Vhl inhibitors for the treatment of anemia and cancer

Abstract

The present disclosure relates to 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4- hydroxy-N-(benzyl)pyrrolidine-2-carboxamide derivatives and structurally related compounds, which are useful as VHL inhibitors for the treatment of, for example, anemia (e.g., chronic anemia or anemia associated with chronic kidney disease, dialysis, or cancer chemotherapy), ischemia, stroke, or injury to the cardiovascular system during ischemia, or for enhancing wound healing, reducing scarring, or enhancing angiogenesis or arteriogenesis, as well as cancer.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 112,609, filed November 11, 2020, the disclosure of which is hereby incorporated by reference in its entirety. TECHNICAL FIELD

[0003] The present disclosure relates to compounds comprising a VHL ligand moiety and methods of using such compounds as ligands for VHL. The present disclosure further relates to the use of the compounds described herein, or a pharmaceutical composition thereof, to prevent and / or treat a range of diseases, conditions, and disorders. BACKGROUND

[0004] E3 ubiquitin ligases, of which there are over 600 known in humans, confer specificity to ubiquitinated substrates. There are known ligands that bind to these ligases. E3 ubiquitin ligase binding groups (E3LBs) are peptides or small molecules that can bind to E3 ubiquitin ligases.

[0005] A particular E3 ubiquitin ligase is the von Hippel-Lindau (VHL) tumor suppressor, which is the substrate recognition subunit of the E3 ligase complex VCB, an important target in cancer, chronic anemia, and ischemia, which also consists of elongins B and C, Cul2, and Rbxl. The primary substrate of VHL is hypoxia-inducible factor la (HIF-la), a transcription factor that upregulates genes in response to low oxygen levels, such as the pro-angiogenic growth factor VEGF and the red blood cell-inducing cytokine erythropoietin. While HIF-la is constitutively expressed, under normoxic conditions, its intracellular levels are kept very low by hydroxylation by prolyl hydroxylase domain (PHD) proteins and subsequent VHL-mediated ubiquitination.

[0006] Crystal structures of VHL with ligands have been obtained, demonstrating that compounds can mimic the binding mode of the primary substrate of VHL, the transcription factor HIF-la. These compounds bind to VHL in competition with the HIF-la substrate, thereby reducing or blocking the activity of the VHL protein. There is a continuing need in the art for small molecule VHL ligands that are effective for a broad range of disease indications. SUMMARY

[0007] The present disclosure relates to VHL ligands, in particular, VHL ligands that bind to VHL E3 ubiquitin ligases.

[0008] In one aspect, the present disclosure relates to a compound of Formula (I):

[0009]

[0010] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0011] X 1 independently at each occurrence H, C 1-12 alkyl or -C(O)-C 1-12 alkyl;

[0012] R 1 independently at each occurrence C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-15 cycloalkyl or 3- to 15-membered heterocyclyl,

[0013] wherein R 1 of C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-15 cycloalkyl or 3- to 15-membered heterocyclyl is independently optionally substituted with one or more C 1-12 alkyl, C 6-20 aryl, -S(O)2-C 1-12 alkyl or -C(O)-C 1-12 alkyl;

[0014] L is independently at each occurrence absent or C 1-12 alkylene, wherein C 1-12 alkylene of L is independently optionally substituted with one or more R t , wherein R t is C 1-12 alkyl or -C(O)NH2, wherein C t alkyl of R 1-12 is further optionally substituted with one or more halo;

[0015] Ring A is independently at each occurrence C 6-20 aryl or C 7-15 cycloalkyl;

[0016] R e is independently at each occurrence halo, C 6-20 aryl or 5- to 20-membered heteroaryl, wherein C e aryl of R 6-20 is independently optionally substituted with one or more C 1-12 alkyl or halo;

[0017] n is independently at each occurrence 0, 1, 2, 3, 4, or 5; and

[0018] Q 1 and Q 2independently at each occurrence H, halo, cyano, C 1-12 alkyl, C 3-15 cycloalkyl, 3- to 15-membered heterocyclyl, C 6-20 aryl, 5- to 20-membered heteroaryl, -C(O)-O(R a ) or -C(O)-N(R b )(R c ), wherein R a , R b and R c are each independently H or C 1-12 alkyl,

[0019] wherein Q 1 or Q 2 C 1-12 alkyl or C 3-15 cycloalkyl is independently optionally substituted with one or more R q , wherein R q is C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-20 aryl, C 1-12 alkoxy or wherein C q alkyl or C 1-12 alkoxy of R 1-12 is independently further optionally substituted with one or more halo or -NHC(O)-C 1-12 alkyl, or Q 1 and Q 2 together with the atom to which they are attached form C 3-15 cycloalkyl, 3- to 15-membered heterocyclyl, C 6-20 aryl or 5- to 20-membered heteroaryl,

[0020] wherein C 1 cycloalkyl, 3- to 15-membered heterocyclyl, C 2 aryl or 5- to 20-membered heteroaryl formed by Q 3-15 and Q 6-20 is independently optionally substituted with one or more R s , wherein R s is OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, -SO2C 1-12 alkyl, -SO2NH2or C 1-12 alkyl, wherein C s alkyl of R 1-12 is further optionally substituted with one or more halo, cyano or OH.

[0021] In another aspect, the present disclosure relates to a pharmaceutical composition comprising one or more compounds described herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0022] In one aspect, the present disclosure relates to a method of inhibiting VHL using one or more compounds described herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or one or more pharmaceutical compositions described herein.

[0023] In another aspect, the present disclosure relates to a method of preventing or treating a disease, disorder, or condition by administering to a subject in need thereof one or more compounds described herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or one or more pharmaceutical compositions described herein. DETAILED DESCRIPTION

[0024] The present disclosure relates to compounds that bind to E3 ubiquitin ligase protein complexes. In particular, compounds are described that bind to Von Hippel-Lindau (VHL), a substrate recognition subunit of the E3 ligase complex VCB.

[0025] The presently disclosed subject matter will now be described more fully hereinafter. However, many modifications and other embodiments of the presently disclosed subject matter set forth herein will be apparent to those skilled in the art upon reading the specification and upon learning the teacher presented in the above description of the presently disclosed subject matter. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein covers any and all modifications and equivalents. If one or more of the incorporated documents, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described technology, or the like, this application controls. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs and are applied herewith in the context of describing the present disclosure. The terminology used in the specification is for describing particular embodiments only and is not intended to be limiting of the present disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.

[0026] I. DEFINITIONS

[0027] The term "residue," "moiety," or "group" refers to a component that is covalently bonded or linked to another component.

[0028] The term "covalently bound" or "covalently linked" refers to a chemical bond formed by the sharing of one or more pairs of electrons.

[0029] A "patient" or "individual" or "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the patient or individual or subject is a human. In some embodiments, the patient can be a "cancer patient," i.e., a patient having one or more symptoms of cancer or at risk of having one or more symptoms of cancer.

[0030] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth / proliferation. A "tumor" comprises one or more cancerous cells. Examples of cancer are provided elsewhere herein.

[0031] The term "chemotherapeutic agent" or "anti-cancer agent" refers to a compound that is useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents, such as thiotepa and cyclosphosphamide alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); δ-9-tetrahydrocannabinol (dronabinol, β-lapachone; lapachol; colchicin; betulinic acid; camptothecins (including the synthetic analog topotecan CPT-11 (irinotecan, Acetylcamptothecin, hyoscyamine, and 9-aminocamptothecin; bryostatin; callystatin; CC-1065 (including its synthetic analogs adolaxine, calcetin, and pyrazin); podophyllotoxin; podophyllic acid; teniposide; cryptophytic acid (especially cryptophytic acid 1 and cryptophytic acid 8); dolasidium; ducamycin (including synthetic analogs KW-2189 and CB1-TM1); eleutheroside; hygrophytic acid; styracidium; spongiform styracidium; nitrogen mustard such as chlorambucil, chlorpheniramine, chlorphosphamide, estradiol, ifosfamide, dichloromethyldiethylamine, dichloromethyldiethylamine hydrochloride, melphalan, neomycin, benzyl mustard cholesterol, prednimustine, trazophosphatide, uracil nitrogen mustard; nitrosourea such as carmustine, chloramphenicol, formustine, lomustine, nimodiphenyl ether. Stimulosin and ramustin; antibiotics, such as endothymic antibiotics (e.g., galicarmycin, especially galicarmycin γ1I and galicarmycin ωI1 (see, e.g., Nicolaou et al., Angew. Chem Intl. edited in English, 33:183-186 (1994)); CDP323, oral α-4 integrin inhibitors; danidin, including danidin A; esporamycin; and new carcinogen chromophores and associated chromoprotein endothymic antibiotic chromophores), aclarubicin, actinomycin, anthramycin, diazoserine, bleomycin, actinomycin C, carrubicin, erythromycin, carcinomamycin, chromomycin, actinomycin D, daunorubicin, detoxin, 6-diazo-5-oxo-L-leucine, doxorubicin (including Morpholin-doxorubicin, Cyanomorpholin-doxorubicin, 2-Pyrrolidine-doxorubicin, Doxorubicin HCl Liposome Injection Liposome doxorubicin TLC D-99 PEGylated liposomal doxorubicin (and deoxydoxomyl), epirubicin, esopycin, idarubicin, ephedrine, mitomycin C, mycophenolic acid, nopramine, oligomycin, pepromycin, pofibromycin, puromycin, triamcinolone acetonide, rodorubicin, streptomycin, streptozotocin, tuberculin, ubenmexicoside, fenestrated statin, zolrubicin; antimetabolites, such as methotrexate, gemcitabine. Tegafur Capecitabine Epothilones and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, nitrosurea, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as folic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamide; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitomycin; mitosporin; mycobacterial cell wall extract; novantrone; ormaplatin, phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; polysaccharide-K (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spiromustine; tenuazonic acid; triaziquone; 2,2',2'-trichlorotriethylamine; a dactinomycin albumin-engineered nanoparticle formulations of paclitaxel (ABRAXANE™) and docetaxel chlorambucil; 6-thioguanine; mercaptopurine; methotrexate; platinum agents such as cisplatin, oxaliplatin (e.g., ELOXATIN® ) and carboplatin; vinca alkaloids including vinblastine vincristine vinorelbine and vinorelbine etoposide (VP-16); ifosfamide; mitoxantrone; leucovorin; mitoxantrone; edatrexate; daunomycin; aminopterin; ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid, including bexarotene bisphosphonates such as clodronate (e.g., or ) etidronate NE-58095, zoledronic acid / zoledronate alendronate pamidronate Tilodronate or risephosphonates Trasatabine (a 1,3-dioxolane cytosine analog); antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways associated with abnormal cell proliferation, such as PKC-α, Raf, H-Ras, and epidermal growth factor receptor (EGF-R); vaccines, for example Vaccines and gene therapy vaccines, such as vaccine, Vaccines and Vaccines; topoisomerase 1 inhibitors (e.g.) ); rmRH (e.g.) ); BAY439006 (Sorafenib; Bayer); SU-11248 (Sunitinib, Pfizer); Perifolfen, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteosome inhibitors (e.g., PS341); Bortezomib CCI-779; tilpifanib (R11577); olafenib, ABT510; Bcl-2 inhibitors, such as olimoxine sodium ( Antisense oligonucleotides); Pickenone; EGFR inhibitors (see definitions below); tyrosine kinase inhibitors; serine-threonine kinase inhibitors, such as rapamycin (sirolimus). ); farnesyltransferase inhibitors, such as lonafazin (SCH 6636, SARASARTM); and pharmaceutical salts, acids, or derivatives of any of the above; and combinations of two or more of the above, such as CHOP, which is an abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; FOLFOX, which is an abbreviation for a treatment regimen of oxaliplatin (ELOXATINTM) in combination with 5-FU and leucovorin.

[0032] As defined herein, chemotherapy agents include “antihormonal agents” or “endocrine therapy agents” that work by modulating, reducing, blocking, or inhibiting the effects of hormones that promote cancer growth. They may themselves be hormones, including but not limited to: antiestrogens with mixed agonist / antagonist properties, including tamoxifen. 4-Hydroxytamoxifen, toremifene Idoxifene, Traloxifene, Raloxifene Trivoxifen, raloxifene, and selective estrogen receptor modulators (SERMs) such as SERM3; pure antiestrogens without agonist properties, such as fulvestrant. and EM 800 (such agents can block dimerization of the estrogen receptor (ER), inhibit DNA binding, increase ER turnover, and / or inhibit ER levels); aromatase inhibitors, including steroidal aromatase inhibitors, such as formestane and exemestane and non-steroidal aromatase inhibitors, such as anastrozole Letrozole and aminoglutethimide, and other aromatase inhibitors including vorozole Megestrol acetate Fadrozole and 4(5)-imidazoles; luteinizing hormone-releasing hormone agonists, including leuprolide ( and ), goserelin, buserelin, and triptorelin; sex steroids, including progestins, such as

[0033] As used herein, “treatment” (and grammatical variations thereof such as “treat” or “treating”) means clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing or reducing the occurrence of disease, alleviating symptoms, diminishing any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. In some embodiments, compounds and compositions of the subject matter described herein are used to delay development of a disease or to slow the progression of a disease. In one embodiment, the treatment is only for prophylactic purposes. In another embodiment, the treatment is only during the course of clinical pathology (i.e., not for prophylactic purposes). In another embodiment, the treatment is during the course of clinical pathology and for prophylactic purposes.

[0034] A drug that is administered “concurrently” with one or more other drugs is administered in the same treatment cycle, on the same day of treatment as the one or more other drugs, and optionally at the same time as the one or more other drugs. For example, for cancer treatments that are performed once every 3 weeks, each drug that is administered concurrently is administered on day 1 of the 3 -week cycle.

[0035] The term "effective" is used to describe the amount of a compound, composition, or component that, when used in the context of its intended use, achieves the desired therapeutic or prophylactic result. The term effective includes other effective amount or effective concentration terms, including therapeutically effective amount, which are otherwise described or used in this application. The term "therapeutically effective amount" as used herein refers to any amount which, as compared to a corresponding subject who has not received such amount, results in treatment of a disease, disorder, or adverse effect, or decreases the progression rate of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. For use in therapy, a therapeutically effective amount of a VHL ligand of the present disclosure, and stereoisomers or tautomers of any of the foregoing, or pharmaceutically acceptable salts of any of the foregoing, can be administered as the raw chemical. In addition, the active ingredients can be present as a pharmaceutical composition.

[0036] As used herein, unless otherwise defined in the claims, the term "optionally" means that the subsequently described event can or can not occur, and includes both instances where the event occurs and instances where it does not.

[0037] As used herein, unless otherwise defined, the phrase "optionally substituted," "substituted," or variations thereof means optionally substituted with one or more substituents (e.g., one, two, three, four, or five substituents), including multiple degrees of substitution. The phrase should not be interpreted to duplicate the substitutions described and depicted herein.

[0038] The term "pharmaceutical formulation" or "pharmaceutical composition" refers to a preparation which is in a form which can be used in the treatment of a subject and which is in a form which is suitable for administration to a subject.

[0039] A "pharmaceutically excipient" refers to an ingredient, other than an active ingredient, used in the formulation of a pharmaceutical. Pharmaceutically excipients include, but are not limited to, buffers, carriers, stabilizers, or preservatives.

[0040] As used herein, the phrase "medicinal salt" refers to a medicinal organic or inorganic salt of a molecule. Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucurons, saccharates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl)ate (i.e., 1,1'-methylenebis-(2-hydroxy3-naphthylcarbamate)). Medicinal salts may include another molecule, such as an acetate ion, a succinate ion, or other counterions. Counterions can be any organic or inorganic portion that stabilizes the charge on the parent compound. Furthermore, a medicinal salt may have more than one charged atom in its structure. An example where multiple charged atoms are part of a medicinal salt may have multiple counterions. Therefore, a medicinal salt may have one or more charged atoms and / or one or more counterions.

[0041] Other non-pharmaceutical salts can be used to prepare the compounds described herein and should be considered as another aspect of forming this subject matter. These salts, such as oxalic acid or trifluoroacetate, while not pharmaceutical in themselves, can be used to prepare intermediates for obtaining the compounds described herein and their pharmaceutical salts.

[0042] "Small molecule" or "small molecule compound" generally refers to an organic molecule with a size less than about 5 kilodaltons (Kd). In some embodiments, the small molecule is less than about 4 Kd, 3 Kd, about 2 Kd, or about 1 Kd. In some embodiments, the small molecule is less than about 800 Daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, the small molecule is less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, the small molecule is non-polymerized. The small molecule is not a protein, polypeptide, oligopeptide, peptide, polynucleotide, oligonucleotide, polysaccharide, glycoprotein, proteoglycan, etc. Derivatives of small molecules refer to molecules that have the same structural core as the original small molecule, but can be prepared from the original small molecule through a series of chemical reactions.

[0043] As used herein, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group (C1-C1) of any length having one to twelve carbon atoms. 12), wherein the alkyl group can be optionally independently substituted with one or more substituents described herein. In another embodiment, the alkyl group is one to eight carbon atoms (Ci-C8), or one to six carbon atoms (Ci-C6), or one to four carbon atoms (Ci-C4), or one to three carbon atoms (Ci-C3). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, isopropyl, -CH(CH3)2), 1 -butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-l -propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, tert-butyl -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l -butyl (-CH2CH2CH(CH3)2), 2-methyl-l -butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, 1-heptyl, 1-octyl, and the like.

[0044] As used herein, the term "alkylene" refers to any length of a saturated straight-chain or branched-chain divalent hydrocarbon radical (Ci-Ci2) having one to twelve carbon atoms (Ci-Ci2), or one to six carbon atoms (Ci-C6), or one to four carbon atoms (Ci-C4), or one to three carbon atoms (Ci-C3). Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), 1,2-ethylene (-CH2CH2-), 1,3- propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and the like. 12), wherein the alkylene group can be optionally independently substituted with one or more substituents described herein. In another embodiment, the alkylene group is one to eight carbon atoms (Ci-C8), one to six carbon atoms (Ci-C6), or one to four carbon atoms (Ci-C4). Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and the like.

[0045] The term“alkenyl” refers to a straight-chain or branched-chain monovalent hydrocarbon group of any length of two to twelve carbon atoms (C2-C 12 ), having at least one site of unsaturation, i.e., a carbon-carbon sp2 double bond, wherein the alkenyl group can be optionally independently substituted with one or more substituents described herein, and includes groups having“cis” and“trans” orientations, or alternatively“E” and“Z” orientations. Examples include, but are not limited to, ethylenyl (or vinyl) (-CH=CH2), propenyl (-CH2CH=CH2), and the like.

[0046] The term“alkenylene” refers to a straight-chain or branched-chain divalent hydrocarbon group of any length of two to twelve carbon atoms (C2-C 12 ), having at least one site of unsaturation, i.e., a carbon-carbon sp2 double bond, wherein the alkenylene group can be optionally independently substituted with one or more substituents described herein, and includes groups having“cis” and“trans” orientations, or alternatively“E” and“Z” orientations. Examples include, but are not limited to, ethylenylene (or vinylene) (-CH=CH-), propenylene (-CH2CH=CH-), and the like.

[0047] The term“alkynyl” refers to a straight-chain or branched-chain monovalent hydrocarbon group of any length of two to twelve carbon atoms (C2-C 12 ), having at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group can be optionally independently substituted with one or more substituents described herein. Examples include, but are not limited to, ethynyl (-CºCH), propynyl (propargyl, -CH2CºCH), and the like.

[0048] The term“alkynylene” refers to a straight-chain or branched-chain divalent hydrocarbon group of any length of two to twelve carbon atoms (C2-C 12 ), having at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, wherein the alkynylene group can be optionally independently substituted with one or more substituents described herein. Examples include, but are not limited to, ethynylene (-CºC-), propynylene (propargylene, -CH2CºC-), and the like.

[0049] The terms "carbocyclic," "carbocyclyl," "carbocyclyl ring," and "cycloalkyl" refer to a monovalent, non-aromatic, saturated or partially unsaturated ring having from 3 to 15 carbon atoms (C3-C 15 ). Such rings can be monocyclic or polycyclic, with 3 to 15 carbon atoms in the monocyclic ring or 7 to 15 carbon atoms in the polycyclic (e.g., bicyclic) ring. Bicyclic carbocyclic rings having 7 to 12 atoms can be arranged, for example, as a bicyclo[4,5], [5,5], [5,6], or [6,6] system, and bicyclic carbocyclic rings having 9 or 10 ring atoms can be arranged as a bicyclo[5,6] or [6,6] system, or as a bridged system, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Polycyclic (e.g., bicyclic) rings that are wholly saturated or partially unsaturated are encompassed by the definition of "carbocyclic," "carbocyclyl," "carbocyclyl ring," and "cycloalkyl," including when one or more of the fused rings in the polycyclic ring is fully unsaturated (i.e., aromatic). Spiro moieties are also included within the scope of this definition. Examples of monocyclic carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalenyl, and the like. Carbocyclyl groups are optionally independently substituted with one or more substituents described herein.

[0050] The term "cycloalkylene" refers to a monovalent, non-aromatic, saturated or partially unsaturated ring having from 3 to 12 carbon atoms (C3-C 12 ) as a monocyclic ring or 7 to 12 carbon atoms as a bicyclic ring. Bicyclic cycloalkylene rings having 7 to 12 atoms can be arranged, for example, as a bicyclo[4,5], [5,5], [5,6], or [6,6] system, and bicyclic cycloalkylene rings having 9 or 10 ring atoms can be arranged as a bicyclo[5,6] or [6,6] system, or as a bridged system, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Spiro moieties are also included within the scope of this definition. Examples of monocyclic cycloalkylene rings include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, 1-cyclopent-1- enylene, 1-cyclopent-2-enylene, 1-cyclopent-3-enylene, cyclohexylene, 1-cyclohex-1- enylene, 1-cyclohex-2-enylene, 1-cyclohex-3-enylene, cyclohexadiene, cycloheptylene, cyclooctylene, cyclononylene, cyclodecylene, cycloundecylene, cyclododecylene, and the like. Cycloalkylene groups are optionally independently substituted with one or more substituents described herein.

[0051] "Aryl" refers to a group of 6-20 carbon atoms derived by removing a hydrogen atom from a single carbon atom in the parent aromatic ring system (C6-C4). 20 Aromatic hydrocarbon groups are monovalent aromatic hydrocarbon groups. Some aryl groups are represented as "Ar" in exemplary structures. Typical aryl groups include, but are not limited to, groups derived from benzene (phenyl), substituted benzene, naphthalene, anthracene, biphenyl, etc. The aryl group may optionally be independently substituted by one or more substituents described herein.

[0052] "Deaaryl" refers to a group of 6-20 carbon atoms derived by removing two hydrogen atoms from two carbon atoms in a parent aromatic ring system (C6-C4). 20 A divalent aromatic hydrocarbon group. Some arylene groups are represented as "Ar" in exemplary structures. Alene groups include bicyclic groups comprising an aromatic ring fused to saturation, partially unsaturated rings, or aromatic carbocyclic rings. Typical arylene groups include, but are not limited to: benzene-derived (phenylene), substituted benzene, naphthalene, anthracene, biphenylene, indenyl, indenylene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, etc. The arylene group may optionally be substituted by one or more substituents described herein.

[0053] The terms “heterocycle,” “heterocyclic group,” and “heterocycle” are used interchangeably herein and refer to a saturated or partially unsaturated (i.e., having one or more double and / or triple bonds within a ring) carbocyclic group having 3 to about 20 ring atoms, wherein at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur, and the remaining ring atoms are carbon, wherein one or more ring atoms are optionally independently substituted by one or more substituents described herein. A heterocycle can be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S) or having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), for example: bicyclic [4,5], [5,5], [5,6], or [6,6] systems. Heterocyclic compounds are described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (WA Benjamin, New York, 1968), especially Chapters 1, 3, 4, 6, 7 and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), especially Volumes 13, 14, 16, 19 and 28; and J. Am. Chem. Soc. (1960) 82: 5566. “Heterocyclic group” also includes groups in which the heterocyclic group is fused with a saturated, partially unsaturated ring or aromatic carbide ring or heterocycle. Examples of heterocycles include, but are not limited to: morpholin-4-yl, piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidine-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, azoalkyl-1-yl, azacyclobutane-1-yl, octahydropyrido[1,2-a]pyrazin-2-yl, [1,4]diazacycloheptane-1-yl, pyrrolylyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholino, thiomorpholino, thiooxyl, piperazinyl, homopiperazinyl, azacyclobutane, oxacyclobutane, thiohexacyclobutane, homopiperidinyl, oxacycloheptane, thiohexacycloheptane, oxacyclobutane basalt, diazoxide Basic, sulfur-nitrogen heterocyclyl groups include, but are not limited to, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3,8-diazabicyclo[3.2.1]octyl, morpholinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3,8-diazabicyclo[3.2.1]octanyl, and quinuclidinyl. Spiro moieties are also included within the scope of this definition. Examples of heterocyclyl groups wherein two ring atoms are replaced by an oxo (=0) moiety are pyrimidinonyl and 1,1-dioxothiomorpholinyl. The heterocyclyl groups herein are optionally independently substituted with one or more substituents described herein.

[0054] The term "heterocyclyl" refers to a saturated or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) carbocyclic group of from 3 to about 20 ring atoms, at least one of which is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur, with the remainder of the ring atoms being C, wherein one or more of the ring atoms are optionally independently substituted with one or more substituents as described below. Heterocyclyl groups can be monocyclic rings having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S), or bicyclic rings having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), e.g., bicyclo[4,5], [5,5], [5,6], or [6,6] systems. Heterocycles are described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968), especially Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), especially Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. "Heterocyclyl" also includes divalent groups in which a heterocyclyl group is fused to a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring. Examples of heterocyclyl groups include, but are not limited to, morpholin-4-ylidene, piperidin-1-ylidene, piperazinylidene, piperazin-4-ylidene-2-one, piperazin-4-ylidene-3-one, pyrrolidin-1-ylidene, thiomorpholin-4-ylidene, S-dioxothiomorpholin-4-ylidene, azomethylenediamine-1-ylidene, azetidin-1-ylidene, octahydropyridopyrazine-2-ylidene, [1,4]diazepan-1-ylidene, pyrrolinyl, tetrahydrofuranylidene, dihydrofuranylidene, tetrahydrothienylidene, tetrahydropyranyliden, dihydropyranyliden, tetrahydrothiopyranyliden, piperidinyl, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azacyclobutylidene, oxacyclobutylidene, thiacyclobutylidene, homopiperidinyl, oxazepinylidene, thiazepinylidene, diazepinylidene, oxazinylidene, thiazinylidene, diazinylidene, triazinylidene, tetrazinylidene, oxazolidinylidene, thiazolidinylidene, imidazolidinylidene, pyrazolidinylidene, isoxazolinylidene, isothiazolinylidene, furazanylidene, and the like. diazepinylidene thiazepinylidene Subunits, 2-pyrrololinyl subunits, 3-pyrrololinyl subunits, indoline subunits, 2H-pyranyl subunits, 4H-pyranyl subunits, dioxanediyl, 1,3-dioxapentyl, pyrazolinyl, dithiazyl, dithioheterocyclic pentylene, dihydropyranyl, dihydrothiophene subunit, dihydrofuranyl, pyrazolyl imidazoline subunits, imidazoline, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[4.1.0]heptane, azabicyclo[2.2.2]hexane, 3H-indolylquinolinyl, and N-pyridylurea. Spirocyclic moieties are also included within the scope of this definition. Examples of heterocyclic subunits in which two ring atoms are replaced by an oxo (=O) moiety are pyrimidinone subunits and 1,1-dioxo-thiomorpholinyl subunits. The heterocyclic groups described herein are optionally substituted independently by one or more of the substituents described herein.

[0055] The term "heteroaryl" refers to a monovalent aromatic group with a 5-, 6-, or 7-membered ring and comprising a fused ring system of 5-20 atoms (at least one of which is aromatic) containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, 1-methyl-1H-benzo[d]imidazolium, [1,2,4]triazolo[1,5-a]pyridine, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, and isothiazolyl. Pyrroleyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cenolinyl, indazoleyl, indoleazinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purineyl, oxadiazolyl, thiadiazolyl, thiadiazolyl, furazonyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphthidyl, and furanpyridyl. The heteroaryl group may optionally be independently substituted by one or more of the substituents described herein.

[0056] The term "heteroaryl" refers to a 5-, 6-, or 7-membered ring divalent aromatic group and includes fused ring systems of 5-20 atoms (where at least one is aromatic) containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryls are pyridyl (including, for example, 2-hydroxypyridyl), imidazolyl, imidazopyridinyl, 1-methyl-1H-benzo[d]imidazole, [1,2,4]triazolo[1,5-a]pyridine, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups are optionally independently substituted with one or more substituents described herein.

[0057] Where possible, a heterocyclic or heteroaryl group can be carbon (carbon-linked) or nitrogen (nitrogen-linked) bonded. By way of example, but not limitation, a carbon- bonded heterocyclic or heteroaryl is bonded at the 2, 3, 4, 5, or 6 position of a pyridine, the 3, 4, 5, or 6 position of a pyridazine, the 2, 4, 5, or 6 position of a pyrimidine, the 2, 3, 5, or 6 position of a pyrazine, the 2, 3, 4, or 5 position of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole ring, the 2, 4, or 5 position of an oxazole, imidazole, or thiazole, the 3, 4, or 5 position of an isoxazole, pyrazole, or isothiazole, the 2 or 3 position of an aziridine, the 2, 3, or 4 position of an azetidine, the 2, 3, 4, 5, 6, 7, or 8 position of a quinoline, or the 1, 3, 4, 5, 6, 7, or 8 position of an isoquinoline.

[0058] By way of example, but not limitation, a nitrogen-bonded heterocyclic or heteroaryl is bonded at the 1 position of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole; the 2 position of isoindole or isoindolinone; the 4 position of morpholine; and the 9 position of carbazole or β-carboline.

[0059] The term "acyl" refers to both substituted and unsubstituted acyl groups. In certain embodiments, "acyl" can be -C(O)-R 16 wherein R 16is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl. In a particular embodiment, it is substituted C1-C3 alkyl.

[0060] The term“oxo” refers to“=0”.

[0061] As provided herein, a symbol comprising a closed circle drawn with a solid line and having a mark in the center thereof (e.g., ) represents a ring moiety, wherein, unless otherwise specified, the ring moiety can comprise any suitable number and type of ring atoms. For example, the ring moiety can include, but is not limited to, a cycloalkyl moiety, an aryl moiety, a heterocyclyl moiety, or a heteroaryl moiety, as defined herein, comprising any suitable number and type of ring atoms. Such a symbol can be used interchangeably with the term“ring”. and the term“ring X” are interchangeable, and both refer to a ring moiety X, wherein, unless otherwise specified, the ring moiety X can comprise any suitable number and type of ring atoms.

[0062] The term“chiral” refers to a molecule that has a nonsuperimposable mirror image partner, while the term“achiral” refers to a molecule that is superimposable with its mirror image partner.

[0063] The term“stereoisomer” refers to compounds that have the same chemical constitution, but differ in the arrangement of atoms or groups in space.

[0064] “Diastereomers” indicate stereoisomers having two or more chiral centers and whose molecules are not a mirror image of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated using high resolution analytical procedures such as electrophoresis and chromatography.

[0065] “Enantiomers” refer to two stereoisomers of a compound that are mirror images of one another that are not superimposable.

[0066] Stereochemical definitions and conventions used herein generally follow: S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound, as typically determined in a solution of about 1 0 to 20% by weight in water or other solvent. (-) or 1 compounds are called levorotatory, while the (+) or d compounds are called dextrorotatory. In the case of compounds that are equally capable of rotating the plane of plane-polarized light in a negative and a positive sense, the (+) or d compound is designated. The term "racemic mixture" or "racemate” refers to an equimolar mixture of two enantiomeric species produced, for example, by the reaction of a compound containing a chiral center with an equal molar amount of a racemate resolving agent, such as an optically active acid.

[0067] The terms "co-administration" or "co-administering" or "combination therapy" refer to simultaneous administration (administration of two or more therapeutic agents at the same time) and administration at different times (administration of one or more therapeutic agents at a different time from administration of another therapeutic agent or agents) as long as all therapeutic agents are present in the patient at the same time, preferably in effective amounts. In certain preferred aspects, one or more compounds described herein are co-administered in combination with at least one additional biologically active agent, particularly including an anti-cancer agent. In particularly preferred aspects, co-administration of the compounds results in synergistic activity and / or therapy, including anti-cancer activity.

[0068] The term "compound" as used herein, unless otherwise indicated, refers to any particular compound disclosed herein and includes tautomers, positional isomers, geometric isomers, and stereoisomers (if applicable) (including optical isomers (enantiomers) and other stereoisomers (diastereomers)), as well as pharmaceutically acceptable salts and derivatives (including prodrug forms) thereof (as applicable in context). The term compound, when used in context, generally refers to a single compound, but can also include other compounds such as stereoisomers, positional isomers, and / or optical isomers (including racemic mixtures) and specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. In context, the term also refers to prodrug forms of the compounds that have been modified to facilitate administration and delivery of the compound to the active site. It should be noted that in describing the compounds of the present application, a number of substituents and variants associated therewith are described. The ordinarily skilled artisan will appreciate that the molecules described herein are stable compounds as generally described below. When a bond is shown as a dashed line both a double and single bond are represented in the context of the illustrated compound; and that the compound can contain either the E isomer or the Z isomer or a mixture of both the E and Z isomers.

[0069] Unless otherwise indicated in context, the terms "VCE3 ubiquitin ligase", "Von Hippel-Lindau (or VHL) E3 ubiquitin ligase", "VHL", or "ubiquitin ligase" can be used interchangeably to describe one or more target enzyme binding sites of a ubiquitin ligase moiety as described herein. A VCE3 is a protein that in combination with an E2 ubiquitin conjugating enzyme can cause ubiquitin to bind to a lysine on a target protein; E3 ubiquitin ligases target specific protein substrates for degradation by the proteasome. Thus, the E3 ubiquitin ligase alone or in complex with an E2 ubiquitin conjugating enzyme is responsible for transferring ubiquitin to a target protein. Typically, ubiquitin ligases are involved in polyubiquitination, such that a second ubiquitin is attached to a first ubiquitin; a third ubiquitin is attached to the second ubiquitin, and so on. Polyubiquitinated proteins are marked for degradation by the proteasome. However, some ubiquitination events are limited to mono-ubiquitination, in which case the ubiquitin ligase adds only a single ubiquitin to the substrate molecule. Mono-ubiquitinated proteins are not targeted to the proteasome for degradation, but can, for example, alter their cellular location or function by binding to other proteins that have domains capable of binding ubiquitin. More complexly, E3s can target different lysines on ubiquitin to make chains. The most prevalent lysine is Lys48 on the ubiquitin chain. This is the lysine that is used to make polyubiquitin, which is recognized by the proteasome.

[0070] As used herein, a moiety that binds to the E3 VHL ubiquitin ligase or a component thereof is referred to as a VHL ligand.

[0071] In certain embodiments disclosed herein, certain groups (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl) are described as “substituted.” In some such embodiments, a “substituted” group can be substituted with 1, 2, 3, 4, 5, or more substituents, as noted herein. In certain embodiments, an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl can be substituted with one or more substituents independently selected from, but not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo (i.e., halogen), haloalkyl, oxo, OH, CN, -O-alkyl, -S-alkyl, -NH-alkyl, -N(alkyl)2, -O-cycloalkyl, -S-cycloalkyl, -NH-cycloalkyl, -N(cycloalkyl)2, -N(cycloalkyl)(alkyl), -NH2, -SH, -SO2-alkyl, -P(O)(O-alkyl)(alkyl), -P(O)(O-alkyl)2, -Si(OH)3, -Si(alkyl)3, -Si(OH)(alkyl)2, -CO-alkyl, -CO2H, -NO2, -SF5, -SO2NH-alkyl, -SO2N(alkyl)2, -SONH-alkyl, -SON(alkyl)2, -CONH-alkyl, -CON(alkyl)2, -N(alkyl)CONH(alkyl), -N(alkyl)CON(alkyl)2, -NHCONH(alkyl), -NHCON(alkyl)2, -NHCONH2, -N(alkyl)SO2NH(alkyl), -N(alkyl)SO2N(alkyl)2, -NHSO2NH(alkyl), -NHSO2N(alkyl)2, and -NHSO2NH2.

[0072] Additional definitions and abbreviations are provided elsewhere herein.

[0073] Where a numerical range is provided, it is understood that every number within that range is also specifically included herein (e.g., every integer within a stated range of “1 to 10” is also specifically recited from “1 to 10”). As used herein, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise (e.g., a molecule of formula (I) includes two or more of such molecules). As used herein, the term “range” includes the range itself, as well as every possible subrange therein (e.g., a range of “1 to 10” includes every possible subrange between and including 1 and 10, e.g., 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-10, 3-10, 4-10, 5-10, 6-10, 7-10, 8-10, 9-10, 1-1, 2-2, 3-3, 4-4, 5-5, 6-6, 7-7, 8-8, 9-9, 10-10, etc.).

[0074] The articles "a" and "an" as used herein and in the appended claims are used herein and in the appended claims to mean one or more than one (i.e., at least one), unless specified otherwise or made clear from context to be the exclusive sense. By way of example, "an element" means one element or more than one element.

[0075] In the claims, as well as in the specification above, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0076] As used herein in the specification and claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that the

[0077] It should also be understood that, unless clearly indicated otherwise, in some methods described herein that include more than one step or action for performing a process, the sequence of steps or actions of the method is not necessarily limited to that set forth herein for carrying out the method.

[0078] II. Compounds

[0079] E3 ubiquitin ligases (over 600 are known in humans) confer specificity to ubiquitinated substrates. Known ligands exist that bind to these ligases. E3 ubiquitin ligase binding groups (E3LBs) are peptides or small molecules that can bind E3 ubiquitin ligases.

[0080] The specific E3 ubiquitin ligase is von Hippel-Lindau (VHL) tumor suppressor, which is the substrate recognition subunit of the E3 ligase complex VCB. It is also composed of elongated proteins B and C, Cul2, and Rbxl. The main substrate of VHL is hypoxia-inducible factor lα (HIF-lα), a transcription factor that upregulates genes such as the pro-angiogenic growth factor VEGF and the erythrocyte-induced cytokine erythropoietin in response to hypoxia levels.

[0081] In one embodiment, this document provides a compound of formula (I):

[0082]

[0083] Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing, wherein

[0084] X 1 Each occurrence is independently H or C. 1-12 Alkyl or -C(O)-C 1-12 alkyl;

[0085] R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups

[0086] Where R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution;

[0087] L is either absent or C each time it appears. 1-12 Alkylene, wherein L is C 1-12 Alkylenes are independently and optionally separated by one or more R t Replace, where R t C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group may be further optionally substituted with one or more halogens;

[0088] Ring A is independently C each time it appears. 6-20Aryl or C 7-15 cycloalkyl;

[0089] R e Each time it appears, it is independently halogenated, C 6-20 Aryl or 5- to 20-membered heteroaryl groups, of which R e C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more C groups. 1-12 Alkyl or halogenated substitutions;

[0090] n is independently 0, 1, 2, 3, 4, or 5 each time it appears; and

[0091] Q 1 and Q 2 Each of them is independent of the others and independently of H, halogen, cyano, and C in each occurrence. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 alkyl,

[0092] Q 1 Or Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, or Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups,

[0093] Among them, Q 1 and Q2 C 3-15 cycloalkyl, 3- to 15-membered heterocyclyl, C 6-20 aryl or 5- to 20-membered heteroaryl is independently optionally substituted with one or more R s , wherein R s is OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, -SO2C 1-12 alkyl, -SO2NH2, or C 1-12 alkyl, wherein R s of C 1-12 alkyl is further optionally substituted with one or more halo, cyano, or OH.

[0094] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is, at each occurrence, independently absent.

[0095] In other embodiments, provided herein is a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is, at each occurrence, independently C 1-12 alkylene, wherein C 1-12 alkylene of L is independently optionally substituted with one or more R t , wherein R t is independently C 1-12 alkyl or -C(O)NH2, wherein R t of C 1-12 alkyl is further independently optionally substituted with one or more halo. In certain embodiments, L is, at each occurrence, independently C 1-6 alkylene, wherein C 1-6 alkylene of L is independently optionally substituted with one or more R t , wherein R t is independently C 1-6 alkyl or -C(O)NH2, wherein R t of C 1-6 alkyl is further independently optionally substituted with one or more halo. In some embodiments, L is, at each occurrence, independently C 1-3 alkylene, wherein C 1-3 alkylene of L is independently optionally substituted with one or more R t , wherein R t is independently C 1-6 alkyl or -C(O)NH2, wherein R t of C 1-6alkyl is further independently optionally substituted with one or more halo. In some embodiments, L is independently, at each occurrence, ethene, wherein the ethene of L is independently optionally substituted with one R t substituted, wherein R t is independently C 1-6 alkyl or -C(O)NH2, wherein R t of C 1-6 alkyl is further independently optionally substituted with one or more halo. In some embodiments, L is independently, at each occurrence, methylene, wherein the methylene of L is independently optionally substituted with one R t substituted, wherein R t is independently C 1-6 alkyl or -C(O)NH2, wherein R t of C 1-6 alkyl is further independently optionally substituted with one or more halo.

[0096] In other embodiments, provided herein is a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is independently, at each occurrence, unsubstituted ethene. In certain embodiments, L is independently, at each occurrence, ethene, wherein the ethene of L is independently substituted with one R t substituted, wherein R t is independently C 1-6 alkyl or -C(O)NH2, wherein R t of C 1-6 alkyl is further independently optionally substituted with one or more halo. In some embodiments, L is independently, at each occurrence, ethene, wherein the ethene of L is substituted with one -C(O)NH2.

[0097] In certain embodiments, provided herein is a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is independently, at each occurrence, unsubstituted methylene. In certain embodiments, L is independently, at each occurrence, methylene, wherein the methylene of L is substituted with one R t substituted, wherein R t is independently C 1-6 alkyl or -C(O)NH2, wherein R t of C 1-6 alkyl is further independently optionally substituted with one or more halo. In certain embodiments, L is independently, at each occurrence, methylene, wherein the methylene of L is substituted with one C 1-6 alkyl. In some embodiments, L is independently, at each occurrence, methylene, wherein the methylene of L is substituted with methyl. In other embodiments, L is independently, at each occurrence, methylene, wherein the methylene of L is substituted with -CF3.

[0098] In some embodiments, provided herein are compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A at each occurrence is independently C 6-20 aryl. In certain embodiments, ring A at each occurrence is independently C 6-16 aryl. In still other embodiments, ring A at each occurrence is independently C 6-12 aryl. In some embodiments, ring A at each occurrence is independently C 6-10 aryl. In other embodiments, ring A at each occurrence is independently C 6-8 aryl. In certain embodiments, ring A at each occurrence is independently phenyl.

[0099] In other embodiments, provided herein are compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A at each occurrence is independently C 7-15 cycloalkyl. In some embodiments, ring A at each occurrence is independently C 7-12 cycloalkyl. In other embodiments, ring A at each occurrence is independently C 7-10 cycloalkyl. In certain embodiments, ring A at each occurrence is independently C 7-8 cycloalkyl. In some embodiments, ring A at each occurrence is independently C 10-15 cycloalkyl. In certain embodiments, ring A at each occurrence is independently C 12-15 cycloalkyl.

[0100] In some embodiments, n at each occurrence is independently 0, 1, 2, 3, 4, or 5. In other embodiments, n at each occurrence is independently 0, 1, 2, 3, or 4. In other embodiments, n at each occurrence is independently 0, 1, 2, or 3. In other embodiments, n at each occurrence is independently 0, 1, or 2. In certain embodiments, n at each occurrence is independently 0 or 1. In some embodiments, n at each occurrence is independently 2. In other embodiments, n at each occurrence is independently 1. In certain embodiments, n at each occurrence is independently 0.

[0101] In some embodiments, provided herein are compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R e is independently halogen, C 6-20 aryl or 5- to 20-membered heteroaryl, wherein R e is independently C 6-20 aryl or 5- to 20-membered heteroaryl is independently optionally substituted with one or more C 1-12 alkyl or halo.

[0102] In some embodiments, R e is halo at each occurrence. In certain embodiments, R e is halo, wherein halo is independently fluoro or chloro. In some embodiments, R e is halo, wherein halo is chloro.

[0103] In other embodiments, R e is C 6-20 aryl, wherein R e of C 6-20 aryl is independently optionally substituted with one or more C 1-12 alkyl or halo. In some embodiments, R e is unsubstituted C 6-20 aryl at each occurrence. In other embodiments, R e is C 6-20 aryl, wherein R e of C 6-20 aryl is independently optionally substituted with one or more halo. In some embodiments, R e is C 6-20 aryl, wherein R e of C 6-20 aryl is independently optionally substituted with one or more halo, wherein halo is fluoro. In some embodiments, R e is In other embodiments, R e is

[0104] In certain embodiments, R e is 5- to 20-membered heteroaryl, wherein R e of 5- to 20-membered heteroaryl is independently optionally substituted with one or more C 1-12 alkyl or halo. In some embodiments, R e is 5- to 20-membered heteroaryl, wherein R e of 5- to 20-membered heteroaryl is independently optionally substituted with one or more C 1-12 alkyl. In some embodiments, R e is 5- to 20-membered heteroaryl, wherein R e of 5- to 20-membered heteroaryl independently comprises 1, 2, 3, or 4 ring-forming heteroatoms. In some embodiments, R e of 5- to 20-membered heteroaryl independently comprises 1 or 2 ring-forming heteroatoms. In other embodiments, Re The 5- to 20-membered heteroaryl independently comprises 2 ring-forming heteroatoms. In still other embodiments, R e The 5- to 20-membered heteroaryl independently comprises 1 ring-forming heteroatom. In some embodiments, R e is independently, at each occurrence, 5- to 20-membered heteroaryl, wherein R e The 5- to 20-membered heteroaryl independently comprises 1, 2, 3, or 4 ring-forming heteroatoms independently selected from the group consisting of N, S, and O. In some embodiments, the 1, 2, 3, or 4 heteroatoms are all the same heteroatom. In other embodiments, the 1, 2, 3, or 4 heteroatoms comprise a combination of different heteroatoms.

[0105] In some embodiments, R e is independently, at each occurrence, 5- to 20-membered heteroaryl, wherein R e The 5- to 20-membered heteroaryl is independently 5- to 16-membered heteroaryl. In some embodiments, R e is independently, at each occurrence, 5- to 12-membered heteroaryl. In other embodiments, R e is independently, at each occurrence, 5- to 10-membered heteroaryl. In still other embodiments, R e is independently, at each occurrence, 5- to 7-membered heteroaryl. In some embodiments, R e is independently, at each occurrence, 5- to 6-membered heteroaryl. In other embodiments, R e is independently, at each occurrence, 6-membered heteroaryl. In certain embodiments, R e is independently, at each occurrence, 5-membered heteroaryl. In certain embodiments, R e is independently, at each occurrence, thiazolyl, wherein R e The thiazolyl of R 1-12 is independently optionally substituted with one or more C e alkyl or halo. In certain embodiments, R e is independently, at each occurrence, thiazolyl, wherein R 1-6 The thiazolyl of R e is independently optionally substituted with one or more C e methyl. In some embodiments, R e is independently, at each occurrence, 5- to 20-membered heteroaryl, wherein R

[0106] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is independently, at each occurrence, C 1-12 alkylene, wherein the C1-12 Alkylenes are independently and optionally separated by one or more R t Replace, where R t Independently for C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group is further optionally and independently substituted with one or more halogens, and ring A is independently C each time it appears. 6-20 Aryl. In other embodiments, L is independently C each time it appears. 1-6 Alkylene, wherein L is C 1-6 Alkylenes are independently and optionally separated by one or more R t Replace, where R t Independently for C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group is further optionally and independently substituted with one or more halogens, and ring A is independently C each time it appears. 6-20 Aryl. In some embodiments, L is independently C each time it occurs. 1-6 Alkylene, wherein L is C 1-6 Alkylenes are independently and optionally separated by one or more R t Replace, where R t Independently for C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group is independently and optionally further substituted with one or more halogens, and ring A is independently phenyl each time it appears. In other embodiments, L is independently ethylene each time it appears, wherein the ethylene of L is independently and optionally substituted with one or more R groups. t Replace, where R t Independently for C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group is independently and optionally further substituted with one or more halogens, and ring A is independently phenyl each time it appears.

[0107] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein L is independently C each time it appears. 1-12 Alkylene, wherein L is C 1-12 Alkylenes are independently and optionally separated by one or more R t Replace, where R t Independently for C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12The alkyl group is further independently and optionally substituted with one or more halogens, and ring A is independently C each time it appears. 6-20 Aryl, n is independently 1 on each occurrence, and R e Each time it appears, it is independently a 5- to 20-membered heteroaryl group, of which R e The 5 to 20 yuan heteroaryl groups are independently and optionally constituting one or more C 1-12 Alkyl or halogenated substitutions. In some embodiments, L is independently C each time it appears. 1-6 Alkylene, wherein L is C 1-6 Alkylenes are independently and optionally separated by one or more R t Replace, where R t Independently for C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group is further independently and optionally substituted with one or more halogens, and ring A is independently C each time it appears. 6-20 Aryl, n is independently 1 on each occurrence, and R e Each time it appears, it is independently a 5- to 20-membered heteroaryl group, of which R e The 5 to 20 yuan heteroaryl groups are independently and optionally constituting one or more C 1-12 Alkyl or halogenated substitutions. In some embodiments, L is independently C each time it appears. 1-6 Alkylene, wherein L is C 1-6 Alkylenes are independently and optionally bound by one or more C 1-12 Alkyl substitution, where ring A is independently C each time it appears. 6-20 Aryl, n is independently 1 on each occurrence, and R e Each time it appears, it is independently a 5- to 20-membered heteroaryl group, of which R e The 5 to 20 yuan heteroaryl groups are independently and optionally constituting one or more C 1-12 Alkyl substitution.

[0108] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IA):

[0109]

[0110] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein:

[0111] X 1 Each occurrence is independently H or C. 1-12 Alkyl or -C(O)-C 1-12 alkyl;

[0112] R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups,

[0113] Where R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution;

[0114] R t For H, C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group may be further optionally substituted with one or more halogens;

[0115] R e Each time it appears, it is independently halogenated, C 6-20 Aryl or 5- to 20-membered heteroaryl groups, of which R e C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more C groups. 1-12 Alkyl or halogenated substitutions; and

[0116] Q 1 and Q 2 Each of them is independent of the others and independently of H, halogen, cyano, and C in each occurrence. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 alkyl,

[0117] Q 1 Or Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more Rq Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, or Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups,

[0118] Among them, Q 1 and Q 2 The formed C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more R groups. s Replace, where R s The radicals are OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, and -SO2C. 1-12 Alkyl, -SO2NH2 or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group may be further optionally substituted with one or more halogenated, cyano, or OH groups.

[0119] In the embodiment, X 1 For H; R 1 C 1-12 Alkyl, C 2-12 alkenyl or C 3-15 cycloalkyl, wherein the C 1-12 Alkyl groups are independently and optionally bound by one or more Cs. 6-20 Aryl substitution; R t C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group is further optionally substituted with one or more halogens; R e C 6-20 Aryl or 5- to 20-membered heteroaryl groups, of which R e C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more C groups.1-12 Alkyl or halogenated substitutions; and Q 1 and Q 2 Each of them is independent of the others and independently of H, halogen, cyano, and C in each occurrence. 1-12 Alkyl, C 3-15 Cycloalkyl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 Alkyl, wherein Q 1 Or Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, or Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups, of which Q 1 and Q 2 The formed C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more R groups. s Replace, where R s The radicals are OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, and -SO2C. 1-12 Alkyl, -SO2NH2 or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group may be further optionally substituted with one or more halogenated, cyano, or OH groups.

[0120] In the embodiment, X 1 For H; R 1 C1-12 Alkyl, C 2-12 alkenyl or C 3-15 cycloalkyl, wherein C 1-12 Alkyl groups are independently and optionally bound by one or more Cs. 6-20 Aryl substitution; R t It is H, methyl, -CF3 or -C(O)NH2, where R t The methyl group is further optionally substituted with one or more halogens; R e Independently for each occurrence And Q 1 and Q 2 Each of them is independent of the others and independently of H, halogen, cyano, and C in each occurrence. 1-5 Alkyl, C 3-15 Cycloalkyl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 Alkyl, wherein Q 1 Or Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, or Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups, of which Q 1 and Q 2 The formed C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more R groups. s Replace, where R sThe radicals are OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, and -SO2C. 1-12 Alkyl, -SO2NH2 or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group may be further optionally substituted with one or more halogenated, cyano, or OH groups.

[0121] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IA-1):

[0122]

[0123] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein:

[0124] R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups,

[0125] Where R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution;

[0126] R t For H, C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group may be further optionally substituted with one or more halogens;

[0127] R e Each time it appears, it is independently halogenated, C 6-20 Aryl or 5- to 20-membered heteroaryl groups, of which R e C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more C groups. 1-12 Alkyl or halogenated substitutions; and

[0128] Q 1Choose from the following groups: H, halogenated, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 alkyl,

[0129] Q 1 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution.

[0130] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IA-2):

[0131]

[0132] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein:

[0133] R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups,

[0134] Where R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups.1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution;

[0135] R t For H, C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group is further optionally substituted with one or more halogens; and

[0136] Q 1 Choose from the following groups: H, halogenated, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 alkyl,

[0137] Q 1 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution.

[0138] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IA-3):

[0139]

[0140] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein:

[0141] R1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups,

[0142] Where R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution;

[0143] R t For H, C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group is further optionally substituted with one or more halogens; and

[0144] R e Each time it appears, it is independently halogenated, C 6-20 Aryl or 5- to 20-membered heteroaryl groups, of which R e C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more C groups. 1-12 Alkyl or halogenated substitutions.

[0145] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IA-4):

[0146]

[0147] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein:

[0148] R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups,

[0149] Where R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution;

[0150] R t For H, C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group is further optionally substituted with one or more halogens; and

[0151] Q 1 and Q 2 Each of them is independent of the others and independently of H, halogen, cyano, and C in each occurrence. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 alkyl,

[0152] Q 1 Or Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, or Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups,

[0153] Among them, Q1 and Q 2 The formed C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more R groups. s Replace, where R s The radicals are OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, and -SO2C. 1-12 Alkyl, -SO2NH2 or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group may be further optionally substituted with one or more halogenated, cyano, or OH groups.

[0154] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IB):

[0155]

[0156] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein:

[0157] X 1 Each occurrence is independently H or C. 1-12 Alkyl or -C(O)-C 1-12 alkyl;

[0158] R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups,

[0159] Where R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution;

[0160] R t For H, C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12The alkyl group may be further optionally substituted with one or more halogens;

[0161] R e Each time it appears, it is independently halogenated, C 6-20 Aryl or 5- to 20-membered heteroaryl groups, of which R e C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more C groups. 1-12 Alkyl or halogenated substitutions; and

[0162] Q 1 and Q 2 Each of them is independent of the others and independently of H, halogen, cyano, and C in each occurrence. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 alkyl,

[0163] Q 1 Or Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, or

[0164] Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups,

[0165] Among them, Q 1 and Q 2 The formed C 3-15Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more R groups. s Replace, where R s The radicals are OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, and -SO2C. 1-12 Alkyl, -SO2NH2 or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group may be further optionally substituted with one or more halogenated, cyano, or OH groups.

[0166] In the embodiment, X 1 For H; R 1 C 1-12 Alkyl, C 2-12 alkenyl or C 3-15 cycloalkyl, wherein the C 1-12 Alkyl groups are independently and optionally bound by one or more Cs. 6-20 Aryl substitution; R t C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group is further optionally substituted with one or more halogens; R e C 6-20 Aryl or 5- to 20-membered heteroaryl groups, of which R e C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more C groups. 1-12 Alkyl or halogenated substitutions; and Q 1 and Q 2 Each of them is independent of the others and independently of H, halogen, cyano, and C in each occurrence. 1-12 Alkyl, C 3-15 Cycloalkyl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 Alkyl, wherein Q 1 Or Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkynyl group, C6-20 Aryl, C 1-12 alkoxy or Where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, or Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups, of which Q 1 and Q 2 The formed C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more R groups. s Replace, where R s The radicals are OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, and -SO2C. 1-12 Alkyl, -SO2NH2 or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group may be further optionally substituted with one or more halogenated, cyano, or OH groups.

[0167] In the embodiment, X 1 For H; R 1 C 1-12 Alkyl, C 2-12 alkenyl or C 3-15 cycloalkyl, wherein C 1-12 Alkyl groups are independently and optionally bound by one or more Cs. 6-20 Aryl substitution; R t It is H, methyl, -CF3 or -C(O)NH2, where R t The methyl group is further optionally substituted with one or more halogens; R e Independently for each occurrence And Q 1 and Q 2 Each of them is independent of the others and independently of H, halogen, cyano, and C in each occurrence. 1-5 Alkyl, C 3-15 Cycloalkyl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and Rc Each independently is H or C 1-12 Alkyl, wherein Q 1 Or Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, or Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups, of which Q 1 and Q 2 The formed C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more R groups. s Replace, where R s The radicals are OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, and -SO2C. 1-12 Alkyl, -SO2NH2 or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group may be further optionally substituted with one or more halogenated, cyano, or OH groups.

[0168] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IB-1):

[0169]

[0170] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein:

[0171] R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups,

[0172] Where R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution;

[0173] R t For H, C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group may be further optionally substituted with one or more halogens;

[0174] R e Each time it appears, it is independently halogenated, C 6-20 Aryl or 5- to 20-membered heteroaryl groups, of which R e C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more C groups. 1-12 Alkyl or halogenated substitutions; and

[0175] Q 1 Choose from the following groups: H, halogenated, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 alkyl,

[0176] Q 1 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution.

[0177] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IB-2):

[0178]

[0179] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein:

[0180] R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups,

[0181] Where R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution;

[0182] R t For H, C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group is further optionally substituted with one or more halogens; and

[0183] Q 1 Choose from the following groups: H, halogenated, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R cEach independently is H or C 1-12 alkyl,

[0184] Q 1 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution.

[0185] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IB-3):

[0186]

[0187] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein:

[0188] R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups,

[0189] Where R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution;

[0190] R t For H, C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group is further optionally substituted with one or more halogens; and

[0191] R e Each time it appears, it is independently halogenated, C 6-20 Aryl or 5- to 20-membered heteroaryl groups, of which R e C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more C groups. 1-12 Alkyl or halogenated substitutions.

[0192] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IB-4):

[0193]

[0194] Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein:

[0195] R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups,

[0196] Where R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; and

[0197] R t For H, C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group may be further optionally substituted with one or more halogens.

[0198] In some embodiments, L is independently an unsubstituted methylene group each time it appears, and ring A is independently a C group each time it appears. 6-20 Aryl, n is independently 1 on each occurrence, and R e Each time it appears, it is independently a 5- to 20-membered heteroaryl group, of which R e The 5 to 20 yuan heteroaryl groups are independently and optionally constituting one or more C 1-12Alkyl substitution. In other embodiments, L is independently an unsubstituted methylene group each time it appears, and ring A is independently a C group each time it appears. 6-20 Aryl, n is independently 1 on each occurrence, and R e Each time it appears, it is independently a thiazolyl group, where R e The thiazolyl group is independently and optionally surrounded by one or more C groups. 1-12 Alkyl substitution. In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IC):

[0199]

[0200] Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

[0201] In other embodiments, L is independently methylene each time it appears, wherein the methylene group of L is independently bound by one or more C groups. 1-12 Alkyl substitution, where ring A is independently C each time it appears. 6-20 Aryl, n is independently 1 on each occurrence, and R e Each time it appears, it is independently a 5- to 20-membered heteroaryl group, of which R e The 5 to 20 yuan heteroaryl groups are independently and optionally constituting one or more C 1-12 Alkyl substitution. In other embodiments, L is independently methylene each time it appears, wherein the methylene group of L is substituted with one or more C atoms. 1-12 Alkyl substitution, where ring A is independently C each time it appears. 6-20 Aryl, n is independently 1 on each occurrence, and R e Each time it appears, it is independently a thiazolyl group, where R e The thiazolyl group is independently and optionally surrounded by one or more C groups. 1-12 Alkyl substitution.

[0202] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (ID):

[0203]

[0204] Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

[0205] In other embodiments, L is independently methylene each time it appears, wherein the methylene group of L is separated by one or more C atoms. 1-12 Alkyl substitution, where ring A is independently C each time it appears. 6-20Aryl, n is independently 2 each time it appears, R e One of them is a 5- to 20-membered heteroaryl group each time it appears, where R e The 5 to 20 yuan heteroaryl groups are independently and optionally constituting one or more C 1-12 Alkyl substitution, and another R e It is halogenated independently each time it appears. In other embodiments, L is methylene independently each time it appears, wherein the methylene group of L is halogenated by one or more C atoms. 1-12 Alkyl substitution, where ring A is independently C each time it appears. 6-20 Aryl, n is independently 2 each time it appears, R e One of them is a thiazolyl group each time it appears, where R e The thiazolyl group is independently and optionally surrounded by one or more C groups. 1-12 Alkyl substitution, and another R e Halogenation occurs independently each time it occurs. In some embodiments, R e The halogenation is independently chlorine each time it appears. In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IE):

[0206]

[0207] Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

[0208] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein L is independently C each time it appears. 1-12 Alkylene, wherein L is C 1-12 Alkylenes are independently and optionally separated by one or more R t Replace, where R t Independently for C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group is further independently and optionally substituted with one or more halogens, and ring A is independently C each time it appears. 6-20 Aryl, n is independently 1 on each occurrence, and R e It is C independently each time it appears. 6-20 Aryl, wherein R e C 6-20 Aryl group is independently and optionally bounded by one or more C 1-12 Alkyl or halogenated substitutions. In some embodiments, L is independently C each time it appears. 1-6 Alkylene, wherein L is C1-6 Alkylenes are independently and optionally separated by one or more R t Replace, where R t It is C independently each time it appears. 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group is further independently and optionally substituted with one or more halogens, and ring A is independently C each time it appears. 6-20 Aryl, n is independently 1 on each occurrence, and R e It is C independently each time it appears. 6-20 Aryl, wherein R e C 6-20 Aryl group is independently and optionally bounded by one or more C 1-12 Alkyl or halogenated substitutions. In some embodiments, L is independently C each time it appears. 1-6 Alkylene, wherein L is C 1-6 The alkylene group is independently and optionally substituted by one or more -C(O)NH2, and ring A is independently C each time it appears. 6-20 Aryl, n is independently 1 on each occurrence, and R e It is C independently each time it appears. 6-20 Aryl, wherein R e C 6-20 Aryl group is independently and optionally bounded by one or more C 1-12 Alkyl or halogenated substitutions.

[0209] In some embodiments, L is independently ethylene each time it appears, wherein the ethylene in L is independently substituted by one or more -C(O)NH2, ring A is independently phenyl each time it appears, n is independently 1 each time it appears, and R e Each occurrence is independently an unsubstituted phenyl group. In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IF):

[0210]

[0211] Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

[0212] In some embodiments, L is independently methylene each time it appears, wherein the methylene group of L is independently converted by one or more C groups. 1-12 Alkyl substitution, ring A is independently phenyl each time it appears, n is independently 1 each time it appears, and R e It is independently phenyl each time it appears, where R eThe phenyl group is independently substituted by one or more halogens. In some embodiments, L is independently methylene each time it appears, wherein the methylene group of L is independently substituted by one or more C... 1-6 Alkyl substitution, ring A is independently phenyl each time it appears, n is independently 1 each time it appears, and R e It is independently phenyl each time it appears, where R e The phenyl group is independently substituted by one or more halogens, wherein the halogen is fluorine. In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IG):

[0213]

[0214] Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

[0215] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein L is independently absent in each occurrence and ring A is independently C in each occurrence. 7-15 Cycloalkyl group. In other embodiments, L is independently absent each time it appears, and ring A is independently C each time it appears. 7-15 Cycloalkyl groups, n is independently 1 each time it appears, and R e Each time it appears, it is independently a 5- to 20-membered heteroaryl group, of which R e The 5 to 20 yuan heteroaryl groups are independently and optionally constituting one or more C 1-12 Alkyl substitution. In some embodiments, L is independently absent each time it appears, and ring A is independently C each time it appears. 7-15 Cycloalkyl groups, n is independently 1 each time it appears, and R e Each time it appears, it is independently a thiazolyl group, where R e The thiazolyl group is independently and optionally surrounded by one or more C groups. 1-12 Alkyl substitution. In some embodiments, this document provides compounds of formula (I), or stereoisomers or tautomers thereof, or pharmaceutical salts of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IH):

[0216]

[0217] Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

[0218] In some embodiments, this document provides compounds of formula (I), such as compounds of formula (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (ID), (IE), (IF), (IG), or (IH), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein Q 1 and Q 2 Each of them is independent of the others and independently of H, halogen, cyano, and C in each occurrence. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 Alkyl, wherein Q 1 Or Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution. In some embodiments, Q 1 H, halogenated, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 Alkyl, wherein Q 1 C 1-12 Alkyl or C3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and Q 2 For H. In some embodiments, Q 2 Each time it appears, it is independently H, halogenated, cyano, or C. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 Alkyl, wherein Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and Q 1 For H. In other embodiments, Q 1 and Q 2 Independently, and each time they appear independently, they are halogenated, cyano, or C. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 Alkyl, wherein Q 1 Or Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution. In other embodiments, Q 1 and Q 2 Each is independent of the others and is independently H each time it appears.

[0219] In some embodiments, Q 1 C 3-15 cycloalkyl, wherein Q 1 C 3-15 cycloalkyl groups are optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution. In other embodiments, Q 1 C 3-12 cycloalkyl, wherein Q 1 C 3-12 cycloalkyl groups are optionally surrounded by one or more R q Replacement. In some embodiments, Q 1 C 3-10 cycloalkyl, wherein Q 1 C 3-10cycloalkyl groups are optionally surrounded by one or more R q Replacement. In some embodiments, Q 1 C 3-8 cycloalkyl, wherein Q 1 C 3-8 cycloalkyl groups are optionally surrounded by one or more R q Replacement. In some embodiments, Q 1 C 3-6 cycloalkyl, wherein Q 1 C 3-6 cycloalkyl groups are optionally surrounded by one or more R q Replacement. In some embodiments, Q 1 C 3-5 cycloalkyl, wherein Q 1 C 3-5 cycloalkyl groups are optionally surrounded by one or more R q Replacement. In some embodiments, Q 1 It is cyclopropyl, where Q 1 The cyclopropyl group is optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 acetylinyl or Where R q C 1-12 The alkyl group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution. In some embodiments, Q 1 It is cyclopropyl, where Q 1 The cyclopropyl group is optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 acetylinyl or Where R q C 1-12 The alkyl group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and Q 2 For H. In some embodiments, Q 1 It is an unsubstituted cyclopropyl group. In some embodiments, Q... 1 It is an unsubstituted cyclopropyl group, and Q 2 For H.

[0220] In some embodiments, Q 1 C 1-12 Alkyl, wherein Q 1 C 1-12 Alkyl groups are optionally surrounded by one or more R q Replace, where Rq Independently for C 6-20 Aryl or C 1-12 Alkoxy, where R q C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, and Q 2 H is independent each time it appears. In some embodiments, Q is... 1 It is methyl and Q 2 H is independent each time it appears. In other embodiments, Q is... 1 For H and Q 2 It is C independently each time it appears. 1-12 Alkyl, wherein Q 2 C 1-12 Alkyl groups are independently and optionally surrounded by one or more R groups. q Replace, where R q It is C independently each time it appears. 6-20 Aryl or C 1-12 Alkoxy, where R q C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution. In some embodiments, Q 1 For H and Q 2 It is independently methyl each time it appears. In other embodiments, Q 1 and Q 2 Each of them is independent and each occurrence is independent of C. 1-12 Alkyl, wherein Q 1 Or Q 2 C 1-12 Alkyl groups are independently and optionally surrounded by one or more R groups. q Replace, where R q It is C independently each time it appears. 6-20 Aryl or C 1-12 Alkoxy, where R q C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution. In some embodiments, Q 1 and Q 2 Each is independent of the others and is independently methyl in each occurrence.

[0221] In some embodiments, Q 1 -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where Ra R b and R c Each independently is H or C 1-12 Alkyl, and Q 2 H is independent each time it appears. In other embodiments, Q is... 1 -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 Alkyl, and Q 2 It is C independently each time it appears. 1-12 Alkyl group. In some embodiments, Q 1 -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 Alkyl, and Q 2 It is methyl in each instance.

[0222] In some embodiments, Q 1 It is a heteroaryl group ranging from 5 to 20 ppm. In some embodiments, Q 1 It is a 5- to 16-membered heteroaryl group. In other embodiments, Q 1 It is a 5- to 12-membered heteroaryl group. In other embodiments, Q 1 It is a 5- to 10-membered heteroaryl group. In some embodiments, Q 1 It is a 5- to 8-membered heteroaryl group. In other embodiments, Q 1 It is a 5- to 6-membered heteroaryl group. In some embodiments, Q 1 It is a 5-membered heteroaryl group. In some embodiments, Q 1 It is furanyl. In other embodiments, Q 1 It is phenylthio group. In some embodiments, Q... 1 It is a heteroaryl compound with a content of 5 to 20 yuan and Q 2 It is H independently each time it appears.

[0223] In some embodiments, Q 1 It is cyano. In some embodiments, Q 1 It is cyano and Q 2 H is independent each time it appears. In some embodiments, Q is... 1 Halogenation. In some embodiments, Q 1Halogenated and Q 2 H is independent each time it appears. In some embodiments, Q is... 1 It is fluorine and Q 2 It is H independently each time it appears.

[0224] In some embodiments, this document provides compounds of formula (I), such as compounds of formula (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (ID), (IE), (IF), (IG), or (IH), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups, of which Q 1 and Q 2 The formed C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more R groups. s Replace, where R s The radicals are OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, and -SO2C. 1-12 Alkyl, -SO2NH2 or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group is further optionally substituted with one or more halogenated or OH groups. In some embodiments, Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-20 Aryl, wherein Q 1 and Q 2 The formed C 6-20 Aryl groups are independently and optionally bounded by one or more R groups. s Replacement. In some embodiments, Q 1 and Q 2 Together with the atoms they are attached to, they form unsubstituted C. 6-20 Aryl. In some embodiments, Q 1 and Q 2 Together with the atoms they are attached to, they form unsubstituted C. 6-10 Aryl. In some embodiments, Q 1 and Q 2 Together with the atoms they are attached to, they form unsubstituted C6 aryl groups.

[0225] In some embodiments, this document provides compounds of formula (I), such as compounds of formula (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (ID), (IE), (IF), (IG), or (IH), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In some embodiments, R 1 It is C independently each time it appears. 1-12 Alkyl, wherein R 1 C 1-12 Alkyl groups are independently and optionally bound by one or more Cs. 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In some embodiments, R 1 Each time it appears, it is independently an unsubstituted C. 1-12 Alkyl group. In other embodiments, R 1 It is C independently each time it appears. 1-6 Alkyl, wherein R 1 C 1-6 Alkyl groups are independently and optionally bound by one or more Cs. 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In other embodiments, R 1 It is C independently each time it appears. 1-6 Alkyl, wherein R 1 C 1-6 Alkyl groups are independently and optionally bound by one or more Cs. 6-20 Aryl substitution. In some embodiments, R 1 Each time it appears, it is independently an unsubstituted C. 1-6Alkyl group. In some embodiments, R 1 Each time it appears, it is independently methyl, tert-butyl, sec-butyl, isopropyl, or tert-pentyl. In some embodiments, R 1 Each time it appears, it is independently methyl, tert-butyl, or isopropyl. In some embodiments, R 1 It is independently tert-butyl or isopropyl each time it appears. In some embodiments, R 1 It is independently tert-butyl each time it appears. In other embodiments, R 1 It is an isopropyl group each time it appears.

[0226] In some embodiments, this document provides compounds of formula (I), such as compounds of formula (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (ID), (IE), (IF), (IG), or (IH), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein R 1 It is C independently each time it appears. 3-15 cycloalkyl, wherein R 1 C 3-15 The cycloalkyl group is independently and optionally bound by one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In some embodiments, R 1 It is C independently each time it appears. 3-12 cycloalkyl, wherein R 1 C 3-12 The cycloalkyl group is independently and optionally bound by one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In other embodiments, R 1 It is C independently each time it appears. 3-10 cycloalkyl, wherein R 1 C 3-10 The cycloalkyl group is independently and optionally bound by one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In still other embodiments, R 1 It is C independently each time it appears. 3-8 cycloalkyl, wherein R 1 C 3-8The cycloalkyl group is independently and optionally bound by one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In some embodiments, R 1 It is C independently each time it appears. 3-6 cycloalkyl, wherein R 1 C 3-6 The cycloalkyl group is independently and optionally bound by one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In other embodiments, R 1 It is C independently each time it appears. 3-5 cycloalkyl, wherein R 1 C 3-5 The cycloalkyl group is independently and optionally bound by one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In some embodiments, R 1 It is independently cyclobutyl each time it appears, where R 1 The cyclobutyl group is independently and optionally constituting one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In some embodiments, R 1 Each time it appears, it is independently an unsubstituted cyclobutyl group. In some embodiments, R 1 It is independently cyclohexyl each time it appears, where R 1 The cyclohexyl group is independently and optionally converted by one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution. In some embodiments, R 1 It is independently an unsubstituted cyclohexyl group each time it appears. In some embodiments, R 1 Each time it appears, it is independently an unsubstituted adamantyl group.

[0227] In some embodiments, this document provides compounds of formula (I), such as compounds of formula (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (ID), (IE), (IF), (IG), or (IH), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein R 1 Each occurrence is independently a 3- to 15-membered heterocyclic group, where R 1 The 3- to 15-membered heterocyclic groups are independently and optionally construed by one or more C groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

[0228] In some embodiments, this document provides compounds of formula (I), such as compounds of formula (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (ID), (IE), (IF), (IG), or (IH), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein R 1 The attached chiral carbon atom has an S stereochemical configuration. In some embodiments, compounds of formula (I) are provided herein, such as compounds of formulas (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (ID), (IE), (IF), (IG), or (IH), or stereoisomers or tautomers thereof, or pharmaceutical salts of any of the foregoing, wherein R 1 The attached chiral carbon atom has an R stereochemical configuration.

[0229] In some embodiments, this document provides compounds of formula (I), such as compounds of formula (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (ID), (IE), (IF), (IG), or (IH), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein X 1 Each occurrence is independently H or C. 1-12 Alkyl or -C(O)-C 1-12 Alkyl group. In some embodiments, X 1 H is independent each time it appears. In other embodiments, X 1It is independently -C(O)-C each time it appears. 1-12 Alkyl group. In other embodiments, X 1 It is independently -C(O)-CH3 each time it appears. In some embodiments, X 1 It is C independently each time it appears. 1-12 Alkyl group. In some embodiments, X 1 C 1-12 The alkyl group is unsubstituted.

[0230] In some embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein: X 1 Each occurrence is independently H or C. 1-12 Alkyl or -C(O)-C 1-12 Alkyl; R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; L is either absent independently or C in each occurrence. 1-12 Alkylene, wherein L is C 1-12 Alkylenes are independently and optionally separated by one or more R t Replace, where R t C 1-12 Alkyl or -C(O)NH2, wherein R t C 1-12 The alkyl group is further optionally substituted with one or more halogens; ring A is independently C each time it appears. 6-20 Aryl or C 7-15 Cycloalkyl; n is independently 1, 2, 3, 4 or 5 each time it appears; R e Each time it appears, it is independently halogenated, C 6-20 aryl or 5- to 20-membered heteroaryl, provided that at least one R e C 6-20 aryl or 5- to 20-membered heteroaryl groups containing one or more sulfur atoms on a ring, wherein R e C 6-20Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more C groups. 1-12 Alkyl or halogenated substitutions; and Q 1 and Q 2 Each of these groups is independent of the others and, each time it appears independently, is H, halogenated, cyano, or C. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 Alkyl, wherein Q 1 Or Q 2 C 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q C 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, or Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups, of which Q 1 and Q 2 The formed C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more R groups. s Replace, where R s The radicals are OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, and -SO2C. 1-12 Alkyl, -SO2NH2 or C 1-12 Alkyl, wherein R s C 1-12 The alkyl group may be further optionally substituted with one or more halogenated, cyano, or OH groups.

[0231] In some of the foregoing embodiments, C 6-20 aryl or at least one R containing one or more 5- to 20-membered heteroaryl groups with sulfur atoms on the ring. e It is bonded to ring A at a position adjacent to ring A. In other embodiments, it is C. 6-20 At least one R of an aryl group or a 5- to 20-membered heteroaryl group containing one or more sulfur atoms on a ring e It is bonded to ring A at the interposition of ring A. In other embodiments, it is C. 6-20 aryl or at least one R containing one or more 5- to 20-membered heteroaryl groups with sulfur atoms on the ring. e It bonds to ring A at the opposite position of ring A.

[0232] In some of the foregoing embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein L is independently an unsubstituted methylene group each time it appears, and ring A is independently a C ring each time it appears. 6-20 Aryl; n is independently 1 each time it appears; R e Each time it appears, it is independently a 5- to 20-membered heteroaryl group, of which R e The 5- to 20-membered heteroaryl groups contain one or more sulfur atoms on the ring and are independently and optionally bounded by one or more C atoms. 1-12 Alkyl substitution; and Q 1 For unsubstituted cyclopropyl, then R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

[0233] In the other embodiments described above, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein L is independently an unsubstituted methylene group each time it appears, and ring A is independently a C ring each time it appears. 6-20 Aryl; n is independently 1 each time it appears; R e Each time it appears, it is independently a thiazolyl group, where R eThe thiazolyl group is independently and optionally surrounded by one or more C groups. 1-12 Alkyl substitution; and Q 1 For unsubstituted cyclopropyl, then R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

[0234] In some of the foregoing embodiments, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein L is independently an unsubstituted methylene group each time it appears, and ring A is independently a C ring each time it appears. 6-20 Aryl; n is independently 1 each time it appears; R e Each time it appears, it is independently a thiazolyl group, where R e The thiazolyl group is independently and optionally substituted with one or more methyl groups; and Q 1 For unsubstituted cyclopropyl, then R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups, wherein R 1 C 1-3 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

[0235] In some of the foregoing aspects, compounds of formula (I), such as (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (ID), (IE), (IF), (IG) or (IH), or stereoisomers or tautomers thereof, or pharmaceutical salts of any of the foregoing, include (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide or pharmaceutical salts thereof. In some of the foregoing aspects, compounds of formula (I), such as (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (ID), (IE), (IF), (IG) or (IH), or stereoisomers or tautomers thereof, or pharmaceutical salts thereof, do not include (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide or pharmaceutical salts thereof.

[0236] The X provided in this article should be understood 1 R 1 Q 1 Q 2 Rings A, n, L, R a R b R c R e R q R s and R t Any variation or embodiment may be related to X 1 R 1 Q 1 Q 2 Rings A, n, L, R a R b R c R e R q R s and R t Each other variation or combination of embodiments is described as if each combination were described individually and specifically.

[0237] In one embodiment, this document provides compounds of formula (I), such as compounds of formula (IA), (IA-1), (IA-2), (IA-3), (IA-4), (IB), (IB-1), (IB-2), (IB-3), (IB-4), (IC), (ID), (IE), (IF), (IG) or (IH), or stereoisomers or tautomers thereof, or pharmaceutical salts of any of the foregoing, wherein the compounds are selected from the compounds in Table 1.

[0238] Table 1

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251] In one embodiment, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein said compound is selected from the group consisting of:

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258] Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

[0259] In one embodiment, this document provides a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein the compound is selected from the group consisting of: N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxypyrrolidine-2-carboxamide;

[0260] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)propionyl)-4-hydroxypyrrolidine-2-carboxamide;

[0261] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide;

[0262] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-(2-cyclobutyl-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxypyrrolidine-2-carboxamide;

[0263] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylpentanoyl)-4-hydroxypyrrolidine-2-carboxamide;

[0264] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylpentanoyl)-4-hydroxypyrrolidine-2-carboxamide;

[0265] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylpent-4-enoyl)-4-hydroxypyrrolidine-2-carboxamide;

[0266] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-(2-(adamantane-1-yl)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxypyrrolidine-2-carboxamide;

[0267] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-(3,3-dimethyl-2-(1H-1,2,3-triazol-1-yl)butyryl)-4-hydroxypyrrolidine-2-carboxamide;

[0268] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-4-hydroxy-1-(2-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)pyrrolidine-2-carboxamide;

[0269] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-(2-(4-benzyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide;

[0270] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-(2-(4-(1-(acetamidomethyl)cyclopropyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-(2-(4-((2- Acetamidoethoxy)methyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide; 1-(1-(2-((3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)-1H-1,2,3-triazolidine-4-carboxylic acid;

[0271] 1-(1-(2-((3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)carbamoyll)-4-hydroxypyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)-1H-1,2,3-triazol-4-carboxamide; 1-(1-(2-((3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl) 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N-methyl-1H-1,2,3-triazol-4-carboxamide;

[0272] 1-(2-cyclohexyl-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxy-N-(1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0273] 1-(2-(adamantane-1-yl)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxy-N-(1-(4-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0274] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylpentanoyl)-4-hydroxy-N-(1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0275] N-(1-(2-chloro-4-(4-methylthiazo-5-yl)phenyl)ethyl)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide;

[0276] 1-(2-(adamantane-1-yl)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-N-(1-(2-chloro-4-(4-methylthiazolyl-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide;

[0277] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0278] 1-(2-cyclohexyl-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0279] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methyl-3-phenylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0280] 1-(2-(4-benzyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0281] 1-(3,3-dimethyl-2-(4-(1-(trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol-1-yl)butyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0282] 1-(3,3-dimethyl-2-(4-(1-methylcyclopropyl)-1H-1,2,3-triazol-1-yl)butyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0283] 1-(2-(4-(1-ethynylcyclopropyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0284] 1,1'-(2,2'-(cyclopropane-1,1-diylbis(1H-1,2,3-triazol-4,1-diyl))bis(3,3-dimethylbutyryl))bis(4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide);

[0285] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-4-hydroxy-1-(3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide;

[0286] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-4-hydroxy-1-(3-methyl-2-(5-methyl-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide;

[0287] 1-(1-(2-((3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)-5-methyl-1H-1,2,3-triazol-4-carboxylic acid methyl ester; 1-(1-(2-((3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl) Carbamoyl)-4-hydroxypyrrolidone-1-yl)-3-methyl-1-oxobutane-2-yl)-5-methyl-1H-1,2,3-triazol-4-carboxylic acid; 1-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-3-methylbutyryl)-N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-4-hydroxypyrrolidone-2-carboxamide;

[0288] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-(2-(4,5-dimethyl-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxypyrrolidine-2-carboxamide;

[0289] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-(2-(4,5-dimethyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide;

[0290] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-4-hydroxy-1-(3-methyl-2-(4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)butyryl)pyrrolidine-2-carboxamide;

[0291] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-(2-(4-(furan-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxypyrrolidine-2-carboxamide;

[0292] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-(2-(4-cyano-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxypyrrolidine-2-carboxamide;

[0293] N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-(2-(4-fluoro-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxypyrrolidine-2-carboxamide;

[0294] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy-N-(2,2,2-trifluoro-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0295] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-N-(1-(2'-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide;

[0296] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-N-((2'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxamide;

[0297] N-(1-([1,1'-biphenyl]-4-yl)-2-amino-2-oxoethyl)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide;

[0298] 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy-N-(2-(4-methylthiazolyl-5-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide; and

[0299] N-(1-(2'-chloro-[1,1'-biphenyl]-4-yl)ethyl)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide

[0300] Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

[0301] The compound names included in Table 1 and the list in the first paragraph are those used in [the following text is incomplete and likely refers to a different topic] This was automatically generated by software version 18.2.0.48.

[0302] As described herein, VHL ligands can exist in solid or liquid form. In the solid state, ligands can exist in crystalline or amorphous form or as mixtures thereof. Those skilled in the art will understand that pharmaceutical solvates can be formed for crystalline or amorphous compounds. In crystalline solvates, solvent molecules are incorporated into the crystal lattice during the crystallization process. Solvates can involve non-aqueous solvents, such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they can involve water as a solvent incorporated into the crystal lattice. Solvates in which water is incorporated into the crystal lattice are generally referred to as “hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing a variable amount of water. Such solvates are included in the subject matter described herein.

[0303] Those skilled in the art will further understand that certain VHL ligands described herein, existing in crystalline form, including their various solvates, can exhibit polymorphism (i.e., the ability to occur in different crystal structures). These different crystalline forms are generally referred to as “polymorphs.” Such polymorphs are included in the subject matter disclosed herein. Polymorphs have the same chemical composition but differ in packing, geometric arrangement, and other descriptive properties of their crystalline solid state. Therefore, polymorphs can have different physical properties, such as shape, density, hardness, deformability, stability, and solubility. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which can be used for identification. Those skilled in the art will understand that different polymorphs can be generated, for example, by changing or adjusting the reaction conditions or reagents used to prepare the compound. For example, changes in temperature, pressure, or solvent can lead to polymorphs. Furthermore, under certain conditions, one polymorph can spontaneously transform into another.

[0304] The VHL ligands or their pharmaceutical salts described herein may exist in stereoisomeric forms (e.g., containing one or more asymmetric carbon atoms). Various stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the subject matter disclosed herein. Similarly, it should be understood that compounds or salts of formula (I) may exist in tautomeric forms other than those shown in that formula, and these are also included within the scope of the subject matter disclosed herein. It should be understood that the subject matter disclosed herein includes combinations and subsets of the specific groups described herein. The scope of the subject matter disclosed herein includes mixtures of stereoisomers as well as purified enantiomers or enantiomer / diastereomer-enriched mixtures. It should be understood that the subject matter disclosed herein includes combinations and subsets of the specific groups defined above herein.

[0305] The subject matter disclosed herein also includes the isotopic labeling of the compounds described herein, but in fact, one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds described herein and their medicinal salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I.

[0306] VHL ligands and their pharmaceutical salts disclosed herein that contain other isotopes of the aforementioned isotopes and / or other atoms are within the scope of the subject matter disclosed herein. This document discloses isotopically labeled compounds, such as those doped with radioactive isotopes (e.g., 3 H, 14 Compounds in group C) can be used for drug and / or substrate tissue distribution assays. Tritium compounds are commonly used (i.e.,...). 3 H) and carbon-14 (i.e. 14 C) Isotopes, because they are easy to prepare and detect. 11 C and 18 F isotopes can be used in PET (positron emission tomography), while 125 I- isotopes can be used in SPECT (single-photon emission computed tomography), all of which can be used for brain imaging. Further, heavier isotopes such as deuterium (i.e.,...) can be used... 2 H) substitution can provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements), and is therefore preferred in some cases. Isotope-labeled compounds of Formula I can generally be prepared by performing the procedures disclosed in the following schemes and / or examples (by replacing the non-isotope-labeled reagent with an readily available isotope-labeled reagent).

[0307] In some embodiments, the VHL ligands provided herein are integrated into a heterobifunctional molecule. In some embodiments, the heterobifunctional molecule is a chemical degradation inducer (CIDE) having (i) a VHL ligand as provided herein, and (ii) a portion capable of binding to a target protein for targeted degradation, wherein (i) and (ii) are covalently linked. In some embodiments, (i) and (ii) are covalently linked via a linker portion, such as a polyethylene glycol (PEG) chain or an alkyl chain. In some embodiments, the CIDE is capable of selectively degrading a target protein by forming a ternary complex between the target protein, the heterobifunctional molecule described herein, and the ubiquitin ligase. In some embodiments, the ubiquitin ligase is a VHL E3 ubiquitin ligase. By way of illustration and not limitation, the target protein may be, for example, a structural protein, an enzyme, a receptor, or a cell surface protein.

[0308] In some embodiments, the heterobifunctional molecule is a compound of formula (II):

[0309] [A]-[B]-[C](II),

[0310] Wherein [A] is the portion of the VHL ligand provided in this paper, [B] is the linker portion, and [C] is the protein-binding portion.

[0311] III. Preparations

[0312] On the other hand, this specification provides therapeutic or pharmaceutical compositions comprising an effective amount of at least one compound described herein, including, for example, at least one VHL ligand. Another aspect of this disclosure represents pharmaceutical compositions comprising an effective amount of at least one VHL ligand of this disclosure and optionally one or more effective amounts of compounds otherwise described herein, combined with an effective amount of a carrier, additive, or excipient, and optionally additional bioactive agents.

[0313] In some embodiments, the composition comprises pharmaceutical salts, particularly acid or base addition salts of compounds as described herein. Acids used to prepare pharmaceutical acid addition salts of the aforementioned base compounds include acids that form non-toxic acid addition salts, i.e., salts containing pharmaceutical anions, such as hydrochlorides, hydrobromides, hydroiodates, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, acetates, lactates, citrates, acid citrates, tartrates, hydrogen tartrates, succinates, maleates, fumarates, gluconates, sucrose salts, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl)ate [i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthylcarbamate)] salts, etc.

[0314] Pharmaceutical base addition salts can also be used to produce pharmaceutical salt forms of compounds or derivatives. The chemical base that can be used as a reagent to prepare pharmaceutical base salts of this compound, which are inherently acidic, is a chemical base that forms a non-toxic base salt with such compounds. Such non-toxic base salts include, but are not limited to, base salts derived from pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, zinc, and magnesium), ammonium or water-soluble amine addition salts (e.g., N-methylglucosamine-(glucosamine)), and lower alkanol ammonium salts of pharmaceutical organic amines, and other base salts.

[0315] The compositions described herein may be administered in single or separate unit doses via oral, parenteral, or topical routes in some embodiments. The range of administration of the compounds can range from continuous (intravenous infusion) to several times daily oral administration (e.g., QID) and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include penetration enhancers), oral, sublingual, and suppository administration, via inhalation spray, rectal, vaginal, or via implantable cartridges, and other routes of administration. Enteric-coated oral tablets may also be used to improve the bioavailability of compounds administered orally. The most effective dosage form will depend on the pharmacokinetics of the selected particular agent and the severity of the patient's disease. The compounds according to this disclosure may also be used as sprays, nebulizers, or aerosols for intranasal, intratracheal, or pulmonary administration. Therefore, this disclosure also relates to pharmaceutical compositions comprising an effective amount of the compounds according to this disclosure, optionally in combination with a pharmaceutical carrier, additive, or excipient. The compounds according to this disclosure may be administered in an immediate-release, intermediate-release, sustained-release, or controlled-release form. Oral administration of sustained-release or controlled-release forms is preferred, but suppositories and transdermal or other localized forms are also possible. Intramuscular injection of liposomes can also be used to control or maintain the release of the compound at the injection site.

[0316] Therefore, in one respect, pharmaceutical formulations of VHL ligands as described herein can be prepared for parenteral administration together with a pharmaceutical parenteral carrier and in a unit-dose injectable form. As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrasheathic, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously. VHL ligands of desired purity are optionally mixed with one or more pharmaceutical excipients (Remington's Pharmaceutical Sciences (1980), 16th edition, Osol, A. ed.) in the form of a lyophilized formulation or an aqueous solution for reconstitution.

[0317] The compositions disclosed herein can be formulated using one or more pharmaceutical carriers in a conventional manner and can also be administered in a controlled-release formulation. The compounds disclosed herein can be formulated as pharmaceutical compositions according to standard pharmaceutical practice. In this respect, a pharmaceutical composition is provided comprising a VHL ligand as described herein, conjugated to one or more pharmaceutical excipients.

[0318] Typical formulations are prepared by mixing the compounds of this disclosure with excipients such as carriers and / or diluents. Suitable carriers, diluents, and other excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. The specific carrier, diluent, or other excipient used will depend on the manner and purpose of applying the compound. Other pharmaceutical carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, partially glycerolized mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polypropylene block polymers, polyethylene glycol, and lanolin.

[0319] Solvents are typically selected based on those generally recognized by those skilled in the art as safe for use in mammals (GRAS). Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), and mixtures thereof. Acceptable diluents, carriers, excipients, and stabilizers are non-toxic to the receptor at the dosage and concentration used, including buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethyl diammonium chloride; benzalkonium chloride; benzyl chloride; phenol, butanol, or benzyl alcohol; alkyl esters of parabens, such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; m-cresol); low molecular weight (less than about 10). (1 residue) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., zinc protein complexes); and / or nonionic surfactants, such as TWEEN. TM PLURONICS TM Or polyethylene glycol (PEG).

[0320] The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, and other known additives to provide an aesthetically pleasing display of the VHL ligand or to aid in the manufacture of the pharmaceutical product. The formulation can be prepared using conventional dissolution and mixing procedures.

[0321] Formulations can be made by mixing the compound with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the receptor at the dose and concentration used) at ambient temperature, appropriate pH, and desired purity. The pH of the formulation depends primarily on the specific application and concentration of the compound, but can be in the range of about 3 to about 8. Formulations in an acetate buffer at pH 5 are suitable examples.

[0322] Pharmaceutical compositions may be in the form of sterile injectable formulations, such as sterile injectable aqueous or oily suspensions. In particular, formulations intended for in vivo administration must be sterile. Such sterilization is readily achieved through filtration using sterile filter membranes. The suspension can be formulated using suitable dispersants or wetting agents and suspending agents already mentioned above, according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents (such as 1,3-butanediol). Sterile injectable formulations may also be prepared as lyophilized powders. Acceptable media and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixed oils are traditionally used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used in the preparation of injectables, as well as natural medicinal oils such as olive oil or castor oil, especially their polyoxyethylene forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[0323] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents and solutes, thereby making the preparation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners.

[0324] The pharmaceutical compositions described herein can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of oral tablets, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are often added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavoring agents, or coloring agents may also be added.

[0325] Alternatively, the pharmaceutical compositions described herein can be administered in the form of rectal suppositories. These suppositories can be prepared by mixing the pharmaceutical agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thus melting in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0326] The pharmaceutical compositions described herein can also be applied topically. Suitable topical formulations can be readily prepared for each of these areas or organs. Topical application to the lower intestine can be made in rectal suppository formulations (see above) or suitable enema formulations. Topical transdermal patches can also be used.

[0327] For topical application, the pharmaceutical composition can be formulated into a suitable ointment containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. In certain preferred aspects of this disclosure, the compound can be coated onto a stent to be surgically implanted into a patient to inhibit or reduce the likelihood of occlusion within the stent.

[0328] Alternatively, the pharmaceutical composition can be formulated into a suitable lotion or cream containing an active ingredient suspended or dissolved in one or more pharmaceutical carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0329] For ophthalmic applications, the pharmaceutical composition can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, with or without the addition of preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated as an ointment such as petrolatum.

[0330] The pharmaceutical compositions disclosed herein can also be administered via nasal aerosol or inhalation. Such compounds are prepared according to techniques known in the field of pharmaceutical formulation and can be prepared as solutions in saline solutions, using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0331] VHL ligand compositions are typically stored as solid compositions, lyophilized formulations, or as aqueous solutions.

[0332] Pharmaceutical compositions containing the VHL ligands of this disclosure can be formulated, administered, and applied in accordance with good medical practice, i.e., dosage, concentration, schedule, duration, medium, and route of administration. Factors to be considered in this context include the specific disease being treated, the specific mammal being treated, the individual patient's clinical condition, the cause of the disease, the site of delivery, the method of administration, the timing of administration, and other factors known to the practicing physician. The "therapeuticly effective amount" of the compound to be administered will be constrained by such considerations and will be the minimum amount required to prevent, improve, or treat the disease. Such an amount is preferably below amounts that would be toxic to the host or significantly increase the host's susceptibility to unwanted side effects.

[0333] VHL ligands are typically formulated into pharmaceutical dosage forms to provide easily controlled drug dosing and enable patient adherence to prescription regimens. Depending on the method of administration, pharmaceutical compositions (or formulations) for administration can be packaged in various ways. Generally, articles for dispensing include containers in which the pharmaceutical formulation is deposited in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, etc. Containers may also include intervention protection components to prevent accidental contact with the packaged contents. Additionally, the container is labeled with a description of its contents. Appropriate warnings may also be included on the label.

[0334] Formulations can be packaged in single-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile injectable liquid carrier, such as water, before use. Temporary injectable solutions and suspensions are prepared from sterile powders, granules, and tablets of the aforementioned types. Preferred single-dose formulations are those containing the active ingredient at the daily dose or a unit daily sub-dose, or an appropriate fraction thereof, as described above herein.

[0335] It should also be understood that the specific dosage and treatment regimen for any particular patient depends on a variety of factors, including the activity of the specific compound being used, age, weight, general health condition, sex, diet, timing of administration, excretion rate, combination of drugs, the judgment of the treating physician, and the severity of the specific disease or condition being treated.

[0336] Patients or subjects requiring therapy with compounds according to this disclosure may be treated by administering to the patient (subject) an effective amount of a compound according to this disclosure, said compound comprising a pharmaceutical salt, solvate or polymorph thereof, optionally in a pharmaceutical carrier or diluent, alone or in combination with other known erythropoiesis stimulants, as otherwise identified herein.

[0337] The active compound is contained in a pharmaceutical carrier or diluent in an amount sufficient to deliver a therapeutically effective dose to the patient for the indication without causing serious toxicity. For the conditions mentioned herein, the preferred dose of the active compound is in the range of about 10 ng / kg to 300 mg / kg, preferably 0.1 to 100 mg / kg daily, and more typically about 0.5 to 25 mg / kg per kilogram of body weight per day for the recipient / patient. Depending on the above factors, a typical daily dose range can be from about 1 μg / kg to 100 mg / kg or more. In a suitable carrier, the general local dose range is 0.01-5% wt / wt.

[0338] The compound can be conveniently administered in any suitable unit dosage form, including but not limited to dosage forms containing less than 1 mg, 1 mg to 3000 mg, and preferably 5 to 500 mg of active ingredient per unit dosage form. Oral doses of about 25-250 mg are generally convenient.

[0339] The active ingredient is preferably administered to achieve a peak plasma concentration of about 0.00001-30 mM, preferably about 0.1-30 mM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in a saline or aqueous medium, or as a granule containing the active ingredient. Oral administration is also suitable for achieving an effective plasma concentration of the active ingredient.

[0340] The concentration of the active compound in a pharmaceutical composition will depend on the rates of absorption, distribution, inactivation, and excretion of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage values ​​will also vary depending on the severity of the condition to be relieved. It should be further understood that, for any given subject, the specific dosage regimen should be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges listed herein are merely illustrative and not intended to limit the scope or practice of the claimed compositions. The active ingredient may be administered once or divided into many smaller doses administered at different time intervals.

[0341] In one embodiment, the active compound is prepared together with a carrier that protects the compound from rapid elimination from the body, such as a controlled-release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art.

[0342] Liposome suspensions can also be pharmaceutical carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (the entire contents of which are incorporated herein by reference). For example, a liposome formulation can be prepared by dissolving one or more suitable lipids (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachidonicylphosphatidylcholine, and cholesterol) in an inorganic solvent and then evaporating it, leaving a thin film of dried lipids on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The container is then rotated by hand to release the lipid material from the side of the container and disperse the lipid aggregates, thereby forming a liposome suspension.

[0343] The term "medicinal salt" as used throughout this specification describes, where applicable, a salt form of one or more of the compounds described herein, which is present to increase the solubility of the compound in the gastric juices of a patient's gastrointestinal tract to promote the dissolution and bioavailability of the compound. Pharmaceutical salts include salts derived from pharmaceutical inorganic bases or organic bases and acids (where applicable). Suitable salts include salts derived from alkali metals (such as potassium and sodium), alkaline earth metals (such as calcium and magnesium), and ammonium salts, as well as many other acids and bases well known in the pharmaceutical industry. Sodium and potassium salts are particularly preferred as neutralizing salts of phosphates according to this disclosure.

[0344] The term "medicinal derivative" is used throughout the product information to describe any pharmaceutical prodrug form (such as esters, amides, or other prodrug groups) that, when administered to a patient, directly or indirectly provides the compound or its active metabolites.

[0345] The subject matter of this invention further provides veterinary compositions comprising at least one active ingredient as defined above and a veterinary carrier. The veterinary carrier is a material that can be used to administer the composition and can be a solid, liquid, or gaseous material that is inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary compositions can be administered parenterally or via any other intended route.

[0346] IV. Indications and Treatments

[0347] The VHL ligands disclosed herein are intended for use in the treatment of a variety of diseases, ailments, or conditions. Therefore, it should be understood that any compound provided herein may be used to treat diseases or conditions regulated by VHL, such as any of the diseases and conditions listed herein. It should also be understood that any compound provided herein may be used to prepare a medicament for the treatment of conditions regulated by VHL, such as any of the diseases and conditions listed herein.

[0348] The compounds disclosed herein are intended for use in therapeutics. Furthermore, the compounds disclosed herein are intended for use in treating diseases or indications associated with VHL activity, such as those described in Zhang et al., J. Med. Chem. 219, 62, 5725-5749, which is incorporated herein by reference in its entirety, and particularly with respect to the indications and diseases disclosed therein (including conditions related to anemia, ischemia, and tumors). Therefore, it should be understood that any of the compounds provided herein can be used to treat conditions regulated by VHL. In some embodiments, the VHL ligands disclosed herein can be used to treat cancers associated with VHL regulation. In some embodiments, the VHL ligands disclosed herein can be used to treat solid tumors. In some embodiments, solid tumors are breast cancer (such as triple-negative breast cancer), lung cancer, multiple myeloma, or renal cell carcinoma (RCC).

[0349] In an alternative aspect, the present invention relates to a method for enhancing erythropoiesis in a patient or subject in need, the method comprising administering to the patient or subject an effective amount of at least one compound as described above, optionally in combination with another erythropoiesis-stimulating compound. The method according to the invention can be used to increase the number of red blood cells (erythrocytes) and / or hematocrit in a patient by administering an effective amount of at least one compound described herein. Another aspect of the invention relates to treating anemia, including chronic anemia or ischemia, in a patient or subject in need, the method comprising administering to the patient in need an effective amount of at least one compound according to the invention. The method according to the invention can be used to treat anemia (including chronic anemia, such as anemia associated with chronic kidney disease, dialysis, and chemotherapy) and ischemia (including local ischemia, stroke, and cardiovascular ischemia), as well as to limit damage caused by those disease states and / or conditions.

[0350] Another aspect of the invention relates to enhancing wound healing and reducing scar tissue formation during wound healing by administering one or more compounds according to the invention to a patient in need. A further method includes inducing local angiogenesis in a patient or subject in need by administering an effective amount of at least one compound of the invention, optionally in combination with another erythropoiesis-stimulating compound. Another aspect of the invention represents methods for stimulating erythropoiesis in a subject or patient, including increasing the number of red blood cells (erythrocytes) and / or hematocrit in the patient, treating anemia (including chronic anemia and anemia associated with chronic kidney disease, dialysis, and cancer chemotherapy), ischemia, stroke, and damage to cardiovascular tissues during cardiovascular ischemia, and enhancing the wound healing process and preventing / reducing scarring associated with or secondary to the healing process.

[0351] Other methods of the invention involve locally enhancing angiogenesis in a patient or subject by inducing VEGF using at least one compound according to the invention, optionally in combination with erythropoiesis-stimulating compounds further described herein. Another method of the invention involves reducing and / or inhibiting occlusion in stents surgically implanted in a patient or subject.

[0352] The compounds described herein can be administered to patients to treat a variety of diseases, disorders, or conditions. In some embodiments, administration of the compounds described herein provides stimulation of erythropoiesis in a patient or subject, including inducing EPO production in the patient or subject. In other embodiments, administration of the compounds described herein is provided for treating chronic anemia and ischemia (which limits local anemia, brain injury during ischemia and / or stroke, and damage to cardiovascular tissues during cardiovascular ischemia), and enhancing wound healing processes. Further therapeutic aspects of the invention represent methods of stimulating erythropoiesis in a subject or patient, including increasing the number of red blood cells (erythrocytes) and / or hematocrit in the patient, treating anemia (including chronic anemia and anemia associated with chronic kidney disease, dialysis, and cancer chemotherapy), ischemia, stroke, and damage to cardiovascular tissues during cardiovascular local ischemia, and enhancing wound healing processes and preventing / reducing scarring or scarring secondary to healing. Other aspects of the invention also relate to locally enhancing angiogenesis by inducing VEGF, including wound healing and reducing stent occlusion.

[0353] This document also provides the use of the compounds described herein in the manufacture of medicaments for the treatment of a variety of diseases, disorders, and conditions. In one embodiment, this document provides the use of the compounds described herein in the manufacture of a medicament for the treatment of anemia. In some embodiments, the anemia is chronic anemia or anemia associated with chronic kidney disease, dialysis, or cancer chemotherapy, or any combination thereof. In other embodiments, this document provides the use of the compounds described herein in the manufacture of a medicament for the treatment of ischemia, stroke, or damage to the cardiovascular system during ischemia, or any combination thereof. In some embodiments, this document provides the use of the compounds described herein in the manufacture of medicaments for enhancing wound healing in persons with this need. In other embodiments, this document provides the use of the compounds described herein in the manufacture of medicaments for reducing scarring secondary to wound healing in persons with this need. In some embodiments, this document provides the use of the compounds described herein in the manufacture of medicaments for enhancing angiogenesis or arteriovenous formation, or both, in persons with this need. In some embodiments, the enhancement of angiogenesis or arteriovenous formation, or both, occurs locally in the person. In some embodiments, this document provides the use of the compounds described herein in the manufacture of medicaments for reducing the likelihood of stent occlusion in persons with this need.

[0354] This document also provides compounds for treating anemia, as described elsewhere herein. In some embodiments, the anemia is chronic anemia or anemia associated with chronic kidney disease, dialysis, or cancer chemotherapy, or any combination thereof. In other embodiments, this document provides compounds, as described elsewhere herein, for treating ischemia, stroke, or damage to the cardiovascular system during ischemia, or any combination thereof. In some embodiments, this document provides compounds, as described elsewhere herein, for enhancing wound healing in persons with this need. In other embodiments, this document provides compounds, as described elsewhere herein, for reducing scarring secondary to wound healing in persons with this need. In some embodiments, this document provides compounds, as described elsewhere herein, for enhancing angiogenesis or arteriovenous formation, or both, in persons with this need. In some embodiments, the enhancement of angiogenesis or arteriovenous formation, or both, occurs locally in the person. In some embodiments, this document provides compounds, as described elsewhere herein, for reducing the likelihood of stent occlusion in persons with this need.

[0355] The terms "co-administration" or "combination therapy" should mean the simultaneous administration of at least two compounds or compositions to a patient such that an effective amount or concentration of each of the two or more compounds is found in the patient at a given time point. While compounds according to the invention can be co-administered to a patient simultaneously, the term includes the administration of two or more agents at the same or different times, provided that an effective concentration of all co-administered compounds or compositions is found in the subject at a given time. In certain preferred aspects of the invention, one or more of the above-described compounds are co-administered in combination with at least one additional bioactive agent having erythropoietic stimulating activity as further described herein to enhance erythropoiesis, treat chronic anemia and ischemia (limiting local anemia, ischemia, and / or brain injury during stroke, and damage to cardiovascular tissues during cardiovascular ischemia), enhance wound healing processes and stimulate angiogenesis, and inhibit or prevent occlusion of surgically implanted stents. In a particularly preferred aspect of the invention, the co-administration of the compounds results in synergistic erythropoietic activity and / or therapy.

[0356] The term “another erythropoietin stimulant” should refer to conventional peptides such as EPO (Procrit or Epogen) or dapoxetine α (the synthetic form of erythropoietin).

[0357] The compositions of the present invention can be formulated in a conventional manner using one or more pharmaceutical carriers and can also be administered in controlled-release formulations. Pharmaceutical carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, partially glycerolized mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polypropylene block polymers, polyethylene glycol, and lanolin.

[0358] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally, or via an implantable cartridge. As used herein, the term "parenterical" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrasheath, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0359] The sterile injectable form of the compositions of the present invention can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable formulation can also be a sterile injectable solution or suspension in a non-toxic, parenteral-acceptable diluent or solvent, for example, a solution of 1,3-butanediol.

[0360] Acceptable media and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are traditionally used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glycerol derivatives, can be used to prepare injectable formulations, as well as natural medicinal oils, such as olive oil or castor oil, especially their polyoxyethylene forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[0361] The pharmaceutical compositions of the present invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of oral tablets, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavoring agents, or coloring agents may also be added.

[0362] Alternatively, the pharmaceutical compositions of the present invention can be administered in the form of rectal suppositories. These suppositories can be prepared by mixing the pharmaceutical agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0363] The pharmaceutical compositions of the present invention can also be applied topically. Suitable topical formulations can be readily prepared for each of these regions or organs. Topical application to the lower intestine can be made in rectal suppository formulations (see above) or suitable enema formulations. Topical transdermal patches can also be used. For topical application, the pharmaceutical compositions can be formulated as suitable ointments containing active ingredients suspended or dissolved in one or more carriers. Carriers for the topical application of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. In some preferred aspects of this aspect, the compounds can be coated onto stents to be surgically implanted into a patient to inhibit or reduce the likelihood of occlusion within the patient's stent.

[0364] Alternatively, the pharmaceutical composition can be formulated as a suitable lotion or cream containing an active ingredient suspended or dissolved in one or more pharmaceutical carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water. For ophthalmic applications, the pharmaceutical composition can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, with or without the addition of preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated as an ointment such as petrolatum.

[0365] The pharmaceutical compositions of the present invention can also be administered via nasal aerosol or inhalation. Such compounds are prepared according to techniques known in the field of pharmaceutical formulation and can be prepared as solutions in saline solutions, using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0366] The amount of compounds in the pharmaceutical compositions of the present invention, which can be combined with carrier materials to produce a single dosage form, will vary depending on the host and disease being treated and the specific method of administration. Preferably, the composition is formulated to contain an active ingredient, alone or in combination with at least one other compound according to the present invention or an erythropoiesis stimulant (EPO, dapoxetine α), in order to particularly enhance erythropoiesis, treat chronic anemia and ischemia (limiting brain injury during local anemia, ischemia and / or stroke and damage to cardiovascular tissues during cardiovascular ischemia), enhance wound healing processes, and stimulate angiogenesis and inhibit or prevent occlusion in surgically implanted stents.

[0367] It should also be understood that the specific dosage and treatment regimen for any particular patient depends on a variety of factors, including the activity of the specific compound being used, age, weight, general health condition, sex, diet, timing of administration, excretion rate, combination of drugs, the judgment of the treating physician, and the severity of the specific disease or condition being treated.

[0368] Patients or subjects requiring therapy with compounds according to the invention may be treated by administering to the patient (subject) an effective amount of a compound according to the invention, said compound comprising its pharmaceutical salts, solvates, or polymorphs, optionally in a pharmaceutical carrier or diluent, alone or in combination with other known erythropoiesis stimulants, as otherwise identified herein. These compounds may be administered via any suitable route, such as oral, parenteral, intravenous, intradermal, subcutaneous, or topical (including transdermal), in liquid, cream, gel, or solid form, or by aerosol. The active compound is included in a pharmaceutical carrier or diluent in an amount sufficient to deliver to the patient a therapeutically effective amount required for the indication without causing serious toxicity to the treated patient. For all conditions mentioned herein, the preferred dose of the active compound is in the range of about 10 ng / kg to 300 mg / kg, preferably 0.1 to 100 mg / kg daily, and more generally about 0.5 to 25 mg / kg per kilogram of body weight per day to the recipient / patient. In a suitable carrier, the general topical dose range is 0.01-5% wt / wt. The compound can be conveniently administered in any suitable unit dosage form, including but not limited to dosage forms containing less than 1 mg, 1 mg to 3000 mg, and preferably 5 to 500 mg of active ingredient per unit dosage form. Oral doses of about 25-250 mg are generally convenient.

[0369] Preferred administration of the active ingredient aims to achieve a peak plasma concentration of about 0.00001-30 mM, preferably about 0.1-30 μM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in a saline or aqueous medium, or as a granule containing the active ingredient. Oral administration is also suitable for achieving an effective plasma concentration of the active ingredient.

[0370] The concentration of the active compound in a pharmaceutical composition will depend on the rates of absorption, distribution, inactivation, and excretion of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage values ​​will also vary depending on the severity of the condition to be relieved. It should be further understood that, for any given subject, the specific dosage regimen should be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges listed herein are merely illustrative and not intended to limit the scope or practice of the claimed compositions.

[0371] The active ingredient can be administered once or divided into many smaller doses administered at different time intervals. Oral compositions typically include an inert diluent or an edible carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic purposes, the active compound or its prodrug derivative may be combined with excipients and used in tablet, lozenge, or capsule form. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; dispersants, such as alginate, Primogel, or corn starch; lubricants, such as magnesium stearate or sterotes; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit is in capsule form, it may also contain a liquid carrier such as fatty oil, in addition to the materials of the types described above. In addition, the dosage unit form can contain various other materials that alter the physical form of the dosage unit, such as sugar coating, shellac, or enteric solvent.

[0372] The active compound or its pharmaceutical salt can be administered as a component of elixirs, suspensions, syrups, wafers, chewing gums, etc. In addition to the active compound, syrups may also contain sucrose as a sweetener and certain preservatives, dyes and colorants, and flavorings. The active compound or its pharmaceutical salt can also be mixed with other active materials that do not impair the desired effect, or with materials that complement the desired effect, such as erythropoietin stimulants, including EPO and dapoxetine α. In some preferred aspects of the invention, one or more compounds according to the invention are administered co-administered with another bioactive agent, such as an erythropoietin stimulant or wound healing agent, including antibiotics, as otherwise described herein.

[0373] Solutions or suspensions intended for parenteral, intradermal, subcutaneous, or topical application may include the following components: sterile diluents, such as water for injection, saline solution, fixative oil, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antimicrobial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetate, citrate, or phosphate; and agents for tonication, such as sodium chloride or glucose. Parenteral formulations may be packaged in glass or plastic ampoules, disposable syringes, or multi-dose vials. If administered intravenously, physiological saline or phosphate-buffered saline (PBS) is a preferred carrier. In one embodiment, the active compound is prepared with a carrier that protects the compound from rapid elimination from the body, such as a controlled-release formulation, including implants and microencapsulated delivery systems. Biodegradable biocompatible polymers, such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, may be used. The methods for preparing such formulations are obvious to those skilled in the art.

[0374] Liposome suspensions can also be pharmaceutical carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (the entire contents of which are incorporated herein by reference). For example, a liposome formulation can be prepared by dissolving one or more suitable lipids (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachidonicylphosphatidylcholine, and cholesterol) in an inorganic solvent and then evaporating it, leaving a thin film of dried lipids on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The container is then rotated by hand to release the lipid material from the side of the container and disperse the lipid aggregates, thereby forming a liposome suspension.

[0375] V. Products

[0376] On the other hand, this document describes a product (e.g., a "kit") containing materials for treating the aforementioned diseases and conditions. The kit includes a container containing VHL ligands. The kit may further include a label or instruction leaflet on or associated with the container. The term "packaging insert" is used to refer to instructions typically included in the commercial packaging of a therapeutic product, containing information regarding indications, usage, dosage, administration, contraindications, and / or warnings related to the use of such therapeutic products.

[0377] Suitable containers include, for example, bottles, vials, syringes, blister packs, etc. A “vial” is a container suitable for containing liquid or lyophilized formulations. In one embodiment, a vial is a disposable vial, such as a 20cc disposable vial with a stopper. Containers can be formed from various materials such as glass or plastic. Containers can contain VHL ligands or formulations thereof that are effective in treating the condition and can have a sterile inlet (e.g., the container can be an intravenous solution bag or a vial with a stopper that can be punctured by a hypodermic needle).

[0378] At least one active agent in the composition is an anti-VHL ligand of this disclosure. The label or packaging insert indicates that the compound is intended to treat a selected condition, such as cancer. Additionally, the label or packaging instructions may indicate that the patient to be treated is a patient suffering from a condition such as hyperproliferative disorders, atherosclerosis, neurodegeneration, cardiomegaly, pain, migraine, or neurotraumatic disorders or events. In one embodiment, the label or packaging instructions indicate that the composition containing the VHL ligand is intended to treat a condition caused by abnormal cell growth. The label or packaging instructions may also indicate that the composition is intended to treat other conditions. Alternatively or additionally, the article may further include a second container containing a pharmaceutical buffer, such as antibacterial water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and glucose solution. Other materials required from a commercial and user perspective may be further included, including other buffers, diluents, filters, needles, and syringes.

[0379] The kit may further include instructions for administering the VHL ligand and a second pharmaceutical preparation (if present). For example, if the kit includes a first composition containing a VHL ligand and a second pharmaceutical preparation, the kit may further include instructions for administering the first pharmaceutical composition and the second pharmaceutical composition simultaneously, sequentially, or separately to a patient in need.

[0380] In another embodiment, the kit is suitable for delivering VHL ligands in solid oral forms, such as tablets or capsules. Such kits preferably comprise a plurality of unit doses. Such kits may include cards with doses oriented in sequence according to their intended use. An example of such kits is blister packaging. Blister packaging is well known in the packaging industry and is widely used for packaging unit dosage forms of pharmaceuticals. If desired, memory aids may be provided, for example, in the form of numbers, letters, or other markings, or by calendar inserts indicating dates on which the dose can be administered in a specified treatment schedule.

[0381] According to one embodiment, the kit may comprise (a) a first container containing a VHL ligand; and optionally (b) a second container containing a second pharmaceutical preparation, wherein the second pharmaceutical preparation comprises a second compound having anti-excessive proliferation activity. Alternatively or additionally, the kit may further comprise a third container containing a pharmaceutical buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and glucose solution. Other materials required from a commercial and user perspective may be further included, including additional buffers, diluents, filters, needles, and syringes.

[0382] In some other embodiments, the kit comprises a VHL ligand and a second therapeutic agent. The kit may include containers (such as separate bottles or separate foil packs) for containing individual compositions; however, individual compositions may also be contained in a single, non-separate container. Typically, the kit includes instructions for administering the individual components. The kit format is particularly advantageous when the individual components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dose intervals, or when the prescribing physician wishes to titrate a combination of various components.

[0383] VI. Examples

[0384] The following examples are provided for illustrative purposes only and not for limitation. Some of the compounds used in the following examples are tautomers. Although the illustrations of the compounds provided below depict only one tautomer, these illustrations should not be considered limiting, but rather, the corresponding tautomers are included in the following examples as if each tautomer of the compound were described separately.

[0385] abbreviation

[0386] The following abbreviations are used in the examples:

[0387] ABPR - Automatic Back Pressure Regulator

[0388] Ac2O-acetic anhydride

[0389] ACN-acetonitrile

[0390] Boc-tert-butyloxycarbonyl

[0391] CDCl3-deuterated chloroform

[0392] Cy3PHBF4-Tricyclohexylphosphine tetrafluoroborate

[0393] DBU-1,8-diazabicyclo[5.4.0]undec-7-ene

[0394] DCE-1,2-Dichloroethane

[0395] DCM-dichloromethane

[0396] DEA-diethanolamine

[0397] DIPEA or DIEA-N,N-diisopropylethylamine

[0398] DME-dimethoxyethane

[0399] DMF-Dimethylformamide

[0400] DMEM-Dulbecco Modified Eagle Medium

[0401] DMSO-dimethyl sulfoxide

[0402] DTT-Dithiothreitol

[0403] EDCI-N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

[0404] EDTA-ethylenediaminetetraacetic acid

[0405] ESI - Electrospray Ionization

[0406] Et3N-Triethylamine

[0407] EtOAc - Ethyl acetate

[0408] EtOH - Ethanol

[0409] FA-formic acid

[0410] Fmoc-fluorenylmethoxycarbonyl

[0411] HATU-1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide

[0412] HEPES-4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid

[0413] Hexane

[0414] HOAc-acetic acid

[0415] HOBt or HOBT-hydroxybenzotriazole

[0416] HPLC-High Performance Liquid Chromatography

[0417] KOAc-potassium acetate

[0418] LC / MS or LCMS-Liquid Chromatography-Mass Spectrometry

[0419] LDA-DiisopropylaminoLithium

[0420] LiHMDS-bis(trimethylsilyl)aminolithium

[0421] MeI-methyliodine

[0422] MeOH - methanol (or methyl alcohol)

[0423] MeONa or NaOMe-sodium methoxide

[0424] MSD - Quality Selection Detector

[0425] MeSO2Na-sodium methanesulfonate

[0426] MTBE (methyl tert-butyl ether)

[0427] NBS-N-bromosuccinimide n-BuLi-n-butyllithium(n-Bu)3SnCl-tributyltin chloride

[0428] NIS-N-iodosuccinimide

[0429] NMP-N-methyl-2-pyrrolidone

[0430] NMR - Nuclear Magnetic Resonance

[0431] PBS-phosphate buffered saline

[0432] Pd / C-Carbon-supported Palladium

[0433] Pd(dppf)Cl2.CH2Cl2-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethanePd(PPh3)4-palladium-tetra(triphenylphosphine)

[0434] PEG-polyethylene glycol

[0435] Ph3P-triphenylphosphine

[0436] PPTS-pyridine p-toluenesulfonate

[0437] SFC-Supercritical Fluid Chromatography

[0438] TAMRA-Carboxytetramethylrhodamine

[0439] TBAF-Tetrabutylammonium Fluoride

[0440] TBS-tert-butyldimethylsilyl

[0441] TBSCl-tert-butyldimethylchlorosilane tBuOK-potassium tert-butoxide

[0442] TCEP-Tris(2-Carboxyethyl)phosphine

[0443] TEA-Triethylamine

[0444] TFA-trifluoroacetic acid

[0445] THF-Tetrahydrofuran

[0446] TMSCN-Trimethylcyanosylsilane

[0447] TMSI-Trimethyliodosilane

[0448] TMSOTf-trimethylsilane trifluoromethanesulfonate

[0449] TsCl-4-Toluenesulfonyl chloride

[0450] TsOH-Toluenesulfonic acid

[0451] UV - ultraviolet rays

[0452] LC / MS method

[0453] Method A: The experiment was performed on a SHIMADZU 2020 HPLC coupled with a SHIMADZU MSD mass spectrometer system. This system used ESI as the ion source, a Shim-Pack XR-ODS C18 50x 3.0 mm 2.2 μm column, and a flow rate of 1.2 mL / min. Solvent A was water containing 0.05% TFA, and solvent B was acetonitrile containing 0.05% TFA. The gradient consisted of: 20%–80% solvent B for 3.6 min, 80%–100% solvent B for 0.4 min, and a hold at 100% B for 0.5 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0454] Method B: The experiment was performed on a SHIMADZU 2020 HPLC coupled with a SHIMADZU MSD mass spectrometer system. This system used ESI as the ion source, a Shim-pack XR-ODS C18 50x 3.0 mm column, and a flow rate of 1.2 mL / min. A gradient solvent system was used, starting with 95% 0.05% TFA aqueous solution (solvent A) and 5% 0.05% TFA in acetonitrile solution (solvent B), increasing to 100% solvent B over 1.1 min. The final solvent system was maintained for another 0.6 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0455] Method C: The experiment was performed on a SHIMADZU 2020 HPLC coupled with a SHIMADZU MSD mass spectrometer system. This system used ESI as the ion source, an Ascentis Express C1850 x 2.1 mm column, and a flow rate of 1.0 mL / min. A gradient solvent system was used, starting with 95% 0.05% TFA aqueous solution (solvent A) and 5% 0.05% TFA in acetonitrile solution (solvent B), increasing to 100% solvent B over 1.1 min. The final solvent system was maintained for 0.5 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0456] Method D: The experiment was performed on a SHIMADZU 2020 HPLC coupled with a SHIMADZU MSD mass spectrometer system. This system used ESI as the ion source, a Shim-pack XR-ODS 50 x 3.0 mm column, and a flow rate of 1.2 mL / min. A solvent gradient was used, starting with 95% 0.05% TFA aqueous solution (solvent A) and 5% 0.05% TFA in acetonitrile solution (solvent B), increasing to 95% solvent B over 2.0 min. The final solvent system was maintained for 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0457] Method E: Experiments were performed on a SHIMADZU 2020 HPLC coupled with a SHIMADZU MSD mass spectrometer system. This system used ESI as the ion source, a CORTECS C18 50x3.1 mm column, and a flow rate of 1.0 mL / min. A gradient solvent system was used, starting with 95% 0.05% TFA aqueous solution (solvent A) and 5% 0.05% TFA in acetonitrile solution (solvent B), increasing to 100% solvent B over 1.1 min. The final solvent system was maintained for 0.5 min. The LC column temperature was 45 °C. UV absorbance was collected from 190 nm to 400 nm.

[0458] Method F: Experiments were performed on a Shimadzu 2020 HPLC coupled with a Shimadzu MSD mass spectrometer system using ESI as the ion source, a Poroshell HPH-C18 50x3.0 mm column, and a flow rate of 1.2 mL / min. Solvent A was water containing 0.05% NH4HCO3, and solvent B was acetonitrile. The gradient consisted of: 10%–50% solvent B for 3.5 min, then 50%–95% solvent B for 0.5 min, and held at 95% B for 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0459] Method G: Experiments were performed on a SHIMADZU 2020 HPLC coupled with a SHIMADZU MSD mass spectrometer system. This system used ESI as the ion source, an XSELECT CSH C18 50x 3.0 mm column, and a flow rate of 1.5 mL / min. A gradient solvent system was used, starting with 90% 0.1% FA aqueous solution (solvent A) and 10% 0.1% FA in acetonitrile solution (solvent B), increasing to 100% solvent B over 1.1 min. The final solvent system was maintained for another 0.6 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0460] Method H: Experiments were performed on a SHIMADZU 2020 HPLC coupled with a SHIMADZU MSD mass spectrometer system. This system used ESI as the ion source, an Accucore C18 50x2.1 mm column, and a flow rate of 1.0 mL / min. A gradient solvent system was used, starting with 90% 0.1% FA aqueous solution (solvent A) and 10% 0.1% FA in acetonitrile solution (solvent B), increasing to 95% solvent B over 2 minutes. The final solvent system was maintained for 0.7 minutes. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0461] Method I: Experiments were performed on a Shimadzu LCMS-2020 coupled with a SHIMADZU MSD mass spectrometer system using ESI as the ion source. LC separation was performed using a CAPCELL CORE C18 50 x 2.1 mm column at a flow rate of 1 mL / min. Solvent A was water containing 0.05% TFA, and solvent B was acetonitrile containing 0.05% TFA. The gradient consisted of 5%–95% solvent B over 2.0 min, followed by a hold of 95% B for 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0462] Method J: Experiments were performed on a Shimadzu LCMS-2020 coupled with a SHIMADZU MSD mass spectrometer system using ESI as the ion source. LC separation was performed using a Shim-pack XR-ODS, 50 x 3.0 mm column at a flow rate of 1.2 mL / min. Solvent A was water containing 0.05% TFA, and solvent B was acetonitrile containing 0.05% TFA. The gradient consisted of: 5%–70% solvent B for 3.7 min, then 70%–95% solvent B for 0.2 min, and a hold of 95% B for 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0463] Method K: Experiments were performed on a Shimadzu LCMS-2020. LC separation was performed using an Ascentis Express C18, 100 x 4.6 mm column at a flow rate of 1.2 mL / min. Solvent A was water containing 0.05% TFA, and solvent B was methanol. The gradient consisted of 30%–95% solvent B over 10 min, followed by a hold of 95% B for 2 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0464] Method L: Experiments were performed on a Shimadzu LCMS-2020 coupled with a SHIMADZU MSD mass spectrometer system using ESI as the ion source. LC separation was performed using a Kinetex EVO C18 50x2.1 mm column at a flow rate of 1.0 mL / min. Solvent A was water containing 0.05% NH4HCO3, and solvent B was acetonitrile. The gradient consisted of 10%–95% solvent B over 1.1 min, followed by a hold of 95% B for 0.5 min. The LC column temperature was 35 °C. UV absorbance was collected from 190 nm to 400 nm.

[0465] Method M: The experiment was performed on an HPLC-MS system using ESI as the ion source. An MK RP18e 25 x 2 mm column was used for LC separation at a flow rate of 1.5 mL / min. Solvent A was 4 L of water containing 1.5 mL TFA, and solvent B was 4 L of acetonitrile containing 0.75 mL TFA. The gradient consisted of 5%–95% solvent B over 0.7 min, followed by a hold of 95% B over 0.4 min. The LC column temperature was 50 °C. UV absorbance was collected from 220 nm to 254 nm.

[0466] Method N: The experiment was performed on an HPLC-MS system using ESI as the ion source. An MK RP18e 25 x 2 mm column was used for LC separation at a flow rate of 1.5 mL / min. Solvent A was 4 L of water containing 1.5 mL TFA, and solvent B was 4 L of acetonitrile containing 0.75 mL TFA. The gradient consisted of 10%–80% solvent B over 7 min, followed by a hold of 95% B for 0.4 min. The LC column temperature was 50 °C. UV absorbance was collected from 220 nm to 254 nm.

[0467] Method O: The experiment was performed on an HPLC-MS system using ESI as the ion source. An MK RP18e 25 x 2 mm column was used for LC separation at a flow rate of 1.5 mL / min. Solvent A was 4 L of water containing 1.5 mL TFA, and solvent B was 4 L of acetonitrile containing 0.75 mL TFA. The gradient consisted of 0%–60% solvent B over 7 min, followed by a hold of 95% B for 0.4 min. The LC column temperature was 50 °C. UV absorbance was collected from 220 nm to 254 nm.

[0468] Method P: Experiments were performed on a SHIMADZU 2020 HPLC coupled with a SHIMADZU MSD mass spectrometer system. This system used ESI as the ion source and a Shim-Pack XR-ODS C18 50x 3.0 mm 2.2 μm column at a flow rate of 1.2 mL / min. Solvent A was water containing 0.05% TFA, and solvent B was acetonitrile containing 0.05% TFA. The gradient consisted of 5%–95% solvent B over 2.0 min, followed by a hold of 95% B for 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0469] Method Q: Experiments were performed on a SHIMADZU 2020 HPLC coupled with a SHIMADZU MSD mass spectrometer system. This system used ESI as the ion source, a Shim-Pack XR-ODS C18 50x 3.0 mm 2.2 μm column, and a flow rate of 1.2 mL / min. Solvent A was water containing 0.05% TFA, and solvent B was acetonitrile containing 0.05% TFA. The gradient consisted of: 5%–60% solvent B for 3.2 min, 60%–100% solvent B for 0.5 min, and a hold of 100% B for 0.8 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0470] Method R: Experiments were performed on a SHIMADZU 2020 HPLC coupled with a SHIMADZU MSD mass spectrometer system. The system used ESI as the ion source and a Shim-Pack XR-ODS C18 50x 3.0 mm 2.2 μm column at a flow rate of 1.2 mL / min. Solvent A was water containing 0.05% TFA, and solvent B was acetonitrile containing 0.05% TFA. The gradient consisted of: 20%–60% solvent B for 3.6 min, 60%–100% solvent B for 0.4 min, and a hold of 100% B for 0.5 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0471] Method S: Experiments were performed on a Shimadzu LCMS-2020. LC separation was performed using an Ascentis Express C18 100x4.6 mm column at a flow rate of 1.5 mL / min. Solvent A was water containing 0.05% TFA, and solvent B was ACN / 0.05% TFA. The gradient consisted of: 5% B held for 0.8 min, 5%–40% solvent B for 7.2 min, 40%–95% solvent B for 2.0 min, and a hold of 95% B for 2.0 min. The LC column temperature was 60 °C. UV absorbance was collected from 190 nm to 400 nm.

[0472] Method T: Experiments were performed on a Shimadzu LCMS-2020. LC separation was performed using an Ascentis Express C18, 100x4.6 mm column at a flow rate of 1.5 mL / min. Solvent A was water with 0.05% TFA, and solvent B was ACN / 0.05% TFA. The gradient consisted of: 10%–60% solvent B for 10 min, then 60%–95% solvent B for 1.0 min, and held at 95% B for 2.0 min. The LC column temperature was 60 °C. UV absorbance was collected from 190 nm to 400 nm.

[0473] Method U: Experiments were performed on a Shimadzu LCMS-2020. LC separation was performed using an Ascentis Express C18, 100x4.6 mm column at a flow rate of 1.0 mL / min. Solvent A was water with 0.05% TFA, and solvent B was ACN / 0.05% TFA. The gradient consisted of: 10%–60% solvent B for 10 min, then 60%–95% solvent B for 2.0 min, and held at 95% B for 2.0 min. The LC column temperature was 60 °C. UV absorbance was collected from 190 nm to 400 nm.

[0474] Method V: Experiments were performed on a Shimadzu LCMS-2020. LC separation was performed using an Ascentis Express C18, 100x4.6 mm column at a flow rate of 1.0 mL / min. Solvent A was water containing 0.05% TFA, and solvent B was ACN / 0.05% TFA. The gradient consisted of 5%–95% solvent B for 8 min, followed by a hold of 95% B for 2.0 min. The LC column temperature was 60 °C. UV absorbance was collected from 190 nm to 400 nm.

[0475] Method W: Experiments were performed on a Shimadzu 2020 HPLC coupled with a Shimadzu MSD mass spectrometer system. This system used ESI as the ion source, a Poroshell HPH-C18 50x3.0 mm column, and a flow rate of 1.2 mL / min. Solvent A was water containing 0.05% NH4HCO3, and solvent B was acetonitrile. The gradient consisted of 10%–95% solvent B over 2.0 min, followed by a hold of 95% B for 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0476] Method X: Experiments were performed on a Shimadzu 2020 HPLC coupled with a Shimadzu MSD mass spectrometer system. This system used ESI as the ion source, a Poroshell HPH-C18 50x3.0 mm column, and a flow rate of 1.2 mL / min. Solvent A was water containing 0.05% NH4HCO3, and solvent B was acetonitrile. The gradient consisted of: 10%–70% solvent B for 3.5 min, then 70%–95% solvent B for 0.5 min, and held at 95% B for 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0477] Method Y: Experiments were performed on a Shimadzu 2020 HPLC coupled with a Shimadzu MSD mass spectrometer system. This system used ESI as the ion source, a Poroshell HPH-C18 50x3.0 mm column, and a flow rate of 1.2 mL / min. Solvent A was water containing 0.05% NH4HCO3, and solvent B was acetonitrile. The gradient consisted of: 30%–70% solvent B for 4.0 min, then 70%–95% solvent B for 0.5 min, and held at 95% B for 0.3 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0478] Method Z: Experiments were performed on a Shimadzu 2020 HPLC coupled with a Shimadzu MSD mass spectrometer system. This system used ESI as the ion source, a Poroshell HPH-C18 50x3.0 mm column, and a flow rate of 1.2 mL / min. Solvent A was water containing 0.05% NH4HCO3, and solvent B was acetonitrile. The gradient consisted of 30%–95% solvent B over 4.0 min, followed by a hold of 95% B for 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0479] Method AA: Experiments were performed on a SHIMADZU 2020 HPLC coupled with a SHIMADZU MSD mass spectrometer system. This system used ESI as the ion source, an Accucore C18 50x2.1 mm column, and a flow rate of 1.0 mL / min. Solvent A was water with 0.1% FA, and solvent B was acetonitrile with 0.1% FA. The gradient consisted of 10%–95% solvent B over 3.0 min, followed by a hold of 95% B for 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0480] Method BB: Experiments were performed on a SHIMADZU 2020 HPLC coupled with a SHIMADZU MSD mass spectrometer system. This system used ESI as the ion source, an Accucore C18 50x2.1 mm column, and a flow rate of 1.0 mL / min. Solvent A was water with 0.1% FA, and solvent B was acetonitrile with 0.1% FA. The gradient consisted of: 10%–50% solvent B for 3.5 min, 50%–95% solvent B for 0.5 min, and a hold of 95% B for 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0481] Methods (CC): Experiments were performed on a Shimadzu LCMS-2020 coupled with a SHIMADZU MSD mass spectrometer system using ESI as the ion source. LC separation was performed using a Shim-pack XR-ODS, 50 x 3.0 mm column at a flow rate of 1.2 mL / min. Solvent A was water containing 0.05% TFA, and solvent B was acetonitrile containing 0.05% TFA. The gradient consisted of: 5%–50% solvent B for 3.5 min, then 50%–100% solvent B for 0.2 min, and a hold of 100% B for 1.0 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0482] Methods: Experiments were performed on a Shimadzu LCMS-2020 coupled with a SHIMADZU MSD mass spectrometer system using ESI as the ion source. LC separation was performed using a Shim-pack XR-ODS, 50 x 3.0 mm column at a flow rate of 1.2 mL / min. Solvent A was water containing 0.05% TFA, and solvent B was acetonitrile containing 0.05% TFA. The gradient consisted of 5%–95% solvent B over 2.0 min, followed by a hold of 95% B for 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0483] Methods: Experiments were performed on a SHIMADZU 2020 HPLC coupled with a SHIMADZU MSD mass spectrometer system. The system used ESI as the ion source, an Ascentis Express C18 50 x 2.1 mm column, and a flow rate of 1.2 mL / min. Solvent A was water containing 0.05% TFA, and solvent B was MeOH. The gradient consisted of 30%–85% solvent B over 10 min, followed by a hold of 80% B for 3.2 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0484] Methods: The experiments were performed using a mass spectrometer on an MK RP18e 25-2 mm column with ESI as the ion source. Solvent A was 1.5 mL / 4 L of TFA aqueous solution, and solvent B was 0.75 mL / 4 L of TFA in acetonitrile. The gradient consisted of 5%–95% solvent B over 0.7 min, followed by 95% at a flow rate of 1.5 mL / min for 0.4 min. The LC column temperature was 50 °C. UV absorbance was collected at 220 nm and 254 nm.

[0485] Methods: The experiments were performed using a mass spectrometer on an Ultimate C18 2.1*30mm, 3μm column, with ESI as the ion source. Solvent A was 1.5 mL / 4 L of TFA aqueous solution, and solvent B was 0.75 mL / 4 L of TFA in acetonitrile. The gradient consisted of 10%–80% solvent B over 6 min, followed by 80% at a flow rate of 0.8 mL / min for 0.5 min. The LC column temperature was 50 °C. UV absorbance was collected at 220 nm and 254 nm.

[0486] SFC method

[0487] Method 1: Column: Chiralpak AD-3 150x4.6 mm ID, 3µm; Mobile phase: A: CO2; B: Ethanol (0.05% DEA); Gradient: 5% to 40% B over 5 min, 40% to 5% B over 0.5 min, hold at 5% B for 1.5 min; Flow rate: 2.5 mL / min; Column temperature: 35 °C; ABPR: 1500 psi.

[0488] Method 2: Column: Chiralcel OD-3 100×4.6mm ID, 3um; Mobile phase: A: CO2; B: Ethanol (0.05% DEA); Gradient: from 5% to 40% B in 4.5 min, hold at 40% for 2.5 min, then hold at 5% B for 1 min; Flow rate: 2.8 mL / min; Column temperature: 40℃.

[0489] Method 3: Column: Chiralcel OJ-3 100×4.6mm ID, 3um; Mobile phase: A: CO2; B: Methanol (0.05% DEA); Gradient: from 5% to 40% B in 4.5 min, hold at 40% for 0.5 min, then hold at 5% B for 1 min; Flow rate: 2.8 mL / min; Column temperature: 40℃.

[0490] Method 4: Column: ChiralCel OJ-H 150×4.6mm ID, 5um; Mobile phase: A: CO2; B: Ethanol (0.05% DEA); Gradient: from 5% to 40% B over 5.5 min, then 5% B for 1.5 min; Flow rate: 2.5 mL / min; Column temperature: 40℃.

[0491] Method 5: Column: Chiralcel OJ-H 150*4.6mm ID, 5um; Mobile phase: A: CO2; B: Ethanol (0.05% DEA); Gradient: Hold 5% B for 0.5 min, then from 5% to 40% B over 3.5 min, then hold 40% B for 2.5 min, then hold 5% B for 1.5 min; Flow rate: 3 mL / min; Column temperature: 40℃.

[0492] Method 6: Column: Chiralpak AD-3 150×4.6mm ID, 3um; Mobile phase: A: CO2; B: Isopropanol (0.05% DEA); Gradient: from 5% to 40% B over 5 minutes, hold at 40% for 2.5 minutes, then 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; ABPR: 1500 psi.

[0493] Method 7: Column: Chiralcel OJ-3 100×4.6mm ID, 3um; Mobile phase: A: CO2; B: Ethanol (0.05% DEA); Gradient: from 5% to 40% B in 4.5 min, hold at 40% for 2.5 min, then hold at 5% B for 1 min; Flow rate: 2.8 mL / min; Column temperature: 40℃.

[0494] The following general protocols are used for the preparation of the disclosed compounds, intermediates, and pharmaceutical salts thereof. The disclosed compounds and intermediates can be prepared using standard organic synthesis techniques and from commercially available starting materials and reagents. It should be understood that the synthetic processes used to prepare the disclosed compounds and intermediates will depend on the specific substituents present in the compound or intermediate and may require various standard protecting, deprotecting, and transforming steps in organic synthesis, but may not be described in the following general protocols. It should also be understood that any of the steps shown in any of the following general protocols can be used in any chemically feasible combination and sequence to obtain the desired intermediate or disclosed compound. Note that in the following general protocols, the various parts are as defined elsewhere herein. In the following general protocols and examples, Indicates the solid support material—for example, RinkAmide resin.

[0495] Option 1

[0496]

[0497] Option 2

[0498] Option 3

[0499] Option 4

[0500]

[0501] Option 5

[0502]

[0503] Option 6

[0504]

[0505] Option 7

[0506]

[0507] The following examples are provided by way of illustration and not limitation only. Some of the compounds used in the following examples may exist as tautomers. Although the illustrations of the compounds provided below depict only one tautomer, these illustrations should not be considered limiting; rather, the corresponding tautomers are included in the following examples as if each tautomer of the compound were described separately.

[0508] Example S1: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxypyrrolidine-2-carboxamide (compound 1)

[0509] The synthesis was carried out according to the solid-state synthesis scheme given below:

[0510]

[0511] Rink Amide resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL of N,N-dimethylformamide was added, and the resin was allowed to swell under nitrogen for 30 min. The resin was then removed under vacuum. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel, and the mixture was reacted under nitrogen for 15 min to deprotect the Fmoc groups. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane, and then removed under vacuum. This washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propionic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was added, and the mixture was then aspirated into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. A mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was added, and the mixture was then aspirated into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. A mixture of (S)-2-azido-3-methylbutyric acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) was added to 10 mL of N,N-dimethylformamide, and the mixture was then drawn into a synthesis vessel and reacted under nitrogen for 2 hours.The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then evacuated under vacuum. This washing procedure was repeated three times. Tetra(acetonitrile)copper(I)hexafluorophosphate (0.2 equivalents) was added directly to the peptide synthesis vessel for a resin-on-resin "click" reaction. A mixture of ethynylcyclopropane (5.0 equivalents), N,N-diisopropylethylamine (10.0 equivalents), and acetylenol in 10 mL of N,N-dimethylformamide (purged with nitrogen) was added to the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then evacuated under vacuum. A lysis solution was prepared by mixing 5% triisopropylsilane with 95% trifluoroacetic acid. The solution was aspirated into the reaction vessel and reacted for 1 hour. The trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20°C) to precipitate the compound. The precipitate was collected and separated by reversed-phase HPLC (30%-60% acetonitrile). The desired product was freeze-dried and characterized by LC-MS. ESI-MS: m / z [M+H]. + Calculated value: 545.3, Measured value: 545.3.

[0512] 1 H NMR (400MHz, DMSO-d6) δ8.47(d,J=8.8Hz,1H),7.83(s,1H),7.70-7.59(m,2H),7.56(dd,J=8.3,2.1Hz,2H),7.50-7.40(m,2H),7.39-7.30(m,1H) ,7.33-7.25(m,3H),7.25-7.19(m,1H),5.15(dd,J=10.3,7.7Hz,1H),4.4 5(ddd,J=10.6,8.8,4.0Hz,1H),4.39-4.27(m,1H),4.23(dp,J=4.3,2.0H z,1H),3.70(td,J=9.9,8.9,4.2Hz,1H),3.23-3.07(m,1H),2.75(dd,J= 13.9,10.5Hz,1H),2.42-2.28(m,1H),1.94(tt,J=8.4,5.0Hz,1H),1.87- 1.76(m,1H),1.54(ddd,J=13.1,8.8,4.5Hz,1H),0.98(dd,J=14.1,6.6Hz ,3H),0.93-0.75(m,2H),0.77-0.64(m,2H),0.62(dd,J=6.6,3.2Hz,3H).

[0513] Example S2: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)propionyl)-4-hydroxypyrrolidine-2-carboxamide (compound 2)

[0514] The synthesis was carried out according to the solid-state synthesis scheme given below:

[0515]

[0516] Rink Amide resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL of N,N-dimethylformamide was added, and the resin was allowed to swell under nitrogen for 30 min. The resin was then removed under vacuum. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel, and the mixture was reacted under nitrogen for 15 min to deprotect the Fmoc groups. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane, and then removed under vacuum. This washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propionic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was added, and the mixture was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. The washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was drawn into the reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. Repeat the washing procedure three times. Add a mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide and aspirate the mixture into a synthesis vessel and react under nitrogen for 2 hours. Wash the resin with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and remove under vacuum. Repeat the washing procedure three times. Aspirate 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine into a reaction vessel and react under nitrogen for 15 minutes to deprotect the Fmoc group. Remove the solvent under vacuum and repeat the deprotection process. Wash the resin with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and remove under vacuum. The washing procedure was repeated 3 times. A mixture of (((9H-fluorene-9-yl)methoxy)carbonyl)-L-alanine (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours.The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then discharged under vacuum. This washing procedure was repeated three times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was drawn into the reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was discharged under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then discharged under vacuum. This washing procedure was repeated three times. 1H-imidazolium-1-sulfonyl azide hydrochloride (3.0 equivalents) and N,N-diisopropylethylamine (6.0 equivalents) were mixed in dichloromethane. The mixture was drawn into the reaction vessel and reacted under nitrogen for 1 hr to convert the amine to the azide. The solvent was discharged under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then discharged under vacuum. This washing procedure was repeated three times. Tetra(acetonitrile)copper(I)hexafluorophosphate (0.2 equivalents) was added directly to the peptide synthesis vessel for a resin-on-resin "click" reaction. A mixture of ethynylcyclopropane (5.0 equivalents), N,N-diisopropylethylamine (10.0 equivalents), and acetylenylcyclopropane in 10 mL of N,N-dimethylformamide (purged with nitrogen) was aspirated into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. A lysis solution was prepared by mixing 5% triisopropylsilane with 95% trifluoroacetic acid. The solution was aspirated into the reaction vessel and reacted for 1 hour. The trifluoroacetic acid was evacuated under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20°C) to precipitate the compound. The precipitate was collected and separated by reversed-phase HPLC (30%-60% acetonitrile). The desired product was lyophilized and characterized by LC-MS. ESI-MS: m / z [M+H]. + Calculated value: 517.3, Measured value: 517.3.

[0517] 1H NMR(400MHz,MeOH-d4)δ8.69(d,J=8.7Hz,1H),7.75(s,1H),7.66-7.51(m,4H),7.46-7.37(m,2H),7.37 -7.27(m,3H),5.67(q,J=7.1Hz,1H),4.74-4.61(m,1H),4.46-4.40(m,1H),4.39(dd,J=6.1,3.9Hz,1H), 3.76(dd,J=10.9,4.1Hz,1H),3.68-3.60(m,1H),3.49-3.40(m,2H),2.83(dd,J=14.2,11.0Hz,1H),1.94 (tt,J=8.6,5.2Hz,2H),1.78-1.69(m,1H),1.67(d,J=7.1Hz,3H),0.99-0.88(m,2H),0.82-0.71(m,2H).

[0518] Example S3: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide (compound 3)

[0519] The synthesis was carried out according to the solid-state synthesis scheme given below:

[0520]

[0521] Rink Amide resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL of N,N-dimethylformamide was added, and the resin was allowed to swell under nitrogen for 30 min. The resin was then removed under vacuum. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel, and the mixture was reacted under nitrogen for 15 min to deprotect the Fmoc groups. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane, and then removed under vacuum. This washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propionic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was added, and the mixture was then aspirated into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. The washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. Repeat the washing procedure three times. A mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into the synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. Repeat the washing procedure three times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was drawn into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. Repeat the washing procedure three times. A mixture of (S)-2-azido-3,3-dimethylbutyric acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then evacuated under vacuum. The washing procedure was repeated three times.Tetra(acetonitrile)copper(I)hexafluorophosphate (0.2 equivalents) was added directly to the peptide synthesis vessel for a resin-on-resin "click" reaction. A mixture of ethynylcyclopropane (5.0 equivalents), N,N-diisopropylethylamine (10.0 equivalents), and 10 mL of N,N-dimethylformamide (purged with nitrogen) was aspirated into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. A lysis solution was prepared by mixing 5% triisopropylsilane with 95% trifluoroacetic acid. The solution was aspirated into the reaction vessel and reacted for 1 hour. The trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20°C) to precipitate the compound. The precipitate was collected and separated by reversed-phase HPLC (30%-60% acetonitrile). The desired product was lyophilized and characterized by LC-MS. ESI-MS: m / z [M+H]. + Calculated value: 559.3, Measured value: 559.3.

[0522] 1 H NMR(400MHz,MeOH-d4)δ8.78(d,J=8.8Hz,1H),7.97-7.88(m,1H),7.63-7.47(m,4H),7.45- 7.38(m,2H),7.38-7.22(m,3H),5.40(s,1H),4.72-4.61(m,1H),4.52-4.34(m,2H),3.81(d d,J=11.0,3.8Hz,1H),3.72-3.65(m,1H),3.51-3.38(m,1H),2.84(dd,J=14.3,11.2Hz,1H) ,2.01-1.86(m,2H),1.80-1.68(m,1H),1.02(s,9H),0.99-0.92(m,2H),0.81-0.71(m,2H). Example S4: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-((S)-2-cyclobutyl-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxypyrrolidine-2-carboxamide (compound 4)

[0523] The synthesis was carried out according to the solid-state synthesis scheme given below:

[0524]

[0525] Rink Amide resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL of N,N-dimethylformamide was added, and the resin was allowed to swell under nitrogen for 30 min. The resin was then removed under vacuum. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel, and the mixture was reacted under nitrogen for 15 min to deprotect the Fmoc groups. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane, and then removed under vacuum. This washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propionic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was drawn into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. A mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was drawn into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. A mixture of (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-2-cyclobutylacetic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was then washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum.Repeat the washing procedure three times. Add 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine to the reaction vessel and react under nitrogen for 15 min to deprotect the Fmoc group. Remove the solvent under vacuum and repeat the deprotection process. Wash the resin with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and remove under vacuum. Repeat the washing procedure three times. Mix 1H-imidazolium-1-sulfonyl azide hydrochloride (3.0 equivalents) and N,N-diisopropylethylamine (6.0 equivalents) in dichloromethane. Add the mixture to the reaction vessel and react under nitrogen for 1 hr to convert the amine to the azide. Remove the solvent under vacuum and repeat the deprotection process. Wash the resin with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and remove under vacuum. Repeat the washing procedure three times. Tetra(acetonitrile)copper(I)hexafluorophosphate (0.2 equivalents) was added directly to the peptide synthesis vessel for a resin-on-resin "click" reaction. A mixture of ethynylcyclopropane (5.0 equivalents), N,N-diisopropylethylamine (10.0 equivalents), and 10 mL of N,N-dimethylformamide (purged with nitrogen) was aspirated into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. A lysis solution was prepared by mixing 5% triisopropylsilane with 95% trifluoroacetic acid. The solution was aspirated into the reaction vessel and reacted for 1 hour. The trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20°C) to precipitate the compound. The precipitate was collected and separated by reversed-phase HPLC (30%-60% acetonitrile). The desired product was lyophilized and characterized by LC-MS. ESI-MS: m / z [M+H]. + Calculated value: 557.3, Measured value: 557.3.

[0526] 1H NMR (400MHz, MeOH-d4) δ8.68 (d, J = 8.7Hz, 1H), 7.74 (s, 1H), 7.61-7.51 (m, 4H), 7.45-7.37 (m, 2H), 7.35-7. 26(m,3H),5.52(d,J=10.0Hz,1H),4.70-4.59(m,1H),4.44-4.33(m,2H),3.83(dd,J=11.0,4.0Hz,1H),3.6 6(dt,J=11.1,1.7Hz,1H),3.43(dd,J=14.3,4.0Hz,2H),3.10(s,1H),2.97-2.79(m,1H),2.10(s,1H),1.98 -1.84(m,6H),1.83-1.76(m,1H),1.72(ddd,J=13.4,9.1,4.4Hz,1H),1.01-0.88(m,2H),0.81-0.70(m,2H).

[0527] Example S5: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-((2S,3S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylpentanoyl)-4-hydroxypyrrolidine-2-carboxamide (compound 5)

[0528] The synthesis was carried out according to the solid-state synthesis scheme given below:

[0529]

[0530] Rink Amide resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL of N,N-dimethylformamide was added, and the resin was allowed to swell under nitrogen for 30 min. The resin was then removed under vacuum. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel, and the mixture was reacted under nitrogen for 15 min to deprotect the Fmoc groups. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane, and then removed under vacuum. This washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propionic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was drawn into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. A mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was drawn into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. A mixture of (((9H-fluorene-9-yl)methoxy)carbonyl)-L-isoleucine (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then evacuated under vacuum. The washing procedure was repeated three times.10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was removed under vacuum and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then removed under vacuum. The washing procedure was repeated 3 times. 1H-imidazolium-1-sulfonyl azide hydrochloride (3.0 equivalents) and N,N-diisopropylethylamine (6.0 equivalents) were mixed in dichloromethane. The mixture was aspirated into the reaction vessel and reacted under nitrogen for 1 hr to convert the amine to the azide. The solvent was removed under vacuum and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then removed under vacuum. The washing procedure was repeated 3 times. Tetra(acetonitrile)copper(I)hexafluorophosphate (0.2 equivalents) was added directly to the peptide synthesis vessel to initiate a "click" reaction on the resin. A mixture of ethynylcyclopropane (5.0 equivalents) and N,N-diisopropylethylamine (10.0 equivalents) in 10 mL of N,N-dimethylformamide (purged with nitrogen) was drawn into a reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. A pyrolysis solution was prepared by mixing 5% triisopropylsilane with 95% trifluoroacetic acid. The solution was drawn into a reaction vessel and reacted for 1 hour. The trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20 °C) to precipitate the compound. The precipitate was collected and separated by reversed-phase HPLC (30%-60% acetonitrile). The desired product was lyophilized and characterized by LC-MS. ESI-MS: m / z [M+H]. + Calculated value: 559.3, Measured value: 559.3.

[0531] 1H NMR(400MHz,MeOH-d4)δ8.80-8.60(m,1H),7.79(s,1H),7.62-7.49(m,4H),7.45-7.36(m,2H),7.36-7.25(m,3H) ,5.23(d,J=10.6Hz,1H),4.70-4.61(m,1H),4.42-4.34(m,2H),3.83(dd,J=11.0,3.9Hz,1H),3.79-3.71(m,1H), 3.44(dd,J=14.3,4.0Hz,1H),2.84(dd,J=14.3,11.1Hz,1H),2.36-2.20(m,1H),2.00-1.86(m,2H),1.73(ddd,J= 13.4, 9.5, 4.3Hz, 1H), 1.02 (dd, J = 6.7, 3.5Hz, 4H), 0.98-0.92 (m, 3H), 0.81 (t, J = 7.3Hz, 3H), 0.78-0.71 (m, 2H).

[0532] Example S6: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylpentanoyl)-4-hydroxypyrrolidine-2-carboxamide (compound 6)

[0533] The synthesis was carried out according to the solid-state synthesis scheme given below:

[0534]

[0535] Rink Amide resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL of N,N-dimethylformamide was added, and the resin was allowed to swell under nitrogen for 30 min. The resin was then removed under vacuum. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel, and the mixture was reacted under nitrogen for 15 min to deprotect the Fmoc groups. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane, and then removed under vacuum. This washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propionic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was drawn into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. A mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was drawn into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. A mixture of (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3,3-dimethylvaleric acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was then washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum.Repeat the washing procedure three times. Add 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine to the reaction vessel and react under nitrogen for 15 min to deprotect the Fmoc group. Remove the solvent under vacuum and repeat the deprotection process. Wash the resin with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and remove under vacuum. Repeat the washing procedure three times. Mix 1H-imidazolium-1-sulfonyl azide hydrochloride (3.0 equivalents) and N,N-diisopropylethylamine (6.0 equivalents) in dichloromethane. Add the mixture to the reaction vessel and react under nitrogen for 1 hr to convert the amine to the azide. Remove the solvent under vacuum and repeat the deprotection process. Wash the resin with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and remove under vacuum. Repeat the washing procedure three times. Tetra(acetonitrile)copper(I)hexafluorophosphate (0.2 equivalents) was added directly to the peptide synthesis vessel for a resin-on-resin "click" reaction. A mixture of ethynylcyclopropane (5.0 equivalents), N,N-diisopropylethylamine (10.0 equivalents), and 10 mL of N,N-dimethylformamide (purged with nitrogen) was aspirated into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. A lysis solution was prepared by mixing 5% triisopropylsilane with 95% trifluoroacetic acid. The solution was aspirated into the reaction vessel and reacted for 1 hour. The trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20°C) to precipitate the compound. The precipitate was collected and separated by reversed-phase HPLC (30%-60% acetonitrile). The desired product was lyophilized and characterized by LC-MS. ESI-MS: m / z [M+H]. + Calculated value: 573.3, Measured value: 573.3.

[0536] 1H NMR (400MHz, MeOH-d4) δ8.77(d,J=8.8Hz,1H),7.93(s,1H),7.61-7.47(m,4H),7.41(dd,J=8.5,6.8Hz,2H),7.34(s,1H ),7.33-7.24(m,2H),5.44(s,1H),4.71-4.61(m,1H),4.44-4.35(m,2H),3.80(dd,J=10.9,3.7Hz,1H),3.67(d,J=11.1 Hz,1H),3.47(dd,J=14.2,3.9Hz,1H),2.84(dd,J=14.3,11.2Hz,1H),2.01-1.85(m,2H),1.74(ddd,J=13.6,9.8,4.2Hz ,1H),1.27(q,J=7.4Hz,2H),1.05(s,3H),0.99-0.93(m,5H),0.87(t,J=7.3Hz,3H),0.76(ddt,J=7.1,4.5,1.3Hz,2H).

[0537] Example S7: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylpent-4-enoyl)-4-hydroxypyrrolidine-2-carboxamide (compound 7)

[0538] The synthesis was carried out according to the solid-state synthesis scheme given below:

[0539]

[0540] Rink Amide resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL of N,N-dimethylformamide was added, and the resin was allowed to swell under nitrogen for 30 min. The resin was then removed under vacuum. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel, and the mixture was reacted under nitrogen for 15 min to deprotect the Fmoc groups. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane, and then removed under vacuum. This washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propionic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was drawn into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. A mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was drawn into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. A mixture of (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3,3-dimethylpent-4-enoic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours.The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then discharged under vacuum. This washing procedure was repeated three times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was discharged under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then discharged under vacuum. This washing procedure was repeated three times. 1H-imidazolium-1-sulfonyl azide hydrochloride (3.0 equivalents) and N,N-diisopropylethylamine (6.0 equivalents) were mixed in dichloromethane. The mixture was aspirated into the reaction vessel and reacted under nitrogen for 1 hr to convert the amine to the azide. The solvent was discharged under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then discharged under vacuum. This washing procedure was repeated three times. Tetra(acetonitrile)copper(I)hexafluorophosphate (0.2 equivalents) was added directly to the peptide synthesis vessel for a resin-on-resin "click" reaction. A mixture of ethynylcyclopropane (5.0 equivalents), N,N-diisopropylethylamine (10.0 equivalents), and 10 mL of N,N-dimethylformamide (purged with nitrogen) was aspirated into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. A lysis solution was prepared by mixing 5% triisopropylsilane with 95% trifluoroacetic acid. The solution was aspirated into the reaction vessel and reacted for 1 hour. The trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20°C) to precipitate the compound. The precipitate was collected and separated by reversed-phase HPLC (30%-60% acetonitrile). The desired product was lyophilized and characterized by LC-MS. ESI-MS: m / z [M+H]. + Calculated value: 571.3, Measured value: 571.3.

[0541] 1H NMR(400MHz,MeOH-d4)δ8.78(d,J=8.8Hz,1H),7.87(s,1H),7.56(ddt,J=16.2,8.7,1.8Hz,4H),7.45-7.37(m,2H),7.36-7 .25(m,3H),6.14-6.01(m,1H),5.48(s,1H),5.07(dd,J=10.8,1.1Hz,1H),4.94(dd,J=17.5,1.1Hz,2H),4.72-4.62(m,1H) ,4.44-4.32(m,2H),3.81(dd,J=11.1,3.8Hz,1H),3.69(d,J=11.1Hz,1H),3.52-3.43(m,1H),2.84(dd,J=14.3,11.2Hz,1H ),1.98-1.86(m,2H),1.74(ddd,J=13.4,9.7,4.2Hz,1H),1.17(s,3H),1.04(s,3H),0.99-0.88(m,2H),0.79-0.67(m,2H).

[0542] Example S8: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-((2S)-2-(adamantane-1-yl)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxypyrrolidine-2-carboxamide (compound 8)

[0543] The synthesis was carried out according to the solid-state synthesis scheme given below:

[0544]

[0545] Rink Amide resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL of N,N-dimethylformamide was added, and the resin was allowed to swell under nitrogen for 30 min. The resin was then removed under vacuum. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel, and the mixture was reacted under nitrogen for 15 min to deprotect the Fmoc groups. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane, and then removed under vacuum. This washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propionic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was drawn into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. A mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was drawn into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. A mixture of (2S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-2-(adamantane-1-yl)acetic acid (3.0 equivalents), cyano(hydroxyimino)ethyl acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours.The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then discharged under vacuum. This washing procedure was repeated three times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was discharged under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then discharged under vacuum. This washing procedure was repeated three times. 1H-imidazolium-1-sulfonyl azide hydrochloride (3.0 equivalents) and N,N-diisopropylethylamine (6.0 equivalents) were mixed in dichloromethane. The mixture was aspirated into the reaction vessel and reacted under nitrogen for 1 hr to convert the amine to the azide. The solvent was discharged under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then discharged under vacuum. This washing procedure was repeated three times. Tetra(acetonitrile)copper(I)hexafluorophosphate (0.2 equivalents) was added directly to the peptide synthesis vessel for a resin-on-resin "click" reaction. A mixture of ethynylcyclopropane (5.0 equivalents), N,N-diisopropylethylamine (10.0 equivalents), and 10 mL of N,N-dimethylformamide (purged with nitrogen) was aspirated into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. A lysis solution was prepared by mixing 5% triisopropylsilane with 95% trifluoroacetic acid. The solution was aspirated into the reaction vessel and reacted for 1 hour. The trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20°C) to precipitate the compound. The precipitate was collected and separated by reversed-phase HPLC (30%-60% acetonitrile). The desired product was lyophilized and characterized by LC-MS. ESI-MS: m / z [M+H]. + Calculated value: 637.3, Measured value: 637.3.

[0546] 1H NMR(400MHz,MeOH-d4)δ7.97-7.87(m,1H),7.62-7.48(m,4H),7.45-7.37(m,2H),7.34(s,1H) ,7.33-7.23(m,2H),5.25(s,1H),4.75-4.63(m,1H),4.45-4.31(m,2H),3.81(dd,J=11.1,3.6H z,1H),3.74-3.60(m,1H),3.47(dd,J=14.2,4.0Hz,1H),2.85(dd,J=14.2,11.1Hz,1H),2.01- 1.87(m,5H),1.80-1.65(m,7H),1.59(t,J=14.7Hz,6H),1.01-0.90(m,2H),0.82-0.67(m,2H).

[0547] Example S9: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-((S)-3,3-dimethyl-2-(1H-1,2,3-triazol-1-yl)butyryl)-4-hydroxypyrrolidine-2-carboxamide (compound 9)

[0548] The synthesis was carried out according to the solid-state synthesis scheme given below:

[0549]

[0550] Rink Amide resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL of N,N-dimethylformamide was added, and the resin was allowed to swell under nitrogen for 30 min. The resin was then removed under vacuum. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel, and the mixture was reacted under nitrogen for 15 min to deprotect the Fmoc groups. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane, and then removed under vacuum. This washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propionic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was aspirated into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. A mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was aspirated into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. A mixture of (S)-2-azido-3,3-dimethylbutyric acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then evacuated under vacuum. The washing procedure was repeated three times.Tetra(acetonitrile)copper(I)hexafluorophosphate (0.2 equivalents) was added directly to the peptide synthesis vessel for a resin-on-resin "click" reaction. A mixture of acetylenyltrimethylsilane (5.0 equivalents) and N,N-diisopropylethylamine (10.0 equivalents) in 10 mL of N,N-dimethylformamide (purged with nitrogen) was drawn into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. A lysis solution was prepared by mixing 5% triisopropylsilane with 95% trifluoroacetic acid. The solution was drawn into the reaction vessel and reacted for 1 hour. The trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20°C) to precipitate the compound. The precipitate was collected and separated by reversed-phase HPLC (30%-60% acetonitrile). The desired product was lyophilized and characterized by LC-MS. ESI-MS: m / z [M+H]. + Calculated value: 519.3, Measured value: 519.3.

[0551] 1 H NMR (400MHz, DMSO-d6) δ8.57(d,J=8.8Hz,1H),8.22(d,J=1.1Hz,1H),7.77-7.69(m,1H),7.68-7.60(m,2H),7.60-7. 51(m,2H),7.50-7.40(m,2H),7.34(tt,J=6.6,1.3Hz,2H),7.30(dd,J=8.5,2.0Hz,3H),5.51(s,1H),4.49-4.31(m,2 H),4.24(dq,J=3.9,2.0Hz,1H),3.68(dd,J=11.1,3.8Hz,1H),3.58(d,J=11.1Hz,1H),3.22(dd,J=14.0,3.9Hz,1H), 2.76(dd,J=14.0,10.7Hz,1H), 1.83(ddt,J=12.9,7.4,1.8Hz,1H), 1.56(ddd,J=13.2,9.3,4.3Hz,1H), 0.94(s,10H).

[0552] Example S10: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-4-hydroxy-1-((S)-2-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)pyrrolidine-2-carboxamide (compound 10)

[0553] The synthesis was carried out according to the solid-state synthesis scheme given below:

[0554]

[0555] Rink Amide resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL of N,N-dimethylformamide was added, and the resin was allowed to swell under nitrogen for 30 min. The resin was then removed under vacuum. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel, and the mixture was reacted under nitrogen for 15 min to deprotect the Fmoc groups. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane, and then removed under vacuum. This washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propionic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was drawn into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. A mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was drawn into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. A mixture of (S)-2-azido-3,3-dimethylbutyric acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then evacuated under vacuum. The washing procedure was repeated three times.Copper(I) tetra(acetonitrile) hexafluorophosphate (0.2 equivalents) was added directly to the peptide synthesis vessel for a resin-on-resin "click" reaction. A mixture of 3-methoxyprop-1-yne (5.0 equivalents) and N,N-diisopropylethylamine (10.0 equivalents) in 10 mL of N,N-dimethylformamide (purged with nitrogen) was aspirated into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. A lysis solution was prepared by mixing 5% triisopropylsilane with 95% trifluoroacetic acid. The solution was aspirated into the reaction vessel and reacted for 1 hour. The trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20°C) to precipitate the compound. The precipitate was collected and separated by reversed-phase HPLC (30%-60% acetonitrile). The desired product was lyophilized and characterized by LC-MS. ESI-MS: m / z [M+H]. + Calculated value: 563.3, Measured value: 563.3.

[0556] 1 H NMR(400MHz, DMSO-d6)δ8.58(d,J=8.8Hz,1H),8.18(s,1H),7.68-7.59(m,2H),7.59-7.50(m,2H), 7.50-7.40(m,2H),7.39-7.18(m,5H),5.46(s,1H),4.52-4.38(m,3H),4.43-4.31(m,1H),4.25(dt ,J=4.4,2.3Hz,1H),3.67(dd,J=11.1,3.7Hz,1H),3.59(d,J=11.2Hz,1H),3.25(d,J=2.7Hz,4H),2 .76(dd,J=14.0,10.8Hz,1H),1.88-1.78(m,1H),1.57(ddd,J=13.3,9.4,4.3Hz,1H),0.95(s,10H).

[0557] Example S11: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-((S)-2-(4-benzyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide (compound 11)

[0558] The synthesis was carried out according to the solid-state synthesis scheme given below:

[0559]

[0560] Rink Amide resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL of N,N-dimethylformamide was added, and the resin was allowed to swell under nitrogen for 30 min. The resin was then removed under vacuum. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel, and the mixture was reacted under nitrogen for 15 min to deprotect the Fmoc groups. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane, and then removed under vacuum. This washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propionic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was drawn into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. A mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was drawn into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated three times. A mixture of (S)-2-azido-3,3-dimethylbutyric acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was drawn into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then evacuated under vacuum. The washing procedure was repeated three times.Tetra(acetonitrile)copper(I)hexafluorophosphate (0.2 equivalents) was added directly to the peptide synthesis vessel for a resin-on-resin "click" reaction. A mixture of prop-2-yn-1-ylbenzene (5.0 equivalents) and N,N-diisopropylethylamine (10.0 equivalents) in 10 mL of N,N-dimethylformamide (purged with nitrogen) was aspirated into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. A lysis solution was prepared by mixing 5% triisopropylsilane with 95% trifluoroacetic acid. The solution was aspirated into the reaction vessel and reacted for 1 hour. The trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20°C) to precipitate the compound. The precipitate was collected and separated by reversed-phase HPLC (30%-60% acetonitrile). The desired product was lyophilized and characterized by LC-MS. ESI-MS: m / z [M+H]. + Calculated value: 609.3, Measured value: 609.3.

[0561] 1 H NMR(400MHz,DMSO-d6)δ8.55(d,J=8.8Hz,1H),7.95(s,1H),7.67-7.59(m,2H),7.59-7.40(m,5H),7.39-7 .14(m,10H),5.42(s,1H),4.46-4.29(m,2H),4.23(dt,J=5.5,2.6Hz,1H),4.00(s,2H),3.98(d,J=7.2Hz, 0H),3.66(dd,J=11.0,3.8Hz,1H),3.57(d,J=11.1Hz,1H),3.21(dd,J=13.9,3.9Hz,1H),2.75(dd,J=14.0 ,10.6Hz,1H),1.92-1.76(m,1H),1.55(ddd,J=13.1,9.2,4.3Hz,1H),0.92(s,8H),0.92(d,J=7.9Hz,1H).

[0562] Example S12: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-((R)-2-(4-(1-(acetamidomethyl)cyclopropyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide (compound 12)

[0563] The synthesis was carried out according to the solid-state synthesis scheme given below:

[0564]

[0565] Rink Amide resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL of N,N-dimethylformamide was added, and the resin was allowed to swell under nitrogen for 30 min. The resin was then removed under vacuum. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel, and the mixture was reacted under nitrogen for 15 min to deprotect the Fmoc groups. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane, and then removed under vacuum. This washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propionic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was added; the mixture was then aspirated into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into a reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. A mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was added; the mixture was then aspirated into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times.A mixture of (S)-2-(4-(1-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)cyclopropyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyric acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was added; the mixture was then aspirated into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. The washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into a reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and discharged under vacuum. This washing procedure was repeated three times. A mixture of acetic anhydride (5.0 equivalents) and N,N-diisopropylethylamine (10.0 equivalents) in 10 mL of dichloromethane was added; the mixture was then aspirated into a synthesis vessel and reacted under nitrogen for 30 min. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and discharged under vacuum. A pyrolysis solution was prepared by mixing 5% triisopropylsilane with 95% trifluoroacetic acid. The solution was aspirated into a reaction vessel and reacted for 1 hour. The trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20 °C) to precipitate the compound. The precipitate was collected and separated by reversed-phase HPLC (30%–60% acetonitrile). The desired product was lyophilized and characterized by LC-MS. ESI-MS: m / z [M+H]. + Calculated value: 630.3, Measured value: 630.3.

[0566] 1H NMR(400MHz, DMSO-d6)δ8.63(d,J=8.7Hz,1H),8.00-7.88(m,1H),7.79(s,1H),7.67-7.58(m,2H),7.61-7.51( m,2H),7.49-7.16(m,8H),5.37(s,1H),5.09(s,1H),4.42(t,J=7.9Hz,1H),4.36-4.23(m,1H),4.22(dq,J=6.5 ,3.8Hz,1H),3.72-3.59(m,2H),3.27-3.17(m,2H),3.12(dd,J=14.0,4.8Hz,1H),2.85-2.71(m,1H),1.89-1.6 7(m,2H),1.75(s,3H),1.54(ddd,J=12.9,8.4,4.7Hz,1H),1.05-0.97(m,1H),0.95(s,9H),0.94-0.84(m,4H).

[0567] Example S13: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-((S)-2-(4-(1-(acetamidomethyl)cyclopropyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide (compound 13)

[0568] The synthesis was carried out according to the solid-state synthesis scheme given below:

[0569]

[0570] Rink Amide resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL of N,N-dimethylformamide was added, and the resin was allowed to swell under nitrogen for 30 min. The resin was then removed under vacuum. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel, and the mixture was reacted under nitrogen for 15 min to deprotect the Fmoc groups. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane, and then removed under vacuum. This washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propionic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was added; the mixture was then aspirated into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into a reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. A mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was added; the mixture was then aspirated into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times.A mixture of (R)-2-(4-(1-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)cyclopropyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyric acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was added; the mixture was then aspirated into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. The washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into a reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was evacuated under vacuum and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and discharged under vacuum. This washing procedure was repeated three times. A mixture of acetic anhydride (5.0 equivalents) and N,N-diisopropylethylamine (10.0 equivalents) in 10 mL of dichloromethane was added; the mixture was then aspirated into a synthesis vessel and reacted under nitrogen for 30 min. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and discharged under vacuum. A pyrolysis solution was prepared by mixing 5% triisopropylsilane with 95% trifluoroacetic acid. The solution was aspirated into a reaction vessel and reacted for 1 hour. The trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20 °C) to precipitate the compound. The precipitate was collected and separated by reversed-phase HPLC (30%–60% acetonitrile). The desired product was lyophilized and characterized by LC-MS. ESI-MS: m / z [M+H]. + Calculated value: 630.3, Measured value: 630.3.

[0571] 1H NMR (400MHz, DMSO-d6) δ8.54(d,J=8.8Hz,1H),8.00(s,1H),7.93(t,J=5.8Hz,1H),7.68-7.51(m,5H),7.45(dd,J=8.4,7 .0Hz,2H),7.40-7.23(m,4H),7.27-7.18(m,1H),5.38(s,1H),4.52-4.30(m,2H),4.23(dq,J=4.0,2.1Hz,1H),3.66(dd,J =11.0,3.8Hz,1H),3.62-3.51(m,2H),3.20(ddd,J=13.8,7.3,4.6Hz,2H),2.77(dd,J=14.0,10.6Hz,1H),1.94-1.72(m, 1H), 1.77 (s, 3H), 1.55 (ddd, J=13.3, 9.3, 4.4Hz, 1H), 1.02 (ddd, J=7.3, 5.3, 2.7Hz, 1H), 0.93 (s, 8H), 0.98-0.79 (m, 4H).

[0572] Example S14: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)-1-((S)-2-(4-((2-acetamidoethoxy)methyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carboxamide (compound 14)

[0573] The synthesis was carried out according to the solid-state synthesis scheme given below:

[0574]

[0575] Rink Amide resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL of N,N-dimethylformamide was added, and the resin was allowed to swell under nitrogen for 30 min. The resin was then removed under vacuum. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel, and the mixture was reacted under nitrogen for 15 min to deprotect the Fmoc groups. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane, and then removed under vacuum. This washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propionic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was added; the mixture was then aspirated into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into a reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. A mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was added; the mixture was then aspirated into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. A mixture of (S)-2-azido-3,3-dimethylbutyric acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) was added to 10 mL of N,N-dimethylformamide; the mixture was then drawn into a synthesis vessel and reacted under nitrogen for 2 hours.The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then evacuated under vacuum. This washing procedure was repeated three times. Tetra(acetonitrile)copper(I)hexafluorophosphate (0.2 equivalents) was added directly to the peptide synthesis vessel for a resin-on-resin "click" reaction. A mixture of N-(2-(prop-2-yn-1-yloxy)ethyl)acetamide (5.0 equivalents) and N,N-diisopropylethylamine (10.0 equivalents) in 10 mL of N,N-dimethylformamide (purged with nitrogen) was drawn into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then evacuated under vacuum. A lysis solution was prepared by mixing 5% triisopropylsilane with 95% trifluoroacetic acid. The solution was drawn into the reaction vessel and reacted for 1 hour. The trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20°C) to precipitate the compound. The precipitate was collected and separated by reversed-phase HPLC (30%-60% acetonitrile). The desired product was freeze-dried and characterized by LC-MS. ESI-MS: m / z [M+H]. + Calculated value: 634.3, Measured value: 634.3.

[0576] 1 H NMR(400MHz, DMSO-d6)δ8.56(d,J=8.8Hz,1H),8.20(s,1H),7.92(t,J=5.8Hz,1H),7.68-7.59(m,2H),7.59-7.51(m,2H),7.50-7.40(m,2H),7 .39-7.29(m,2H),7.30(dd,J=8.6,2.2Hz,3H),6.51(s,0H),5.46(s,1H),5.10(d,J=3.5Hz,1H),4.53(s,2H),4.44(ddd,J=10.8,8.8,3.9Hz,1H ),4.36(dd,J=9.3,7.4Hz,1H),4.24(s,1H),3.67(dd,J=11.1,3.7Hz,1H),3.60(d,J=11.2Hz,1H),3.52-3.36(m,2H),3.19(s,1H),3.27-3.14( m,2H),2.76(dd,J=14.0,10.7Hz,1H),1.89-1.76(m,1H),1.79(s,3H),1.56(ddd,J=13.2,9.4,4.3Hz,1H),0.95(d,J=7.6Hz,2H),0.95(s,8H).

[0577] Example S15: Synthesis of 1-((S)-1-((2S,4R)-2-(((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)-1H-1,2,3-triazol-4-carboxylic acid (compound 15)

[0578] The synthesis was carried out according to the solid-state synthesis scheme given below:

[0579]

[0580] Rink Amide resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL of N,N-dimethylformamide was added, and the resin was allowed to swell under nitrogen for 30 min. The resin was then removed under vacuum. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel, and the mixture was reacted under nitrogen for 15 min to deprotect the Fmoc groups. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane, and then removed under vacuum. This washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propionic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was added; the mixture was then aspirated into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into a reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. A mixture of (2S,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was added; the mixture was then aspirated into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. A mixture of (S)-2-azido-3,3-dimethylbutyric acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) was added to 10 mL of N,N-dimethylformamide; the mixture was then drawn into a synthesis vessel and reacted under nitrogen for 2 hours.The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then evacuated under vacuum. This washing procedure was repeated three times. Tetra(acetonitrile)copper(I)hexafluorophosphate (0.2 equivalents) was added directly to the peptide synthesis vessel for a resin-on-resin "click" reaction. A mixture of tert-butyl propynate (5.0 equivalents) and N,N-diisopropylethylamine (10.0 equivalents) in 10 mL of N,N-dimethylformamide (purged with nitrogen) was drawn into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and then evacuated under vacuum. A lysis solution was prepared by mixing 5% triisopropylsilane with 95% trifluoroacetic acid. The solution was drawn into the reaction vessel and reacted for 1 hour. The trifluoroacetic acid was removed under vacuum. The remaining residue was mixed with 50 mL of cold diethyl ether (-20°C) to precipitate the compound. The precipitate was collected and separated by reversed-phase HPLC (30%-60% acetonitrile). The desired product was freeze-dried and characterized by LC-MS. ESI-MS: m / z [M+H]. + Calculated value: 563.3, measured value: 563.2.

[0581] 1 H NMR (400MHz, DMSO-d6) δ13.19 (s, 1H), 8.66-8.58 (m, 2H), 7.68-7.49 (m, 4H), 7.45 (dd, J = 8. 5,6.9Hz,2H),7.39-7.30(m,1H),7.35-7.24(m,4H),5.59(s,1H),5.10(d,J=6.7Hz,1H),4. 48-4.33(m,2H),4.25(s,1H),3.66(d,J=3.2Hz,2H),3.23(dd,J=14.0,3.9Hz,1H),2.76(dd ,J=14.0,10.8Hz,1H),1.90-1.79(m,1H),1.57(ddd,J=13.3,9.4,4.3Hz,1H),0.96(s,9H).

[0582] Example S16: Synthesis of 1-((S)-1-((2S,4R)-2-(((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropane-2-yl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)-1H-1,2,3-triazol-4-carboxamide (compound 16)

[0583] The synthesis was carried out according to the solid-state synthesis scheme given below:

[0584]

[0585] Rink Amide resin (0.100 mmol) was added to a plastic peptide synthesis vessel. 10 mL of N,N-dimethylformamide was added, and the resin was allowed to swell under nitrogen for 30 min. The resin was then removed under vacuum. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into the reaction vessel, and the mixture was reacted under nitrogen for 15 min to deprotect the Fmoc groups. The solvent was removed under vacuum, and the deprotection process was repeated. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane, and then removed under vacuum. This washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propionic acid (3.0 equivalents), ethyl cyano(hydroxyimino)acetate (3.0 equivalents), and N,N'-diisopropylcarbodiimide (3.0 equivalents) in 10 mL of N,N-dimethylformamide was added; the mixture was then aspirated into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide followed by 10 mL of dichloromethane and evacuated under vacuum. This washing procedure was repeated 3 times. 10 mL of N,N-dimethylformamide containing 20% ​​4-methylpiperidine was aspirated into a reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was evacuated under vacuum, and the deprotection ...

Claims

1. A compound of formula (I): Or its stereoisomers or tautomers, or pharmaceutical salts of any of the foregoing, wherein: X 1 Each occurrence is independently H or C. 1-12 Alkyl or -C(O)-C 1-12 alkyl; R 1 It is C independently each time it appears. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups Where R 1 The C mentioned 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclic groups are independently and optionally surrounded by one or more C14 groups. 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution; L is either absent or C each time it appears. 1-12 Alkylene, wherein the C of L 1-12 Alkylenes are independently and optionally separated by one or more R t Replace, where R t C 1-12 Alkyl or -C(O)NH2, wherein R t The C mentioned 1-12 The alkyl group may be further optionally substituted with one or more halogens; Ring A is independently C each time it appears. 6-20 Aryl or C 7-15 cycloalkyl; R e Each time it appears, it is independently halogenated, C 6-20 aryl or 5- to 20-membered heteroaryl, provided that at least one R e C 6-20 aryl or 5- to 20-membered heteroaryl groups containing one or more sulfur atoms on a ring, wherein R e The C mentioned 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more C groups. 1-12 Alkyl or halogenated substitutions; n is independently 1, 2, 3, 4, or 5 each time it appears; and Q 1 and Q 2 Each of them is independent of the others and independently of H, halogen, cyano, and C in each occurrence. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 alkyl, Q 1 Or Q 2 The C mentioned 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q The C mentioned 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution, Or Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups, Among them, Q 1 and Q 2 The C formed 3-15 cycloalkyl, 3- to 15-membered heterocyclic groups C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more R groups. s Replace, where R s The radicals are OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, and -SO2C. 1-12 Alkyl, -SO2NH2 or C 1-12 Alkyl, wherein R s The C mentioned 1-12 The alkyl group may further be optionally substituted with one or more halogenated, cyano, or OH groups. The condition is that the compound of formula (I) or its pharmaceutical salt is not (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide or its pharmaceutical salt.

2. The compound according to claim 1, or its stereoisomers or tautomers, or a pharmaceutical salt of any of the foregoing, wherein L is independently C each time it appears. 1-6 Alkylene, wherein the C of L 1-6 Alkylenes are independently and optionally separated by one or more R t Replace, where R t C 1-6 Alkyl or -C(O)NH2, wherein R t The C mentioned 1-6 The alkyl group may be further optionally substituted with one or more halogens.

3. The compound according to claim 1, or its stereoisomers or tautomers, or a pharmaceutical salt of any of the foregoing, wherein ring A is independently C each time it appears. 6-20 Aryl.

4. The compound according to claim 1, or its stereoisomers or tautomers, or a pharmaceutical salt of any of the foregoing, wherein... n is 1, and R e Each time it appears, it is independently a 5- to 20-membered heteroaryl group, of which R e The 5- to 20-membered heteroaryl group comprises one or more sulfur atoms on the ring and is independently and optionally bounded by one or more C atoms. 1-12 Alkyl substitution.

5. The compound according to claim 4, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein R e Each time it appears, it is independently a 5-membered heteroaryl group, where R e The 5-membered heteroaryl group comprises one or more sulfur atoms on the ring and is independently and optionally bounded by one or more C atoms. 1-12 Alkyl substitution.

6. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IA): Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

7. The compound according to claim 6, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (IA) is a compound selected from the group consisting of: Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

8. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IB): Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

9. The compound according to claim 8, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (IB) is a compound selected from the group consisting of: Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

10. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IC): Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

11. The compound of claim 10, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (IC) is a compound selected from the group consisting of: Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

12. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein... n is 1, and R e It is C independently each time it appears. 6-20 Aryl, wherein R e The C mentioned 6-20 Aryl group is independently and optionally bounded by one or more C 1-12 Alkyl or halogenated substitutions.

13. The compound according to claim 9, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein R e It is independently phenyl each time it appears, where R e The phenyl group is independently and optionally subjected to one or more C 1-12 Alkyl or halogenated substitutions.

14. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (ID): Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

15. The compound according to claim 14, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (ID) is a compound selected from the group consisting of: Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

16. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IE): Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

17. The compound of claim 16, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (IE) is a compound selected from the group consisting of: Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

18. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein: L does not exist independently each time it appears, and Ring A is independently C each time it appears. 7-15 Cycloalkyl.

19. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein... n is independently 1 on each occurrence, and R e Each time it appears, it is independently a 5- to 20-membered heteroaryl group, of which R e The 5- to 20-membered heteroaryl group comprises one or more sulfur atoms on the ring and is independently and optionally bounded by one or more C atoms. 1-12 Alkyl substitution.

20. The compound according to claim 19, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein R e Each time it appears, it is independently a 5-membered heteroaryl group, where R e The 5-membered heteroaryl group comprises one or more sulfur atoms on the ring and is independently and optionally bounded by one or more C atoms. 1-12 Alkyl substitution.

21. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IF): Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

22. The compound of claim 21, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound of formula (IF) is a compound selected from the group consisting of: Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

23. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein Q 1 and Q 2 Each of them is independent of the others and independently of H, halogen, cyano, and C in each occurrence. 1-12 Alkyl, C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl, 5- to 20-membered heteroaryl, -C(O)-O(R) a ) or -C(O)-N(R b (R) c ), where R a R b and R c Each independently is H or C 1-12 Alkyl, wherein Q 1 Or Q 2 The C mentioned 1-12 Alkyl or C 3-15 The cycloalkyl group is independently and optionally surrounded by one or more R q Replace, where R q C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q The C mentioned 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution.

24. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein Q 1 C 3-15 cycloalkyl, wherein Q 1 The C mentioned 3-15 cycloalkyl groups are optionally surrounded by one or more R q Replace, where R q Independently for C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 6-20 Aryl, C 1-12 alkoxy or Where R q The C mentioned 1-12 Alkyl or C 1-12 The alkoxy group is independently and optionally further halogenated or -NHC(O)-C 1-12 Alkyl substitution.

25. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein Q 1 For unreplaced C 3-15 Cycloalkyl.

26. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein Q 1 It is an unsubstituted cyclopropyl group.

27. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein Q 2 For H.

28. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein Q 1 and Q 2 Together with the atoms they are attached to, they form C 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups, of which Q 1 and Q 2 The C formed 3-15 Cycloalkyl, 3- to 15-membered heterocyclic groups, C 6-20 Aryl or 5- to 20-membered heteroaryl groups are independently and optionally bounded by one or more R groups. s replace, Where R s The radicals are OH, cyano, halogen, oxo, -NH2, -NO2, -CHO, -C(O)OH, -C(O)NH2, -SH, and -SO2C. 1-12 Alkyl, -SO2NH2 or C 1-12 Alkyl, wherein R s The C mentioned 1-12 The alkyl group may be further optionally substituted with one or more halogens or OH groups.

29. The compound according to claim 28, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein Q 1 and Q 2 Together with the atoms they are attached to, they form C 6-20 Aryl.

30. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein R 1 It is C independently each time it appears. 1-12 Alkyl, wherein R 1 The C mentioned 1-12 Alkyl groups are independently and optionally bound by one or more Cs. 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

31. The compound according to claim 30, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein R 1 Each time it appears, it is independently either tert-butyl or isopropyl.

32. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein R 1 It is C independently each time it appears. 3-15 cycloalkyl, wherein R 1 The C mentioned 3-15 cycloalkyl groups are optionally surrounded by one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

33. The compound according to claim 32, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein R 1 It is C independently each time it appears. 3-6 cycloalkyl, wherein R 1 The C mentioned 3-6 cycloalkyl groups are optionally surrounded by one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O)2-C 1-12 Alkyl or -C(O)-C 1-12 Alkyl substitution.

34. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein R 1 The attached chiral carbon atom has an S stereochemical configuration.

35. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein X 1 It is H independently each time it appears.

36. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, wherein the compound is selected from the group consisting of: Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

37. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutical salt of any of the foregoing, wherein the compound is selected from the group consisting of: Or its stereoisomers or tautomers, or medicinal salts of any of the foregoing.

38. A pharmaceutical composition comprising a compound according to any one of claims 1 to 37, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, and one or more pharmaceutical excipients.

39. The pharmaceutical composition according to claim 38, further comprising additional bioactive agents.

40. A method for regulating VHL in cells for non-therapeutic purposes, the method comprising exposing the cells to a composition comprising: an effective amount of a compound according to any one of claims 1 to 37, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, or a composition according to claim 38 or claim 39.

41. A method for inhibiting VHL in cells, the method being used for non-therapeutic purposes, the method comprising exposing the cells to a composition comprising: an effective amount of a compound according to any one of claims 1 to 37, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, or a composition according to claim 38 or claim 39.

42. The use of the compound of any one of claims 1 to 37, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, or the composition of claim 38 or claim 39, in the preparation of a medicament for treating a disease, ailment, or condition in a person in need of it.

43. The use according to claim 42, wherein the disease, ailment or condition is anemia.

44. The use according to claim 43, wherein the anemia is chronic anemia or anemia associated with chronic kidney disease, dialysis or cancer chemotherapy, or any combination thereof.

45. The use of the compound of any one of claims 1 to 37, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, or the use of the composition of claim 38 or claim 39 in the preparation of a medicament for treating ischemia, stroke, or damage to the cardiovascular system during ischemia, or any combination thereof.

46. ​​The use of the compound according to any one of claims 1 to 37, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, or the composition according to claim 38 or claim 39 in the preparation of a medicament for enhancing wound healing in a person in need.

47. The use of the compound of any one of claims 1 to 37, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, or the composition of claim 38 or claim 39 in the preparation of a medicament for reducing secondary scarring of wound healing in persons in need of such treatment.

48. The use of the compound of any one of claims 1 to 37, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, or the use of the composition of claim 38 or claim 39 in the preparation of a medicament for enhancing angiogenesis or arterialization or both in a person who requires such enhancement.

49. The use according to claim 48, wherein the enhancement of angiogenesis or arterialization or both occurs locally in the person.

50. The use of the compound of any one of claims 1 to 37, or a stereoisomer or tautomer thereof, or a pharmaceutical salt thereof, or the composition of claim 38 or 39 in the preparation of a medicament for reducing the likelihood of stent occlusion in a person requiring such a medicament.

51. The use of the compound, stereoisomer or tautomer thereof, or pharmaceutical salt thereof, or the composition according to claim 38 or claim 39 in the preparation of a medicament for treating a proliferative disorder.

52. The use according to claim 51, wherein the hyperproliferative disorder is cancer.

Images