1-(2-(4-cyclopropyl-1h-1,2,3-triazol-1-yl)acetyl)-4-hydroxy-n-(benzyl)pyrrolidin e-2-carboxamide derivatives as VHL inhibitors for treatment of anemia and cancer

Abstract

To provide 1-(2-(4-cyclopropyl-1H-1,2,3- triazol-1-yl)acetyl)-4-hydroxy-N-(benzyl)pyrrolidine E-2-carboxamide derivatives as VHL inhibitors for the treatment of anemia and cancer.SOLUTION: 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 as VHL inhibitors for the treatment of, e.g., anemia (e.g. chronic anemia or anemia associated with chronic kidney disease, dialysis or cancer chemotherapy), ischemia, stroke or damage to the cardiovascular system during ischemia, or for enhancing wound healing, reducing scarring, or enhancing angiogenesis or arteriogenesis, and cancer.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS 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 incorporated by reference in its entirety herein.

[0002] Field of Disclosure The present disclosure relates to compounds that include 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 pharmaceutical compositions thereof for the prevention and / or treatment of various diseases, disorders and conditions. [Background technology]

[0003] Background of the disclosure E3 ubiquitin ligases (of which over 600 are known in humans) confer substrate specificity for ubiquitination. 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.

[0004] A particular E3 ubiquitin ligase is the von Hippel-Lindau (VHL) tumor suppressor, a substrate recognition subunit of the E3 ligase complex VCB (a key target in cancer, chronic anemia and ischemia), which also consists of elongins B and C, Cul2, and Rbxl. The main substrate of VHL is hypoxia-inducible factor Iα (HIF-Iα), a transcription factor that upregulates genes such as the proangiogenic growth factor VEGF and the erythroid-inducing cytokine erythropoietin in response to low oxygen levels. Although HIF-1α is constitutively expressed, its intracellular levels are kept very low under normoxic conditions by hydroxylation by prolyl hydroxylase domain (PHD) proteins and subsequent ubiquitination via VHL.

[0005] Crystal structures of VHL with ligands have been obtained, confirming that the compounds can mimic the binding mode of the transcription factor HIF-1α, which is the primary substrate of VHL. These compounds bind to VHL in competition with HIF-1α substrates, 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 across a broad range of disease indications. Summary of the Invention [Means for solving the problem]

[0006] Brief Description of Disclosure The present disclosure relates to VHL ligands, and in particular to VHL ligands that bind to VHL E3 ubiquitin ligase.

[0007] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein X 1 is independently in each occurrence H, C 1-12 Alkyl, or -C(O)-C 1-12 is alkyl; R 1 is, independently in each occurrence, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 cycloalkyl, or 3- to 15-membered heterocyclyl; R 1 C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclyl independently has one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12alkyl, or -C(O)-C 1-12 may be substituted with alkyl; L, in each occurrence, is independently absent or is C 1-12 alkylene, and the C of L 1-12 alkylene may be independently substituted with one or more R t wherein R t is C 1-12 alkyl or -C(O)NH 2 and the C of R t alkyl may be further substituted with one or more halo; 1-12 Ring A, in each occurrence, is independently C aryl or C 6-20 cycloalkyl; 7-15 ; R e , in each occurrence, is independently halo, C 6-20 aryl or 5- to 20-membered heteroaryl, and the C of R e aryl or 5- to 20-membered heteroaryl may be independently substituted with one or more C 6-20 alkyl or halo; 1-12 ; n, in each occurrence, is independently 0, 1, 2, 3, 4 or 5; Q 1 and Q 2 , independently of each other and in each occurrence, are 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 ), where R a , R b and R c are each independently H or C 1-12 alkyl, Q 1 or Q 2 and the C of 1-12 alkyl or C 3-15 cycloalkyl may be independently substituted with one or more Rq and R q is C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-20 Aryl, C 1-12 Alkoxy, or [ka] and R q C 1-12 Alkyl or C 1-12 Alkoxy is independently one or more halo or -NHC(O)-C 1-12 may be further substituted with alkyl; Or, Q 1 and Q 2 together with the atoms to which they are attached, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 aryl, or 5- to 20-membered heteroaryl; Q 1 and Q 2 Formed by C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl or 5- to 20-membered heteroaryl may independently be one or more R s and R s is OH, cyano, halogen, oxo, -NH 2 , -NO 2 , -CHO, -C(O)OH, -C(O)NH 2 , -SH, -SO 2 C 1-12 Alkyl, -SO 2 NH 2 , or C 1-12 is alkyl, R s C 1-12 Alkyl refers to a compound which may be further substituted with one or more halo, cyano, or OH, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0008] In another aspect, the present disclosure relates to pharmaceutical compositions comprising one or more compounds as described herein, or stereoisomers or tautomers thereof, or a pharma- ceutically acceptable salt of any of the foregoing, and one or more pharma- ceutically acceptable excipients.

[0009] In one aspect, the disclosure relates to a method of inhibiting VHL using one or more of the compounds described herein, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, or one or more of the pharmaceutical compositions described herein.

[0010] In a further aspect, the present disclosure relates to a method of preventing or treating a disease, disorder, or condition by administering to a subject in need of prevention or treatment one or more of the compounds described herein, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, or one or more of the pharmaceutical compositions described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Detailed Description of the Disclosure The present disclosure relates to compounds that bind to E3 ubiquitin ligase protein complexes. In particular, compounds that bind to von Hippel-Lindau (VHL), the substrate recognition subunit of the E3 ligase complex VCB, are described.

[0012] The subject matter disclosed herein will now be described more fully below. However, many modifications and other embodiments of the subject matter disclosed herein described herein will occur to those skilled in the art to which the subject matter disclosed herein pertains having the benefit of the teachings presented in the foregoing description. Therefore, the subject matter disclosed herein should not be limited to the specific embodiments disclosed, and modifications and other embodiments should be considered as intended to be included within the scope of the appended claims. That is, the subject matter described herein covers alternatives, modifications, and equivalents. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to the terms defined, the usage of terms, the techniques described, etc., this application shall control. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs, applying the terms in the context in which they are used to describe this disclosure. The terms used herein are used only to describe specific embodiments, and are not intended to limit this disclosure. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0013] I. Definition The terms "residue," "moiety," or "group" refer to a moiety that is covalently bonded or linked to another moiety.

[0014] The terms "covalently bound" or "covalently linked" refer to a chemical bond formed by the sharing of one or more electron pairs.

[0015] A "patient" or "individual" or "subject" is a mammal. Mammals include, but are not limited to, domestic animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates, e.g., monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the patient, individual, or subject is a human. In some embodiments, the patient may be a "cancer patient," i.e., a patient suffering from or at risk of suffering from one or more symptoms of cancer.

[0016] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by uncontrolled cell growth / proliferation. A "tumor" contains one or more cancer cells. Examples of cancer are provided elsewhere herein.

[0017] "Chemotherapeutic agent" or "anticancer agent" refers to a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, metoledopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylmelamine; acetogenins, especially bullatacin and bullatacinone; delta-9-tetrahydrocannabinol (dronabinol, Marinol®); beta-lapachone; lapachol; colchicine; betulinic acid; camptothecins (including synthetic analogs topotecan (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetylcamptothecin, scopolectin, 9-aminocamptothecin); bryostatin; kallistatin; CC-1065 (its adzere sine, carzelesin, and bizelesin synthetic analogs); podophyllotoxin; podophyllic acid; teniposide; cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictin; spongiostatins; chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, nitrogen mustards, such as methylamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trophosphamide, and uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; enediyne antibiotics, such as the calicheamicins, particularly calicheamicin gamma 1I and calicheamicin omega 11 (see, e.g., Nicolaou et al., Angew. Chem Intl. Ed. Engl., 33:183-186 (1994)); CDP323, an oral alpha-4 integrin inhibitor; dynemicins (including dynemicin A); esperamicin;and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, ausramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (ADRIAMYCIN®, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolidine-doxorubicin, doxorubicin HCl liposome injection (DOXIL®), liposomal doxorubicin TLC Antibiotics such as D-99 (MYOCET®), pegylated liposomal doxorubicin (including CAELYX® and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins, e.g., mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, queramycin, lodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and doxorubicin; antimetabolites such as methotrexate, gemcitabine (GEMZAR®), tegafur (UFTORAL®), capecitabine (XELODA®), epothilones, and 5-fluorouracil (5-FU); Folic acid analogues such as thotrexate, pteropterin, trimetrexate;purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmoful, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone;antiadrenergics such as aminoglutethimide, mitotane, trilostane;folic acid supplements such as floric acid;aceglatone;aldophosphamide glycosides;aminolevulinic acid;eniluracil;amsacrine;bestrabucil;bisantrene;edatraxate;defofamine;demecolcine;diazicon;erfornitine;Elliptinium acetate;Epothilone;Toglucid;Gallium nitrate;Hydroxyurea;Lentinan;Lonidynin;Maytansinoids such as maytansine and ansamitocins;Mitoguazone;Mitoxantrone;Mopidanmol;Nitrelin;Pentostatin;Phenamet;Pirarubicin;Rosoxantrone;2-Ethylhydrazide;Procarbazine;PSK® polysaccharide complex (JHS Natural Products, Eugene, OR);Razoxane;Rhizoxin;Schizofiran;Spirogermaniu ; tenuazonic acid; triazicon; 2,2',2'-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veracrine A, roridin A and anguidin); urethane; vindesine (ELDISINE®, FILDESIN®); dacarbazine; mannommustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); thiotepa; taxoids, such as paclitaxel (TAXOL®), paclitaxel albumin engineered nanoparticle formulations of cerebrospinal fluid (ABRAXANETM), and other anti-cancer drugs such as docetaxel (TAXOTERE®); chlorambucil; 6-thioguanine; mercaptopurine; methotrexate; platinum agents such as cisplatin, oxaliplatin (e.g., ELOXATIN®), and carboplatin; vinblastine (VELBAN®), vincristine (ONCOVIN®), vindesine (ELDISINE®, FILDESIN®), and other anti-cancer drugs. vincas that prevent tubulin polymerization to form microtubules, including vinorelbine (NAVELBINE®), etoposide (VP-16); ifosfamide; mitoxantrone; leucovorin; novantrone; edatrexate; daunomycin; aminopterin; ibandronate; the topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid, e.g., bexarotene (TARGRETIN®);bisphosphonates such as clodronate (e.g., BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, e.g., PKC-alpha, Raf, H-Ras and epidermal growth factor receptor (EGF-R); vaccines such as THERATOP® vaccine and gene therapy vaccines, e.g., ALLOVECTIN® vaccine, LEUVECTIN® vaccine and VAXID® vaccine; topoisomerase 1 inhibitors (e.g., LURTOTECAN®); rmRH (e.g., AB ARELIX®); BAY439006 (sorafenib; Bayer); SU-11248 (sunitinib, SUTENT®, Pfizer); perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteosome inhibitors (e.g., PS341); bortezomib (VELCADE®); CCI-779; tipifarnib (R11577); orafenib, ABT510; oblimersen sodium (GENASENSE®, antisense oligonucleotides) and other Bc l-2 inhibitors; pixantrone; EGFR inhibitors (see definition below); tyrosine kinase inhibitors; serine-threonine kinase inhibitors, e.g., rapamycin (sirolimus, RAPAMUNE®); farnesyltransferase inhibitors, such as lonfarnib (SCH6636, SARASARTM); and pharma- ceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of the above, such as CHOP, an abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone;and FOLFOX, an abbreviation for the treatment regimen of oxaliplatin in combination with 5-FU and leucovorin (DMFO).

[0018] Chemotherapeutic agents, as defined herein, include "anti-hormonal agents" or "endocrine therapeutic agents" that act to regulate, reduce, block, or inhibit the effects of hormones that may promote cancer growth.They may be hormones themselves, antiestrogens with mixed agonist / antagonist profiles, including selective estrogen receptor modulators (SERMs) such as tamoxifen (NOLVADEX®), 4-hydroxytamoxifen, toremifene (FARESTON®), idoxifene, droloxifene, raloxifene (EVISTA®), trioxyfene, ketoxifene, and SERM3; pure antiestrogens without agonist properties, such as fulvestrant (FASLODEX®), and EM800 (such agents may block estrogen receptor (ER) dimerization, inhibit DNA binding, increase ER turnover, and / or suppress ER levels); steroidal aromatase inhibitors such as formestane and exemestane (AROMASIN®). aromatase inhibitors, including nonsteroidal aromatase inhibitors such as anastrazole (ARIMIDEX®), letrozole (FEMARA®), and aminoglutethimide, as well as other aromatase inhibitors including vorozole (RIVISOR®), megestrol acetate (MEGASE®), fadrozole, and 4(5)-imidazole; luteinizing hormone releasing hormone agonists, including leuprolide (LUPRON® and ELIGARD®), goserelin, buserelin, and tripterelin; progestins such as megestrol acetate and medroxyprogesterone acetate, estrogens such as diethylstilbestrol and premarin, and fluoxymesterone, transretionic acid (transretionic acid), steroids such as ... onapristone; antiprogesterones; estrogen receptor down-modulators (ERDs); antiandrogens such as flutamide, nilutamide, and bicalutamide; and pharmaceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of the above.

[0019] As used herein, "treatment" (and grammatical variants thereof, e.g., "treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, reducing direct or indirect pathological consequences of disease, preventing metastasis, slowing the rate of disease progression, remission or mitigation of disease symptoms, and remission or improved prognosis. In some embodiments, the subject compounds and compositions described herein are used to slow the progression of disease or to slow the progression of disease. In one embodiment, treatment is performed solely for prophylaxis. In another embodiment, treatment is performed solely during the course of clinical pathology (i.e., not for prophylaxis). In another embodiment, treatment is performed both during the course of clinical pathology and for prophylaxis.

[0020] A drug that is administered "concurrently" with one or more other drugs is administered on the same treatment day as the one or more other drugs, and optionally at the same time as the one or more other drugs during the same treatment cycle. For example, in the case of a cancer therapy given every three weeks, each of the concurrently administered drugs is administered on day 1 of a three-week cycle.

[0021] The term "effective" is used to describe an amount of a compound, composition, or component that, when used within the context of the intended use, achieves a desired therapeutic or prophylactic result. The term effective encompasses other effective amount or effective concentration terms, including therapeutically effective amount, as otherwise described or used in this application. As used herein, the term "therapeutically effective amount" refers to any amount that results in the treatment of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, as compared to a corresponding subject not receiving such amount. The term also includes within its scope an amount effective to enhance normal physiological function. For use in therapy, a therapeutically effective amount of the VHL ligands of the present disclosure, as well as stereoisomers or tautomers thereof, or pharma- ceutically acceptable salts of any of the foregoing, may be administered as raw chemicals. In addition, the active ingredient may be provided as a pharmaceutical composition.

[0022] As used herein, and unless otherwise defined in the claims, the term "optionally" means that the subsequently described event(s) may or may not occur, and includes both the event(s) occurring and the event(s) not occurring.

[0023] As used herein, unless otherwise defined, the phrases "optionally substituted," "substituted," or variations thereof, refer to optional substitution, including multiple degrees of substitution with one or more substituents, e.g., 1, 2, 3, 4, or 5 substituents. This phrase should not be construed as redundant with the substitutions described and illustrated herein.

[0024] The term "pharmaceutical formulation" or "pharmaceutical composition" refers to a preparation in which the biological activity of the active ingredient contained therein is effective and which does not contain any ingredients that are unacceptably toxic to the subject to which the formulation is administered.

[0025] "Pharmaceutically acceptable excipient" refers to an ingredient in a pharmaceutical formulation other than an active ingredient that is non-toxic to a subject. Pharmaceutically acceptable excipients include, but are not limited to, buffers, carriers, stabilizers, or preservatives.

[0026] As used herein, the term "pharmaceutical acceptable salt" refers to a pharmaceutical acceptable organic or inorganic salt of a molecule. Representative salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Pharmaceutically acceptable salts may contain another molecule, such as acetate, succinate or other counter ions. Counter ions may be any organic or inorganic moiety that stabilizes the charge of the parent compound. In addition, pharmaceutically acceptable salts may have multiple charged atoms in their structure. When multiple charged atoms are part of the pharmaceutically acceptable salt, they may have multiple counter ions. Thus, pharmaceutically acceptable salts may have one or more charged atoms and / or one or more counter ions.

[0027] Other salts, which are not pharma-ceutically acceptable, may be useful in the preparation of the compounds described herein and these should be considered to form a further aspect of the subject matter. These salts, such as oxalates or trifluoroacetates, may not themselves be pharma-ceutically acceptable but may be useful in the preparation of salts that are useful as intermediates in obtaining the compounds described herein and their pharma-ceutically acceptable salts.

[0028] A "small molecule" or "small molecule compound" generally refers to an organic molecule less than about 5 kilodaltons (Kd) in size. In some embodiments, a small molecule is less than about 4Kd, 3Kd, 2Kd, or 1Kd. In some embodiments, a small molecule is less than about 800 Daltons (D), about 600D, about 500D, about 400D, about 300D, about 200D, or about 100D. In some embodiments, a small molecule is less than about 2000 g / mol, about 1500 g / mol, about 1000 g / mol, about 800 g / mol, or about 500 g / mol. In some embodiments, a small molecule is non-polymeric. A small molecule is not a protein, polypeptide, oligopeptide, peptide, polynucleotide, oligonucleotide, polysaccharide, glycoprotein, proteoglycan, or the like. A derivative of a small molecule refers to a molecule that shares the same structural core as the original small molecule, but can be prepared by a series of chemical reactions from the original small molecule.

[0029] The term "alkyl" as used herein means an alkyl group having 1 to 12 carbon atoms (C 1 -C 12 ) in which the alkyl radical may be optionally substituted independently with one or more substituents described herein. In other embodiments, the alkyl radical is a saturated linear or branched monovalent hydrocarbon radical having any length from 1 to 8 carbon atoms (C 1 -C 8 ), or 1 to 6 carbon atoms (C 1 -C 6 ), or 1 to 4 carbon atoms (C 1 -C 4 ), or 1 to 3 carbon atoms (C 1 -C 3 Examples of alkyl groups are methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, isopropyl, -CH(CH 3 )2 ), 1-Butyl (n-Bu, n-Butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-Butyl (s-Bu, s-Butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, tert-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 , 1-heptyl, 1-octyl, and the like.

[0030] The term "alkylene" as used herein refers to an alkylene group having 1 to 12 carbon atoms (C 1 ~C 12 ) in which the alkylene radicals may be optionally substituted independently with one or more substituents described herein. In another embodiment, an alkylene group is a hydrocarbon radical having 1 to 8 carbon atoms (C 1 -C 8 ), 1 to 6 carbon atoms (C 1 -C 6 ) or 1 to 4 carbon atoms (C1 -C 4 An example of an alkylene group is methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), but are not limited to these.

[0031] The term "alkenyl" refers to an alkyl group having 2 to 12 carbon atoms (C 2 ~C 12 ) a straight or branched chain monovalent hydrocarbon radical of any length, where alkenyl radicals may be optionally substituted independently with one or more substituents described herein, including radicals having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. Examples include ethylenyl or vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), but are not limited to these.

[0032] The term "alkenylene" refers to an alkenylene having 2 to 12 carbon atoms (C 2 ~C 12 ), where the alkenylene radical may be optionally substituted independently with one or more substituents described herein, including radicals having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. Examples include ethylene or vinylene (-CH=CH-), allyl (-CH 2 Examples include, but are not limited to, CH=CH-.

[0033] The term "alkynyl" refers to an alkynyl group having 2 to 12 carbon atoms (C 2 ~C12 ) in which the alkynyl radical may be optionally substituted independently with one or more substituents described herein. Examples include ethynyl (-C≡CH), propynyl (propargyl, -CH 2 C≡CH), but are not limited to these.

[0034] The term "alkynylene" refers to an alkynylene having 2 to 12 carbon atoms (C 2 ~C 12 ) a linear or branched divalent hydrocarbon radical of any length, where the alkynylene radical may be independently optionally substituted with one or more substituents described herein. Examples include ethynylene (-C≡C-), propynylene (propargylene, -CH 2 C≡C-), but are not limited to these.

[0035] The terms "carbocycle", "carbocyclyl", "carbocycle" and "cycloalkyl" refer to a monovalent non-aromatic saturated or partially unsaturated ring having 3 to 15 carbon atoms (C 3 -C 15). Such rings may be monocyclic or polycyclic, with 3 to 15 carbons in a monocyclic ring or 7 to 15 carbon atoms in a polycyclic (e.g., bicyclic) ring. Bicyclic carbocycles having 7 to 12 atoms may be arranged, for example, as bicyclo[4,5], [5,5], [5,6], or [6,6] systems, and bicyclic carbocycles having 9 or 10 atoms may be arranged as bicyclo[5,6] or [6,6] systems, or as bridged systems 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 fully saturated or partially unsaturated overall are encompassed within the definition of the terms "carbocycle," "carbocyclyl," "carbocycle," and "cycloalkyl," including cases where one or more of the fused rings within the polycyclic ring are fully unsaturated (i.e., aromatic). Spiro moieties are also included within the scope of this definition. Examples of monocyclic carbocycles 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-tetrahydronaphthyl, and the like. Carbocyclyl groups may be independently substituted with one or more substituents described herein.

[0036] The term "cycloalkylene" refers to a group of 3 to 12 carbon atoms (C 3 -C 12), or a divalent non-aromatic saturated or partially unsaturated ring having 7 to 12 carbon atoms as a bicycle. Bicyclic cycloalkylenes having 7 to 12 atoms may be arranged, for example, as bicyclo[4,5], [5,5], [5,6] or [6,6] systems, and bicyclic cycloalkylenes having 9 or 10 ring atoms may be arranged as bicyclo[5,6] or [6,6] systems, or as bridged systems 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 cycloalkylenes 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, cyclohexadienylene, cycloheptylene, cyclooctylene, cyclononylene, cyclodecylene, cycloundecylene, cyclododecylene, etc. Cycloalkylene groups are optionally independently substituted with one or more substituents described herein.

[0037] "Aryl" means an aromatic ring system having 6 to 20 carbon atoms (C 6 ~C 20 ) monovalent aromatic hydrocarbon radical. Some aryl groups are represented in the exemplary structures as "Ar". Typical aryl groups include, but are not limited to, groups derived from benzene (phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like. Aryl groups may be optionally substituted independently with one or more substituents described herein.

[0038] "Arylene" means a divalent aromatic hydrocarbon radical (C ) of 6 to 20 carbon atoms derived by the removal of two hydrogen atoms from two carbon atoms of a parent aromatic ring system. 6 -C 20). Some arylene groups are represented in the exemplary structures as "Ar". Arylene includes bicyclic radicals that include an aromatic ring fused to a saturated, partially unsaturated, or aromatic carbocyclic ring. Typical arylene groups include, but are not limited to, radicals derived from benzene (phenylene), substituted benzene, naphthalene, anthracene, biphenylene, indenylene, indanylene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like. Arylene groups may be optionally substituted with one or more substituents described herein.

[0039] The terms "heterocycle", "heterocyclyl", and "heterocyclic ring" are used interchangeably herein to refer to a saturated or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) carbocyclic radical of 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur, and the remaining ring atoms are C, and one or more ring atoms are optionally independently substituted with one or more substituents described herein. The heterocycle may be a monocyclic ring of 3 to 7 members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S) or a bicyclic ring of 7 to 10 members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), such as a bicyclo[4,5], [5,5], [5,6], or [6,6] system. Heterocycles 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. "Heterocyclyl" also includes radicals in which the heterocyclic radical is fused to a saturated, partially unsaturated ring, or an aromatic carbocyclic or heterocyclic ring. Examples of the heterocyclic ring include morpholin-4-yl, piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, azocan-1-yl, azetidin-1-yl, octahydropyrido[1,2-a]pyrazin-2-yl, [1,4]diazepan-1-yl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azopyranyl, tetra ... Examples of aryl groups include, but are not limited to, zetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolinylimidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolylquinolizinyl, and N-pyridylurea. Spiro moieties are also included within the scope of this definition. Examples of heterocyclic groups in which two ring atoms are substituted with oxo (=O) moieties are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocyclic groups herein are optionally substituted independently with one or more substituents described herein.

[0040] The term "heterocyclylene" refers to a divalent saturated or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) carbocyclic radical of 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur and the remaining ring atoms are C, and one or more ring atoms are optionally substituted independently with one or more substituents described herein. The heterocyclylene can be a monocyclic ring (2-6 carbon atoms and 1-4 heteroatoms selected from N, O, P, and S) having 3-7 ring members or a bicyclic ring (4-9 carbon atoms and 1-6 heteroatoms selected from N, O, P, and S) having 7-10 ring members, for example, a bicyclo[4,5], [5,5], [5,6], or [6,6] system. Heterocycles 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. "Heterocyclylene" also includes divalent radicals in which a heterocyclic radical is fused to a saturated, partially unsaturated ring, or an aromatic carbocyclic or heterocyclic ring. Examples of heterocyclylenes include morpholin-4-ylene, piperidin-1-ylene, piperazinylene, piperazin-4-ylene-2-one, piperazin-4-ylene-3-one, pyrrolidin-1-ylene, thiomorpholin-4-ylene, S-dioxothiomorpholin-4-ylene, azocan-1-ylene, azetidin-1-ylene, octahydropyrido[1,2-a]pyrazin-2-ylene, [1,4]diazepan-1-ylene, pyrrolidinylene, tetrahydrofuranylene, dihydrofuranylene, tetrahydrothienylene, tetrahydropyranylene, dihydropyranylene, tetrahydrothiopyranylene, piperidino, morpholino, thiomorpholino, thioxanylene, piperazinylene, homopiperazinylene, azetidin ... Examples of aryl groups include, but are not limited to, dinylene, oxetanylene, thietanylene, homopiperidinylene, oxepanylene, thiepanylene, oxazepinylene, diazepinylene, thiazepinylene, 2-pyrrolylene, 3-pyrrolylene, indolinylene, 2H-pyranylene, 4H-pyranylene, dioxanylene, 1,3-dioxolanylene, pyrazolinylene, dithianylene, dithiolanylene, dihydropyranylene, dihydrothienylene, dihydrofuranylene, pyrazolidinylimidazolinylene, imidazolidinylene, 3-azabicyclo[3.1.0]hexanylene, 3-azabicyclo[4.1.0]heptanylene, azabicyclo[2.2.2]hexanylene, 3H-indolylquinolizinyl, and N-pyridyl urea. Spiro moieties are also included within the scope of this definition. Examples of heterocyclylene groups in which two ring atoms are substituted with oxo (=O) moieties are pyrimidinonylene and 1,1-dioxo-thiomorpholinylene. The heterocyclylene groups herein may be independently substituted with one or more substituents described herein.

[0041] The term "heteroaryl" refers to a monovalent aromatic radical of a 5-, 6-, or 7-membered ring, including fused ring systems of 5 to 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]imidazole, [1,2,4]triazolo[1,5-a]pyridine, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isopropyl, phenyl ... Heteroaryl groups are optionally independently substituted with one or more substituents described herein.

[0042] The term "heteroarylene" refers to a divalent aromatic radical of 5, 6 or 7 rings, including fused ring systems of 5 to 20 atoms (at least one of which is aromatic) containing one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of heteroarylene groups are pyridinylene (including, for example, 2-hydroxypyridinylene), imidazolylene, imidazopyridinylene, 1-methyl-1H-benzo[d]imidazole, [1,2,4]triazolo[1,5-a]pyridine, pyrimidinylene (including, for example, 4-hydroxypyrimidinylene), pyrazolylene, triazolylene, pyrazinylene, tetrazolylene, furylene, thienylene, isoxazolylene, thiazolylene, oxadiazolylene, oxazolylene, isothiazolylene, pyrrolylene, quinolinylene, iso-, phenylene ... quinolinylene, tetrahydroisoquinolinylene, indolylene, benzimidazolylene, benzofuranylene, cinnolinylene, indazolylene, indolizinylene, phthalazinylene, pyridazinylene, triazinylene, isoindolylene, pteridinylene, purinylene, oxadiazolylene, thiadiazolylene, thiadiazolylene, furazanylene, benzofurazanylene, benzothiophenylene, benzothiazolylene, benzoxazolylene, quinazolinylene, quinoxalinylene, naphthyridinylene, and furopyridinylene. Heteroarylene groups are optionally independently substituted with one or more substituents described herein.

[0043] The heterocycle or heteroaryl group may be carbon (carbon-linked) or nitrogen (nitrogen-linked) linked, where possible. By way of example and not limitation, a carbon-linked heterocycle or heteroaryl is linked 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, 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.

[0044] By way of example, and without limitation, a nitrogen-linked heterocycle or heteroaryl is bonded at the 1-position of 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, 2-position of isoindole or isoindoline, 4-position of morpholine, and 9-position of carbazole or β-carboline.

[0045] The term "acyl" refers to both substituted and unsubstituted acyl. In certain embodiments, "acyl" refers to -C(O)-R 16 where R 16 is 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. 1 -C 3 It is an alkyl.

[0046] The term "oxo" means =O.

[0047] As provided herein, the symbols are drawn with a solid line and have a label (e.g. [ka] A symbol containing a closed circle with a cyclic atom ( ) represents a ring moiety, which, unless otherwise indicated, may contain any suitable number and type of ring atoms. For example, a ring moiety may include, but is not limited to, a cycloalkyl moiety, an aryl moiety, a heterocyclyl moiety, or a heteroaryl moiety as defined herein, which may contain any suitable number and type of ring atoms. Such symbols may be used interchangeably with the term "ring." By way of example, the symbol " [ka] " and the terms "ring X" are interchangeable and both refer to the ring moiety X, which, unless otherwise indicated, may contain any suitable number and type of ring atoms.

[0048] The term "chiral" refers to molecules that have the property of being non-superimposable on their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0049] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0050] "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.

[0051] "Enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0052] 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 optically active compounds, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule around its chiral center or centers. The prefixes d and l, or (+) and (-), are used to denote the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0053] The terms "co-administration" and "co-administering" or "combination therapy" refer to both simultaneous administration (administration of two or more therapeutic agents at the same time) and staggered administration (administration of one or more therapeutic agents at a time that differs from the administration time of an additional therapeutic agent or agent), so long as the therapeutic agents are present in the patient at some time, preferably in effective amounts. In certain preferred embodiments, one or more of the present compounds described herein are co-administered in combination with at least one additional bioactive agent, including, in particular, anti-cancer agents. In particularly preferred embodiments, co-administration of the compounds results in synergistic activity and / or therapy, including anti-cancer activity.

[0054] As used herein, the term "compound" means, unless otherwise specified, any specific chemical compound disclosed herein, and includes tautomers, positional isomers, geometric isomers, and, where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), thereof, and, where applicable in the context, pharma- ceutically acceptable salts and derivatives (including prodrug forms) thereof. As used in context, the term "compound" generally refers to a single compound, but may also include stereoisomers, positional isomers, and The term may also include other compounds such as enantiomers and / or optical isomers (including racemic mixtures), as well as specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. The term also refers, in context, to prodrug forms of the compounds, which are modified to facilitate administration and delivery of the compounds to the active site. It should be noted that in describing the compounds, among other things, a number of substituents and variables associated with the compounds are described. It will be understood by those skilled in the art that the molecules described herein are generally stable compounds, as described below. Bonding [ka] When shown, both double and single bonds are presented within the context of the compound shown. [ka] ), both E and Z configurations are represented within the context of the compound shown; it may include a mixture of the E or Z isomer, or both the E and Z isomers.

[0055] Unless the context indicates otherwise, the terms "VCB E3 ubiquitin ligase", "von Hippel-Lindau (or VHL) E3 ubiquitin ligase", "VHL" or "ubiquitin ligase", which are generally used interchangeably, are used to describe the target enzyme binding site of the ubiquitin ligase moiety described herein. VCB E3s are proteins that, in combination with E2 ubiquitin conjugating enzymes, cause the attachment of ubiquitin to lysines on target proteins; E3 ubiquitin ligases target specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligases alone or in complex with E2 ubiquitin conjugating enzymes are involved in the transfer of ubiquitin to target proteins. Generally, ubiquitin ligases are involved in polyubiquitination, where a second ubiquitin is attached to the first, a third to the second, and so on. Polyubiquitination tags proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, where only a single ubiquitin is added to the substrate molecule by ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but instead may change their cellular location or function, for example by binding to other proteins that have domains that can bind to ubiquitin. To further complicate things, various lysines on ubiquitin can be targeted by E3s to create chains. The most common lysine is Lys48 on the ubiquitin chain. This is used to create polyubiquitin that is recognized by the proteasome.

[0056] As used herein, a moiety that binds to E3VHL ubiquitin ligase or a component thereof is referred to as a VHL ligand.

[0057] In certain embodiments disclosed herein, certain groups (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl) are described as being "substituted." In some such embodiments, a "substituted" group may be substituted with 1, 2, 3, 4, 5, or more substituents as set forth herein. In certain embodiments, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be independently substituted with an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl. Quinyl, 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), NH 2 , SH, SO 2 -alkyl, P(O)(O-alkyl)(alkyl), P(O)(O-alkyl) 2 , Si(OH) 3 , Si(alkyl) 3 , Si(OH)(alkyl) 2 , CO-alkyl, CO 2 H, NO 2 ,SCIENCE FICTION 5 , S.O. 2 NH-Alkyl, SO 2 N(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 , N.H.C.O.N. 2 , N(alkyl)SO 2 NH(alkyl), N(alkyl)SO 2 N(alkyl) 2 , N.H.S.O. 2NH(alkyl), NHSO 2 N(alkyl) 2 , and N.H.S.O. 2 NH 2 It may be substituted with one or more substituents selected from, but not limited to:

[0058] Further definitions and abbreviations are provided elsewhere herein.

[0059] Where a range of values ​​is provided, it is understood that each intermediate value between the upper and lower limits of that range, to the tenth of the unit of the lower limit, and any other stated or intermediate value in that stated range, is encompassed within the disclosure unless the context clearly dictates otherwise (e.g., in the case of a group containing multiple carbon atoms, where each carbon number falling within the range is provided). The upper and lower limits of these smaller ranges may be independently included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0060] As used in this specification and the appended claims, the articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article, unless the context clearly indicates otherwise. By way of example, "element" means one element or more than one element.

[0061] In the claims, as in the specification above, transitional phrases such as "comprising / including," "carrying / having," "containing," "involving," "holding," "consisting of," and the like, shall be understood to be open-ended, i.e., meaning inclusive but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as explained in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0062] As used herein in the specification and claims, the phrase "at least one" in connection with a list of one or more elements should be understood to mean at least one element selected from any or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows for elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related to those elements specifically identified or not, may optionally be present. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently, "at least one of A and / or B") may, in one embodiment, refer to at least one A, including two or more, where B is absent (and optionally including elements other than B). in another embodiment, it can refer to no A (and optionally including elements other than A) and at least one B, optionally including more than one; in yet another embodiment, it can refer to at least one A, optionally including more than one, and at least one B, optionally including more than one (and optionally including other elements); and so forth.

[0063] It should also be understood that in any particular method described herein that includes two or more steps or actions, the order of the method steps or actions is not necessarily limited to the order in which the method steps or actions are described, unless the context indicates otherwise.

[0064] II. Compounds E3 ubiquitin ligases (of which over 600 are known in humans) confer substrate specificity for ubiquitination. 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.

[0065] A specific E3 ubiquitin ligase is the von Hippel-Lindau (VHL) tumor suppressor, which is the substrate recognition subunit of the E3 ligase complex VCB, which is composed of elongins B and C, Cul2, and Rbxl. The primary substrate of VHL is hypoxia-inducible factor Iα (HIF-Iα), a transcription factor that upregulates genes such as the proangiogenic growth factor VEGF and the erythropoietin-inducing cytokine in response to low oxygen levels.

[0066] In one embodiment, formula (I) [ka] or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein X 1 is independently in each occurrence H, C 1-12 Alkyl, or -C(O)-C 1-12 is alkyl; R 1 is, independently in each occurrence, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 cycloalkyl, or 3- to 15-membered heterocyclyl; R 1 C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclyl independently has one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 optionally substituted with alkyl; L, independently at each occurrence, is absent or C 1-12 Alkylene, L is C 1-12 The alkylene may independently be one or more R t and R t is C 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 The alkyl may be further substituted with one or more halo; Ring A, independently in each occurrence, is C 6-20 Aryl or C 7-15 is cycloalkyl; R e independently in each occurrence, halo, C 6-20 aryl or 5-20 membered heteroaryl; R e C 6-20 The aryl or 5- to 20-membered heteroaryl independently comprises one or more C 1-12 optionally substituted with alkyl or halo; n is independently in each occurrence 0, 1, 2, 3, 4 or 5; Q 1 and Q 2 are, independently of each other and independently at each occurrence, H, halo, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl, 5-20 membered heteroaryl, -C(O)-O(R a ) or -C(O)-N(R b )(Rc ) and R a , R b and R c are each independently H or C 1-12 is alkyl, Q 1 or Q 2 C 1-12 Alkyl or C 3-15 Cycloalkyl can independently be one or more R q and R q is C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-20 Aryl, C 1-12 Alkoxy, or [ka] and R q C 1-12 Alkyl or C 1-12 Alkoxy is independently one or more halo or -NHC(O)-C 1-12 may be further substituted with alkyl; Or, Q 1 and Q 2 together with the atoms to which they are attached, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 aryl, or 5- to 20-membered heteroaryl; Q 1 and Q 2 Formed by C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl or 5- to 20-membered heteroaryl may independently be one or more R s and R s is OH, cyano, halogen, oxo, -NH 2 , -NO 2 , -CHO, -C(O)OH, -C(O)NH 2 , -SH, -SO 2 C 1-12 Alkyl, -SO 2 NH2 , or C 1-12 is alkyl, R s C 1-12 Provided herein are compounds, or stereoisomers or tautomers thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein the alkyl is optionally further substituted with one or more halo, cyano, or OH.

[0067] In some embodiments, provided herein are compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein L is, independently at each occurrence, absent.

[0068] In other embodiments, L is independently at each occurrence C 1-12 Alkylene, L is C 1-12 The alkylene may independently be one or more R t and R t But independently, C 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 Provided herein are compounds of formula (I), or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein alkyl is, independently, optionally further substituted with one or more halo. In certain embodiments, L is, independently at each occurrence, C 1-6 Alkylene, L is C 1-6 The alkylene may independently be one or more R t Replace with It may be R t is independently 1-6 Alkyl or -C(O)NH 2 and R t C 1-6 The alkyl may be further independently substituted with one or more halo. In some embodiments, L is independently at each occurrence C 1-3 Alkylene, L is C 1-3 The alkylene may independently be one or more R t and Rt is independently 1-6 Alkyl or -C(O)NH 2 and R t C 1-6 The alkyl may be further independently substituted with one or more halo. In some embodiments, L is independently at each occurrence ethylene, and the ethylene of L is independently substituted with one or more R t and R t is independently 1-6 Alkyl or -C(O)NH 2 and R t C 1-6 The alkyl may be further independently substituted with one or more halo. In some embodiments, L is independently at each occurrence methylene, and the methylene of L is independently selected from one or more R t and R t is independently 1-6 Alkyl or -C(O)NH 2 and R t C 1-6 The alkyl may be further substituted independently with one or more halo.

[0069] In other embodiments, provided herein are compounds of formula (I), or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein L, at each occurrence, is independently unsubstituted ethylene. In certain embodiments, L, at each occurrence, is independently ethylene, and the ethylene of L, is independently selected from one R t is replaced by R t is independently 1-6 Alkyl or -C(O)NH 2 and R t C 1-6 The alkyl may be further independently substituted with one or more halo. In some embodiments, L is independently at each occurrence ethylene, and the ethylene of L is selected from one -C(O)NH 2 has been replaced with.

[0070] In certain embodiments, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein L, at each occurrence, is independently unsubstituted methylene. In certain embodiments, L, at each occurrence, is independently methylene, and the methylene of L is not selected from one R t is replaced by R t is independently 1-6 Alkyl or -C(O)NH 2 and R t C 1-6 The alkyl may be further independently substituted with one or more halo. In certain embodiments, L is independently at each occurrence methylene, and the methylene of L is selected from one C 1-6 In some embodiments, L is independently at each occurrence methylene and the methylene of L is substituted with methyl. In other embodiments, L is independently at each occurrence methylene and the methylene of L is substituted with -CF 3 has been replaced with.

[0071] In some embodiments, ring A is independently at each occurrence C 6-20 Provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein the ring A is aryl. In certain embodiments, ring A is independently at each occurrence C 6-16 In yet other embodiments, ring A is independently at each occurrence C 6-12 In some embodiments, ring A is independently at each occurrence C 6-10 In other embodiments, ring A is independently at each occurrence C 6-8 In certain embodiments, ring A is, independently at each occurrence, phenyl.

[0072] In other embodiments, ring A is independently at each occurrence C 7-15Provided herein are compounds of formula (I), or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein the compound is cycloalkyl. In some embodiments, ring A is independently at each occurrence C 7-12 In another embodiment, ring A is independently at each occurrence C 7-10 In certain embodiments, ring A is independently at each occurrence C 7-8 In some embodiments, ring A is independently at each occurrence C 10-15 Cycloalkyl. In embodiments, ring A is independently at each occurrence C 12-15 It is cycloalkyl.

[0073] In some embodiments, n is, independently at each occurrence, 0, 1, 2, 3, 4, or 5. In other embodiments, n is, independently at each occurrence, 0, 1, 2, 3, or 4. In other embodiments, n is, independently at each occurrence, 0, 1, 2, or 3. In other embodiments, n is, independently at each occurrence, 0, 1, or 2. In other embodiments, n is, independently at each occurrence, 0 or 1. In some embodiments, n is, independently at each occurrence, 2. In other embodiments, n is, independently at each occurrence, 1. In certain embodiments, n is, independently at each occurrence, 0.

[0074] In some embodiments, R e But independently in each occurrence, halo, C 6-20 aryl, or 5-20 membered heteroaryl; R e C 6-20 The aryl or 5- to 20-membered heteroaryl is independently one or more C 1-12 Provided herein are compounds of formula (I), or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, which may be optionally substituted with alkyl or halo.

[0075] In some embodiments, Re is independently at each occurrence halo. In certain embodiments, R e is independently at each occurrence halo, and halo is independently fluoro or chloro. e is independently at each occurrence halo, and halo is chloro.

[0076] In other embodiments, R e is, independently in each occurrence, C 6-20 aryl, R e C 6-20 Aryl is independently one or more C 1-12 In some embodiments, R e is independently, in each occurrence, an unsubstituted C 6-20 In another embodiment, R e is, independently in each occurrence, C 6-20 aryl, R e C 6-20 The aryl may be independently substituted with one or more halo. In some embodiments, R e is, independently in each occurrence, C 6-20 aryl, R e C 6-20 The aryl may be independently substituted with one or more halo, where halo is fluoro. In some embodiments, R e is, independently in each occurrence, [ka] In another embodiment, R e is, independently in each occurrence, [ka] It is.

[0077] In certain embodiments, R e is, independently in each occurrence, a 5- to 20-membered heteroaryl; R eThe 5-20 membered heteroaryl is independently one or more C 1-12 In some embodiments, R e is, independently in each occurrence, a 5- to 20-membered heteroaryl; R e The 5-20 membered heteroaryl is independently one or more C 1-12 In some embodiments, R e is, independently in each occurrence, a 5- to 20-membered heteroaryl; R e 5 to 20 members Heteroaryl independently contains 1, 2, 3, or 4 ring heteroatoms. In some embodiments, R e The 5-20 membered heteroaryl independently contains 1 or 2 ring heteroatoms. e The 5-20 membered heteroaryl independently contains 2 ring heteroatoms. e The 5- to 20-membered heteroaryl independently contains 1 ring heteroatom.

[0078] In some embodiments, R e is, independently in each occurrence, a 5- to 20-membered heteroaryl; R e The 5-20 membered heteroaryl of R contains 1, 2, 3, or 4 ring 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 contain a combination of different heteroatoms. In some embodiments, R e is, independently in each occurrence, a 5- to 20-membered heteroaryl; R e The 5-20 membered heteroaryl is independently 5-16 membered heteroaryl. e is independently at each occurrence 5-12 membered heteroaryl. In other embodiments, R e is independently at each occurrence 5-10 membered heteroaryl. In still other embodiments, R eis independently at each occurrence 5-7 membered heteroaryl. In some embodiments, R e is independently at each occurrence 5-6 membered heteroaryl. In other embodiments, R e is independently at each occurrence a 6-membered heteroaryl. In certain embodiments, R e is independently at each occurrence a 5-membered heteroaryl. In certain embodiments, R e is, independently in each occurrence, thiazolyl; R e The thiazolyl may independently have one or more C 1-12 In certain embodiments, R e is, independently in each occurrence, thiazolyl; R e The thiazolyl may independently have one or more C 1-6 In some embodiments, R e is, independently in each occurrence, thiazolyl; R e The thiazolyl in R is optionally independently substituted with one or more methyl. e is, independently in each occurrence, [ka] It is.

[0079] In some embodiments, L is independently at each occurrence C 1-12 Alkylene, L is C 1-12 The alkylene is independently selected from one or more R t and R t But independently, C 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 The alkyl may be further substituted, independently, with one or more halo, and ring A, independently at each occurrence, is selected from the group consisting of C 6-20Provided herein are compounds of formula (I), or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein L is aryl. In other embodiments, L is independently at each occurrence C 1-6 Alkylene, L is C 1-6 The alkylene may independently be one or more R t and R t is independently 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 The alkyl may be further substituted, independently, with one or more halo, and ring A, independently at each occurrence, is selected from the group consisting of C 6-20 In some embodiments, L is independently at each occurrence C 1-6 Alkylene, L is C 1-6 The alkylene may independently be one or more R t and R t is independently 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 The alkyl may be further substituted, independently, with one or more halo, and Ring A is independently at each occurrence phenyl.

[0080] In other embodiments, L is, independently at each occurrence, ethylene; and the ethylene of L is , independently, one or more R t and R t is independently 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 The alkyl may be further substituted, independently, with one or more halo, and ring A is, independently at each occurrence, phenyl. In some embodiments, L is, independently at each occurrence, C 1-12 Alkylene, L is C 1-12 The alkylene is independently selected from one or more R t and Rt But independently, C 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 The alkyl may be further substituted, independently, with one or more halo, and Ring A may be independently, at each occurrence, C 6-20 aryl, n is, independently in each occurrence, 1; R e is independently in each occurrence 5- to 20-membered heteroaryl; R e The 5-20 membered heteroaryl may independently have one or more C 1-12 Provided herein are compounds of formula (I), or stereoisomers or tautomers thereof, or pharma- ceutically acceptable salts of any of the foregoing, optionally substituted with alkyl or halo. In certain embodiments, L is independently at each occurrence C 1-6 Alkylene, L is C 1-6 The alkylene may independently be one or more R t and R t is independently 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 The alkyl may be further substituted, independently, with one or more halo, and ring A, independently at each occurrence, is selected from the group consisting of C 6-20 aryl, n is, independently in each occurrence, 1, and R e is, independently in each occurrence, a 5- to 20-membered heteroaryl; R e The 5-20 membered heteroaryl may independently have one or more C 1-12 In some embodiments, L is independently at each occurrence C 1-6 Alkylene, L is C 1-6 Alkylene independently represents one or more C 1-12 Ring A is independently, at each occurrence, C 6-20 aryl, n is, independently in each occurrence, 1, and R e is, independently in each occurrence, a 5- to 20-membered heteroaryl; Re The 5-20 membered heteroaryl may independently have one or more C 1-12 It may be substituted with alkyl.

[0081] In certain embodiments, the compound of formula (I) has the formula (IA) [ka] or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein X 1 is independently in each occurrence H, C 1-12 Alkyl, or -C(O)-C 1-12 is alkyl; R 1 is, independently in each occurrence, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 cycloalkyl, or 3- to 15-membered heterocyclyl; R 1 C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclyl independently has one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 optionally substituted with alkyl; R t , H, C 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 a The alkyl may be further substituted with one or more halo; R e independently in each occurrence, halo, C 6-20 aryl or 5-20 membered heteroaryl; R e C6-20 The aryl or 5- to 20-membered heteroaryl independently comprises one or more C 1-12 optionally substituted with alkyl or halo; Q 1 and Q 2 are, independently of each other and independently at each occurrence, H, halo, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl, 5-20 membered heteroaryl, -C(O)-O(R a ) or -C(O)-N(R b )(R c ) and R a , R b and R c are each independently H or C 1-12 is alkyl, Q 1 or Q 2 C 1-12 Alkyl or C 3-15 Cycloalkyl can independently be one or more R q and R q is C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-20 Aryl, C 1-12 Alkoxy, or [ka] or R q C 1-12 Alkyl or C 1-12 Alkoxy is independently one or more halo or -NHC(O)-C 1-12 may be further substituted with alkyl, or 1 and Q 2 together with the atoms to which they are attached, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 aryl, or 5- to 20-membered heteroaryl; Q 1 and Q2 Formed by C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl or 5- to 20-membered heteroaryl may independently be one or more R s and R s is OH, cyano, halogen, oxo, -NH 2 , -NO 2 , -CHO, -C(O)OH, -C(O)NH 2 , -SH, -SO 2 C 1-12 Alkyl, -SO 2 NH 2 , or C 1-12 is alkyl, R s C 1-12 Provided herein are compounds, or stereoisomers or tautomers thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein the alkyl is optionally further substituted with one or more halo, cyano, or OH.

[0082] In some embodiments, X 1 is H;R 1 is C 1-12 Alkyl, C 2-12 Alkenyl or C 3-15 Cycloalkyl, C 1-12 Alkyl is independently one or more C 6-20 optionally substituted with aryl; R t is C 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 The alkyl may be further substituted with one or more halo; R e is C 6-20 aryl or 5-20 membered heteroaryl; R e C 6-20 The aryl or 5- to 20-membered heteroaryl independently comprises one or more C 1-12 Optionally substituted with alkyl or halo; Q 1 and Q 2 are, independently of each other and independently in each occurrence, H, halo, cyano, C 1-12Alkyl, C 3-15 Cycloalkyl, 5-20 membered heteroaryl, -C(O)-O(R a ), or -C(O)-N(R b )(R c ) and R a , R b , and R c are each independently H or C 1-12 is alkyl, Q 1 or Q 2 C 1-12 Alkyl or C 3-15 Cycloalkyl can independently be one or more R q may be substituted with R q is C 1-12 Alkyl, C 2-12 Alkynyl, C 6-20 Aryl, C 1-12 Alkoxy, or [ka] and R q C 1-12 Alkyl or C 1-12 independently represents one or more halo or -NHC(O)-C 1-12 may be further substituted with alkyl, or 1 and Q 2 together with the atoms to which they are attached, C 3-15 Cyclopropyl, 3-15 membered heterocyclyl, C 6-20 aryl, or 5- to 20-membered heteroaryl; Q 1 and Q 2 Formed by C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl or 5- to 20-membered heteroaryl may independently be one or more R s and R s is OH, cyano, halogen, oxo, -NH 2 , -NO 2 , -CHO, -C(O)OH, -C(O)NH 2 , -SH, -SO 2 C1-12 Alkyl, -SO 2 NH 2 , or C 1-12 is alkyl, R s C 1-12 The alkyl may be further substituted with one or more halo, cyano or OH.

[0083] In some embodiments, X 1 is H;R 1 is C 1-12 Alkyl, C 2-12 Alkenyl, or C 3-15 Cycloalkyl; C 1-12 Alkyl is independently one or more C 6-20 Aryl; R t is H, methyl, -CF 3 , or -C(O)NH 2 and R t The methyl in R may be further substituted with one or more halo; e is, independently in each occurrence, [ka] And Q 1 and Q 2 are, independently of each other and independently in each occurrence, H, halo, cyano, C 1-5 Alkyl, C 3-15 Cycloalkyl, 5-20 membered heteroaryl, -C(O)-O(R a ), or -C(O)-N(R b )(R c ) and R a , R b , and R c are each independently H or C 1-12 is alkyl, Q 1 or Q 2 C 1-12 Alkyl or C 3-15 Cycloalkyl can independently be one or more R q and R q is C 1-12 Alkyl, C 2-12 Alkynyl, C6-20 Aryl, C 1-12 Alkoxy, or [ka] and R q C 1-12 Alkyl or C 1-12 Alkoxy is independently one or more halo or -NHC(O)-C 1-12 may be further substituted with alkyl, or 1 and Q 2 together with the atoms to which they are attached, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 aryl, or 5- to 20-membered heteroaryl; Q 1 and Q 2 Formed by C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl or 5- to 20-membered heteroaryl may independently be one or more R s and R s is OH, cyano, halogen, oxo, -NH 2 , -NO 2 , -CHO, -C(O)OH, -C(O)NH 2 , -SH, -SO 2 C 1-12 Alkyl, -SO 2 NH 2 , or C 1-12 is alkyl, R s C 1-12 The alkyl may be further substituted with one or more halo, cyano, or OH.

[0084] In certain embodiments, the compound of formula (I) has the formula (IA-1): [ka] (IA-1), or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein R 1 is, independently in each occurrence, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 cycloalkyl, or 3- to 15-membered heterocyclyl; R 1 C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclyl independently has one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 optionally substituted with alkyl; R t , H, C 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 The alkyl may be further substituted with one or more halo; R e independently in each occurrence, halo, C 6-20 aryl or 5-20 membered heteroaryl; R e C 6-20 The aryl or 5- to 20-membered heteroaryl independently comprises one or more C 1-12 optionally substituted with alkyl or halo; Q 1 H, halo, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl, 5-20 membered heteroaryl, -C(O)-O(R a ) or -C(O)-N(R b )(R c ), R a , R b and R c are each independently H or C 1-12 is alkyl, Q1 C 1-12 Alkyl or C 3-15 Cycloalkyl can independently be one or more R q and R q is C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-20 Aryl, C 1-12 Alkoxy, or [ka] and R q C 1-12 Alkyl or C 1-12 Alkoxy is independently one or more halo or -NHC(O)-C 1-12 Provided herein are compounds, or stereoisomers or tautomers thereof, or a pharma- ceutically acceptable salt of any of the foregoing, which may be further substituted with alkyl.

[0085] In certain embodiments, the compound of (I) has the formula (IA-2): [ka] or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein R 1 is, independently in each occurrence, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 cycloalkyl, or 3- to 15-membered heterocyclyl; R 1 C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclyl independently has one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O)2 -C 1-12 Alkyl, or -C(O)-C 1-12 optionally substituted with alkyl; R t , H, C 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 The alkyl may be further substituted with one or more halo; Q 1 H, halo, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl, 5-20 membered heteroaryl, -C(O)-O(R a ) or -C(O)-N(R b )(R c ), R a , R b and R c are each independently H or C 1-12 is alkyl, Q 1 C 1-12 Alkyl or C 3-15 Cycloalkyl can independently be one or more R q and R q is C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-20 Aryl, C 1-12 Alkoxy, or [ka] and R q C 1-12 Alkyl or C 1-12 Alkoxy is independently one or more halo or -NHC(O)-C 1-12 Provided herein are compounds, or stereoisomers or tautomers thereof, or a pharma- ceutically acceptable salt of any of the foregoing, which may be further substituted with alkyl.

[0086] In certain embodiments, the compound of formula (I) has the formula (IA-3): [ka] or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein R 1 is, independently in each occurrence, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 cycloalkyl, or 3- to 15-membered heterocyclyl; R 1 C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclyl independently has one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 optionally substituted with alkyl; R t , H, C 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 The alkyl may be further substituted with one or more halo; R e independently in each occurrence, halo, C 6-20 aryl or 5-20 membered heteroaryl; R e C 6-20 The aryl or 5- to 20-membered heteroaryl independently comprises one or more C 1-12 Provided herein are compounds, or stereoisomers or tautomers thereof, or a pharma- ceutically acceptable salt of any of the foregoing, which may be optionally substituted with alkyl or halo.

[0087] In certain embodiments, the compound of formula (I) has the formula (IA-4): [ka] or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein R 1 is, independently in each occurrence, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 cycloalkyl, or 3- to 15-membered heterocyclyl; R 1 C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclyl independently has one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 optionally substituted with alkyl; R t , H, C 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 The alkyl may be further substituted with one or more halo; Q 1 and Q 2 are, independently of each other and independently at each occurrence, H, halo, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl, 5-20 membered heteroaryl, -C(O)-O(R a ) or -C(O)-N(R b )(R c ) and R a , R b and R c are each independently H or C 1-12 is alkyl, Q 1 or Q 2 C 1-12 Alkyl or C 3-15 Cycloalkyl can independently be one or more R q and R q is C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-20 Aryl, C 1-12 Alkoxy, or [ka] or R q C 1-12 Alkyl or C 1-12 Alkoxy is independently one or more halo or -NHC(O)-C 1-12 may be further substituted with alkyl, or 1 and Q 2 together with the atoms to which they are attached, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 aryl, or 5- to 20-membered heteroaryl; Q 1 and Q 2 Formed by C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl or 5- to 20-membered heteroaryl may independently be one or more R s and R s is OH, cyano, halogen, oxo, -NH 2 , -NO 2 , -CHO, -C(O)OH, -C(O)NH 2 , -SH, -SO 2 C 1-12 Alkyl, -SO 2 NH 2 , or C 1-12 is alkyl, R s C 1-12Provided herein are compounds, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein:

[0088] In certain embodiments, the compound of formula (I) has the formula (IB) [ka] or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein X 1 is independently in each occurrence H, C 1-12 Alkyl, or -C(O)-C 1-12 is alkyl; R 1 is, independently in each occurrence, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 cycloalkyl, or 3- to 15-membered heterocyclyl; R 1 C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclyl independently has one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 optionally substituted with alkyl; R t , H, C 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 The alkyl may be further substituted with one or more halo; R e independently in each occurrence, halo, C 6-20aryl or 5-20 membered heteroaryl; R e C 6-20 The aryl or 5- to 20-membered heteroaryl independently comprises one or more C 1-12 optionally substituted with alkyl or halo; Q 1 and Q 2 are, independently of each other and independently at each occurrence, H, halo, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl, 5-20 membered heteroaryl, -C(O)-O(R a ) or -C(O)-N(R b )(R c ) and R a , R b and R c are each independently H or C 1-12 is alkyl, Q 1 or Q 2 C 1-12 Alkyl or C 3-15 Cycloalkyl is independently one or more R q and R q But, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-20 Aryl, C 1-12 Alkoxy, or [ka] and R q C 1-12 Alkyl or C 1-12 Alkoxy is independently one or more halo or -NHC(O)-C 1-12 may be further substituted with alkyl, or Q 1 and Q 2 together with the atoms to which they are attached, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20which forms aryl or 5- to 20-membered heteroaryl, Q 1 and Q 2 formed C 3-15 cycloalkyl, 3- to 15-membered heterocyclyl, C 6-20 aryl, or 5- to 20-membered heteroaryl may each independently be substituted with one or more R s where R s is OH, cyano, halogen, oxo, -NH 2 -, -NO 2 -, -CHO, -C(O)OH, -C(O)NH 2 -, -SH, -SO 2 C 1-12 alkyl, -SO 2 NH 2 -, or C 1-12 alkyl, and the C s alkyl of R 1-12 may be further substituted with one or more halo, cyano, or OH, and a compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing is provided herein.

[0089] In a plurality of embodiments, X 1 is H; R 1 is C 1-12 alkyl, C 2-12 alkenyl or C 3-15 cycloalkyl, and the C 1-12 alkyl may each independently be substituted with one or more C 6-20 aryl; R t is C 1-12 alkyl or -C(O)NH 2 -, and the C t alkyl of R 1-12 may be further substituted with one or more halo; R e is C 6-20 aryl or 5- to 20-membered heteroaryl, and the C e aryl or 5- to 20-membered heteroaryl of R 6-20 may each independently be substituted with one or more C 1-12 alkyl or halo; Q 1 and Q2 are, independently of each other and independently in each occurrence, H, halo, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 5-20 membered heteroaryl, -C(O)-O(R a ), or -C(O)-N(R b )(R c ) and R a , R b , and R c are each independently H or C 1-12 is alkyl, Q 1 or Q 2 C 1-12 Alkyl or C 3-15 Cycloalkyl can independently be one or more R q may be substituted with R q is C 1-12 Alkyl, C 2-12 Alkynyl, C 6-20 Aryl, C 1-12 Alkoxy, or [ka] and R q C 1-12 Alkyl or C 1-12 independently represents one or more halo or -NHC(O)-C 1-12 may be substituted with alkyl, or 1 and Q 2 together with the atoms to which they are attached, C 3-15 Cyclopropyl, 3-15 membered heterocyclyl, C 6-20 aryl, or 5- to 20-membered heteroaryl; Q 1 and Q 2 Formed by C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl or 5- to 20-membered heteroaryl is independently one or more R s and R s is OH, cyano, halogen, oxo, -NH 2 , -NO 2 , -CHO, -C(O)OH, -C(O)NH2 , -SH, -SO 2 C 1-12 Alkyl, -SO 2 NH 2 , or C 1-12 is alkyl, R s C 1-12 The alkyl may be further substituted with one or more halo, cyano or OH.

[0090] In some embodiments, X 1 is H;R 1 is C 1-12 Alkyl, C 2-12 Alkenyl, or C 3-15 Cycloalkyl; C 1-12 Alkyl is independently one or more C 6-20 optionally substituted with aryl; R t is H, methyl, -CF 3 , or -C(O)NH 2 and;R t The methyl in R may be further substituted with one or more halo; e is, independently in each occurrence, [ka] And Q 1 and Q 2 are, independently of each other and independently in each occurrence, H, halo, cyano, C 1-5 Alkyl, C 3-15 Cycloalkyl, 5-20 membered heteroaryl, -C(O)-O(R a ), or -C(O)-N(R b )(R c ) and R a , R b , and R c are each independently H or C 1-12 is alkyl, Q 1 or Q 2 C 1-12 Alkyl or C 3-15 Cycloalkyl can independently be one or more R q and R qis C 1-12 Alkyl, C 2-12 Alkynyl, C 6-20 Aryl, C 1-12 Alkoxy, or [ka] and R q C 1-12 Alkyl or C 1-12 Alkoxy is independently one or more halo or -NHC(O)-C 1-12 may be further substituted with alkyl, or 1 and Q 2 together with the atoms to which they are attached, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 aryl, or 5- to 20-membered heteroaryl; Q 1 and Q 2 Formed by C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl or 5- to 20-membered heteroaryl may independently be one or more R s and R s is OH, cyano, halogen, oxo, -NH 2 , -NO 2 , -CHO, -C(O)OH, -C(O)NH 2 , -SH, -SO 2 C 1-12 Alkyl, -SO 2 NH 2 , or C 1-12 is alkyl, R s C 1-12 The alkyl may be further substituted with one or more halo, cyano, or OH.

[0091] In certain embodiments, the compound of formula (I) has the formula (IB-1): [ka] or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein R 1 is, independently in each occurrence, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 cycloalkyl, or 3- to 15-membered heterocyclyl; R 1 C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclyl independently has one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 optionally substituted with alkyl; R t , H, C 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 The alkyl may be further substituted with one or more halo; R e independently in each occurrence, halo, C 6-20 aryl or 5-20 membered heteroaryl; R e C 6-20 The aryl or 5- to 20-membered heteroaryl independently comprises one or more C 1-12 optionally substituted with alkyl or halo; Q 1 H, halo, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl, 5-20 membered heteroaryl, -C(O)-O(R a ) or -C(O)-N(R b )(R c ), R a , R b and R care each independently H or C 1-12 is alkyl, Q 1 C 1-12 Alkyl or C 3-15 Cycloalkyl can independently be one or more R q and R q is C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-20 Aryl, C 1-12 Alkoxy, or [ka] and R q C 1-12 Alkyl or C 1-12 Alkoxy is independently one or more halo or -NHC(O)-C 1-12 Provided herein are compounds, or stereoisomers or tautomers thereof, or a pharma- ceutically acceptable salt of any of the foregoing, which may be further substituted with alkyl.

[0092] In certain embodiments, the compound of formula (I) has the formula (IB-2): [ka] or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein R 1 is, independently in each occurrence, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 cycloalkyl, or 3- to 15-membered heterocyclyl; R 1 C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclyl independently has one or more C1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 optionally substituted with alkyl; R t , H, C 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 The alkyl may be further substituted with one or more halo; Q 1 H, halo, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl, 5-20 membered heteroaryl, -C(O)-O(R a ) or -C(O)-N(R b )(R c ), R a , R b and R c are each independently H or C 1-12 is alkyl, Q 1 C 1-12 Alkyl or C 3-15 Cycloalkyl can independently be one or more R q and R q is C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-20 Aryl, C 1-12 Alkoxy, or [ka] and R q C 1-12 Alkyl or C 1-12 Alkoxy is independently one or more halo or -NHC(O)-C 1-12Provided herein are compounds, or stereoisomers or tautomers thereof, or a pharma- ceutically acceptable salt of any of the foregoing, which may be further substituted with alkyl.

[0093] In certain embodiments, the compound of formula (I) has the formula (IB-3): [ka] or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein R 1 is, independently in each occurrence, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 cycloalkyl, or 3- to 15-membered heterocyclyl; R 1 C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclyl independently has one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 optionally substituted with alkyl; R t , H, C 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 The alkyl may be further substituted with one or more halo; R e independently in each occurrence, halo, C 6-20 aryl or 5-20 membered heteroaryl; R e C 6-20 The aryl or 5- to 20-membered heteroaryl independently comprises one or more C 1-12Provided herein are compounds, or stereoisomers or tautomers thereof, or a pharma- ceutically acceptable salt of any of the foregoing, which may be optionally substituted with alkyl or halo.

[0094] In certain embodiments, the compound of formula (I) has the formula (IB-4): [ka] or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein R 1 is, independently in each occurrence, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 cycloalkyl, or 3- to 15-membered heterocyclyl; R 1 C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 Cycloalkyl or 3- to 15-membered heterocyclyl independently has one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 optionally substituted with alkyl; R t , H, C 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 Provided herein are compounds in which the alkyl is optionally further substituted with one or more halo, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0095] In some embodiments, L, at each occurrence, is independently unsubstituted methylene and ring A, at each occurrence, is independently C 6-20aryl, n is, independently in each occurrence, 1, and R e is, independently in each occurrence, a 5- to 20-membered heteroaryl; R e The 5-20 membered heteroaryl may independently have one or more C 1-12 In another embodiment, L, at each occurrence, is independently unsubstituted methylene and ring A, at each occurrence, is independently C 6-20 aryl, n is, independently in each occurrence, 1, and R e is, independently in each occurrence, thiazolyl; R e The thiazolyl may independently have one or more C 1-12 In certain embodiments, the compound of formula (I) has the formula (IC): [ka] or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0096] In other embodiments, L is independently at each occurrence methylene, and the methylene of L is independently selected from one or more C 1-12 alkyl, and ring A is independently selected from the group consisting of C 6-20 aryl, n is, independently in each occurrence, 1, and R e is, independently in each occurrence, a 5- to 20-membered heteroaryl; R e The 5-20 membered heteroaryl may independently have one or more C 1-12 In another embodiment, L is independently at each occurrence methylene, and the methylene of L is optionally substituted with one or more C 1-12 alkyl, and ring A is independently selected from the group consisting of C 6-20 aryl, n is, independently in each occurrence, 1, and R eis, independently in each occurrence, thiazolyl; R e The thiazolyl may independently have one or more C 1-12 It may be substituted with alkyl.

[0097] In certain embodiments, the compound of formula (I) has the formula (ID): [ka] or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0098] In other embodiments, L is independently at each occurrence methylene and the methylene of L is selected from one or more C 1-12 alkyl, and ring A is independently selected from the group consisting of C 6-20 aryl, n is, independently in each occurrence, 2, and R e is independently in each occurrence 5- to 20-membered heteroaryl; e The 5-20 membered heteroaryl may independently have one or more C 1-12 may be substituted with alkyl, and other R e In other embodiments, L is independently at each occurrence halo. In other embodiments, L is independently at each occurrence methylene, wherein the methylene of L is selected from one or more C 1-12 alkyl, and ring A is independently selected from the group consisting of C 6-20 aryl, n is, independently in each occurrence, 2, and R e is independently in each occurrence thiazolyl; e The thiazolyl may independently have one or more C 1-12 may be substituted with alkyl, and other R e is independently at each occurrence halo. In some embodiments, R eand halo is, independently at each occurrence, chloro. In certain embodiments, the compound of formula (I) has the formula (IE): [ka] or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0099] In certain embodiments, L is independently at each occurrence C 1-12 Alkylene, L is C 1-12 The alkylene is independently selected from one or more R t and R t But independently, C 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 The alkyl may be further substituted, independently, with one or more halo, and Ring A may be independently, at each occurrence, C 6-20 aryl, n is, independently in each occurrence, 1; R e But independently in each occurrence, C 6-20 aryl, R e C 6-20 Aryl is independently one or more C 1-12 Provided herein are compounds of formula (I), or stereoisomers or tautomers thereof, or a pharma- ceutically acceptable salt of any of the foregoing, optionally substituted with alkyl or halo. In some embodiments, L is independently at each occurrence C 1-6 Alkylene, L is C 1-6 The alkylene may independently be one or more R t and R t is, independently in each occurrence, C 1-12 Alkyl or -C(O)NH 2 and R t C 1-12The alkyl may be further substituted, independently, with one or more halo, and ring A, independently at each occurrence, is selected from the group consisting of C 6-20 aryl, n is, independently in each occurrence, 1, and R e is, independently in each occurrence, C 6-20 aryl, R e C 6-20 Aryl is independently one or more C 1-12 In certain embodiments, L is independently at each occurrence C 1-6 Alkylene, L is C 1-6 Alkylene independently represents one or more -C(O)NH 2 Ring A is optionally substituted at each occurrence with 6-20 aryl, n is, independently in each occurrence, 1, and R e is, independently in each occurrence, C 6-20 aryl, R e C 6-20 Aryl is independently one or more C 1-12 It may be substituted with alkyl or halo.

[0100] In certain embodiments, L is, independently at each occurrence, ethylene, and the ethylene of L is, independently, one or more -C(O)NH 2 Ring A is, independently at each occurrence, phenyl; n is, independently at each occurrence, 1; and R e is independently at each occurrence unsubstituted phenyl. In certain embodiments, the compound of formula (I) has formula (IF): [ka] or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0101] In some embodiments, L is independently at each occurrence methylene, and the methylene of L is independently selected from one or more C 1-12 ring A is, independently at each occurrence, phenyl; n is, independently at each occurrence, 1; R e is independently at each occurrence phenyl; R e In certain embodiments, L is independently at each occurrence methylene, and the methylene of L is independently substituted with one or more C 1-6 ring A is, independently at each occurrence, phenyl; n is, independently at each occurrence, 1; R e is independently at each occurrence phenyl; R e is independently substituted with one or more halo, and the halo is fluoro. In certain embodiments, the compound of formula (I) has formula (IG): [ka] or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0102] In some embodiments, L is, independently at each occurrence, absent, and ring A is, independently at each occurrence, C 7-15 Provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein L is, independently at each occurrence, absent, and ring A is, independently at each occurrence, C 7-15 cycloalkyl, n is, independently in each occurrence, 1, and R e is, independently in each occurrence, a 5- to 20-membered heteroaryl; R e The 5-20 membered heteroaryl may independently have one or more C1-12 In some embodiments, L is, independently at each occurrence, not present, and ring A is, independently at each occurrence, C 7-15 cycloalkyl, n is, independently in each occurrence, 1, and R e is, independently in each occurrence, thiazolyl; R e The thiazolyl may independently have one or more C 1-12 In some embodiments, the compound of formula (I) has the formula (IH): [ka] or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0103] In some embodiments, Q 1 and Q 2 independently of each other and independently in each occurrence, H, halo, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl, 5-20 membered heteroaryl, -C(O)-O(R a ), or -C(O)-N(R b )(R c ) and R a , R b and R c are each independently H or C 1-12 is alkyl, Q 1 or Q 2 C 1-12 Alkyl or C 3-15 Cycloalkyl is independently one or more R q and R q But, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C6-20 Aryl, C 1-12 Alkoxy, or [ka] and R q C 1-12 Alkyl or C 1-12 Alkoxy is independently one or more halo or -NHC(O)-C 1-12 Provided herein are 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 a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, optionally further substituted with alkyl. In some embodiments, Q 1 H, halo, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl, 5-20 membered heteroaryl, -C(O)-O(R a ) or -C(O)-N(R b )(R c ) and R a , R b and R c are each independently H or C 1-12 is alkyl, Q 1 C 1-12 Alkyl or C 3-15 Cycloalkyl can independently be one or more R q and R q is C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-20 Aryl, C 1-12 Alkoxy, or [ka] or R q C1-12 Alkyl or C 1-12 Alkoxy is independently one or more halo, -NHC(O)-C 1-12 may be further substituted with alkyl; 2 is H. In some embodiments, Q 2 is independently at each occurrence H, halo, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl, 5-20 membered heteroaryl, -C(O)-O(R a ) or -C(O)-N(R b )(R c ) and R a , R b and R c are each independently H or C 1-12 is alkyl, Q 2 C 1-12 Alkyl or C 3-15 Cycloalkyl can independently be one or more R q and R q is, independently in each occurrence, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-20 Aryl, C 1-12 Alkoxy, or [ka] and R q C 1-12 Alkyl or C 1-12 Alkoxy is independently one or more halo or -NHC(O)-C 1-12 alkyl, which may be further substituted; Q 1 is H. In other embodiments, Q 1 and Q 2 are, independently of each other and independently at each occurrence, halo, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20Aryl, 5-20 membered heteroaryl, -C(O)-O(R a ) or -C(O)-N(R b )(R c ) and R a , R b and R c are each independently H or C 1-12 is alkyl, Q 1 or Q 2 C 1-12 Alkyl or C 3-15 Cycloalkyl can independently be one or more R q and R q is, independently in each occurrence, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-20 Aryl, C 1-12 Alkoxy, or [ka] and R q C 1-12 Alkyl or C 1-12 Alkoxy is independently one or more halo or -NHC(O)-C 1-12 In yet another embodiment, Q is further substituted with alkyl. 1 and Q 2 are H, independently of each other and independently in each occurrence.

[0104] In some embodiments, Q 1 is C 3-15 is cycloalkyl, Q 1 C 3-15 Cycloalkyl is one or more R q and R q is C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-20 Aryl, C 1-12 Alkoxy, or [ka] and R q C 1-12 Alkyl or C 1-12 Alkoxy independently represents one or more halo or -NHC(O)-C 1-12 In another embodiment, Q 1 is C 3-12 is cycloalkyl, Q 1 C 3-12 Cycloalkyl is one or more R q In some embodiments, Q 1 is C 3-10 is cycloalkyl, Q 1 C 3-10 Cycloalkyl is one or more R q In certain embodiments, Q 1 is C 3-8 is cycloalkyl, Q 1 C 3-8 Cycloalkyl is one or more R q In some embodiments, Q 1 is C 3-6 is cycloalkyl, Q 1 C 3-6 Cycloalkyl is one or more R q In some embodiments, Q 1 is C 3-5 is cycloalkyl, Q 1 C 3-5 Cycloalkyl is one or more R q In some embodiments, Q 1 is cyclopropyl, and Q 1 The cyclopropyl group has one or more R q and R q is C 1-12 Alkyl, C 2-12 alkynyl, or [ka] and R qC 1-12 Alkyl is independently one or more halo or -NHC(O)-C 1-12 In some embodiments, Q may be further substituted with alkyl. 1 is cyclopropyl, and Q 1 The cyclopropyl group may have one or more R q and R q is C 1-12 Alkyl, C 2-12 alkynyl, or [ka] and R q C 1-12 Alkyl independently represents one or more halo or -NHC(O)-C 1-12 Q may be further substituted with alkyl. 2 is H. In some embodiments, Q 1 is unsubstituted cyclopropyl. In certain embodiments, Q 1 is unsubstituted cyclopropyl, and Q 2 is H.

[0105] In some embodiments, Q 1 is C 1-12 is alkyl, Q 1 C 1-12 Alkyl is one or more R q and R q is independently 6-20 Aryl or C 1-12 Alkoxy, R q C 1-12 Alkoxy is independently one or more halo or -NHC(O)-C 1-12 Q may be further substituted with alkyl. 2 is independently at each occurrence H. In some embodiments, Q 1 is methyl and Q 2 is independently at each occurrence H. In other embodiments, Q 1 is H and Q 2 is, independently in each occurrence, C 1-12is alkyl, and Q 2 's C 1-12 alkyl may be independently substituted with one or more R q 's, and R q is independently, in each occurrence, C 6-20 aryl or C 1-12 alkoxy, and R q 's C 1-12 alkoxy may be independently further substituted with one or more halo or -NHC(O)-C 1-12 alkyl. In some embodiments, Q 1 is H, and Q 2 is independently, in each occurrence, methyl. In other embodiments, Q 1 and Q 2 are independently of each other and independently, in each occurrence, C 1-12 alkyl, and Q 1 or Q 2 's C 1-12 alkyl may be independently substituted with one or more R q 's, and R q is independently, in each occurrence, C 6-20 aryl or C 1-12 alkoxy, and R q 's C 1-12 alkoxy may be independently further substituted with one or more halo or -NHC(O)-C 1-12 alkyl. In some embodiments, Q 1 and Q 2 are independently of each other and independently, in each occurrence, methyl.

[0106] In some embodiments, Q 1 is -C(O)-O(R a ) or -C(O)-N(R b )(R c ), where R a , R b and R c are each independently H or C 1-12 alkyl, and Q 2 is independently, in each occurrence, H. In other embodiments, Q 1is -C(O)-O(R a ) or -C(O)-N(R b )(R c ) and R a , R b and R c are each independently H or C 1-12 is alkyl, Q 2 is, independently in each occurrence, C 1-12 In some embodiments, Q is alkyl. 1 is -C(O)-O(R a ) or -C(O)-N(R b )(R c ) and R a , R b and R c are each independently H or C 1-12 is alkyl, Q 2 is independently at each occurrence methyl.

[0107] In some embodiments, Q 1 is 5-20 membered heteroaryl. In some embodiments, Q 1 is 5-16 membered heteroaryl. 1 In yet another embodiment, Q is a 5-12 membered heteroaryl. 1 is 5-10 membered heteroaryl. In some embodiments, Q 1 is 5-8 membered heteroaryl. 1 is 5-6 membered heteroaryl. In some embodiments, Q 1 is a 5-membered heteroaryl. In certain embodiments, Q 1 In another embodiment, Q is furanyl. 1 is thiophenyl. In some embodiments, Q 1 is a 5- to 20-membered heteroaryl; Q 2 is independently at each occurrence H.

[0108] In some embodiments, Q 1 is cyano. In certain embodiments, Q 1 is cyano and Q is2 is independently at each occurrence H. In some embodiments, Q 1 is halo. In some embodiments, Q 1 is a halo, and Q 2 is independently at each occurrence H. In certain embodiments, Q 1 is fluoro and Q 2 is independently at each occurrence H.

[0109] In some embodiments, Q 1 and Q 2 together with the atoms to which they are bonded, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 aryl, or 5- to 20-membered heteroaryl; Q 1 and Q 2 Formed by C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 aryl, or 5- to 20-membered heteroaryl, independently, one or more R s and R s OH, cyano, halogen, oxo, -NH 2 , -NO 2 , -CHO, -C(O)OH, -C(O)NH 2 , -SH, -SO 2 C 1-12 Alkyl, -SO 2 NH 2 , or C 1-12 is alkyl, R s C 1-12 Provided herein are 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 a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein alkyl is optionally further substituted with one or more halo or OH. In certain embodiments, Q 1 and Q 2together with the atoms to which they are attached, C 6-20 Form an aryl, Q 1 and Q 2 C formed by 6-20 Aryl is independently one or more R s In some embodiments, Q 1 and Q 2 together with the atoms to which they are attached form unsubstituted C 6-20 In certain embodiments, Q 1 and Q 2 together with the atoms to which they are attached form unsubstituted C 6-10 In certain embodiments, Q 1 and Q 2 together with the atoms to which they are attached form unsubstituted C 6 Form an aryl.

[0110] In some embodiments, R 1 But independently in each occurrence, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 cycloalkyl, or 3- to 15-membered heterocyclyl; R 1 C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 Cycloalkyl, or 3- to 15-membered heterocyclyl, independently, one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12Provided herein are 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 a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, optionally substituted with alkyl. 1 is, independently in each occurrence, C 1-12 is alkyl, R 1 C 1-12 Alkyl is independently one or more C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 In some embodiments, R 1 is independently, in each occurrence, an unsubstituted C 1-12 In another embodiment, R 1 is, independently in each occurrence, C 1-6 is alkyl, R 1 C 1-6 Alkyl is independently one or more C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 In another embodiment, R 1 is, independently in each occurrence, C 1-6 is alkyl, R 1 C 1-6 Alkyl is independently one or more C 6-20 In some embodiments, R 1 is independently, in each occurrence, an unsubstituted C 1-6 In some embodiments, R 1 is independently at each occurrence methyl, tert-butyl, sec-butyl, iso-propyl, or tert-pentyl. In certain embodiments, R 1is independently at each occurrence methyl, tert-butyl, or iso-propyl. In some embodiments, R 1 is independently at each occurrence tert-butyl or iso-propyl. In some embodiments, R 1 is independently at each occurrence tert-butyl. In other embodiments, R 1 is independently at each occurrence is iso-propyl.

[0111] In some embodiments, R 1 is, independently in each occurrence, C 3-15 cycloalkyl, R 1 C 3-15 Cycloalkyl independently represents one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 Provided herein are 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 a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, optionally substituted with alkyl. 1 is, independently in each occurrence, C 3-12 cycloalkyl, R 1 C 3-12 Cycloalkyl independently represents one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 In another embodiment, R 1 is, independently in each occurrence, C 3-10 cycloalkyl, R 1 C 3-10 Cycloalkyl independently represents one or more C 1-12 Alkyl, C6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 In yet another embodiment, R 1 is, independently in each occurrence, C 3-8 cycloalkyl, R 1 C 3-8 Cycloalkyl independently represents one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 In certain embodiments, R 1 is, independently in each occurrence, C 3-6 cycloalkyl, R 1 C 3-6 Cycloalkyl independently represents one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 In certain embodiments, R 1 is, independently in each occurrence, C 3-5 cycloalkyl, R 1 C 3-5 Cycloalkyl independently represents one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 In certain embodiments, R 1 is independently in each occurrence cyclobutyl; R 1 The cyclobutyl in each of the formulas is independently one or more 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 In certain embodiments, R 1is independently at each occurrence unsubstituted cyclohexyl. In some embodiments, R 1 is, independently in each occurrence, cyclohexyl; R 1 The cyclohexyl may independently be one or more 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 In certain embodiments, R 1 is independently at each occurrence unsubstituted cyclohexyl. In some embodiments, R 1 is independently at each occurrence unsubstituted adamantyl.

[0112] In some embodiments, R 1 is independently at each occurrence 3- to 15-membered heterocyclyl; R 1 The 3- to 15-membered heterocyclyl may independently have one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 C 1-12 Alkyl, or -C(O)-C 1-12 Provided herein are 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 a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, optionally substituted with alkyl.

[0113] In some embodiments, R 1Provided herein are 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 a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein the chiral carbon atom to which R is attached is in the S configuration. 1 Provided herein are 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 a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein the chiral carbon atom to which is attached is in the R configuration.

[0114] In some embodiments, X 1 But independently in each occurrence, H, C 1-12 Alkyl, or -C(O)-C 1-12 Provided herein are 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 a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein X is an alkyl group. 1 is independently at each occurrence H. In other embodiments, X 1 is independently in each occurrence -C(O)-C 1-12 In another embodiment, X is an alkyl group. 1 is independently at each occurrence -C(O)-CH 3 In some embodiments, X 1 is, independently in each occurrence, C 1-12 In certain embodiments, X is alkyl. 1 C 1-12 The alkyl is unsubstituted.

[0115] In some embodiments, X 1 But independently in each occurrence, H, C 1-12 Alkyl, or -C(O)-C 1-12 R is alkyl; 1 But independently in each occurrence, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 cycloalkyl, or 3- to 15-membered heterocyclyl; R 1 C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 Cycloalkyl, or 3- to 15-membered heterocyclyl, independently, one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 L is, independently at each occurrence, absent or substituted with C 1-12 Alkylene, L is C 1-12 The alkylene is independently selected from one or more R t and R t But, C 1-12 Alkyl or -C(O)NH 2 and R t C 1-12 The alkyl may be further substituted with one or more halo; Ring A is independently at each occurrence C 6-20 Aryl or C 7-15 cycloalkyl; n is, independently in each occurrence, 1, 2, 3, 4, or 5; R e But independently in each occurrence, halo, C 6-20 aryl, or 5- to 20-membered heteroaryl, provided that at least one R e is C 6-20 aryl or 5-20 membered heteroaryl containing one or more cyclic sulfur atoms; R e C 6-20The aryl or 5- to 20-membered heteroaryl is independently one or more C 1-12 Optionally substituted with alkyl or halo; Q 1 and Q 2 independently of each other and independently in each occurrence: H, halo, cyano, C 1-12 Alkyl, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 Aryl, 5-20 membered heteroaryl, -C(O)-O(R a ), or -C(O)-N(R b )(R c ) and R a , R b , and R c are each independently H or C 1-12 is alkyl, Q 1 or Q 2 C 1-12 Alkyl or C 3-15 Cycloalkyl is independently one or more R q Optionally substituted with cycloalkyl; R q But, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-20 Aryl, C 1-12 Alkoxy, or [ka] and R q C 1-12 Alkyl or C 1-12 Alkoxy is independently one or more halo or NHC(O)-C 1-12 may be further substituted with alkyl, or 1 and Q 2 together with the atoms to which they are bonded, C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C 6-20 aryl, or 5- to 20-membered heteroaryl; Q 1 and Q 2 Formed by C 3-15 Cycloalkyl, 3-15 membered heterocyclyl, C6-20 aryl, or 5- to 20-membered heteroaryl, independently, one or more R s and R s is OH, cyano, halogen, oxo, -NH 2 , -NO 2 , -CHO, -C(O)OH, -C(O)NH 2 , -SH, -SO 2 C 1-12 Alkyl, -SO 2 NH 2 , or C 1-12 is alkyl, R s C 1-12 Provided herein are compounds of formula (I), or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein alkyl is optionally further substituted with one or more halo, cyano, or OH.

[0116] In some of the foregoing embodiments, C 6-20 At least one R is an aryl or a 5- to 20-membered heteroaryl containing one or more cyclic sulfur atoms. e is attached to Ring A at the ortho position of Ring A. 6-20 At least one R is an aryl or a 5- to 20-membered heteroaryl containing one or more cyclic sulfur atoms. e is attached to ring A at the meta position of ring A. 6-20 At least one R is an aryl or a 5- to 20-membered heteroaryl containing one or more cyclic sulfur atoms. e is attached to ring A at the para position of ring A.

[0117] In some of the foregoing embodiments, when L, at each occurrence, is independently unsubstituted methylene, ring A, at each occurrence, is independently C 6-20 aryl; n is, independently in each occurrence, 1; R e is independently in each occurrence 5- to 20-membered heteroaryl; R e The 5-20 membered heteroaryl contains one or more cyclic sulfur atoms and independently has one or more C 1-12Optionally substituted with alkyl; Q 1 is unsubstituted cyclopropyl, R 1 But, C 1-3 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 cycloalkyl, or 3- to 15-membered heterocyclyl; R 1 C 1-3 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 Cycloalkyl, or 3- to 15-membered heterocyclyl, independently, one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 Provided herein are compounds of formula (I), or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, which may be optionally substituted with alkyl.

[0118] In some of the foregoing embodiments, when L, at each occurrence, is independently unsubstituted methylene, ring A, at each occurrence, is independently C 6-20 aryl; n is, independently in each occurrence, 1; R e is, independently at each occurrence, thiazolyl; R e thiazolyl independently has one or more C 1-12 Optionally substituted with alkyl; Q 1 is unsubstituted cyclopropyl, R 1 But, C 1-3 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 cycloalkyl, or 3- to 15-membered heterocyclyl; R 1 C 1-3 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 Cycloalkyl, or 3- to 15-membered heterocyclyl, independently, one or more C 1-12 Alkyl, C 6-20Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 Provided herein are compounds of formula (I), or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, which may be optionally substituted with alkyl.

[0119] In some of the foregoing embodiments, when L, at each occurrence, is independently unsubstituted methylene, ring A, at each occurrence, is independently C 6-20 aryl; n is, independently in each occurrence, 1; R e is, independently at each occurrence, thiazolyl; R e Q is optionally substituted, independently, with one or more methyl groups; 1 is unsubstituted cyclopropyl, R 1 But, C 1-3 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 cycloalkyl, or 3- to 15-membered heterocyclyl; R 1 C 1-3 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-15 Cycloalkyl, or 3- to 15-membered heterocyclyl, independently, one or more C 1-12 Alkyl, C 6-20 Aryl, -S(O) 2 -C 1-12 Alkyl, or -C(O)-C 1-12 Provided herein are compounds of formula (I), or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, which may be optionally substituted with alkyl.

[0120] In some of the foregoing embodiments, the compound of formula (I), such as compound (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 a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, comprises (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, or a pharma- ceutically acceptable salt thereof. In some of the foregoing embodiments, the compound of formula (I), such as compound (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 a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, does not include (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, or a pharma- ceutically acceptable salt thereof.

[0121] X as provided herein 1 , R 1 , Q 1 , Q 2 , ring A, n, L, R a , R b , R c , R e , R q , R s , and R t Any variation or embodiment of X 1 , R 1 , Q 1 , Q 2 , ring A, n, L, R a , R b , R c , R e , R q , Rs , and R t It is to be understood that the present invention can be combined with all other variations or embodiments of the above and are equivalent as if each and every combination was individually and specifically set forth.

[0122] In one embodiment, provided herein is a compound of formula (I), such as a compound 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 a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein the compound is selected from the compounds of Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12]

[0123] In one embodiment, a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, [ka] [ka] [ka] [ka] [ka] [ka] Provided herein is a compound of formula (I), selected from the group consisting of: or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0124] In one embodiment, a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)propanoyl)-4-hydroxypyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-(2-cyclobutyl-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxypyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylpentanoyl)-4-hydroxypyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylpentanoyl)-4-hydroxypyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylpent-4-enoyl)-4-hydroxypyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-(2-(adamantan-1-yl)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxypyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-(3,3-dimethyl-2-(1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxypyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-4-hydroxy-1-(2-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-(2-(4-benzyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-(2-(4-(1-(acetamidomethyl)cyclopropyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-(2-(4-((2-acetamidoethoxy)methyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide; 1-(1-(2-((3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazole-4-carboxylic acid; 1-(1-(2-((3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazole-4-carboxamide; 1-(1-(2-((3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N-methyl-1H-1,2,3-triazole-4-carboxamide; 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; 1-(2-cyclohexyl-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxy-N-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; 1-(2-(adamantan-1-yl)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxy-N-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylpentanoyl)-4-hydroxy-N-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; N-(1-(2-chloro-4-(4-methylthiazol-5-yl)phenyl)ethyl)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide; 1-(2-(adamantan-1-yl)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-N-(1-(2-chloro-4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide; 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 1-(2-cyclohexyl-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methyl-3-phenylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 1-(2-(4-benzyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 1-(3,3-dimethyl-2-(4-(1-(trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 1-(3,3-dimethyl-2-(4-(1-methylcyclopropyl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 1-(2-(4-(1-ethynylcyclopropyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 1,1'-(2,2'-(cyclopropane-1,1-diylbis(1H-1,2,3-triazole-4,1-diyl))bis(3,3-dimethylbutanoyl))bis(4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide); N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-4-hydroxy-1-(3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-4-hydroxy-1-(3-methyl-2-(5-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide; Methyl 1-(1-(2-((3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxylate; 1-(1-(2-((3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid; 1-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-3-methylbutanoyl)-N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-4-hydroxypyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-(2-(4,5-dimethyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-(2-(4,5-dimethyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-4-hydroxy-1-(3-methyl-2-(4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-(2-(4-(furan-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-(2-(4-cyano-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide; N-(3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-(2-(4-fluoro-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide; 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2,2,2 trifluoro-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-(1-(2'-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide; 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((2'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxamide; N-(1-([1,1'-biphenyl]-4-yl)-2-amino-2-oxoethyl)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide; 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-(4-methylthiazol-5-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)pyrrolidine-2-carboxamide; and N-(1-(2'-chloro-[1,1'-biphenyl]-4-yl)ethyl)-1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, are provided herein.

[0125] The compound names contained in Table 1 and the list in the above paragraphs were obtained from ChemDraw (登録商標) Auto-generated using software version 18.2.0.48.

[0126] The VHL ligands described herein may exist in solid or liquid form. In the solid state, the ligands may exist in crystalline or non-crystalline form, or as a mixture thereof. Those skilled in the art will understand that pharma- ceutically acceptable solvates may be formed for crystalline or non-crystalline compounds. In crystalline solvates, solvent molecules are incorporated into the crystal lattice during crystallization. Solvates may include non-aqueous solvents, such as but not limited to ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or may include water as the solvent incorporated into the crystal lattice. Solvates in which water is the solvent incorporated into the crystal lattice are generally referred to as "hydrates". Hydrates include stoichiometric hydrates, as well as compositions containing varying amounts of water. The subject matter described herein includes such solvates.

[0127] Those skilled in the art will further appreciate that certain VHL ligands described herein that exist in crystalline forms, including various solvates thereof, may exhibit polymorphism (i.e., the ability to occur in different crystal structures). These different crystalline forms are typically known as "polymorphs". The subject matter disclosed herein includes such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometric arrangement, and other descriptive properties of the crystalline solid state. Thus, polymorphs may have different physical properties, such as shape, density, hardness, deformability, stability, and dissolution properties. 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 appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents used to prepare the compound. For example, changes in temperature, pressure, or solvents may result in polymorphism. Additionally, one polymorph may spontaneously transform into another polymorph under certain conditions.

[0128] The VHL ligands described herein, or pharma- ceutically acceptable salts thereof, may exist in stereoisomeric forms (e.g., containing one or more asymmetric carbon atoms). Each stereoisomer (enantiomer and diastereomer) and mixtures thereof are within the scope of the subject matter disclosed herein. Similarly, it is understood that compounds or salts of formula (I) may exist in tautomeric forms other than those shown in the formula, which are also within the scope of the subject matter disclosed herein. It should be understood that the subject matter disclosed herein includes combinations and subgroups of the specific groups described herein. The scope of the subject matter disclosed herein includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically / diastereomerically enriched mixtures. It should be understood that the subject matter disclosed herein includes combinations and subgroups of the specific groups defined hereinabove.

[0129] The subject matter disclosed herein also includes isotopically labeled forms of the compounds described herein except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds described herein and their pharma- ceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, e.g., 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 can be mentioned.

[0130] Pharmaceutically acceptable salts of the VHL ligands disclosed herein, and which contain the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of the presently disclosed subject matter. Isotopically labeled compounds, e.g. 3 H, 14 Disclosed herein are those incorporating radioactive isotopes such as C, which are useful for drug and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) Isotopes are commonly used because of their ease of preparation and detectability. 11 C and 18 F isotopes are useful in PET (positron emission tomography), 125 I isotopes are useful in SPECT (single photon emission computed tomography), all of which are useful in brain imaging. In addition, deuterium, i.e. 2Substitution with heavier isotopes such as H can confer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopically labeled compounds of formula I can generally be prepared by following the procedures disclosed in the following schemes and / or examples by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0131] In some embodiments, the VHL ligands provided herein are incorporated into heterobifunctional molecules. In some embodiments, the heterobifunctional molecules are (i) VHL ligands provided herein, and (ii) chemical decomposition inducers (CIDEs) having a moiety capable of binding to a protein of interest targeted for degradation, where (i) and (ii) are covalently linked. In some embodiments, (i) and (ii) are covalently linked via a linker moiety, such as a polyethylene glycol (PEG) chain or an alkyl chain. In some embodiments, the CIDE can selectively degrade a target protein by forming a ternary complex between the target protein, the heterobifunctional molecule described herein, and a ubiquitin ligase. In some aspects, the ubiquitin ligase is a VHL E3 ubiquitin ligase. By way of example and not limitation, the target protein can be, for example, a structural protein, an enzyme, a receptor, or a cell surface protein.

[0132] In some embodiments, the heterobifunctional molecule has formula (II): [A]-[B]-[C](II) wherein [A] is a portion of a VHL ligand provided herein, [B] is a linker moiety, and [C] is a protein-binding moiety.

[0133] III. Preparations In a further aspect, the present disclosure provides therapeutic or pharmaceutical compositions comprising an effective amount of at least one compound described herein, including, for example, at least one VHL ligand. A pharmaceutical composition comprising an effective amount of at least one VHL ligand of the present disclosure, and optionally one or more of the compounds otherwise described herein, in combination with a pharma- ceutical effective amount of a carrier, excipient, or diluent, and optionally an additional bioactive agent, represents a further aspect of the present disclosure.

[0134] In certain embodiments, the composition comprises pharmaceutically acceptable salts, particularly acid or base addition salts of the compounds described herein.The acids used to prepare the pharmaceutically acceptable acid addition salts of the above-mentioned base compounds include those that form non-toxic acid addition salts, i.e., salts that contain pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, sugar, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3 naphthonate)], among many others.

[0135] Pharmaceutically acceptable base addition salts can also be used to make pharmaceutically acceptable salt forms of compounds or derivatives.The chemical salts that can be used as reagents to prepare pharmaceutically acceptable base salts of the compounds of the present invention that are acidic in nature are those that form non-toxic base salts of such compounds.Such non-toxic base salts include, but are not limited to, those 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 such as N-methylglucamine-(meglumine), and the lower alkanol ammonium and other base salts of pharmaceutically acceptable organic amines.

[0136] The compositions described herein can be administered in certain embodiments by oral, parenteral, or topical routes in single or divided unit doses. Administration of the compounds can range from continuous (intravenous drip) to multiple oral doses per day (e.g., QID) and can include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may contain a penetration enhancer), buccal, sublingual, and suppository administration, by inhalation spray, rectal, vaginal, or by implanted reservoir, among other routes of administration. Enteric-coated oral tablets can also be used to improve the bioavailability of the compounds from oral routes of administration. The most effective dosage form will vary depending on the pharmacokinetics of the particular agent selected and the severity of the disease in the patient. Administration of the compounds according to the present disclosure as a spray, mist, or aerosol for intranasal, intratracheal, or pulmonary administration can also be used. Therefore, the present disclosure also relates to pharmaceutical compositions comprising an effective amount of the compound according to the present disclosure, optionally combined with a pharma- ceutically acceptable carrier, additive, or excipient.The compound according to the present disclosure can be administered in immediate release, intermediate release, or sustained or controlled release form.The sustained or controlled release form is preferably administered orally, but may also be administered in suppository, transdermal, or other topical form.Intramuscular injection in liposomal form can also be used to control or sustain the release of the compound at the injection site.

[0137] Thus, in one embodiment, the pharmaceutical formulations of the VHL ligands described herein may be prepared for parenteral administration in unit dose injectable form using a pharma- ceutical acceptable parenteral vehicle. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. The VHL ligands with the desired purity may be mixed with one or more pharma- ceutical acceptable excipients (Remington's Pharmaceutical Sciences (1980) 16th ed., Osol, A. Ed.) in the form of a lyophilized formulation or an aqueous solution for reconstitution.

[0138] The compositions of the present disclosure can be formulated in a conventional manner using one or more pharma-ceutically acceptable carriers, and can also be administered in controlled release formulations.The compounds of the present disclosure can be formulated according to standard pharmaceutical practice as pharmaceutical compositions.According to this aspect, there is provided a pharmaceutical composition comprising a VHL ligand as described herein in combination with one or more pharma-ceutically acceptable excipients.

[0139] A typical formulation is prepared by mixing the compound of the present disclosure with an excipient, such as a carrier and / or diluent.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 water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, and water.The specific carrier, diluent, or other excipient used depends on the means and purpose for which the compound is utilized. Other pharma- ceutically acceptable 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, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, and partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, polyethylene glycol, and wool fat).

[0140] Solvents are generally selected based on those recognized by those skilled in the art as safe (GRAS) for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), and the like, and mixtures thereof. Acceptable diluents, carriers, additives, and stabilizers are non-toxic to recipients at the dosages and concentrations used, and include buffers and other organic acids, such as phosphate, citrate, and methionine; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; blood 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 dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt forming counterions such as sodium; metal complexes (e.g. Zn-protein complexes); and / or non-ionic surfactants such as TWEEN®, PLURONICS® or polyethylene glycol (PEG).

[0141] The formulations may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, aromas, flavoring agents, and other known additives to provide an elegant presentation of the VHL ligand or to aid in the manufacture of pharmaceutical preparations. The formulations may be prepared using conventional dissolution and mixing procedures.

[0142] Formulation may be carried out by mixing at ambient temperature, at an appropriate pH, and at the desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to recipients at the dosages and concentrations employed. The pH of the formulation will depend primarily on the particular application and concentration of compound, but may range from about 3 to about 8. Formulation in acetate buffer at pH 5 is a suitable embodiment.

[0143] The pharmaceutical composition may be in the form of a sterile injectable preparation, such as a sterile aqueous or oleaginous injectable suspension. In particular, preparations used for in vivo administration must be sterile. Such sterilization is easily achieved by filtration through a sterile filtration membrane. The suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as 1,3-butanediol. The sterile injectable preparation may also be prepared as a lyophilized powder. Acceptable excipients and solvents that may be utilized include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils may be conventionally used as a solvent or suspending medium. For this purpose, any bland, fixed oil may be employed, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used in the preparation of injectables, and natural pharma- ceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. Such oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, such as Ph.Helv or a similar alcohol.

[0144] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0145] The pharmaceutical compositions described herein can be orally administered in any orally acceptable dosage form, including but not limited to capsule, tablet, aqueous suspension or solution.For tablets for oral use, commonly used carriers include lactose and cornstarch.Lubricants such as magnesium stearate are also usually added.For oral administration in capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspension is required for oral use, active ingredient is combined with emulsifier and suspending agent.If desired, certain sweeteners, flavors or colorants can also be added.

[0146] Alternatively, the pharmaceutical compositions described herein can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the agent. Such materials include cocoa butter, beeswax and polyethylene glycol.

[0147] The pharmaceutical compositions described herein can also be administered locally.Suitable topical formulations are readily prepared for each of these areas or organs.Local administration to the lower digestive tract can be achieved by a rectal suppository formulation (see above) or a suitable enema formulation.Topically acceptable transdermal patches can also be used.

[0148] For topical administration, pharmaceutical compositions can be formulated in suitable ointments, which contain active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.In certain preferred embodiments of the present disclosure, the compounds can be coated on the stent that is surgically implanted in the patient, so as to inhibit or reduce the possibility of the stent causing blockage in the patient.

[0149] Alternatively, the pharmaceutical composition may be formulated with a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharma- ceutically acceptable carriers, including but not limited to mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0150] For ophthalmic use, the pharmaceutical composition may 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 a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment such as petrolatum.

[0151] The pharmaceutical compositions of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the art of pharmaceutical formulation and may be prepared as a saline solution using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0152] The VHL ligand compositions may typically be stored as a solid composition, a lyophilized formulation, or an aqueous solution.

[0153] Pharmaceutical compositions comprising the VHL ligands of the present disclosure may be formulated, dosed and administered in a manner consistent with good medical practice, i.e., in amounts, concentrations, schedules, courses, vehicles and routes of administration. Factors to be considered in this regard include the particular disease being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disease, the site of delivery of the drug, the method of administration, the administration schedule, and other factors known to medical practitioners. The "therapeutically effective amount" of the compound administered is governed by such considerations and is the minimum amount necessary to prevent, ameliorate or treat the disorder. Such an amount is preferably below an amount that is toxic to the host or makes the host more susceptible to unwanted side effects.

[0154] VHL ligands are formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug, allowing patients to comply with the prescribed regimen. Pharmaceutical compositions (or formulations) for application may be packaged in a variety of ways, depending on the method used to administer the drug. Generally, the article for distribution includes a container in which the pharmaceutical formulation is disposed in a suitable form. Suitable containers are well known to those skilled in the art, and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may include a tamper-proof assembly to prevent unintentional access to the contents of the package. In addition, the container has a label disposed thereon that describes the contents of the container. The label may also include appropriate warnings.

[0155] The formulations may be packaged in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water, immediately prior to use for injection. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or daily sub-dose of the active ingredient, as herein above recited, or an appropriate fraction thereof.

[0156] It must also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician, and the severity of the particular disease or condition being treated.

[0157] A patient or subject in need of treatment with a compound according to the present disclosure may be treated by administering to the patient (subject) an effective amount of a compound according to the present disclosure, including a pharma- ceutically acceptable salt, solvate or polymorph thereof, optionally in a pharma- ceutically acceptable carrier or diluent, either alone or in combination with other known erythropoiesis stimulating agents otherwise identified herein.

[0158] The active compound is included in a pharma- ceutically acceptable carrier or diluent in an amount sufficient to deliver to the patient a therapeutically effective amount for the desired indication without causing serious toxic effects to the patient being treated. Preferred doses of the active compound for the conditions referred to herein are in the range of about 10 ng / kg to 300 mg / kg, preferably 0.1 to 100 mg / kg per day, more typically 0.5 to about 25 mg per kg of recipient / patient body weight per day. Typical daily dosages may range from about 1 μg / kg to 100 mg / kg, depending on the factors mentioned above. Typical topical doses range from 0.01 to 5% wt / wt in a suitable carrier.

[0159] The compounds are conveniently administered in any suitable unit dosage form, including, but not limited to, those containing less than 1 mg, between 1 mg and 3000 mg, preferably between 5 and 500 mg of active ingredient per unit dosage form. An oral dose of about 25 to 250 mg is often convenient.

[0160] The active ingredient is preferably administered to achieve a peak plasma concentration of the active compound 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 saline or aqueous medium, or administered as a bolus of the active ingredient. Oral administration is also suitable for producing an effective plasma concentration of the active agent.

[0161] The concentration of active compound in pharmaceutical composition depends on the absorption, distribution, inactivation and excretion rate of the drug, and other factors known to those skilled in the art. It should be noted that dosage value also varies according to the severity of the condition to be alleviated. It should be further understood that for any particular subject, specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration range described herein is merely exemplary and is not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered once or divided into multiple small doses that are administered at various time intervals.

[0162] In one embodiment, active compound is prepared with carriers that prevent compound from being rapidly removed from the body, such as controlled release formulations, such as implants and microencapsulated delivery systems.Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used.The method of preparing such formulations will be clear to those skilled in the art.

[0163] The liposome suspension can also be a pharmaceutically acceptable carrier. These can be prepared according to methods known to those skilled in the art, such as those described in U.S. Patent No. 4,522,811, which is incorporated herein by reference in its entirety. For example, liposome formulations can be prepared by dissolving appropriate lipids (e.g., stearoyl phosphatidylethanolamine, stearoyl phosphatidylcholine, arachidoyl phosphatidylcholine, and cholesterol) in an inorganic solvent and then evaporating to leave a thin film of dried lipid on the surface of the container. Next, an aqueous solution of the active compound is introduced into the container. Then, the container is rotated by hand to release the lipid material from the sides of the container and disperse the lipid aggregates to form a liposome suspension.

[0164] The term "pharmaceutically acceptable salt" is used throughout this specification, where applicable, to describe the salt forms of one or more of the compounds described herein that are presented to increase the solubility of the compound in the gastric juice of the patient's gastrointestinal tract in order to facilitate the dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include, where applicable, those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include, among many other acids and bases well known in the pharmaceutical art, those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium, and ammonium salts. Sodium and potassium salts are particularly preferred as neutralizing salts of phosphates according to the present disclosure.

[0165] The term "pharmaceutically acceptable derivative" is used throughout this specification to describe any pharmaceutically acceptable prodrug form (e.g., ester, amide, other prodrug groups) that, when administered to a patient, directly or indirectly provides the compound of the invention, or an activated metabolite of the compound of the invention.

[0166] The subject matter further provides veterinary compositions comprising at least one active ingredient as defined above together with a veterinary carrier for the active ingredient. The veterinary carrier is a material useful for the purposes of administration of the composition and may be a solid, liquid, or gaseous material that is otherwise inert or acceptable in the veterinary arts and compatible with the active ingredient. These veterinary compositions may be administered parenterally or by any other desired route.

[0167] IV. Indications and Treatment Methods It is contemplated that the VHL ligand disclosed herein can be used to treat various diseases, disorders or conditions.Therefore, it is understood that any one of the compounds provided herein can be used to treat the disease or condition regulated by VHL, such as any of the diseases and conditions listed herein.It is also understood that any one of the compounds provided herein can find use in the preparation of medicine for the treatment of the condition regulated by VHL, such as any of the diseases and conditions listed herein.

[0168] It is contemplated that the compounds disclosed herein can be used for treatment. The compounds disclosed herein can also be referred to for diseases or indications related to VHL activity, such as diseases or indications in Zhang et al., J.Med.Chem.219,62,5725-5749, the entirety of which is incorporated herein by reference, in particular indications and diseases disclosed therein, including anemia, ischemia and tumor-related conditions. It is therefore understood that any one of the compounds provided herein can be used in the treatment of conditions regulated by VHL. In some embodiments, the VHL ligands disclosed herein can be used to treat cancers involved by VHL regulation. In some embodiments, the VHL ligands disclosed herein can be used to treat solid tumors. In some embodiments, the solid tumor is breast cancer (such as triple-negative breast cancer), lung cancer, multiple myeloma or renal cell carcinoma (RCC).

[0169] In another aspect, the present invention relates to a method for enhancing erythropoiesis in a patient or subject, comprising administering to said patient or subject an effective amount of at least one compound described above, optionally in combination with an additional erythropoiesis-promoting compound. The method according to the present invention can be used to increase the patient's red blood cells (red blood cells) and / or hematocrit by administering an effective amount of at least one compound described herein. A further method aspect of the present invention relates to treating anemia, including chronic anemia or ischemia, in a patient or subject in need of such treatment, comprising administering to a patient in need thereof an effective amount of at least one compound according to the present invention. The method according to the present invention can be used to treat chronic anemia, such as anemia associated with chronic kidney disease, dialysis and chemotherapy, and ischemia, including focal ischemia, stroke and cardiovascular ischemia, and limit the damage resulting from these disease states and / or conditions.

[0170] Further method aspects of the present invention relate to promoting wound healing and reducing scar tissue formation during wound healing by administering one or more compounds according to the present invention to a patient in need thereof. Further methods include inducing local angiogenesis in a patient or subject in need thereof by administering an effective amount of at least one compound of the present invention, optionally in combination with an additional erythropoiesis-promoting compound. Methods of promoting erythropoiesis, including increasing red blood cell count and / or hematocrit in a subject or patient, anemia, including chronic anemia and anemia associated with chronic kidney disease, dialysis, and cancer chemotherapy, ischemia, cardiovascular tissue damage during stroke and cardiovascular ischemia, and enhancing the wound healing process and preventing / reducing scarring associated with or secondary to the healing process represent additional aspects of the present invention.

[0171] Another method of the invention relates to the local enhancement of angiogenesis by induction of VEGF in a patient or subject using at least one compound according to the invention in combination with an erythropoiesis-promoting compound as described elsewhere herein.A further method of the invention relates to the reduction and / or inhibition of occlusion of a stent surgically implanted in a patient or subject.

[0172] The compounds described herein can be administered to patients to treat some diseases, disorders, or conditions. In some embodiments, the administration of the compounds described herein promotes erythropoiesis in patients or subjects, including inducing EPO production in patients or subjects. In other embodiments, the administration of the compounds described herein promotes the treatment of chronic anemia and ischemia (which limits brain damage during ischemia, ischemia, and / or stroke episodes, and cardiovascular tissue damage during cardiovascular ischemia), and wound healing processes. Methods of treating the erythropoiesis of a subject or patient, including increasing the number of red blood cells and / or hematocrit in patients, treating anemia including chronic anemia and anemia associated with chronic kidney disease, dialysis, and cancer chemotherapy, ischemia, stroke, and cardiovascular tissue damage during cardiovascular ischemia, and enhancing wound healing processes, and preventing / reducing scarring secondary to healing, represent further treatment aspects of the present invention. Local enhancement of angiogenesis through induction of VEGF, including wound healing and reduction of stent occlusion, remains a further aspect of the present invention.

[0173] Also provided herein is the use of the compounds described herein in the manufacture of a medicament for use in the treatment of some diseases, disorders, and conditions. In one embodiment, provided herein is the use of the compounds described herein in the manufacture of a medicament for use in 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, provided herein is the use of the compounds described herein in the manufacture of a medicament for use in the treatment of ischemia, stroke, or damage to the cardiovascular system during ischemia, or any combination thereof. In some embodiments, provided herein is the use of the compounds described herein in the manufacture of a medicament for use in promoting wound healing in a human in need thereof. In other embodiments, provided herein is the use of the compounds described herein in the manufacture of a medicament for use in reducing scarring secondary to wound healing in a human in need thereof. In some embodiments, provided herein is the use of the compounds described herein in the manufacture of a medicament for use in enhancing angiogenesis or arteriogenesis or both in a human in need thereof. In certain embodiments, the enhancement of angiogenesis or arteriogenesis or both occurs locally in the human. In some embodiments, provided herein is the use of a compound as described herein in the manufacture of a medicament for use in reducing the likelihood of stent obstruction in a human in need thereof.

[0174] Also provided herein are compounds as described elsewhere herein for use in treating 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, provided herein are compounds as described elsewhere herein for use in treating ischemia, stroke, or damage to the cardiovascular system during ischemia, or any combination thereof. In some embodiments, provided herein are compounds as described elsewhere herein for use in promoting wound healing in a human in need of wound healing. In other embodiments, provided herein are compounds as described elsewhere herein for use in reducing scarring secondary to wound healing in a human in need of reduced scarring secondary to wound healing. In some embodiments, provided herein are compounds as described elsewhere herein for use in enhancing angiogenesis or arteriogenesis or both in a human in need of enhanced angiogenesis or arteriogenesis or both. In some embodiments, the enhanced angiogenesis or arteriogenesis or both occurs locally in the human. In some embodiments, provided herein are compounds, as described elsewhere herein, for use in reducing the likelihood of stent occlusion in a human in need thereof.

[0175] The term "co-administration" or "combination therapy" must mean that at least two compounds or compositions are administered to a patient at the same time, so that the effective amount or concentration of each of the two or more compounds can be found in the patient at a given time. The compounds according to the present invention can be administered to a patient at the same time, but this term encompasses both administration of two or more agents at the same time or at different times, provided that the effective concentration of all co-administered compounds or compositions is found in the subject at a given time. In certain preferred embodiments of the present invention, the one or more compounds described above are co-administered in combination with at least one additional bioactive agent having erythropoiesis stimulating activity as described elsewhere herein to enhance erythropoietin, treat chronic anemia and ischemia (limiting brain damage during ischemia, ischemia and / or stroke episodes, and damage to cardiovascular tissue during cardiovascular ischemia), and enhance wound healing processes, promote angiogenesis, and inhibit or prevent occlusion in surgically implanted stents. In particularly preferred embodiments of the invention, the co-administration of the compounds results in synergistic erythropoietic activity and / or therapy.

[0176] The term "additional erythropoietin enhancer" is intended to mean a conventional polypeptide such as EPO (procrete or epogen) or dalbapoietin alfa (a synthetic form of erythropoietin).

[0177] The composition of the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, and can be administered in controlled release formulations.The pharmaceutically acceptable 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, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0178] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0179] The sterile injectable form of the composition of the present invention can be aqueous or oily suspension.These suspensions can be formulated according to the techniques known in the art using suitable dispersing or wetting agents and suspending agents.Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol.

[0180] Acceptable excipients and solvents that can be utilized include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for the preparation of injectables, as are natural pharma-ceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated versions. Such oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as Ph.Helv or similar alcohols.

[0181] The pharmaceutical composition of the present invention can be orally administered in any orally acceptable dosage form, including but not limited to capsule, tablet, aqueous suspension or solution.For oral tablets, commonly used carriers include lactose and cornstarch.Lubricants such as magnesium stearate are also usually added.For oral administration in capsule form, useful diluents include lactose and dry cornstarch.When aqueous suspension is required for oral use, active ingredient is combined with emulsifier and suspending agent.If desired, certain sweeteners, flavors or colorants can also be added.

[0182] Alternatively, the pharmaceutical composition of the present invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the agent. Such materials include cocoa butter, beeswax and polyethylene glycol.

[0183] The pharmaceutical composition of the present invention may also be administered locally. Suitable topical formulations are readily prepared for each of these areas or organs. Local administration to the lower digestive tract can be achieved by a rectal suppository formulation (see above) or a suitable enema formulation. Topically acceptable transdermal patches may also be used. For topical administration, the pharmaceutical composition may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. In certain preferred embodiments of the present invention, the compound may be coated on a stent that is surgically implanted in a patient to inhibit or reduce the possibility of blockage occurring in the patient's stent.

[0184] Alternatively, the pharmaceutical composition may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharma- ceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyl dodecanol, benzyl alcohol and water.For use in the ophthalmic field, the pharmaceutical composition may 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 a preservative, such as benzylalkonium chloride.Alternatively, for use in the ophthalmic field, the pharmaceutical composition may be formulated in an ointment, such as petrolatum.

[0185] The pharmaceutical compositions of the invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the art of pharmaceutical formulation and may be prepared as saline solutions using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0186] The amount of compound in the pharmaceutical composition of the present invention that can be combined with carrier materials to produce a single dosage form varies depending on the host and disease to be treated, the specific mode of administration.Preferably, the composition should be formulated to contain about 0.05 milligrams to about 750 milligrams or more, more preferably about 1 milligram to about 600 milligrams, even more preferably about 10 milligrams to about 500 milligrams of active ingredient alone or in combination with at least one other compound according to the present invention or erythropoiesis-promoting agent (EPO, dalbapoetin alpha), particularly for enhancing red blood cell production, treating chronic anemia and ischemia (limiting brain damage during ischemia, ischemia and / or stroke episodes and cardiovascular tissue damage during cardiovascular ischemia), and enhancing wound healing process, promoting angiogenesis, inhibiting or preventing occlusion in surgically implanted stents.

[0187] It must also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician, and the severity of the particular disease or condition being treated.

[0188] Patients or subjects in need of treatment using the compounds according to the invention may be treated by administering to the patient (subject) an effective amount of the compounds according to the invention (including pharma- ceutically acceptable salts, solvates or polymorphs thereof), optionally in a pharma- ceutically acceptable carrier or diluent, alone or in combination with other known erythropoiesis-stimulating agents as otherwise specified herein. These compounds may be administered by any suitable route, for example orally, parenterally, intravenously, intradermally, subcutaneously, or topically, including transdermally, in liquid, cream, gel, or solid form, or in aerosol form. The active compound is included in the pharma- ceutical acceptable carrier or diluent in an amount sufficient to deliver to the patient a therapeutically effective amount for the desired indication without causing serious toxic effects to the patient being treated. The preferred dose of the active compound for all conditions mentioned herein ranges from about 10 ng / kg to 300 mg / kg per kilogram of recipient / patient body weight per day, preferably 0.1 to 100 mg / kg per day, more typically 0.5 to about 25 mg per day. Typical topical doses range from 0.01 to 5% wt / wt in a suitable carrier. The compounds are conveniently administered in any suitable unit dosage form, including but not limited to those containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. An oral dose of about 25 to 250 mg is often convenient.

[0189] The active ingredient is preferably administered to achieve a peak plasma concentration of the active compound of about 0.00001-30 mM, preferably about 0.1-30 μM. This may be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in saline or aqueous medium, or administered as a bolus of the active ingredient. Oral administration is also suitable for producing an effective plasma concentration of the active agent.

[0190] The concentration of active compound in pharmaceutical composition depends on the absorption, distribution, inactivation and excretion rate of drug and other factors known to those skilled in the art.It should be noted that dosage value also varies according to the severity of the condition to be alleviated.It should be further understood that for any specific subject, specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person who administers or monitors the administration of the composition, and the concentration ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions.

[0191] The active ingredient may be administered at once or may be divided into a number of small doses to be administered at various time intervals. Oral compositions generally include an inert diluent or an edible carrier. Oral compositions may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative may be incorporated with an excipient and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, troches, and the like may contain any of the following ingredients, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch, lactose, dispersing agents such as alginic acid, primogel, corn starch, and the like; lubricants such as magnesium stearate, sterotes, and the like; lubricants such as colloidal silicon dioxide; sweeteners such as sucrose, saccharin, and the like; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.Furthermore, the unit dosage form may contain various other materials which modify the physical form of the unit dosage form, for example, coatings of sugar, shellac, or enteric agents.

[0192] The active compound or its pharmaceutically acceptable salts can be administered as a component of elixirs, suspensions, syrups, wafers, chewing gums, etc. The syrups can contain, in addition to the active compound, sucrose as a sweetener, as well as certain preservatives, dyes and colorings, and flavorings. The active compound or its pharmaceutically acceptable salts can also be mixed with other active substances that do not impair the desired action, or with substances that complement the desired action, such as erythropoietin stimulating agents, including EPO and dalbapoetin alpha, among others. In certain preferred embodiments of the present invention, one or more compounds according to the present invention are co-administered with another bioactive agent, such as a red blood cell purification promoter or a wound healing agent, including antibiotics, as described in other ways herein.

[0193] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may contain the following components: a sterile diluent, such as water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol, methylparaben; antioxidants such as ascorbic acid, sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates, and agents for adjusting isotonicity, such as sodium chloride or dextrose. Parenteral preparations may be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic. For intravenous administration, the preferred carrier is saline or phosphate buffered saline (PBS). 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, such as implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid may be used. Methods for preparation of such formulations will be apparent to those skilled in the art.

[0194] Liposomal suspensions can also be pharma- ceutically acceptable carriers. They 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 (incorporated herein by reference in its entirety). For example, liposomal formulations can be prepared by dissolving suitable lipids (e.g., stearoyl phosphatidylethanolamine, stearoyl phosphatidylcholine, aracadyl phosphatidylcholine, and cholesterol) in an inorganic solvent, followed by evaporation, leaving a thin film of dry lipid on the surface of the container. An aqueous solution of active compound is then introduced into the container. The container is then rotated by hand to free lipid material from the sides of the container and disperse lipid aggregates, forming a liposomal suspension.

[0195] V. Manufactured products In another aspect, articles of manufacture are described herein, for example "kits" are provided that contain materials useful for treating the above diseases and disorders. The kits include a container that contains a VHL ligand. The kits may further include a label or package insert on or associated with the container. The term "package insert" is used to refer to instructions that are typically included in commercial packages of therapeutic agents, including information about the indications, usage, dosage, administration, contraindications, and / or warnings regarding the use of such therapeutic agents.

[0196] Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. A "vial" is a container suitable for holding a liquid or lyophilized preparation. In one embodiment, the vial is a single-use vial, e.g., a 20cc single-use vial with a stopper. The container can be formed from a variety of materials, such as glass or plastic. The container can hold a VHL ligand or a formulation thereof effective to treat a condition and can have a sterile access port (e.g., the container can be an intravenous solution bag or a vial with a stopper that can be punctured by a hypodermic needle).

[0197] At least one active agent in the composition is a VHL ligand of the present disclosure. The label or package insert indicates that the composition is used to treat a selected condition, such as cancer. Additionally, the label or package insert can indicate that the patient being treated is a patient with a disorder, such as a hyperproliferative disorder, neurodegeneration, cardiac hypertrophy, pain, migraine, or neurotraumatic disease or event. In one embodiment, the label or package insert indicates that the composition comprising a VHL ligand can be used to treat a disorder resulting from abnormal cell growth. The label or package insert may also indicate that the composition can be used to treat other disorders. Alternatively or additionally, the article of manufacture may further comprise a second container comprising a pharma- ceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. The article of manufacture may further comprise other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0198] The kit may further comprise instructions for administration of the VHL ligand and, if present, the second pharmaceutical formulation. For example, if the kit comprises a first composition comprising a VHL ligand and a second pharmaceutical formulation, the kit may further comprise instructions for simultaneous, sequential or separate administration of the first and second pharmaceutical compositions to a patient in need thereof.

[0199] In another embodiment, the kit is suitable for delivery of solid oral forms of VHL ligand, such as tablets or capsules. Such kits preferably include several unit dosages. Such kits may include a card with dosages arranged in the order of their intended use. An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used to package pharmaceutical unit dosage forms. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings, or with a calendar insert, that designates the days in the treatment schedule on which dosages can be administered.

[0200] According to one embodiment, the kit may include (a) a first container containing a VHL ligand, and optionally (b) a second container containing a second pharmaceutical formulation comprising a second compound having anti-hyperproliferative activity. Alternatively or additionally, the kit may further include a third container containing a pharma- ceutical acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. The article of manufacture may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0201] In certain other embodiments where the kit comprises a VHL ligand and a second therapeutic agent, the kit may comprise a container for containing the separate compositions, such as a divided bottle or a divided foil packet, although the separate compositions may be contained within a single undivided container. Typically, the kit comprises instructions for administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician. EXAMPLES

[0202] VI. Working Examples The following examples are provided by way of illustration, not by way of limitation. Some of the compounds used in the following examples are tautomers. Although the examples of these compounds provided below show only single tautomers, these examples should not be viewed in a limiting sense, rather, the corresponding tautomers are also intended and encompassed by the following examples as if each and every tautomer of the compound was shown individually.

[0203] Abbreviation The following abbreviations are used in the examples:

[0204] ABPR-Automatic Back Pressure Regulator

[0205] Ac 2 O-Acetic anhydride

[0206] ACN - Acetonitrile

[0207] Boc-tert-butyloxycarbonyl

[0208] CDCl 3 -Deuterated chloroform

[0209] Cy 3 PHBF 4 -Tricyclohexylphosphine tetrafluoroborate

[0210] DBU-1,8-diazabicyclo[5.4.0]undec-7-ene

[0211] DCE-1,2-Dichloroethane

[0212] DCM - Dichloromethane

[0213] DEA - Diethanolamine

[0214] DIPEA or DIEA-N,N-Diisopropylethylamine

[0215] DME - Dimethoxyethane

[0216] DMF - Dimethylformamide

[0217] DMEM - Dulbecco's Modified Eagle Medium

[0218] DMSO - Dimethyl sulfoxide

[0219] DTT-Dithiothreitol

[0220] EDCI-N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

[0221] EDTA-Ethylenediaminetetraacetic acid

[0222] ESI-electrospray ionization

[0223] Et 3 N-Trimethylamine

[0224] EtOAc - Ethyl acetate

[0225] EtOH - Ethanol

[0226] FA-Formic Acid

[0227] Fmoc-Fluorenylmethyloxycarbonyl

[0228] HATU-1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0229] HEPES-4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid

[0230] Hex

[0231] HOAc - Acetic acid

[0232] HOBt or HOBT- Hydroxybenzotriazole

[0233] HPLC - High Performance Liquid Chromatography

[0234] KOAc - Potassium Acetate

[0235] LC / MS or LCMS - Liquid Chromatography Mass Spectrometry

[0236] LDA - Lithium Diisopropylamide

[0237] LiHMDS - Lithium bis(trimethylsilyl)amide

[0238] MeI - Methyl iodide

[0239] MeOH - Methanol or Methyl Alcohol

[0240] MeONa or NaOMe - Sodium Methoxide

[0241] MSD - Mass Selective Detector

[0242] MeSO 2 Sodium methanesulfinate

[0243] MTBE: Methyl tert-butyl ether

[0244] NBS-N-Bromosuccinimide

[0245] n-BuLi - Butyl lithium

[0246] (n-Bu) 3 SnCl - Tributyrin chloride

[0247] NIS-N-iodosuccinimide

[0248] NMP-N-Methyl-2-pyrrolidone

[0249] NMR-Nuclear Magnetic Resonance

[0250] PBS - Phosphate Buffered Saline

[0251] Pd / C - Palladium on carbon

[0252] Pd(dppf)Cl 2 .CH 2 Cl 2 -[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane

[0253] Pd(PPh 3 ) 4-Tetrakis(triphenylphosphine)palladium

[0254] PEG - Polyethylene glycol

[0255] Ph 3 P-Triphenylphosphine

[0256] PPTS-Pyridinium p-Toluenesulfonate

[0257] SFC - Supercritical Fluid Chromatography

[0258] TAMRA-Carboxytetramethylrhodamine

[0259] TBAF-Tetrabutylammonium Fluoride

[0260] TBS-tert-butyldimethylsilyl

[0261] TBSCl-tert-butyldimethylsilyl chloride

[0262] tBuOK - Potassium tert-butoxide

[0263] TCEP-Tris(2-carboxyethyl)phosphine

[0264] TEA - Triethylamine

[0265] TFA - Trifluoroacetic acid

[0266] THF - Tetrahydrofuran

[0267] TMSCN - Trimethylsilyl cyanide

[0268] TMSI - Trimethylsilyl iodide

[0269] TMSOTf-Trimethylsilyl trifluoromethanesulfonate

[0270] TsCl-4-Toluenesulfonyl Chloride

[0271] TsOH-Toluenesulfonic acid

[0272] UV-ultraviolet light

[0273] LC / MS method Method A: Experiments performed on a SHIMADZU 2020 HPLC with a SHIMADZU MSD mass spectrometer using ESI as the ionization source, using a Shim-Pack XR-ODS C18 50 x 3.0 mm 2.2 μm column and a flow rate of 1.2 ml / min. Solvent A was water with 0.05% TFA, solvent B was acetonitrile with 0.05% TFA, and the gradient consisted of 20-80% solvent B over 3.6 min, 80-100% solvent B over 0.4 min, and held at 100% B for 0.5 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0274] Method B: SHIMADZU using ESI as the ionization source using a Shim-Pack XR-ODS C18 50 x 3.0 mm column and a flow rate of 1.2 ml / min. Experiments performed on a SHIMADZU 2020 HPLC with an MSD mass spectrometer. The solvent system was a gradient starting with 95% water with 0.05% TFA (solvent A) and 5% acetonitrile with 0.05% TFA (solvent B) and increasing to 100% solvent B in 1.1 min. The final solvent system was maintained for an additional 0.6 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0275] Method C: SHIMADZU using ESI as the ionization source, using an Ascentis Express C18 50x2.1mm column and a flow rate of 1.0ml / min. Experiments performed on a SHIMADZU 2020 HPLC with an MSD mass spectrometer. The solvent system was a gradient starting from 95% water with 0.05% TFA (solvent A) and 5% acetonitrile with 0.05% TFA (solvent B) and increasing to 100% solvent B in 1.1 min. The final solvent system was maintained for an additional 0.5 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0276] Method D: Experiments performed on a SHIMADZU 2020 HPLC with a SHIMADZU MSD mass spectrometer using ESI as the ionization source, using a Shim-Pack XR-ODS 50 x 3.0 mm column and a flow rate of 1.2 ml / min. The solvent system was a gradient starting from 95% water with 0.05% TFA (solvent A) and 5% acetonitrile with 0.05% TFA (solvent B) and increasing to 95% solvent B in 2.0 min. The final solvent system was maintained for an additional 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0277] Method E: Experiments performed on a SHIMADZU 2020 HPLC with a SHIMADZU MSD mass spectrometer using ESI as the ionization source, using a CORTECS C18 50x3.1mm column and a flow rate of 1.0ml / min. The solvent system was a gradient starting from 95% water with 0.05% TFA (solvent A) and 5% acetonitrile with 0.05% TFA (solvent B) and increasing to 100% solvent B in 1.1 minutes. The final solvent system was maintained for an additional 0.5 minutes. The LC column temperature was 45°C. UV absorbance was collected from 190nm to 400nm.

[0278] Method F: Experiments performed on a SHIMADZU 2020 HPLC with a SHIMADZU MSD mass spectrometer using ESI as the ionization source, using a Poroshell HPH-C18 50x3.0mm column and a flow rate of 1.2ml / min. Solvent A was 0.05% NH 4 HCO 3Solvent B was water containing 10% CO and solvent B was acetonitrile. The gradient consisted of 10-50% solvent B over 3.5 min, then 50-95% solvent B over 0.5 min, with a hold at 95% B for 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0279] Method G: Experiments performed on a SHIMADZU 2020 HPLC with a SHIMADZU MSD mass spectrometer using ESI as the ionization source, using an XSELECT CSH C18 50x3.0mm column and a flow rate of 1.5ml / min. The solvent system was a gradient starting from 90% water with 0.1% FA (solvent A) and 10% acetonitrile with 0.1% FA (solvent B) increasing to 100% solvent B over 1.1 min. The final solvent system was maintained for an additional 0.6 min. The LC column temperature was 40°C. UV absorbance was collected from 190nm to 400nm.

[0280] Method H: Experiments performed on a SHIMADZU 2020 HPLC with a SHIMADZU MSD mass spectrometer using ESI as the ionization source, using an Accucore C18 50x2.1mm column and a flow rate of 1.0ml / min. The solvent system was a gradient starting from 90% water with 0.1% FA (solvent A) and 10% acetonitrile with 0.1% FA (solvent B) increasing to 95% solvent B over 2 min. The final solvent system was maintained for an additional 0.7 min. The LC column temperature was 40°C. UV absorbance was collected from 190nm to 400nm.

[0281] Method I: Experiments performed on a Shimadzu LCMS-2020 coupled to a SHIMADZU MSD mass spectrometer using ESI as the ionization source. LC separation used a CAPCELL CORE C18, 50 x 2.1 mm column with a flow rate of 1 ml / min. Solvent A was water with 0.05% TFA and solvent B was acetonitrile with 0.05% TFA. The gradient included 5-95% solvent B over 2.0 min, with 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.

[0282] Method J: Experiments performed on a Shimadzu LCMS-2020 coupled to a SHIMADZU MSD mass spectrometer using ESI as the ionization source. LC separation used a Shim-Pack XR-ODS, 50x3.0mm column with a flow rate of 1.2mL / min. Solvent A was water with 0.05% TFA and solvent B was acetonitrile with 0.05% TFA. The gradient included 5-70% solvent B over 3.7 min, 70-95% solvent over 0.2 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.

[0283] Method K: Experiments were performed on a Shimadzu LCMS-2020. LC separation used an Ascentis Express C18, 100 x 4.6 mm column with a flow rate of 1.2 ml / min. Solvent A was water with 0.05% TFA and solvent B was methanol. The gradient included 30-95% solvent B over 10 min with 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.

[0284] Method L: Experiments performed on a Shimadzu LCMS-2020 coupled to a SHIMADZU MSD mass spectrometer using ESI as the ionization source. LC separation was performed using a Kinetex EVO C18, 50 x 2.1 mm column with a flow rate of 1.0 ml / min. Solvent A was 0.05% NH 4 HCO 3 Solvent B was water containing 10% ethanol and solvent B was acetonitrile. The gradient included 10-95% solvent B over 1.1 min, with a hold at 95% B for 0.5 min. The LC column temperature was 35 °C. UV absorbance was collected from 190 nm to 400 nm.

[0285] Method M: Experiments were performed on an HPLC column coupled to a mass spectrometer using ESI as the ionization source. LC separation used an MK RP18e, 25 x 2 mm column with a flow rate of 1.5 mL / min. Solvent A was 1.5 mL TFA in 4 L water and solvent B was 0.75 mL TFA in 4 L acetonitrile. The gradient included 5-95% solvent B over 0.7 min, holding at 95% for 0.4 min. The LC column temperature was 50 °C. UV absorbance was collected from 220 nm to 254 nm.

[0286] Method N: Experiments were performed on an HPLC column coupled to a mass spectrometer using ESI as the ionization source. LC separation used an MK RP18e, 25 x 2 mm column with a flow rate of 1.5 mL / min. Solvent A was 1.5 mL TFA in 4 L water and solvent B was 0.75 mL TFA in 4 L acetonitrile. The gradient included 10-80% solvent B over 7 min, with a hold of 95% for 0.4 min. The LC column temperature was 50 °C. UV absorbance was collected from 220 nm to 254 nm.

[0287] Method O: Experiments were performed on an HPLC column coupled to a mass spectrometer using ESI as the ionization source. LC separation used an MK RP18e, 25 x 2 mm column with a flow rate of 1.5 mL / min. Solvent A was 1.5 mL TFA in 4 L water and solvent B was 0.75 mL TFA in 4 L acetonitrile. The gradient included 0-60% solvent B over 7 min, holding at 95% for 0.4 min. The LC column temperature was 50 °C. UV absorbance was collected from 220 nm to 254 nm.

[0288] Method P: Experiments performed on a SHIMADZU 2020 HPLC with a SHIMADZU MSD mass spectrometer using ESI as the ionization source, using a Shim-Pack XR-ODS C18 50x3.0mm 2.2μm column and a flow rate of 1.2ml / min. Solvent A was water with 0.05% TFA and solvent B was acetonitrile with 0.05% TFA. The gradient included 5-95% solvent B over 2.0 min, with 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.

[0289] Method Q: Experiments performed on a SHIMADZU 2020 HPLC with a SHIMADZU MSD mass spectrometer using ESI as the ionization source, using a Shim-Pack XR-ODS C18 50x3.0mm 2.2μm column and a flow rate of 1.2ml / min. Solvent A was water with 0.05% TFA and solvent B was acetonitrile with 0.05% TFA. The gradient included 5-60% solvent B over 3.2 min, 60-100% solvent B over 0.5 min, and held at 100% B for 0.8 min. The LC column temperature was 40°C. UV absorbance was collected from 190nm to 400nm.

[0290] Method R: Experiments performed on a SHIMADZU 2020 HPLC with a SHIMADZU MSD mass spectrometer using ESI as the ionization source, using a Shim-Pack XR-ODS C18 50x3.0mm 2.2μm column and a flow rate of 1.2ml / min. Solvent A was water with 0.05% TFA and solvent B was acetonitrile with 0.05% TFA. The gradient included 20-60% solvent B over 3.6 min, 60-100% solvent B over 0.4 min, and held at 100% B for 0.5 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0291] Method S: Experiments performed on a Shimadzu LCMS-2020. LC separation used an Ascentis Express C18, 100 x 4.6 mm column with 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 included 5% solvent B over 0.8 min, 5-40% solvent B over 7.2 min, 40-95% solvent B over 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.

[0292] Method T: Experiments performed on a Shimadzu LCMS-2020. LC separation used an Ascentis Express C18, 100 x 4.6 mm column with 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 included 10-60% solvent B over 10 min, 60-95% solvent B over 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.

[0293] Method U: Experiments performed on a Shimadzu LCMS-2020. LC separation used an Ascentis Express C18, 100 x 4.6 mm column with 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 included 10-60% solvent B over 10 min, 60-95% solvent B over 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.

[0294] Method V: Experiments conducted on Shimadzu LCMS-2020. LC separation was performed using an Ascentis Express C18, 100×4.6 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 included 5 - 95% solvent B over 8 minutes and held 95% B for 2.0 minutes. The LC column temperature was 60 °C. UV absorbance was collected at 190 nm - 400 nm.

[0295] Method W: Experiments conducted on SHIMADZU 2020 HPLC using a Poroshell HPH-C18 50x3.0 mm column and a flow rate of 1.2 ml / min with a SHIMADZU MSD mass spectrometer using ESI as the ionization source. Solvent A was water containing 0.05% NH 4 HCO 3 and solvent B was acetonitrile. The gradient included 10 - 95% solvent B over 2.0 minutes and held 95% B for 0.7 minutes. The LC column temperature was 40 °C. UV absorbance was collected at 190 nm - 400 nm.

[0296] Method X: Experiments conducted on SHIMADZU 2020 HPLC using a Poroshell HPH-C18 50x3.0 mm column and a flow rate of 1.2 ml / min with a SHIMADZU MSD mass spectrometer using ESI as the ionization source. Solvent A was water containing 0.05% NH 4 HCO 3 and solvent B was acetonitrile. The gradient included 10 - 70% solvent B over 3.5 minutes, 70 - 95% solvent B over 0.5 minutes, and held 95% B for 0.7 minutes. The LC column temperature was 40 °C. UV absorbance was collected at 190 nm - 400 nm.

[0297] Method Y: Experiments conducted on SHIMADZU 2020 HPLC using a Poroshell HPH-C18 50x3.0 mm column and a flow rate of 1.2 ml / min with a SHIMADZU MSD mass spectrometer using ESI as the ionization source. Solvent A was water containing 0.05% NH 4HCO 3 Solvent B was water containing 100% ethanol and solvent B was acetonitrile. The gradient included 30-70% solvent B over 4.0 min, 70-95% solvent B over 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.

[0298] Method Z: Experiments performed on a SHIMADZU 2020 HPLC with a SHIMADZU MSD mass spectrometer using ESI as the ionization source, using a Poroshell HPH-C18 50x3.0mm column and a flow rate of 1.2ml / min. Solvent A was 0.05% NH 4 HCO 3 Solvent B was water containing 100% ethanol and solvent B was acetonitrile. The gradient included 30-95% solvent B over 4.0 min, with a hold at 95% B for 0.7 min. The LC column temperature was 40 °C. UV absorbance was collected from 190 nm to 400 nm.

[0299] Method AA: Experiments performed on a SHIMADZU 2020 HPLC with a SHIMADZU MSD mass spectrometer using ESI as the ionization source, using an Accucore C18 50x2.1mm column and a flow rate of 1.0ml / min. Solvent A was water with 0.1% FA and solvent B was acetonitrile with 0.1% FA. The gradient included 10-95% solvent B over 3.0 min, with a hold of 95% B for 0.7 min. The LC column temperature was 40°C. UV absorbance was collected from 190nm to 400nm.

[0300] Method BB; An experiment performed on a SHIMADZU 2020 HPLC using a SHIMADZU MSD mass spectrometer with ESI as the ionization source, with an Accucore C18 50x2.1mm column and a flow rate of 1.0 ml / min. Solvent A is water containing 0.1% FA, and solvent B is acetonitrile containing 0.1% FA. The gradient included 10 - 50% solvent B over 3.5 minutes, 50 - 95% solvent B over 0.5 minutes, and held at 95% B for 0.7 minutes. The LC column temperature was 40°C. UV absorbance was collected at 190nm - 400nm.

[0301] Method CC: An experiment performed on a Shimadzu LCMS - 2020 connected to a SHIMADZU MSD mass spectrometer using ESI as the ionization source. LC separation was performed using a Shim - Pack XR - ODS, 50x3.0mm column, and the flow rate was 1.2 mL / min. Solvent A is water with 0.05% TFA, and solvent B is acetonitrile with 0.05% TFA. The gradient included 5 - 50% solvent B over 3.5 minutes, 50 - 100% solvent over 0.2 minutes, and held at 100% B for 1.0 minutes. The LC column temperature was 40°C. UV absorbance was collected at 190nm - 400nm.

[0302] Method DD: An experiment performed on a Shimadzu LCMS - 2020 connected to a SHIMADZU MSD mass spectrometer using ESI as the ionization source. LC separation was performed using a Shim - Pack XR - ODS, 50x3.0mm column, and the flow rate was 1.2 mL / min. Solvent A is water with 0.05% TFA, and solvent B is acetonitrile with 0.05% TFA. The gradient included 5 - 95% solvent B over 2.0 minutes, and held at 95% B for 0.7 minutes. The LC column temperature was 40°C. UV absorbance was collected at 190nm - 400nm.

[0303] Method EE: Experiments performed on a SHIMADZU 2020 HPLC with a SHIMADZU MSD mass spectrometer using ESI as the ionization source, using an Ascentis Express C18 50x2.1mm column and a flow rate of 1.2ml / min. Solvent A is water with 0.05% TFA and solvent B is MeOH. The gradient included 30-85% solvent B over 10 min, with a hold of 80% B for 3.2 min. The LC column temperature was 40°C. UV absorbance was collected from 190nm to 400nm.

[0304] Method FF: Experiments performed on a MK RP18e 25-2mm column with a mass spectrometer using ESI as the ionization source. Solvent A was 1.5mL / 4L TFA in water and solvent B was 0.75mL / 4L TFA in acetonitrile. The gradient comprised 5-95% solvent B over 0.7 min, with a flow rate of 1.5mL / min, and a hold of 95% for 0.4 min. The LC column temperature was 50°C. UV absorbance was collected from 220nm to 254nm.

[0305] Method GG: Experiments performed on an Xtimate C18 2.1 x 30 mm, 3 μm column with a mass spectrometer using ESI as the ionization source. Solvent A was 1.5 mL / 4 L TFA in water and solvent B was 0.75 mL / 4 L TFA in acetonitrile. The gradient included 10-80% solvent B over 6 min, with a flow rate of 0.8 mL / min, and a hold of 80% for 0.5 min. The LC column temperature was 50 °C. UV absorbance was collected from 220 nm to 254 nm.

[0306] SFC method Method 1: Column: Chiralpak AD-3 150×4.6mm ID, 3μm; Mobile phase: A:CO 2 B: ethanol (0.05% DEA); gradient: 5% to 40% B in 5 min, 40% to 5% B in 0.5 min, hold at 5% B for 1.5 min; flow rate: 2.5 mL / min; column temperature: 35 °C; ABPR: 1500 psi.

[0307] Method 2: Column: Chiralcel OD-3 100×4.6mm ID, 3μm; Mobile phase: A:CO 2 B: ethanol (0.05% DEA); gradient: 5% to 40% B in 4.5 min, hold 40% B for 2.5 min, then hold 5% B for 1 min; flow rate: 2.8 mL / min; column temperature: 40 °C.

[0308] Method 3: Column: Chiralcel OJ-3 100×4.6mm ID, 3μm; Mobile phase: A:CO 2 B: methanol (0.05% DEA); gradient: 5% to 40% B in 4.5 min, hold 40% for 0.5 min, then hold 5% B for 1 min; flow rate: 2.8 mL / min; column temperature: 40 °C.

[0309] Method 4: Column: ChiralCel OJ-H 150×4.6mm ID, 5μm; Mobile phase: A:CO 2 B: ethanol (0.05% DEA); gradient: 5% to 40% B in 5.5 min, then 5% B in 1.5 min; flow rate: 2.5 mL / min; column temperature: 40 °C.

[0310] Method 5: Column: Chiralcel OJ-H 150×4.6mm ID, 5μm; Mobile phase: A:CO 2 B: ethanol (0.05% DEA); gradient: 0.5 min at 5%, then 5% to 40% in 3.5 min, 2.5 min at 40%, then 1.5 min at 5% B; flow rate: 3 mL / min; column temperature: 40 °C.

[0311] Method 6: Column: Chiralpak AD-3 150×4.6mm ID, 3μm; Mobile phase: A:CO 2 B: isopropanol (0.05% DEA); Gradient: 5% to 40% B in 5 min, 40% for 2.5 min, then hold at 5% B for 2.5 min; Flow rate: 2.5 mL / min; Column temperature: 35 °C; ABPR: 1500 psi.

[0312] Method 7: Column: Chiralcel OJ-3 100×4.6mm ID, 3μm; Mobile phase: A:CO 2B: ethanol (0.05% DEA); gradient: 5% to 40% B in 4.5 min, 40% for 2.5 min, then hold 5% B for 1 min; flow rate: 2.8 mL / min; column temperature: 40° C.

[0313] The following generalized schemes are used to prepare the disclosed compounds, intermediates, and pharma- ceutically acceptable salts thereof. The disclosed compounds and intermediates can be prepared from commercially available starting materials and reagents using standard organic synthesis techniques. It is understood that the synthetic procedures used to prepare the disclosed compounds and intermediates will depend on the particular substituents present in the compounds or intermediates, and that various protection, deprotection, and transformation steps that are standard in organic synthesis may be required, but may not be shown according to the generalized schemes. It is also understood that any of the steps shown in any of the generalized schemes below can be used in any combination and in any order that is chemically feasible to obtain the desired intermediate or disclosed compound. It is noted that in the generalized schemes below, the various moieties are as defined elsewhere herein. In the generalized schemes and examples below, [ka] indicates a solid support, such as Rink amide resin. Scheme 1 [ka] [ka] [ka] [ka] [ka] [ka]

[0314] The following examples are provided by way of illustration, not by way of limitation.Some of the compounds used in the following examples may exist as tautomers.Although the examples of these compounds provided below show only single tautomers, these examples should not be viewed in a limiting sense, rather, the corresponding tautomers are also intended and encompassed by the following examples as if each and every tautomer of the compound was shown individually.

[0315] Example S1: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (compound 1) The synthesis was carried out according to the solid phase synthesis scheme shown below: [ka]

[0316] 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 drained under reduced pressure. 10 mL of 20% 4-Methylpiperidine was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was added, then the mixture was introduced into a synthesis vessel and reacted under nitrogen for 2 h. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% in N,N-dimethylformamide was added. 4-Methylpiperidine was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)-1,2-dichloromethane in 10 mL of N,N-dimethylformamide was added. ) A mixture of pyrrolidine-2-carboxylic acid (3.0 eq.), ethyl cyano(hydroxyimino)acetate (3.0 eq.) and N,N'-diisopropylcarbodiimide (3.0 eq.) was added, then the mixture was introduced into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times.A mixture of (S)-2-azido-3-methylbutanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was added, the mixture was introduced into the synthesis vessel and reacted under nitrogen for 2 h. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. Tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 equiv.) was added directly to the peptide synthesis vessel to perform the "click" reaction on the resin. A mixture of ethynylcyclopropane (5.0 equiv.), N,N-diisopropylethylamine (10.0 equiv.) in 10 mL of N,N-dimethylformamide (nitrogen purged) was added to the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. The cleavage solution was prepared by mixing 5% triisopropylsilane in 95% trifluoroacetic acid. The solution was introduced into a reaction vessel and allowed to react for 1 h. The trifluoroacetic acid was removed under reduced pressure and the remaining residue was mixed with 50 mL of cold 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: 545.3, Actual value: 545.3.

[0317] 1H 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).

[0318] Example S2: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)propanoyl)-4-hydroxypyrrolidine-2-carboxamide (compound 2) The synthesis was carried out according to the solid phase synthesis scheme shown below: [ka]

[0319] 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 drained under reduced pressure. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced to the reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (R)-2-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was added, the mixture was introduced into a synthesis vessel and reacted for 2 h under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% in N,N-dimethylformamide was added. 4-Methylpiperidine was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butanoyl)-1,2-dichloromethane in 10 mL of N,N-dimethylformamide was added. A mixture of N,N'-diisopropylcarbodiimide (3.0 eq.), ethyl cyano(hydroxyimino)acetate (3.0 eq.) and N,N'-diisopropylcarbodiimide (3.0 eq.) was added and the mixture was introduced into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated.The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (((9H-fluoren-9-yl)methoxy)carbonyl)-L-alanine (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was introduced into the synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. 1H-imidazole-1-sulfonyl azide hydrochloride (3.0 equiv.) and N,N-diisopropylethylamine (6.0 equiv.) were mixed in dichloromethane. The mixture was introduced into a reaction vessel and reacted under nitrogen for 1 h to convert the amine to the azide. The solvent was aspirated under reduced pressure, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. Tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 equiv.) was added directly to the peptide synthesis vessel to perform the "click" reaction on the resin. A mixture of ethynylcyclopropane (5.0 equiv.), N,N-diisopropylethylamine (10.0 equiv.) in 10 mL of N,N-dimethylformamide (nitrogen purged) was introduced into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. A cleavage solution was prepared by mixing 5% triisopropylsilane in 95% trifluoroacetic acid. The solution was introduced into the reaction vessel and reacted for 1 hour. The trifluoroacetic acid was drained under reduced pressure. The remaining residue was mixed with 50 mL of cold ether (-20°C) to precipitate the compound.The precipitate was collected and separated by reverse 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, Actual value: 517.3.

[0320] 1 H NMR (400MHz, MeOH-d 4 )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).

[0321] Example S3: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (compound 3) The synthesis was carried out according to the solid phase synthesis scheme shown below: [ka]

[0322] 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 drained under reduced pressure. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced to the reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was added, then the mixture was introduced into a synthesis vessel and reacted under nitrogen for 2 h. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% in N,N-dimethylformamide was added. 4-Methylpiperidine was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butyl)-1,2-dichloromethane in 10 mL of N,N-dimethylformamide was washed with 10 mL of dichloromethane and drained under reduced pressure. A mixture of t-butoxy)pyrrolidine-2-carboxylic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) was introduced into the synthesis vessel and reacted under nitrogen for 2 h. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated.The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (S)-2-azido-3,3-dimethylbutanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was introduced into the synthesis vessel and reacted for 2 h under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. Tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 equiv.) was added directly to the peptide synthesis vessel to perform the "click" reaction on the resin. A mixture of ethynylcyclopropane (5.0 equiv.), N,N-diisopropylethylamine (10.0 equiv.) in 10 mL of N,N-dimethylformamide (nitrogen purged) was introduced into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. The cleavage solution was prepared by mixing 5% triisopropylsilane in 95% trifluoroacetic acid. The solution was introduced into the reaction vessel and reacted for 1 h. The trifluoroacetic acid was removed under reduced pressure and the remaining residue was mixed with 50 mL of cold ether (-20 °C) to precipitate the compound. The precipitate was collected and separated by reverse 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, Actual value: 559.3.

[0323] 1 H NMR (400MHz, MeOH-d 4)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(dd,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),2.0 1-1.86(m,2H),1.80-1.68(m,1H),1.02(s,9H),0.99-0.92(m,2H),0.81-0.71(m,2H).

[0324] Example S4: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-((S)-2-cyclobutyl-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxypyrrolidine-2-carboxamide (compound 4) The synthesis was carried out according to the solid phase synthesis scheme shown below: [ka]

[0325] 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 drained under reduced pressure. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced to the reaction vessel and allowed to react under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was introduced into a synthesis vessel and reacted under nitrogen for 2 h. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of Washed with dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was introduced into the synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated.The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-cyclobutylacetic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was introduced into the synthesis vessel and reacted under nitrogen for 2 h. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. N,N- 10 mL of 20% 4-methylpiperidine in dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 1H-imidazole-1-sulfonyl azide hydrochloride (3.0 equiv.) and N,N-diisopropylethylamine (6.0 equiv.) were mixed in dichloromethane. The mixture was added to the reaction vessel. The amine was converted to the azide by reaction under nitrogen for 1 h. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. The "click" reaction was performed on the resin by adding tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 equiv.) directly to the peptide synthesis vessel. Ethynylcyclopropane (5. A mixture of N,N-diisopropylethylamine (10.0 equiv.) and N,N-dimethylformamide (10.0 equiv.) was introduced into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. A cleavage solution was prepared by mixing 5% triisopropylsilane in 95% trifluoroacetic acid. The solution was introduced into the reaction vessel and reacted for 1 h. The trifluoroacetic acid was removed under reduced pressure, and the remaining residue was mixed with 50 mL of cold ether (-20 °C) to precipitate the compound.The precipitate was collected and separated by reverse 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, Actual value: 557.3.

[0326] 1 H NMR (400MHz, MeOH-d 4 )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),3.66(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).

[0327] Example S5: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-((2S,3S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylpentanoyl)-4-hydroxypyrrolidine-2-carboxamide (compound 5) The synthesis was carried out according to the solid phase synthesis scheme shown below: [ka]

[0328] 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 drained under reduced pressure. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced to the reaction vessel and allowed to react under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was introduced into a synthesis vessel and reacted under nitrogen for 2 h. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of Washed with dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was introduced into the synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated.The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (((9H-fluoren-9-yl)methoxy)carbonyl)-L-isoleucine (3.0 eq.), ethyl cyano(hydroxyimino)acetate (3.0 eq.) and N,N'-diisopropylcarbodiimide (3.0 eq.) in 10 mL of N,N-dimethylformamide was introduced into the synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. 1H-imidazole-1-sulfonyl azide hydrochloride (3.0 equiv.) and N,N-diisopropylethylamine (6.0 equiv.) were mixed in dichloromethane. The mixture was introduced into a reaction vessel and reacted under nitrogen for 1 h to convert the amine to the azide. The solvent was drained under reduced pressure, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. Tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 equiv.) was added directly to the peptide synthesis vessel to perform the "click" reaction on the resin. A mixture of ethynylcyclopropane (5.0 equiv.), N,N-diisopropylethylamine (10.0 equiv.) in 10 mL of N,N-dimethylformamide (nitrogen purged) was introduced into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. A cleavage solution was prepared by mixing 5% triisopropylsilane in 95% trifluoroacetic acid. The solution was introduced into the reaction vessel and reacted for 1 h. The trifluoroacetic acid was removed under reduced pressure, and the remaining residue was mixed with 50 mL of cold ether (-20 °C) to precipitate the compound.The precipitate was collected and separated by reverse 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, Actual value: 559.3.

[0329] 1 H NMR (400MHz, MeOH-d 4 )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).

[0330] Example S6: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylpentanoyl)-4-hydroxypyrrolidine-2-carboxamide (compound 6) The synthesis was carried out according to the solid phase synthesis scheme shown below: [ka]

[0331] Link 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 swollen under nitrogen for 30 minutes. The resin was drained under reduced pressure. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide and then 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated 3 times. A mixture of (R)-2-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propanoic 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 introduced into the synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide and then 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated 3 times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide and then 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated 3 times. A mixture of (2S,4R)-1-(((9H-fluoren-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 introduced into the synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide and then 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated 3 times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure, and the deprotection was repeated.The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3,3-dimethylpentanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was introduced into a synthesis vessel and reacted under nitrogen for 2 h. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. N, 10 mL of 20% 4-methylpiperidine in N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 1H-imidazole-1-sulfonyl azide hydrochloride (3.0 equiv.) and N,N-diisopropylethylamine (6.0 equiv.) were mixed in dichloromethane. The mixture was allowed to react. The amine was converted to the azide by introducing it into a vessel and reacting under nitrogen for 1 h. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. The "click" reaction was performed on the resin by adding tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 equiv.) directly to the peptide synthesis vessel. Ethynylcyclopropane (5 A mixture of N,N-diisopropylethylamine (10.0 equiv.) and N,N-dimethylformamide (10.0 equiv.) was introduced into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. A cleavage solution was prepared by mixing 5% triisopropylsilane in 95% trifluoroacetic acid. The solution was introduced into the reaction vessel and reacted for 1 hour. The trifluoroacetic acid was removed under reduced pressure and the remaining residue was mixed with 50 mL of cold ether (-20 °C) to precipitate the compound.The precipitate was collected and separated by reverse 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, Actual value: 573.3.

[0332] 1H NMR (400MHz, MeOH-d 4 )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=11.1Hz,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).

[0333] Example S7: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-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) The synthesis was carried out according to the solid phase synthesis scheme shown below: [ka]

[0334] 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 drained under reduced pressure. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced to the reaction vessel and allowed to react under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was introduced into a synthesis vessel and reacted for 2 h under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% in N,N-dimethylformamide was added. 4-Methylpiperidine was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equiv.), cyano(hyd)-2 ... A mixture of ethyl acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) was introduced into the synthesis vessel and reacted under nitrogen for 2 h. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated.The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3,3-dimethylpent-4-enoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was introduced into a synthesis vessel and reacted under nitrogen for 2 h. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 1H-imidazole-1-sulfonyl azide hydrochloride (3.0 equiv.) and N,N-diisopropylethylamine (6.0 equiv.) were mixed in dichloromethane. The mixture was The amine was converted to the azide by introducing it into a reaction vessel and reacting under nitrogen for 1 h. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. Tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 equiv.) was added directly to the peptide synthesis vessel to perform the "click" reaction on the resin. Ethynylcyclopropane ( A mixture of N,N-diisopropylethylamine (10.0 equiv.) and N,N-dimethylformamide (5.0 equiv.) was introduced into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. A cleavage solution was prepared by mixing 5% triisopropylsilane in 95% trifluoroacetic acid. The solution was introduced into the reaction vessel and reacted for 1 h. The trifluoroacetic acid was removed under reduced pressure, and the remaining residue was mixed with 50 mL of cold ether (-20 °C) to precipitate the compound.The precipitate was collected and separated by reverse 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, Actual value: 571.3.

[0335] 1 H NMR (400MHz, MeOH-d 4 )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),6.1 4-6.01(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),4.44-4.3 2(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).

[0336] Example S8: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-((2S)-2-(adamantan-1-yl)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxypyrrolidine-2-carboxamide (compound 8) The synthesis was carried out according to the solid phase synthesis scheme shown below: [ka]

[0337] 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 drained under reduced pressure. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced to the reaction vessel and allowed to react under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was introduced into a synthesis vessel and reacted for 2 h under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% in N,N-dimethylformamide was added. 4-Methylpiperidine was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butyl)-1,2-dichloromethane in 10 mL of N,N-dimethylformamide was washed with 10 mL of dichloromethane and drained under reduced pressure. A mixture of t-butoxy)pyrrolidine-2-carboxylic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) was introduced into the synthesis vessel and reacted under nitrogen for 2 h. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated.The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (2S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(adamantan-1-yl)acetic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was introduced into the synthesis vessel and reacted under nitrogen for 2 h. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. The resin was washed with 10 mL of N,N-dimethylformamide, followed by 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 1H-imidazole-1-sulfonyl azide hydrochloride (3.0 equiv.) and N,N-diisopropylethylamine (6.0 equiv.) were mixed in dichloromethane. The mixture was cooled to 10° C. for 15 min. to 30° C. for 15 min. The amine was converted to the azide by introducing it into a reaction vessel and reacting under nitrogen for 1 h. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. Tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 equiv.) was added directly to the peptide synthesis vessel to perform the "click" reaction on the resin. Ethynylcyclopropane ( A mixture of N,N-diisopropylethylamine (10.0 equiv.) and N,N-dimethylformamide (5.0 equiv.) was introduced into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. A cleavage solution was prepared by mixing 5% triisopropylsilane in 95% trifluoroacetic acid. The solution was introduced into the reaction vessel and reacted for 1 h. The trifluoroacetic acid was removed under reduced pressure, and the remaining residue was mixed with 50 mL of cold ether (-20 °C) to precipitate the compound.The precipitate was collected and separated by reverse 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, Actual value: 637.3.

[0338] 1 H NMR (400MHz, MeOH-d 4 )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,2 H),5.25(s,1H),4.75-4.63(m,1H),4.45-4.31(m,2H),3.81(dd,J=11.1,3.6Hz,1H),3.7 4-3.60(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).

[0339] Example S9: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-((S)-3,3-dimethyl-2-(1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxypyrrolidine-2-carboxamide (compound 9) The synthesis was carried out according to the solid phase synthesis scheme shown below: [ka]

[0340] 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 drained under reduced pressure. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced to the reaction vessel and allowed to react under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (R)-2-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was introduced into the synthesis vessel and reacted for 2 h under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% in N,N-dimethylformamide was added. 4-Methylpiperidine was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equiv.), cyano(hydroxyisocyano)-1,2-dihydro-1,3-tetrahydrofuran-2-one (1.0 equiv.), ... A mixture of ethyl acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) was introduced into the mixture, introduced into the synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated.The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (S)-2-azido-3,3-dimethylbutanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was introduced into the synthesis vessel and reacted for 2 h under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. Tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 equiv.) was added directly to the peptide synthesis vessel to perform the "click" reaction on the resin. A mixture of ethynyltrimethylsilane (5.0 equiv.), N,N-diisopropylethylamine (10.0 equiv.) in 10 mL of N,N-dimethylformamide (nitrogen purged) was introduced into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. A cleavage solution was prepared by mixing 5% triisopropylsilane in 95% trifluoroacetic acid. The solution was introduced into the reaction vessel and reacted for 1 h. The trifluoroacetic acid was removed under reduced pressure and the remaining residue was mixed with 50 mL of cold ether (-20 °C) to precipitate the compound. The precipitate was collected and separated by reverse 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, Actual value: 519.3.

[0341] 1H 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).

[0342] Example S10: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-4-hydroxy-1-((S)-2-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide (compound 10) The synthesis was carried out according to the solid phase synthesis scheme shown below: [ka]

[0343] 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 drained under reduced pressure. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced to the reaction vessel and allowed to react under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was introduced into a synthesis vessel and reacted for 2 h under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% in N,N-dimethylformamide was added. 4-Methylpiperidine was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butyl)-1,2-dichloromethane in 10 mL of N,N-dimethylformamide was washed with 10 mL of dichloromethane and drained under reduced pressure. A mixture of t-butoxy)pyrrolidine-2-carboxylic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) was introduced into the synthesis vessel and reacted under nitrogen for 2 h. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated.The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (S)-2-azido-3,3-dimethylbutanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was introduced into the synthesis vessel and reacted for 2 h under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. Tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 equiv.) was added directly to the peptide synthesis vessel to perform the "click" reaction on the resin. A mixture of 3-methoxyprop-1-yne (5.0 equiv.), N,N-diisopropylethylamine (10.0 equiv.) in 10 mL of N,N-dimethylformamide (nitrogen purged) was introduced into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. The cleavage solution was prepared by mixing 5% triisopropylsilane in 95% trifluoroacetic acid. The solution was introduced into the reaction vessel and reacted for 1 h. The trifluoroacetic acid was removed under reduced pressure and the remaining residue was mixed with 50 mL of cold ether (-20 °C) to precipitate the compound. The precipitate was collected and separated by reverse 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, Actual value: 563.3.

[0344] 1H 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).

[0345] Example S11: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-((S)-2-(4-benzyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (compound 11) The synthesis was carried out according to the solid phase synthesis scheme shown below: [ka]

[0346] 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 drained under reduced pressure. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced to the reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was introduced into a synthesis vessel and reacted for 2 h under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% in N,N-dimethylformamide was added. 4-Methylpiperidine was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 equiv.), cyano(hyd)-2 ... A mixture of ethyl acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) was introduced into the synthesis vessel and reacted under nitrogen for 2 h. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated.The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (S)-2-azido-3,3-dimethylbutanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was introduced into the synthesis vessel and reacted for 2 h under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. Tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 equiv.) was added directly to the peptide synthesis vessel to perform the "click" reaction on the resin. A mixture of prop-2-yn-1-ylbenzene (5.0 equiv.), N,N-diisopropylethylamine (10.0 equiv.) in 10 mL of N,N-dimethylformamide (nitrogen purged) was introduced into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. A cleavage solution was prepared by mixing 5% triisopropylsilane in 95% trifluoroacetic acid. The solution was introduced into the reaction vessel and reacted for 1 h. The trifluoroacetic acid was removed under reduced pressure and the remaining residue was mixed with 50 mL of cold ether (-20 °C) to precipitate the compound. The precipitate was collected and separated by reverse 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, Actual value: 609.3.

[0347] 1H 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).

[0348] Example S12: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-((R)-2-(4-(1-(acetamidomethyl)cyclopropyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (compound 12) The synthesis was carried out according to the solid phase synthesis scheme shown below: [ka]

[0349] 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 drained under reduced pressure. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced to the reaction vessel and allowed to react under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was added, then the mixture was introduced into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of Washed with dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 eq.), ethyl cyano(hydroxyimino)acetate (3.0 eq.) and N,N'-diisopropylcarbodiimide (3.0 eq.) in 10 mL of N,N-dimethylformamide was added, then the mixture was introduced into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated.The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three 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-dimethylbutanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was then added, and the mixture was then purified by HPLC. The resin was introduced into the vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated ... , then washed with 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of acetic anhydride (5.0 equiv.) and N,N-diisopropylethylamine (10.0 equiv.) in 10 mL of dichloromethane was added, and then the mixture was introduced into the synthesis vessel and reacted for 30 min under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane and drained under reduced pressure. The cleavage solution was prepared by mixing 5% triisopropylsilane in 95% trifluoroacetic acid. The solution was introduced into the reaction vessel and reacted for 1 h. The trifluoroacetic acid was removed under reduced pressure and the remaining residue was mixed with 50 mL of cold ether (-20 °C) to precipitate the compound. The precipitate was collected and separated by reverse 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, Actual value: 630.3.

[0350] 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).

[0351] Example S13: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-((S)-2-(4-(1-(acetamidomethyl)cyclopropyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (compound 13) The synthesis was carried out according to the solid phase synthesis scheme shown below: [ka]

[0352] 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 drained under reduced pressure. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced to the reaction vessel and allowed to react under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was added, then the mixture was introduced into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of Washed with dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 eq.), ethyl cyano(hydroxyimino)acetate (3.0 eq.) and N,N'-diisopropylcarbodiimide (3.0 eq.) in 10 mL of N,N-dimethylformamide was added, then the mixture was introduced into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated.The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three 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-dimethylbutanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was then added, and the mixture was then purified by HPLC. The resin was introduced into the vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated ... , then washed with 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of acetic anhydride (5.0 equiv.) and N,N-diisopropylethylamine (10.0 equiv.) in 10 mL of dichloromethane was added, and then the mixture was introduced into the synthesis vessel and reacted for 30 min under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane and drained under reduced pressure. The cleavage solution was prepared by mixing 5% triisopropylsilane in 95% trifluoroacetic acid. The solution was introduced into the reaction vessel and reacted for 1 h. The trifluoroacetic acid was removed under reduced pressure and the remaining residue was mixed with 50 mL of cold ether (-20 °C) to precipitate the compound. The precipitate was collected and separated by reverse 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, Actual value: 630.3.

[0353] 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).

[0354] Example S14: Synthesis of (2S,4R)-N-((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)-1-((S)-2-(4-((2-acetamidoethoxy)methyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (compound 14) The synthesis was carried out according to the solid phase synthesis scheme shown below: [ka]

[0355] 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 drained under reduced pressure. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced to the reaction vessel and allowed to react under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was added, then the mixture was introduced into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of Washed with dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 eq.), ethyl cyano(hydroxyimino)acetate (3.0 eq.) and N,N'-diisopropylcarbodiimide (3.0 eq.) in 10 mL of N,N-dimethylformamide was added, then the mixture was introduced into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated.The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (S)-2-azido-3,3-dimethylbutanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was added, and then the mixture was introduced into the synthesis vessel and reacted under nitrogen for 2 h. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. Tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 equiv.) was added directly to the peptide synthesis vessel to perform the "click" reaction on the resin. A mixture of N-(2-(prop-2-yn-1-yloxy)ethyl)acetamide (5.0 equiv.), N,N-diisopropylethylamine (10.0 equiv.) in 10 mL of N,N-dimethylformamide (nitrogen purged) was introduced into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. The cleavage solution was prepared by mixing 5% triisopropylsilane in 95% trifluoroacetic acid. The solution was introduced into the reaction vessel and reacted for 1 h. The trifluoroacetic acid was removed under reduced pressure and the remaining residue was mixed with 50 mL of cold ether (-20 °C) to precipitate the compound. The precipitate was collected and separated by reverse phase HPLC (30%-60% acetonitrile). The desired product was lyophilized and characterized by LC-MS. ESI-MS: m / z [M+H]. + Calculated value: 634.3, Actual value: 634.3.

[0356] 1H 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).

[0357] Example S15: Synthesis of 1-((S)-1-((2S,4R)-2-(((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazole-4-carboxylic acid (compound 15) The synthesis was carried out according to the solid phase synthesis scheme shown below: [ka]

[0358] 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 drained under reduced pressure. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced to the reaction vessel and allowed to react under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was added, then the mixture was introduced into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of Washed with dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 eq.), ethyl cyano(hydroxyimino)acetate (3.0 eq.) and N,N'-diisopropylcarbodiimide (3.0 eq.) in 10 mL of N,N-dimethylformamide was added, then the mixture was introduced into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated.The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (S)-2-azido-3,3-dimethylbutanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was added, then the mixture was introduced into the synthesis vessel and reacted under nitrogen for 2 h. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. Tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 equiv.) was added directly to the peptide synthesis vessel to perform the "click" reaction on the resin. A mixture of tert-butyl propiolate (5.0 equiv.), N,N-diisopropylethylamine (10.0 equiv.) in 10 mL of N,N-dimethylformamide (nitrogen purged) was introduced into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. The cleavage solution was prepared by mixing 5% triisopropylsilane in 95% trifluoroacetic acid. The solution was introduced into the reaction vessel and reacted for 1 h. The trifluoroacetic acid was removed under reduced pressure and the remaining residue was mixed with 50 mL of cold ether (-20 °C) to precipitate the compound. The precipitate was collected and separated by reverse 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, actual value: 563.2.

[0359] 1H 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).

[0360] Example S16: Synthesis of 1-((S)-1-((2S,4R)-2-(((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazole-4-carboxamide (compound 16) The synthesis was carried out according to the solid phase synthesis scheme shown below: [ka]

[0361] 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 drained under reduced pressure. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced to the reaction vessel and allowed to react under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was added, then the mixture was introduced into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of Washed with dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 eq.), ethyl cyano(hydroxyimino)acetate (3.0 eq.) and N,N'-diisopropylcarbodiimide (3.0 eq.) in 10 mL of N,N-dimethylformamide was added, then the mixture was introduced into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated.The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (S)-2-azido-3,3-dimethylbutanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was added, and then the mixture was introduced into the synthesis vessel and reacted under nitrogen for 2 h. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. Tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 equiv.) was added directly to the peptide synthesis vessel to perform the "click" reaction on the resin. A mixture of propiolamide (5.0 equiv.), N,N-diisopropylethylamine (10.0 equiv.) in 10 mL of N,N-dimethylformamide (nitrogen purged) was introduced into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. A cleavage solution was prepared by mixing 5% triisopropylsilane in 95% trifluoroacetic acid. The solution was introduced into the reaction vessel and reacted for 1 h. The trifluoroacetic acid was removed under reduced pressure and the remaining residue was mixed with 50 mL of cold ether (-20 °C) to precipitate the compound. The precipitate was collected and separated by reverse phase HPLC (30%-60% acetonitrile). The desired product was lyophilized and characterized by LC-MS. ESI-MS: m / z [M+H]. + Calculated value: 562.3, actual value: 562.2.

[0362] 1H NMR(400MHz,DMSO-d6)δ8.61(d,J=8.8Hz,1H),8.59(s,1H),7.91(s,1H),7.68-7.51(m,5H) ,7.51-7.40(m,4H),7.39-7.30(m,1H),7.35-7.27(m,4H),5.57(s,1H),4.49-4.33(m,2H), 4.25(dq,J=4.7,2.3Hz,1H),3.66(d,J=2.6Hz,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=13.3,9.4,4.2Hz,1H),0.96(s,10H).

[0363] Example S17: Synthesis of 1-((S)-1-((2S,4R)-2-(((R)-3-([1,1'-biphenyl]-4-yl)-1-amino-1-oxopropan-2-yl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (compound 17) The synthesis was carried out according to the solid phase synthesis scheme shown below: [ka]

[0364] 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 drained under reduced pressure. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced to the reaction vessel and allowed to react under nitrogen for 15 min to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-([1,1'-biphenyl]-4-yl)propanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was added, then the mixture was introduced into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure, and the deprotection was repeated. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of Washed with dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxy)pyrrolidine-2-carboxylic acid (3.0 eq.), ethyl cyano(hydroxyimino)acetate (3.0 eq.) and N,N'-diisopropylcarbodiimide (3.0 eq.) in 10 mL of N,N-dimethylformamide was added, then the mixture was introduced into a synthesis vessel and reacted under nitrogen for 2 hours. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane and drained under reduced pressure. The washing procedure was repeated three times. 10 mL of 20% 4-methylpiperidine in N,N-dimethylformamide was introduced into the reaction vessel and reacted under nitrogen for 15 minutes to deprotect the Fmoc group. The solvent was drained under reduced pressure and the deprotection was repeated.The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. A mixture of (S)-2-azido-3,3-dimethylbutanoic acid (3.0 equiv.), ethyl cyano(hydroxyimino)acetate (3.0 equiv.) and N,N'-diisopropylcarbodiimide (3.0 equiv.) in 10 mL of N,N-dimethylformamide was added, then the mixture was introduced into the synthesis vessel and reacted under nitrogen for 2 h. The resin was washed with 10 mL of N,N-dimethylformamide, then with 10 mL of dichloromethane, and drained under reduced pressure. The washing procedure was repeated three times. Tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 equiv.) was added directly to the peptide synthesis vessel to perform the "click" reaction on the resin. A mixture of N-methylpropiolamide (5.0 equiv.), N,N-diisopropylethylamine (10.0 equiv.) in 10 mL of N,N-dimethylformamide (nitrogen purged) was introduced into the reaction vessel and reacted overnight under nitrogen. The resin was washed with 10 mL of N,N-dimethylformamide, then 10 mL of dichloromethane, and drained under reduced pressure. A cleavage solution was prepared by mixing 5% triisopropylsilane in 95% trifluoroacetic acid. The solution was introduced into the reaction vessel and reacted for 1 h. The trifluoroacetic acid was removed under reduced pressure and the remaining residue was mixed with 50 mL of cold ether (-20 °C) to precipitate the compound. The precipitate was collected and separated by rev...

Claims

[Claim 1] The invention described in the present specification.

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