syndrome (Guillain-Barre syndrome); HTLV-1-related myelopathy; Hallervorden-Spatz disease (Hallervorden-Spatz disease) Head injury; headache; hemifacial spasm; hereditary spastic paraplegia; hereditary ataxia, polyneuritis; herpes zoster auris; herpes zoster; Hirayama syndrome; HIV-related dementia and neuropathy ( It is also a manifestation of the nervous system of AIDS); forebrain nonscission malformation; Huntington's disease and other polyglutamic acid duplication diseases; hydrocephalus; hydrocephalus; hypercortisolism; hypoxia; immune mediation Induced encephalomyelitis; Inclusion body myositis; Pigment disorder; Infant phytanic acid storage disease; Infantile refsum disease (infantile refsum disease); Infantile spasm; Inflammatory myopathy; Intracranial cyst; Intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Creepie Klippel Feil syndrome (Klippel Feil syndrome); Krabbe disease (Krabbe disease); Kugelberg-Welander disease (Kugelberg-Welander disease); Kuru's disease (kuru); Lafora's disease Disease (Lafora dise ase); Lambert-Eaton myasthenic syndrome (Lambert-Eaton myasthenic syndrome); Landau-Kleffner syndrome (Landau-Kleffner syndrome); lateral medulla (Wallenberg) syndrome ; Learning disabilities; Leigh's disease (Leigh's disease); Lennox-Gustaut syndrome (Lennox-Gustaut syndrome); Lesch-Nyhan syndrome (Lesch-Nyhan syndrome); Leukodystrophy; Lewy body dementia; Atresia syndrome; Lou Gehrig's disease (ie, motor neuron disease or amyotrophic lateral sclerosis); Intervertebral disc disease; Lyme disease-Nervous system sequelae; Machado- Machado-Joseph disease (Machado-Joseph disease); macro brain (macrencephaly); megalencephaly (megalencephaly); Melkersson-Rosenthal syndrome (Melkersson-Rosenthal syndrome); Menieres disease (Menieres disease); meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; small stroke; mitochondrial myopathy; Mouby Mobius syndrome; Single limb muscle atrophy; Motor neuron disease; Moyamoya disease; Mucopolysaccharidosis; Multi-infarct dementia; Multifocal motor neuropathy; Multiple sclerosis and other demyelination Sheath disorders; multiple system atrophy with orthostatic hypotension; p muscular dystrophy; myasthenia gravis; diffuse demyelinating sclerosis; infantile myoclonic encephalopathy; myoclonus; myopathy; congenital myotonia; paroxysmal Sleep sickness; neurofibromas; malignant syndrome of antipsychotic drugs; neurological manifestations of AIDS; neurological sequelae of lupus; neuromuscular rigidity; neuronal ceroid lipofuscinosis; neuronal migration disorder; Niemann-Pick's Niemann-Pick disease; O'Sullivan-McLeod syndrome; Occipital neuralgia; Recessive spinal neural tube closure sequence sign; Ohtahara syndrome; Olive body Pontine cerebellar atrophy; ocular clonus myoclonus; optic neuritis; postural hypotension; overuse syndrome; paresthesia; Parkinson's disease; congenital paramuscular rigidity; paraneoplastic disease; paroxysmal ; Parry Lombok syndrome ( Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralysis; peripheral neuropathy; painful neuropathy and neuralgia; persistent vegetative state; extensive developmental disorder; light Sneeze reflex; phytanic acid storage disease; Pick's disease; pinched nerve; pituitary tumor; polymyositis; brain penetrating malformation; post-polio syndrome; post-herpetic neuralgia; post-infection encephalomyelitis ; Orthostatic hypotension; Prader-Willi syndrome; Primary lateral sclerosis; Prion disease; Progressive hemifacial atrophy; Progressive multifocal leukoencephalopathy; Progressive sclerosis Gray matter atrophy; progressive supranuclear palsy; pseudo-brain tumor; Ramsay-Hunt syndrome (type I and II); Rasmussen's encephalitis; reflex sexual intercourse Sensory dystrophy syndrome; Revesum's disease; repetitive movement disorder; repetitive stress injury; restless leg syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye's syndrome syndrome; Saint Vitus dance; Sandhoff disease; Schilder's disease; split brain malformation; septal-optical dysplasia; infant shaking syndrome; belt Herpes; Shy-Drager syndrome; Sjögren's syndrome; sleep apnea; Soto's syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumor ; Spinal muscular atrophy; Stiff person syndrome; Stroke; Sturge-Weber syndrome; Subacute sclerosing panencephalitis; Subcortical arteriosclerotic encephalopathy; Sydenham chorea ); syncope; syringomyelia; delayed dyskinesia; Tay-Sachs disease; temporal arteritis; tethered cord syndrome; Thomsen disease; thoracic outlet syndrome; trigeminal nerve Pain; Todd's paralysis; Tourette syndrome; transient ischemic attack; infectious spongiform encephalopathy; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical Spastic paraplegia; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau disease (Von Hippel-Lindau disease); Wallenberg's syndrome (Wallenberg's syndrome); Werdnig-Hoffman disease (Werdnig-Hoffman disease); West syndrome (West syndrome) ; Whiplash; Williams syndrome; Wildon's disease; Amyotrophic lateral sclerosis; and Zellweger syndrome.

In some embodiments, the condition, disease, or disorder is a STING-related condition, such as type I interferon lesions (such as STING-related infantile-onset vascular disease (SAVI)), Icardi-Gortiers syndrome (AGS ), hereditary lupus and inflammation-related disorders, such as systemic lupus erythematosus and rheumatoid arthritis. In certain embodiments, the condition, disease, or disorder is an autoimmune disease (eg, cytoplasmic DNA triggered auto-inflammatory disease). Non-limiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (IBD), IBD including Crohn disease (CD) and ulcerative colitis (UC), It is a chronic inflammatory condition with polygenic susceptibility. In certain embodiments, the condition is inflammatory bowel disease. In certain embodiments, the condition is Crohn’s disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, Cell therapy to treat induced colitis, colitis, radiation enteritis, collagenous colon associated with one or more alloimmune diseases (such as graft-versus-host disease, such as acute graft-versus-host disease and chronic graft-versus-host disease) Inflammation, lymphocytic colitis, microscopic colitis and radiation enteritis. In some of these embodiments, the condition is an alloimmune disease (such as 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 (such as oral mucositis, esophageal mucositis or intestinal mucositis).

In some embodiments, STING modulates the immune system to provide treatment for diseases including diseases caused by foreign factors. Exemplary infections caused by external factors that can be treated and/or prevented by the method of the present invention include bacterial (eg, Gram-positive or Gram-negative bacteria) infections, fungal infections, parasitic infections, and viral infections. In an embodiment of the present invention, the infection is bacterial infection (for example, Escherichia coli ( E. coli ), Klebsiella pneumoniae ), Pseudomonas aeruginosa ( Pseudomonas aeruginosa ), Salmonella spp. , Staphylococcus aureus , Streptococcus spp. , or vancomycin-resistant enterococcus (infection caused by vancomycin-resistant enterococcus) or sepsis. In another embodiment, the infection is a fungal infection (for example, an infection caused by mold, yeast, or higher fungi). In yet another embodiment, the infection system is infected by parasites (for example, by unicellular or multicellular parasites, including Giardia duodenalis , Cryptosporidium parvum , Cyclosporidium ( Cyclospora cayetanensis ) and Toxoplasma gondiz ( Toxoplasma gondiz ). In yet another embodiment, the infection is a viral infection (for example, caused by AIDS, avian influenza, chickenpox, cold sore, cold, gastroenteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS and the Respiratory or upper respiratory tract infections (such as infections caused by viruses related to respiratory fusion virus).

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

In some embodiments, the condition, disease, or disorder is selected from cardiovascular disease (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 from chemotherapy or radiation therapy alone or in combination, and damage caused by exposure to radiation outside the radiation therapy environment.

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

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

Yet other examples may include the indications discussed herein and below in the covered combination therapy regimens. Combination therapy

This disclosure covers both monotherapy regimens and combination therapy regimens.

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

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

The one or more other cancer therapies may include, but are not limited to, surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, cancer vaccines (such as HPV vaccine, hepatitis B vaccine, Oncophage, Provenge), and gene therapy, and Its combination. Immunotherapy includes but is not limited to adoptive cell therapy, stem cell and/or dendritic cell derivation, blood transfusion, lavage and/or other treatments, including but not limited to cryotumor.

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

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

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

In certain embodiments, the additional chemotherapeutic agent is an alkylating agent. The alkylating agent is so named because it can alkylate many nucleophilic functional groups under the conditions that exist in cells, including but not limited to cancer cells. In another embodiment, the alkylating agent includes but is not limited to cisplatin, carboplatin, chlorambucil, cyclophosphamide, chlorambucil, ifosfamide, and/or oxaliplatin. In one embodiment, the alkylating agent can act by forming covalent bonds with the amine, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules to impair cell function, or it can act It works by modifying cell DNA. In another embodiment, the alkylating agent is a synthetic, semi-synthetic or derivative.

In certain embodiments, the additional chemotherapeutic agent is an antimetabolite. Antimetabolites disguise themselves as purines or pyrimidines, which are structural fragments of DNA, and generally prevent these substances from being incorporated into DNA during the "S" phase (of the cell cycle), preventing normal development and division. Antimetabolites can also affect RNA synthesis. In one embodiment, the anti-metabolite includes but is not limited to azathioprine and/or mercaptopurine. In another embodiment, the antimetabolite is a synthetic, semi-synthetic or derivative.

In certain embodiments, the additional chemotherapeutic agent is a plant alkaloid and/or terpenoid. These alkaloids are derived from plants and generally prevent cell division by preventing microtubule function. In one embodiment, the plant alkaloids and/or terpenoids are vinca alkaloids, podophyllotoxin and/or taxanes. Generally speaking, during the M phase of the cell cycle, vinca alkaloids generally bind to specific sites on tubulin, thereby inhibiting the assembly of tubulin into microtubules. In one embodiment, the vinca alkaloid is derived from, but not limited to, Madagascar periwinkle, Catharanthus roseus (previously known as Vinca rosea). In one embodiment, the vinca alkaloids include, but are not limited to, vincristine, vinblastine, vinorelbine, and/or vindesine. In one embodiment, the taxane includes, but is not limited to, paclitaxel, paclitaxel and/or docetaxel. In another embodiment, the plant alkaloids or terpenoids are synthetic, semi-synthetic or derivatives. In another embodiment, the podophyllotoxin is, but not limited to, etoposide and/or teniposide. In one embodiment, the taxane is based on, but not limited to, docetaxel and/or ortataxel. [021] In one embodiment, the cancer therapeutic agent is topoisomerase. Topoisomerase is an essential enzyme for maintaining the topological structure of DNA. Inhibition of type I or type II topoisomerase interferes with DNA transcription and replication by disrupting proper DNA supercoiling. In another embodiment, the topoisomerase is, but not limited to, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In one embodiment, the type I topoisomerase inhibitor is but not limited to camptothecin. In another embodiment, camptothecin is based on but not limited to exatecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67) And/or ST 1481. In one embodiment, the type II topoisomerase inhibitor is, but not limited to, epipodophyllotoxin. In another embodiment, the epipodophyllotoxin is but not limited to amsacrine, etoposide, etoposide phosphate and/or teniposide. In another embodiment, topoisomerases are synthetic, semi-synthetic or derivatives, including substances found in nature, such as, but not limited to, epipodophyllotoxin, which is naturally present in American Podophyllum (American Mayapple ) (Podophyllum peltatum) (Podophyllum peltatum).

In certain embodiments, the additional chemotherapeutic agent is a stilbene. In another embodiment, stilbenes include, but are not limited to, Resveratrol (Resveratrol), Paclitaxel (Piceatannol), Pinosylvin (Pinosylvin), Pterostilbene (Pterostilbene), Alpha-Viniferin , Ampelopsin A (Ampelopsin A), Ampelopsin E, Diptoindonesin C, Diptoindonesin F, ε-Vine, Flexuosol A, Gnetin H, Hemsleyanol D, Hopeaphenol, Trans-Diptoindonesin B, Astringin, Piceid ) And Diptoindonesin A. In another embodiment, stilbenes are synthetic, semi-synthetic or derivatives.

In certain embodiments, the additional chemotherapeutic agent is a cytotoxic antibiotic. In one embodiment, the cytotoxic antibiotic is, but not limited to, actinomycin, anthracenedione, anthracycline, thalidomide, dichloroacetic acid, nicotinic acid, 2-deoxyglucose and/or Chlorophenazine (chlofazimine). In one embodiment, the actinomycin is based on but not limited to actinomycin D, subtilisin, colistin (polymyxin E) and/or polymyxin B. In another embodiment, the anthrapenedione is based on but not limited to mitoxantrone and/or pixantrone. In another embodiment, anthracycline is based on but not limited to bleomycin, cranberry (Adriamycin), daunomycin (daunomycin), epirubicin Bicin, idarubicin, mitomycin, pracamycin and/or varrubicin. In another embodiment, the cytotoxic antibiotic is a synthetic, semi-synthetic or derivative.

In certain embodiments, the additional chemotherapeutic agent is selected from the group consisting of endostatin, angiopoietin, angiostatin, chemokine, angiostatin, angiostatin (plasminogen fragment), substrate Membrane collagen-derived anti-angiogenic factor (tumorstatin, angiostatin or inhibitory protein), anti-angiogenic antithrombin III, signal transduction inhibitor, chondrogenic inhibitor (CDI), CD59 complement fragment , Fibronectin fragment, gro-β, heparinase, heparin hexasaccharide fragment, human chorionic gonadotropin (hCG), interferon α/β/γ, interferon inducible protein (IP-10), interleukin -12. Semi-photosine crimp zone 5 (plasminogen fragment), metalloproteinase inhibitor (TIMP), 2-methoxyestradiol, placental ribonuclease inhibitor, plasminogen activator inhibitor Agent, platelet factor-4 (PF4), 16 kD fragment of prolactin, proliferation protein related protein (PRP), various retinoids, tetrahydrocortisol-S, thromboplastin-1 (TSP-1), transformation growth Factor-β (TGF-β), angiostatin, angiostatin (calreticulin fragment) and their analogs.

In certain embodiments, the additional 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-valinyl-L-valinyl-N-methyl-L-valinyl-L-proline-1-proline-third Butylamide, cachexia, cemadotin, chlorambucil, cyclophosphamide, 3',4'-didehydro-4'-deoxy-8'-demethylvinca Alkali (norvin-caleukoblastine), docetaxol (docetaxol), docetaxel, cyclophosphamide, carboplatin, carmustine (carmustine), cisplatin, cryptophycin (cryptophycin), cyclophosphamide , Cytarabine, dacarbazine (DTIC), Actinomycin D, Daunorubicin, Decitabine dolastatin, Cranberry (Adriamycin) , Etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyureataxanes, ifosfamide, liarozole, chlorine Nidamin (lonidamine), lomustine (CCNU), MDV3100, chlorambucil (nitrogen mustard), melphalan, mivobulin isethionate, rhizobia Rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxane, nilutamide, onapristone ), paclitaxel, prednimustine, procarbazine, RPR109881, stramustine phosphate, tamoxifen, tasonermin, paclitaxel, Retinoic acid (tretinoin), vinblastine, vincristine, vindesine sulfate and vinflunine.

In certain embodiments, the additional chemotherapeutic agent is platinum, cisplatin, carboplatin, oxaliplatin, chlorambucil, cyclophosphamide, chlorambucil, azathioprine, mercaptopurine, vincristine , Vinblastine, Vinorelbine, Vindesine, Etoposide and Teniposide, Paclitaxel, Docetaxel, Irinotecan, Topotecan, Amsacrine, Etoposide, Etoposide Phosphate , Teniposide, 5-fluorouracil, methotrexate, gemcitabine, taxane, leucovorin, mitomycin C, tegafur-urine Pyrimidine (tegafur-uracil), idarubicin, fludarabine, mitoxantrone, ifosfamide and cranberries. Additional agents include inhibitors of mammalian target of rapamycin (mTOR), including but not limited to rapamycin, everolimus, temsirolimus and dephos Moss (deforolimus).

In still other embodiments, the additional chemotherapeutic agent may be selected from the chemotherapeutic agents described in US Patent 7,927,613, which is incorporated herein by reference in its entirety.

In some embodiments, additional therapeutic agents and/or regimens can be used to treat other STING-related conditions, such as type I interferon lesions (such as STING-related infantile-onset vascular disease (SAVI)), Icardi-Gottier Therapeutic agents and/or regimens for Ster's Syndrome (AGS), hereditary lupus, and inflammation-related disorders, such as systemic lupus erythematosus and rheumatoid arthritis.

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

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of lupus include steroids, surface immunomodulators (such as tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel ®)), Thalidomide (Thalomid®), non-steroidal anti-inflammatory drugs (NSAIDs; such as ibuprofen and naproxen), antimalarials (such as hydroxychloroquine (chloroquinine)), corticosteroids (such as prednisone) Pine) and immunomodulators (such as ivotinib, iberdomide, voclosporin, cenerimod, azathioprine (Imuran®), cyclophosphamide ( Cytoxan®, Neosar®, Endoxan®) and cyclosporine (Neoral, Sandimmune®, Gengraf®) and mycophenolate mofetil) baricitinb, ilamore Germany (iguratimod), filotinib (filogotinib), GS-9876, rapamycin and PF-06650833), and biological products (such as belimumab (Benlysta®), anifrolizumab (Anifrolumab), prezalumab, MEDI0700, obinutuzumab, wabalimumab, lulizumab, ascecept, PF-06823859 and rupzo ( lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirolizumab (dapirolizumab), edratide, IFN-α-kinoid ), OMS721, RC18, RSLV-132, Ceralizumab (theralizumab), XmAb5871 and Ustekinumab (Stelara®)). For example, non-limiting treatments for systemic lupus erythematosus include non-steroidal anti-inflammatory drugs (NSAIDs; such as ibuprofen and naproxen), antimalarials (such as hydroxychloroquine (chloroquinine)), and corticosteroids (such as chloroquine) Nisone) and immunomodulators (e.g. Iberidamide, Fusporine, Azathioprine (Imuran®), Cyclophosphamide (Cytoxan®, Neosar®, Endoxan®) and Cyclosporine (Neoral, Sandimmune) ®, Gengraf®), and mycophenolate mofetil, baritinib, felotinib and PF-06650833), and biological products (such as belimumab (Benlysta®), anifrolizumab , Preluzumab, MEDI0700, Vobalizumab, Lulizumab, Acecept, PF-06823859 and Rupzo, Rituximab, BT063, BI655064, BIIB059, Aldesleukin (Proleukin® ), Dapirocumab, Ilatizumab, IFN-α-Ginonode, RC18, RSLV-132, Cerazumab, XmAb5871 and Ustekinumab (Stelara®)). As another example, non-limiting examples of the treatment of skin lupus include steroids, immunomodulators (such as tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel®)), GS-9876, felox Tinib and Thalidomide (Thalomid®). It is also possible to administer drugs and programs for the treatment of drug-induced lupus and/or neonatal lupus.

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of STING-related infantile-onset vascular disease (SAVI) include JAK inhibitors (e.g. tofacitinib, ruxolitinib, felotinib) And Baritinib).

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of Aicadi-Gortiers syndrome (AGS) include physical therapy, treatment of respiratory complications, anticonvulsant therapy for seizures, tube feeding, Nucleoside reverse transcriptase inhibitors (eg emtricitabine (eg Emtriva®), tenofovir (eg Viread®), emtricitabine/tenofovir (eg Truvada®), Zidovudine (zidovudine), lamivudine (lamivudine) and abacavir (abacavir), and JAK inhibitors (such as tofacitinib, luzotinib, felatinib and baritinib) .

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of IBD include 6-mercaptopurine, AbGn-168H, ABX464, ABT-494, adalimumab, AJM300, alicaforsen, AMG139, Anrukinzumab, apremilast, ATR-107 (PF0530900), autologous CD34 selected peripheral blood stem cell transplantation, azathioprine, bertilimumab, BI 655066, BMS-936557, PEGylated Certuzumab (Cimzia®), Cobitolimod, corticosteroids (such as prednisone, methylprednisolone, prednisone), CP-690,550, CT-P13, cyclosporine, DIMS0150, E6007, E6011, etrasimod, etrolizumab, fecal microbial transplantation, felotinib, fingolimod, non Firategrast (SB-683699) (previously known as T-0047), GED0301, GLPG0634, GLPG0974, guselkumab, golimumab, GSK1399686, HMPL-004 ( Andrographis paniculata extract), IMU-838, infliximab (infliximab), interleukin 2 (IL-2), Janus kinase (JAK) inhibitor, laquinimod, Masitinib (AB1010), matrix metalloproteinase 9 (MMP 9) inhibitors (eg GS-5745), MEDI2070, mesalamine, methotrexate, mirikizumab (LY3074828), natalizumab, NNC 0142-0000-0002, NNC0114-0006, ozanimod, peficitinib (JNJ-54781532), PF-00547659, PF -04236921, PF-06687234, QAX576, RHB-104, rifaximin, risankizumab, RPC1063, SB012, SHP647, sulfasalazine, TD-1473, thalidomide, Tilatrakizumab (MK 3222), TJ301, TNF-K inoid®, tofacitinib, tralokinumab, TRK-170, upadacitinib, ustekinumab, UTTR1147A, V565, vatelizumab (vatelizumab), VB -201, vedolizumab and vidofludimus.

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of irritable bowel syndrome include alosetron (alosetron), bile acid sequestrants (such as cholestyramine, colestipol), Colesevelam), chloride channel activators (such as lubiprostone), coated peppermint oil capsules, desipramine, dicyclomine, iba Ebastine, eluxadoline, farnesol X receptor agonists (such as obeticholic acid), fecal microbiota transplantation, fluoxetine, gabapentin ), guanylate cyclase-C agonist (such as linaclotide, plecanatide), ibodutant, imipramine, JCM-16021 , Loperamide (loperamide), lubiprostone, nortriptyline (nortriptyline), ondansetron (ondansetron), opioids, paroxetine (paroxetine), pinaverium (pinaverium), polyethylene two Alcohol, pregabalin, probiotics, ramosetron, rifaximin and tanpanor.

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

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of Crohn's disease (CD) include adalimumab autologous CD34-selected peripheral blood stem cell transplantation 6-mercaptopurine, azathioprine, polyethylene glycol Alcoholized Certuzumab (Cimzia®), corticosteroids (such as prednisone), Itolizumab, E6011, fecal microbial transplantation, felatinib, gusecuzumab, infliximab, IL- 2. JAK inhibitors, matrix metalloproteinase 9 (MMP 9) inhibitors (such as GS-5745), MEDI2070, meteramine, methotrexate, natalizumab, ozanimol, RHB-104, Rifaximin, Risenkizumab, SHP647, Sulfasalazine, Thalidomide, Yopatinib, V565 and Vedolizumab.

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of UC include AbGn-168H, ABT-494, ABX464, apremilast, PF-00547659, PF-06687234, 6-mercaptopurine, Ada Lumumab, azathioprine, bertilimumab, brazikumab (MEDI2070), cobitolimod, pegylated ertuzumab (Cimzia®) , CP-690,550, corticosteroids (such as multimax budesonide, methylprednisolone), cyclosporine, E6007, irasmo, idolizumab, fecal microbial transplantation, felotinib, Gusecumab, golimumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitors (such as GS-5745), mexelamine, mexelamine , Milikizumab (LY3074828), RPC1063, Risenkizumab (BI 6555066), SHP647, Sulfasalazine, TD-1473, TJ301, Tiralizumab (MK 3222), Tofacitinib, Tofacitinib, ustekinumab, UTTR1147A and vedolizumab.

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of autoimmune colitis include corticosteroids (eg budesonide, prednisone, prednisolone, Beclometasone dipropionate) , Diphenoxylate/atropine, infliximab, loperamide, mexylamine, TIP60 inhibitor (see, for example, US Patent Application Publication No. 2012/0202848) and Vedolizumab.

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

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of colitis induced by one or more chemotherapeutic agents include corticosteroids (e.g. budesonide, prednisone, prednisolone, beclosan dipropionate) Methasone), diphenoxylate/atropine, infliximab, loperamide, mexylamine, TIP60 inhibitor (see, for example, US Patent Application Publication No. 2012/0202848) and vedolizumab.

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of colitis induced by adoptive cell therapy treatment include corticosteroids (eg budesonide, prednisone, prednisolone, beclomethasone dipropionate) , Phenethylpiperidine/atropine, infliximab, loperamide, mexylamine, TIP60 inhibitor (see, for example, US Patent Application Publication No. 2012/0202848) and vedolizumab.

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

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

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of collagenous colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, Boswellia serrata extract, cholestyramine , Cholestap, corticosteroids (such as budesonide, prednisone, prednisolone, beclomethasone dipropionate), loperamide, meteramine, methotrexate, probiotics and salix Azosulfapyridine.

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of lymphocytic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, cholestyramine, colestipro, corticosteroids (such as Budesonide, prednisone, prednisolone, beclomethasone dipropionate), loperamide, meteramine, methotrexate and sulfasalazine.

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of microscopic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, Boswellia serrata extract, cholestyramine, colestyrol Prednisone, corticosteroids (such as budesonide, prednisone, prednisolone, beclomethasone dipropionate), fecal microbial transplantation, loperamide, meteramine, methotrexate, probiotics and willow Azosulfapyridine.

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of alloimmune diseases include intrauterine platelet transfusion, intravenous immunoglobulin, maternal use of steroids, abatacept, alemtuzumab, α1-antitrypsin , AMG592, antithymocyte globulin, baritinib, basiliximab, bortezomib, bentuximab, cannabidiol, corticosteroids (such as methylprednisone, prednisone), ring Sporomycin, dacilzumab, defibrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, infliximab Anti-, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, nehulizumab, pentostatin, Pevonedistat, photobiomodulation, photoremoval, luzotinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vermodil.

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

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of graft-versus-host disease include abatacept, alemtuzumab, α1-antitrypsin, AMG592, antithymocyte globulin, baritinib, Basiliximab, bortezomib, pentuximab, cannabidiol, corticosteroids (such as methylprednisone, prednisone), cyclosporine, darcilizumab, defibrin, Dini Interleukin, Glacibe, Ibrutinib, IL-2, Imatinib, Infliximab, Itatinib, LBH589, Maraviroc, Mycophenolate Morpholinate, Natalizidine Antibodies, Nehulizumab, Penstatin, Pervotat, Photobiomodulation, Photoremoval, Luzotinib, Sirolimus, Sondesine, Tacrolimus, Tocilizumab and Vitamin Modji.

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of acute graft-versus-host disease include alemtuzumab, alpha-1 antitrypsin, antithymocyte globulin, basiliximab, pentuximab Monoclonal antibodies, corticosteroids (such as methylprednisone, prednisone), cyclosporine, daclizumab, defibrillation, dini-interleukin, ibrutinib, infliximab, itatidine Ni, LBH589, mycophenolate mofetil, natalizumab, nerolizumab, pentostatin, photoremoval method, luzotinib, sirolimus, tacrolimus, and tocilizumab anti.

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of chronic graft-versus-host disease include abatacept, alemtuzumab, AMG592, antithymocyte globulin, basiliximab, bortezomib, Corticosteroids (such as methylprednisone, prednisone), cyclosporine, darcilizumab, dini-interleukin, glasdegib, ibrutinib, IL-2, imatinib, Infliximab, mycophenolate mofetil, pentostatin, photobiomodulation, photoremoval method, luzotinib, sirolimus, sondeji, tacrolimus, tocilizumab and Vimodji.

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

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of psoriasis include corticosteroids for surface, crisaborole/AN2728 for surface, SNA-120 for surface, SAN021 for surface, and tapinarol for surface (Tapinarof), tocafinib for surface, IDP-118 for surface, M518101 for surface, calcipotriene and betamethasone dipropionate (such as MC2-01 cream and Taclonex® ), P-3073 for surface, LEO 90100 for surface (Enstilar®), betamethasone dipropionate (Sernivo®) for surface, halobetasol propionate (Ultravate®), vitamin D analogs ( Such as calcipotriol (Dovonex®) and calcitriol (Vectical®), anthralin (such as Dritho-scalp® and Dritho-crème®), surface retinoids (such as Tazarotene (such as Tazorac® and Avage®), calcineurin inhibitors (such as tacrolimus (Prograf®) and pimecrolimus (Elidel®)), salicylic acid, coal Tar, moisturizers, light therapy (such as exposure to sunlight, UVB light therapy, narrow-band UVB light therapy, Goeckerman therapy, psoralen plus UV A (PUVA) therapy, and excimer Laser), retinoids (such as acitretin (Soriatane®)), methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), Apo805K1, baritinib, FP187, KD025 , Prurisol, VTP-43742, XP23829, ZPL-389, CF101 (piclidenoson), LAS41008, VPD-737 (serlopitant), Yopatinib (ABT -494), aprmilast, tofacitibin, cyclosporine (Neoral®, Sandimmune®, Gengraf®), biological products (such as etanercept (Enbrel®), enamel Cipro-szzs (Elrezi®), Infliximab (Remicade®), Adalimumab (Humira®), Adalimumab-adbm (Cyltezo®), Ustekinumab (Stelara®), Goli Simpo ni®), apramilast (Otezla®), seculizumab (Cosentyx®), pegylated certuzumab, seculizumab, tilatuzumab-asmn, infliximab Anti-dyyb, abatacept, ixekizumab (Taltz®), ABP 710, BCD-057, BI695501, bimekizumab (UCB4940), CHS-1420, GP2017, Gusaicu Monoclonal antibody (CNTO 1959), HD203, M923, MSB11022, Milikimab (LY3074828), PF-06410293, PF-06438179, Risenkiimab (BI655066), SB2, SB4, SB5, siliq (Broda Brodalumab (brodalumab), namilumab (MT203, tildrakizumab (MK-3222) and ixekizumab (Taltz®)), thioguanine and Hydroxyurea (such as Droxia® and Hydrea®).

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of cutaneous T-cell lymphoma include phototherapy (e.g. exposure to sunlight, UVB phototherapy, narrow-band UVB phototherapy, Gockman therapy, psoralen plus ultraviolet Light A (PUVA) therapy and excimer laser), external light removal method, radiation therapy (such as spot radiation and whole body electron beam therapy), stem cell transplantation, corticosteroids, imiquimod, bexarotene coagulation Glue (bexarotene gel), dichloroethyl nitrourea for surface, chlorambucil gel, vorinostat (Zolinza®), romidepsin (Istodax®), Pratroxa (Pralatrexate) (Folotyn®) biological products (such as alemtuzumab (Campath®), Bentuximab (SGN-35), mogamulizumab and IPH4102).

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of uveitis include corticosteroids (such as intravitreal triamcinolone acetonide injectable suspension), antibiotics, antiviral agents (such as acyclovir) , Dexamethasone, immunomodulators (such as tacrolimus, leflunomide, cyclophosphamide (Cytoxan®, Neosar®, Endoxan®) and cyclosporine (Neoral®, Sandimmune®, Gengraf®), Chlorambucil, azathioprine, methotrexate and mycophenolate mofetil), biological products (such as infliximab (Remicade®), adalimumab (Humira®), etanercept (Enbrel®), Golimumab (Simponi®), Certuzumab (Cimzia®), Rituximab (Rituxan®), Abatacept (Orencia®), Basiliximab (Simulect ®), Anakinra (Kineret®), Canakinumab (Ilaris®), Gevokixumab (XOMA052), Tocilizumab (Actemra®), Alemtuzumab (Campath®), ifazizumab (Raptiva®), LFG316, sirolimus (Santen®), abatacept, sarilumab (Kevzara®) and daclizumab (Zenapax®) ), cytotoxic drugs, surgical implants (e.g., peptone insert), and vitrectomy.

Non-limiting examples of additional therapeutic agents and/or regimens for the treatment of mucositis include AG013, SGX942 (dusquetide), amifostine (Ethyol®), cryotherapy, Xipaco Cepacol lonzenges, capsaicin tablets, mucosal adhesives (such as MuGard®), oral diphenhydramine (such as Benadry® elixirs), oral bioadhesives (such as polyvinylpyrrolidone-sodium hyaluronate) Gel (Gelclair®)), oral lubricants (such as oral Balance®), carfeso (caphosol), German chamomilla (chamomilla recutita) mouthwash, edible grape plant exosomes, disinfectant mouthwash (such as Portuguese Chlorhexidine gluconate (such as Peridex® or Period®), topical pain relievers (such as lidocaine, benzocaine, dyclonine hydrochloride) , Xylocaine (such as viscous xylocaine 2%) and Ulcerease® (0.6% phenol), corticosteroids (such as prednisone), analgesics (such as ibuprofen, naproxen, Acetaminophen and opioids), GC4419, palifermin (keratinocyte growth factor; Kepivance®), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide (Rebamipide), nepidermin, soluble β-1,3/1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, Including granules of vaccinium myrtillus extract, macleaya cordata alkaloids and echinacea angustifolia extracts (such as SAMITAL®) and gastrointestinal mixtures (acid reducing agents, such as Aluminum hydroxide and magnesium hydroxide (such as Maalox), antifungal agents (such as nystatin) and analgesics (such as hurricane liquid). For example, non-limiting treatment of oral mucositis Sexual examples include AG013, Amifostine (Ethyol®), cryotherapy, Cipaco ear lozenges, mucosal adhesives (such as MuGard®), oral diphenhydramine (such as Benadry® elixirs), oral bioadhesives (Such as polyvinylpyrrolidone-sodium hyaluronate gel (Gelclai r®)), oral lubricants (such as Oral Balance®), carfeso, German chamomile mouthwash, edible grape plant extracellular bodies, disinfectant mouthwashes (such as chlorhexidine gluconate (such as Peridex® or Periogard®), topical pain relievers (such as lidocaine, benzocaine, dyclonine hydrochloride, syrocaine (such as viscous syrocaine 2%) and Ulcerease® (0.6% phenol) ), corticosteroids (such as prednisone), analgesics (such as ibuprofen, naproxen, acetaminophen and opioids), GC4419, Palivum (keratinocyte growth factor; Kepivance®), ATL- 104, Clonidine Lored, IZN-6N4, SGX942, Rebamipide, Nepidamine, Soluble β-1,3/1,6-Glucan, P276, LP-0004-09, CR-3294, ALD- 518, IZN-6N4, quercetin and gastrointestinal mixed liquid (acid reducing agents, such as aluminum hydroxide and magnesium hydroxide (such as Maalox), antifungal agents (such as antiseptic) and analgesics (such as hurricane liquid) ). As another example, a non-limiting example of treatment for esophageal mucositis includes syroccaine (eg, viscous syroccaine gel 2%). As another example, the treatment of intestinal mucositis, the treatment of regulating intestinal mucositis, and the treatment of intestinal mucositis signs and symptoms include gastrointestinal mixtures (acid reducing agents such as aluminum hydroxide and magnesium hydroxide (such as Maalox)), antifungal Agents (such as antiseptic and analgesics (such as hurricane liquid)).

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

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

In still other embodiments, the second therapeutic agent or regimen is after contact with or administration of the chemical entity (for example, after about one hour, or after about 6 hours, or after about 12 hours, or after about After 24 hours, or after about 48 hours, or after about 1 week, or after about 1 month), the subject is administered. Patient selection

In some embodiments, the methods described herein further include the step of identifying individuals (eg patients) in need of such treatment (eg, by means of biopsy, endoscopy, or other conventional methods known in the art). In certain embodiments, the STING protein can serve as a biomarker for certain types of cancer, such as colon cancer and prostate cancer. In other embodiments, identifying an individual may include analyzing the absence of T cells and/or the presence of depleted T cells in the tumor microenvironment of the patient, such as patients with one or more cold tumors. Such patients may include patients who are resistant to checkpoint inhibitor therapy. In certain embodiments, such patients can be treated with the chemical entities described herein, for example to recruit T cells into the tumor, and in some cases, for example, after T cell exhaustion, further treatment with one or more checkpoint inhibitors treatment.

In some embodiments, the chemical entities, methods, and compositions described herein can be administered to certain groups of treatment-resistant patients (for example, patients who are resistant to checkpoint inhibitors; for example, have one or more cold tumors, such as Patients without T cells or T cell depleted tumors). Compound preparation

Those familiar with the art can understand that the methods for synthesizing the compounds of various formulae herein will be obvious to those familiar with the art. For example, the compounds described herein can be synthesized, for example, using one or more methods described herein and/or using methods such as those described in US 2015/0056224, and the contents of each of these documents are hereby incorporated by reference in their entirety. . The synthetic chemical transformation and protecting group methods (protection and deprotection) that can be used to synthesize the compounds described herein are known in the art and include, for example, the methods described in: R. Larock, "Comprehensive Organic Transformation (Comprehensive Organic Transformation) Organic Transformations), VCH Publishers (1989); TWGreene and RGM. Wuts, "Protective Groups in Organic Synthesis", 2nd edition, John Wiley and Sons (1991); L. Fieser and M. Fieser, "Fieser and Fieser's Reagents for Organic Synthesis", John Wiley and Sons (1994); and L. Paquette, "Encyclopedia of Reagents for Organic Synthesis" (Encyclopedia of Reagents) for Organic Synthesis)", John Wiley and Sons (1995), and subsequent versions. The starting materials used to prepare the compounds of the present invention are known, prepared by known methods, or are commercially available. Those familiar with the technology will also recognize that the conditions and reagents described herein are interchangeable with the recognized equivalents in the alternative technology. For example, in many reactions, triethylamine can be combined with other bases, such as non-nucleophilic bases (such as diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di Tertiary butyl pyridine or tetrabutyl phosphazene) interchange.

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

To further illustrate the foregoing, the following non-limiting exemplary synthesis schemes are included. Variations of these examples within the scope of the patent application are within the skill of those skilled in the art and are deemed to be within the scope of the present invention as described and claimed herein. The reader will recognize that those skilled in the present disclosure and familiar with the art can make and use the present invention without detailed examples. Instance

流程 1 For illustrative purposes, general methods for the synthesis of compounds of formula I are depicted in Schemes 1 and 2 .

Process 1

流程 2 With reference to Scheme 1 , the compound of formula I (shown as compound 3-I in Scheme 1) can be connected via carboxylic acid 1-I and amine 2- I (in 1-I , ring B is as defined for formula I ; and in 2 -I, ring A is as defined for formula I) prepared by coupling, in the compound of formula I, W ¹ based NH; W ² based chemical bond, CH _2, CH R ^a or C R ^a ₂ (e.g. CH _2); and Ring A and Ring B are as defined for Formula I. Coupling can be carried out under standard conditions for the formation of amide bonds (for example, in the presence of carboxyl activators such as HATU, DCC, EDCI, etc.).

Process 2

Referring to Scheme 2 , the compound of formula I (shown as compound 3-II in Scheme 2) can be passed through carboxylic acid 2-II and amine 1-II (in 1-II , ring B is as defined for formula I ; and in 2 -II, ring A is as defined for formula I) prepared by coupling, in the compound of formula I, W ¹ based bond or CH _2, CH R ^a or C R ^a ₂ (e.g. CH ^_2); W ₂ based NH; and Ring A and Ring B are as defined for Formula I. Coupling can be carried out under standard conditions for the formation of amide bonds (for example, in the presence of carboxyl activators such as HATU, DCC, EDCI, etc.).

The following examples are prepared according to the methods shown in Schemes 1 and 2 . LC-MS uses the following columns and settings to perform compound analysis: Shim-pack XR-ODS, C18, 3×50 mm, 2.5 μm column, 1.0 μL injection, 1.5 mL/min flow rate, 90-900 amu scanning range , 190-400 nm UV range, 5-100% (1.1 minutes), 100% (0.6 minutes) ACN (0.05% TFA) / water (0.05% TFA) gradient, and the total running time is 2.0 minutes. Abbreviation of chemical terms ACN = Acetonitrile AcOH = Acetic acid BTC = Trichloromethyl chloroformate DBU = 1,8-Diazabicycloundec-7-ene DCM = Dichloromethane Dess-Martin = (1,1,1 -Triacetoxy)-1,1-dihydro-1,2-benzodioxol-3(1H)-one DIEA = N-ethyl-N-isopropylpropan-2-amine DMEDA = N,N'-dimethylethylenediamine DMF = N,N-dimethylformamide DMSO = dimethyl sulfide Et = ethyl EtOH = ethanol FA = formic acid HATU = N-((dimethyl Amino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylammonium hexafluorophosphate N-oxide HPLC = high efficiency Liquid chromatography LC-MS = liquid chromatography-mass spectrometry LDA = lithium diisopropylamine Me = methyl MeOH = methanol n-Bu = n-butyl NBS = N-bromosuccinimide NCS = N -Chlorosuccinimidyl NIS = N-iodosuccinimidyl NMR = Nuclear magnetic resonance Pd(dppf)Cl ₂ = Dichloro[1,1'-bis(diphenylphosphino)ferrocene] Palladium Pd (PPh3) ₄ = Si (triphenylphosphine) Palladium (0) Ph = phenyl HPLC = high performance liquid chromatography PTSA = p-toluenesulfonic acid Py = pyridine RT = room temperature Speedvac = Savant SC250EXP SpeedVac concentrator TBAF = fluorine Tetrabutylammonium chloride TBDPSCl = tertiary butyl diphenylchlorosilane t-Bu = tertiary butyl TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran Ti(i-PrO) ₄ = tetraisopropyl titanate Ester TLC = thin layer chromatography materials and methods

The progress of the reaction is usually monitored by TLC or LC-MS. Product attributes are usually determined by LC-MS. LC-MS was recorded using one of the following methods.

Method A : Titank C18, 50×3 mm, 3 um column, 0.3 uL injection, 1.5 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water + 5mM NH ₄ HCO ₃ and mobile phase B: acetonitrile. 10% MPB to 95.0% in 1.39 minutes, hold for 0.8 minutes at 95% MPB, 95% to 10% MPB in 0.03 minutes, then equilibrate to 10% MPB, hold for 0.27 minutes.

Method B : XBridge C18, 50×3mm, 2.8 um column, 0.2 uL injection, 1.2 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water + 5mM NH ₄ HCO ₃ and mobile phase B: acetonitrile. 10% MPB to 95.0% in 1.99 minutes, hold for 0.6 minutes at 95% MPB, 95% to 10% MPB in 0.20 minutes, then equilibrate to 10% MPB, hold for 0.2 minutes.

Method C : Shim-pack XR-ODS, 50×3 mm, 2.2 um column, 2 uL injection, 1.2 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water/0.05% TFA and mobile phase B: acetonitrile/0.05% TFA. 5% MPB to 100.0% in 1.09 minutes, hold at 100% MPB for 0.6 minutes, 100% MPB to 5% in 0.02 minutes, then equilibrate to 5% MPB, hold for 0.38 minutes.

Method D : CORTECS C18+, 50×2.1 mm, 2.7 um column, 0.8 uL injection, 0.8 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water/0.1% FA and mobile phase B: acetonitrile/0.1% FA. 10% MPB to 95.0% in 1.09 minutes, hold at 95% MPB for 0.5 minutes, 95% MPB to 5% in 0.03 minutes, then equilibrate to 5% MPB, hold for 0.2 minutes.

Method E : SPD-M20A, 0.8 uL injection, 0.8 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water/5mM NH ₄ HCO ₃ and mobile phase B: acetonitrile. 10% MPB to 95.0% in 1.09 minutes, hold for 0.5 minutes at 95% MPB, 95% to 5% MPB in 0.1 minutes, then equilibrate to 10% MPB, hold for 0.1 minutes.

Method F : Shim-pack XR-ODS, 50×3 mm, 3.0 um column, 0.5 uL injection, 0.2 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water/0.05% TFA and mobile phase B: acetonitrile/0.05% TFA. 5% MPB to 100.0% in 1.09 minutes, hold for 0.6 minutes at 100% MPB, 100% to 5% MPB in 0.05 minutes, then equilibrate to 5% MPB, hold for 0.15 minutes.

Method G : Shim-pack XR-ODS, 50×3 mm, 2.2 um column, 0.5 uL injection, 1.2 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water/0.05% TFA and mobile phase B: acetonitrile/0.05% TFA. 5% MPB to 95.0% in 1.99 minutes, hold for 0.7 minutes at 95% MPB, 95% to 5% MPB in 0.05 minutes, then equilibrate to 5% MPB, hold for 0.25 minutes.

Method H : Shim-pack XR-ODS, 50*3.0 mm, 2.2 uL injection, 1.2 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water (0.05% TFA) and mobile phase B: acetonitrile/0.05% TFA. 20% MPB to 70.0% in 2.49 minutes, 70.0% MPB to 95.0% in 0.5 minutes, hold at 95% MPB for 0.6 minutes, 95% MPB to 5% in 0.1 minutes, then balance to 5% MPB, keep 0.3 minutes.

Method I : CORTECS C18+ MVK, 50 * 2.1 mm 0.4 uL injection, 1.0 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water + 0.1% FA, mobile phase B: acetonitrile + 0.05% FA. 10% MPB to 100% in 2.0 minutes, hold at 100% MPB for 0.75 minutes, 100% MPB to 10% in 0.02 minutes, then equilibrate to 10% MPB, hold for 0.23 minutes. Method J : EVO C18, 50*3.0 mm, 2.6 um, 1.2 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water/5mM NH ₄ HCO ₃ , mobile phase B: acetonitrile; 10% MPB to 95% in 1.99 minutes, hold at 95% MPB for 0.6 minutes, and 95% MPB to 10% in 0.15 minutes, then Equilibrate to 10% MPB and hold for 0.25 minutes.

Method K : Shim-pack XR-ODS, 50*3.0 mm, 1.0 uL injection, 1.2 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water/5mM NH ₄ HCO ₃ ; mobile phase B: acetonitrile; 65% MPB to 95% in 2.79 minutes, hold at 95% MPB for 0.6 minutes, and 95% MPB to 5% in 0.15 minutes, then Equilibrate to 5% MPB and hold for 0.15 minutes.

Method L : XBridge C18, 50*3.0 mm, 0.3 uL injection, 1.2 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water (5 mmoL/L NH ₄ HCO ₃ ) and mobile phase B: MeCN. 10% MPB to 70.0% in 3.0 minutes, 70% MPB to 95% in 0.25 minutes, hold at 95% MPB for 0.35 minutes, 95% MPB to 10% in 0.3 minutes, then balance to 10% MPB, hold 0.10 minutes.

Method M : kinetex XB-C18 100A, 30*2.1mm, 1.7 um, 0.8 uL injection, 1.0 mL/min flow rate, 90-900 amu scanning range, 210 nm UV detection. Mobile phase A: water + 0.05% TFA; mobile phase B: acetonitrile + 0.05% TFA, 5% MPB to 100% in 1.5 minutes, hold at 100% MPB for 0.8 minutes, and 100% MPB to 5% in 0.03 minutes , Then equilibrate to 5% MPB and hold for 0.17 minutes.

Method N : XBridge C18, 50 * 2.1 mm, 0.7 uL injection, 1.2 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water (5 mmoL/L NH ₄ HCO ₃ ) and mobile phase B: MeCN. 30% MPB to 80.0% in 1.79 minutes, 80% MPB to 95% in 0.2 minutes, hold at 95% MPB for 0.3 minutes, 95% MPB to 10% in 0.1 minutes, then balance to 10% MPB, hold 0.20 minutes.

Method O : Kinetex EVO C18, 50 * 3 mm, 3 uL injection, 1.2 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water (5 mmoL/L NH ₄ HCO ₃ ) and mobile phase B: MeCN. 10% MPB to 95.0% in 1.99 minutes, hold for 0.6 minutes at 95% MPB, 95% to 10% MPB in 0.15 minutes, then equilibrate to 10% MPB, hold for 0.25 minutes.

Method P : SPD-M20A, 0.8 uL injection, 1.2 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: 0.04% NH ₃ .H ₂ O and mobile phase B: MeCN. 10% MPB to 95.0% in 1.10 minutes, hold at 95% MPB for 0.5 minutes, 95% MPB to 10% in 0.01 minutes, then equilibrate to 10% MPB, hold for 0.21 minutes.

Method Q : Shim-pack XR-ODS, 50*3.0 mm, 5.0 uL injection, 1.2 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water/0.05% TFA; mobile phase B: acetonitrile/0.05% TFA; 5% MPB to 95% in 1.99 minutes, hold at 95% MPB for 0.7 minutes, and 95% MPB to 5% in 0.05 minutes , Then equilibrate to 5% MPB and hold for 0.25 minutes.

Method R : Titank C18, 50×3 mm, 3 um column, 0.3 uL injection, 1.5 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water + 5mM NH ₄ HCO ₃ and mobile phase B: acetonitrile. 10% MPB to 95.0% in 1.79 minutes, hold for 0.8 minutes at 95% MPB, 95% to 10% MPB in 0.15 minutes, then equilibrate to 10% MPB, hold for 0.25 minutes.

Method S : Titank C18, 50*3.0 mm, 2.2 uL injection, 1.5 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water (0.05% NH ₄ HCO ₃ ) and mobile phase B: MeCN. 20% MPB to 70% in 2.25 minutes, 70% MPB to 95% in 0.75 minutes, hold at 95% MPB for 0.5 minutes, 95% MPB to 10% in 0.05 minutes, then balance to 10% MPB, hold 0.25 minutes.

Method T : Titank C18, 50*3.0 mm, 1 uL injection, 1.5 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water (0.05% NH ₄ HCO ₃ ) and mobile phase B: MeCN. 10% MPB to 95% in 1.79 minutes, hold for 0.8 minutes at 95% MPB, 95% to 10% MPB in 0.15 minutes, then equilibrate to 10% MPB, hold for 0.25 minutes.

Method U : SPD-M20A, 0.5 uL injection, 1.5 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water (0.05% NH ₄ HCO ₃ ) and mobile phase B: MeCN. 40% MPB to 95% in 1.99 minutes, hold for 0.6 minutes at 95% MPB, 95% to 10% MPB in 0.15 minutes, then equilibrate to 10% MPB, hold for 0.25 minutes.

Method V : SPD-M20A, 0.5 uL injection, 1.2 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water/5mM NH ₄ HCO ₃ and mobile phase B: acetonitrile. 10% MPB to 95.0% in 1.99 minutes, hold for 0.6 minutes at 95% MPB, 95% to 10% MPB in 0.15 minutes, then equilibrate to 10% MPB, hold for 0.25 minutes.

Method W : SPD-M20A, 1.2 mL/min flow rate, 90-900 amu scanning range, 254 nm UV detection. Mobile phase A: water (0.05% TFA) and mobile phase B: acetonitrile/0.05% TFA. 30% MPB to 100.0% in 2.99 minutes, hold at 100% MPB for 0.7 minutes, 100% MPB to 5% in 0.05 minutes, then equilibrate to 5% MPB, hold for 0.25 minutes.

method X : Instrument: Agilent LCMS system equipped with DAD and ELSD detectors Ion mode: positive ion To Column: Waters X-Bridge C18, 50*2.1 mm*5 μm or equivalent To Mobile phase: A: H ₂ O (0.04% TFA); B: CH ₃ CN (0.02% TFA) To Gradient: 4.5-minute gradient method, the actual method will depend on the clogP of the compound. Flow rate: 0.6 mL/min or 0.8 mL/min To Column temperature: 40℃ or 50℃ UV: 220 nm To

method Y : Instrument: Agilent LCMS system equipped with DAD and ELSD detectors Ion mode: positive ion To Column: Waters X-Bridge ShieldRP18, 50*2.1 mm*5 μm or equivalent To Mobile phase: A: H ₂ O (0.05% NH ₃ ·H ₂ O) or 10 mM ammonium bicarbonate; B: CH ₃ CN To Gradient: 4.5 minute gradient method; the actual method will depend on the clogP of the compound. Flow rate: 0.6 mL/min or 0.8 mL/min To Column temperature: 40℃ UV: 220 nm To

Some compounds were purified by preparative HPLC. The parameters of the preparative HPLC used are described below. instrument: 1. GILSON 281 and Shimadzu LCMS 2010A 2. GILSON 215 and Shimadzu LC-20AP 3. GILSON 215 mobile phase: A: NH ₄ OH/H ₂ O = 0.05% v/v; B: ACN A: FA/H ₂ O = 0.225% v/v; B: ACN column Xtimate C18 150*25mm*5µm Flow rate: 25 mL/min or 30 mL/min Monitor wavelength: 220&254 nm Gradient: The actual method will depend on the compound's clog P detection Device: MS Trigger or UV preparation example

1. 合成 2-(2- 側氧基 -2- 苯基乙基 )-2,3- 二氫 -1H- 異吲哚 -1,3- 二酮

The preparation process of the intermediate: The following process illustrates the preparation of the intermediate. Intermediate preparation process: Process 1 : Synthesis of intermediate 1 ( 3- phenyl -1H- pyrazole- 4- amine)

1. Synthesis of 2-(2- side oxy -2 -phenylethyl )-2,3 -dihydro- 1H- isoindole- 1,3 -dione

Dissolve 2-bromo-1-phenylethan-1-one (10.0 g, 50.2 mmol, 1.0 equiv) in DMF (100 mL). Potassium 2,3-dihydro-1H-isoindole-1,3-dione (18.7 g, 100.5 mmol, 2.0 equiv) was added, and the resulting solution was stirred at 80°C for 4 hours. The resulting solution was extracted with 3×500 mL ethyl acetate. The resulting mixture was washed with 5 x 500 mL H ₂ O. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column and ethyl acetate/petroleum ether (1:1) was used as the eluent. 2-(2-Penoxy-2-phenylethyl)-2,3-dihydro-1H-isoindole-1,3-dione (12.9 g, 96.8%) was obtained as a yellow solid. LCMS method A, MS-ESI, 266.2 [M+H ⁺ ]. 2. Synthesis of 2-[(1Z)-1-( dimethylamino )-3- side oxy- 3 -phenylprop- 1 -en -2- yl ]-2,3 -dihydro -1H- Isoindole- 1,3 -dione

Add 2-(2-oxo-2-phenylethyl)-2,3-dihydro-1H-isoindole-1,3-dione (12.5 g, 41.5 mmol, 1.0 equiv, 88%) Dissolve in (dimethoxymethyl)dimethylamine (200 mL) and stir at 90°C for 3 hours. The resulting solution was extracted with 3 x 500 mL EtOAc. The resulting mixture was washed with 3 x 1 LH ₂ O. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column, using ethyl acetate/petroleum ether (1:1) as the eluent. 2-[(1Z)-1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl]-2,3-dihydro was obtained as a yellow solid -1H-Isoindole-1,3-dione (9.5 g, 71.5%). LCMS method B, MS-ESI: 321.1M+H ⁺ ]. 3. Synthesis of 3- phenyl -1H- pyrazol- 4- amine

1. 合成 3- 硝基 -1- 苯基吡唑

The 2-[(1Z)-1-(dimethylamino)-3-side oxy-3-phenylprop-1-en-2-yl]isoindole-1,3-dione (9.5 g, 29.7 mmol, 1.0 equiv) was dissolved in EtOH (100.0 mL). Hydrazine hydrate (3.7 g, 59.3 mmol, 2.0 equiv, 80%) was added, and the solution was stirred at 70°C for 3 hours. The resulting solution was extracted with 3×500 mL EtOAc. The resulting mixture was washed with 3×500 mL H ₂ O. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column, using ethyl acetate/petroleum ether (1:1) as the eluent. 3-Phenyl-1H-pyrazol-4-amine (3.7 g, 78.4%) was obtained as a dark yellow solid. LCMS method A, MS-ESI: 160.1M+H ⁺ ]. Scheme 2 : Synthesis of intermediate 2 ( 1- phenyl -1H- pyrazol- 3- amine)

1. Synthesis of 3- nitro- 1 -phenylpyrazole

Dissolve 3-nitro-1H-pyrazole (500.0 mg, 4.4 mmol, 1.0 equiv) in DCM (20 mL). Under a nitrogen atmosphere, TEA (894.9 mg, 8.8 mmol, 2.0 equiv) and phenylboronic acid (647.0 mg, 5.3 mmol, 1.2 equiv) were added. The resulting mixture was stirred for 16 hours at room temperature. The resulting mixture was diluted with H ₂ O (50 mL) and extracted with DCM (3×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column and dissolved with ethyl acetate/petroleum ether (1:5). 3-nitro-1-phenylpyrazole (300 mg, 35.9%) was isolated as a yellow solid. LCMS method E, MS-ESI: 190.2 [M+H ⁺ ]. 2. Synthesis of 1- phenyl -1H- pyrazol- 3- amine

1. 合成 5- 硝基 -1- 苯基吡唑

Dissolve 3-nitro-1-phenylpyrazole (300.0 mg, 1.6 mmol, 1.0 equiv) in MeOH (20 mL). Under nitrogen atmosphere, Pd/C (10% wt, 30 mg) was added to the solution. The resulting mixture was degassed and backfilled with hydrogen. The resulting mixture was stirred for 5 hours at room temperature. The resulting mixture was filtered, and the filtrate was collected and concentrated. Thus, 300 mg (crude product) of 1-phenyl-1H-pyrazol-3-amine was obtained as a pale yellow crude solid. LCMS method E, MS-ESI: 160.1 [M+H ⁺ ]. Scheme 3 : Synthesis of intermediate 3 ( 1- phenyl -1H- pyrazol- 5- amine)

1. Synthesis of 5 -nitro- 1 -phenylpyrazole

Use the method described in Scheme 2 to synthesize. LCMS method E, MS-ESI: 190.2 [M+H ⁺ ]. 2. Synthesis of 1- phenyl -1H- pyrazol- 5- amine

1. 合成 4- 硝基 -1- 苯基 -1H- 咪唑

Use the method described in Scheme 2 to synthesize. LCMS method C, MS-ESI: 160.0 [M+H ⁺ ]. Scheme 4 : Synthesis of intermediate 4 ( 1- phenyl -1H- imidazol- 4- amine)

1. Synthesis of 4- nitro- 1 -phenyl -1H- imidazole

Use the method described in Scheme 2 to synthesize. LCMS method E, MS-ESI: 190.2 [M+H ⁺ ]. 2. Synthesis of 1- Phenyl -1H- imidazol- 4- amine

1. 合成 2-(2- 苯基 -1H- 咪唑 -1- 基 ) 乙酸酯

Use the method described in Scheme 2 to synthesize . LCMS method E, MS-ESI: 160.2 [M+H ⁺ ]. Scheme 5 : Synthesis of intermediate 5 ( 2-(2- phenyl -1H- imidazol- 1 -yl ) acetic acid)

1. Synthesis of 2-(2- phenyl -1H- imidazol- 1 -yl ) acetate

Dissolve 2-phenyl-1H-imidazole (3.0 g, 20.8 mmol, 1.0 equiv) in THF (100 mL). Ethyl 2-bromoacetate (7.0 g, 41.6 mmol, 2.0 equiv) and Cs ₂ CO ₃ (13.6 g, 41.6 mmol, 2.0 equiv) were added to the solution. The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified on a silica gel column and eluted with EtOAc/PE (1:5) to give 2-(2-phenyl-1H-imidazol-1-yl)acetate (1.1 g, 22.9%). LCMS method B, MS-ESI: 231.2 [M+H ⁺ ]. 2. Synthesis of 2-(2- phenyl -1H- imidazol- 1 -yl ) acetic acid

1. 合成 2-(1H- 苯并 [d] 咪唑 -1- 基 ) 丙酸甲酯

Dissolve 2-(2-phenyl-1H-imidazol-1-yl) ethyl acetate (1.0 g, 4.3 mmol, 1.0 equiv) in THF/H ₂ O (5:1) (30 mL). Me ₃ SiOK (1.11 g, 8.7 mmol, 2.0 equiv) was added to the solution in portions. The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified with a silica gel column and eluted with EtOAc/PE (1:1) to obtain 2-(2-phenyl-1H-imidazol-1-yl)acetic acid (300 mg, 34.6%) as a white solid . LCMS method D, MS-ESI: 203.3 [M+H ⁺ ]. Scheme 6 : Synthesis of intermediate 6 ( 2-(1H -benzo [d] imidazol- 1 -yl ) propionic acid)

1. Synthesis of methyl 2-(1H -benzo [d] imidazol- 1 -yl ) propionate

Synthesize using the method described in Scheme 5 . LCMS method F, MS-ESI: 205.3 [M+H ⁺ ]. 2. Synthesis of 2-(1H -benzo [d] imidazol- 1 -yl ) propionic acid

Methyl 2-(1H-benzo[d]imidazol-1-yl)propionate (900.0 mg, 4.4 mmol, 1.0 equiv) was dissolved in THF (20.0 mL) and H ₂ O (5 mL). LiOH (528.0 mg, 22.1 mmol, 5.0 equiv) was added to this solution. The resulting mixture was stirred for 3 hours at room temperature. The resulting mixture was concentrated. The residue was purified by reverse phase chromatography under the following conditions: column, C18; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ) and mobile phase B: MeCN, 0 to 50% in 20 minutes Gradient; detector, UV 210 nm. 2-(1H-Benzo[d]imidazol-1-yl)propionic acid (600 mg, 71.6%) was obtained as a dark yellow solid. LCMS method C, MS-ESI: 191.1 [M+H ⁺ ]. Process 7 : Synthesis of intermediate 7 ( 3 -cyclohexyl- 4- isocyanate- 1H- pyrazole)

1. 合成 3-( 噻吩 -3- 基 )-1H- 吡唑 -4- 胺

3-cyclohexyl-1H-pyrazol-4-amine (150.0 mg, 0.9 mmol, 1.0 equiv) was added to THF (10.0 mL). Add TEA (183.7 mg, 1.8 mmol, 2.0 equiv) and BTC (62.1 mg, 0.3 mmol, 0.3 equiv). The resulting mixture was stirred for 1 hour at 60°C. The resulting mixture was concentrated and then used directly in the next step. Scheme 8 : Synthesis of intermediate 8 ( 4- isocyanato- 3-( thiophen- 3 -yl )-1H- pyrazole)

1. Synthesis of 3-( thiophen- 3 -yl )-1H- pyrazole- 4- amine

Dissolve 3-bromo-1H-pyrazol-4-amine (200.0 mg, 1.2 mmol, 1.0 equiv) in dioxane (10.0 mL) and H ₂ O (1 mL). Add Cs ₂ CO ₃ (804.6 mg, 2.5 mmol, 2.0 equiv), thiophen-3-ylboronic acid (237.0 mg, 1.9 mmol, 1.5 equiv) and Pd(dppf)Cl ₂ (100.8 mg, 0.1 mmol, 0.1 equiv). The resulting mixture was purged and maintained an inert nitrogen atmosphere, and stirred at 90°C for 12 hours. The resulting mixture was diluted with H ₂ O (20 mL) and extracted with 3×20 mL EtOAc. The organic layers were combined and concentrated. The residue was applied to a silica gel column and dissolved with ethyl acetate/petroleum ether (1/1). 3-(Thien-3-yl)-1H-pyrazol-4-amine (120 mg, 58.8%) was isolated as a yellow solid. LCMS method S, MS-ESI: 166.1 [M+H ⁺ ]. 2. Synthesis of 4- isocyanato- 3-( thiophen- 3 -yl )-1H- pyrazole

1. 合成 7- 氟 -1H- 吡咯并 [3,2-c] 吡啶 -3- 羰基疊氮化物

Synthesize using the method described in Scheme 7 . The crude product was used directly in the next step without further purification. Scheme 9 : Synthesis of intermediate 6 ( 7- fluoro -1H- pyrrolo [3,2-c] pyridin- 3- amine hydrochloride)

1. Synthesis of 7- fluoro -1H- pyrrolo [3,2-c] pyridine- 3- carbonyl azide

Same as the synthesis method in Scheme 2. LCMS: Method L, MS-ESI, 206.2 [M+H ⁺ ]. 2. Synthesis of (7- fluoro -1H- pyrrolo [3,2-c] pyridin- 3 -yl ) tertiary butyl carbamate

Dissolve 7-fluoro-1H-pyrrolo[3,2-c]pyridine-3-carbonyl azide (1.0 g, 4.9 mmol, 1.0 equiv) in t- BuOH (50 mL) and stir at 80°C 12 hours. The resulting mixture was concentrated in vacuo and purified on a silica gel column using EtOAc/PE (1:8) as the eluent. Tertiary butyl (7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl)carbamate (430.0 mg, 17.6%) was isolated as a brown solid. LCMS: Method L, MS-ESI, 252.3 [M+H ⁺ ]. 3. Synthesis of 7- fluoro -1H- pyrrolo [3,2-c] pyridin- 3- amine hydrochloride

(7-Fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl)carbamic acid tert-butyl ester (430.0 mg, 1.7 mmol, 1.0 equiv) was dissolved in 1,4-dioxane ( 10.0 mL). Then, a 1,4-dioxane solution of HCl (4 M, 10 mL) was added dropwise. At room temperature, the resulting mixture was stirred for 3 hours and concentrated in vacuo. 7-Fluoro-1H-pyrrolo[3,2-c]pyridin-3-amine hydrochloride (400 mg, crude product) was obtained as a yellow solid. LCMS: Method L, MS-ESI, 188.6 [M+H ⁺ ]. Scheme 10 : Synthesis of intermediate 10 : ( 1H- pyrrolo [3,2-b] pyridine- 3- amine dihydrochloride)

Synthesized using the method described in Scheme 9 . LCMS: Method A, MS-ESI, 206.0 [M+H ⁺ ]. Process for the preparation of Example 1 Example 1: Synthesis of 2- (4-butylphenyl) -N- (3- -1H- pyrazol-4-yl-phenyl) acetyl amine (Compound 5)

方法 G ： MS-ESI: 334.0[M+H ⁺ ]¹ H NMR (DMSO-d ₆ , 400MHz, ppm): δ 12.70 (s, 1H), 9.47 (s, 1H), 7.56 (s, 3H), 7.35-7.33 (d,J =7.6 Hz, 3H), 7.25-7.23 (d,J =8.0 Hz, 2H), 7.16-7.14 (d,J =8.0 Hz, 2H), 3.56 (s, 2H), 2.58-2.52 (m, 2H), 1.59-1.51 (m, 2H), 1.35-1.28 (m, 2H), 0.91-0.87 (t,J =7.6 Hz, 3H)。 2 56 中間物 1 （3-苯基-1H-吡唑-4-胺）； 2-(4-丁基苯基)丙酸

方法 R ： MS-ESI: 346.2[M-H ⁺ ]¹ H NMR(400 MHz, DMSO-d₆ ) δ 13.05-12.80 (m, 1H), 9.35-9.21 (m, 1H), 7.83-7.46 (m, 3H)，7.38 -7.27 (m, 5H), 7.24-7.14 (m, 2H), 3.83-3.81 (m, 1H), 2.72 -2.57 (m, 2H), 1.61-1.51 (m, 2H), 1.39-1.29 (m, 5H), 0.80-0.90 (t,J = 7.3 Hz, 3H)。 3 20 中間物 2 （1-苯基-1H-吡唑-3-胺）； 4-(三氟甲基)苯甲酸

方法 G ： MS-ESI: 330.2[M-H ⁺ ]¹ H NMR(400 MHz, DMSO-d₆ )δ 11.44 (s, 1H), 8.50 (d,J = 2.8 Hz, 1H), 8.24 (d,J = 8.0 Hz, 2H), 7.98-7.82 (m, 4H), 7.60-7.49 (m, 2H), 7.32-7.25 (m, 1H), 6.98 (d,J = 3.2 Hz, 1H)。 4 15 中間物 2 （1-苯基-1H-吡唑-3-胺）； 4-丁基苯甲酸

方法 G ： MS-ESI: 320.1[M+H ⁺ ]¹ H NMR(400 MHz, DMSO-d₆ )δ 11.05 (s, 1H), 8.47 (d,J = 2.8 Hz, 1H), 7.99-7.97 (m, 2H), 7.84-7.81 (m, 2H), 7.53-7.48 (m, 2H), 7.34-7.27 (m, 3H), 6.95 (d,J = 2.4 Hz, 1H), 2.68-2.64 (m, 2H), 1.63-1.56 (m, 2H), 1.37 (d,J = 14.6, 7.2 Hz, 2H), 0.92 (t,J = 7.3 Hz, 3H)。 5 19 中間物 3 （1-苯基-1H-吡唑-5-胺）； 4-(三氟甲基)苯甲酸

方法 J ： MS-ESI:332.1[M+H ⁺ ]¹ H NMR(400 MHz, DMSO-d₆ ) δ 10.64 (s, 1H), 8.05 (d,J = 8.4 Hz, 2H), 7.90 (d,J = 8.0 Hz, 2H), 7.73 (d,J = 1.6 Hz, 1H), 7.58-7.56 (m, 2H), 7.50-7.46 (m, 2H), 7.39-7.37 (m, 1H), 6.53 (d,J = 1.6 Hz, 1H)。 6 18 （1-苯基-1H-吡唑-4-胺）； 4-(三氟甲基)苯甲酸

方法 I ： MS-ESI: 332.1[M+H ⁺ ]¹ H NMR(300 MHz, DMSO-d₆ )δ 10.90 (s, 1H), 8.72 (s, 1H), 8.18 (d,J = 10.4 Hz, 2H), 7.96-7.94 (m, 3H), 7.96-7.94 (m, 2H), 7.54 (t,J = 10.0 Hz, 2H), 7.31 (t,J = 9.6 Hz, 1H)。 7 16 中間物 4 （1-苯基-1H-咪唑-4-胺）； 4-(三氟甲基)苯甲酸

方法 C ： MS-ESI: 332.1[M+H ⁺ ]¹ H NMR(400 MHz, DMSO-d₆ ) δ11.27 (s, 1H), 8.24-8.22 (m, 3H), 7.94-7.88 (m, 3H), 7.70-7.68 (m, 2H), 7.56-7.52 (m, 2H), 7.40-7.37 (m, 1H)。 8 9 中間物 5 （2-(2-苯基-1H-咪唑-1-基)乙酸）；4-丁基苯胺   

方法 L ： MS-ESI: 334.2[M+H ⁺ ]¹ H NMR(300 MHz, DMSO-d₆ ) δ10.25 (s, 1H), 7.61-7.58 (m, 2H), 7.50-7.48 (m, 2H), 7.46-7.40 (m, 3H), 7.33 (d,J = 1.2 Hz, 1H), 7.16-7.13 (m, 2H), 7.04 (d,J = 1.2 Hz, 1H), 4.91 (s, 2H), 2.56-2.53(m, 2H), 1.59-1.49 (m, 2H), 1.36-1.24 (m, 2H), 0.90 (t,J = 7.3 Hz, 3H)。 9 4 （2-苯基-1,3-噻唑-4-胺二鹽酸鹽）； 4-丁基苯甲酸

方法 M ： MS-ESI: 337.1[M+H ⁺ ]¹ H NMR(400 MHz, DMSO-d₆ ) δ11.39 (s, 1H), 8.02-7.95 (m, 4H), 7.86 (s, 1H), 7.56-7.49 (m, 3H), 7.35-7.33 (m, 2H), 2.66 (t,J = 7.6 Hz, 2H), 1.59 (tt,J = 7.6, 6.4 Hz, 2H), 1.33-1.28 (m, 2H), 0.91 (t,J = 7.3 Hz, 3H)。 10 6 中間物 6 （2-(1H-苯并[d]咪唑-1-基)丙酸）； 4-丁基苯胺

方法 C ： MS-ESI: 322.2[M+H ⁺ ]¹ H NMR(300 MHz, DMSO-d₆ ) δ10.40 (s, 1H), 8.40 (s, 1H), 7.68-7.65 (m, 1H), 7.57 (d,J = 7.5 Hz, 1H), 7.48-7.45 (m, 2H), 7.28-7.20 (m, 2H), 7.13 (d,J = 8.4 Hz, 2H), 5.35 (q,J = 6.9 Hz, 1H), 2.53 (s, 1H), 2.50 (s, 1H), 1.85 (d,J = 3.9 Hz, 3H), 1.55-1.45 (m, 2H), 1.32-1.14 (m, 2H), 0.86 (t,J = 7.3 Hz, 3H)。 Dissolve 3-phenyl-1H-pyrazol-4-amine (200.0 mg, 1.3 mmol, 1.0 equiv) in THF (15 mL). Add 2-(4-butylphenyl)acetic acid (265.7 mg, 1.4 mmol, 1.1 equiv), T ₃ P (2.4 g, 3.8 mmol, 3.0 equiv, 50%) and TEA (254.3 mg, 2.5 mmol, 2.0 equiv) ) And stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (2#SHIMADZU (HPLC-01)): Column: XBridge Shield RP18 OBD column, 30×150mm, 5um; mobile phase: water (10MMOL/L NH ₄ HCO ₃ ) and ACN (38% phase B reaches 68% in 8 minutes); detector: UV 254nm. 2-(4-butylphenyl)-N-(3-phenyl-1H-pyrazol-4-yl)acetamide (73.5 mg, 17.5%) was isolated as a white solid. LCMS method G, MS-ESI: 334.0 [M+H ⁺ ]. Analogs prepared by the above method Example # Compound # Starting material Final compound LCMS and NMR data 1 5 Intermediate 1 (3-phenyl-1H-pyrazole-4-amine); 2-(4-butylphenyl)acetic acid

Method G : MS-ESI: 334.0[M+H ⁺ ] ¹ H NMR (DMSO- d ₆ , 400MHz, ppm): δ 12.70 (s, 1H), 9.47 (s, 1H), 7.56 (s, 3H), 7.35-7.33 (d, J =7.6 Hz, 3H), 7.25-7.23 (d, J =8.0 Hz, 2H), 7.16-7.14 (d, J =8.0 Hz, 2H), 3.56 (s, 2H), 2.58 -2.52 (m, 2H), 1.59-1.51 (m, 2H), 1.35-1.28 (m, 2H), 0.91-0.87 (t, J =7.6 Hz, 3H). 2 56 Intermediate 1 (3-phenyl-1H-pyrazole-4-amine); 2-(4-butylphenyl)propionic acid

Method R : MS-ESI: 346.2[MH ⁺ ] ¹ H NMR(400 MHz, DMSO- d ₆ ) δ 13.05-12.80 (m, 1H), 9.35-9.21 (m, 1H), 7.83-7.46 (m, 3H ), 7.38 -7.27 (m, 5H), 7.24-7.14 (m, 2H), 3.83-3.81 (m, 1H), 2.72 -2.57 (m, 2H), 1.61-1.51 (m, 2H), 1.39-1.29 (m, 5H), 0.80-0.90 (t, J = 7.3 Hz, 3H). 3 20 Intermediate 2 (1-phenyl-1H-pyrazol-3-amine); 4-(trifluoromethyl)benzoic acid

Method G : MS-ESI: 330.2[MH ⁺ ] ¹ H NMR(400 MHz, DMSO- d ₆ )δ 11.44 (s, 1H), 8.50 (d, J = 2.8 Hz, 1H), 8.24 (d, J = 8.0 Hz, 2H), 7.98-7.82 (m, 4H), 7.60-7.49 (m, 2H), 7.32-7.25 (m, 1H), 6.98 (d, J = 3.2 Hz, 1H). 4 15 Intermediate 2 (1-phenyl-1H-pyrazole-3-amine); 4-butylbenzoic acid

Method G : MS-ESI: 320.1[M+H ⁺ ] ¹ H NMR(400 MHz, DMSO- d ₆ )δ 11.05 (s, 1H), 8.47 (d, J = 2.8 Hz, 1H), 7.99-7.97 ( m, 2H), 7.84-7.81 (m, 2H), 7.53-7.48 (m, 2H), 7.34-7.27 (m, 3H), 6.95 (d, J = 2.4 Hz, 1H), 2.68-2.64 (m, 2H), 1.63-1.56 (m, 2H), 1.37 (d, J = 14.6, 7.2 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H). 5 19 Intermediate 3 (1-phenyl-1H-pyrazol-5-amine); 4-(trifluoromethyl)benzoic acid

Method J : MS-ESI: 332.1[M+H ⁺ ] ¹ H NMR(400 MHz, DMSO- d ₆ ) δ 10.64 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 1.6 Hz, 1H), 7.58-7.56 (m, 2H), 7.50-7.46 (m, 2H), 7.39-7.37 (m, 1H), 6.53 (d , J = 1.6 Hz, 1H). 6 18 (1-Phenyl-1H-pyrazole-4-amine); 4-(trifluoromethyl)benzoic acid

Method I : MS-ESI: 332.1[M+H ⁺ ] ¹ H NMR(300 MHz, DMSO- d ₆ )δ 10.90 (s, 1H), 8.72 (s, 1H), 8.18 (d, J = 10.4 Hz, 2H), 7.96-7.94 (m, 3H), 7.96-7.94 (m, 2H), 7.54 (t, J = 10.0 Hz, 2H), 7.31 (t, J = 9.6 Hz, 1H). 7 16 Intermediate 4 (1-phenyl-1H-imidazol-4-amine); 4-(trifluoromethyl)benzoic acid

Method C : MS-ESI: 332.1[M+H ⁺ ] ¹ H NMR(400 MHz, DMSO- d ₆ ) δ11.27 (s, 1H), 8.24-8.22 (m, 3H), 7.94-7.88 (m, 3H), 7.70-7.68 (m, 2H), 7.56-7.52 (m, 2H), 7.40-7.37 (m, 1H). 8 9 Intermediate 5 (2-(2-phenyl-1H-imidazol-1-yl)acetic acid); 4-butylaniline

Method L : MS-ESI: 334.2[M+H ⁺ ] ¹ H NMR(300 MHz, DMSO- d ₆ ) δ10.25 (s, 1H), 7.61-7.58 (m, 2H), 7.50-7.48 (m, 2H), 7.46-7.40 (m, 3H), 7.33 (d, J = 1.2 Hz, 1H), 7.16-7.13 (m, 2H), 7.04 (d, J = 1.2 Hz, 1H), 4.91 (s, 2H ), 2.56-2.53(m, 2H), 1.59-1.49 (m, 2H), 1.36-1.24 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). 9 4 (2-Phenyl-1,3-thiazol-4-amine dihydrochloride); 4-butylbenzoic acid

Method M : MS-ESI: 337.1[M+H ⁺ ] ¹ H NMR(400 MHz, DMSO- d ₆ ) δ11.39 (s, 1H), 8.02-7.95 (m, 4H), 7.86 (s, 1H) , 7.56-7.49 (m, 3H), 7.35-7.33 (m, 2H), 2.66 (t, J = 7.6 Hz, 2H), 1.59 (tt, J = 7.6, 6.4 Hz, 2H), 1.33-1.28 (m , 2H), 0.91 (t, J = 7.3 Hz, 3H). 10 6 Intermediate 6 (2-(1H-benzo[d]imidazol-1-yl)propionic acid); 4-butylaniline

Method C : MS-ESI: 322.2[M+H ⁺ ] ¹ H NMR(300 MHz, DMSO- d ₆ ) δ10.40 (s, 1H), 8.40 (s, 1H), 7.68-7.65 (m, 1H) , 7.57 (d, J = 7.5 Hz, 1H), 7.48-7.45 (m, 2H), 7.28-7.20 (m, 2H), 7.13 (d, J = 8.4 Hz, 2H), 5.35 (q, J = 6.9 Hz, 1H), 2.53 (s, 1H), 2.50 (s, 1H), 1.85 (d, J = 3.9 Hz, 3H), 1.55-1.45 (m, 2H), 1.32-1.14 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H).

方法 K ： MS-ESI: 320.2 [M+H ⁺ ]¹ H NMR(400 MHz, DMSO-d₆ ) δ10.23 (s, 1H), 8.47 (d,J = 2.8 Hz, 1H), 8.09-8.07 (m, 2H), 7.68-7.65 (m, 2H), 7.53-7.49 (m, 2H), 7.45-7.41 (m, 1H), 7.23-7.21 (m, 2H), 7.13 (d,J = 2.8 Hz, 1H), 2.58-2.56 (m, 2H), 1.60-1.53 (m, 2H), 1.37-1.24 (m, 2H), 0.90 (t,J = 7.3 Hz, 3H)。 12 69 （4-苯基-1H-吡唑）； 1-丁基-4-異氰酸酯基苯

方法 C ： MS-ESI: 320.2 [M+H ⁺ ]¹ H NMR(400 MHz, DMSO-d₆ ) δ10.42 (s, 1H), 8.90 (d,J = 0.8 Hz, 1H), 8.41 (d,J = 0.8 Hz, 1H), 7.82-7.80 (m, 2H), 7.67-7.62 (m, 2H), 7.42 (t,J = 7.7 Hz, 2H), 7.37-7.28 (m, 1H), 7.21-7.16 (m, 2H), 2.57-2.55 (m, 2H), 1.60-1.52 (m, 2H), 1.36-1.30 (m, 2H), 0.91 (t,J = 7.3 Hz, 3H)。 13 70 中間物 8 （3-(噻吩-3-基)-1H-吡唑-4-胺）； 1-丁基-4-異氰酸酯基苯

方法 J ： MS-ESI: 341.1 [M+H ⁺ ]¹ H NMR(400 MHz, DMSO-d₆ ) δ9.87 (s, 1H), 8.02 (dd,J = 2.8, 1.3 Hz, 1H), 7.77 (dd,J = 5.1, 1.3 Hz, 1H), 7.69-7.57 (m, 2H), 7.65-7.59 (m, 2H), 7.19-7.16 (m, 2H), 4.52 (s, 2H), 2.56-2.50 (m, 2H), 1.60-1.50 (m, 2H), 1.34-1.25 (m, 2H), 0.90 (t,J = 7.3 Hz, 3H)。 14 71 （3-環己基-1H-吡唑-4-胺）； 1-丁基-4-異氰酸酯基苯

方法 G ： MS-ESI: 341.2 [M+H ⁺ ]¹ H NMR(300 MHz, DMSO-d₆ ) δ9.51 (s, 1H), 7.58 (d,J = 8.4 Hz, 2H), 7.45 (s, 1H), 7.16 (d,J = 8.4 Hz, 2H), 4.23 (s, 2H), 2.70-2.64 (m, 1H), 2.57-2.50 (m, 2H), 1.89 (d,J = 12.4 Hz, 2H), 1.80-1.77 (m, 2H), 1.72 (d,J = 12.8 Hz, 1H), 1.69-1.54 (m, 3H), 1.52 (d,J = 8.0 Hz, 1H), 1.40-1.33 (m, 5H), 0.91 (t,J = 7.3 Hz, 3H)。 實例 15 ：合成 N-(1H- 吡咯并 [3,2-b] 吡啶 -3- 基 ) 螺 [3.5] 壬烷 -7- 甲醯胺（化合物 51 ）

The following compounds were synthesized from corresponding starting materials using TEA as a base and THF as a solvent. Example # Compound # Starting material Final compound LCMS and NMR data 11 68 (3-Phenyl-1H-pyrazole); 1-Butyl-4-isocyanatobenzene

Method K : MS-ESI: 320.2 [M+H ⁺ ] ¹ H NMR(400 MHz, DMSO- d ₆ ) δ10.23 (s, 1H), 8.47 (d, J = 2.8 Hz, 1H), 8.09-8.07 (m, 2H), 7.68-7.65 (m, 2H), 7.53-7.49 (m, 2H), 7.45-7.41 (m, 1H), 7.23-7.21 (m, 2H), 7.13 (d, J = 2.8 Hz , 1H), 2.58-2.56 (m, 2H), 1.60-1.53 (m, 2H), 1.37-1.24 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). 12 69 (4-Phenyl-1H-pyrazole); 1-Butyl-4-isocyanatobenzene

Method C : MS-ESI: 320.2 [M+H ⁺ ] ¹ H NMR(400 MHz, DMSO- d ₆ ) δ10.42 (s, 1H), 8.90 (d, J = 0.8 Hz, 1H), 8.41 (d , J = 0.8 Hz, 1H), 7.82-7.80 (m, 2H), 7.67-7.62 (m, 2H), 7.42 (t, J = 7.7 Hz, 2H), 7.37-7.28 (m, 1H), 7.21- 7.16 (m, 2H), 2.57-2.55 (m, 2H), 1.60-1.52 (m, 2H), 1.36-1.30 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). 13 70 Intermediate 8 (3-(thiophen-3-yl)-1H-pyrazol-4-amine); 1-butyl-4-isocyanatobenzene

Method J : MS-ESI: 341.1 [M+H ⁺ ] ¹ H NMR(400 MHz, DMSO- d ₆ ) δ9.87 (s, 1H), 8.02 (dd, J = 2.8, 1.3 Hz, 1H), 7.77 (dd, J = 5.1, 1.3 Hz, 1H), 7.69-7.57 (m, 2H), 7.65-7.59 (m, 2H), 7.19-7.16 (m, 2H), 4.52 (s, 2H), 2.56-2.50 (m, 2H), 1.60-1.50 (m, 2H), 1.34-1.25 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). 14 71 (3-cyclohexyl-1H-pyrazole-4-amine); 1-butyl-4-isocyanatobenzene

Method G : MS-ESI: 341.2 [M+H ⁺ ] ¹ H NMR(300 MHz, DMSO- d ₆ ) δ9.51 (s, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.45 (s , 1H), 7.16 (d, J = 8.4 Hz, 2H), 4.23 (s, 2H), 2.70-2.64 (m, 1H), 2.57-2.50 (m, 2H), 1.89 (d, J = 12.4 Hz, 2H), 1.80-1.77 (m, 2H), 1.72 (d, J = 12.8 Hz, 1H), 1.69-1.54 (m, 3H), 1.52 (d, J = 8.0 Hz, 1H), 1.40-1.33 (m , 5H), 0.91 (t, J = 7.3 Hz, 3H). Example 15 : Synthesis of N-(1H- pyrrolo [3,2-b] pyridin- 3 -yl ) spiro [3.5] nonane- 7- formamide (Compound 51 )

N-(1H-pyrrolo[3,2-b]pyridin-3-yl)spiro[3.5]nonane-7-carboxamide is based on 1H-pyrrolo[3,2-b]pyridin-3-amine The dihydrochloride ( intermediate 10 ) is synthesized by coupling with spiro[3.5]nonane-7-carboxylic acid.

LCMS (Method A ): MS-ESI: 284.2 [M+H ⁺ ]

合成 N-(5,6- 二氟 -1H- 吲哚 -3- 基 )-4-( 嘧啶 -2- 基 ) 苯甲醯胺 ¹ HNMR (400 MHz, DMSO- d ₆ ) δ 10.96 (d, J = 12.9 Hz, 1H), 9.85 (d, J = 12.8 Hz, 1H), 8.38-8.30 (m, 1H), 8.01 (d, J = 13.0 Hz, 1H), 7.75 (dd, J = 14.1, 7.9 Hz, 1H), 7.21-7.10 (m, 1H), 2.85-2.62 (m, 1H), 1.93-1.62 (m, 8H), 1.59- 1.39 (m, 3H), 1.37-1.20 (m, 3H). LC-MS methods X and Y can be used to analyze examples 16-67. Example 16 : Preparation of compound 114

Synthesis of N- (5,6- difluoro--1H- indol-3-yl) -4- (pyrimidin-2-yl) benzoyl amine

Combine 5,6-difluoro-1H-indole-3-amine (48.1 mg, 0.286 mmol, 1.0 equiv.) and 4-(pyrimidin-2-yl)benzoic acid (74.3 mg, 0.343 mmol, 1.2 equiv.) Dissolve in DMF (2.0 mL). Next, DIEA (188 µl, 1.14 mmol, 4 equiv.) and HATU (114.1 mg, 0.3 mmol, 1.1 equiv.) dissolved in 1 mL DMF were added. The reaction mixture was stirred at 30°C for 16 hours. The reaction mixture was concentrated by Speedvac. The residue was purified by preparative HPLC to obtain N-(5,6-difluoro-1H-indol-3-yl)-4-(pyrimidin-2-yl)benzamide (41.6 mg, 0.119 mmol ). MS-ESI, 351.2 [M+H ⁺ ].

3-環戊基-N-(5,6-二氟-1H-吲哚-3-基)苯甲醯胺 18 151

N-(5,6-二氟-1H-吲哚-3-基)-2-苯基戊醯胺 329.1 19 154

N-(5,6-二氟-1H-吲哚-3-基)-6-(2-(吡咯啶-1-基)乙基)菸鹼醯胺 20 155

5-氯-N-(5,6-二氟-1H-吲哚-3-基)嘧啶-2-甲醯胺 21 143

6-(環丙基甲氧基)-N-(5,6-二氟-1H-吲哚-3-基)菸鹼醯胺 344.2 22 113

2-(3-氯苯基)-N-(5,6-二氟-1H-吲哚-3-基)乙醯胺 321.1 23 112

N-(5,6-二氟-1H-吲哚-3-基)-6-(2,2,2-三氟乙氧基)菸鹼醯胺 372.2 24 111

N-(5,6-二氟-1H-吲哚-3-基)-2-(4-(三氟甲基)苯基)乙醯胺 355.1 25 110

N-(5,6-二氟-1H-吲哚-3-基)-3-(2-甲基噻唑-4-基)苯甲醯胺 370.1 26 109

4-氰基-N-(5,6-二氟-1H-吲哚-3-基)苯甲醯胺 298.2 27 118

N-(5,6-二氟-1H-吲哚-3-基)-2,5-二氟苯甲醯胺 309 28 108

N-(5,6-二氟-1H-吲哚-3-基)-6-(三氟甲基)菸鹼醯胺 342.1 29 107

N-(5,6-二氟-1H-吲哚-3-基)-2-(4-異丙基苯基)乙醯胺 329.2 30 106

N-(5,6-二氟-1H-吲哚-3-基)-4-己基苯甲醯胺 357.2 31 105

2-(4-氰基苯基)-N-(5,6-二氟-1H-吲哚-3-基)乙醯胺 312.2 32 104

N-(5,6-二氟-1H-吲哚-3-基)-2-(三氟甲基)苯甲醯胺 341.1 33 103

2-(3-氰基苯基)-N-(5,6-二氟-1H-吲哚-3-基)乙醯胺 312.2 34 102

N-(5,6-二氟-1H-吲哚-3-基)-4-(反-4-乙基環己基)苯甲醯胺 383.2 35 101

5-氯-N-(5,6-二氟-1H-吲哚-3-基)噻吩-2-甲醯胺 313.1 36 100

5,6-二氯-N-(5,6-二氟-1H-吲哚-3-基)菸鹼醯胺 342 37 99

4-丁基-N-(5,6-二氟-1H-吲哚-3-基)苯甲醯胺 329.2 38 117

N-(5,6-二氟-1H-吲哚-3-基)-6-苯基菸鹼醯胺 350.1 39 98

4,5-二氯-N-(5,6-二氟-1H-吲哚-3-基)噻吩-2-甲醯胺 347 40 97

N-(5,6-二氟-1H-吲哚-3-基)-2-(4-戊基苯基)乙醯胺 357.2 41 96

N-(5,6-二氟-1H-吲哚-3-基)-4-(4,4-二甲基哌啶-1-基)苯甲醯胺 384.3 42 95

N-(5,6-二氟-1H-吲哚-3-基)-6-(1H-吡唑-1-基)菸鹼醯胺 340.2 43 142

N-(5,6-二氟-1H-吲哚-3-基)-4-((三氟甲基)硫基)苯甲醯胺 373.1 44 116

N-(5,6-二氟-1H-吲哚-3-基)-1H-吡唑并[3,4-b]吡啶-5-甲醯胺 314 45 141

N-(5,6-二氟-1H-吲哚-3-基)-4-(2-乙氧基乙氧基)苯甲醯胺 361.2 46 94

N-(5,6-二氟-1H-吲哚-3-基)-5-(三氟甲基)吡嗪-2-甲醯胺 343 47 93

N-(5,6-二氟-1H-吲哚-3-基)-6-(哌啶-1-基)菸鹼醯胺 357.2 48 92

N-(5,6-二氟-1H-吲哚-3-基)-4-(1-羥基乙基)苯甲醯胺 317.1 49 91

N-(5,6-二氟-1H-吲哚-3-基)-4-異丙基噻唑-2-甲醯胺 322.2 50 90

N-(5,6-二氟-1H-吲哚-3-基)-4-(1-甲基-1H-吡唑-4-基)苯甲醯胺 353.2 51 89

N-(5,6-二氟-1H-吲哚-3-基)-4-(2-羥基丙-2-基)苯甲醯胺 331.2 52 88

N-(5,6-二氟-1H-吲哚-3-基)-4-(4,4,4-三氟丁氧基)苯甲醯胺 399.2 53 149

N-(5,6-二氟-1H-吲哚-3-基)-4-(吡啶-2-基)噻唑-2-甲醯胺 54 153

N-(5,6-二氟-1H-吲哚-3-基)-2-(3-(吡啶-3-基)苯基)乙醯胺 55 115

N-(5,6-二氟-1H-吲哚-3-基)-6-苯基嘧啶-4-甲醯胺 351 56 87

N-(5,6-二氟-1H-吲哚-3-基)-3-(1-甲基-1H-吡唑-5-基)苯甲醯胺 353.2 57 86

N-(5,6-二氟-1H-吲哚-3-基)-4-(1H-吡唑-1-基)苯甲醯胺 339.2 58 85

N-(5,6-二氟-1H-吲哚-3-基)-3-(2-羥基乙基)苯甲醯胺 317.2 59 84

N-(5,6-二氟-1H-吲哚-3-基)-6-苯基吡嗪-2-甲醯胺 351 60 83

4-(3-氯吡啶-2-基)-N-(5,6-二氟-1H-吲哚-3-基)苯甲醯胺 384 61 82

N-(5,6-二氟-1H-吲哚-3-基)噻唑并[5,4-c]吡啶-2-甲醯胺 331 62 81

4-環己基-N-(5,6-二氟-1H-吲哚-3-基)苯甲醯胺 355.3 63 123

N-(5,6-二氟-1H-吲哚-3-基)-4-(噻吩-2-基)苯甲醯胺 355 64 122

2,6-二氯-N-(5,6-二氟-1H-吲哚-3-基)苯甲醯胺 341.1 65 121

3,4-二氯-N-(5,6-二氟-1H-吲哚-3-基)苯甲醯胺 341 66 120

N-(5,6-二氟-1H-吲哚-3-基)-3-(三氟甲基)苯甲醯胺 341.1 67 119

N-(5,6-二氟-1H-吲哚-3-基)-2-(3-(三氟甲基)苯基)乙醯胺 355 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 11.12 (br s, 1 H) 10.33 (s, 1 H) 8.97 (d, 2 H) 8.54 (d, 2 H) 8.15 (d, 2 H) 7.90-7.99 (m, 2 H) 7.52 (t, 1 H) 7.39 (dd, 1 H). Table 1. The compounds in Table 1 were prepared using the above procedure. Example # Compound # Final compound IUPAC name LC-MS, MS-ESI, - [M+H ⁺ ]. 17 152

3-cyclopentyl-N-(5,6-difluoro-1H-indol-3-yl)benzamide 18 151

N-(5,6-Difluoro-1H-indol-3-yl)-2-phenylpentanamide 329.1 19 154

N-(5,6-Difluoro-1H-indol-3-yl)-6-(2-(pyrrolidin-1-yl)ethyl)nicotinamide 20 155

5-chloro-N-(5,6-difluoro-1H-indol-3-yl)pyrimidine-2-carboxamide twenty one 143

6-(Cyclopropylmethoxy)-N-(5,6-difluoro-1H-indol-3-yl)nicotinamide 344.2 twenty two 113

2-(3-chlorophenyl)-N-(5,6-difluoro-1H-indol-3-yl)acetamide 321.1 twenty three 112

N-(5,6-Difluoro-1H-indol-3-yl)-6-(2,2,2-trifluoroethoxy)nicotinamide 372.2 twenty four 111

N-(5,6-Difluoro-1H-indol-3-yl)-2-(4-(trifluoromethyl)phenyl)acetamide 355.1 25 110

N-(5,6-Difluoro-1H-indol-3-yl)-3-(2-methylthiazol-4-yl)benzamide 370.1 26 109

4-cyano-N-(5,6-difluoro-1H-indol-3-yl)benzamide 298.2 27 118

N-(5,6-Difluoro-1H-indol-3-yl)-2,5-difluorobenzamide 309 28 108

N-(5,6-Difluoro-1H-indol-3-yl)-6-(trifluoromethyl)nicotinamide 342.1 29 107

N-(5,6-Difluoro-1H-indol-3-yl)-2-(4-isopropylphenyl)acetamide 329.2 30 106

N-(5,6-Difluoro-1H-indol-3-yl)-4-hexylbenzamide 357.2 31 105

2-(4-cyanophenyl)-N-(5,6-difluoro-1H-indol-3-yl)acetamide 312.2 32 104

N-(5,6-Difluoro-1H-indol-3-yl)-2-(trifluoromethyl)benzamide 341.1 33 103

2-(3-cyanophenyl)-N-(5,6-difluoro-1H-indol-3-yl)acetamide 312.2 34 102

N-(5,6-Difluoro-1H-indol-3-yl)-4-(trans-4-ethylcyclohexyl)benzamide 383.2 35 101

5-chloro-N-(5,6-difluoro-1H-indol-3-yl)thiophene-2-carboxamide 313.1 36 100

5,6-Dichloro-N-(5,6-difluoro-1H-indol-3-yl)nicotinamide 342 37 99

4-butyl-N-(5,6-difluoro-1H-indol-3-yl)benzamide 329.2 38 117

N-(5,6-Difluoro-1H-indol-3-yl)-6-phenylnicotinamide 350.1 39 98

4,5-Dichloro-N-(5,6-difluoro-1H-indol-3-yl)thiophene-2-carboxamide 347 40 97

N-(5,6-Difluoro-1H-indol-3-yl)-2-(4-pentylphenyl)acetamide 357.2 41 96

N-(5,6-Difluoro-1H-indol-3-yl)-4-(4,4-dimethylpiperidin-1-yl)benzamide 384.3 42 95

N-(5,6-Difluoro-1H-indol-3-yl)-6-(1H-pyrazol-1-yl)nicotinamide 340.2 43 142

N-(5,6-Difluoro-1H-indol-3-yl)-4-((trifluoromethyl)sulfanyl)benzamide 373.1 44 116

N-(5,6-Difluoro-1H-indol-3-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 314 45 141

N-(5,6-Difluoro-1H-indol-3-yl)-4-(2-ethoxyethoxy)benzamide 361.2 46 94

N-(5,6-Difluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrazine-2-carboxamide 343 47 93

N-(5,6-Difluoro-1H-indol-3-yl)-6-(piperidin-1-yl)nicotinamide 357.2 48 92

N-(5,6-Difluoro-1H-indol-3-yl)-4-(1-hydroxyethyl)benzamide 317.1 49 91

N-(5,6-Difluoro-1H-indol-3-yl)-4-isopropylthiazole-2-carboxamide 322.2 50 90

N-(5,6-Difluoro-1H-indol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)benzamide 353.2 51 89

N-(5,6-Difluoro-1H-indol-3-yl)-4-(2-hydroxyprop-2-yl)benzamide 331.2 52 88

N-(5,6-Difluoro-1H-indol-3-yl)-4-(4,4,4-trifluorobutoxy)benzamide 399.2 53 149

N-(5,6-Difluoro-1H-indol-3-yl)-4-(pyridin-2-yl)thiazole-2-carboxamide 54 153

N-(5,6-Difluoro-1H-indol-3-yl)-2-(3-(pyridin-3-yl)phenyl)acetamide 55 115

N-(5,6-Difluoro-1H-indol-3-yl)-6-phenylpyrimidine-4-carboxamide 351 56 87

N-(5,6-Difluoro-1H-indol-3-yl)-3-(1-methyl-1H-pyrazol-5-yl)benzamide 353.2 57 86

N-(5,6-Difluoro-1H-indol-3-yl)-4-(1H-pyrazol-1-yl)benzamide 339.2 58 85

N-(5,6-Difluoro-1H-indol-3-yl)-3-(2-hydroxyethyl)benzamide 317.2 59 84

N-(5,6-Difluoro-1H-indol-3-yl)-6-phenylpyrazine-2-carboxamide 351 60 83

4-(3-chloropyridin-2-yl)-N-(5,6-difluoro-1H-indol-3-yl)benzamide 384 61 82

N-(5,6-Difluoro-1H-indol-3-yl)thiazolo[5,4-c]pyridine-2-carboxamide 331 62 81

4-cyclohexyl-N-(5,6-difluoro-1H-indol-3-yl)benzamide 355.3 63 123

N-(5,6-Difluoro-1H-indol-3-yl)-4-(thiophen-2-yl)benzamide 355 64 122

2,6-Dichloro-N-(5,6-difluoro-1H-indol-3-yl)benzamide 341.1 65 121

3,4-Dichloro-N-(5,6-difluoro-1H-indol-3-yl)benzamide 341 66 120

N-(5,6-Difluoro-1H-indol-3-yl)-3-(trifluoromethyl)benzamide 341.1 67 119

N-(5,6-Difluoro-1H-indol-3-yl)-2-(3-(trifluoromethyl)phenyl)acetamide 355

The compounds in Table C1 below were prepared according to procedures similar to those described elsewhere herein. LC-MS uses the following columns and settings to perform compound analysis: Shim-pack XR-ODS, C18, 3×50 mm, 2.5 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan Range, 190-400 nm UV range, 5-100% (1.1 minutes), 100% (0.6 minutes) ACN (0.05% TFA) and water (0.05% TFA) gradient, and the total running time is 2.0 minutes. Compound number LC-MS [M+H] ⁺ 1 320.1 2 328 10 341.05 11 265.15 12 305.1 twenty one 324.1 29 90.4 35 293.15 55 302 80 404.1 81 355.3 82 331 83 384 84 351 85 317.2 86 339.2 87 353.2 88 399.2 89 331.2 90 353.2 91 322.2 92 317.1 93 357.2 94 343 95 340.2 96 384.3 97 357.2 98 347 99 329.2 100 342 101 313.1 102 383.2 103 312.2 104 341.1 105 312.2 106 357.2 107 329.2 108 342.1 109 298.2 110 370.1 111 355.1 112 372.2 113 321.1 114 351.2 115 367.1 116 351 117 314 118 350.1 119 309 120 355 121 341.1 122 341 123 341.1 124 367.1 125 421.1 126 407.1 127 421 128 334.1 129 319 130 331.1 131 278.1 132 356 133 322.2 134 344 135 280.2 136 340.9 137 341.1 138 413.9 139 352 140 354 141 361.2 142 373.1 143 344.2 144 421.0 145 422.0 146 421.0 147 422.0 148 421.0 149 357.1

Compounds 156-168 ( Table C1 ) were prepared according to procedures similar to those described elsewhere herein. Biological analysis

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

The THP1-Dual™ KO-IFNAR2 cells (obtained from Invivogen) were maintained in RPMI, 10% FCS, 5 ml P/S, 2 mM L-glut, 10 mM Hepes, and 1 mM sodium pyruvate. Echo was used to spot the compound in an empty 384-well tissue culture dish (Greiner 781182), with a final concentration of 0.0017-100 µM. The cells were plated on the TC dish at 40 μL per well and 2×10E6 cells per ml. For activation with STING ligand, 2'3' cGAMP (MW 718.38, available from Invivogen) was prepared in Optimem medium.

For each 1×384 plate, prepare the following solution: o Solution A: 2 mL Optimem containing one of the following stimuli: ▪ 60 uL of 10 mM 2'3'cGAMP -> 150 μM stock solution o Solution B: 2 mL Optimem containing 60 μL Lipofectamine 2000 → incubate at room temperature for 5 minutes

Mix 2 mL of solution A with 2 ml of solution B and incubate at room temperature (RT) for 20 minutes. Add 20 uL of transfection solution (A+B) to the top of the plated cells, and the final 2'3'cGAMP concentration is 15 μM. Then, the plates were immediately centrifuged at 340 g for 1 minute, after which they were incubated at 37°C, 5% CO ₂ , and >98% humidity for 24 hours. Next, the luciferase reporter activity was measured. The EC ₅₀ and/or IC ₅₀ values are calculated by using standard methods known in the art.

Luciferase reporter assay: Transfer 10 µL of the supernatant from the assay to a white 384-well flat tray with square wells. Dissolve a sachet of QUANTI-Luc™ Plus in 25 mL of water. Add 100 µL of QLC stabilizer per 25 mL of QUANTI-Luc™ Plus solution. Next, add 50 µL QUANTI-Luc™ Plus/QLC solution per well. Measure the luminescence on a disc reader (such as Spectramax I3X (Molecular Devices GF3637001)). Next, the luciferase reporter activity was measured. The EC ₅₀ and/or IC ₅₀ values are calculated by using standard methods known in the art.

Table BA shows the activity of the compound in the conductor analysis reported by STING: <0.008 µM = "++++++"; ≥0.008 and <0.04 µM = "+++++"; ≥0.04 and <0.2 µM = "++ ++"; ≥0.2 and <1 µM = "+++"; ≥1 and <5 µM = "++"; ≥5 and <100 µM = "+". Table BA. Compound number People THP1 STING reported analyzer EC ₅₀ (μM) 1 +++ 2 +++ 3 ＞ 100.0000 4 + 5 + 6 + 7 ＞ 100.0000 8 ＞ 100.0000 9 + 10 +++ 11 +++ 12 ++ 13 + 14 + 15 + 16 ＞ 100.0000 17 + 18 ＞ 100.0000 19 + 20 + twenty one +++ twenty two + twenty three + twenty four + 25 ＞ 100.0000 26 + 27 + 28 ＞ 100.0000 29 +++ 30 + 31 32 ＞ 100.0000 33 + 34 ＞ 100.0000 35 ++ 36 + 37 ＞ 100.0000 38 + 39 ＞ 100.0000 40 + 41 + 42 + 43 ＞ 100.0000 44 ＞ 100.0000 45 ＞ 100.0000 46 + 47 + 48 + 49 ＞ 100.0000 50 ＞ 30.0000 51 + 52 + 53 + 54 ++ 55 ++ 56 + 80 ＞ 30.0000 115 ＞ 30.0000 116 ＞ 30.0000 117 +++ 118 +++ 119 + 120 ++ 121 +++ 122 + 123 +++ 124 +++ 125 ++ 126 +++ 127 +++ 128 + 129 + 130 + 131 + 132 + 133 ++ 134 + 135 + 136 + 137 + 138 + 139 + 140 + 144 ++ 145 + 146 +++ 147 ++++ 148 +++ 150 + 151 + 152 + 156 ++ 157 +++ 158 +++ 159 ++ 160 ++ 161 ++ 162 ＞ 30.0000 163 + 164 +++ 165 +++ 166 +++ 167 ++ 168 +++

no

no

Claims (279)

A method for inhibiting the activity of STING, the method comprising combining STING with a compound of formula I :

Or a pharmaceutically acceptable salt or tautomer contact thereof, wherein: one of W ¹ and W ² is -N(H)-, -N( R ^d )- (for example, -N(H)- Or -N(C _1-3 alkyl)-), -N(H)-( W ¹² )- or -N( R ^d )-( W ¹² )-, the other of W ¹ and W ² is a chemical bond , -O -, - O- (W 12) - or optionally substituted with 1-3 of R ^a C ₁ -C ₆ alkylene (e.g., C ₁ -C _3, e.g. CH _2, CH R ^a or C R ^a ₂ ); wherein W ¹² is ^a C ₁ -C ₆ alkylene substituted by 1-3 R ^{a as appropriate} , provided that one of W ¹ and W ² is connected to C of formula I via a nitrogen atom (= Part O); A is selected from the group consisting of (A-1) , (A-2) and (A-3) :

Where Z is selected from the group consisting of: chemical bond, CH, C R ¹ , C R ³ , N, NH, N( R ¹ ), and N( R ² ) ; Y ¹ , Y ² and Y ³ are each independently selected Free from the following groups: O, S, CH, C R ¹ , C R ³ , N, NH, N( R ¹ ) and N R ² ; Y ⁴ is C or N; X ⁰ is C or N; X ^{1 is} selected from the group consisting of: O, S, N, NH, NR ¹ , NR ² , CH, C R ¹ and C R ³ ; X ^{2 is} selected from the group consisting of: O, S, N , NH, N R ¹ , N R ² , CH, C R ¹ and C R ³ ; and each

Independently a single bond or a double bond, provided that the five-membered ring system heteroaryl group including Y ⁴ , X ⁰ , X ¹ and X ² ; and the ring system including Z , Y ¹ , Y ² , Y ³ and Y ⁴ Aromatic ring (ie, carbocyclic aromatic or heteroaromatic ring);

Among them: Z is selected from the group consisting of: chemical bond, CH, C R ¹ , C R ³ , N, NH, N( R ¹ ) and N( R ² ) ; Y ¹ and Y ³ are each independently selected from the following Group consisting of: O, S, CH, C R ¹ , C R ³ , N, NH, N( R ¹ ) and N R ² ; Y ⁴ is C or N; X ^{0 is} selected from the following groups: O, S, N, NH, N R 1, N R 2, CH, C R 1 , and C R ^3; X ¹ is selected from the group consisting of: O, S, N, NH , N R 1, N R ^2. CH, C R ¹ and C R ³ ; X ^{2 is} selected from the group consisting of O, S, N, NH, N R ¹ , N R ² , CH, C R ¹ and C R ³ ; and each

Independently is a single bond or a double bond, provided that the five-membered ring system heteroaryl group including Y ⁴ , X ¹ and X ² ; and the ring system aromatic ring including Z , Y ¹ , Y ³ and Y ⁴ (ie , Carbocyclic aromatic or heteroaromatic ring);

; Wherein: Y ⁷ is N or C; Z ^{2 is} selected from CH, C R ² and N; X ^{3 is} selected from O, S, N, NH, NR ¹ , NR ² , CH, CR ¹ and CR ³ ; Y ⁵ and Y ⁶ are each independently selected from O, S, CH, C R ¹ , C R ³ , N R ¹ , N R ² , NH and N; and each

Independently is a single bond or a double bond, provided that the five-membered ring system including Y ⁵ , Y ⁶ , Y ⁷ , X ³ and Z ² is a heteroaromatic ring, and the other conditions are: When X ³ is N R ¹ or C R ^1, then Y ⁵ and Y ⁶ are each independently selected from O, S, CH, C R 3, N R 2, NH , and N; and when X ³ is selected from O, S, N, NH, N R ^{2. For} CH and C R ³ , then one of Y ⁵ and Y ⁶ is CR ¹ or N R ¹ ; B is: ( a) C _1-15 alkyl group, which can be independently selected by 1-6 as the case may be the substituents R ^a; (b) C _3-20 cycloalkyl, which is optionally substituted with 1-4 R ^b; (c) substitution of phenyl with 1-4 R ^c; (d) optionally substituted with 1 -4 C _8-20 aryl groups substituted by R ^c ; ( e ) Heteroaryl groups containing 5-20 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of : N, N(H), N( R ^d ), O and S(O) _0-2 , and the heteroaryl ring is optionally substituted with 1-4 independently selected R ^c ; or ( f ) includes 3- A heterocyclic group of 16 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 , and the heterocyclic ring is optionally substituted by 1-4 independently selected R ^b ; R ¹ is: (i) -( U ¹ ) _q - U ² , where: ● q is 0 or 1; ● U ¹ Department C _1-6 alkylene which is optionally substituted with 1-6 R ^a; and ● U ² system: (a) C _3-12 cycloalkyl, which is optionally substituted with 1-4 R ^b Substitution: ( b ) C _6-10 aryl group, optionally substituted by 1-4 R ^c ; ( c ) Heteroaryl group containing 5-20 ring atoms, of which 1-4 ring atoms are heteroatoms, Each is independently selected from the group consisting of: N, N(H), N( R ^d ), O, and S(O) _0-2 , and the heteroaryl ring is optionally selected by 1-4 independently R ^c substituted, or ( d ) a heterocyclic group containing 3-12 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 , and the heterocyclyl ring is optionally substituted by 1-4 independently selected R ^b , or ( ii ) C _1-10 alkyl, which is optionally substituted by 1- six of independently selected R ^a substituents; R ² is independently selected at each occurrence from the group consisting of: (i) C _1-6 alkyl, which is optionally substituted with 1-4 independently selected R ^a of ; ( Ii ) C _3-6 cycloalkyl; ( iii ) containing 3-10 A heterocyclic group of three ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _{0 -2} ; ( iv ) -C(O)(C _1-4 alkyl); ( v ) -C(O)O(C _1-4 alkyl); ( vi ) -CON(R')(R''); ( vii ) -S(O) _1-2 (NR'R''); ( viii )-S(O) _1-2 (C _1-4 alkyl); ( ix ) -OH; and ( x ) C _1-4 alkoxy; R ³ is independently selected from the group consisting of: halo, cyano, C _2-6 alkenyl, C _2-6 alkynyl, as the case may be C _3-6 cycloalkyl substituted C _1-4 alkoxy, C _1-4 haloalkoxy, -S(O) _1-2 (C _1-4 alkyl), -N R ^e R ^f , -OH, pendant oxy, -S(O) _1-2 (NR'R''), -C _1-4 thioalkoxy, -NO ₂ , -C(=O)(C _1-4 alkane基), -C(=O)O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R''); R ^a appears every time Is independently selected from the group consisting of: -OH; -F; -Cl; -Br; -N R ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C( =O)O(C _1-4 alkyl); -C(=O)(C _1-4 alkyl); -C(=O)OH; -CON(R')(R''); -S (O) _1-2 (NR'R''); -S(O) _1-2 (C _1-4 alkyl); cyano; and optionally 1-4 independently selected C _1-4 alkyl C _3-6 cycloalkyl substituted with a group; each occurrence of R ^b is independently selected from the group consisting of: optionally ^a C _1-10 alkyl substituted with 1-6 independently selected Ra ; C _1-4 haloalkyl; -OH; pendant oxy; -F; -Cl; -Br; -NR ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(= O)(C _1-4 alkyl); -C(=O)O(C _1-4 alkyl); -C(=O)OH; -C(=O)N(R')(R''); -S(O) _1-2 (NR'R''); -S(O) _1-2 (C _1-4 alkyl); cyano; and -L ¹ -L ² -R ^h ; R Each occurrence of ^c is independently selected from the group consisting of: (a) halo; (b) cyano; (c) C _1-15 alkyl, which is optionally selected from 1-6 independently selected R ^a substituted; (d) C _2-6 alkenyl; (e) C _2-6 alkynyl; (g) optionally C _1-4 alkoxy substituted by C _1-4 alkoxy; (h) C _1-4 haloalkoxy; (i) -S(O) _1-2 (C _1-4 alkyl); (j) -N R ^e R ^f ; (k) -OH; (l) -S( O) _1-2 (N R ' R ''); (m) -C _1-4 thioalkoxy substituted with 1-4 halo groups as appropriate; (n) -NO ₂ ; (o)- C(=O)(C _1-4 alkyl); (p) -C(=O)O(C _1-4 alkyl); (q) -C(=O)OH; (r) -C( =O)N(R')(R''); and (s) -L ¹ -L ² -R ^h ; R ^{d is} selected from the group consisting of: C _1-6 alkyl; C _3-6 ring Alkyl; -C(O)(C _1-4 alkyl); -C(O)O(C _1-4 alkyl); -CON(R')(R''); -S(O) _{1 -2} (NR'R''); -S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; R ^e and R ^f are independent at each occurrence Is selected from the group consisting of: H; C _1-6 alkyl; C _1-6 haloalkyl; C _3-6 cycloalkyl; -C(O)(C _1-4 alkyl); -C (O)O(C _1-4 alkyl); -CON(R')(R''); -S(O) _1-2 (NR'R'');-S(O) _1-2 ( C _1-4 alkyl); -OH; and C _1-4 alkoxy; or R ^e and R ^f together with the nitrogen atom to which they are each connected form a ring containing 3-8 ring atoms, wherein the ring contains : ( A ) 1-7 ring carbon atoms, each of which is substituted by 1-2 substituents independently selected from H and C _1-3 alkyl; and ( b ) 0-3 ring heteroatoms (except for linking To the nitrogen atoms of R ^e and R ^f ), which are each independently selected from the group consisting of N ( R ^d ), NH, O and S; -L ¹ is a chemical bond or a C _1-3 alkylene group; -L ² is -O-, -N(H)-, -S- or chemical bond; R ^{h is} selected from: ● C _3-8 cycloalkyl, which is independently selected from the following composition via 1-4 as appropriate Substituent substitution of the group: halo, C _1-4 alkyl and C _1-4 haloalkyl (in certain embodiments, the condition is that when R ^h is optionally selected from 1-4 independently C _{In the case} of C _3-6 cycloalkyl substituted with _1-4 alkyl, -L ¹ is a chemical bond, or -L ² is -O-, -N(H)- or -S-); ● Heterocyclic group, wherein The heterocyclic group contains 3-16 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S( O) _0-2 , wherein the heterocyclic group is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C _1-4 alkyl and C _{1 -4} haloalkyl; ● Heteroaryl groups containing 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 , and the heteroaryl ring is optionally substituted by 1-4 substituents independently selected from the group consisting of halo, C _1-4 alkyl and C _1-4 haloalkyl; and C _6-10 aryl, optionally substituted with _1-4 substituents independently selected from the group consisting of halo, C _1-4 alkyl or C _1-4 haloalkyl; and R ′ and R ″ are independently selected from the group consisting of H, C _1-4 alkyl, and optionally 1-2 halo groups at each occurrence , C _1-4 alkyl and C _1-4 haloalkyl substituents substituted C _6-10 aryl; or R 'and R '' together with the nitrogen atom to which they are each connected form a ring containing 3-8 A ring of atoms, wherein the ring comprises: ( a ) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C _1-3 alkyl; and ( b) a group (except for connection to the R 'and R' 'of the nitrogen atom), each of which is independently selected from the group consisting of 0-3 ring heteroatoms: N (H), N ( R d), O and S. Such as the method of claim 1, where A is (A-1) . Such as the method of claim 2, where Z is selected from the group consisting of CH, C R ¹ , C R ³ , N, and N( R ² ) . Such as the method of any one of claims 2 to 3, wherein Z is selected from the group consisting of CH, C R ¹ , C R ³ and N. Such as the method of any one of claims 2 to 4, wherein Z is selected from the group consisting of CH, C R ¹ and C R ³ (for example, Z is CH). Such as the method of any one of claims 2 to 5, wherein Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of CH, C R ¹ , C R ³ and N. Such as the method of any one of claims 2 to 6, wherein Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of CH, C R ¹ and C R ³ . Such as the method of any one of claims 2 to 7, wherein

Part of the department

, Where m1 = 0, 1, 2 or 3; and m3 = 0, 1, 2 or 3 (for example, m1 = 0 or 1; and m3 = 0, 1 or 2 (for example, m1 = 0; and m3 = 2)) . Such as the method of any one of claims 2 to 6, wherein 1-2 of Y ¹ , Y ² and Y ³ are independently N. Such as the method of any one of claims 2 to 6 and 9, wherein one of Y ¹ , Y ² and Y ³ is N independently. Such as the method of any one of claims 2 to 6 and 9 to 10, wherein

Part of the department

, Where the asterisk indicates the connection point with Y ⁴ ; and m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1). Such as the method of any one of claims 2 to 6 and 9 to 10, wherein

Part of the department

, Where: the asterisk indicates the connection point with Y ⁴ ; and m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1). Such as the method of any one of claims 2 to 6 and 9, wherein two of Y ¹ , Y ² and Y ³ are N independently. Such as the method of any one of claims 2 to 6, 9 and 13, wherein

Part of the department

, Where: the asterisk indicates the connection point with Y ⁴ ; and m1 = 0 or 1; and m3 = 0 or 1. Such as the method of any one of Claims 2 to 14, wherein Y ⁴ is C. Such as the method of any one of claims 2 to 15, wherein X ^{1 is} selected from the group consisting of NH, NR ¹ and NR ² . Such as the method of any one of claims 2 to 16, wherein X ^{1 is} selected from the group consisting of NH and NR ² , such as X ¹ is NH or NAc, such as X ¹ is NH. Such as the method of any one of claims 2 to 17, wherein X ^{2 is} selected from the group consisting of N, CH, C R ¹ and C R ³ . Such as the method of any one of claims 2 to 18, wherein X ^{2 is} selected from the group consisting of N, C (C _1-3 alkyl) and CH. Such as the method of any one of claims 2 to 19, wherein X ² is CH. Such as the method of any one of claims 2 to 20, wherein X ⁰ is C. Such as the method of any one of claims 2 to 15, wherein X ¹ is NH, NR ¹ or NR ² ; and X ⁰ is C. Such as the method of claim 22, wherein X ¹ is NH or N R ² , such as X ¹ is NH or NAc, such as X ¹ is NH. Such as the method of any one of claims 22 to 23, wherein X ² is CH; X ¹ is NH; and X ⁰ is C. Such as the method of any one of claims 1 to 2, where A is:

(E.g

), where m1 = 0, 1, 2 or 3; and m3 = 0, 1, 2 or 3 (for example, m1 = 0 or 1; and m3 = 0, 1 or 2). Such as the method of request item 25, where m3 = 2; and m1 = 0. Such as the method of any one of claims 1 to 2, where A is:

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1). Such as the method of any one of claims 1 to 2, where A is

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1). Such as the method of any one of claims 1 to 2, where A is

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1). Such as the method of claim 1, where A is (A-2 ). Such as the method of claim 30, where Z is selected from the group consisting of CH, C R ¹ , C R ³ and N. Such as the method of any one of claims 30 to 31, wherein Z is selected from the group consisting of CH, C R ¹ and C R ³ , such as Z is CH. Such as the method of any one of claims 30 to 32, wherein Y ¹ and Y ³ are each independently selected from the group consisting of CH, C R ¹ , C R ³ and N. Such as the method of any one of claims 30 to 33, wherein Y ¹ and Y ³ are each independently selected from the group consisting of CH, C R ¹ and C R ³ . Such as the method of any one of claims 30 to 34, wherein

Part of the department

, Where m1 = 0, 1, 2 or 3; and m3 = 0, 1, 2 or 3 (for example, m1 = 0 or 1; and m3 = 0, 1 or 2); and the asterisk indicates the connection point with W ¹ . Such as the method of any one of claims 30 to 35, wherein Y ⁴ is C. The method according to any one of claims 30 to 36, wherein X ^{1 is} selected from NH and NR ² , such as X ¹ is NH. Such as the method of any one of claims 30 to 37, wherein X ^{0 is} selected from the group consisting of CH and N, such as X ⁰ is CH. Such as the method of any one of claims 30 to 37, wherein X ⁰ is CR ³ . Such as the method of any one of claims 30 to 39, wherein X ^{2 is} selected from the group consisting of C R ¹ , CH and N, such as X ² is CH. Such as the method of any one of claims 30 to 40, where A is:

, Where m1 = 0, 1 or 2; and m3 = 0, 1 or 2 (for example, m1 = 0 or 1; and m3 = 0 or 1). Such as the method of claim 1, where A is (A-3) . Such as the method of claim 42, wherein X ³ is N R ¹ or C R ¹ . Such as the method of claim 43, wherein Z ^{2 is} selected from N or CH. The method according to any one of claims 43 to 44, wherein Y ^{6 is} selected from S, CH, CR ³ and N. The method according to any one of claims 43 to 45, wherein Y ^{6 is} selected from S, N and CH (for example, Y ⁶ is CH; or Y ⁶ is S). The method according to any one of claims 43 to 46, wherein Y ^{5 is} selected from CH, C R ³ and N (for example, CH and N). Such as the method of any one of claims 42 to 47, wherein Y ⁷ is C. Such as the method of any one of claims 42 to 43, wherein A is selected from:

. Such as the method of claim 42, wherein X ³ is S, N, CH, C R ³ , NH or N R ² . Such as the method of claim 50, wherein X ^{3 is} selected from N, CH or NH (for example, CH or NH). Such as the method of any one of claims 50 to 51 and, wherein Z ^{2 is} selected from N or CH (for example, Z ² is CH). Such as the method of any one of claims 50 to 52, wherein Y ^{6 is} selected from CH and N (for example, Y ⁶ is N). The method according to any one of claims 50 to 53, wherein Y ^{5 is} selected from N R ¹ and C R ¹ , such as C R ¹ The method of any one of 42 and 50, wherein A is selected from:

. Such as the method of claim 55, where A is

, Such as

. Such as the method of any one of claims 1 to 56, where R ¹ is independently selected from the group consisting of: (i) -( U ¹ ) _q - U ² each time it appears, where: q is 0 or ^1; ● U 1 line C _1-6 alkylene which is optionally substituted with 1-6 R ^a; and ● U ² system: o C _3-10 cycloalkyl, which is optionally substituted with 1-4 R ^b substitution, o C _6-10 aryl group, optionally substituted by 1-4 R ^c ; o Heteroaryl group containing 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently Ground is selected from the group consisting of: N, N(H), N( R ^d ), O and S(O) _0-2 , and the heteroaryl ring is optionally substituted by 1-4 independently selected R ^c , Or o heterocyclic group containing 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 , wherein the heterocyclyl ring is optionally substituted by 1-4 independently selected R ^b , and ( ii ) C _1-6 alkyl, which optionally is independently selected by 1-6 The R ^{a is} replaced. Such as the method of any one of claims 1 to 57, wherein R ¹ is -( U ¹ ) _q - U ² . Such as the method of any one of claims 1 to 58, where q is 0. The method according to any one of claims 1 to 59, wherein U ² is a C _6-10 aryl group, which is optionally substituted with 1-4 R ^c . The method according to any one of claims 1 to 60, wherein U ² is a C _6-10 aryl group, which is optionally substituted with 1-2 R ^c . The method according to any one of claims 1 to 61, wherein U ² is a phenyl group, which is optionally substituted with 1-2 (for example, 1) R ^c . Such as the method of any one of claims 57 to 62, wherein each occurrence of the R ^c substituent on U ² is selected from the group consisting of: halo (such as Cl, F); cyano; as the case may be 1-6 independently selected R ^a substituted C _1-10 alkyl; C _1-4 haloalkyl; C _1-4 alkoxy; C _1-4 haloalkoxy; and -C _1-4 sulfur Substituted alkoxy. Such as the method of any one of claims 57 to 62, wherein the R ^c substituent on U ² is selected from the group consisting of: halo (such as Cl, F; such as F), cyano, C _1-6 alkyl and C _1-4 haloalkyl. The method according to any one of claims 57 to 58, wherein R ¹ is a phenyl group, which is optionally substituted with 1-2 (for example, 1) R ^c . The method according to item 65 of the request, wherein each R ^c is independently selected from the group consisting of: halo (e.g. Cl, F); a cyano group; optionally substituted with 1-6 independently selected substituents of the R ^a C _{1- 10} alkyl; C _1-4 haloalkyl; C _1-4 alkoxy; C _1-4 haloalkoxy; and -C _1-4 thioalkoxy, optionally, R ^c on U ² The substituents are independently selected from the group consisting of halo (e.g. Cl, F; e.g. F), cyano, C _1-6 alkyl, and C _1-4 haloalkyl at each occurrence. The method according to any one of claims 1 to 57, wherein R ¹ is ^a C _1-6 alkyl substituted with 1-6 independently selected Ra (in certain embodiments, each of R ¹ The R ^a substituent is independently selected from: -OH; -F; -Cl; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)O(C _1-4 alkyl) ; -C(=O)OH; and optionally C _3-6 cycloalkyl substituted with 1-4 independently selected C _1-4 alkyl groups). The method according to any one of claims 1 to 67, wherein each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 halo Alkoxy, -S(O) _1-2 (C _1-4 alkyl), -NR ^e R ^f , -OH, -S(O) _1-2 (NR'R''), -C _{1- 4} thioalkoxy, -C (= O) (C 1-4 alkyl), - C (= O) O (C 1-4 alkyl), - C (= O) OH and -C (= O)N(R')(R''). The method according to any one of claims 1 to 68, wherein each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 halo Alkoxy, -S(O) _1-2 (C _1-4 alkyl), -S(O) _1-2 (NR'R''), -C(=O)(C _1-4 alkyl ), -C(=O)O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R''). The method according to any one of claims 1 to 69, wherein each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy and C _1-4 halo Alkoxy (e.g. halo or cyano). The method according to any one of claims 1 to 70, wherein each occurrence of R ² is independently selected from the group consisting of: C _1-6 alkyl (for example, methyl); C _3-6 cycloalkyl ; C(O)(C _1-4 alkyl) (such as C(O)Me); -C(O)O(C _1-4 alkyl); -CON(R')(R'');- S(O) _1-2 (NR'R''); and S(O) _1-2 (C _1-4 alkyl) (for example, S(O) ₂ Me). The method according to any one of claims 1 to 71, wherein each occurrence of R ² is independently selected from ( viii )-S(O) _1-2 (C _1-4 alkyl) (for example, S(O) ₂ Me) and ( iv ) -C(O)(C _1-4 alkyl) (for example, C(O)Me). The method of any one of 11, 12, 14, 25 to 29, 35, and 41, wherein m1=0. Such as the method of claim 73, where m3 = 0, 1 or 2. Such as the method of any one of claims 73 to 74, where m3 = 0. Such as the method of any one of claims 73 to 74, where m3 = 1 or 2. Such as the method of claim 76, wherein each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy, -S (O) _1-2 (C _1-4 alkyl), -NR ^e R ^f , -OH, -S(O) _1-2 (NR'R''), -C _1-4 thioalkoxy , -C(=O)(C _1-4 alkyl), -C(=O)O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R' ) (R''), such as R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy,- S(O) _1-2 (C _1-4 alkyl), -S(O) _1-2 (NR'R''), -C(=O)(C _1-4 alkyl), -C( =O)O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R''), such as R ³ is independently selected for each occurrence The group consisting of halo, cyano, C _1-4 alkoxy and C _1-4 haloalkoxy (for example, halo or cyano). Such as the method of claim 77, wherein R ³ is a halogen group (for example, F) or a cyano group. The method according to any one of claims 49 and 55 to 56, wherein R ^{1 is} as defined in any one of claims 57 to 67 (for example, any one of claims 58 to 66). Such as the method of claim 79, wherein R ¹ is a phenyl group, which is optionally substituted with 1-2 (eg 1) R ^c , optionally wherein each R ^{c is} independently selected from the group consisting of: halo (eg cl, F); a cyano group; optionally substituted with 1-6 independently selected R ^a substituents of C _1-10 alkyl; C _1-4 haloalkyl; C _1-4 alkoxy; C _1-4 halo Alkoxy; and -C _1-4 thioalkoxy, such as the R ^c substituent on U ² is independently selected from the group consisting of: halo (e.g. Cl, F; for example F ), cyano, C _1-6 alkyl and C _1-4 haloalkyl. The method according to any one of claims 49 and 55 to 56, wherein R ¹ is a phenyl substituted with one R ^c as appropriate. Such as the method of claim 81, wherein R ¹ is an unsubstituted phenyl group. Such as the method of any one of claims 1 to 82, wherein W ¹ is -NH-. The method according to any one of claims 1 to 82, wherein W ¹ is CH ₂ or CH (C _1-3 alkyl) (for example, CH ₂ ). Such as the method of any one of claims 1 to 82, wherein W ¹ is a chemical bond. Such as the method of any one of claims 1 to 83, wherein W ² is a chemical bond. The method according to any one of claims 1 to 83, wherein W ² is CH ₂ or CH (C _1-3 alkyl) (for example, CH ₂ ). Such as the method of any one of claims 1 to 82 and 84 to 86, wherein W ² is -NH-. Such as the method of any one of claims 1 to 82, wherein W ¹ is -NH-; and W ² is a chemical bond. The method according to any one of claims 1 to 82, wherein W ¹ is -NH-; and W ² is CH ₂ or CH (C _1-3 alkyl) (for example, CH ₂ or CH(Me)). The method according to any one of claims 1 to 82, wherein W ² is -NH-; and W ¹ is a chemical bond. The method according to any one of claims 1 to 82, wherein W ² is -NH-; and W ¹ is CH ₂ or CH (C _1-3 alkyl) (for example, CH ₂ ). The method according to any one of claims 1 to 92, wherein B is a phenyl substituted with 1-4 R ^c . The requested item 1 of the process according to 93, wherein the B-based substituted by a phenyl group with 1-2 R ^c, wherein R ^c 1-2 lines located formula I - W ¹ - C (= O ) -W ² -part of the ring carbon at the para or meta position of the connection point (for example, an R ^c is located at the ring carbon at the para position of the connection point). Such as the method of any one of claims 1 to 94, wherein B is located at the ring carbon in the para position to the connection point of the- W ¹ - C(=O) -W ² -part in formula I through an R ^c Substituted phenyl. Such as the method of any one of claims 93 to 95, wherein each R ^c substituent of B is independently selected from the group consisting of: halo; cyano; optionally 1-6 independently selected ^Ra Substituted C _1-10 alkyl; C _1-4 alkoxy; C _1-4 haloalkoxy; -S(O) _1-2 (C _1-4 alkyl); -C _1-4 thio Alkoxy; -C(=O)(C _1-4 alkyl); -C(=O)O(C _1-4 alkyl); -C(=O)N(R')(R''); and -L ¹ -L ² -R ^h . Such as the method of any one of claims 93 to 96, wherein each R ^c substituent of B is independently selected from the group consisting of: halo; cyano; optionally 1-6 independently selected ^Ra Substituted C _1-10 alkyl; C _1-4 alkoxy; and C _1-4 haloalkoxy. The requested item 93 to 97 of the method according to any of R B ^c wherein each substituent group independently selected from C _1-10 alkyl, which is optionally substituted with 1-6 independently selected of R ^a. The method of claim 98, wherein each occurrence of ^Ra is independently selected from:-halo (for example, F); -OH; C _1-4 alkoxy; and C _1-4 haloalkoxy. The method according to any one of claims 98 to 99, wherein each R ^c substituent of B is C _1-10 (eg C _1-6 , C _1-3 , C _1-2 , C ₁ ) alkyl (for example, R ^c is CF ₃ ). The method according to any one of claims 93 to 97, wherein each R ^c substituent of B is independently selected from unsubstituted C _1-10 (for example, C _2-10 (for example, C _3-8 )) alkyl . The method of claim 101, wherein each R ^c substituent of B is independently selected from unsubstituted C _1-6 alkyl. The method of claim 102, wherein each R ^c substituent of B is independently selected from unsubstituted C _2-6 (for example, C _2-4 , for example, C ₂ or C ₄ ) alkyl. The method of any one of claims 101 to 103, wherein each R ^c substituent of B is ethyl or butyl (for example, n-butyl). The method according to any one of claims 93 to 95, wherein R ^c is ^a C _1-6 alkyl substituted with 1-3 independently selected Ra as appropriate . The method according to any one of claims 1 to 92, wherein B is a C _3-20 cycloalkyl group, which is optionally substituted with 1-4 R ^b . The method according to any one of claims 1 to 92 and 106, wherein B is a C _3-12 cycloalkyl group, which is optionally substituted with 1-2 R ^b . The method according to any one of claims 1 to 92 and 106 to 107, wherein B is a C _6-12 cycloalkyl group, which is optionally substituted with 1-2 R ^b . Such as the method of any one of claims 1 to 92 and 106 to 108, wherein B is a C _6-12 (for example, _C7-12 ) cycloalkyl group (for example, B may be

). The method according to any one of claims 1 to 92, wherein B is a heterocyclic group containing 3-16 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 heterocyclic ring is optionally substituted with 1-4 independently selected R ^b . The method according to any one of claims 1 to 92 and 110, wherein B is a heterocyclic group containing 3-12 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of Group: N, N(H), N( R ^d ), O and S(O) _0-2 , and the heterocyclic ring is optionally substituted with 1-4 independently selected R ^b . The method according to any one of claims 1 to 92 and 110 to 111, wherein B is a heterocyclic group containing 3-8 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the following components The group of: N, N(H), N( R ^d ), O and S(O) _0-2 , and the heterocyclic ring is optionally substituted by 1-3 independently selected R ^b . The method according to any one of claims 1 to 92 and 110 to 112, wherein B is a heterocyclic group containing 5-6 (for example, 6) ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently Selected from the group consisting of: N, N(H), N( R ^d ), O and S(O) _0-2 , and the heterocyclic ring is optionally substituted with 1-2 independently selected R ^b ( For example, B can be

). The method of any one of claims 106 to 113, wherein each occurrence of R ^b is independently selected from the group consisting of: C _1-10 alkyl; C _1-4 haloalkyl; -OH; side -F; -Cl; -NR ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)(C _1-4 alkyl); -C( =O) O(C _1-4 alkyl); -S(O) _1-2 (C _1-4 alkyl); cyano; and -L ¹ -L ² -R ^h . The method of any one of claims 106 to 114, wherein each occurrence of R ^b is independently selected from the group consisting of: C _1-10 alkyl; C _1-4 haloalkyl; -OH; side Oxy; -F; -Cl; C _1-4 alkoxy; and C _1-4 haloalkoxy. The method of claim 1, wherein the compound is selected from the compounds in Table C1 , or a pharmaceutically acceptable salt thereof. A compound of formula II ,

Or a pharmaceutically acceptable salt or tautomer thereof, wherein: Z is selected from the group consisting of CH, C R ¹ , C R ³ , N, NH, N( R ¹ ), and N( R ² ) ; Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of: CH, C R ¹ , C R ³ , N, NH, N( R ¹ ), and N R ² ; each

Independently is a single bond or a double bond, provided that: a 6-membered ring system including Z , Y ¹ , Y ² and Y ³ is an aromatic ring; provided that Y ¹ , Y ² and Y ³ are each independently selected from CH , C R ¹ , C R ³ , Y ³ cannot be N; and when Z , Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of CH, C R ¹ and C R ³ When Z , Y ¹ , Y ² and Y ³ are selected from the group consisting of C R ¹ and C R ³ ; R ^2N is H or R ² ; R ^{6 is} selected from the group consisting of H and R ^d Group; B is a monocyclic heteroaryl group containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N( R ^d ), O and S(O) _0-2 , and the heteroaryl ring is optionally substituted by 1-2 independently selected R ^c ; -L ³ is a chemical bond or C _1-3 alkylene; R ^{4 is} selected Free from the group consisting of: ( a ) C _3-12 cycloalkyl, optionally substituted by 1-4 independently selected R ⁴ ', ( b ) heterocyclic group containing 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 , and wherein the heterocyclic group One or more ring carbon atoms are optionally substituted with 1-4 independently selected R ⁴ '; (c) Heteroaryl groups containing 5-12 ring atoms, of which 1-3 ring atoms are heteroatoms, each Independently selected from the group consisting of: N, N(H), N( R ^d ), O and S(O) _0-2 , and one or more of the ring carbon atoms of the heteroaryl ring may be 1-4 independently selected R ⁴ 'substitutions; and (d) C _6-10 aryl, optionally substituted with 1-4 independently selected R ⁴ 's; wherein each R ⁴ ' is independently selected from the following components group: halo; -CN; -NO _2; -OH; optionally substituted with 1-2 independently selected substituents of the R ^a -C _1-4 alkyl; -C _2-4 alkenyl; -C _{2 -4} alkynyl; -C _1-4 haloalkyl; optionally substituted with 1-2 independently selected substituents of the R ^a -C _1-6 alkoxy; -C _1-6 haloalkoxy; S (O ) _1-2 (C _1-4 alkyl); -N R ' R " ; pendant oxy; -S (O) _1-2 (N R ' R ''); -C _1-4 thioalkoxy Group; -C(=O)(C _1-4 alkyl); -C(=O)O(C _1-4 alkyl); -C(=O)OH; and -C(=O)N( R ')( R ''); R ¹ series: (i) -( U ¹ ) _q - U ² , where: ● q is 0 or 1; ● U ¹ is a C _1-6 alkylene group, as appropriate By 1 -6 ^Ra substituted; and ● U ² is: ( a ) C _3-12 cycloalkyl, optionally substituted by 1-4 R ^b , ( b ) C _6-10 aryl, optionally 1-4 R ^c substitutions; ( c ) Heteroaryl groups containing 5-20 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H ), N( R ^d ), O and S(O) _0-2 , and the heteroaryl ring is optionally substituted by 1-4 independently selected R ^c , or ( d ) contains 3-12 ring atoms Cyclic groups, in which 1-3 ring atoms are heteroatoms, are each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 , and wherein when R ² at each occurrence; heterocyclic ring optionally substituted with 1-4 independently selected substituents of R ^b, or (ii) C _1-10 alkyl, which is optionally substituted with 1-6 independently selected R ^a of independently selected from the group consisting of: (i) C _1-6 alkyl, which is optionally substituted with 1-4 independently selected of R ^a; (ii) C _3-6 cycloalkyl; (iii) comprises A heterocyclic group of 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S( O) _0-2 ; ( iv ) -C(O)(C _1-4 alkyl); ( v ) -C(O)O(C _1-4 alkyl); ( vi ) -CON(R') (R''); ( vii ) -S(O) _1-2 (NR'R''); ( viii )-S(O) _1-2 (C _1-4 alkyl); ( ix ) -OH ; And ( x ) C _1-4 alkoxy; R ³ is independently selected from the group consisting of: halo, cyano, C _2-6 alkenyl, C _2-6 alkynyl, _Optionally , C _1-4 alkoxy substituted by C _3-6 cycloalkyl, C _1-4 haloalkoxy, -S(O) _1-2 (C _1-4 alkyl), -N R ^e R ^f , -OH, pendant oxy, -S(O) _1-2 (NR'R''), -C _1-4 thioalkoxy, -NO ₂ , -C(=O)(C _{1 -4} alkyl), - C (= O) O (C 1-4 alkyl), - C (= O) OH and -C (= O) N (R ') (R''); R a in Each occurrence is independently selected from the group consisting of: -OH; -F; -Cl; -Br; -N R ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)O(C _1-4 alkyl); -C(=O)(C _1-4 alkyl); -C(=O)OH; -CON( R ')( R '') ;-S(O) _1-2 (N R ' R ''); -S(O) _1-2 (C _1-4 alkyl); cyano; and optionally C ₃ substituted with 1-4 independently selected C _1-4 alkyl groups _-6 cycloalkyl group; R ^b at each occurrence is independently selected from the group consisting of: optionally substituted with 1-6 independently selected R ^a substituents of C _1-10 alkyl; C _1-4 haloalkyl -OH; pendant oxy; -F; -Cl; -Br; -NR ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)(C _{1 -4} alkyl); -C(=O)O(C _1-4 alkyl); -C(=O)OH; -C(=O)N( R ')( R ''); -S( O) _1-2 (N R ' R ''); -S(O) _1-2 (C _1-4 alkyl); cyano; and -L ¹ -L ² -R ^h ; R ^c in each independently selected from the group consisting upon the occurrence of: (a) halo; (b) cyano; (c) C _1-15 alkyl, which is optionally substituted with 1-6 independently selected of R ^a; ( d) C _2-6 alkenyl; (e) C _2-6 alkynyl; (g) C _1-4 alkoxy substituted with C _1-4 alkoxy as appropriate; (h) C _1-4 halo Alkoxy; (i) -S(O) _1-2 (C _1-4 alkyl); (j) -N R ^e R ^f ; (k) -OH; (l) -S(O) _{1- 2} (N R ' R ''); (m) -C _1-4 thioalkoxy substituted by 1-4 halo groups as appropriate; (n) -NO ₂ ; (o) -C(=O )(C _1-4 alkyl); (p) -C(=O)O(C _1-4 alkyl); (q) -C(=O)OH; (r) -C(=O)N (R')(R''); and (s) -L ¹ -L ² -R ^h ; R ^{d is} selected from the group consisting of: C _1-6 alkyl; C _3-6 cycloalkyl;- C(O)(C _1-4 alkyl); -C(O)O(C _1-4 alkyl); -CON(R')(R''); -S(O) _1-2 (NR 'R''); -S(O) _1-2 (C _1-4 alkyl); -OH; and C _1-4 alkoxy; each occurrence of R ^e and R ^f is independently selected from the following Composition group: H; C _1-6 alkyl; C _1-6 haloalkyl; C _3-6 cycloalkyl; -C(O)(C _1-4 alkyl); -C(O)O (C _1-4 alkyl); -CON(R')(R''); -S(O) _1-2 (NR'R'');-S(O) _1-2 (C _1-4 Alkyl); -OH; and C _1-4 alkoxy; or R ^e and R ^f together with the nitrogen atom to which they are each connected form a ring containing 3-8 ring atoms, wherein the ring comprises: ( a ) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from H and C _1-3 alkyl; and ( b ) 0-3 ring heteroatoms (except for being connected to R ^e and R ^f except for the nitrogen atom), which are each independently selected from the group consisting of N ( R ^d ), NH, O and S; -L ¹ series chemical bond or C _1-3 alkylene; -L ² series -O-, -N(H)-, -S- or chemical bond; R ^{h is} selected from: ● C _3-8 cycloalkyl, optionally substituted by 1-4 independently selected from the following groups Substitution: halo, C _1-4 alkyl and C _1-4 haloalkyl (in certain embodiments, the condition is that when R ^h is optionally selected from _1-4 independently selected C _1-4 alkane When the C _3-6 cycloalkyl group is substituted by the group, -L ¹ is a chemical bond, or -L ² is -O-, -N(H)- or -S-); ● a heterocyclic group, wherein the heterocyclic group contains 3-16 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _{0- 2} , wherein the heterocyclic group is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C _1-4 alkyl and C _1-4 haloalkyl; ● including 5- Heteroaryl groups with 10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N( R ^d ), O and S(O) _0-2 , and the heteroaryl ring is optionally substituted with _1-4 substituents independently selected from the group consisting of halo, C _1-4 alkyl and C _1-4 haloalkyl; and ● A C _6-10 aryl group, optionally substituted with _1-4 substituents independently selected from the group consisting of halo, C _1-4 alkyl or C _1-4 haloalkyl; and R ′ Each occurrence of R '' is independently selected from the group consisting of H, C _1-4 alkyl, and optionally 1-2 selected from halo, C _1-4 alkyl and C _{1 -4} C _6-10 aryl substituted by the substituent of haloalkyl; or R ′ and R ″ together with the nitrogen atom to which they are each connected form a ring containing 3-8 ring atoms, wherein the ring contains: ( a ) 1-7 ring carbon atoms, each of which is substituted by 1-2 substituents independently selected from the group consisting of H and C _1-3 alkyl; and ( b ) 0-3 ring heteroatoms ( Except for the nitrogen atoms connected to R ′ and R ″ ), they are each independently selected from the group consisting of N(H), N( R ^d ), O and S. Such as the compound of claim 117, wherein Z , Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of CH, C R ¹ , C R ³ and N. The compound of any one of claims 117 to 118, wherein Z , Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of CH, C R ¹ and C R ³ . Such as the compound of any one of claims 117 to 119, wherein 1-2 of Z , Y ¹ , Y ² and Y ³ are independently selected from the group consisting of C R ¹ and C R ³ ; and the remaining Z , Y ¹ , Y ² and Y ³ are each CH. The compound of claim 120, wherein the compound has formula II-a :

. The compound of claim 120, wherein the compound has formula II-b or II-c :

. The compound of claim 120, wherein the compound has the formula II-d , II-e or II-f :

. Such as the compound of any one of claims 117 to 118, wherein one of Z , Y ¹ and Y ² is N; and the remaining Z , Y ¹ , Y ² and Y ³ are each independently selected from the group consisting of : CH, C R ¹ and C R ³ . Such as the compound of claim 124, wherein Z is N. Such as the compound of claim 124, wherein Y ¹ is N. Such as the compound of claim 124, wherein Y ² is N. The compound of claim 124, wherein the compound has the formula II-g , II-h or II-i :

, Where m1 is 0 or 1; and m3 is 0, 1 or 2. Such as the compound of claim 128, wherein m1 is 0. Such as the compound of claim 128, wherein m1 is 1. Such as the compound of claim 128, wherein m3 is 0. Such as the compound of claim 128, wherein m3 is 1 or 2. Such as the compound of claim 128, wherein m1 is 0; and m3 is 1 or 2. Such as the compound of claim 128, wherein m1 is 1; and m3 is 0. Such as the compound of claim 128, wherein m1 is 1; and m3 is 1. A compound according to any one of claims 117 to 135, wherein R ^2N is H. The compound of any one of claims 117 to 135, wherein R ^2N is R ² , wherein the R ^{2 is} selected from the group consisting of: ( iv ) -C(O)(C _1-4 alkyl) (for example -C(O)Me); ( v ) -C(O)O(C _1-4 alkyl); ( vi ) -CON(R')(R''); ( vii ) -S(O) _{1 -2} (NR'R''); and ( viii )-S(O) _1-2 (C _1-4 alkyl) (for example, S(O) ₂ Me). Such as the compound of claim 137, wherein R ^2N is ( iv ) -C(O)(C _1-4 alkyl) (for example -C(O)Me) or ( viii ) -S(O) _1-2 (C _1-4 alkyl) (e.g. S(O) ₂ Me). The requested item 117 to 138 of a compound in any system in which R ¹ C _1-6 alkyl, which is optionally substituted with 1-6 (e.g., 1-3) selected independently of R ^a substituents. The requested item 117 to 138 of a compound in any system in which R ¹ C _1-3 alkyl, which is optionally substituted with 1-3 independently selected of R ^a. The compound of any one of claims 117 to 138, wherein R ¹ is -( U ¹ ) _q - U ² , wherein: ● q is 0 or 1, such as q is 0; ● U ¹ is C _1-6 alkyl, which is optionally substituted with 1-6 substituents R ^a; and ● U ² system: o (C _3-10 cycloalkyl, which is optionally substituted with 1-4 R ^b, o (C _6-10 aryl Group, optionally substituted with 1-2 R ^c ; o (heteroaryl group containing 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N( R ^d ), O and S(O) _0-2 , and the heteroaryl ring is optionally substituted with 1-2 independently selected R ^c , or o (including 3-6 The heterocyclic group of 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 ring is optionally substituted with 1-4 independently selected R ^b . The compound of any one of claims 117 to 141, wherein each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 halo Alkoxy, -S(O) _1-2 (C _1-4 alkyl), -NR ^e R ^f , -OH, -S(O) _1-2 (NR'R''), -C _{1- 4} thioalkoxy, -C (= O) (C 1-4 alkyl), - C (= O) O (C 1-4 alkyl), - C (= O) OH and -C (= O)N(R')(R''). The compound of any one of claims 117 to 142, wherein each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy, C _1-4 halo Alkoxy, -S(O) _1-2 (C _1-4 alkyl), -S(O) _1-2 (NR'R''), -C(=O)(C _1-4 alkyl ), -C(=O)O(C _1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R''). The compound of any one of claims 117 to 143, wherein each occurrence of R ³ is independently selected from the group consisting of halo, cyano, C _1-4 alkoxy and C _1-4 halo Alkoxy. The compound of claim 144, wherein each occurrence of R ³ is halo or cyano, such as -F or cyano. The compound according to any one of claims 117 to 145, wherein B is a monocyclic heteroaryl group containing 5 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 heteroaryl ring is optionally substituted with 1-2 independently selected R ^c . The compound according to any one of claims 117 to 146, wherein B is a monocyclic heteroaryl group containing 5 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 the heteroaryl ring is optionally substituted with 1-2 independently selected R ^c . The compound of any one of claims 117 to 147, wherein B is a monocyclic heteroaryl group containing 5 ring atoms, wherein 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N( R ^d ), O and S, and the heteroaryl ring is optionally substituted with 1-2 independently selected R ^c . The compound of claim 148, wherein B is a monocyclic heteroaryl group containing 5 ring atoms, wherein 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H) And N( R ^d ), and the heteroaryl ring is optionally substituted with 1-2 independently selected R ^c . The compound of claim 149, wherein B is imidazolyl, pyrazolyl or triazolyl, each of which is optionally substituted by an independently selected R ^c . The compound of claim 150, wherein B is imidazolyl or triazolyl, each of which is substituted with an independently selected R ^c as appropriate. Such as the compound of any one of claims 150 to 151, wherein B is selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ . Such as the compound of claim 152, where B is selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ . Such as the compound of any one of claims 150 to 151, wherein B is selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ . Such as the compound of claim 154, where B is selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ . Such as the compound of claim 150, where B is selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ . Such as the compound of claim 156, where B is selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ . The compound according to any one of claims 117 to 148, wherein B is a monocyclic heteroaryl group containing 5 ring atoms, wherein 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N( ^Rd ), O and S, provided that one ring atom is O or S, and the heteroaryl ring is optionally substituted with 1-2 independently selected R ^c . The compound of claim 158, wherein B is selected from the group consisting of oxazolyl, thiazolyl, thiadiazolyl and oxadiazolyl, each of which is optionally substituted with one R ^c . Such as the compound of claim 159, where B is selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ . The compound according to any one of claims 117 to 146, wherein B is a monocyclic heteroaryl group containing 5 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 the heteroaryl ring is optionally substituted with 1-2 independently selected R ^c , which is the same as the C(=O)NR ⁶ group of formula II The connection point of the group is in the meta position to the connection point of L ³ . Such as the compound of claim 161, where B is selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ . The compound according to any one of claims 117 to 145, wherein B is a monocyclic heteroaryl group containing 6 ring atoms, wherein 1-3 ring atoms are ring nitrogen atoms, and wherein the heteroaryl ring optionally passes through 1- 2 independently selected R ^c substitutions. The compound of claim 163, wherein B is pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which is optionally substituted with 1-2 independently selected R ^c , such as optionally substituted with R ^c pyridyl . A compound according to any one of claims 163 to 164, wherein the point of attachment between B and the C(=0)NR ⁶ group of formula II is in the para position to the point of attachment to L ³ . The compound of any one of claims 163 to 165, wherein B is

, Which is optionally replaced by an R ^c , where aa represents the point of connection with L ³ . The compound according to any one of claims 163 to 164, wherein the point of attachment of B and the C(=0)NR ⁶ group of formula II is in the meta position of the point of attachment to L ³ . Such as the compound of any one of claims 163 to 164 and 167, wherein B is selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ . A compound according to any one of claims 117 to 168, wherein L ³ is a chemical bond. The compound according to any one of claims 117 to 168, wherein L ³ is a C _1-3 alkylene group. Such as the compound of claim 170, wherein L ³ is CH ₂ . A compound according to any one of claims 117 to 171, wherein R ⁴ is a C _6-10 aryl group substituted with 1-4 independently selected R ⁴ ′ as appropriate. A compound according to any one of claims 117 to 172, wherein R ⁴ is a phenyl substituted with 1-4 independently selected R ⁴ ′ as appropriate. A compound according to any one of claims 117 to 173, wherein R ⁴ is a phenyl substituted with 1-2 independently selected R ⁴ ′ as appropriate. The compound of claim 174, wherein R ⁴ is an unsubstituted phenyl group. The compound of claim 174, wherein R ⁴ is a phenyl substituted with 1-2 independently selected R ⁴ ′. The compound of claim 176, wherein R ⁴ is a phenyl substituted with 1-2 independently selected R ⁴ ′, and one of R ⁴ ′ appears in the para position of the connection point with L ³ , such as

. The compound of any one of claims 117 to 171, wherein R ⁴ is a heteroaryl group containing 5-10 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 one or more of the heteroaryl ring carbon atoms are independently selected by 1-4 R ⁴ 'replace. The compound of any one of claims 117 to 171 and 178, wherein R ⁴ is a heteroaryl group containing 5-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from Group: N, N(H), N( R ^d ), O and S(O) _0-2 , and one or more of the heteroaryl ring carbon atoms are independently selected from 1-4 as appropriate R ⁴ 'substituent. The compound of claim 179, wherein R ⁴ is a heteroaryl group containing 6 ring atoms, wherein 1-3 ring atoms are ring nitrogen atoms, and wherein one or more ring carbon atoms of the heteroaryl ring may be of 1-4 independently selected R ⁴ 'substituents, such as optionally substituted with 1-2 independently selected of R ^4' is substituted pyridyl. The compound according to any one of claims 117 to 171, wherein R ⁴ is a C _3-8 cycloalkyl group, which is optionally substituted with 1-4 independently selected R ⁴ ′. The compound of any one of claims 117 to 171, wherein R ⁴ is a C _4-6 cycloalkyl group, which is optionally substituted with 1-4 independently selected R ⁴ ′. The compound of claim 182, wherein R ⁴ is an unsubstituted C _4-6 cycloalkyl group, such as unsubstituted cyclohexyl and unsubstituted cyclopentyl. The compound of claim 182, wherein R ⁴ is a C _4-6 cycloalkyl group, which is substituted with 1-3 (for example, 2 to 3) independently selected R ⁴ ′, such as

. The compound according to any one of claims 117 to 171, wherein R ⁴ is a heterocyclic group containing 4-7 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of : N, N(H), N( R ^d ), O and S(O) _0-2 , and one or more ring carbon atoms of the heterocyclic group are optionally selected R ⁴ 'replace. The compound of one of the group requested item 117 to 185, wherein each R ⁴ 'are independently selected from the group consisting of: halo; -CN; optionally substituted with 1-2 independently selected R ^a of the -C _4alkyl; -C _1-4 haloalkyl; optionally substituted with 1-2 independently selected substituents of the R ^a -C _1-6 alkoxy; -C _1-6 haloalkoxy; S ( O) _1-2 (C _1-4 alkyl); -S(O) _1-2 (N R ' R ''); -C _1-4 thioalkoxy; -C(=O)(C _1-4 alkyl); -C(=O)O(C _1-4 alkyl); and -C(=O)N( R ')( R ''). The compound of one of the group requested item 117 to 186, wherein each R ⁴ 'are independently selected from the group consisting of: halo; -CN; optionally substituted with one of R ^a independently selected substituted -C _1-4 Alkyl; and -C _1-4 haloalkyl. The compound of claim 187, wherein each R ⁴ ′ is independently selected from the group consisting of halo (such as -F), -CN, -C _1-4 alkyl, and -C _1-4 haloalkyl. The compound of any one of claims 117 to 171, wherein L ³ is a chemical bond or CH ₂ ; R ⁴ is a phenyl substituted with 1-2 independently selected R ⁴ ′ as appropriate; and R ⁴ ′ is independently selected the group consisting of: halo; -CN; optionally substituted with 1-2 independently selected substituents of the R ^a -C _1-4 alkyl; -C _1-4 haloalkyl; optionally substituted with 1-2 One independently selected ^Ra substituted -C _1-6 alkoxy; -C _1-6 haloalkoxy; S(O) _1-2 (C _1-4 alkyl); -S(O) _{1- 2} (N R ' R ''); -C _1-4 thioalkoxy; -C(=O)(C _1-4 alkyl); -C(=O)O(C _1-4 alkyl ); and -C(=O)N( R ')( R ''). Such as the compound of claim 189, wherein R ⁴ is

, Which is replaced by additional R ⁴ as appropriate. The compound of claim 190, wherein each R ⁴ ′ is independently selected from the group consisting of halo (such as -F), -CN, -C _1-4 alkyl, and -C _1-4 haloalkyl. The compound according to any one of claims 190 to 191, wherein R ⁴ 'at the para position is -CF ₃ . The requested item groups 117 to 192 of a compound, wherein R ^c is independently at each occurrence selected from the group consisting of: halo; cyano; optionally substituted with 1-6 independently selected R ^a of C _1-6 alkyl; optionally C _1-4 alkoxy substituted by C _1-4 alkoxy; C _1-4 haloalkoxy; S(O) _1-2 (C _1-4 alkyl Group); -S(O) _1-2 (N R ' R ''); -C _1-4 thioalkoxy substituted by 1-4 halo groups as appropriate; -C(=O)(C _1-4 alkyl); -C(=0)O(C _1-4 alkyl); and -C(=0)N(R')(R''). The compound according to item 193 the request, wherein R ^c at each occurrence is independently selected from the group consisting of: halo; cyano; optionally substituted with 1-3 independently selected R ^a sum of a C _1-3 alkoxy Group (such as methyl or CF ₃ ); optionally C _1-4 alkoxy substituted with C _1-4 alkoxy; and C _1-4 haloalkoxy. Such as the compound of claim 194, where one of the occurrences of R ^c is ^a C _1-3 alkyl group (such as methyl or CF ₃ ) substituted with 1-3 independently selected Ra as appropriate. The compound of claim 117, wherein the compound has formula II-1 :

m1 is 0 or 1; m3 is 0, 1 or 2, provided that m1+m3 ＞0; and B is a monocyclic heteroaryl group containing 5 ring atoms, of which 2-3 ring atoms are heteroatoms, each independently The ground is selected from the group consisting of N, N(H), N( ^Rd ), O and S, and the heteroaryl ring is optionally substituted with 1-2 independently selected ^Rc . Such as the compound of claim 196, wherein m3 is 1 or 2. Such as the compound of claim 197, wherein m3 is 2. A compound according to any one of claims 196 to 198, wherein m1 is 0. A compound according to any one of claims 196 to 199, wherein the compound has formula II-1a :

. The compound according to any one of claims 196 to 200, wherein each R ^{3 is} independently selected from the group consisting of halo and cyano. The compound of claim 201, wherein each R ³ is a halogen group, such as -F. A compound according to any one of claims 196 to 202, wherein R ^2N is H. As the compound of any one of claims 196 to 202, wherein R ^2N is ( iv ) -C(O)(C _1-4 alkyl) (for example -C(O)Me) or ( viii ) -S(O ) _1-2 (C _1-4 alkyl) (such as S(O) ₂ Me). A compound according to any one of claims 196 to 204, wherein B is a monocyclic heteroaryl group containing 5 ring atoms, wherein 2-3 ring atoms are heteroatoms, each independently selected from the group consisting of: N, N(H), N( R ^d ), O, and S, and the heteroaryl ring is optionally substituted with 1-2 independently selected R ^c , which is the same as the C(=O)NH group of formula II-1 based on the point of attachment of the group is connected to L ³ between the position of the point. The compound according to any one of claims 196 to 205, wherein B is selected from the group consisting of imidazolyl and triazolyl, each of which is optionally substituted with one R ^c . Such as the compound of claim 206, where B is selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ . A compound according to any one of claims 196 to 205, wherein B is a pyrazolyl substituted with one R ^{c as appropriate} . Such as the compound of claim 208, where B is

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ . The compound according to any one of claims 196 to 205, wherein B is selected from the group consisting of oxazolyl, thiazolyl, oxadiazolyl and thiadiazolyl, wherein the oxazolyl and thiazolyl are optionally selected Replaced by an R ^c . Such as the compound of claim 210, where B is selected from the group consisting of:

, Each of which is replaced by an R ^c as appropriate, where aa represents the point of connection with L ³ . The independently selected from the group consisting of a compound according to any request of 205 to 211, wherein when present each R ^c group: halo; cyano; optionally substituted with 1-3 of R ^a independently selected of C _1-3 alkyl (such as methyl or CF ₃ ); optionally C _1-4 alkoxy substituted with C _1-4 alkoxy; and C _1-4 haloalkoxy. For the compound of any one of claims 205 to 211, one of the occurrences of R ^c is ^a C _1-3 alkyl group (such as methyl or CF ₃ ) substituted with 1-3 independently selected Ra as the case may be. A compound according to any one of claims 205 to 211, wherein B is not substituted with R ^c . The compound of any one of claims 200 to 215, wherein L ³ is a chemical bond. The compound of any one of claims 200 to 215, wherein L ³ is CH ₂ . The compound of any one of claims 200 to 216, wherein R ^{4 is} selected from the group consisting of: C _4-6 cycloalkyl, optionally substituted with 1-4 independently selected R ⁴ ′; including 6 A heteroaryl group with three ring atoms, wherein 1-3 ring atoms are ring nitrogen atoms, and one or more of the ring carbon atoms of the heteroaryl ring are optionally substituted with 1-4 independently selected R ⁴ ′, such as Optionally, pyridyl substituted with 1-2 independently selected R ⁴ '; heterocyclic group containing 4-7 ring atoms, of which 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of Group: N, N(H), N( R ^d ), O and S(O) _0-2 , and one or more of the ring carbon atoms of the heterocyclic group is optionally selected by 1-4 independently R ⁴ 'substituted; and optionally substituted with 1-2 independently selected of R ^4' substituted phenyl. The compound of claim 217, wherein R ⁴ is a phenyl substituted with 1-2 independently selected R ⁴ ′ as appropriate. Such as the compound of claim 218, where R ⁴ is

, Which is replaced by additional R ⁴ 'as appropriate. The compound of claim 219, wherein each R ⁴ ′ is independently selected from the group consisting of halo (such as -F), -CN, -C _1-4 alkyl, and -C _1-4 haloalkyl. The compound according to any one of claims 219 to 220, wherein R ⁴ 'at the para position is -CF ₃ . Such as the compound of claim 219, wherein R ⁴ is

, Which is replaced by additional R ⁴ as appropriate. Such as the compound of claim 222, where R ⁴ is

. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 116 or a compound of formula II as claimed in any one of claims 117 to 223, and one or more pharmaceutically acceptable excipients Shape agent. A method for inhibiting the activity of STING, the method comprising contacting STING with a compound of formula II as in any one of claims 117 to 223. The method of any one of claims 1 to 116 and 225, wherein the inhibition includes antagonizing STING. Such as the method of any one of claims 1 to 116 and 225 to 226, which is performed in vitro. The method of claim 227, wherein the method includes contacting a sample with the compound, and the sample includes one or more cells containing STING. The method of claim 228, wherein the one or more cell lines are one or more cancer cells. The method of claim 228 or 229, wherein the sample further includes one or more cancer cells (for example, where the cancer is selected from the group consisting of: melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer , Urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular carcinoma, malignant Dermatoma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilm's tumor or hepatocellular carcinoma). Such as the method of any one of claims 1 to 116 and 225, which is performed in vivo. The method of claim 231, wherein the method comprises administering the compound to an individual suffering from a disease in which increased (for example, excessive) STING signaling contributes to the disease and/or symptoms and/or progression of the disease. Such as the method of claim 232, in which the system person. Such as the method of claim 232, wherein the disease is cancer. Such as the method of claim 234, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small Cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple Myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilm’s tumor or hepatocellular carcinoma. The method of claim 234 or 235, wherein the cancer is refractory cancer. The method of claim 236, wherein the compound is administered in combination with one or more additional cancer therapies. The method of claim 237, wherein the one or more additional cancer therapies include surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy, or a combination thereof. The method of claim 238, wherein the chemotherapy includes administration of one or more additional chemotherapeutic agents. The method of claim 239, wherein the one or more additional chemotherapeutic agents are selected from alkylating agents (for example, cisplatin, carboplatin, mechlorethamine, cyclophosphamide) , Chlorambucil, ifosfamide and/or oxaliplatin); antimetabolites (such as azathioprine and/or mercaptopurine); terpenoids (E.g. vinca alkaloid and/or taxane; e.g. vincristine, vinblastine, vinorelbine and/or vindesine paclitaxel (Taxol), Pacllitaxel and/or Docetaxel); topoisomerase (such as type I topoisomerase and/or type 2 topoisomerase; such as camptothecin (Camptothecins), such as irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide ); Cytotoxic antibiotics (such as actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin ), epirubicin (epirubicin), bleomycin (bleomycin), plicamycin (plicamycin) and/or mitomycin (mitomycin)); hormones (such as luteinizing hormone releasing hormone agonists; for example Leuprolidine (leuprolidine), goserelin (goserelin), triptorelin (triptorelin), histrelin (histrelin), bicalutamide (bicalutamide), flutamide (flutamide) and/or Nilutamide; antibodies (such as Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab) , Belimumab, Bevacizumab, Bretuximab vedotin, Canak inumab), cetuximab (Cetuximab), pegylated cetuzumab (Ceertolizumab pegol), daclizumab (Daclizumab), denosumab (Denosumab), eculizumab (Eculizumab) , Efalizumab (Efalizumab), Gemtuzumab (Gemtuzumab), Golimumab (Golimumab), Golimumab, Ibritumomab tiuxetan, Infliximab (Infliximab) , Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab ( Palivizumab, Panitumumab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab Monoclonal antibody (Trastuzumab); anti-angiogenesis agent; cytokines; thrombosis agent; growth inhibitor; anti-worm agent; and immune checkpoint suppression targeting immune checkpoint receptors selected from the group consisting of Agents: CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-double Oxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9-TIM3, phospholipid serine-TIM3, Lymphocyte activation gene 3 protein (LAG3), class II MHC-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25- TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, lactophilic protein containing BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30 and CD155 (such as CTLA-4 or PD1 or PD-L1). The method according to any one of claims 232 to 240, wherein the compound is administered intratumorally. A method for treating cancer, which comprises administering to an individual in need of such treatment an effective amount of a compound of formula I as in any one of claims 1 to 116 or a compound of formula II as in any one of claims 117 to 223 A compound, or a pharmaceutical composition as in claim 224. Such as the method of claim 242, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small Cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple Myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilm’s tumor or hepatocellular carcinoma. The method of claim 242 or 243, wherein the cancer is refractory cancer. The method of claim 242, wherein the compound is administered in combination with one or more additional cancer therapies. The method of claim 245, wherein the one or more additional cancer therapies include surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy, or a combination thereof. The method of claim 246, wherein the chemotherapy comprises administration of one or more additional chemotherapeutic agents. The method of claim 247, wherein the one or more additional chemotherapeutic agents are selected from alkylating agents (for example, cisplatin, carboplatin, chlorambucil, cyclophosphamide, chlorambucil, ifosfamide And/or oxaliplatin); antimetabolites (such as azathioprine and/or mercaptopurine); terpenoids (such as vinca alkaloids and/or taxanes; such as vincristine, vinblastine, vinorelbine) And/or vindesine paclitaxel, paclitaxel and/or docetaxel); topoisomerases (such as type I topoisomerase and/or type 2 topoisomerase; for example camptothecin, such as Irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); cytotoxic antibiotics (such as actinomycin, anthracycline, cranberry, Daunorubicin, varrubicin, idarubicin, epirubicin, bleomycin, pracamycin and/or mitomycin); hormones (such as luteinizing hormone releasing hormone agonists; for example Lepirudine, goserelin, triptorelin, histaminerelin, bicalutamide, flutamide and/or nilutamide); antibodies (such as abciximab, adalimumab, a Lemizumab, alizumab, basiliximab, belizumab, bevacizumab, bentuximab, canalizumab, cetuximab, pegylated cetuzumab Antibody, daclizumab, denosumab, eculizumab, ifazizumab, gemtuzumab, golimumab, golimumab, ibrituzumab, infliximab Antibody, Ipilimumab, Moromona-CD3, Natalizumab, Ovalizumab, Omalizumab, Palivizumab, Panitumumab, Ranibizumab, Rituxan Anti-, tocilizumab, tositumomab and/or trastuzumab); anti-angiogenic agents; cytokines; thrombosis agents; growth inhibitors; anti-worm agents; and targets selected from the following Immune checkpoint inhibitors of immune checkpoint receptors of the group: CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), half Lactose agglutinin 9-TIM3, phospholipid serine-TIM3, lymphocyte activation gene 3 protein (LAG3), class II MHC-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR Ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160 , CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B 7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, lactophilic protein including BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neurobacteria Mao Su, CD160, CD30 and CD155 (such as CTLA-4 or PD1 or PD-L1). The method according to any one of claims 242 to 248, wherein the compound is administered intratumorally. A method for inducing an immune response in an individual in need, the method comprising administering to the individual an effective amount of the compound of formula I as in any one of claims 1 to 116 or as any one of claims 117 to 223 The compound of formula II , or the pharmaceutical composition of claim 224. The method of claim 250, wherein the individual has cancer. The method of claim 251, wherein the individual has experienced and/or is experiencing and/or is about to undergo one or more cancer therapies. The method of claim 251, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small Cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple Myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilm’s tumor or hepatocellular carcinoma. Such as the method of claim 253, wherein the cancer is refractory cancer. The method of claim 250, wherein the immune response is an innate immune response. The method of claim 255, wherein the at least one or more cancer therapies include surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy, or a combination thereof. The method of claim 256, wherein the chemotherapy comprises administration of one or more additional chemotherapeutic agents. The method of claim 257, wherein the one or more additional chemotherapeutic agents are selected from alkylating agents (for example, cisplatin, carboplatin, chlorambucil, cyclophosphamide, chlorambucil, ifosfamide And/or oxaliplatin); antimetabolites (such as azathioprine and/or mercaptopurine); terpenoids (such as vinca alkaloids and/or taxanes; such as vincristine, vinblastine, vinorelbine) And/or vindesine paclitaxel, paclitaxel and/or docetaxel); topoisomerases (such as type I topoisomerase and/or type 2 topoisomerase; for example camptothecin, such as Irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); cytotoxic antibiotics (such as actinomycin, anthracycline, cranberry, Daunorubicin, varrubicin, idarubicin, epirubicin, bleomycin, pracamycin and/or mitomycin); hormones (such as luteinizing hormone releasing hormone agonists; for example Lepirudine, goserelin, triptorelin, histaminerelin, bicalutamide, flutamide and/or nilutamide); antibodies (such as abciximab, adalimumab, a Lemizumab, alizumab, basiliximab, belizumab, bevacizumab, bentuximab, canalizumab, cetuximab, pegylated cetuzumab Antibody, daclizumab, denosumab, eculizumab, ifazizumab, gemtuzumab, golimumab, golimumab, ibrituzumab, infliximab Antibody, Ipilimumab, Moromona-CD3, Natalizumab, Ovalizumab, Omalizumab, Palivizumab, Panitumumab, Ranibizumab, Rituxan Anti-, tocilizumab, tositumomab and/or trastuzumab); anti-angiogenic agents; cytokines; thrombosis agents; growth inhibitors; anti-worm agents; and targets selected from the following Immune checkpoint inhibitors of immune checkpoint receptors of the group: CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), half Lactose agglutinin 9-TIM3, phospholipid serine-TIM3, lymphocyte activation gene 3 protein (LAG3), class II MHC-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR Ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160 , CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B 7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, lactophilic protein including BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neurobacteria Mao Su, CD160, CD30 and CD155 (such as CTLA-4 or PD1 or PD-L1). A method for treating diseases in which increased (for example, excessive) STING signal conduction contributes to disease and/or symptoms and/or progression, which comprises administering an effective amount of any one of claims 1 to 116 to an individual in need of such treatment The compound of formula I in item or the compound of formula II in any one of claims 117 to 223, or the pharmaceutical composition of claim 224. A method of treatment, comprising administering an effective amount of any one of claims 1 to 116 to an individual suffering from a disease in which increased (for example, excessive) STING signal conduction contributes to disease and/or symptoms and/or progression The compound of I or the compound of formula II according to any one of claims 117 to 223, or the pharmaceutical composition of claim 224. A method of treatment, which comprises administering to an individual a compound of formula I according to any one of claims 1 to 116 or a compound of formula II according to any one of claims 117 to 223, or a pharmaceutical combination according to claim 224 Wherein, the compound or composition is administered in an amount effective to treat the pathology and/or symptoms and/or progression of the disease that is caused by increased (for example, excessive) STING signaling, thereby treating the disease. The method according to any one of claims 259 to 261, wherein the disease is cancer. Such as the method of claim 262, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small Cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple Myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilm’s tumor or hepatocellular carcinoma. Such as the method of claim 262 or 263, wherein the cancer is refractory cancer. The method of any one of claims 262 to 264, wherein the compound is administered in combination with one or more additional cancer therapies. The method of claim 265, wherein the one or more additional cancer therapies include surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy, or a combination thereof. The method of claim 266, wherein the chemotherapy comprises administration of one or more additional chemotherapeutic agents. The method of claim 267, wherein the one or more additional chemotherapeutic agents are selected from alkylating agents (for example, cisplatin, carboplatin, chlorambucil, cyclophosphamide, chlorambucil, ifosfamide And/or oxaliplatin); antimetabolites (such as azathioprine and/or mercaptopurine); terpenoids (such as vinca alkaloids and/or taxanes; such as vincristine, vinblastine, vinorelbine) And/or vindesine paclitaxel, paclitaxel and/or docetaxel); topoisomerases (such as type I topoisomerase and/or type 2 topoisomerase; for example camptothecin, such as Irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); cytotoxic antibiotics (such as actinomycin, anthracycline, cranberry, Daunorubicin, varrubicin, idarubicin, epirubicin, bleomycin, pracamycin and/or mitomycin); hormones (such as luteinizing hormone releasing hormone agonists; for example Lepirudine, goserelin, triptorelin, histaminerelin, bicalutamide, flutamide and/or nilutamide); antibodies (such as abciximab, adalimumab, a Lemizumab, alizumab, basiliximab, belizumab, bevacizumab, bentuximab, canalizumab, cetuximab, pegylated cetuzumab Antibody, daclizumab, denosumab, eculizumab, ifazizumab, gemtuzumab, golimumab, golimumab, ibrituzumab, infliximab Antibody, Ipilimumab, Moromona-CD3, Natalizumab, Ovalizumab, Omalizumab, Palivizumab, Panitumumab, Ranibizumab, Rituxan Anti-, tocilizumab, tositumomab and/or trastuzumab); anti-angiogenic agents; cytokines; thrombosis agents; growth inhibitors; anti-worm agents; and targets selected from the following Immune checkpoint inhibitors of immune checkpoint receptors of the group: CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), half Lactose agglutinin 9-TIM3, phospholipid serine-TIM3, lymphocyte activation gene 3 protein (LAG3), class II MHC-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR Ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160 , CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B 7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, lactophilic protein including BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neurobacteria Mao Su, CD160, CD30 and CD155 (such as CTLA-4 or PD1 or PD-L1). The method according to any one of claims 259 to 268, wherein the compound is administered intratumorally. A method for treating diseases, disorders or conditions associated with STING, which comprises administering to an individual in need of such treatment an effective amount of a compound of formula I as in any one of claims 1 to 116 or as in claims 117 to 223 Any one of the compound of formula II , or the pharmaceutical composition of claim 224. The method of claim 270, wherein the disease, disorder, or condition is selected from the group consisting of type I interferon lesions, Icardi-Gortiers syndrome (AGS), hereditary lupus, inflammation-related disorders, and rheumatoid arthritis. The method of claim 271, wherein the disease, disorder, or condition is type I interferon pathology (for example, STING-related infantile-onset vascular disease (SAVI)). Such as the method of claim 272, wherein the type I interferon disease is STING-related infantile-onset vascular disease (SAVI)). The method of claim 271, wherein the disease, disorder, or condition is Ecardi-Gortiers syndrome (AGS). The method of claim 271, wherein the disease, disorder or condition is hereditary lupus. The method of claim 271, wherein the disease, disorder or condition is an inflammation-related disorder. The method of claim 276, wherein the inflammation-related disorder is systemic lupus erythematosus. The method of any one of claims 225 to 277, wherein the method further comprises identifying the individual. A compound selected from the compounds in Table C1 , or a pharmaceutically acceptable salt thereof.